Clinical trial NCT05600322
Conditions: Bladder Cancer
Sponsor: Photocure
Start date: 2022-11-03; Completion date: 2023-07-12
Enrollment: 158 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A study to compare Hexvix Blue light cstoscopy with standard White light cystoscopy in the detection of bladder cancer.

Detailed description:
A phase III, prospective, within patient controlled, multi-center study to compare Blue light cystoscopy with Hexvix and standard White light cystoscopy in the detection of bladder cancer, to evaluate the efficacy and safety of Hexvix Blue light cystoscopy in Chinese population.

Patients with suspicious or confirmed bladder cancer will participate in the trial and undergo Blue light cystoscopy with Hexvix in addition to the standard White light cystoscopy. Specific clinical questions will be asked:

* What is the proportion of patients who have at least one specific kind of tumor found by Blue light cystoscopy with Hexvix but not by White light cystoscopy?
* What is the proportion of patients who have at least one specific kind of lesion found by Blue light cystoscopy with Hexvix but not by White light cystoscopy?
* What is the proportion of false positive lesions detected with Hexvix Blue light cystoscopy and White light cystoscopy?
* What is the proportion of patients with Adverse Events (AE) during the study?

Arms: arm 1: In this study, enrolled patients will undergo standard White light cystoscopy and Blue light cystoscopy following Hexvix administration. Lesions detected during the cystoscopies will be resected or biopsied.
Interventions: intervention 1: Hexaminolevulinate Hydrochloride intervention 2: Richard Wolf Photodynamic Diagnostic Equipment (PDD) system
Intervention descriptions: intervention 1: Enrolled patients will be instilled with 50 mL hexaminolevulinate hydrochloride as intravesical solution (Hexvix) in the bladder for one hour at Visit 2. After bladder evacuation, the cystoscopic examinations will be performed in both white and blue light. intervention 2: Cystoscopy in White and Blue light will be done using the Richard Wolf PDD system.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
Clinical Study Protocol 
 
Study Title: A prospective, comparative within patient controlled, multi-center 
study of Hexvix blue light cystoscopy and white light cystoscopy in the 
detection of bladder cancer 
 
Study Number： 
YHCT-HEX-B1 
Version： 
V 2.2 
Date： 
Feb 6th, 2023 
 
Sponsor: 
Photocure ASA 
China Registration Agent： 
Jiangsu Yahong Meditech Co., Ltd. 
 
 
 
Confidentiality Statement 
All information contained within this study protocol is the property of the sponsor and is therefore 
only for review by the investigators, co-investigators, Ethics Committee, regulatory authorities and 
other relevant medical institutions. Without a prior written permission of the sponsor, except during 
signing an informed consent form with subjects and offering necessary explanations, disclosure of 
any information to a third party unrelated to the present trial is strictly prohibited. 


HEXVIX® 
Study Number：YHCT-HEX-B1   
V 2.2, Feb 6th 2023           
 2 / 60 
 
Protocol Signature Page 
(Sponsor) 
I agree that: 
 
In strict accordance with the protocol, the current ICH Good Clinical Practice for drug 
Clinical trials (GCP) and the National Medical Products Administration (NMPA) GCP 
guidelines as well as applicable regulations and guidelines for conducting the study. 
 
Be responsible for initiating, applying for, organizing and funding this clinical trial, and 
implementing the audit of the clinical trial. 
I have already read the clinical trial protocol entirely, and I fully agree all the provisions 
listed in the protocol. 
 
Sponsor: Photocure ASA 
 
Signature: 
Date: 


HEXVIX® 
Study Number：YHCT-HEX-B1   
V 2.2, Feb 6th 2023           
 3 / 60 
 
Protocol Signature Page 
(Principal Investigator) 
 
I agree that: 
 
This clinical trial shall be conducted in strict accordance with the protocol, current ICH 
GCP and NMPA GCP guidelines, and applicable regulations and guidelines. 
 
All information provided by the sponsor shall be maintained in accordance with the 
confidentiality requirements and shall be marked as confidential when submitted to the 
Independent Ethics Committee (IEC). 
I have already read the clinical trial protocol entirely, and I fully agree all the provisions 
listed in the protocol. 
 
Clinical trial institution: Peking Union Medical College Hospital 
Principal Investigator: Professor Hanzhong Li 
Signature: 
Date: 


HEXVIX® 
Study Number：YHCT-HEX-B1   
V 2.2, Feb 6th 2023           
 4 / 60 
 
Protocol Signature Page 
(Statistician) 
I agree that: 
 
The statistical analysis of this clinical trial shall be carried out in strict accordance with the 
protocol, current ICH GCP and NMPA GCP guidelines, and applicable regulations and 
guidelines. 
 
Keep all information of sponsor in accordance with confidentiality requirement. 
I have already read the clinical trial protocol entirely, and I fully agree all the provisions 
listed in the protocol. 
 
 
 
 
Statistical institution: 
Statistician: 
Signature: 
Date: 


HEXVIX® 
Study Number：YHCT-HEX-B1   
V 2.2, Feb 6th 2023           
 5 / 60 
 
Protocol Signature Page (Sub-centers) 
Protocol No. 
YHCT-HEX-B1 
Version and date 
V2.2 / Feb 6th, 2023 
Study title 
 
A prospective, comparative, within patient controlled, multi-center study of 
Hexvix blue light cystoscopy and white light cystoscopy in the detection of 
bladder cancer 
Study center 
No. 
 
Investigator:  
Study center 
 
 
I have already read the clinical trial protocol entirely, and and understand its requirements. I agree to 
follow the protocol and schedule for the clinical trial. Any modification that is not approved by the 
sponsor and/or CRO and IEC is considered to be a protocol violation. 
I agree to conduct the trial in accordance with the current ICH GCP and NMPA GCP guidelines and 
applicable regulations and guidelines, and to accept the monitoring / audit of the clinical trial by the 
sponsor and/or CRO and the verification/inspection by the drug regulatory authorities. 
I agree to use only the trial supplies specified in the protocol including investigational drugs. 
 
Principal Investigator signature 
Name 
Date 
Signature 
 
 
            
 
 
 


HEXVIX® 
Study Number：YHCT-HEX-B1   
V 2.2, Feb 6th 2023           
 6 / 60 
 
PROTOCOL SYNOPOSIS 
Study 
Number 
YHCT-HEX-B1 
Study Title 
A prospective, comparative, within patient controlled, multi-center study of 
Hexvix blue light cystoscopy and white light cystoscopy in the detection of 
bladder cancer  
Version 
V 2.2 
Date 
Feb 6th, 2023 
Sponsor 
Photocure ASA 
China 
Registration 
Agent 
Jiangsu Yahong Meditech Co., Ltd. 
Clinical 
Phase 
Phase 3 
Objective 
Primary Objective: 
• 
To compare Hexvix blue light cystoscopy with white light cystoscopy 
in the detection of bladder cancer. 
Secondary Objectives: 
• 
Comparison of detection of patients with CIS lesions by Hexvix blue 
light cystoscopy and white light cystoscopy. 
• 
Comparison of detection rates of bladder lesions of Hexvix blue light 
cystoscopy and white light cystoscopy per lesion type (PUNLMP, CIS, 
Ta, T1, T2-4). 
• 
Comparison of the proportion of false positive lesions detected with 
Hexvix blue light cystoscopy and white light cystoscopy. 
• 
Evaluation of the safety of Hexvix in patients with bladder cancer. 
Study Design 
A prospective, comparative, within patient controlled, multi-center study of 
Hexvix blue light cystoscopy and white light cystoscopy in the detection of 
bladder cancer. Approximately 380 patients with suspected or confirmed bladder 
cancer will be enrolled until a total of 94 patients with pathological confirmed 
Ta, T1 or CIS are included. 
There will be a maximum of three regular study visits: 
A screening visit (-2 weeks), a cystoscopy examination (Day 0), and the safety 
follow-up period (1 week±3 days), in which the screeing visit and cystoscopy 
examination could be conducted in the same visit. 
 


HEXVIX® 
Study Number：YHCT-HEX-B1   
V 2.2, Feb 6th 2023           
 7 / 60 
 
 
 
Study design 
At the start of the study, a minimum of four subjects included at each center will 
be training subjects. These subjects will receive the Hexvix administration and 
undergo white and blue light cystoscopy with tumor resection as below. They 
will receive the same safety follow up as all the other included patients, after 
completing the safety follow-up for 1 week, the subjects will be treated according 
to hospital’s clinical routine by the investigator. These patients are not part of the 
efficacy analyses. 
To reduce possible bias in assessment of the objectives, a small number of 
subjects will be randomized to not continue with Hexvix blue light cystoscopy 
following white light cystoscopy. 
Consented, eligible subjects (Visit 1) will be instilled with 50 mL Hexvix 8 mM 
solution for one hour (Visit 2). After bladder evacuation, the following procedure 
will be utilized to accomplish the cystoscopic examination of each subject： 
1. Turn on the white light. Inspection of the bladder and mapping of all 
papillary lesions and flat and suspicious lesions seen under white light, 
record lesion number, size and location. 
2. Randomization: 
a) If the patient is not randomized to undergo blue light mapping, 
proceed to step 3.  
b) If the patient is randomized to continue with blue light mapping, 
or subjects for investigator training procedure, then they will 
undergo blue light cystoscopy. Turn to the blue light. Inspection 
of the bladder and mapping of all papillary lesions and flat and 
suspicious lesions seen under blue light, record lesion number, 
size and location. 
3. All papillary lesions detected will be resected using Transurethral 
Resection of the Bladder Tumor (TURBT) and all flat and suspicious 
lesions detected will be biopsied. The lesions resected and biopsied 
should be marked and pathologically examined seperately. For patients 
randomized to undergo blue light cystoscopy and for training patients, 


HEXVIX® 
Study Number：YHCT-HEX-B1   
V 2.2, Feb 6th 2023           
 8 / 60 
 
the completeness of the resection should always be checked under blue 
light before finalizing the TURBT procedure until it is ensured that all 
lesions and suspicious areas are completely resected. Both biopsied and 
resected tissue will be examined by the local pathologist, then evaluated 
by independent and blinded central pathologists. Central pathology 
results will be used as reference standard in the study efficacy endpoints. 
All subjects (including the training patients) will receive a safety follow-up at 
day 7 (visit 3) after day 0 cystoscopy (visit 2), after completing the safety follow-
up for 1 week, the patients will be treated according to hospital routines by 
investigator. 
Number of 
Patients  
Approximately 380 patients are planned to be included in the study, to ensure 94 
patients with pathological confirmed bladder cancer (Ta, T1 and CIS). 
Number of 
Centers 
About 5-10 centers in China 
Study 
Duration 
The duration of each patient's participation in the study is about 3 weeks 
(including a 2-week screening period, a day 0 test period, and a 1-week safety 
follow-up period) 
Patients 
 
Inclusion Criteria： 
1. Volunteer to participate in the study; fully understand with signing of 
informed consent; willing to follow and have the ability to complete all 
experimental procedures. 
2. Suspicious or confirmed patients with bladder cancer. 
3. Age 18 or older.  
Exclusion Criteria： 
1. Gross haematuria. (Note: Gross haematuria is defined as a heavy bladder 
bleed resulting in marked 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 possible interference 
with cystoscopy). 
2. Patients 
who 
received 
BCG 
immunotherapy 
or 
intravesical 
chemotherapy within 6 weeks prior to the procedure. 
3. Porphyria. 
4. Known allergy to hexaminolevulinate hydrochloride or a similar 
compound. 
5. Pregnancy or breast feeding or patients of child-bearing potential, 
including men with partners of child-bearing potential, who are unwilling 
to take barrier contraceptives from 2 weeks before medication to 28 days 


HEXVIX® 
Study Number：YHCT-HEX-B1   
V 2.2, Feb 6th 2023           
 9 / 60 
 
after the medication. (Note: Child-bearing potential is defined as women 
who are ovulating, pre-menopausal or not surgically sterilized. All 
women of child-bearing potential must document a negative pregnancy 
test before study inclusion and use adequate contraception during the 
study). 
6. Participation 
in 
other 
clinical 
studies 
with 
investigational 
drugs/investigational device either concurrently or within the last 30 days 
prior to the first study cystoscopy. 
7. Patient who 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. 
8. Patients that the investigator believed were unlikely to comply with the 
protocol. 
9. Subjects with contraindications to white light cystoscopy. 
Drug / 
Device 
Drug name: 
Hexvix (hexaminolevulinate hydrochloride, for intravesical solution, for bladder 
instillation only) as the photosensitizer to use with blue light cystoscopy 
Active ingredient: Hexaminolevulinate hydrochloride 
Device: 
Cystoscopic equipment with necessary filters to allow both standard white light 
cystoscopy and blue light (wavelength 380–450 nm) fluorescence cystoscopy 
Comparative 
Drug 
Not applicable 
Efficacy 
Endpoint 
Primary Efficacy Endpoint： 
• The proportion of patients with histology-confirmed tumors (Ta, T1, or 
CIS) who have at least one such tumor found by Hexvix but not by white 
light cystoscopy. 
Secondary Efficacy Endpoint： 
• The proportion of patients with one or more CIS lesions detected only by 
Hexvix blue light cystoscopy not by white light cystoscopy. 
• The lesion detection rate for Hexvix blue light cystoscopy compared to 
white light cystoscopy per lesion type (PUNLMP, CIS, Ta, T1, T2-4). 
• The proportion of false positive lesions detected with Hexvix blue light 
cystoscopy and white light cystoscopy. 
Safety 
Endpoint 
The proportion of patients with AEs during the study. 


