Clinical trial NCT03558503
Conditions: Bladder Cancer Urothelial Carcinoma Urothelial Carcinoma Bladder
Keywords: Non-muscle invasive bladder cancer Low grade non-muscle invasive bladder cancer Intermediate risk non-muscle invasive bladder cancer NMIBC UGN-102 Mitomycin
Sponsor: UroGen Pharma Ltd.
Start date: 2018-10-15; Completion date: 2020-10-21
Enrollment: 63 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This Phase 2b, single-arm, multicenter study evaluated the efficacy and safety of UGN-102 as primary chemoablative therapy in patients with low grade intermediate risk non-muscle-invasive bladder cancer (LG IR NMIBC).

Detailed description:
Eligible patients were treated with 6 once-weekly intravesical instillations of UGN-102.

The ablative effect of UGN-102 was evaluated at the 3-month Visit, which occurred 5 weeks ± 1 week after the last weekly instillation (3 months after initiation of study drug). Response was determined based on visual evaluation by cystoscopy (appearance, number, and size of the lesions) and, if there were remaining lesions, by histopathology of the remaining lesions. Complete response (CR) was defined as having no detectable disease (NDD) and was assessed visually during cystoscopy and also by urine cytology. In the event that the investigator was not sure, and there was suspect tissue, a small biopsy was taken from the suspect tissue to confirm CR in addition to cystoscopy and urine cytology.

Patients who achieved a CR continued to have monthly telephone contacts to document any adverse events (AEs) and changes in concomitant medications and were assessed at 6, 9, and 12 months after the first instillation of UGN-102 for evidence of disease recurrence. Patients who had a non-complete response (non-CR) discontinued the study and continued with standard of care according to their treating physician.

Safety was determined based on a review of AEs, laboratory assessments, and physical examination findings.

Arms: arm 1: Patients were treated with 6 once-weekly intravesical instillations of UGN-102.
Interventions: intervention 1: UGN-102
Intervention descriptions: intervention 1: UGN-102 consists of mitomycin and sterile hydrogel (a proprietary thermally responsive gel) that is used to reconstitute mitomycin before instillation. The reverse thermal properties of UGN-102 allow for local administration of mitomycin as a liquid, with subsequent conversion to a semi-solid gel depot following instillation into the bladder.

The UGN-102 admixture for intravesical instillations contains 75 mg mitomycin in 56 mL admixture (1.33 mg mitomycin per 1 mL).

Protocol documents:
Prot_000.pdf: 
A Phase 2b, Single-Arm, Multicenter Trial to Evaluate 
the Efficacy and Safety of UGN-102 as Primary 
Chemoablative Therapy in Patients with Low Grade 
(LG) Non-Muscle-Invasive Bladder Cancer (NMIBC) 
at Intermediate Risk of Recurrence
Protocol Number: TC-BC-12
Sponsor: UroGen Pharma
Country: USA, Israel
TC-BC-12 - UGN-102 - IND Clinical Trial Protocol
Document ID: CLP-0002410
Version: 5.0
Effective Date: 15-Apr-2019
Document State: Effective (Controlled)
Confidential
Page 1 of 56


TABLE OF CONTENTS
STATEMENT OF COMPLIANCE.................................................................................5
1
PROTOCOL SUMMARY.........................................................................................6
1.1
Synopsis...................................................................................................................6
1.2
Schema ....................................................................................................................8
1.3
Schedule of Activities (SoA)..................................................................................9
1.3.1
Screening to 3 MONTH Visit..........................................................................9
1.3.2
Complete Responder at 3 MONTH Visit: Visit 8 to End of Study............10
2
Abbreviations............................................................................................................11
3
Key Roles and Contact Information .......................................................................13
4
INTRODUCTION ....................................................................................................14
4.1
Study Rationale....................................................................................................14
4.2
Background ..........................................................................................................15
4.3
Risk/Benefit Assessment......................................................................................15
4.3.1
Known Potential Risks ..................................................................................15
4.3.2
Known Potential Benefits..............................................................................16
4.3.3
Assessment of Potential Risks and Benefits.................................................16
5
OBJECTIVES AND ENDPOINTS.........................................................................17
6
STUDY DESIGN ......................................................................................................17
6.1
Overall Design......................................................................................................17
6.2
Scientific Rationale for Study Design.................................................................18
6.3
Justification for Dose...........................................................................................18
6.4
End of Study Definition.......................................................................................19
7
STUDY POPULATION...........................................................................................19
7.1
Inclusion Criteria.................................................................................................19
7.2
Exclusion Criteria................................................................................................20
7.3
Lifestyle Considerations......................................................................................20
7.4
Screen Failures.....................................................................................................20
7.5
Strategies for Recruitment and Retention.........................................................20
8
STUDY MEDICATION...........................................................................................21
8.1
Study Medication Administration......................................................................21
8.1.1
Study Medication Description ......................................................................21
8.1.2
Preparation and Administration Ancillary Supplies and Devices ............22
8.1.3
Dosing and Administration...........................................................................22
8.2
Preparation/Handling/Storage/Accountability .................................................22
8.2.1
Acquisition and Accountability ....................................................................22
8.2.2
Formulation, Appearance, Packaging, and Labeling.................................23
8.2.3
Product Storage and Stability.......................................................................24
8.2.4
Preparation.....................................................................................................24
8.2.5
Product Quality Complaint Handling..........................................................24
8.3
Measures to Minimize Bias: Randomization and Blinding .............................25
8.4
Study Medication Compliance............................................................................25
8.5
Concomitant and Prohibited Therapy...............................................................25
8.5.1
Rescue Medicine.............................................................................................25
9
STUDY MEDICATION DISCONTINUATION AND PATIENT 
DISCONTINUATION/WITHDRAWAL...............................................................26
9.1
Discontinuation of Study Medication.................................................................26
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Effective Date: 15-Apr-2019
Document State: Effective (Controlled)
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9.2
Patient Discontinuation/Withdrawal from the Study.......................................26
9.3
Lost to Follow-Up.................................................................................................27
10 STUDY ASSESSMENTS AND PROCEDURES...................................................27
10.1
Study Assessments and Procedures by Visit .....................................................27
10.1.1
Screening Period (Day  -28 to Day -1 or Day -14 to Day -1) ......................27
10.1.2
Enrollment and Baseline Visit (Visit 1, Day 1)............................................28
10.1.3
Visits 2*, 3*, 4*, 5*, and 6* (Days 8*, 15*, 22*, 29*, and 36*)...................28
10.1.4
Visit 7 (Month 3 ± 1 week) ............................................................................29
10.1.5
Monthly Telephone Contact Visits (Visits 8*, 9*, 11*, 12*, 14*, and 15*) * 
± 1 week...........................................................................................................29
10.1.6
Visits 10* and 13* (Months 6 and 9)* ± 2 weeks.........................................29
10.1.7
End of Study Visit, Visit 16 (Month 12) ± 2 weeks .....................................29
10.1.8
Unscheduled Visits.........................................................................................30
10.2
Efficacy Assessments ...........................................................................................30
10.2.1
Measurements for Evaluation of Response at 3 MONTH Visit ................30
10.2.2
Evaluation of Response .................................................................................30
10.2.3
Assessment of Tumor Progression ...............................................................31
10.2.4
Assessment of Tumor Recurrence................................................................31
10.2.5
Pathological Evaluation.................................................................................32
10.3
Safety and Other Assessments............................................................................32
10.3.1
The safety of the study medication will be assessed by the following:......32
10.3.2
Quality of Life Assessment EORTC QLQ – NMIBC24.............................32
10.4
Adverse Events and Serious Adverse Events ....................................................32
10.4.1
Definition of Adverse Events.........................................................................32
10.4.2
Definition of Serious Adverse Events...........................................................32
10.4.3
Classification of an Adverse Event...............................................................33
10.4.4
Time Period and Frequency for Event Assessment and Follow-Up..........33
10.4.5
Adverse Event Reporting ..............................................................................34
10.4.6
Serious Adverse Event Reporting.................................................................34
10.4.7
Reporting Events to Patients.........................................................................35
10.4.8
Adverse Events of Special Interest...............................................................35
10.4.9
Reporting of Pregnancy.................................................................................36
10.5
Other Safety Assessments....................................................................................36
10.5.1
Laboratory Assessments................................................................................36
10.5.2
Pharmacokinetic (PK) Assessments.............................................................37
10.5.3
Urinalysis ........................................................................................................37
10.5.4
Physical Examination Findings ....................................................................37
10.5.5
Pregnancy Test...............................................................................................38
10.5.6
Reporting Unanticipated Problems to Patients...........................................38
11 STATISTICAL CONSIDERATIONS....................................................................38
11.1
Statistical Hypotheses..........................................................................................38
11.2
Sample Size Determination.................................................................................38
11.3
Populations for Analyses.....................................................................................39
11.3.1
Intent-to-Treat (ITT) Analysis Set (Safety Analysis Set)...........................39
11.3.2
Modified Intent-to-Treat (mITT) Analysis Set ...........................................39
11.3.3
Per Protocol (PP) Analysis Set......................................................................39
11.3.4
Complete Response at Primary Outcome Analysis Set..............................39
11.4
Statistical Analyses...............................................................................................39
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Document ID: CLP-0002410
Version: 5.0
Effective Date: 15-Apr-2019
Document State: Effective (Controlled)
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11.4.1
General Approach..........................................................................................39
11.4.2
Analysis of the Primary Efficacy Endpoint.................................................40
11.4.3
Sensitivity Analysis of the Primary Efficacy Endpoint ..............................40
11.4.4
Analysis of the Secondary Efficacy Endpoints............................................40
11.4.5
Safety Analyses...............................................................................................40
11.4.6
Baseline Descriptive Statistics.......................................................................42
11.4.7
Planned Interim Analyses .............................................................................42
11.4.8
Sub-Group Analyses......................................................................................42
11.4.9
Tabulation of Individual Patient Data.........................................................43
11.4.10
Exploratory Analyses.....................................................................................43
12 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS................................................................................................43
12.1
Regulatory, Ethical, and Study Oversight Considerations..............................43
12.1.1
Informed Consent Process ............................................................................43
12.1.2
Study Discontinuation and Closure..............................................................43
12.1.3
Confidentiality and Privacy ..........................................................................44
12.1.4
Future Use of Stored Specimens and Data ..................................................44
12.1.5
Safety Oversight.............................................................................................45
12.1.6
Clinical Monitoring........................................................................................45
12.1.7
Quality Assurance and Quality Control ......................................................45
12.1.8
Data Handling and Record Keeping ............................................................46
12.1.9
Protocol Deviations........................................................................................46
12.1.10
Publication and Data Sharing Policy ...........................................................47
12.1.11
Conflict of Interest Policy..............................................................................47
12.2
Additional Considerations ..................................................................................47
12.2.1
Finance and Insurance ..................................................................................47
13 Protocol Amendment History..................................................................................48
14 REFERENCES .........................................................................................................51
15 Appendix 1.................................................................................................................54
15.1
EORTC QLQ – NMIBC24..................................................................................54
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STATEMENT OF COMPLIANCE
The trial will be conducted in accordance with International Council on Harmonisation Good 
Clinical Practice (ICH GCP) and the applicable United States (US) Code of Federal Regulations 
(CFR). The Principal Investigator will assure that no deviation from, or changes to the protocol 
will take place without prior agreement from the sponsor, except where necessary to eliminate an 
immediate hazard(s) to the trial patients. All personnel involved in the conduct of this study have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all patient materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent 
form must be obtained before any patient is enrolled. Any amendment to the protocol will require 
review and approval by the IRB before the changes are implemented to the study. All changes to 
the consent form will be IRB approved; a determination will be made regarding whether a new 
consent needs to be obtained from patients who provided consent, using a previously approved 
consent form.
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Document ID: CLP-0002410
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Document State: Effective (Controlled)
Confidential
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1
PROTOCOL SUMMARY
1.1
Synopsis 
Title:
A Phase 2b, Single-Arm, Multicenter Trial to Evaluate the Efficacy and 
Safety of UGN-1021 as Primary Chemoablative Therapy in Patients with 
Low Grade (LG) Non-Muscle-Invasive Bladder Cancer (NMIBC) at 
Intermediate Risk of Recurrence.
Study Description:

Trial TC-BC-12 is a prospective Phase 2b single-arm trial to 
evaluate the efficacy and safety of 6 weekly instillations of 
UGN-102 in patients with LG NMIBC.