HEXVIX® 
Study Number：YHCT-HEX-B1   
V 2.2, Feb 6th 2023           
 10 / 60 
 
Statistics 
Sample Size: 
Sample size calculation for the primary efficacy analysis is based on an exact 
test for a single proportion. Statistical assumption is based on primary endpoint 
that P (null hypothesis) is 10%, P (alternative hypothesis) is 20% and a power of 
80%, α (1-side) is 0.025, a total of 94 patients with histologically confirmed Ta, 
T1, and CIS stage bladder cancer are needed. 
Assuming that 35% of subjects will have bladder cancer after Hexvix-assisted 
blue light cystoscopy and/or white light cystoscopy, bladder cancer with Ta, T1 
and CIS stage accounting for 75%, 359 subjects are expected to be enrolled in 
this trial. Considering the 5% drop-out rate, a total of about 380 subjects are 
required. The study will continue until 94 subjects have bladder cancer after 
Hexvix-assisted blue light cystoscopy and/or white light cystoscopy and are 
pathologically confirmed as Ta, T1, and CIS stage bladder cancer. 
Note: A minimum of 4 subjects included at each center will be training subjects, 
and those training subjects are in addition to the estimated sample size. 
Moreover, training subjects are not included in the randomization procedure and 
efficacy endpoints analysis, but included in the safety analysis. 
Statistical Analysis Method: 
Efficacy: 
Efficacy endpoint analysis will be based on full analysis set (FAS) / modified 
full analysis set (mFAS) and per protocol set (PPS) / modified per protocol set 
(mPPS). Primary efficacy endpoint will be analyzed based on subjects who 
received Hexvix instillation and continue with blue light cystoscopy, and are 
pathologically confirmed as Ta, T1, and CIS stage bladder cancer, training 
patients will not be included. 
For analysis of the primary efficacy endpoint (The proportion of patients with 
histology-confirmed tumors (Ta, T1, or CIS) who have at least one such tumor 
found by Hexvix but not by white light cystoscopy), an exact test for single 
proportion, using the cumulative binominal distribution, with a significance 
level of 0.025 (1-sided) will be used, based on the mFAS and mPPS, and the 
95% confidence interval for the detection rate will be calculated. 
Secondary efficacy endpoints will be analyzed descriptively, including event rate 
and 95% confidence intervals based on the FAS and PPS. Exact 95% confidence 
interval will be calculated similarly to that of the primary efficacy endpoint. But 
no formal statsitical inference will be made to the secondary efficacy endpoints. 
If the establishment of confidence intervals is based on biopsy/TURBT data, 
Bladder biopsy/TURBT data should be assumed to be independent of each other. 
Efficacy data will be tabulated in detail. 
Safety: 
Safety analysis will be based on safety set. 
The reported adverse events (including local reactions) will be coded according 
to MedDRA terminology. The events will be tabulated by System Organ Class 
and by Preferred term. 


HEXVIX® 
Study Number：YHCT-HEX-B1   
V 2.2, Feb 6th 2023           
 11 / 60 
 
Adverse events will also be tabulated versus severity and relation to treatment. 
Physical examination and vital signs at each visit will be presented using 
descriptive statistics. 
Interim Analysis: 
No interim analysis is planned for this study. 


HEXVIX® 
Study Number：YHCT-HEX-B1   
V 2.2, Feb 6th 2023           
 12 / 60 
 
Study Flow Chart 
Visit Number 
Visit 1 
Visit 29 
Visit 310 
Visit Type 
Screening 
Detection 
Safety follow-up  
Visit (D) 
2 weeks 
（D-14~D0） 
D0 
1 week 
（D7±3 ） 
Informed consent 1 
√ 
 
 
Demography 2, Medical history,  
and Surgery history 3 
√ 
 
 
Medication history 
√ 
 
 
Inclusion/exclusion 
√ 
 
 
Vital signs 4 
√ 
√ 
√12 
Physical exam 5 
√ 
√ 
 
Pregnancy test 6 
√ 
√ 
 
Randomization 7 
 
√ 
 
Assessment of bladder symptoms 
 
√ 
 
Cytology 
 
√ 
 
Hexvix administration（bladder instillation） 
 
√ 
 
White light, or white light and blue light 
cystoscopy 
 
√ 
 
Lesion assessment/mapping 
 
√ 
 
Biopsies/TURBT histology 
 
√11 
 
Complications, Adverse events 8 
√ 
√ 
√ 
Concomitant medications/procedures 
√ 
√ 
√ 
1. 
Before any study related procedures are performed, patient must then sign and date the informed consent 
form. 
2. 
Demographic information includes: gender, age, ethnicity, height, weight, body mass index, and history of 
allergies, drug abuse, smoking, alcohol abuse, and blood donation. 
3. 
All bladder cancer-related medical history and surgical history should be recorded in detail and distinguished 
from other diseases without the time limitation. Other medical history and surgical history within the past 2 
years should be recorded. 
4. 
Vital signs include: body temperature, sitting blood pressure, heart rate, and breathing rate. Vital signs should 
be measured when the investigator judges that the subject’s condition is stable. 
Note: Vital signs should be examined before and after surgery on Visit 2. 
5. 
According to organs and systems, a comprehensive physical examination includes: general conditions, head 
and neck, lymph nodes, skin, chest, abdomen, musculoskeletal system (including limbs and spine) and 
nervous system. If the subject has already undergone the examination within 7 days before the administration, 
visit 2 can no longer perform the examination. 
6. 
Pregnancy test (only for women of childbearing age): The pregnancy test for women of childbearing age 
during the screening period must be negative. If the subject has undergone a pregnancy test within 7 days 


HEXVIX® 
Study Number：YHCT-HEX-B1   
V 2.2, Feb 6th 2023           
 13 / 60 
 
before the administration, visit 2 can no longer perform the test. During the study period, urine pregnancy 
test can be performed as needed. If the urine pregnancy result is positive, a serum pregnancy test is required 
to confirm. If it is confirmed positive, the subject needs to withdraw from the test, and the investigator will 
continue to follow up the subject until the end of the pregnancy. 
7. 
To reduce possible bias in the white light cystoscopy (the comparator standard is white light cystoscopy in 
the study design), randomization will be done: a) The subjects randomized to not continue with Hexvix 
cystoscopy will receive TURBT and safety follow-up after 1week and routine clinical practice by the 
investigator. b) The subjects randomized to continue with Hexvix cystoscopy or for training purpose of the 
investigator, will undergo Hexvix cystoscopy, TURBT and later process. 
8. 
All adverse events that occurred between ICF signed and the last visit, regardless of their severity and 
relationship with the study drug, should be recorded. New adverse events occurred from ICF to drug 
administration or worsened AEs should be recorded and reported as adverse events/serious adverse events. 
9. 
Visit 2 should be conducted within 14 days after the end of Visit 1, and can be combined with Visit 1. 
10. 
Visit 3 can be conducted by telephone visit, if AEs are identified during the follow-up, the investigator should 
evaluate whether subjects need to return to the investigational site according to their conditions. 
11. 
Visit 2 is for cystoscopy and pathological tissue resection/biopsy sampling. Actual clinical finishing time 
shall be recorded as record time points for histopathological evaluation results. 
12. 
The vital signs in Visit 3 are optional and needs to be taken only in case the subject comes into the hospital. 


Hexvix® 
Study Number：YHCT-HEX-B1 
Version 2.2  Date: Feb 6th, 2023                                                                       14 | 60 
Confidential 
TABLE OF CONTENT 
Protocol Signature Page (Sub-centers) .................................................................................................. 5 
Table of Content .................................................................................................................................. 14 
List of Abbreviations and Definitions of Terms ................................................................................... 18 
1. Introduction and Study Rationale .................................................................................................. 20 
1.1 Disease Introduction .............................................................................................................. 20 
1.2 Drug Introduction................................................................................................................... 20 
1.2.1 
Nonclinical Study..................................................................................................... 21 
1.2.2 
Clinical Study........................................................................................................... 21 
2. Study Objectives ........................................................................................................................... 23 
2.1 Primary Objective .................................................................................................................. 23 
2.2 Secondary Objective .............................................................................................................. 23 
3. Selection and Withdrawal of Subjects ........................................................................................... 24 
3.1 Inclusion Criteria ................................................................................................................... 24 
3.2 Exclusion Criteria .................................................................................................................. 24 
3.3 Elimination criteria ................................................................................................................ 24 
3.4 Withdrawal criteria ................................................................................................................. 24 
3.5 Early Termination of Study/ Closure of Study Center ........................................................... 26 
3.6 Definition of The End of the Study ........................................................................................ 26 
4. Study Design ................................................................................................................................. 27 
4.1 Study Type and Design Principle ........................................................................................... 27 
4.2 Randomization and Blinding ................................................................................................. 28 
4.3 Study Procedure and Stage .................................................................................................... 28 
4.3.1 
Diagnosis and Pre-treatment Evaluation (visit1) ..................................................... 28 
4.3.2 
Treatment (visit2) ..................................................................................................... 29 
4.3.3 
Seven Day Safety Follow up (visit 3) ...................................................................... 32 
4.3.4 
Unplanned Visits ...................................................................................................... 32 
5. Investigational Medicinal Product and Device ............................................................................. 33 


Hexvix® 
Study Number：YHCT-HEX-B1 
Version 2.2  Date: Feb 6th, 2023                                                                       15 | 60 
Confidential 
5.1 Investigational Drug............................................................................................................... 33 
5.1.1 
Drug name, Dosage Form and Specification ........................................................... 33 
5.1.2 
Administration ......................................................................................................... 33 
5.1.3 
Packaging ................................................................................................................. 33 
5.1.4 
Labelling .................................................................................................................. 33 
5.1.5 
Drug Distribution, Recording and Recover ............................................................. 33 
5.2 Photodynamic Diagnostic Equipment (PDD) System ........................................................... 34 
6. Treatment of Subjects .................................................................................................................... 37 
6.1 IMP ........................................................................................................................................ 37 
6.2 Concomitant Medication ........................................................................................................ 37 
6.3 Compliance ............................................................................................................................ 37 
7. Assessment of Efficacy ................................................................................................................. 38 
7.1 Primary Efficacy Endpoint .................................................................................................... 38 
7.2 Secondary Efficacy Endpoint ................................................................................................ 38 
7.3 Central Pathology Evaluation ................................................................................................ 38 
7.4 Efficacy Parameters ............................................................................................................... 38 
7.4.1 
Detection of Lesions by White light Cystoscopy .................................................... 38 
7.4.2 
Detection of Lesions by Blue Light Cystoscopy ..................................................... 39 
7.4.3 
Subject Diagnosis..................................................................................................... 39 
8. Assessment of Safety .................................................................................................................... 40 
8.1 Adverse Events ...................................................................................................................... 40 
8.1.1 
Definition Adverse Event ........................................................................................ 40 
8.1.2 
Period of Observation .............................................................................................. 40 
8.1.3 
Reporting of Adverse Events ................................................................................... 40 
8.1.4 
Severity of Adverse Events ...................................................................................... 41 
8.1.5 
Relationship of Adverse Event to the Drug ............................................................. 41 
8.1.6 
Outcome of Adverse Events .................................................................................... 41 
8.2 Serious Adverse Events ......................................................................................................... 42 


Hexvix® 
Study Number：YHCT-HEX-B1 
Version 2.2  Date: Feb 6th, 2023                                                                       16 | 60 
Confidential 
8.2.1 
Definition of Serious Adverse Event ....................................................................... 42 
8.2.2 
Reporting of Serious Adverse Events ...................................................................... 42 
8.3 Suspicious and Unexpected Serious Adverse Reactions ....................................................... 43 
8.3.1 
Definition of Suspicious and Unexpected Serious Adverse Reactions ................... 43 
8.3.2 
Reporting of Suspicious and Unexpected Serious Adverse Reactions .................... 43 
8.4 Reporting of Pregnancies ....................................................................................................... 44 
8.5 Sensitization Risks and Management Measures .................................................................... 44 
9. Data Management ......................................................................................................................... 45 
9.1 Data Management Process ..................................................................................................... 45 
9.2 Database Design and Establishment ...................................................................................... 45 
9.3 Data Entry .............................................................................................................................. 45 
9.4 DataVerification ..................................................................................................................... 45 
9.5 Medical Coding ...................................................................................................................... 45 
10. 
Statistical Considerations ......................................................................................................... 47 
10.1 General Principle ................................................................................................................. 47 
10.2 Determination of Sample Size ............................................................................................. 47 
10.3 Statistical Analysis Populations ........................................................................................... 47 
10.3.1 Safety Set ................................................................................................................. 47 
10.3.2 Full Analysis Set ...................................................................................................... 47 
10.3.3 Per Protocol Set........................................................................................................ 48 
10.4 Statistical Analysis Method.................................................................................................. 48 
10.4.1 Subject Disposion and Baseline Characteristic Analysis ......................................... 48 
10.4.2 Efficacy Ananlyses ................................................................................................... 49 
10.4.3 Safety Analysis......................................................................................................... 49 
10.4.4 Interim Analysis ....................................................................................................... 50 
11. 
Management of Clinical Trials................................................................................................. 51 
11.1 Statement .............................................................................................................................. 51 
11.2 Ethics .................................................................................................................................... 51 