All enrolled patients will undergo treatment with intravesical UGN-
102.

Approximately 60 patients with LG NMIBC who meet the 
inclusion/exclusion criteria will be enrolled in the trial.

Following a successful screening period, eligible patients will be 
enrolled in the study.

Eligible patients will receive 6 weekly intravesical instillations of 
UGN-102. The primary endpoint assessment (complete response 
[CR]) will take place 5 weeks 1 week after the last instillation 
(approximately 3 months after initiation of study treatment), at 
which time the patients will be evaluated for treatment response. 

Patients who achieve a CR will continue to be monitored monthly 
for safety, and will be assessed at 6, 9, and 12 months (±2 weeks) 
after the first instillation of UGN-102 for evidence of disease 
recurrence. Nonresponders (non-CR) will exit the study and 
continue with standard of care according to their treating physician.
Objectives:
Primary Objective: To evaluate the tumor ablative effect of UGN-102 in 
patients with LG NMIBC.
Secondary Objectives:
To evaluate the durability of response in patients with LG NMIBC who 
achieve CR at the 3 MONTH Visit
To evaluate the safety and tolerability of intravesical UGN-102 instillations 
in patients with LG NMIBC.
Additional Objective: 
To assess the pharmacokinetic profile of Mitomycin C (MMC) in plasma of 
a subset of patients treated with UGN-102.
Endpoints:
Primary Endpoint: CR rate for UGN-102 treatment in patients with LG 
NMIBC at the 3 MONTH Visit (3 months after the first instillation of 
UGN-102) as assessed by cystoscopy, with or without biopsy, and urine 
cytology. 
Secondary Endpoints:
1 UGN-102 was formerly known as VesiGel.
TC-BC-12 - UGN-102 - IND Clinical Trial Protocol
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Document State: Effective (Controlled)
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Efficacy: Durable complete response (DCR) rate: proportion of patients 
with no evidence of disease at 6, 9, and 12 months after the first instillation 
of UGN-102 in patients who achieved CR at the 3 MONTH Visit.
Safety: Frequency, severity, and types of adverse events (AEs), including 
AEs of special interest; changes from baseline in laboratory values and 
incidence of measurements defined as potentially clinically significant; and 
clinically meaningful changes in physical examination findings.
Tertiary/Exploratory Endpoints: 
Pharmacokinetic: The pharmacokinetic (PK) profile of the first MMC 
instillation in the blood will be examined in a subset of six patients.
Quality of Life (QoL): To examine patient reported outcome of health-
related quality of life
Study Population:
Patients who have been diagnosed with LG NMIBC, and determined to 
have intermediate risk of recurrence, defined as 1 or 2 of the following: 
multiple tumors, solitary tumor >3 cm, or recurrence (≥ 1 occurrence of LG 
NMIBC within 1 year of the current diagnosis). 
Phase:
Phase 2b
Description of 
Sites/Facilities 
Enrolling Patients:
This study will be conducted by appropriately trained urologists at 
approximately 30 sites in North America and Israel.
Description of Study 
Medication:
UGN-102 preparation for intravesical instillations, containing Mitomycin C 
(MMC) 80 mg and 60 mL UG-1 gel, in order to administer 75 mg MMC in 
a 56 mL instillation (1.33 mg mitomycin per mL).
Treatment duration: 6 instillations, administered once weekly over 6 weeks.
Study Duration:
Approximately 26 months (from first center initiated [FCI] until last patient 
last visit [LPLV]).
Patient Duration:
Approximately 13 months per patient (from enrollment through last visit).
TC-BC-12 - UGN-102 - IND Clinical Trial Protocol
Document ID: CLP-0002410
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Document State: Effective (Controlled)
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1.2
Schema
LG = low grade; NMIBC = non-muscle-invasive bladder cancer
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1.3
Schedule of Activities (SoA)
1.3.1 Screening to 3 MONTH Visit
Procedures
Screening 
Day -14 to 
Day -1 or 
Day -28 to 
Day -1§
Enrollment 
and Baseline
Study Visit 1
Day 1
Study Visit 
2
Day 8
-1/ +3 days*
Study Visit 
3
Day 15
-1/ +3 days *
Study Visit 
4
Day 22
-1/ +3 days *
Study Visit 
5
Day 29
-1/ +3 days *
Study Visit 
6
Day 36
-1/ +3 days *
3 MONTH
Study Visit 7
5 weeks 
±1 week after 
last instillation 
(3 months post 
initiation)†
Unscheduled 
Visit^
Informed consent
X
Inclusion/exclusion criteria
X
Demographics
X
Medical history
X
Administer study medication
X
X
X
X
X
X
Concomitant medication review
X
X
X
X
X
X
X
X
X
Directed physical examination‡ 
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
Hematology 
X
X
X
X
X
X
X
X
X
Serum chemistry 
X
X
X
X
X
X
X
X
X
Urinalysis#
X
X
X
X
X
X
X
X
X
Pregnancy test 
X
X
Administer QLQ – NMIBC24
X
X
X
PK (in a subset of 6 patients)
X
Adverse event review and 
evaluation
X
X
X
X
X
X
X
X
X
Cystoscopy/urine cytology***
X
X***
X
Cold cup biopsy****
X
CT Urogram*****
X
Complete eCRFs
X
X
X
X
X
X
X
X
X
§ The screening period is up to 14 days for patients that do not need a screening biopsy and up to 28 days for patients that need a screening biopsy (see sect. 10.1.1)
3 MONTH = Primary endpoint assessment; CT; eCRF =; Non-CR = nonresponder.
* Windows are provided to accommodate patient logistics in scheduling. In any case, instillations should not occur more frequently than 6 days apart.
† Patients who discontinue before the 3 MONTH Visit or who are discontinued as Non-CR at the MONTH 3 Visit should have all assessments specified for the 3 MONTH Visit as their end-of-study assessments. Patients 
discontinued as Non-CR will be managed according to best practice according to their treating physician (refer to Section 10.2.2).
^ If an unscheduled visit is required, assessments should be performed as appropriate to the needs of the visit, although safety assessments should be performed, if feasible.
‡ Full physical examination at Screening; urology-oriented physical examination at Visits 1, 4, and 7 (Refer to Section 10.5.4: Table 5).
#To include culture and sensitivity at Screening. 
** No cytology needed if results from a prior cytology within 6 weeks of screening are available)
*** Biopsies may be needed at 3 months if any remaining lesions are visualized during cystoscopy (Sect.10.2.1, 10.2.2)
**** Cold cup biopsy to confirm LG performed only if not already performed within 6 weeks of screening
***** Acceptable if performed within 6 months prior to Screening
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1.3.2 Complete Responder at 3 MONTH Visit: Visit 8 to End of Study
Procedures
Telephone 
Visit 8
4 months 
post 
initiation 
±1 week
Telephone 
Visit 9
5 months 
post 
initiation 
±1 week
Study 
Visit 10
6 months 
post 
initiation 
±2 weeks
Telephone 
Visit 11
7 months 
post 
initiation 
±1 week
Telephone 
Visit 12
8 months 
post 
initiation 
±1 week
Study 
Visit 13
9 months 
post 
initiation 
±2 weeks
Telephone
Visit 14
10 months 
post 
initiation 
±1 week
Telephone
Visit 15
11 months 
post 
initiation 
±1 week
END OF 
STUDY
Study Visit 16
12 months 
post initiation 
±2 weeks
Unscheduled 
Visit^
Concomitant medication review
X
X
X
X
X
X
X
X
X
X
Full physical examination
X
Vital signs
X
X
X
X
Weight
X
Hematology 
X
X
X
X
Serum chemistry 
X
X
X
X
Urinalysis
X
X
X
X
Pregnancy test
Administer QLQ - NMIBC24
X
X
X
X
Adverse event review and evaluation
X
X
X
X
X
X
X
X
X
X
Cystoscopy/urine cytology§
X
X
X
X
Complete eCRFs
X
X
X
X
X
X
X
X
X
X
^ If an unscheduled visit is required, assessments should be performed as appropriate to the needs of the visit, although safety assessments should be performed, if feasible.
§ Any patient with evidence of disease recurrence post-CR will be documented as such, discontinued from the study, and should have all assessments specified for the END OF 
STUDY Visit as their end-of-study assessments. Patients discontinued with disease recurrence will be managed according to best practice according to their treating physician 
Refer to Section 10.2.4.
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2
ABBREVIATIONS
3 MONTH 
3 Month Visit
3 MONTHCR
Complete Response at 3 MONTH Visit
ADL
Activities of daily living
ADR
Adverse drug reaction
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the concentration time curve
BCG
Bacille de Calmette et Guérin
CBC
Complete blood count
CFR
Code of Federal Regulations
CI
Confidence interval
CIS
Carcinoma in situ
CONSORT
Consolidated Standards of Reporting Trials
CR
Complete response
CT
Computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
DCR
Durable complete response
eCRF
Electronic Case Report Form
EORTC
European Organization for Research and Treatment of Cancer
FCI
First center initiated
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
Gamma-glutamyltransferase
GLP
Good Laboratory Practice
GMP
Good Manufacturing Practice
HG
High grade
HRQoL
Health Related Quality of Life
ICF
Informed Consent form
ICH
International Council on Harmonization
IDE
Investigational Device Exemption
IND
Investigational New Drug
IP
Investigational Product
IQR
Interquartile range
IRB
Institutional Review Board
ITT
Intent-to-Treat
LG
Low grade
LPLV
Last patient last visit
LUTS
Lower urinary tract symptoms
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MedDRA
Medical Dictionary for Regulatory Activities
mITT
Modified Intent-to-Treat
MMC
Mitomycin C
NCI
National Cancer Institute
NDD
No detectable disease
NMIBC
Non-muscle-invasive bladder cancer
non-CR
Nonresponders
PCS
Potentially clinically significant
PI
Principal Investigator
PK
Pharmacokinetics
PP
Per Protocol
PQC
Product Quality Complaint
PT
Preferred Term
PUNLMP
Papillary Urothelial Neoplasm of Low Malignant Potential
QLQ
Quality of Life Questionnaire
QC
Quality control
SAE
Serious adverse event
SD
Standard deviation
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SMP
Study Monitoring Plan
SoA
Schedule of Activities
SoC
Standard of care
SOC
System Organ Class
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
ST
Safety
TEAE
Treatment-emergent adverse event
TNM
Tumor Node Metastases
TURBT
Transurethral resection of bladder tumor
UADR
Unexpected Adverse Drug Reaction
UC
Urothelial carcinoma/cancer
UG-1
UG-1 Sterile Hydrogel by UroGen Pharma Ltd.
UGN-102
UGN-102 preparation of UG-1 hydrogel mixed with mitomycin C, using the 
kit components
US
United States
USP
United States Pharmacopeia
UTI
Urinary tract infection
UTUC
Upper tract urothelial carcinoma
WHO
World Health Organization
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3
KEY ROLES AND CONTACT INFORMATION
Study Director
Robert Kirshoff, MS, UroGen
Sr. Director of Clinical Development
+1 646-768-0772
robert.kirshoff@urogen.com
Study Manager
Nimrod Gabai
Study Manager, UroGen
+1 646-793-3606
nimo.gabai@urogen.com
Medical Director/Medical Monitor 
Elyse Seltzer, MD, UroGen
+1 646-492-8518
elyse.seltzer@urogen.com
Chief Medical Officer
Mark P. Schoenberg, MD, UroGen
+1 646-492-8509
mark.schoenberg@urogen.com
Quality Assurance
Gilad Bernadsky, PhD
VP, Quality Assurance, Urogen  
+972 9-770-7600
qa@urogen.com
Study Logistics
Dimitry Zolotaryov, RN, UroGen
+1 917-810-5535
dima.zolotaryov@urogen.com 
Data Programming and Statistics
MMS Holdings Inc.
6880 Commerce Blvd
Canton, MI 48187
NA@mmsholdings.com
Tel: (734) 245-0310
Pharmacokinetics Central Lab
AIT Bioscience
7840 Innovation Blvd
Indianapolis, Indiana 46278, USA
Tel: (317)-715-8800
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4
INTRODUCTION
4.1
Study Rationale
Non-Muscle-Invasive Bladder Cancer
Urothelial cancer (UC) of the bladder is the second most common genitourinary malignancy, 
with almost 80,000 new cases diagnosed annually in the United States (US) and nearly 17,000 
deaths from the disease per year. Non-muscle-invasive bladder cancer (NMIBC) accounts for 
about 80% of all bladder cancers (Heney, 1992). Patients with NMIBC can be segmented into 
3 staging groups: patients with Ta tumors (70%), patients with T1 tumors (20%), and patients 
with carcinoma in situ (CIS) or Tis tumors (10%). Of these patients, approximately 70% have a 
tumor that is classified as low grade (LG), and approximately 30% have a tumor that is classified 
as high grade (HG). Ta and CIS tumors are limited to the urothelial layer, and T1 is limited to the 
lamina propria.
The standard treatment of NMIBC is transurethral resection of bladder tumor (TURBT) (Brausi, 
2002), often followed by adjuvant intravesical chemotherapy or immunotherapy (Hall, 2007). 
TURBT is associated with the typical risks of surgery including injury to the bladder and 
postoperative bleeding. Recurrence rates following standard of care (SoC) management range 
from 31% to 78% with the risk of progression to muscle invasion approaching 50% in patients 
with HG cancer (Sylvester, 2006). Tumor recurrence following TURBT can be attributed 
primarily to incomplete initial resection and, at least hypothetically, to tumor cell reimplantation 
following surgery (Brausi, 2002; Miladi, 2003, Anastasiadis, 2012). The effectiveness of 
intravesical therapy is limited by urine production, which results in drug dilution and periodic 
bladder emptying, and which limits the agent’s time on target (Audenet, 2013; Barlogie, 1980; 
De Bruijn, 1992; Deb, 2011; Eastham, 1993; Nozue, 1995a; Ozawa, 1988; Perry, 1992; Sadeghi, 
1998; Schmittgen, 1991; Slee, 1986; Walker, 1986; Wang, 2013, O’Donoghue, 2004).
Chemoablation represents an attractive alternative to surgical therapy. It could avoid the 
morbidity and expense of surgery and may offer a more rational therapeutic approach to UC, 
which is generally multifocal and refractory to focal ablative interventions. Preliminary evidence 
documents the ablative capabilities of aqueous Mitomycin C (MMC), which has been applied 
successfully to the primary management of small UCs (Bono, 1996; Bracken, 1980; Brausi, 
1998; Colombo, 2001; Ost, 2015; Hamdy, 1993; Harrison, 1983; Hetherington, 1987; Maffezzini, 
1996; Mishina, 1975; Soloway, 1985.) 
UGN-102
The Sponsor performed a Phase 2 study (Study TAS-4M-CS-002) in 65 evaluable patients with 
LG NMIBC and showed that UGN-102 therapy is associated with a complete response (CR) rate 
of 86% and significant durability of response (77% recurrence free survival at 12 months) in 
those patients achieving an initial CR. Based on this initial experience, the Sponsor proposes to 
conduct a Phase 2b UGN-102 trial in the US to corroborate the data provided by the European 
Trial. 
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Study TC-BC-12
This study is a prospective, Phase 2b, single-arm, open-label trial to evaluate the efficacy and 
safety of UGN-102 75 mg given once weekly intravesically, for a total of 6 doses, in the 
treatment of patients with LG NMIBC at intermediate risk of recurrence. 
4.2
Background 
UGN-102 is a reverse thermal hydrogel formulated with MMC. The product is specifically 
formulated to achieve a liquid state at 4C and to transition to a water-soluble gel at body 
temperature. The advantage of delivering Mitomycin to the urinary bladder using UGN-102 relies 
on preclinical and clinical literature documenting that concentration and dwell time correlate 
directly with the therapeutic efficacy of MMC when used to treat UC (Barlogie, 1980; Slee, 
1986; Walker, 1986; Ozawa, 1988; Perry, 1992; Nozue, 1995b; Sadeghi, 1998).
MMC functions as a bifunctional or trifunctional alkylating agent. It is most sensitive in the late 
G1 and early S phases, but overall is considered cell cycle phase non-specific (Badalament, 
1997). The cell killing induced by MMC, as well as by other topical chemotherapy drugs, is 
proportional to the duration of exposure and to concentration (Serreta, 2008; DeBruijn, 1992; 
Sadeghi, 1998; Barlogie, 1980; Nozue, 1995b; Schmittgen, 1991; Ozawa, 1988; Walker, 1986; 
Slee, 1986; Giesbers, 1989). 
UGN-102 Investigational Product
UGN-102 is provided by UroGen Pharma as a kit containing 2 vials of 40 mg MMC for injection, 
one 60 mL vial of UG-1 (UG-1 sterile hydrogel), 3 × 30 mL sterile syringes, and sterile syringe 
stoppers. The proprietary hydrogel, UG-1, allows for a sustained release of MMC at the target 
site of administration, resulting in prolonged exposure of the tumor cells to MMC, where it can 
exert a chemical ablative effect.
Preclinical studies of UGN-102 performed by UroGen demonstrated limited systemic absorption 
of MMC. In a porcine model, all MMC plasma concentrations were found to be substantially 
below 400 ng/mL, which is the drug concentration associated with myelosuppression (Dalton, 
1991). In clinical studies, systemic levels of MMC were low and well within the range 
considered safe. Systemic toxicity following intravesical therapy is uncommon because of the 
limited absorption of MMC. Myelosuppression occurs in <1% of patients (de Bruijn, 1992). 
Investigators have reported that extended dwell times appear safe in humans (de Bruijn, 1992).
For further details of the preclinical and clinical studies conducted with UGN-102, refer to the 
Investigator Brochure for UGN-101 (MitoGel) and UGN-102 (VesiGel).
4.3
Risk/Benefit Assessment  
4.3.1 Known Potential Risks 
Toxicity Associated with Systemic Absorption/Local Irritation
Although literature review did not demonstrate any side effects associated with the systemic 
absorption when MMC was administered topically, bone marrow toxicity (thrombocytopenia and 
leukopenia) and bladder toxicity are considered possible risks for patients. The complete blood 
count (CBC) and renal and liver function tests will be checked regularly during the treatment 
period. In case of clinically significant abnormalities, the investigator will continue to follow the 
abnormal parameter until resolution, stabilization, or otherwise managed. 
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Allergic Response to MMC
MMC bladder instillations have been shown to cause allergic reactions in various degrees of 
toxicity in treated patients. Toxicities were found to be manageable most of the time by treating 
the patients with antihistamine drugs prior to and after the treatment, and with systemic steroids 
as needed. Signs of an allergic response will be closely monitored during the trial.
Cystitis
Cystitis and other lower urinary tract symptoms (LUTS) may develop. Urine tests, including 
urine culture and urinalysis, will be checked regularly during the trial to exclude urinary 
infection. Any symptoms will be treated by the Investigator according to local practice. 
All of the symptoms described above are all well known in relation to standard MMC 
instillations and are not exclusive to UGN-102. 
Currently, the SoC for NMIBC is TURBT. This surgical procedure has its own potential risks 
such as bladder perforation resulting in MMC leak, bladder scarring, and decreased bladder 
capacity; urinary retention requiring catheterization; and the need for anesthesia. Moreover, 
during TURBT, tumor cells are released into the bladder cavity and may be seeded in denuded 
areas of the bladder where the urothelium is surgically interrupted. This is one of the reasons for 
the high rate of tumor recurrence and the need of immediate post-TURBT chemotherapy (usually 
MMC instillations). The high recurrence rate of NMIBC indicates that the current SoC is far from 
optimal. 
4.3.2 Known Potential Benefits 
The potential advantages of instillation of MMC in gel are as follows:

Sustained release of drug for up to 8 hours (compared with 1.5 to 2 hours in standard 
instillation). Published literature indicates that duration of tumor exposure to 
chemotherapy is critical to its ablative response. Thus, the effectiveness of tumor ablation 
is increased by longer dwell times.

The gel protects MMC from both breaking down in urine and being diluted by urine, 
which leads to longer stable chemotherapy concentration levels.
These characteristics of UGN-102 (MMC+UG-1) are expected to improve MMC treatment 
efficacy and provide an alternative mode of ablation for NMIBC, which may be simpler and 
potentially better tolerated than current treatment modalities.
4.3.3 Assessment of Potential Risks and Benefits 
The potential benefits exceed the risks observed so far in the development program. Since the 
risks are similar to those observed with intravesical MMC alone, and the expected benefits are to 
improve MMC’s therapeutic efficacy and to expand its use, the overall risk:benefit ratio at this 
stage supports continued development of UGN-102.
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5
OBJECTIVES AND ENDPOINTS
OBJECTIVES
ENDPOINTS
JUSTIFICATION FOR 
ENDPOINTS
Primary
To evaluate the tumor 
ablative effect of UGN-
102 in patients with LG 
NMIBC
CR rate for UGN-102 treatment in patients 
with LG NMIBC at the 3 MONTH Visit 
(3 months after the first instillation of UGN-
102) as assessed by cystoscopy, with or 
without biopsy, and urine cytology
Consistent with clinical 
practice for disease 
response to intervention.
Regulatory guidance.
Secondary
To evaluate the durability 
of response in patients 
with LG NMIBC who 
achieve CR at the 3 
MONTH Visit
Durable complete response (DCR) rate: 
proportion of patients with no evidence of 
disease at 6, 9, and 12 months after the first 
instillation of UGN-102 in patients who 
achieved CR at the 3 MONTH Visit
Consistent with clinical 
practice for disease 
response to intervention.
Regulatory guidance.
To evaluate the safety and 
tolerability of intravesical 
UGN-102 instillations in 
patients with LG NMIBC
Frequency, severity, and type of adverse 
events (AEs), including adverse events of 
special interest (AESIs), changes from baseline 
in laboratory values and incidence of 
measurements defined as Potentially Clinically 
Significant (PCS); and clinically meaningful 
changes in physical examination findings
Standard endpoints for 
safety evaluation in the 
patient population.
Tertiary/Exploratory 
To assess the 
pharmacokinetic (PK) 
profile of the first MMC 
instillation in six (6) 
patients
Concentration data as well as PK parameters 
(e.g., AUC, Cmax, etc.)
To evaluate the PK 
profile of intravesicular 
UGN-102 in order to 
understand the risk of 
systemic mitomycin 
exposure
To examine patient 
reported outcome of 
health-related quality of 
life as compared to 
baseline
QLQ - NMIBC24 at 3, 6, 9, 12 months or ET
Exploratory
6
STUDY DESIGN 
6.1
Overall Design
This study is a prospective, proof of concept, open-label, single-arm, multicenter Phase 2b trial 
designed to assess the efficacy and safety of UGN-102 treatment instilled in patients diagnosed 
with LG NMIBC including newly-diagnosed patients, and determined to have intermediate risk 
of progression, defined as 1 or 2 of the following: multiple tumors, tumors >3 cm, or recurrence 
(≥ 1 occurrence of LG NMIBC within 1 year of the current diagnosis). Eligible patients will be 
treated with 6 weekly instillations of UGN-102.
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Upon signing of informed consent, patients will undergo a Screening Visit for eligibility 
evaluation.  The screening period is 2 weeks if the patient’s cold cup biopsy to confirm LG tumor 
is historic (taken within 6 weeks of the screening visit) or 4 weeks if the patient’s cold cup biopsy 
to confirm LG tumor is current (taken at the screening visit). 
Starting at the Baseline Visit (Day 1), eligible patients will be treated with UGN-102 once 
weekly for a total of 6 doses; the UGN-102 concentration to be used in this trial will be 1.33 mg 
MMC per 1mL. The volume of UGN-102 to be instilled will be 56 mL (75 mg of MMC). 
The ablative effect of UGN-102 will be evaluated at the 3-month assessment, which will take 
place 5 weeks ±1 week after the last weekly instillation (3 months after initiation of study 
medication). Response will be determined based on visual evaluation by cystoscopy (appearance, 
number, and size of the lesions) and, if there are remaining lesions, by histopathology of the 
remaining lesions. CR is defined as having no detectable disease (NDD) and will be assessed 
visually during cystoscopy and also upon urine cytology. In the event that the investigator is not 
sure, and there is suspect tissue, a small biopsy will be taken from the suspect tissue to confirm 
CR in addition to cystoscopy and urine cytology. Patients who achieve a CR will continue to 
have monthly telephone contacts to document any adverse events and changes in concomitant 
medications  and will be assessed at 6, 9, and 12 months after the first instillation of UGN-102 
for evidence of disease recurrence. The group of patients considered nonresponders (non-CR) 
will discontinue the study and continue with SoC according to their treating physician.
Safety will be determined based on physical examination, laboratory assessments, and a review 
of AEs. All safety data will be reviewed on an ongoing basis, including close review and follow 
up of any unexpected AE related to UGN-102 and qualified per National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) as Grade 3 or 4.
6.2
Scientific Rationale for Study Design
The single-arm, noncomparative design was chosen to confirm the results of a previous study 
(Study TAS-4M-CS-002), which indicated that a dose regimen of 6 weekly instillations of 
UGN-102 75 mg was effective and well tolerated in patients with LG NMIBC. Based on data 
from an ongoing Phase 3 trial in a similar indication, UTUC, monthly maintenance treatments do 
not appear to have a meaningful effect on durability of response in those patients who were CR at  
the 3-month assessment (primary endpoint). This study also aims to treat a slightly more 
challenging population: those at increased risk for recurrence. 
6.3
Justification for Dose
The UGN-102 dose of 75 mg was chosen based on both efficacy and tolerability. 
Study TAS-4M-CS-002 demonstrated numerically higher CR rates for the 75 mg dose than for 
the 37.5 mg dose. In Study TC-BC-10, 120 mg of UGN-102 had a similar response rate to 75 mg 
and a higher rate of AEs.
Although this is a single-arm, noncomparative study, patients who do not achieve CR after 
6 weekly instillations of UGN-102 75 mg will exit the study and be treated according to best 
practice according to their treating physician.
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6.4
End of Study Definition
A patient is considered to have completed the study when he or she has completed all phases of 
the study, including the last visit or the last scheduled procedure and assessment according to the 
Schedule of Activities (SoA), Section 1.3.
The end of the study is defined as the last patient’s last visit (LPLV).
7
STUDY POPULATION
7.1
Inclusion Criteria
In order to be eligible to participate in this study, a patient must meet all of the following criteria:
1. ≥ 18 years of age.
2. Willing and able to sign an informed consent and comply with the protocol.
3. Has newly diagnosed or historic LG NMIBC (Ta) histologically confirmed by cold cup 
biopsy at screening or within 6 weeks of screening.
4. Is at intermediate risk for progression, defined as having 1 or 2 of the following:
a.
presence of multiple tumors,
b. solitary tumor >3 cm
c.
recurrence (≥ 1 occurrence of LG NMIBC within 1 year of the current diagnosis). 
5. Has negative voiding cytology for HG disease at or within 6 weeks of enrollment.
6. Willing to use 2 acceptable forms of effective contraception from enrollment through 
6 months post treatment if the participant is female or the female partner of a male participant 
is of childbearing potential (defined as premenopausal women who have not been sterilized).
7. Has adequate organ and bone marrow function as determined by routine laboratory tests as 
below:

Leukocytes ≥3,000/μL (≥3×109/L),

Absolute neutrophil count ≥1,500/μL (≥1.5×109/L),

Platelets ≥100,000/μL (≥100×109/L),

Hemoglobin ≥9.0 mg/dL,

Total bilirubin ≤1.5 upper limit of normal (ULN),

AST (SGOT)/ALT (SGPT) ≤2.5 × upper limit of normal (ULN),

ALP ≤2.5 × ULN, and

Estimated glomerular filtration rate (eGFR) ≥30 mL/min.
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8. Has no evidence of active urinary tract infection* (UTI) at Screening and Baseline visits.
*In the case of symptomatic UTI, the patient will be treated with a full course of antibiotics, and 
study medication will be postponed until resolution. In the case of asymptomatic bacteriuria, 
the use of prophylactic antibiotics and postponement of study medication is left to the discretion 
of the Principal Investigator (PI).
7.2
Exclusion Criteria
A patient who meets any of the following criteria will be excluded from participation in this 
study:
1. History of CIS on preliminary cystoscopy within 5 years of enrollment.
2. Received BCG treatment for UC within previous 2 years.
3. History of HG papillary UC in the past 2 years
4. Known allergy or sensitivity to mitomycin.
5. Clinically significant urethral stricture that would preclude passage of a urethral catheter.
6. History of pelvic radiotherapy.
7. History of:
a) neurogenic bladder
b) active urinary retention
c) any other condition that would prohibit normal voiding
8. Past or current muscle invasive (i.e., T2, T3, T4) or metastatic UC or concurrent upper tract 
urothelial carcinoma (UTUC).
9. Has participated in a study with an investigational agent or device within 30 days of 
enrollment.
10. History of prior treatment with an intravesical chemotherapeutic agent with the exception of a 
single dose of chemotherapy immediately post any previous TURBT
11. Has an underlying substance abuse or psychiatric disorder such that, in the opinion of the 
investigator, the patient would be unable to comply with the protocol.
7.3
Lifestyle Considerations
Not applicable.
7.4
Screen Failures
Screen failures are defined as patients who consent to participate in the clinical trial but are not 
subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure patients, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements, and to respond to queries from 
regulatory authorities. Minimal information includes demography, reason for screen failure, 
eligibility criteria, and any serious adverse event (SAE).
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7.5
Strategies for Recruitment and Retention
Approximately 66 patients will be screened and recruited to ensure that approximately 60 patients 
with LG NMIBC who meet the eligibility criteria complete the study (assuming a 10% dropout 
rate). The study will be conducted primarily by appropriately trained urologists at approximately 
20 to 30 study sites in North America and Israel who provide care to patients with bladder cancer.
8
STUDY MEDICATION
8.1
Study Medication Administration
8.1.1 Study Medication Description
The UGN-102 preparation for intravesical instillations contains MMC 75 mg in 56 mL admixture 
(1.33 mg MMC per 1 mL of admixture). UGN-102 admixture is prepared in advance of use by 
the pharmacy, up to 48 hours before administration (this time is supported by in-use stability data 