Hexvix® 
Study Number：YHCT-HEX-B1 
Version 2.2  Date: Feb 6th, 2023                                                                       17 | 60 
Confidential 
11.3 Check the Original Records ................................................................................................. 51 
11.4 Quality Assurance and Audit ................................................................................................ 52 
11.5 Informed Consent ................................................................................................................. 52 
11.6 Modification of Clinical Protocols ....................................................................................... 53 
11.7 Protocol Deviation ............................................................................................................... 53 
11.8 Electronic Case Report Form（eCRF） .............................................................................. 53 
11.9 Monitoring ........................................................................................................................... 54 
11.10 Intellectual Property Rights ............................................................................................... 55 
11.11 Subject Privacy ................................................................................................................... 55 
12. 
Publication ............................................................................................................................... 56 
13. 
Data preservation ..................................................................................................................... 57 
13.1 Source Data and Source files ............................................................................................... 57 
13.2 Data preservation of the sites ............................................................................................... 57 
13.2.1 Information related to the ethics committee ............................................................ 57 
13.2.2 Material related to trial conduction .......................................................................... 57 
13.3 Data preservation of the sponsor .......................................................................................... 57 
14. 
Reference ................................................................................................................................. 59 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       18 | 60 
Confidential 
List of Abbreviations and Definitions of Terms 
Abbreviation 
Full name in English 
Full name in Chinese 
AE 
Adverse event 
不良事件 
BCG 
Bacillus calmette guerin 
卡介苗 
BL 
Blue light 
蓝光 
CTCAE 
Common terminology criteria for 
adverse events 
不良事件通用术语标准 
CIS 
Carcinoma in situ 
原位癌 
CRA 
Clinical research associate 
临床监察员 
CRF 
Case report form 
病历报告表 
CRO 
Contract research organization 
合同研究组织 
DM 
Data management 
数据管理 
DVP 
Data verification plan 
数据核查计划 
eCRF 
Electronic case report form 
电子病历报告表 
EDC 
Electronic data capture 
电子数据采集系统 
FDA 
Food and drug administration 
美国食品药品监督管理局 
GCP 
Good clinical practice 
药物临床试验质量管理规范 
HAL 
Hexaminolevulinate 
5-氨基酮戊酸己酯 
IEC 
Independent ethics committee 
独立的伦理委员会 
IRB 
Institutional review board 
机构审查委员会 
ITT 
Intention to treat 
意向治疗 
MedDRA 
Medical dictionary for regulatory 
activities 
ICH 国际医学用语词典 
mFAS 
modified full analysis set 
调整的全分析集 
mPPS 
modified per protocol set 
调整的符合方案集 
NCI 
National cancer institute 
国立癌症研究所 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       19 | 60 
Confidential 
Abbreviation 
Full name in English 
Full name in Chinese 
NMIBC 
Non-muscle invasive bladder cancer 非肌层浸润性膀胱癌 
NMPA 
National medical products 
administration 
国家药品监督管理局 
PAP 
Photoactive porphyrines 
光敏卟啉 
PP 
Per protocol 
符合方案 
PT 
Prefered term 
首选术语 
PUNLMP 
Papillary urothelial neoplasm of low 
malignant potential 
低度恶性潜能乳头状尿路上皮肿
瘤 
QA 
Quality assurance 
质量保证 
SAE 
Serious adverse event 
严重不良事件 
SOC 
Systematic organ classification 
系统器官分类 
SUSAR 
Suspected unexpected serious 
adverse reaction 
可疑且非预期严重不良反应 
TURBT 
Transurethral resection of the 
bladder tumor 
经尿道膀胱肿瘤电切术 
WHO DD 
World health organization drug 
dictionary 
世界卫生组织药物词典 
WL 
White light 
白光 
 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       20 | 60 
Confidential 
1. Introduction and Study Rationale 
1.1 Disease Introduction 
In the Western world, bladder cancer is the fourth most common malignancy in men and the eighth 
most common in women. An estimated 80,470 new cases of urinary bladder cancer (61,700 men and 
18,770 women) be diagnosed in the United States in 2019 with approximately 17,670 deaths (12,870 
men and 4,800 women) occurring during this same period. [1]. In China, bladder cancer is the eighth 
most common in malignant cancer, and the sixth most common in men [2]. Although the incidence of 
bladder cancer in China is about half of Western countries, " Morbidity and Mortality data in Cancer 
Registry Area of China" released from 2009 to 2012 shows that the incidence of bladder cancer has 
steadily increased from 6.41 per 100,000 to 7.49 per 100,000, with a compound annual growth rate of 
5.3%, from 2005 to 2008. 
Over ninety percent of bladder tumors are urothelial cell carcinoma, usually papillary and multi centric, 
while squamous cell carcinoma accounts for 5% and adenocarcinoma accounts for 2% [3,4]. In patients 
with the diagnosis of bladder cancer, about 70% present initially as non-muscle invasive bladder cancer 
(NMIBC), and the remainder as muscle invasive cancer. Among the NMIBC, approximately 70% are 
present as Ta lesions, 20% as T1, and approximately 10% as carcinoma in situ (CIS or Tis) [5]. 
Diagnosis of bladder cancer is mainly confirmed by a combination of cystoscopic examination, biopsy 
and urine cytology [6,7]. NMIBC is treated by transurethral resection of the bladder (TURBT) to 
remove the tumor and allow for pathologic analysis of the biopsied specimen, establishing the 
diagnosis and providing important information about the tumor grade and depth of bladder invasion. 
Recurrence of bladder tumors is common, and may be caused by residual tumor after incomplete 
resection, microsatellites missed during initial TURBT or true recurrence [8,9,10]. Depending on a 
patient’s characteristics, after transurethral resection the probability of recurrence at one-year ranges 
from about 15% to 61% and from 31% to 78% at 5 years. The major prognostic factors for recurrence 
and progression are presence of CIS, tumor multiplicity, size, previous recurrence rates, tumor stage 
and tumor grade [11]. 
White light (WL) cystoscopy has been the major technique for detecting primary and recurrent bladder 
carcinomas. While papillary tumors usually can be detected with white light cystoscopy, flat lesions 
such as CIS may be more difficult to detect under these conditions. However, techniques based on 
photoactive porphyrins, such as hexaminolevulinate (HAL), that accumulate preferentially in 
neoplastic tissue, have been developed to improve detection of non-muscle invasive bladder lesions. 
Under blue light (BL) exposure tumor lesions emit red light and can easily be detected with a 
cystoscope. 
1.2 Drug Introduction 
Hexaminolevulinate hydrochloride is approved in Europe under the brand name Hexvix for the 
following indication: “Hexvix blue light fluorescence cystoscopy is indicated as adjunct to standard 
white light cystoscopy to contribute to the diagnosis and management of bladder cancer in patients 
with known or high suspicion of bladder cancer”. In the United States the product is approved under 
the brand name Cysview for the following indication: Cysview is an optical imaging agent indicated 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       21 | 60 
Confidential 
for use in the cystoscopic detection of carcinoma of the bladder, including carcinoma in situ (CIS), 
among patients suspected or known to have lesion(s) on the basis of a prior cystoscopy, or in patients 
undergoing surveillance cystoscopy for carcinoma of the bladder.  
1.2.1 
Nonclinical Study 
Hexaminolevulinate (HAL) hydrochloride (HCl) is the drug substance of Hexvix. Hexvix has been 
globally approved for use in diagnosis of bladder cancer following intravesical administration. Hence, 
a complete package of nonclinical pharmacology and toxicology documentation exists for this 
indication. For use of HAL HCl in other indications in development, additional studies have been 
performed to investigate reproductive and developmental toxicology and local tolerance data after 
cervical application. The toxicology program performed for HAL has included safety pharmacology 
and assessments of systemic toxicity that might be due to systemic absorption after local administration. 
In addition, the potential for systemic toxicity of HAL has been assessed after single-dose (mice and 
rats) and repeat-dose (rats and dogs) intravenous administration. An extensive package of genotoxicity 
studies and a reproduction toxicity program has been completed. The combination of HAL and light 
has also been investigated in both local tolerance and genotoxicity studies. With the completed 
nonclinical studies, the safety of HAL is considered adequately documented. More information is 
available in the investigator brochure. 
1.2.2 
Clinical Study 
Belowing are brief presentation of Hexvix clinical studies, more information is available in the 
investigator brochure [12]. 
Blue light cystoscopy with Hexvix offers considerable benefits over white light cystoscopy in the 
detection of NMIBC. This has been supported by a number of clinical phase III trials [13,14,15], which 
have demonstrated that 16-29% of patients had one or more Ta or T1 tumor that were detected by blue 
light cystoscopy with Hexvix and not by white light cystoscopy. A pivotal phase III study showed that 
in 16% of the patients with Ta or T1 tumors at least one additional tumor was detected with blue light 
cystoscopy with Hexvix that was missed with white light cystoscopy (p=0.001) [15]. This phase III 
study also demonstrated that improved detection of Ta/T1 bladder tumors enables a more complete 
resection, resulting in a significant reduction of recurrence rates within 9 months. During the 
surveillance period, for ITT (the Intention-To Treat) analysis 128/271 patients (47%) in the Hexvix 
group and 157/280 patients (56%) in the white light group had tumor recurrence (p=0.026). The PP 
(Per Protocol) results were similar to those for the ITT group. The relative reduction in cancer 
recurrence at 9 months was 16% for the ITT analysis and 21% for the PP analysis. There was a trend 
that more patients in the group treated with white light only experienced recurrence of higher stage 
tumors (T1 or CIS) compared to patients treated with blue light cystoscopy with Hexvix. 
Results from three phase III studies demonstrated that blue light cystoscopy with Hexvix improves the 
detection of CIS lesions significantly, which has consequences for patient management and may 
improve prognosis [11, 16, 17]. One study included 211 patients with suspicion or known bladder 
cancer. CIS lesions were found in 39% of evaluable patients and in 22% of these patients CIS lesions 
were detected only with blue light cystoscopy with Hexvix. Data from the other study showed that 30% 
of the patients had CIS and among these 16% were detected only by blue light cystoscopy with Hexvix. 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       22 | 60 
Confidential 
In the last study [17], among 26 patients with CIS, 34.6% had CIS detected only with blue light 
cystoscopy with Hexvix. 
Two small single center studies reported improved detection of bladder cancer lesions using blue light 
cystoscopy with Hexvix [18, 19], and another small single center study documented the use of Hexvix 
in the early follow up of high-risk patients [20]. The studies were conducted in the OR setting, and 
concluded that blue light cystoscopy with Hexvix helps to detect evolving CIS and dysplasia which 
can be considered a precursor of CIS, and plays an important role in preventing disease progression. 
The safety of Hexvix instillation into the bladder has been evaluated in all clinical trials, and similar 
AE profiles have been reported for patients undergoing blue light cystoscopy with Hexvix versus 
patients treated with white light cystoscopy only [15]. Most AEs were mild to moderate and were 
expected during bladder examination by cystoscopy, and were considered to be related to general 
anesthesia, biopsy, tumor resection, cystoscopy or the patients’ underlying disease. The conclusions 
were that Hexvix is well tolerated. A review of safety information from clinical studies and 
postmarketing data did not reveal additional toxicity during repeated use of Hexvix [21]. 
The trial is a phase III, prospective, comparative, within patient controlled, multi-center study of 
Hexvix blue light cystoscopy and white light cystoscopy in the detection of bladder cancer and will be 
conducted only in China to evaluate the efficacy and safety of Hexvix blue light cystoscopy in Chinese 
population.


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       23 | 60 
Confidential 
2. Study Objectives 
2.1 Primary Objective 
• 
To compare Hexvix blue light cystoscopy with white light cystoscopy in the detection of 
bladder cancer  
2.2 Secondary Objective 
• 
Comparison of detection of patients with CIS lesions by Hexvix blue light cystoscopy and 
white light cystoscopy. 
• 
Comparison of detection rates of bladder lesions of Hexvix blue light cystoscopy and white 
light cystoscopy per lesion type (PUNLMP, CIS, Ta, T1, T2-4). 
• 
Comparison of the proportion of false positive lesions detected with Hexvix blue light 
cystoscopy and white light cystoscopy. 
• 
Evaluation of safety of Hexvix in patients with bladder cancer. 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       24 | 60 
Confidential 
3. Selection and Withdrawal of Subjects 
3.1 Inclusion Criteria 
The subject must fulfil all the following criteria to be included in the study： 
1. Volunteer to participate in clinical study; thoroughly informed, signed and dated the informed 
consent form; willing to follow and have the ability to complete all trial procedures. 
2. Suspicious or confirmed patients with bladder cancer. 
3. Age 18 or older. 
3.2 Exclusion Criteria 
Patients presenting with any of the following will not be included in the study： 
1. Gross haematuria. (Note: Gross haematuria is defined as a heavy bladder bleed resulting in 
marked 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 possible interference with 
cystoscopy). 
2. Patients who have received BCG immunotherapy or intravesical chemotherapy within the 
past 6 weeks prior to the procedure. 
3. Porphyria. 
4. Known allergy to hexaminolevulinate hydrochloride or a similar compound. 
5. Pregnancy or breast feeding or patients of child-bearing potential, including men with 
partners of child-bearing potential, who are unwilling to take barrier contraceptives from 2 
weeks before medication to 28 days after the medication. (Note: Child-bearing potential is 
defined as females who are ovulating, pre-menopausal or not surgically sterilized. All women 
of child-bearing potential must document a negative pregnancy test before study inclusion 
and use adequate contraception during the study). 
6. Participation in other clinical studies with investigational drugs/investigational device either 
concurrently or within the last 30 days prior to the first study cystoscopy. 
7. 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. 
8. Patients that the investigator assessed unsuitable to the study. 
9. Subjects with contraindications to white light cystoscopy. 
3.3 Elimination criteria 
Data will be submitted to the principal investigator, sponsor and statistical institution during data 
review meeting to determine if there is any individual case that needs to be eliminated before statistical 
analysis of the data is performed. 
3.4 Withdrawal criteria 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       25 | 60 
Confidential 
1）Investigator's decision to withdraw 
Withdrawal from the study refers to the fact that the selected subjects are unsuitable to continue the 
study during the course of the study, and the investigator decides to withdraw the case from the study. 
For subjects withdrawn from the study, the investigator should fill in the reason for withdrawal in the 
electronic case report form (eCRF), complete the evaluation items that can be completed, and fill in 
the end-of-treatment follow-up record form including the last time of contact. In the following, the 
criteria for the investigator’s decision to withdraw are listed. Beware that this is only applicable before 
dispensing of the Investigational Drug and Device. 
• 
The investigator believes that continuing treatment will be detrimental to the subject. [such as 
in the clinical trial, the subject has some comorbidities (documented as medical history), 
complications or worsening of the condition, and it is not suitable to continue the trial. (Note: 
this is only applicable to the time frame between Visit 1 and Visit 2. It stays unchanged that 
comorbidities should be evaluated accordingly before inclusion. Complications or worsening 
of the condition of the patient (AE) after dispensing of the Investigational Drug and after the 
procedure should not lead to a withdrawal of the patient, but should stay in the study for the 
Follow Up of AEs or complications for safety reasons.)] 
• 
Major protocol deviations. 
• 
The subject did not follow the doctor's advice and used other treatments without authorization, 
which affected the evaluation. 
• 
The subject’s poor compliance affects the efficacy and safety assessments. 
• 
Other. (Note: The specific reason should be recorded in the "Specific Description" section of 
the electronic case report form (eCRF), for example: non-compliance.) 
2）Subject's decision to withdraw 
Subjects, unwilling to continue to participate in clinical research, have the right to withdraw from the 
study at any time of the study according to the provisions of the informed consent form, or subjects 
have not explicitly asked to withdraw from the study, but no longer undergo test and lost to follow-up, 
also belonging to " withdraw " (or "drop out"). The reasons for their withdrawal should be understood 
as much as possible and recorded. Such as consciously feel intolerable to some adverse reactions; 
unable to continue to receive clinical study due to other reasons; or lost to follow-up without explaining 
the reason, etc. 
3）Handling of withdrawal cases 
Subjects, unwilling to continue to participate in clinical research, have the right to withdraw from the 
study at any time of the study according to the provisions of the informed consent form, or subjects 
have not explicitly asked to withdraw from the study, but no longer undergo test and lost to follow-up, 
also belonging to " withdraw " (or "drop out"). The reasons for their withdrawal should be understood 
as much as possible and recorded. Such as consciously feel intolerable to some adverse reactions; 
unable to continue to receive clinical study due to other reasons; or lost to follow-up without explaining 
the reason, etc. Regardless of the reason, for withdrawal cases, the case report form should be retained, 
and the last examination result transferred as the final result, and full data analysis of the efficacy and 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       26 | 60 
Confidential 
adverse reactions should be conducted. 
All study-related toxicity and serious adverse events (SAE) that existed at the time the study was 
discontinued must be followed up to their resolved, unless, according to the investigator’s opinion, the 
condition cannot be remitted because of the subject’s disease itself. 
After the subject terminates the study treatment, the investigator must follow up all existing or new 
AEs during the study period. And report all new AEs and SAEs that occurred within this period of time 
(if an SAE, it must be reported to the sponsor in time, and tracked until the above-mentioned adverse 
events are resolved.) After subject terminates the study, the investigator must immediately notify the 
sponsor. Any SAE needs to contact the sponsor in time with the corresponding SAE reporting process. 
There will be no replacement of withdrawn patients. 
3.5 Early Termination of Study/ Closure of Study Center 
The sponsor has the right to terminate this study at any time, and the sponsor and the investigator have 
the right to close the study center at any time. Of course, this situation can only be implemented after 
mutual negotiation. When terminating the study, the independent ethics committee (IEC) and the 
institutional review board (IRB) must be reported. The ethics committee has the right to suspend or 
terminate clinical trials that are not implemented in accordance with relevant requirements or that the 
subjects have suffered unexpectedly severe damage. When the study is terminated early or the study 
center is closed early, all study materials (except for the documents that must be kept in the center) 
must be returned to the sponsor. The investigator must keep other documents until notified by the 
sponsor to destroy it. The reasons leading to the early termination of the trial or the closure of the study 
center can be, but not limited to, the following reasons: 
• New information leads to unfavorable risk-benefit assessments of the investigational drug, for 
example, due to: 
– The investigational drug lacks efficacy, whether in this study or other studies; 
– The occurrence of significant previously unknown adverse reactions or unexpectedly 
higher severity/incidence of known adverse reactions; or 
–  Other adverse safety findings, including clinical examination and non-clinical 
manifestations; 
• The sponsor believes that it is unreasonable to continue the above study due to Health care, 
ethical, or commercial reasons; 
• It is unlikely that the study will be completed within an acceptable time frame due to the 
difficulties in enrolling subjects; 
• Suspended or terminated at the request of the health authority. 
3.6 Definition of The End of the Study 
The end of the study is defined as the last subject who completes his/her last visit, unless the end of 
the study is for a reason in Section 3.5. 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       27 | 60 
Confidential 
4. Study Design 
4.1 Study Type and Design Principle 
A Prospective, within patient controlled multicenter study. 
This study includes 3 regular visits: screening visit(-2w), cystoscopic examination (day 0), safety 
follow-up(1w). Study design as below: 
 
Fig2. Study design 
At the start of the study, a minimum of four subjects included at each center will be training subjects. 
These subjects will receive the Hexvix administration and undergo white and blue light cystoscopy 
with tumor resection as below. They will receive the same safety follow up as all the other included 
patients, after completing the safety follow-up for 1 week, the patients will be treated according to 
hospital’s clinical routine by the Investigator. These patients are not part of the efficacy analyses. 
To reduce possible bias in assessment of the objectives, a small number of subjects will be randomized 
to not continue with Hexvix blue light cystoscopy following white light cystoscopy. 
Consented, eligible subjects (Visit 1) will be instilled with 50 mL Hexvix 8 mM solution for one hour. 
After bladder evacuation, the following procedure will be utilized to accomplish the cystoscopic 
examination of each subject： 
1. Turn on the white light. Inspection of the bladder and mapping of all papillary lesions and flat 
and suspicious lesions seen under white light, record lesion number, size and location. 
2. Randomization:  
a) If the patient is not randomized to undergo blue light mapping, proceed to step 3.  
b) If the patient is randomized to continue with blue light mapping, or subjects for 
investigator training procedure, then they will undergo blue light cystoscopy. Turn to the 
blue light. Inspection of the bladder and mapping of all papillary lesions and flat and 
suspicious lesions seen under blue light, record lesion number, size and location. 
3. All papillary lesions detected will be resected using TURBT and all flat and suspicious lesions 
detected will be biopsied. The lesions resected and biopsied should be marked and 
pathologically examined separately. For patients randomized to undergo blue light cystoscopy 
and for training patients, the completeness of the resection should always be checked under 
blue light before finalizing the TURBT procedure until it is ensured that all lesions and 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       28 | 60 
Confidential 
suspicious areas are completely resected. Both biopsied and resected tissue will be examined 
by the local pathologist, then evaluated by independent and blinded central pathologists. 
Central pathology results will be used as reference standard in the study efficacy endpoints. 
All subjects (including the training patients) will receive a safety follow-up at day 7 (visit 3) after day 
0 cystoscopy (visit 2), after completing the safety follow-up for 1 week, the patients will be treated 
according to hospital routines by investigator. 
Training subjects are not included in the randomization procedure and efficacy analysis, but included 
in the safety analysis. 
4.2 Randomization and Blinding  
 
In this trial, a central random system is used for randomization, subjects will be randomized by an 
interactive web response system (IWRS) automatically according to grouping sequences to reduce 
study bias caused by sampling error. The random table is generated by an independent statistician or 
designated personnel, which is generated by the SAS software based on the number of seeds and blocks 
pre-set. A block randomization design stratified by sites is adopted. Subject information will be entered 
by the investigators into the IWRS after verification of inclusion/exclusion criteria. After all subjects 
undergo Hexvix administration for one hour and then undergo a white light cystoscopy inspection 
including mapping of the bladder (record lesion number, size and location), subjects will be 
automatically randomized by the system and grouping information will be feedback to the investigators 
whether the investigator should continue with a blue light inspection, mapping (record the lesion 
number, size and location) and biopsy/TURBT (in the same procedure) or to stop the procedure and 
receive standard treatment by clicking the “Randomization” button in the IWRS. Throughout the trial, 
the investigators will not be able to modify the group information of subjects. 
At each center the Investigator will be blinded to the number of subjects not continuing with Hexvix 
cystoscopy. A number of subjects (how many should not be known by the investigators) will not 
continue with Hexvix cystoscopy and these subjects will be distributed randomly among all the centers. 
For any subject who has completed the randomization but has dropped out of the trial prior to the 
initiation of treatment will retain their randomization number (the randomization number assigned to 
the subject will not be reused). In addition, there will be no replacement for subjects who withdraw 
early from this clinical trial. 
At the start of the study, a minimum of four subjects included at each center will be training subjects. 
These subjects will undergo Hexvix administration and white and blue light cystoscopy and will have 
the same safety follow up as all the other included, and treated according to hospital routine practice 
by the investigator. These subjects should not be included in the randomization procedure, and the 
subjects will receive subject numbers from a separate series of numbers. 
4.3 Study Procedure and Stage 
Study will be conducted as study procedures and flow chart in this chapter. 
4.3.1 
Diagnosis and Pre-treatment Evaluation (visit1) 
Pre-treatment evaluation at Visit 1 will only be performed after the patient has agreed to participate, 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       29 | 60 
Confidential 
has signed and dated the informed consent form. No treatment will be initiated before the informed 
consent has been given. 
Pre-treatment evaluation will be performed according to the inclusion and exclusion criteria, including： 
1. Patient informed consent. 
2. Record demography information (gender, age, ethnicity, height, weight, body mass index, and 
history of allergies, drug abuse, smoking, alcohol abuse, and blood donation), medical history, 
and surgery history. 
3. Record medication history. 
4. Vital signs include: body temperature, sitting blood pressure, heart rate, and breathing rate. 
Vital signs should be measured when the investigator judges that the subject’s condition is stable. 
5. Physical examination: general conditions, head and neck, lymph nodes, skin, chest, abdomen, 
musculoskeletal system (including limbs and spine) and nervous system. 
6. Pregnancy test (only for women of childbearing age): The pregnancy test for women of 
childbearing age during the screening period must be negative. If the subject has undergone a 
pregnancy test within 7 days before the administration, visit 2 can no longer perform the test. 
During the study period, urine pregnancy test can be performed as needed. If the urine pregnancy 
result is positive, a serum pregnancy test is required to confirm. If it is confirmed positive, the 
subject needs to withdraw from the test, and the investigator will continue to follow up the subject 
until the end of the pregnancy. 
Note: Women of childbearing age must take effective contraceptive measures during the study 
period. 
7. Review the inclusion and exclusion criteria. 
8. Record complications, adverse events and concomitant medications/procedures. 
4.3.2 
Treatment (visit2) 
Following successful completion of the pre-treatment evaluations, subjects will continue intoVisit 2. 
Visit 2 should take place within 14 days of Visit 1 and can be combined with Visit 1. 
The following examinations will be performed at Visit 2： 
1. Vital signs include: body temperature, sitting blood pressure, heart rate, and breathing rate. 
Vital signs should be measured when the investigator judges that the subject’s condition is stable. 
Note: Vital signs should be examined before and after surgery. 
2. Physical examination: general conditions, head and neck, lymph nodes, skin, chest, abdomen, 
musculoskeletal system (including limbs and spine) and nervous system. 
3. Pregnancy test (only for women of childbearing age): If the subject has undergone a pregnancy 
test within 7 days before the administration, visit 2 can no longer perform the test. During the 
study period, urine pregnancy test can be performed as needed. If the urine pregnancy result is 
positive, a serum pregnancy test is required to confirm. If it is confirmed positive, the subject 
needs to withdraw from the test, and the investigator will continue to follow up the subject until 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       30 | 60 
Confidential 
the end of the pregnancy. 
Note: Women of childbearing age must take effective contraceptive measures during the study 
period. 
4. Assessment of bladder sympotoms before Hexvix instillation. 
5. Urine cytology before Hexvix instillation. 
6. Hexvix instillation. 
7. White light cystoscopy and lesion evaluation/mapping. 
8. Randomization. 
9. Randomization out or blue light cystoscopy with lesion evaluation/mapping. 
10. Biopsy/TURBT/histology. 
11. Record complication, adverse events and concomitant medications/procedures. 
4.3.2.1 Hexvix instillation Cystoscopy Procedure 
1）Instillation 
All subjects will have a catheter inserted into their bladder to administer Hexvix solution. The bladder 
should be evacuated before administering the Hexvix solution. A 50 mL volume of Hexvix 8 mM will 
then be administered through the catheter. The catheter will be removed, and the subject asked to retain 
the fluid for 1 hour. 
At the end of the instillation period, the subject will be given either local or general anesthesia at the 
discretion of the Investigator, and the bladder will be evacuated after retaining the Hexvix fluid for 1 
hour. 
Cystoscopy should not be earlier than 60 minutes after Hexvix instillation to allow tumor cells to 
synthesize sufficient amount of photoactive porphyrin. The cystoscopic examination should start no 
more than 3 hours after the start of bladder instillation. 
Subjects who fail to retain the Hexvix solution for 60 minutes will complete the procedure, however, 
cystoscopic examination should not be performed before 60 minutes after instillation. 
Cytology will be obtained before Hexvix instillation for all patients. 
2）Cystoscopy 
All subjects will receive bladder instillation with 50 mL Hexvix 8 mM solution for one hour. After 
bladder evacuation, cystoscopic examination performed on each subject using following procedures:  
1. Turn on the white light. Inspection of the bladder and mapping of all papillary lesions and flat 
and suspicious lesions seen under white light, record lesion number, size and location. 
2. Randomization:  
a) If the patient is not randomized to undergo blue light mapping, proceed to step 3.  
b) If the patient is randomized to continue with blue light mapping, or subjects for 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       31 | 60 
Confidential 
investigator training procedure, then they will undergo blue light cystoscopy. Turn to the 
blue light. Inspection of the bladder and mapping of all papillary lesions and flat and 
suspicious lesions seen under blue light, record lesion number, size and location. 
3. All papillary lesions detected will be resected using TURBT and all flat and suspicious lesions 
detected will be biopsied. The lesions resected and biopsied should be marked and pathologically 
examined separately. For patients randomized to undergo blue light cystoscopy and for training 
patients, the completeness of the resection should always be checked under blue light before 
finalizing the TURBT procedure until it is ensured that all lesions and suspicious areas are 
completely resected. Both biopsied and resected tissue will be examined by the local pathologist, 
then evaluated by independent and blinded central pathologists. Central pathology results will be 
used as reference standard in the study efficacy endpoints. 
Registration of lesions on the bladder chart will include presence of lesion, type (papillary, or flat), 
number of lesions and location (bladder neck anterior, trigone, around ureteric orifice right, around 
ureteric orifice left, posterior floor, right lateral wall, cranial wall, left lateral wall, dome, anterior 
bladder wall and bladder neck posterior). 
The cystoscopy will be videotaped, and the video will be used as the source data for the cystoscopy 
procedure. The cystoscopy video recording of all training subjects (at least 4 subjects) per study site 
will be reviewed by sponsor for site qualification. After sponsor’s written approval, the site can start 
with cystoscopic examination for randomized subjects.  
If assigned investigator and / or sub-investigator failed to fulfil the requirements continuously, more 
training subjects can be requested and reviewed by the sponsor. It needs to be discussed to see if more 
trainings can be delivered, or tentatively to evaluate if change of investigator is possible 
3）Handling and Interpretation of blue light cystoscopy 
When using the blue light cystoscopy, there are several points to consider obtaining the best results. 
Correct handling of the endoscope is important to optimize the results. False fluorescence may appear 
and correct interpretation of the fluorescing areas is important. 
In general, false fluorescence from normal tissue will be weak and diffuse. The endothelium of blood 
vessels and inflamed areas may show false fluorescence, but fluorescence from neoplastic lesions will 
be more intense and usually well demarcated. To avoid false fluorescence and get a brighter picture, 
the endoscope should be held perpendicular and close to the bladder wall. Tangential light will give 
false fluorescence. Changing of fluorescence intensity when varying the observation angle indicates 
false fluorescence, as true fluorescence is persistent. A brighter picture will be achieved using a low 
magnification if a zoom lens is used. Bleeding will reduce the image brightness and good irrigation 
should be used. Photo bleaching, which is caused by destruction of the photosensitizer and leads to 
reduced fluorescence intensity, should be kept at a minimum by avoiding unnecessary delay during 
inspection and mapping of the bladder. Photo bleaching is normally not a problem during inspection 
and mapping of the bladder, but may be noticed during extensive use of fluorescence-guided resection. 
However, regeneration of fluorescence may be seen in areas kept 'in the dark' for a few minutes. To 
minimize photobleaching, the use of white light should be performed under the lowest possible light 
intensity. Viewing conditions may be altered by the presence of urine, and the bladder should therefore 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       32 | 60 
Confidential 
be adequately evacuated before starting the procedure together with proper irrigation during the 
examination. Please ensure that the bladder is sufficiently distended as a folded bladder wall may result 
in increased fluorescence 
4）Biopsy/TURBT/Histology 
Biopsies/TURBT will be obtained as part of the cystoscopic procedures. Perform biopsy and resection 
of all lesions and suspicious areas seen in blue light and white light. Both biopsied and resected tissue 
will be examined by the local pathologist, then evaluated by independent and blinded central 
pathologists. Central pathology results will be used as reference standard in the study efficacy 
endpoints. 
4.3.3 
Seven Day Safety Follow up (visit 3) 
The Investigator will contact the patient seven days after the initial cystoscopy/TURBT to record 
complications, adverse events and concomitant medication or procedures. This contact may be by 
telephone. 
4.3.4 
Unplanned Visits 
Temporary visits should be made based on clinical needs. Corresponding laboratory abnormalities and 
adverse events with significant clinical use should be recorded in the CRF and original data. 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       33 | 60 
Confidential 
5. Investigational Medicinal Product and Device 
5.1 Investigational Drug 
5.1.1 
Drug name, Dosage Form and Specification 
Name： 
Hexvix (hexaminolevulinate hydrochloride for intravesical solution) 
Dosage Form： 
Powder 
Specification： 
Hexvix is supplied as a kit containing a 10 mL glass vial containing 85 mg powder of Hexvix 
(hexaminolevulinate hydrochloride, HAL HCl) for Intravesical Solution, and a prefilled 
syringe containing 50 mL solvent for Hexvix. 
Administration： The HAL solution is prepared by reconstituting 85 mg HAL HCL with 50 mL solvent. 
Instillation of the Hexvix solution into the bladder through a catheter, retaining in bladder 
for 1 to 3 hours before the cystoscopy. Detailed administration sees drug instructions. 
Storage： 
Hexvix Kit for Intravesical Solution should be stored at 10-30℃. Detailed storage see the 
drug instructions. 
5.1.2 
Administration 
Investigational drug: Hexvix (hexaminolevulinate hydrochloride for intravesical solution), bladder 
instillation, single administration. The HAL solution is prepared by reconstituting 85 mg HAL HCL 
with 50 mL solvent. Instillation of the HAL solution into the bladder through a catheter, retaining in 
bladder for 1 hours before the cystoscopy. Detailed administration sees drug instructions. 
5.1.3 
Packaging 
The sponsor or delegate CRO will design the label for investigational drug and perform packaging and 
labeling according to Good clinical practice (GCP) and applicable regulations. 
5.1.4 
Labelling 
The content of the drug label at least includes the followings: 
• 
Clinical trial drug name, strength and dosage form (For clinical trial use only) 
• 
Sponsor 
• 
Protocol number 
• 
Storage conditions 
• 
Expiry date 
• 
Administration method 
• 
Batch number 
5.1.5 
Drug Distribution, Recording and Recover 
Drugs used in this trial are provided and processed according to with GCP regulations. Special 
personnel from study site are responsible for receipt, inventory management, medication for each 
subject, drug recover and maintenance of related records. Study drugs must be distributed in 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       34 | 60 
Confidential 
accordance with the requirements of the protocol. Study drugs are provided by the sponsor in free of 
charge and distributed to each study site, kept and distributed by special personnel from study site. The 
"Investigational Drug Registration Form" should be filled in and confirmed by the drug administrator 
and investigator each time the drug is distributed and recovered.  
All investigational drugs provided by the sponsor can only be used in this clinical study, and not for 
purposes out of this protocol. The investigator must promise not to provide the investigational drug to 
anyone unrelated to this trial. The investigator is required to keep proper records of all investigational 
drugs distributed, including the date, quantity, and which subjects used.  
Un-used study drugs must be returned to the sponsor or destroyed in accordance with the procedures 
of the relevant regulatory in effect. 
5.2 Photodynamic Diagnostic Equipment (PDD) System 
The PDD system used in clinical research, namely Richard Wolf PDD system (System blue), is a 
complete cystoscopy equipment developed for white light and blue light cystoscopy. The system 
includes any of the following: 
- 
Camera controller, Camera head, Light source, Light cable 
- 
PANOVIEW blue telescopes 
ENDOLIGHT LED blue light source and system blue: 
The ENDOLIGHT LED blue light source is intended to be used for PDD. The system enables to use 
of a white light mode, and a blue light mode enabling fluorescence excitation for PDD.  
For the application for PDD, the ENDOLIGHT LED blue light source is equipped with two separate 
LEDs, one for the “white light mode” with an emission spectrum covering almost the entire visible 
light range and one for the “blue light mode” with peak emission at about 410 nm. This is used to 
induce and observe tissue fluorescence after hexvix administration. The different LEDs are activated 
independently from each other, depending on the desired mode of operation, with only one of the LEDs 
can be operated at once. 
The diagnostic approach is selected and configured using the camera controller in the camera menu, a 
process that normally takes place once at the start of the application. The user can switch between 
white light and blue light mode using a mode selection button on the light source, or a button on the 
camera head. Normally, a user switches between white light and blue light several times during an 
application. 
The Richard Wolf PDD system (System blue) for optical diagnosis has been approved for marketing 
in the European Union and Japan. PDD system (System blue) has not yet been approved for marketing 
in China. In conjunction with the photosensitizer used and in blue light mode, the PDD system (System 
blue) respectively the blue light mode is used as an extension of the white light mode for improved 
detection of superficial bladder tumors. PDD system (System blue) is prohibited for: 
1. The PDD system (System blue) must not be used in patients who are not suitable for white light 
endoscopy.  
2. The following patient groups are not suitable for blue light mode: 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       35 | 60 
Confidential 
• 
Patients who were treated with chemotherapy or immune therapy within the previous six weeks;  
• 
Patient with a florid infection of the urinary tract; 
• 
Patients who already showed an immunological reaction to one of the photosensitizers used in 
photodynamic diagnostics. 
 