of at least 48 hours). The UGN-102 Kit contains 4 components (Table 1):
Table 1
UGN-102 Kit Components
Component
Quantity (per kit) †
Function
Mitomycin for Injection, USP (vial)
2  40-mg 
Active Ingredient
UG-1 Sterile Hydrogel (vial) 
1  60 mL
Vehicle
Labels
7
Preparation labels
Preparation Leaflet
1
Instructions for preparation
† For the proposed indication, each 40 mg MMC will be mixed with 3 mL sterile WFI and 27 mL UG-1 sterile hydrogel. A total of 
56 mL of the 1.33 mg/mL preparation will be instilled in each patient. The gel and MMC excess included in the kit are to allow 
for the required UGN-102 volume withdrawal from the vials.
MMC = Mitomycin C; USP = United States Pharmacopeia; WFI = water for injection.
The vials of 40 mg MMC for injection are manufactured for UroGen Pharma Ltd, 9 Ha’Ta’asiya 
Street, Ra’anana, Israel, by Cenexi-Laboratoires Thissen, S.A. rue de la Papyrée 2-4-6, B-1420 
Braine-l’Alleud, Belgium. MMC is provided as a dry lyophilized powder in 100 mL vials and 
will be stored at 15C to 30C.
The contents of each MMC for injection United States Pharmacopeia (USP) vial are listed in 
Table 2.
Table 2
Vial Composition of Mitomycin for Injection, USP
Component
Quantity (mg per vial)
Pharmaceutical Grade
Function
Mitomycin C
40 mg
USP
Active ingredient
Mannitol
80 mg
USP
Bulking agent
USP = United States Pharmacopeia.
The 60 mL vials of UG-1 sterile hydrogel are manufactured for UroGen Pharma Ltd, 
9 Ha’Ta’asiya Street, Ra’anana, Israel, by Isorad Ltd., P.O. Box 239, Yavne, 8110102, Israel. 
UG-1 sterile hydrogel is provided in a 100-mL glass vial and will be stored at 15C to 30C.
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The contents of each UG-1 sterile hydrogel vial are a proprietary blend of Poloxamer 407, 
hydroxypropyl methyl cellulose, polyethylene glycol (molecular weight 400), and water for 
injection.
The components of the UGN-102 Kit are produced under aseptic conditions and according to 
current Good Manufacturing Practice (GMP) (European Commission, May 2003 Guidelines). 
The UGN-102 Kit lots to be used in this trial are tested and released under supervision and 
approval by the UroGen Quality Assurance Department.
8.1.2 Preparation and Administration Ancillary Supplies and Devices
All ancillary supplies and devices used to prepare and administer the study medication are 
detailed in the Instructions for Use (IFP) and Instructions for Pharmacy (IFP) Document 
Numbers: IFU-Phy0002696) and IFP (IFP-0002643).
8.1.3 Dosing and Administration
The patients entering this trial will undergo 6 weekly instillations of UGN-102.
Mitomycin concentration
UGN-102 volume
Route of administration*
1.33 mg/mL
56 mL
Local administration into the bladder
* Refer to UroGen’s Injector Device Instructions for Use Manual for detailed instillation instructions.
The UGN-102 preparation will be administered for therapy in the bladder as 6 weekly, 
consecutive instillations, at Study Visits 1, 2, 3, 4, 5, and 6. Study drug administration will be 
documented in the patient file, electronic Case Report Forms (eCRFs), and in the Drug 
Administration Records.
8.2
Preparation/Handling/Storage/Accountability
8.2.1 Acquisition and Accountability
The UGN-102 Kit assembled for UroGen Pharma Ltd. 9 Ha’Ta’asiya St., Ra’anana, Israel by 
CSM Europe sa, Watson & Crick Hill, Rue Granbonpré 11 | B-1435 Mont-Saint-Guibert, 
Belgium, will be provided by the Sponsor. All clinical supplies will be packaged and labeled in 
compliance with GMP guidelines. The shipment process should comply with the rules of Good 
Distribution Practices. Prior to shipment of clinical supplies, the Sponsor must notify the PI 
regarding the anticipated date of arrival at the hospital/clinic pharmacy. The investigational 
product (IP) will be sent to the site only after trial approval by the Institutional Review Board 
(IRB) has been received. The shipment will be sent to the investigator’s authorized trial personnel 
at the site’s pharmacy. 
All trial medications dispensed will be appropriately documented to ensure proper handling in 
case of emergency.
The Sponsor will ship all drugs to the pharmacy/approved designee at a controlled room 
temperature between 15C and 30C. The shipping temperature will be monitored and recorded 
by temperature-monitoring device loggers.
If, upon arrival, the IP supplies appear to be damaged or the temperature was above or below the 
specified limit during shipment, the clinical site pharmacy will contact the Sponsor’s Quality 
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Assurance Group by email (qa@urogen.com) immediately and complete the product quality 
complaint (PQC) form (see Section 8.2.5). The impacted IP must be marked “not for use” and 
quarantined during investigation until a decision has been made regarding the drug’s validity.
Each shipment of IP supplies for the trial will contain at minimum, a shipment form describing 
the content of shipment. This form will assist in maintaining current and accurate inventory 
records. When a shipment is received, the appropriate site personnel will acknowledge receipt of 
the IP supply.
Unused UGN-102 Kits must be available for verification by the sponsor’s site monitor during on-
site monitoring visits. Unused or expired UGN-102 Kits returned to the Sponsor must be 
documented on the drug return form.
The investigator agrees to neither dispense the trial drug from, nor store it at, any site other than 
the site agreed upon with the sponsor.
Unusable UGN-102 Kits will be marked “not for use” in pen over the label and stored separately 
from usable UGN-102 Kits. 
Replacement UGN-102 Kits will be supplied after request for additional kits has been issued to 
the Sponsor, the distributor for the trial, or the US depot.
Following completion of drug accountability by the CRA, used trial drug vials should be 
discarded locally according to local institution guidelines for cytotoxic waste destruction. 
Discarding of the used UGN-102 preparation vials must be documented in the drug disposal 
form. 
8.2.2 Formulation, Appearance, Packaging, and Labeling
The formulation of the study medication and the contents of the UGN-102 Kit are described in 
Section 8.1.1. All clinical supplies will be packaged and labeled in compliance with GMP 
guidelines. All information regarding trial medications provided will be appropriately 
documented (i.e., batch records, Certificate of Analysis, etc.). The original product packaging 
will be used in the trial (UroGen Pharma Ltd., Israel).
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The kit will be labeled as follows:
8.2.3 Product Storage and Stability
The UGN-102 Kit must be stored at a controlled room temperature of 25°C (77°F), excursion 
permitted between 15°C (59°F) and 30°C (86°F). Avoid excessive heat (over 40°C or 104°F) in 
accordance with applicable regulatory requirements for cytotoxic substances.
The clinical supplies storage area at the study site must be monitored by the site staff for 
temperature consistency with the acceptable storage temperature range as specified on the label. 
Documentation of temperature monitoring should be maintained and available for review.
8.2.4 Preparation
The UGN-102 preparation (UG-1 gel mixed with MMC) is stable for 48 hours at 25C (77F), 
with variation permitted between 15°C (59°F) and 30°C (86°F). Exposure to excessive heat (over 
40°C, 104°F) should be avoided. Up to 1 hour before administration, the admixture should be 
cooled down to between -3°C and +5°C in order to liquify the UGN-102. The elapsed cooling 
time must be documented from the point the mixture is prepared until it is instilled, which 
includes the length of time at room temperature, as well as length of time at a refrigerated 
temperature. 
8.2.5 Product Quality Complaint Handling
A Product Quality Complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging; i.e., any dissatisfaction relative to the identity, quality, 
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durability, or reliability of a product, including its labeling or packaging integrity. In such cases, 
and also in cases of temperature deviation, either during transport or storage at the pharmacy, the 
investigator is responsible for notifying the Sponsor in writing using the PQC form about the 
defect/temperature deviation. Any written PQC report must be reported to the Sponsor by email 
to: qa@urogen.com.
ATTN: Quality Assurance
Reporting must be done upon first awareness, and the site should await the Sponsor’s decision 
regarding the drug’s validity prior to drug dispensing.
If the defect is combined with an SAE, the investigational staff must report the PQC to the 
Sponsor according to the SAE reporting timelines (refer to Section 10.4.6; Serious Adverse Event 
Reporting). The affected trial products must be quarantined and marked “not for use” during 
investigation until a decision has been made regarding the drug’s usability.
Product quality complaints may have an impact on the safety and efficacy of the product. Timely, 
accurate, and complete reporting and analysis of PQC information from clinical studies are 
crucial for the protection of patients, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The Sponsor has established procedures in conformity with 
regulatory requirements worldwide to ensure appropriate reporting of PQC information; all 
clinical studies conducted by the Sponsor or its affiliates will be conducted in accordance with 
those procedures.
8.3
Measures to Minimize Bias: Randomization and Blinding
Not applicable; this is an open-label, single-arm study.
8.4
Study Medication Compliance
The study medication will be administered at specified treatment visits by properly trained study 
site staff members. Each drug administration will be documented in the patient’s file and eCRF.
8.5
Concomitant and Prohibited Therapy
For this protocol, a prescription medication is defined as a medication that can be prescribed only 
by a properly authorized/licensed clinician. Medications to be reported in the eCRF are 
concomitant prescription medications, over-the-counter medications, and supplements. Prohibited 
concomitant medications include systemic chemotherapy, intravesical chemotherapy, and 
immunotherapy for bladder cancer treatment including but not limited to BCG.
In cases of symptomatic UTI, the patient will be treated with a full course of antibiotics, and 
study medication will be postponed until resolution. In the case of asymptomatic bacteriuria, the 
use of prophylactic antibiotics and postponement of study medication is left to the discretion of 
the Principal Investigator (PI).
8.5.1 Rescue Medicine
Patients considered non-CR at the 3 MONTH Visit (Visit 7) will exit the study and will be 
treated according to best practice according to their treating physician.
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9
STUDY MEDICATION DISCONTINUATION AND PATIENT 
DISCONTINUATION/WITHDRAWAL
9.1
Discontinuation of Study Medication
Discontinuation from study medication does not mean discontinuation from the study, and 
remaining study procedures should be completed as indicated by the study protocol. If a 
clinically significant finding is identified (including, but not limited to, changes from baseline) 
after enrollment, the investigator or qualified designee will determine if any change in patient 
management is needed. Any new clinically relevant finding will be reported as an AE.
If a patient discontinues study medication during the treatment period or at any time prior to the 3 
MONTH Visit, the following unscheduled visit activities should be performed:

All 3 MONTH Visit (Visit 7) procedures should be conducted.

If the patient appears to have a CR (refer to Section 10.2.2), the patient has the option to 
continue participating in the follow-up assessments conducted at Months 6, 9, and 12 
(Visits 10, 13, and 16, respectively) to assess for disease recurrence and monthly 
telephone contacts for safety checks.

If patient agrees to complete the follow-up visits within the trial or agrees to continue to 
share information regarding his/her disease status, information collected during the 
follow-up care of the patient should be recorded in the eCRF.
9.2
Patient Discontinuation/Withdrawal from the Study
Patients in this trial are free to withdraw from participation in the study at any time.
An investigator may discontinue or withdraw a patient from the study for the following reasons:

Pregnancy

Significant study medication non-compliance

If any clinical AE, laboratory abnormality, or other medical condition or situation occurs 
such that continued participation in the study would not be in the best interest of the 
patient

Disease progression that requires discontinuation of the study medication

If the patient meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation

Patient becomes unable to receive study medication for 4 weeks.

Patient is lost to follow-up (see section 9.3)
The reason for patient discontinuation or withdrawal from the study will be recorded on the 
eCRF. Patients who sign the informed consent form but do not receive the study medication may 
be replaced. Patients who sign the informed consent form, receive the study medication, and 
subsequently withdraw, or are withdrawn or discontinued from the study, will not be replaced.
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9.3
Lost to Follow-Up
A patient will be considered lost to follow-up if he or she fails to return for 2 sequential 
scheduled visits and is unable to be contacted by the study site staff. 
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit:

The site will attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain if the patient wishes to and/or should continue in the study.

Before a patient is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the patient (where possible, 3 telephone calls and, if 
necessary, a certified letter to the patient’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the patient’s study file. 
Should the patient continue to be unreachable, he or she will be considered to have withdrawn 
from the study with a primary reason of lost to follow-up.
10 STUDY ASSESSMENTS AND PROCEDURES
10.1
Study Assessments and Procedures by Visit
10.1.1 Screening Period (Day  -28 to Day -1 or Day -14 to Day -1)
For patients that need a biopsy, the screening period is up to 28 days. For patients that do not 
need a biopsy, the screening period is up to 14 days. The following procedures will be performed 
at Screening:

Obtain written informed consent before any study-related procedures are performed

Inclusion and exclusion criteria

Demographics

Medical history

Concomitant medication review

Full physical examination (including height and weight) and urology-oriented physical 
examination

Vital signs (blood pressure, heart rate, respiration rate, and body temperature)

Clinical laboratory tests (serum chemistry and hematology)

Urinalysis (dipstick on-site and culture and sensitivity at local lab)

Urine pregnancy test (if appropriate)

Cystoscopy and urine cytology (if not performed within 6 weeks of screening)

Collection of a single representative cold cup biopsy, if no histologic confirmation of LG 
tumor within 6 weeks of screening

Computerized tomography (CT) Urogram, retrograde pyelogram, or MRI (if other tests 
are contraindicated) to rule out UTUC (acceptable if performed within 6 months of 
Screening)
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
AE review
10.1.2 Enrollment and Baseline Visit (Visit 1, Day 1)
The following procedures will be performed at Visit 1:

Administer QLQ-NMIBC24 questionnaire 

Concomitant medication review

Urology-oriented physical examination

Body weight

Vital signs (blood pressure, heart rate, respiration rate, and body temperature)

Clinical laboratory tests (serum chemistry and hematology)

Urinalysis

Blood collection for PK at select sites in 6 patients at 0 hr. pre-instillation and 0.5, 1.0, 
2.0, 3.0, 4.0, 5.0, and 6.0 hrs. post instillation

AE review

Confirm all inclusion and exclusion criteria are met

Administer study medication*

Keep patient in clinic for 30 to 60 minutes post instillation
* The Principal Investigator must perform the first instillation on the first patient at his/her site. 
Thereafter, an appropriately trained and delegated site staff member (as per site standard 
practice for instillations) may perform subsequent instillations, provided an appropriately 
trained study physician is on site during the procedure.
10.1.3 Visits 2*, 3*, 4*, 5*, and 6* (Days 8*, 15*, 22*, 29*, and 36*) 
* -1+ 3 days. Windows are provided to accommodate patient logistics in scheduling. Instillations 
should not occur more frequently than 6 days apart.
The following procedures will be performed at Visit 2 (Day 8) through Visit 6 (Day 36):

Concomitant medication review

Urology-oriented physical examination (Visit 4 only)

Vital signs (blood pressure, heart rate, respiration rate, and body temperature)

Body weight (Visits 3 and 5 only)

Clinical laboratory tests (serum chemistry and hematology)

Urinalysis

AE review

Administer study medication
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10.1.4 Visit 7 (Month 3 ± 1 week)
The following procedures will be performed at Visit 7 (Month 3):

Administer QLQ-NMIBC24 questionnaire 

Concomitant medication review

Urology-oriented physical examination

Vital signs (blood pressure, heart rate, respiration rate, and body temperature)

Body weight

Clinical laboratory tests (serum chemistry and hematology)

Urinalysis

Urine pregnancy test (if appropriate)

AE review

Cystoscopy and urine cytology for evaluation of response (Sections 10.2.1 and 10.2.2)

Biopsy of remaining lesions (if applicable; Sections 10.2.1 and 10.2.2)
The following visits apply only to patients with CR at Visit 7.
10.1.5 Monthly Telephone Contact Visits (Visits 8*, 9*, 11*, 12*, 14*, and 15*) * ± 1 
week
At Visits 8, 9, 11, 12, 14, and 15 patients will be contacted by phone to check for the following:

Concomitant medication review

AE review
10.1.6 Visits 10* and 13* (Months 6 and 9)* ± 2 weeks
The following procedures will be performed at Visits 10 and 13 (Months 6 and 9, respectively):

Administer QLQ-NMIBC24 questionnaire 

Concomitant medication review

Vital signs (blood pressure, heart rate, respiration rate, and body temperature)

Body weight (Visit 13 only)

Clinical laboratory tests (serum chemistry and hematology)

Urinalysis

AE review

Cystoscopy and urine cytology for evaluation of recurrence (see Section 10.2.4)
10.1.7 End of Study Visit, Visit 16 (Month 12) ± 2 weeks
The following procedures will be performed at Visit 16 (Month 12):

Administer QLQ-NMIBC24 questionnaire 
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
Concomitant medication review

Full physical examination 

Vital signs (blood pressure, heart rate, respiration rate, and body temperature)

Clinical laboratory tests (serum chemistry and hematology)

Urinalysis

AE review

Cystoscopy and urine cytology for evaluation of recurrence (see Section 10.2.4)
10.1.8 Unscheduled Visits
When required, based on patient needs relating to the study, unscheduled visits can occur. The 
following procedures are recommended, subject to the investigator’s judgement:

Administer QLQ-NMIBC24 questionnaire if indicated (i.e., early termination)

Concomitant medication review

Vital signs (blood pressure, heart rate, respiration rate, and body temperature)

Clinical laboratory tests (serum chemistry and hematology)

Urinalysis

AE review

Cystoscopy/urine cytology (if indicated by reasons for patient visit)
10.2
Efficacy Assessments
10.2.1 Measurements for Evaluation of Response at 3 MONTH Visit
Assessment of response will be based on the following:

Visual observation (cystoscopy)

Biopsy of remaining lesions, if applicable (non-CR or suspected tissue)

Voiding urine cytology
10.2.2 Evaluation of Response
Patient response will be evaluated according to the following criteria: 

CR: A patient will be considered to have had CR if there is NDD. To determine NDD, the 
following conditions should be fulfilled:
1. If visual assessment indicates no remaining tumors and urine cytology is negative, the 
patient has NDD and CR.  In the event that the bladder is free of tumor 
endoscopically, but the cytology is positive, the investigator is required to exclude 
urothelial carcinoma of the upper tract and occult carcinoma of the bladder or urethra. 
If   UTUC is confirmed, the patient will be considered as CR.
2. If any remaining lesions appear, even if they appear necrotic, the physician should 
biopsy the lesion(s). If a biopsy is taken from the necrotic lesion and found to be 
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negative, the patient should be classified as having CR; if positive for cancer, the 
patient should be classified as non-CR.

Non-CR:
1. If tumors are still visible, all remaining lesions should be biopsied for histopathology 
and viability assessment. If histopathology still indicates cancer, then the patient is 
considered non-CR. Note that biopsy results showing PUNLMP are not considered 
cancer and in such cases the patient would be considered CR.

Recurrence: For patients with CR at the 3 MONTH Visit, recurrence will be assessed at 
Study Visit 10, Visit 13, and Visit 16.

If evidence of disease is identified, patients will be staged according to their local 
Investigator practice. Progression is defined as change in either stage according to the 
Tumor-Node-Metastases (TNM) classification or grade according to the 2004 World 
Health Organization (WHO) classification of tumors.
Since the patient is recruited into the trial as a patient with LG NMIBC (based on a small 
biopsy for LG confirmation), it is unlikely that the tumor will progress to HG during the 
6-week study medication period. 
10.2.3 Assessment of Tumor Progression
Diagnosis of bladder cancer at the 3 MONTH Visit with an increase in stage or grade compared 
to baseline will be tracked; however, it likely does not represent true progression for the 
following reason:

The overall risk of progression for patients with LG papillary NMIBC at intermediate risk 
of recurrence ranges from 5 to 20% at 1 and 5 years (Sylvester, 2006). A 12-week 
interval, during which the patient is exposed to MMC treatment, is not considered long 
enough for progression to occur in patients with non-invasive UC.
Upstaging/upgrading detected at the 3-MONTH Visit will be recorded, and the overall incidence 
will be compared with that reported in the literature.
10.2.4 Assessment of Tumor Recurrence
Follow-up will be conducted in patients who were defined as having CR at the 3 MONTH Visit.
Starting with the first follow-up visit (Study Visit 10, Month 6) and continuing at Visit 13 and 16 
(Months 9 and 12), information regarding disease status based on cystoscopy, cytology, and 
biopsy (when applicable) should be recorded. If a patient is defined as having recurrence, 
complete documentation should be obtained. If a patient has a positive urine cytology and/or a 
positive biopsy for cancer, they are considered as having urothelial cell cancer with likely 
recurrence. If urine cytology is positive but the biopsy is negative, the patient should be evaluated 
for the presence of UTUC, either by repeat CT Urogram or by retrograde pyelogram. In cases 
where CT Urogram or retrograde pyelogram are contraindicated, MRI may be performed. If the 
patient is positive for UTUC that was not present at baseline and there is no evidence of tumor 
within the bladder, this is considered new disease and the patient remains a CR for their NMIBC.
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10.2.5 Pathological Evaluation
Biopsies and urine cytology specimens obtained at screening or any other visit should be 
evaluated by the local institutional pathologist. 
10.3
Safety and Other Assessments
10.3.1 The safety of the study medication will be assessed by the following:

Evaluation (frequency, seriousness, severity, and type) of AEs including adverse events of 
special interest (AESIs)

Changes from baseline in laboratory values and incidence of measurements defined as 
potentially clinically significant (PCS)

Clinically meaningful changes in physical examination findings including vital signs
10.3.2 Quality of Life Assessment EORTC QLQ – NMIBC24 
The QLQ- NMIBC24 is a 24-item validated, evidence-driven survey that assesses Health Related 
Quality of Life (HRQOL) for patients with intermediate to high risk NMIBC (Appendix 1). It is 
designed to be administered at baseline and at, 3, 6 and 12-month intervals. The NMIBC24 is the 
only instrument exclusively designed to compare HRQOL between non-muscle-invasive 
treatment modalities. 
10.4
Adverse Events and Serious Adverse Events
10.4.1 Definition of Adverse Events
An AE means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 Code of Federal Regulations [CFR] 
312.32 [a]). An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory, physical examination, or vital signs finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product (“Note for Guidance on Good Clinical Practice” 
CPMP/ICH/135/95). Any patient who reports an AE shall be examined by a doctor as soon as 
possible, making whatever intervention is necessary for the safety and well-being of the patient. 
All anomalies shall be monitored through to the patient’s recovery or clinical stabilization. AEs 
must be recorded in the eCRF using CTCAE to avoid the use of vague, ambiguous, or colloquial 
expressions. The investigator shall evaluate all AEs in terms of severity and their relationship 
with the product being tested, indicating the test results and the measures to be taken.
10.4.2 Definition of Serious Adverse Events 
An AE or suspected adverse reaction is considered serious if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening AE, 
inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, 
or require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such medical events include 
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allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse.
10.4.3 Classification of an Adverse Event
10.4.3.1 Intensity of Event
The intensity of an AE is to be graded by the investigator according to CTCAE version 4.03. 
General rules are as follows:
0
No AE (or within normal limits)
1
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only, 
intervention not indicated
2
Moderate: minimal, local, or noninvasive intervention (e.g., packing, cautery) 
indicated; limiting age-appropriate instrumental activities of daily living (ADL)
3
Severe or medically significant but not immediately life-threatening: hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL
4
Life-threatening consequences: urgent intervention indicated (SAE)
5
Death related to AE (SAE)
10.4.3.2 Relationship to Study Medication
All AEs must have their relationship to study medication assessed by the clinician who examined 
and evaluated the patient based on temporal relationship and his/her clinical judgment. In a 
clinical trial, the study product must always be suspect. Investigators will be asked to grade each 
AE as either related or unrelated.
10.4.3.3 Expectedness
The investigator will be responsible for determining whether an AE is expected or unexpected. 
An AE will be considered unexpected if the nature, intensity, or frequency of the event is not 
consistent with the risk information previously described for the study medication.
An Unexpected Adverse Drug Reaction (UADR) is any noxious and unintended response that is 
related to the administration of an IP that has not been reported as expected in this protocol or the 
Investigator’s Brochure, either from previous clinical studies or the nonclinical studies.
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is any UADR that at any dose also 
meets the criteria for SAE.
10.4.4 Time Period and Frequency for Event Assessment and Follow-Up
The occurrence of an AE or SAE may come to the attention of study personnel during study 
visits and interviews of a study patient presenting for medical care, or upon review by a study 
monitor.
All AEs, including local and systemic reactions not meeting the criteria for SAEs, will be 
captured on the appropriate eCRF. Information to be collected includes event description, time of 
onset, clinician’s assessment of intensity, relationship to study product (assessed only by those 
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with the training and authority to make a diagnosis), and time of resolution/stabilization of the 
event. All AEs occurring while on study must be documented appropriately regardless of 
relationship. All AEs will be followed to adequate resolution/stabilization.
Any medical condition that is present at the time that the patient signs the informed consent form 
(ICF) until the first study drug administration will be considered as baseline and recorded as 
medical history. However, if the study patient’s condition deteriorates at any time during the 
study, it will be recorded as an AE. AEs reported from the time of study drug administration until 
30 days after the last dose of study medication will be considered as treatment emergent adverse 
events (TEAEs).
Changes in the intensity of an AE will be documented to allow an assessment of the duration of 
the event at each level of intensity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode.
At each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last 
visit. The investigator or designated investigational staff member will record the start date of all 
reportable events. Events will be followed for outcome information until resolution or 
stabilization and the dates of outcome must be recorded.
10.4.5 Adverse Event Reporting 
Each patient must be given a patient card containing details of the contact person at the site 
he/she should contact in case any unusual or serious signs or symptoms develop after treatment. 
Where required, patients will be examined at the center and will be clinically monitored until 
they recover.
Expedited reporting to the sponsor is required in the following conditions:
1. Any SAE and follow-up SAE report, if required
2. Death of study patient 
3. Pregnancy and outcome of the pregnancy
The investigator must inform the Sponsor about the above by writing using the relevant form 
signed by the investigator, to be sent by email/fax within 24 hours after its occurrence first came 
to his/her knowledge.
10.4.6 Serious Adverse Event Reporting
The investigator will immediately report to the sponsor any SAE, whether or not considered 
study medication-related, including those listed in the protocol or Investigators Brochure and 
must include an assessment of whether there is a reasonable possibility that the study medication 
caused the event. Study endpoints that are SAEs (e.g., all-cause mortality) must be reported in 
accordance with the protocol, unless there is evidence suggesting a causal relationship between 
the study medication and the event (e.g., death from anaphylaxis). In that case, the investigator 
must immediately report the event to the Sponsor.
All SAEs will be followed until satisfactory resolution or until the investigator deems the event to 
be chronic or the patient is stable. Other supporting documentation of the event may be requested 
by the Sponsor and should be provided as soon as possible.
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The Sponsor will be responsible for notifying the Food and Drug Administration (FDA) of any 
unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case 
later than 7 calendar days after the Sponsor’s initial receipt of the information. In addition, the 
Sponsor must notify FDA and all participating investigators in an IND safety report of potential 
serious risks, from clinical trials or any other source, as soon as possible, but in no case later than 
15 calendar days after the Sponsor determines that the information qualifies for reporting.
10.4.6.1 SAE Reporting Instructions
The investigator must inform the sponsor within 24 hours of becoming
aware of an SAE with an email to:
safety@urogen.com with copies to sponsor@urogen.com
In addition, initial SAE/Death/Pregnancy must be recorded in the electronic Case Report Form 
(eCRF) within 24 hours of becoming aware of the event. 
10.4.7 Reporting Events to Patients 
Not applicable.
10.4.8 Adverse Events of Special Interest 
Adverse events of special interest are defined by the FDA (E2F Development Update Safety 
Report) as an AE, serious or nonserious, which is of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and rapid communication by the 
investigator to the sponsor can be appropriate. Such an event might warrant further investigation 
in order to characterize and understand it.
Events of Special Interest that may require expedited reporting and/or safety evaluation include, 
but are not limited to, the following:
1. Overdose of an IP
2. Suspected abuse/misuse of IP
3. Inadvertent or accidental exposure to IP
4. Medication error involving IP (with or without patient/patient exposure to the Sponsor 
medicinal product, e.g., name confusion)
5. Identified significant safety issue either from an individual case report or review of 
aggregate data
In addition, 
lists specific AEs defined as AESIs with suggested actions to be taken to address them.
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Table 3
Adverse Events of Special Interest
Adverse Events of Special Interest
Suggested Method to Address
Allergic reaction to MMC (CTCAE Grade 
3 or 4)
Discontinue study medication and continue to follow patient off 
medication per the protocol (Section 9.1). 
Unexpected ADR (CTCAE Grade 3 or 4)
Laboratory tests, physical examination, vital signs.
Voiding interruption due to urethral/penile 
edema (unrelated to prostatic hypertrophy)
Phone calls to the patients, input/output monitoring while patient is 
at the clinic pre- and post-instillation, physical examination.
Indication of bone marrow suppression
Hematologic laboratory tests, treatment suspension to allow for a 
recuperation period.
LUTS (CTCAE Grade 3 or 4)
Anti-cholinergic agents as well as local/systemic analgesics as 
needed.
ADR = adverse drug reaction; AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; LUTS = lower 
urinary tract symptoms; MMC = Mitomycin C.
10.4.9 Reporting of Pregnancy 
In the event of a patient becoming pregnant, the investigator shall immediately discontinue study 
treatment and ensure expedited reporting of the event (see Section 10.4.5). The pregnancy will be 
followed to term and the outcome reported.
10.5
Other Safety Assessments
10.5.1 Laboratory Assessments
Samples for hematology and serum chemistry assessments will be taken according to the SoA in 
Section 1.3 and tested at the local laboratory. The amount of blood required for hematology and 
serum chemistry tests per visit is 15 to 20 mL. The assessments to be performed are listed in 
Table 4. Additional tests may be part of a clinical site’s local lab’s standard panel and therefore 
reported along with these specified tests.
10.5.1.1 Other significant laboratory derangements
If at any time the investigator identifies myelosuppression or other significant laboratory 
derangements during the study defined by the parameters below, treatment may be
postponed for up to 4 weeks until laboratory values improve:

Absolute neutrophil count ≥1,000/μL (≥1.0×109/L),

Platelets ≥80,000/μL (≥80×109/L)

AST (SGOT)/ALT (SGPT) ≥5 × upper limit of normal (ULN)

ALP ≥2.5 institutional ULN

For patients whose baseline GFR is ~30 mL/min/1.73m2, decreases of up to 15% will be 
allowed

For patients with normal baseline creatinine, increases of up to 2x will be allowed

For all other patients, changes in creatinine should not result in GFR less than 
30mL/min/1.73m2
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10.5.2 Pharmacokinetic (PK) Assessments
At select sites, six (6) patients will be asked to participate and consent to provide blood samples 
for PK analysis. On the day of first instillation, this subset of patients will provide blood samples 
at 0 hours (pre-instillation), 0.5, 1, 2, 3, 4, 5, and 6 hours post instillation. Sites will be 
encouraged to use a catheter to lessen the number of needle sticks to the patient. Patients will be 
required to remain in the clinic for approximately 6 hours post instillation or agree to return for 
each blood draw at the appropriate time. The total amount of blood drawn for PK will be 
approximately 40 mL.
Table 4
Laboratory Safety and Pharmacokinetic (PK) Assessments
Liver Function Tests:
SGOT/AST
SGPT/ALT
GGT
Alkaline phosphatase
Total bilirubin
Direct bilirubin
Albumin
Total protein
Kidney Function Tests:
Creatinine
Blood urea nitrogen
Uric acid
Sodium
Potassium
Phosphorus 
Calcium
Bicarbonate
Chloride
eGFR (calculated in EDC)
Hematology Tests:
CBC, including red blood 
cell indices and white 
blood cell differential
Platelet count
PK
MMC Levels (6 Patients)* 
Plasma
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CBC = complete blood count; 
GGT = gamma-glutamyltransferase; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum glutamic pyruvic 
transaminase.
* The amount of blood required for each MMC PK level measurement time point is 5 cc; approximate total of 24 cc for PK visit. 
PK samples will be kept in -70 freezer in a light-blocking box until shipped to central lab for analysis.
10.5.3 Urinalysis
At the visits specified in Section 1.3, samples will be taken for urinalysis, including culture and 
sensitivity at the screening visit.
10.5.4 Physical Examination Findings
At the visits specified in Section 1.3, a full physical examination or urology-oriented physical 
examination will be performed. The patient’s physical condition will be examined and 
documented. This includes examination of main body systems, with focus on the urinary system. 
The examinations to be performed are summarized in Table 5.
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Table 5
Physical Examinations
General/Full Physical Examination will be 
performed at Screening Visit and Study Visit 16
Urology–Oriented Physical Examination will be 
performed at Screening Visit and Study Visits 1, 4, 
and 7, and for CR patients at Visits 8, 9, 11, 12, 14, 15, 
and 16
General appearance
Cardiovascular system
Respiratory system
HEENT (head, eyes, ears, nose, and throat) and 
neck
Abdomen
Extremities
Neurologic system
Skin
Urethral meatus
Perineal skin and mucus membranes
Scrotum and testes (for male patients)
Lymphadenopathy
Rectal examination (Screening visit only)
Bimanual examination (female patients – Screening visit 
only)
At each visit, the following vital signs measurements are to be taken after having the patient rest 
quietly in the sitting position for at least 3 minutes: blood pressure, heart rate, respiration rate, 
and body temperature.
10.5.5 Pregnancy Test
A urine pregnancy test will be conducted in female patients of childbearing potential at the 
Screening Visit and at Study Visits 7. If positive, a serum pregnancy test will be performed to 
verify. A female is considered of childbearing potential unless:

At least 12 months have elapsed since the last menstrual bleeding; or

She is without a uterus and/or both ovaries; or

She has been surgically sterile for at least 6 months prior to trial drug administration.
10.5.6 Reporting Unanticipated Problems to Patients 
Not applicable.
11 STATISTICAL CONSIDERATIONS 
11.1
Statistical Hypotheses
Analyses are descriptive and exploratory in nature and no formal hypotheses will be tested.
11.2
Sample Size Determination
Approximately 66 patients will enter the study, with 60 expected to complete, assuming 10% 
dropout rate. Given the patient population under study, i.e., those at intermediate risk of 
recurrence, a more conservative CR rate than previous studies of UGN-102 in the treatment of 
LG NMIBC has been assumed. The primary objective will be successfully achieved if complete 
responses from 36 out of 60 patients with CR rate of 60% will be observe, which would yield a 
95% confidence interval of (46.5%, 72.4%) based on the exact (Clopper-Pearson) binomial 
distribution.
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11.3
Populations for Analyses
11.3.1 Intent-to-Treat (ITT) Analysis Set (Safety Analysis Set)
The Intent-to-Treat (ITT) Analysis set will consist of all patients who have been enrolled into the 
trial and who have received any instillation of UGN-102 preparation. This analysis set, which 
will include all data captured in the database for these patients, will serve as the primary set for 
the primary efficacy endpoint analysis and will serve as the analysis set for the secondary safety 
endpoint analyses.
11.3.2 Modified Intent-to-Treat (mITT) Analysis Set
The Modified Intent-to-Treat (mITT) Analysis Set will consist of all patients who have been 
enrolled into the trial, who have a confirmed diagnosis of LG NMIBC based on the local 
pathology reading, who received at least 1 instillation of UGN-102 preparation, and who have 
undergone the 3 MONTH Visit (since it is the first visit for the outcome evaluation). 
11.3.3 Per Protocol (PP) Analysis Set
The Per Protocol (PP) Analysis Set will consist of all patients who have been enrolled into the 
trial, who have a confirmed diagnosis of LG NMIBC based on the local pathology reading, who 
received all 6 weekly instillations of UGN-102 preparation, and who have undergone the 
3 MONTH Visit. Patients who are identified as HG by local pathology reading at the 3 MONTH 
visit will be excluded from this analysis set. This analysis set, which will include all data 
captured in the database for these patients, will serve as supportive data for the primary efficacy 
endpoint analysis.
11.3.4 Complete Response at Primary Outcome Analysis Set
The Complete Response at 3 MONTH Visit (3 MONTHCR) Analysis Set will consist of all 
patients who achieved CR at the 3 MONTH Visit (Study Visit 7). This analysis set, which will 
include all data captured in the database for these patients, will serve as the primary set for the 
secondary efficacy endpoint analysis.
11.4
Statistical Analyses
A formal Statistical Analysis Plan (SAP) will be developed and finalized prior to database lock. 
The SAP will supersede this statistical analysis section.
11.4.1 General Approach
All measured variables and derived parameters will be listed individually and, if appropriate, 
tabulated using descriptive statistics. For categorical variables, summary tables will be provided 
giving sample size, absolute and relative frequency, and 95% confidence interval (CI) for 
proportions using the exact approach. For continuous variables, summary tables will be provided 
giving sample size, arithmetic mean, standard deviation (SD), coefficient of variation (if 
appropriate), median, minimum and maximum, percentiles, and 95% CI for means of variables. 
For variables with non-normal distribution, medians and interquartile range (IQR) will be 
calculated, and the appropriate non-parametric tests will be applied.
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11.4.2 Analysis of the Primary Efficacy Endpoint
The analysis of the primary endpoint will test the CR rate defined as percentage of patients with 
CR at the 3 MONTH Visit using the ITT Analysis Set.
A test for binomial proportions (SAS PROC FREQ with binomial option) will be used to derive 
the exact 95% CI for the true CR rate.
11.4.3 Sensitivity Analysis of the Primary Efficacy Endpoint
Sensitivity analysis of the primary endpoint will include repeat of the primary efficacy analysis 
(Section 11.4.2) using the PP Analysis Set, i.e., including only patients who received all 
6 instillations of UGN-102 preparation and are LG at baseline (patients with HG at 3 MONTH 
Visit will be excluded).
11.4.4 Analysis of the Secondary Efficacy Endpoints
One key secondary endpoint is pre-defined for this trial: the durable complete response (DCR) 
rate at 6, 9, and 12 months after the first instillation of UGN-102 preparation, defined as the 
percentage of patients who continue to display CR at Study Visits 10, 13, and 16, respectively.
Analysis will use the 3 MONTHCR Analysis Set, implying that the denominator for this analysis 
will be the number of patients who demonstrated CR at the 3 MONTH Visit. Patients who 
withdraw early from the trial between the 3-MONTH Visit and Study Visit 16 for whom 
follow-up data regarding the disease status (i.e., recurrence) is not available will be treated as 
follows:

Patients who discontinue during this time window due to adverse reactions from the study 
medication, lack of efficacy, death, or any other cancer-related reason will be considered 
as treatment failures for the purpose of this analysis.

Patients who withdraw during this time window due to reasons other than those given 
above will be excluded from the analysis.
A test for binomial proportions (SAS PROC FREQ with binomial option) will be used to derive 
the exact 95% CI for the true DCR rate at 6, 9, and 12 months.
11.4.5 Safety Analyses
11.4.5.1 Adverse Events and Serious Adverse Events
Adverse events will be recorded from the time a patient has signed the informed consent until 
30 days after the last instillation of study medication. AEs reported by the investigators will be 
coded according to the Medical Dictionary for Regulatory Activities (MedDRA).
The following will be incorporated into the analysis of AEs:

All analyses to be provided will include coded AEs.