Type no 
Product description 
Country 
Certificate 
Valid since 
5525833 
LOGIC HD PENDUAL 
CAMERA HEAD BLUE 
EU 
501,125  
19.08.2016 
Japan 
13B1X10183P00046  
16.01.2019 
5165001 
LIGHT SOURCE LED BLUE 
EU 
900,056a  
19.08.2016 
Japan 
13B1X10183P00047 
08.01.2019 
8650514 
TELESCOPE BLUE 0° Ø 4MM 
WL 298MM 
EU 
441,063e  
20.01.2006 
Japan 
303AIBZI00003000  
16.03.2021 
8654531 
TELESCOPE BLUE 12° Ø 4MM 
WL 298MM 
EU 
441,063e  
20.01.2006 
Japan 
303AIBZI00003000  
16.03.2021 
8654522 
TELESCOPE BLUE 30° Ø 4MM 
WL 299MM 
EU 
441,063e 
20.01.2006 
Japan 
303AIBZI00003000  
16.03.2021 
8650515 
TELESCOPE BLUE 70° Ø 4MM 
WL 303MM 
EU 
441,063e 
20.01.2006 
Japan 
303AIBZI00003000 
 
16.03.2021 
The light detection procedure involves irradiating the bladder wall with blue light. Due to the limited 
penetration of blue light in the tissue, the photoactivation of PAP only occurs on the surface of bladder 
wall. The light dose given by PDD system is small, and no complications are expected in rgards to 
light application in patients who undergo blue fluorescence cystoscopy [22]. 
The irradiance at the distal end of cystoscope is about 200 mW. Assuming that the typical light 
diagnostic procedure in the patient lasts about 30 minutes, a total light dose of 360 J is applied to the 
bladder wall. When uniformly distributed on the bladder wall (about 300 cm2), a total light dose of 
about 1.2 J / cm2 is applied. In a rat study [22], no or slight loss of healthy urothelium and no necrosis 
of urothelium and lamina propria were observed after perfusion of ALA (1%) and application of 50 J 
light dose (about 25 J / cm2). Therefore, the light dose (1.2 J / cm2) for human diagnostic purposes is 
not enough to cause any damage to urothelial cells in vivo. 
System blue and its components (for PDD blue light cystoscopy) have been proved to have good 
clinical efficacy and safety in several studies [23-28]. The main risk associated with the application of 
System blue is the potential failure of cystoscopy examination due to device deficiencies. Due to the 
strict adherence to all standard design and production safety protocols, the possibility of a technical 
failure during cystoscopy with the System blue is extremely low. In addition, appropriate measures 
have been taken to minimize the risk to the study subjects, and if unrecoverable device deficiencies 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       36 | 60 
Confidential 
occurred in some or all components of the System blue during the trial, e.g ①In the case of blue light 
mode failure, subjects could still be examined by the investigator using the white light mode and 
resection can be performed in the white light mode; ②In the event of a malfunction of the System 
blue, the investigator can immediately withdraw the investigational device and do the examination and 
surgery with their standard equipment they use for all their patients diagnosed with bladder cancer. 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       37 | 60 
Confidential 
6. Treatment of Subjects 
6.1 IMP 
All eligible subjects well receive instillation of 50 mL Hexvix solution for 1hour 
All eligible subjects well receive single administration (visit 2). 
6.2 Concomitant Medication 
Concomitant medications include any drugs (including prescription drugs, over-the-counter drugs, 
natural extracts, nutritional supplements, traditional Chinese medicines, etc.) used by the subject from 
signing the informed consent form (ICF) to the completion of the last visit specified in the flowchart. 
Note: There is no need to record normal saline. The medications used by subjects during the screening 
period are recorded as medication history. Any prescription drugs and over-the-counter drugs, herbal 
medicines, vitamins and nutritional supplements used by the subjects must be reviewed and approved 
by the investigators. Information on concomitant medications should be recorded in detail. 
During the study period, symptomatic treatment drugs that will not affect the efficacy and safety of the 
study drug can be used in combination, and the medication should be specified in detail. 
6.3 Compliance 
The investigator must emphasize compliance to the subjects when they agree to the interview. 
During the trial, if the subject’s compliance is poor, the investigator should find out the reason, actively 
take corresponding measures (such as emphasizing the importance of protocol compliance to the 
subject), and fully record the non-compliance, the reason, and the corresponding measures taken. 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       38 | 60 
Confidential 
7. Assessment of Efficacy 
All efficacy endpoints assessments will be based on central pathology results, which will be used for 
statistical comparisons. 
7.1 Primary Efficacy Endpoint 
The primary efficacy endpoint of this study as below:  
• 
The proportion of patients with histology-confirmed tumors (Ta, T1, or CIS) who have at least one 
such tumor found by Hexvix but not by white light cystoscopy. 
7.2 Secondary Efficacy Endpoint 
The secondary efficacy endpoint of this study as below: 
• 
The proportion of patients with one or more CIS lesions detected with Hexvix blue light 
cystoscopy not by white light cystoscopy. 
• 
The lesion detection rate of Hexvix blue light cystoscopy, compared to white light cystoscopy per 
lesion type (PUNLMP, CIS, Ta, T1, T2-T4). 
• 
The proportion of false positive lesions detected with Hexvix blue light cystoscopy and white light 
cystoscopy. 
7.3 Central Pathology Evaluation 
All efficacy endpoints assessment will be based on central pathology consensus panel results to reduce 
the difference between the pathological evaluations used in the efficacy analysis. 
The WHO 2016 World Health Organization/International Society of Urologic Pathology consensus 
classification and the Union for International Cancer Prevention (UICC) 2017 8th edition of 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 final 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 discuss together. 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 CIS, Ta, T1 orT2-T 4 by the 
consensus panel. Lesions can be classified to PUNLMP, low grade and high grade. 
7.4  Efficacy Parameters 
Efficacy parameters recorded in eCRF will be used in both analyses of the primary and secondary 
endpoints.  
7.4.1 
Detection of Lesions by White Light Cystoscopy 
• 
Number of lesions and suspicious areas seen. 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       39 | 60 
Confidential 
• 
Type of lesion and suspicious area seen (flat or papillary). 
• 
Location of lesions and suspicious areas (Bladder neck anterior, trigone, around ureteric 
orifice right, around ureteric orifice left, posterior floor, right lateral wall, cranial wall, left 
lateral wall, dome, anterior bladder wall, bladder neck posterior). 
7.4.2 
Detection of Lesions by Blue Light Cystoscopy 
• 
Number of fluorescent lesions and suspicious areas seen. 
•  Type of fluorescence lesions and suspicious areas seen (flat or papillary). 
•  Location of fluorescent lesions and suspicious areas (Bladder neck anterior, trigone,around 
ureteric orifice right, around ureteric orifice left, posterior floor, right lateral wall, cranial 
wall, left lateral wall, dome, anterior bladder wall, bladder neck posterior) 
7.4.3 
Subject Diagnosis 
Subject diagnosis will be recorded including the assessments performed. This will include the staging 
and grading based on the use of cystoscopy, biopsies/histology, cytology, markers and/or other test(s). 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       40 | 60 
Confidential 
8. Assessment of Safety 
8.1 Adverse Events 
8.1.1 
Definition Adverse Event 
An adverse event is defined as any untoward medical occurrence in a patient from signing the ICF to 
the completion of the last visit specified in the flowchart (visit 3) and which does not necessarily have 
to have a causal relationship with this treatment. 
An adverse event can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not related to the medicinal product. 
Symptoms/signs that begin or worsen in severity and/or frequency after Hexvix instillation will be 
recorded as AEs in the eCRF. 
Examples of adverse events may include the following factors: 
• 
A new sign, symptom, illness, or syndrome 
• 
Worsening of a concomitant disease, sign or symptom at baseline 
• 
An effect of investigational product, including comparator or concomitant medication 
• 
An effect of an invasive procedure required by the protocol 
• 
An accident or injury 
Surgical procedures themselves are not adverse events; they are therapeutic measures for conditions 
that require surgery. The condition for which the surgery is required is an adverse event, if it occurs or 
is detected after the administration of Hexvix. Planned surgical measures permitted by the clinical 
study protocol, i.e., surgical treatment for bladder cancer, are not adverse events. 
8.1.2 
Period of Observation 
The period of observation is defined as the period from instillation of Hexvix until the end of the study. 
8.1.3 
Reporting of Adverse Events 
All adverse events occurring during the period of screen and observation must be documented on the 
adverse event form in the eCRF. 
A baseline recording of clinical bladder cancer symptoms will be performed before administration of 
Hexvix. Only symptoms that increase in severity or new symptoms of any illness will be recorded as 
adverse events in the eCRF. 
Every attempt should be made to describe the adverse event in terms of a diagnosis. If a clear diagnosis 
has been made, individual signs and symptoms will not be recorded unless they represent atypical or 
extreme manifestations of the diagnosis. For example, if myocardial infarction is reported as an AE, 
there is no need to report elevated creatine phosphokinase and abnormal ECG, or other related signs, 
symptoms, or laboratory values as separate AEs. However, if both occurred in isolation and myocardial 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       41 | 60 
Confidential 
infarction was not diagnosed, then each event would be reported as an AE. In this case they should be 
reported as separate events. If a clear diagnosis cannot be established, each sign and symptom must be 
recorded individually. 
AEs will be recorded as follows: 
• 
All AEs occurring in the period of observation, whether or not considered related to Hexvix 
and/or blue light, will be recorded 
• 
All SAEs that are considered related to Hexvix and/or blue light occurring after the period of 
observation, but before database lock, will be recorded in the eCRF and included in the 
clinical database 
All SAEs that are considered related to Hexvix and/or blue light occurring after database lock will be 
reported to the sponsor and included in the safety database only. The sponsor will code all adverse 
events according to current standard dictionary (MedDRA). 
8.1.4 
Severity of Adverse Events 
The intensity of all AEs will be graded as mild, moderate, or severe using the following definitions: 
Mild 
the adverse event is transient and easily tolerated 
Moderate 
the adverse event causes the patient discomfort and interrupts the 
patient’s usual activities 
Severe 
the adverse event causes considerable interference with the patient’s 
usual activities and may be incapacitating or life-threatening 
8.1.5 
Relationship of Adverse Event to the Drug 
The causality assessment of adverse events will be done by the performing clinical investigator 
urologist. Relationship to Hexvix and/or blue light will be categorized as“yes” or “no” or “uncertain”, 
of which the “yes” and “uncertain” are considered as Adverse Drug Reaction (ADR): 
Yes 
an adverse event which after careful examination at the time of evaluation, 
appears to be related to Hexvix and/or blue light 
No 
an adverse event which after careful examination at the time of evaluation, 
is judged to be clearly and incontrovertibly due to extraneous causes 
(disease, environment, etc) and do not meet the criteria described under 
“yes” 
Uncertain 
there is no clear relevance between the event and the time of administration, 
the event is similar to the known reaction type of the investigational drug, 
while the same reaction may be caused due to the use of other drugs. 
Therefore, there is no sufficient basis for the determination. 
8.1.6 
Outcome of Adverse Events 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       42 | 60 
Confidential 
All adverse events must be followed for a final outcome until the end of the period of observation. 
Related and/or serious adverse events must be followed until resolved, or at the latest until the database 
is locked. In case of permanent impairment, the event must be followed until the condition stabilizes 
and the investigator considers is medically justifiable to terminate follow-up, or until database lock. 
For adverse events resulting in death, a full pathologist report should be supplied if possible. 
Outcome will be recorded in the eCRF as one of the following: 
• 
Resolved 
• 
Resolving 
• 
Not resolved 
• 
Resolved with sequelae 
• 
Unknown 
• 
Death 
8.2 Serious Adverse Events 
8.2.1 
Definition of Serious Adverse Event 
A serious adverse event is any untoward medical occurrence that at any dose: 
1) Results in death 
2) Is life threatening, the term “life threatening” in the definition of “serious” refers to an event in 
which the patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
3) Requires inpatient hospitalization or prolongation of existing hospitalizationiii 
4) Results in persistent or significant disability/incapacityiv 
5) Is a congenital anomaly/birth defect 
6) Other medically important condition 
In addition, medical and scientific judgment is required to decide if prompt notification is required in 
other situations, i.e., any event which the investigator regards as serious that did not strictly meet the 
criteria above but may have jeopardized the patient or required intervention to prevent one of the 
outcomes listed above, or which would suggest any significant hazard, contraindication, side effect or 
precaution that may be associated with the use of the drug. 
8.2.2 
Reporting of Serious Adverse Events 
All SAEs occurring in the period of observation, whether or not related to the study intervention, must 
be collected and reported to the sponsor / CRO safety contacts and regulatory authority. 
SAE occurring after the period of observation should be reported by the investigator to the sponsor 
/CRO if the investigator considers the SAE to be causally related to the study intervention. 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       43 | 60 
Confidential 
An SAE report consists of the following: 
• 
SAE form (available in Investigator Site File and electronically) 
• 
Adverse event form 
• 
Concomitant medication form 
• 
Medical history form 
• 
Bladder cancer medical history 
The initial report must be as complete as possible, including all items on the SAE form, otherwise the 
complete SAE form will need to be sent to the sponsor /CRO Security contacts. The SAE form should 
preferably be completed electronically. The investigator should report SAE to the sponsor /CRO 
Security contacts via SAE Manager System (preferred) or email to DS-CT@asieris.cn and 
PPC.China.PV@ppccro.com (when system error) within 24 hours following knowledge of the event. 
The investigator should not await additional information to fully document the event before reporting 
an SAE, although additional information may be requested. Where applicable, information from 
relevant laboratory results, hospital case records and autopsy reports should be obtained. The 
investigator is also required to submit follow-up reports until the SAE resolves, or in the case of 
permanent impairment, until the SAE stabilises. 
Information not available at the time of the initial report (e.g., end date for the adverse event or 
laboratory values received after the report) must be documented as a follow-up report. A new SAE 
form must be completed, and marked as “Follow-up”. 
Details of all SAEs must also be reported on the adverse event form in the eCRF. 
If an adverse event initially recorded as non-serious event, becomes serious, this must also be reported 
within 24 hours following knowledge. 
The sponsor will report all SAEs to local health authorities and investigators as required by local 
regulations and sponsor standard operating procedures (SOPs). The investigator is responsible for 
reporting SAEs to the Institutional Review Board (IRB) according to local requirements. 
8.3 Suspicious and Unexpected Serious Adverse Reactions 
8.3.1 Definition of Suspicious and Unexpected Serious Adverse Reactions 
Suspicious and unexpected serious adverse reactions (SUSAR) refer to those with the nature and 
severity of the clinical manifestation beyond the information of the existing materials such as the 
Investigator's Brochure of the investigational drug. 
8.3.2 Reporting of Suspicious and Unexpected Serious Adverse Reactions 
There is no time limit for the collection of serious adverse events judged to be related to the 
investigational drug. This means that serious adverse events related to the investigational drug that 
even occur after the last visit specified in the protocol should still be reported. The reporting method 
for SUSAR that occurs after the clinical trial is completed and before the approval conclusion is 
obtained is consistent with that before the trial is completed. 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       44 | 60 
Confidential 
The sponsor and/or sponsor representative will report SUSARs to health authorities, ethics committees 
and investigators, etc. as required by local regulations, sponsor standard operating procedures (SOPs) 
and other internal references (e.g. Safety Management Plan). 
8.4 Reporting of Pregnancies 
If a patient or patient partner becomes pregnant during study participation, the investigator must report 
the pregnancy to the sponsor / CRO safety contacts within 24 hours following knowledge of the 
pregnancy, reporting method is the same as the SAEs above. The pregnancy should also be recorded 
in the eCRF. 
Patients who become pregnant during study participation will be followed until completion of 
pregnancy. The pregnancy outcome information must be submitted to the sponsor as soon as it becomes 
available by completing the pregnancy surveillance form part II. The investigator is responsible for 
reporting any pregnancies to the IRB. 
8.5 Sensitization Risks and Management Measures 
Hexvix® has the potential to cause rapid-onset severe allergic reactions / hypersensitivity reactions, for 
which the Sponsor has developed a risk management plan and is managing this as a "significant 
identified risk". 
The routine risk preventive measures that the Sponsor takes concerning this risk are as follows: 
1. In this clinical trial, subjects with allergy to hexaminolevulinate hydrochloride or a similar 
compound will be excluded;  
2. The information on the safety profile of Hexvix concerning allergy occurring in preclinical studies, 
clinical studies and postmarketing exposure is fully described and prompted in the investigator 
brochure. 
3. Information on risks is provided in the clinical use instructions: 【Contraindications 】
Hypersensitivity to the active substance or to any of the excipients. Porphyria. 【Special warnings and 
precautions for use】The possibility of hypersensitivity including serious anaphylactic/anaphylactoid 
reactions should always be considered. Advanced life support facilities should be readily available. 
【Undesirable effects】Adverse reactions from clinical trials and spontaneous reporting: immune 
system disorders - anaphylactoid shock. 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       45 | 60 
Confidential 
9. Data Management 
9.1 Data Management Process 
Sponsor or delegate CRO is responsible for the study data management to ensure the authenticity, 
integrity, privacy and traceability of clinical trial data. 
9.2 Database Design and Establishment  
The eCRF database is constructed by Sponsor or delegate CRO. The database should manage data 
traces such as system login, data entry, modification, or deletion, and the establishment of the database 
shall adopt the CDISC standard. 
9.3 Data Entry 
Information will be entered into the Electronic Data Capture (EDC) database by the investigator or a 
person authorized by the investigator within 3-5 working days after completion of the visit. And strictly 
follow the "what you see is what you record" principle of data entry. After the original data is entered, 
any changes made to the eCRF are automatically recorded in the system. 
9.4 DataVerification 
According to the finalized Data Verification Plan (DVP), Data Manager (DM) will set up Data logic 
verification procedures in the EDC system. 
After data entry into the EDC system, if there is any illogical data, the system check will start operation 
and trigger the challenge. These queries need to be reviewed and answered by the investigator or a 
person authorized by the investigator. When the updated data makes the logical check no longer valid, 
the data challenge is closed immediately; If the site confirms the data and provides a response, the DM 
will review the response information. When the reason is reasonable, turn off the data query; When 
the data problem is not solved, DM can continue to communicate with the site by adding data query 
until the final solution. 
Generate subject data lists/reports programmatically to support manual data verification throughout 
the study. When there is data that needs to be clarified/verified/confirmed by the researcher, human 
questioning can be added to the EDC system. The data manager should confirm that all queries have 
been resolved and the investigator should complete the electronic signature in the EDC system to 
ensure the integrity and accuracy of the subject data in the EDC system. 
9.5 Medical Coding 
The data manager (DM) is responsible for the medical coding of this study. The code includes 
medical history, concomitant medications, and adverse events. 
Previous medical history and adverse events will be coded according to the Medical Dictionary for 
Regulatory Activities (MedDRA) dictionary. The concomitant drug use was coded by the World 
Health Organization Drug Dictionary (WHO DD), which adopted the version confirmed by the 
sponsor. 
In the process of coding, DM will ask investigators to verify and confirm any data problems that 
cannot be encoded due to improper, inaccurate or vague medical terms. 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       46 | 60 
Confidential 
Before the database is locked, DM will send a medical coding report to the sponsor and it will be 
reviewed by the sponsor. 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       47 | 60 
Confidential 
10. Statistical Considerations 
10.1 General Principle 
The Statistical Analysis Plan is prepared by the Biostatistician and the Principal Investigator according 
to the study protocol and will be finalized and documented prior to the first database lock. Detailed 
statistical analysis methods will also be specified in the statistical analysis plan. 
All statistical analyses will be completed using SAS version 9.4 or higher. See statistical analysis plan 
for specific statistical methods. 
Continuous variables will be described by mean, standard deviation, median, first quartile, third 
quartile, maximum and minimum. 
Categorical variables will be described by frequency and percentage. If necessary, 95% confidence 
interval (95% CI) of the percentage will be calculated. 
10.2 Determination of Sample Size 
Approximately 380 subjects will participate in the study and will continue until 94 subjects with 
pathologically confirmed of bladder cancer at Ta, T1, and CIS stages. 
The sample size calculation for this study is as follows: 
The primary efficacy endpoint of this study is "The proportion of patients with histology-confirmed 
tumors (Ta, T1, or CIS) who have at least one such tumor found by Hexvix but not by white light 
cystoscopy. A proportion of 10% is considered clinically significant, and if the actual proportion is 
20%, that is, the null hypothesis is P null hypothesis = 10% and the alternative hypothesis is P 
alternative hypothesis = 20%, a total of 94 subjects with pathologically confirmed Ta, T1, and CIS 
stage bladder cancer are required at a one-sided significance level of 0.025 with 80% power based on 
an exact test for one proportion. 
Assuming that 35% of subjects will have bladder cancer after Hexvix-assisted blue light cystoscopy 
and/or white light cystoscopy, bladder cancer with Ta, T1 and CIS stage accounting for 75%, 359 
subjects are expected to be enrolled in this trial. Considering the 5% drop-out rate, a total of about 380 
subjects are required. The study will continue until 94 subjects have bladder cancer after Hexvix-
assisted blue light cystoscopy and/or white light cystoscopy and are pathologically confirmed as Ta, 
T1, and CIS stage bladder cancer. 
Note: A minimum of 4 subjects included at each center will be training subjects, and those training 
subjects are in addition to the estimated sample size. Moreover, training subjects are not included in 
the randomization procedure and efficacy endpoints analysis set, but included in the safety analysis 
set. 
10.3 Statistical Analysis Populations 
10.3.1 Safety Set 
All subjects who receive Hexvix instillation will be included in the safety population (including 
training subjects for investigators). 
10.3.2 Full Analysis Set 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       48 | 60 
Confidential 
10.3.2.1 Full Analysis Set (FAS) 
All secondary efficacy analysis will be based on full analysis set (FAS). Subjects who receive Hexvix 
instillation and undergo blue light cystoscopy will be included in FAS. Efficacy data of subjects who 
received Hexvix and white light cystoscopy but did not continue with blue light cystoscopy will be 
shown in individual table. Training patients who receive Hexvix and white light cystoscopy and blue 
light cystoscopy and have evaluable data will not be included in FAS. 
10.3.2.2 Modified Full Analysis Set (mFAS) 
Primary efficay analysis will be based on modified full analysis set (mFAS). Subjects who receive 
Hexvix instillation and undergo blue light cystoscopy, and are pathologically confirmed as Ta, T1, and 
CIS stage bladder cancer will be included in mFAS. Efficacy data of subjects who received Hexvix 
and white light cystoscopy but did not continue with blue light cystoscopy will not be included in 
mFAS. Training patients who receive Hexvix and white light cystoscopy and blue light cystoscopy and 
have evaluable data will not be included in mFAS. 
10.3.3 Per Protocol Set 
10.3.3.1 Per Protocol Set (PPS) 
The analysis of secondary efficacy endpoints will be based on the per protocol set (PPS). PPS is a 
subset of FAS. A subject will be excluded from the PPS for the following reasons: 
• Failure to fulfill inclusion criteria / exclusion criteria but still entered into the study. 
• Failure to retain the Hexvix solution for at least 30 minutes. 
Protocol violations that are thought to affect the result of the cystoscopy or the histologic result may 
result in subjects being excluded from the PPS (will be documented before data base lock). 
10.3.3.2 Modified Per Protocol Set (mPPS) 
The analysis of primary efficacy endpoints will be based on the modified per protocol set (mPPS). 
mPPS is a subset of mFAS. A subject will be excluded from the mPPS for the following reasons: 
• Failure to fulfill inclusion criteria / exclusion criteria but still entered into the study. 
• Failure to retain the Hexvix solution for at least 30 minutes. 
• Subjects who protocol deviations that affected the evaluation of primary endpoint. 
Protocol violations that are thought to affect the result of the cystoscopy or the histologic result may 
result in subjects being excluded from the mPPS (will be documented before data base lock). 
The mPPS analysis is done as a supportive analysis of the primary efficacy endpoints, and will show 
if the exclusion of subjects from the mFAS will affect the overall conclusions of the results. 
10.4 Statistical Analysis Method 
10.4.1 Subject Disposion and Baseline Characteristic Analysis  
All baseline and demographic data analysis will be performed on the basis of FAS and mFAS. 
List the information of subjects who failed screening, including screening number and reasons for 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       49 | 60 
Confidential 
screening failure. Subjects who failed screening will be summarized, including number of screen 
failures, number of screen failures, and percentage of each screen failure reason. 
The number of subjects enrolled in the study, the number/percentage of subjects undergoing white and 
blue light cystoscopy, the number/percentage of subjects included in the efficacy, safety evaluations, 
the number/percentage of subjects completing each period of the study, and the reasons for withdrawal 
will be summarized. 
Listings of demographic data and baseline characteristics will be provided. Descriptive statistics will 
be performed for all demographic data and baseline characteristics (e.g., gender, age, ethnicity, height, 
weight, previous medical history, current medical history, medication history, urine cytology). 
Details will be described in the statistical analysis plan. 
10.4.2 Efficacy Ananlyses 
Efficacy endpoint analysis will be based on FAS/mFAS and PPS/mPPS. 
10.4.2.1 Primary Efficacy Endpoint 
The analysis on primary efficacy endpoint will be performed on the basis of mFAS and mPPS. Primary 
efficacy endpoint will be analyzed based on subjects who received Hexvix instillation and continue 
with blue light cystoscopy, and are pathologically confirmed as Ta, T1, and CIS stage bladder cancer. 
Training patients will not be included. 
For analysis of the primary efficacy endpoint (The proportion of patients with histology-confirmed 
tumors (Ta, T1, or CIS) who have at least one such tumor found by Hexvix but not by white light 
cystoscopy), an exact test for single proportion, using the cumulative binominal distribution, with a 
significance level of 0.025 (1-sided) will be used, based on the mFAS and mPPS, and the 95% 
confidence interval for the detection rate will be calculated. 
10.4.2.2 Secondary Efficacy Endpoints 
Secondary efficacy endpoints analysis will be based on FAS and PPS. 
Secondary efficacy endpoints will be analyzed descriptively, including event rate and 95% confidence 
intervals based on the FAS and PPS. Exact 95% confidence interval will be calculated similarly to that 
of the primary efficacy endpoint. But no formal statsitical inference will be made to the secondary 
efficacy endpoints. 
If the establishment of confidence intervals is based on biopsy/TURBT data, Bladder biopsy/TURBT 
data should be assumed to be independent of each other. 
Efficacy data will be tabulated in detail. 
10.4.3 Safety Analysis 
Safety analysis will be based on safety set. 
The reported adverse events (including local reactions) will be coded according to MedDRA 
terminology. The events will be tabulated by System Organ Class and by Preferred term. 
Adverse events will also be tabulated versus severity and relation to treatment. 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       50 | 60 
Confidential 
Physical examination and vital signs at each visit will be presented using descriptive statistics. 
10.4.3.1 Adverse Event 
Adverse event will be coded according to MedDRA terminology, using descriptive statistics and 
annlysis by System Organ Class and by Preferred term. 
The overall incidence of adverse events, adverse reactions, treatment-emergent adverse events, study 
drug-related adverse events, significant adverse events, serious adverse events, and the incidence by 
SOC/PT will be calculated. The number and number of patients with treatment-emergent adverse 
events, adverse events will be summarized by SOC and severity. Adverse events, adverse reactions, 
treatment-emergent adverse events, adverse events related to the study drug, significant adverse events 
and serious adverse events should be listed in detail. 
10.4.3.2 Pregnancy Test 
For pregnancy tests, results were summarized and tabulated in detail using descriptive statistics. See 
general principles for analytical methods. 
10.4.3.3 Other Safety Information（Including Vital Signs and Physical Examination, Device 
Events） 
The results of vital signs and physical examination indicators at each visit will be analyzed and listed 
in detail. See general principles for analytical methods. Details will be described in the statistical 
analysis plan. 
10.4.4 Interim Analysis 
No interim analysis is planned for this study. 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       51 | 60 
Confidential 
11. Management of Clinical Trials 
11.1 Statement 
The clinical trial will be conducted in accordance with the sponsor's and CRO's standard of practices 
and sponsor is responsible to ensure CRO’s standard of practices, which are designed to ensure that 
the trial is conducted in accordance with the requirements of the Declaration of Helsinki, China's GCP 
and pharmaceutical Clinical Trial regulations. 
In signing the protocol, the investigator agrees to follow the instructions and procedures set forth in 
the Protocol and to adhere to the principle of the ICH GCP for quality management of Pharmaceutical 
Clinical Trials and all the principles governing local regulations and medical study.  
11.2 Ethics 
This study is designed and prepared in accordance with the Declaration of Helsinki of the World 
Medical Association, considering the rights and welfare of subjects in. The principal investigator or 
investigator of the clinical trial explains to the subjects the purpose of the trial and all the potential 
possibilities, and the subjects who voluntarily agree to participate in the clinical trial and sign the 
informed consent form will be the subjects. 
Clinical trial investigators and participants should properly analyze and understand the study plan and 
be able to prepare in advance, such as response to unexpected adverse events, required reporting and 
adequate training. Clinical investigators conducting clinical trials are required to comply with the 
regulations for Clinical Trials of Investigational Drugs (SFDA Order No. 5). 
The principal investigator and the study participants should comply with the content in the study 
protocol and scientifically maintain the current recognized technical level to conduct the trial. 
In accordance with national policies and regulations, the investigator provides relevant trial documents 
to the ethics committee. 
A copy of the IRB approval, along with a list of review documents, must be submitted to the sponsor 
before the drug is shipped to the investigator. The Ethics Committee approval document should be 
accompanied by a list of all committee members participating in the discussion of the approval 
document and their respective responsibilities.  
After the study protocol is approved by the ethics committee, the sponsor will submit the clinical study 
protocol to the NMPA for filing. 
Clinical trials must be approved by the ethics committee and the pharmaceutical administration before 
they can begin. 
Changes to the study protocol should be submitted to the ethics committee for approval and informed 
to health authorities as required locally. 
During the period of a clinical study, the investigator must inform the ethics committee of any serious 
adverse event or unexpected adverse events related to the safety of the clinical study that may affect 
the safety of patients and the conduct of the study. 
11.3 Check the Original Records 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       52 | 60 
Confidential 
All data obtained during clinical studies must be handled appropriately by the investigator to ensure 
the rights and privacy of patients participating in clinical studies. The investigator must consent to the 
monitor/auditor/inspector's access and review of the clinical study data as required to verify the 
accuracy of the original data and to understand the progress of the study. If it is not possible to verify 
the original records, the investigator should agree to assist the monitor/auditor/inspector in further 
verifying the quality control of the data. 
11.4 Quality Assurance and Audit 
All drugs and materials used in clinical study must be quality controlled. The sponsor, the sponsor's 
authorized personnel or the relevant medical regulatory agency should have the right to audit the 
clinical study in order to ensure the authenticity of the clinical study data and to comply with the 
provisions of the clinical study protocol. 
The study will be organized, conducted and reported in accordance with the protocol, sponsor and 
CRO's standard operating procedures. In ICH E6(R2), Quality assurance (QA) is defined as "planned 
and systematic actions that are established to ensure that the trial is performed and the data are 
generated, documented(recorded), and reported in compliance with Good Clinical Practice (GCP) and 
the applicable regulatory requirements". Sponsor QA work will be carried out in accordance with the 
study audit plan. ICH E6, Section 5.19.3 (b), provides that sponsor's audit plan and procedures for a 
trial audit should be guided by the importance of the trial to submissions to regulatory authorities, the 
number of subjects in the trial, the type and complexity of the trial, the level of risks to the trial subjects, 
and any identified problem(s).QA work can be transfered to a CRO or an independent consultancy. 
Require the investigator to support the audit, attend the audit as required, and allow the investigator 
direct access to raw data/documentation, including all medical records, study-related documents and 
correspondence, and informed consent documents for the clinical trial. Clinical study subjects will be 
informed of the clinical study review process, but subject privacy and data will be strictly protected. 
11.5 Informed Consent 
It is the investigator's responsibility to explain to each subject the purpose, method, benefits and 
potential risks of the clinical trial, alternative treatment options, and the subject's rights and obligations 
in accordance with the Declaration of Helsinki. Subjects should be informed that they have the right 
to withdraw from the study at any time and that their personal interests will not be harmed. An informed 
consent form signed by the subject must be obtained prior to any procedure related to the clinical trial. 
Written informed consent must be given orally. Informed consent must be dated and signed by each 
subject or his or her legal guardian or agent. The signed informed consent and information pages will 
be retained by the subject and another signed informed consent will be retained and retained as a study 
file by the subject prior to the commencement of any study related procedures. 
The consent form must be approved and signed by the subject prior to the commencement of any study 
related procedures. Prior to obtaining informed consent, the investigator or his designee shall provide 
the subject with sufficient time and opportunity to ask about the details of the study and to decide 
whether to participate in the study. The process of informed consent should be recorded in the course 
record on the day of screening visit. 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       53 | 60 
Confidential 
The investigator is responsible for the informed consent process. If any information regarding the 
subject's willingness to continue participating in the study is obtained during the study, the written 
informed consent must be updated and given to the subject to confirm the subject's willingness to 
continue participating. The revised informed consent is provided to subjects only after ethical approval 
is obtained. 
By signing the informed consent, the subject/patient must also agree to allow the sponsor, fda, auditors, 
and/or clinical trial monitors authorized by the sponsor to review the obtained raw data related to the 
clinical study, and the auditor must abide by the confidentiality statement. 
11.6 Modification of Clinical Protocols 
After the approval of the ethics Committee, if there is any major modification during the 
implementation of the program, the principal researcher of the responsible unit shall write the 
"Program Modification Manual" and sign it. At the same time, it can be implemented only after the 
approval of the ethics committee. 
Any non-principled amendment shall be decided by the main researchers, statisticians and sponsoring 
units of the responsible units through joint discussion, and shall be notified to other participating units. 
The Investigator shall not perform any protocol departure or change without the sponsor's consent and 
prior EC review and written approval (ICH E6 4.5.2). 
Any changes to the program, whether major or non-major, are required to be made in writing. Any 
substantive protocol modification that would affect the subject's safety, study scope, or scientific 
quality of this study would require approval from the EC of all study centers. In order to protect the 
safety of all subjects in the study, the above requirements shall not prevent the investigator or sponsor 
from taking any urgent measures. If the investigator considers that an immediate protocol change is 
necessary for safety reasons, he/she must promptly notify the sponsor's designated institution and the 
EC in accordance with the policies, local regulations and policies of the EC approving the study. 
Changes affecting study management only do not require substantive protocol revision or EC approval, 
but such changes must be notified to the EC. In these cases, the sponsor will send an official letter to 
the EC detailing these changes. 
11.7 Protocol Deviation 
The investigator should follow the clinical trial protocol approved by the ethics committee and comply 
with the GCP regulations to conduct the clinical trial. Protocol was developed to enable the investigator 
to comply with ICH E6 (R2), Section 4. During the study, the investigator should not deviate from the 
protocol unless urgent measures are taken to eliminate direct harmness to the subject. The investigator 
should consult with the monitor (and the IRB or IEC, if necessary) to determine appropriate action in 
the event of other unexpected circumstances that require departure from protocol procedures. 
The site should record all protocol deviations in the subject's original data, including but not limited 
to the occurrence time of protocol deviations, discovery time, event description and measures taken, 
etc. In the event of serious protocol deviation, the center should promptly notify the medical monitor, 
Clinical Research associate (CRA), IRB, or EC. 
11.8 Electronic Case Report Form（eCRF） 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       54 | 60 
Confidential 
The CRO database programmer will set up the eCRF and approved by sponsor. Only appropriate 
identification codes (e.g., study center number and subject number) and initials are used to identify 
individual subjects on the eCRF. The eCRF is used to record the clinical study data of the subject and 
is an integral part of the study and related study reports, so the entry must be accurate and complete. 
The eCRF is entered into the EDC system by the investigator or authorizer (indicated on the study 
authorization form). All data entry must be ensured to be completed and stored. The investigator must 
declare that all information in the eCRF is authentic by electronic signature. 
In clinical studies, the eCRF is usually completed within 3-5 business days after each visit to record 
the subject's condition. 
Medical records and other records related to the subjects' disease progression during the study will be 
maintained by the investigator. These records should include original or photocopies of laboratory data 
and other medical test results, which must be kept at the center along with the subject's medical records. 
11.9 Monitoring 
The sponsor or delegate CRO responsible monitoring 
Prior to selecting a center to participate in the study, a center selection visit will be conducted to 
confirm that the center, instruments and staff meet protocol requirements and GCP guidelines. 
During the study, the monitor conducted regular on-site monitoring of the center, and each monitoring 
should record the visit date on the central visit record of the center. 
The monitor's activities for study monitoring includes: 
 
Study center initiation visits, collect and distribute necessary pre-study documents; provide 
guidance to investigators and center staff on protocols, study procedures and expectations; 
Obtain the investigator's assurance that the study will be conducted in accordance with the 
study requirements and GCP guidelines, and introduce the study materials to the investigator 
and corresponding study staff. 
 
Monitoring visit: As required by the GCP, the monitor participating in the current study were 
fully aware of confidentiality issues and compared the data in the eCRF with data from 
hospital or clinical records (raw data). Prior to the start of the study, the monitor should 
discuss with the investigator the specific items required as source data, determine the nature 
and location of all source data to ensure that the sponsor or investigator knows the source of 
the source data used to complete the eCRF table, and the sponsor authorises the monitor's 
right to check; All observations and findings made during an monitoring must be verifiable. 
If electronic records are kept at the study site, methods of verification must be discussed with 
study members. 
The source material must be at least verifiable: 
- 
Subject identity, eligibility and participation; 
- 
Appropriate informed consent procedures; 
- 
Visit date; 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       55 | 60 
Confidential 
- 
Recording of safety and efficacy parameters; 
- 
Adequate reporting and visits of adverse events; 
- 
treatment with concomitant drugs; 
- 
Records of receipt/distribution/return of drugs; 
- 
Research drug administration information; 
- 
Subject's completion of treatment, termination of treatment or withdrawal from the study, 
and appropriate reasons; 
- 
The data is true, accurate and complete; 
- 
The safety and rights of the subjects are protected; 
- 
The investigator implements compliance with the currently approved protocol, GCP, and all 
relevant regulatory requirements. 
• 
Objectives to be achieved in the inspection include: 
• 
Review and evaluate study progress 
• 
Review collected study data 
• 
Implement source document verification process 
During the study period, the monitor will have direct access to all relevant documents with the 
consent of the investigator, and the investigator will ensure that himself and the investigator meet 
regularly with the monitor to discuss findings from the visit and any relevant issues. 
11.10 Intellectual Property Rights 
All information received from the trial sponsor is the intellectual property of the trial sponsor. 
Therefore, the clinical trial investigator and all other relevant personnel must keep it strictly 
confidential and should not disclose it to any third party without the prior consent of the trial 
sponsor. 
11.11 Subject Privacy 
Investigators must ensure that the privacy of clinical trial subjects is maintained. In all documents 
submitted to the sponsor, clinical trial subjects should be identified only by the clinical trial screeni-
ng/randomization number and initials, and not by name. The investigator must maintain the name 
and address of the subject and the enrollment form corresponding to the drug number of the clinical 
study. These entry forms are kept strictly confidential by the investigator and cannot be submitted to 
the sponsor. 
 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       56 | 60 
Confidential 
12. Publication 
Photocure ASA, as the sponsor, has exclusive rights to this study. The authors and contributions will 
reflect the collaboration between multiple researchers and the staff of the research base and Photocure 
ASA. Authors should be determined before writing a manuscript. Because many sites participating in 
this study, individual publications are not allowed until the final report of the multicenter study is 
completed, unless the agreement are obtained from Photocure ASA. Photocure ASA has the final say 
on the manuscript and publication. 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       57 | 60 
Confidential 
13.  Data preservation 
13.1 Source Data and Source files 
In this trial, the source data includes records of clinical findings, observations, and other relevant 
activities needed for reconstructing and evaluating the clinical trial. Raw data is contained in the 
source file. 
Source documents involved in clinical studies are original records, documents and data (such as 
hospital records, medical images, laboratory records, memos, subject diaries or evaluation forms, drug 
delivery records, data automatically recorded by instruments, microfilm, photographic plates, 
magnetic media, X-rays, subject files, Documents and records relating to clinical trials maintained by 
pharmacies, laboratories and medical technology departments, including certified copies, etc. The 
source files must be preserved to support the information provided in the eCRF. 
13.2 Data preservation of the sites 
13.2.1 Information related to the ethics committee 
The data preservation staff of the research unit shall retain the minutes and summaries of the ERC 
meetings until 5 years after the termination or completion of the study. If the sponsor wishes to stay 
longer, the two sides will discuss and decide how long and how to stay. In the event of any changes 
in documentation retention by the test unit, the person or researcher responsible for documentation 
retention should contact the sponsor. 
13.2.2 Material related to trial conduction 
The following documents must be retained by the data preservation staff of the sites for minimum 5 
years after the approval of the investigational drug for marketing. If the sponsor wishes to stay 
longer, the two sides will discuss and decide how long and how to stay. In the event of any changes 
in documen-tation retention by the site, the person or investigator responsible for data retention 
should contact the sponsor. 
• 
Source material; 
• 
Original or copy of the study contract, informed consent, and other information related to GCP 
provided by the staff of the site; 
• 
Study protocol, GCP-related data obtained from the ethics committee, or other GCP-related 
data obtained; 
• 
Records of the administration of the investigational drug and other records related to the 
conduct of the trial 
13.3 Data preservation of the sponsor 
The following information (including documents and data) will be retained by the sponsor until 5 
years after the trial drug is approved for marketing. A longer shelf life may be required according to 
relevant regulations. It is the sponsor's responsibility to inform the investigator/site when such data 
are no longer required to be kept. 
• 
The original or copy of the study protocol, the study contract, the study report, or the 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       58 | 60 
Confidential 
materials related to GCP provided by the sponsor; 
• 
Case report form, GCP related notification, or GCP related data obtained from investigator; 
• 
Monitoring, auditing related records, or other relevant operation records; 
• 
The data obtained in the study 
• 
Relevant records as required by GCP. 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       59 | 60 
Confidential 
14. Reference 
【1】 NCCN Guidelines on bladder cancer, version 3, 2020. 
【2】 Huang jian et al. Chinese guideline on bladder cancer. 2019. 
【3】 Jocham, D. et al. Improved detection and treatment of bladder cancer using 
hexaminolevulinate imaging: A prospective, Phase Ill multicenter study. Journal of 
Urology 174, 862-866. 2005. 
【4】 Bassi, P. et al. Non-invasive diagnostic tests for bladder cancer: a review of the literature. 
Urol Int.  75(3), 193-200. 2005. 
【5】 Zaak, D. et al.  Diagnosis of urothelial carcinoma of the bladder using fluorescence 
endoscopy. BJU International 96, 217-222. 2005. 
【6】 Klan, R. et al. Residual tumor discovered in routine second transurethral resection in 
patients with stage T1 transitional cell carcinoma of the baldder. Journal of Urology 146, 
316-318. 1991.  
【7】 Kohrmann, K.U. et al. The value of secondary transurethral resection of superficial bladder 
tumors. Akt. Urol 25, 208-213. 1994. 
【8】 Pawinski, A et al. A combined analysis of European organization for research and treatment 
of cancer, and medical research council randomized clinical trials for the prophylactic 
treatment of stage TaT1 bladder cancer. Journal of Urology 156, 1934-1941. 1996.  
【9】 Smith, J. A et al. Bladder cancer clinical guidelines panel summary report on the 
management of non-muscle invasive bladder cancer (stages Ta, T1, and Tis). Journal of 
Urology 162, 1697-1701. 1999. 
【10】Sylvester, R. et al. Predicting recurrence and progression in individual patients with stage 
TaT1 bladder cancer using EORTC risk tables: A combined analysis of 2596 patients from 
seven EORTC trials. European Urology 49, 466-477. 2006. 
【11】Fradet, Y. et al. A comparison of hexaminolevulinate fluorescence cystoscopy and WL  
cystoscopy for the detection of carcinoma in situ in patients with bladder cancer: A phase 
Ill, multicenter study. Journal of Urology 178, 68-73. 2007. 
【12】IB（V12,Sep,28th,2018） 
【13】Grossman, H. B. A phase Ill, multicenter comparison of hexaminolevulinate fluo rescence 
cystoscopy and WL cystoscopy for the detection of superficial papillary lesions in patients 
with bladder cancer. Journal of Urology 178, 62-67. 2007.  
【14】Stenzl, A et al. Hexaminolevulinate guided fluorescence cytoscopy reduces recurrence in 
patients with nonmuscle invasive bladder cancer. Journal of Urology 184, 1907-1914. 
2010. 
【15】Geavlete, B. et al. Hexaminolevulinate fluorescence cystoscopy and transurethral resection 
of the bladder in noninvasive bladder tumors. Journal of Endourology 23(6), 977-981. 
2009. 
【16】Schmidbauer, J. et al. Improved detection of urothelial carcinoma in situ with 


HEXVIX® 
Study Number：YHCT-HEX-B1      
Version 2.2  Date: Feb 6th, 2023                                                                       60 | 60 
Confidential 
hexaminolevulinate fluorescence cystoscopy. Journal of Urology 171, 135-138. 2004. 
【17】Daneshmand et al. Efficacy and Safety of Blue Light Flexible Cystoscopy with 
Hexaminolevulinate in the Surveillance of Bladder Cancer: A Phase III, Comparative, 
Multicenter Study. J Urol. May;199(5):1158-1165. 2018. 
【18】Loidl W. et al. Flexible cystoscopy assisted by hexaminolevulinate induced fluorescence: 
a new approach for bladder cancer detection and surveillance? Eur Urol. 47(3), 323-6. 
2005. 
【19】Witjes J.A. et al. Comparison of hexaminolevulinate based flexible and rigid fluorescence 
cystoscopy with rigid white light cystoscopy in bladder cancer: results of a prospective 
Phase II study. Eur Urol. 47(3), 319-22. 2005. 
【20】Blanco S. et al. Early detection of urothelial premalignant lesions using 
hexaminolevulinate fluorescence cystoscopy in high-risk patients. Journal of Translational 
Medicine 8, 122. 2010. 
【21】Witjes J.A. et al. Safety of hexaminolevulinate for blue light cystoscopy in bladder cancer. 
A combined analysis of the trials used for registration and postmarketing data. Urology 
84(1), 122-6. 2014. 
【22】Chang S C, MacRobert A J, Bown S G. Photodynamic therapy on rat urinary bladder with 
intravesical instillation of 5-aminolevulinic acid: light diffusion and histological 
changes[J]. The Journal of urology, 1996, 155(5): 1749-1753. 
【23】Hermann G G, Mogensen K, Toft B G, et al. Outpatient diagnostic of bladder tumours in 
flexible cystoscopes: evaluation of fluorescence-guided flexible cystoscopy and bladder 
biopsies[J]. Scandinavian journal of urology and nephrology, 2012, 46(1): 31-36. 
【24】Loidl W, Schmidbauer J, Susani M, et al. Flexible cystoscopy assisted by 
hexaminolevulinate induced fluorescence: a new approach for bladder cancer detection 
and surveillance?[J]. European urology, 2005, 47(3): 323-326. 
【25】Schmidbauer J, Remzi M, Klatte T, et al. Fluorescence cystoscopy with high-resolution 
optical coherence tomography imaging as an adjunct reduces false-positive findings in the 
diagnosis of urothelial carcinoma of the bladder[J]. European urology, 2009, 56(6): 914-
919. 
【26】Colombo R, Naspro R, Bellinzoni P, et al. Photodynamic diagnosis for follow-up of 
carcinoma in situ of the bladder[J]. Therapeutics and clinical risk management, 2007, 3(6): 
1003-1007. 
【27】Blanco S, Raber M, Leone B E, et al. Early detection of urothelial premalignant lesions 
using hexaminolevulinate fluorescence cystoscopy in high risk patients[J]. Journal of 
translational medicine, 2010, 8(1): 1-4. 
【28】 Rolevich A I, Zhegalik A G, Mokhort A A, et al. Results of a prospective randomized study 
assessing the efficacy of fluorescent cystoscopy-assisted transurethral resection and single 
instillation of doxorubicin in patients with non-muscle-invasive bladder cancer[J]. World 
journal of urology, 2017, 35(5): 745-752.