AE analyses will include both all AEs and treatment-emergent AEs (TEAEs), i.e., events 
that started on the day of first administration of study medication or afterwards, or that 
were present before first administration of study medication and increased in intensity 
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after first administration of study medication. Listings of both TEAEs and non-TEAEs 
will be provided.

The incidence (number of patients) and frequency (number of events) of TEAEs will be 
provided, broken down by System Organ Class (SOC) and by Preferred Term (PT) 
according to MedDRA.

The incidence (number of patients) and frequency (number of events) of TEAEs will be 
provided, broken down by descending frequency by PT according to MedDRA.

Breakdowns of TEAEs by all AE attributes will also be provided.

Breakdowns of TEAEs by age and sex will also be provided.

The derived dictionary used in the analyses displaying the MedDRA SOC and PT and the 
AE verbatim term as specified by the investigator, will be provided.

The incidence and frequency of treatment-emergent SAEs will be provided, broken down 
by SOC and by PT according to MedDRA, as well as by SAE attributes and by age and 
sex. Listings of both treatment-emergent and non-treatment-emergent SAEs will be 
provided.
11.4.5.2 Laboratory Assessments
Analyses of safety laboratory data will be performed for all collected laboratory parameters. 
Quantitative laboratory measurements will be categorized with reference to the normal ranges as 
Low, Normal, or High. Shift analysis of the categorical change from baseline to each scheduled 
visit and to the last observed assessment will also be performed.
A list of parameters and related cut-off values defining the PCS abnormal values will be outlined 
by the Sponsor prior to initiation of the first trial instillation. Measurements used in the analysis 
are those taken following first trial instillation. The incidence tables of PCS laboratory values as 
well as the individual patient listing will be provided using the denominator that is the number of 
patients with at least 1 post-baseline administration of trial medication. Individual patients’ 
listings of PCS measurements will also be presented.
11.4.5.3 Physical Examination
Any clinically relevant changes occurring from Screening until the last trial visit will be recorded 
on the Adverse Event Sections of the eCRF and reported with AEs as described above.
11.4.5.4 Vital Signs
Analyses of vital signs (blood pressure, heart rate, respiration rate, and body temperature) will be 
performed using descriptive statistics of vital signs before Screening, instillation, and during the 
trial, and by presenting changes from baseline by scheduled visit.
11.4.5.5 Concomitant Medications
The WHO drug dictionary will be used to classify medications verbatim for concomitant and pre-
trial medications. Analysis of concomitant drug use will be performed in the following manner:
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
Pre-instillation concomitant medications use: Analyses will include coded medications 
that were initiated prior to first instillation, regardless if stopped after the first instillation. 
An incidence table including patient counts (number of patients) and percentages broken 
down by Medication Class and PT will be provided.

Concomitant medications use (post-first instillation): Analyses will include only coded 
medications that were administered following the first instillation, regardless if drug 
initiation date was before or after first instillation. An incidence table including patient 
counts (number of patients) and percentages broken down by Medication Class and PT 
will be generated.
11.4.5.6 MMC Levels (Pharmacokinetics) Profiling
Pharmacokinetic (PK) profile during the 6 hours following the first administration of UGN-102 
will be based on PK sampling at 0 (pre-instillation), 0.5, 1, 2, 3, 4, 5, and 6 hours post instillation. 
PK will be performed with just 6 patients who provide informed consent for PK testing. 
Concentration data as well as PK parameters (e.g., AUC) will be provided using descriptive 
statistics. Plasma samples for evaluation of PK properties of MMC following instillation with 
UGN-102 Admixture will be collected and archived. These samples are to be used to characterize 
the plasma concentration of MMC during the 6 hours post instillation, which is the estimated 
duration of the dwell-time of UGN-102 Admixture. The PK parameters obtained, specifically the 
Cmax, will be compared to the threshold of MMC plasma concentration (400 ng/mL) known to be 
associated with myelosuppression, as well as to the known PK profile of MMC obtained with 
different routes/methods of administration (e.g., intravesical instillation with WFI).
Additionally, these data, combined with data emerging from other trials may be used in 
population pharmacokinetic model development and analysis. 
11.4.6 Baseline Descriptive Statistics
Disposition data from patients who were screened but not treated, patients in the ITT, mITT, PP, 
and 3 MONTHCR Analysis Sets, as well as trial withdrawal data will be summarized using 
descriptive statistics.
Demographics and baseline data, as well as disease prognostic factors, medical history, and prior 
medications, will be summarized for the ITT Analysis Set using descriptive statistics. For 
continuous variables, descriptive statistics (number, mean, SD, standard error, median, minimum, 
and maximum) will be provided. For categorical variables, patient counts and percentages will be 
provided. Categories for missing data will be presented if necessary. Missing categories will be 
presented if necessary.
11.4.7 Planned Interim Analyses 
When approximately 12 patients have reached their Month 3 visit an interim analysis will be 
performed for primary endpoint.  
11.4.8 Sub-Group Analyses
To be addressed in the SAP
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11.4.9 Tabulation of Individual Patient Data
Individual patient data will be listed by measure and time point.
11.4.10
Exploratory Analyses
PK and QoL will be evaluated.
12 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
12.1
Regulatory, Ethical, and Study Oversight Considerations
12.1.1 Informed Consent Process
12.1.1.1 Consent/Assent and Other Informational Documents Provided to Patients
Consent forms describing in detail the study medication, study procedures, and risks are given to 
the patient, and written documentation of informed consent is required prior to initiating any 
study procedures and starting medication/administering study medication. The informed consent 
form (ICF) template is submitted with this protocol. 
12.1.1.2 Consent Procedures and Documentation
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Consent forms will be 
IRB-approved, and the patient will be asked to read and review the document. The 
investigator/designee will explain the research study to the patient and answer any questions that 
may arise. A verbal explanation will be provided in terms suited to the patient’s comprehension 
of the purposes, procedures, and potential risks of the study and of their rights as research 
patients. Patients will have the opportunity to carefully review the written consent form and ask 
questions prior to signing. The patients should have the opportunity to discuss the study with 
their family or surrogates or think about it prior to agreeing to participate. The patient will sign 
the informed consent document prior to any procedures being done specifically for the study. 
Patients must be informed that participation is voluntary and that they may withdraw from the 
study at any time, without prejudice. A copy of the informed consent document will be given to 
the patients for their records. The informed consent process will be conducted and documented in 
the source document (including the date), and the form signed, before the patient undergoes any 
study-specific procedures. The rights and welfare of the patients will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in this study.
12.1.2 Study Discontinuation and Closure
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study patients, 
investigator, Sponsor, and regulatory authorities. If the study is prematurely terminated or 
suspended, the investigator will promptly inform study patients, the IRB, and the Sponsor and 
will provide the reason(s) for the termination or suspension. Study patients will be contacted, as 
applicable, and be informed of changes to the study visit schedule.
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Circumstances that may warrant termination or suspension include, but are not limited to, the 
following:

Determination of unexpected, significant, or unacceptable risk to patients

Demonstration of efficacy that would warrant stopping

Insufficient compliance to protocol requirements

Data that are not sufficiently complete and/or evaluable

Determination that the primary endpoint has been met
The study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB, and/or FDA.
12.1.3 Confidentiality and Privacy 
Patient confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the Sponsor and their interventions. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to patients. 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the Sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the Sponsor, representatives of the IRB, 
regulatory agencies, or pharmaceutical company supplying the study product may inspect all 
documents and records required to be maintained by the investigator, including, but not limited 
to, medical records (office, clinic, or hospital) and pharmacy records for the patients in this study. 
The clinical study site will permit access to such records.
The study patient’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB, institutional policies, or sponsor 
requirements.
Study patient research data, which are for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored by the Sponsor. This will not include the patient’s contact or 
identifying information. Rather, individual patients and their research data will be identified by a 
unique study identification number. The study data entry and study management systems used by 
clinical sites and by the Sponsor’s research staff will be secured and password-protected. At the 
end of the study, all study databases will be de-identified and archived by the Sponsor.
12.1.4 Future Use of Stored Specimens and Data
Data collected for this study will be analyzed and stored by the Sponsor. After the study is 
completed, the de-identified, archived data will be transmitted to and stored by the Sponsor, for 
use by other researchers including those outside of the study. Permission to transmit data to the 
Sponsor will be included in the informed consent. 
When the study is completed, access to study data and/or samples will be provided through the 
Sponsor.
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12.1.5 Safety Oversight
Safety oversight will be under the direction of the Sponsor. Safety oversight will be independent 
from the study conduct and free from conflict of interest. 
12.1.6 Clinical Monitoring
The sponsor will perform on-site monitoring visits as frequently as necessary, depending on 
recruitment frequency at each site. The monitor will record dates of the visits in a trial site visit 
log that will be kept at the site. Remote monitoring of patient screening data will be performed on 
all patients, to ensure eligibility. The first post-initiation visit will be made as soon as possible 
(approximately 2-3 weeks) after enrollment has begun. At these visits, the monitor will compare 
the data entered into the eCRF with the hospital or clinic records (source documents). The nature 
and location of all source documents will be identified to ensure that all sources of original data 
required to complete the eCRF are known to the sponsor and investigational staff and are 
accessible for verification by the sponsor site contact. If electronic records are maintained at the 
investigational site, the method of verification must be discussed with the investigational staff.
Direct access to source documentation (medical records) must be allowed for verifying that the 
data recorded in the eCRF are consistent with the original source data. Findings from this review 
of eCRFs and source documents will be discussed with the investigational staff. The sponsor 
expects that, during monitoring visits, the relevant investigational staff will be available, the 
source documentation will be accessible, and a suitable environment will be provided for review 
of trial-related documents. The monitor will meet with the investigator on a regular basis during 
the trial to provide feedback on the trial conduct. Further details of clinical site monitoring will be 
provided in a Study Monitoring Plan (SMP). The SMP will describe in detail who will conduct 
the monitoring, at what frequency monitoring will be done, at what level of detail monitoring will 
be performed, and the distribution of monitoring reports.
Independent audits may be conducted by representatives of the Sponsor’s clinical quality 
assurance department or their designee to ensure that monitoring practices are performed 
consistently across all participating sites and that monitors are following the SMP.
12.1.7 Quality Assurance and Quality Control
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation, and completion. An individualized quality management plan 
will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database. Any missing data or data anomalies will be 
communicated to the sites for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted, data are generated, and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, ICH GCP, and applicable regulatory 
requirements (e.g., Good Laboratory Practices [GLP], GMP). 
The investigational site will provide direct access to all trial-related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the Sponsor and inspection by local 
and regulatory authorities.
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12.1.8 Data Handling and Record Keeping 
12.1.8.1 Data Collection and Management Responsibilities 
This study will use an Electronic Data Capture (EDC) system; the designated investigator staff 
will enter the data required by the protocol into the eCRFs. The eCRFs are built using fully 
validated, secure, web-enabled software that conforms to 21 CFR Part 11 requirements. 
Investigator site staff will not be given access to the electronic data capture system until they 
have been trained. Automatic validation programs check for data discrepancies in the eCRFs and 
allow modification or verification of the entered data by the investigator staff.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. It is the sponsor’s expectation that data required by 
the protocol will be entered by the clinical site staff no later than 5 days from each visit. 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data and if applicable, signed or initialed and dated.
Hard copies of the study visit worksheets may be provided for use as source document 
worksheets for recording data for each patient enrolled in the study. Data recorded in the eCRF 
derived from source documents should be consistent with the data recorded on the source 
documents.
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and 
clinical laboratory data will be entered in the eCRF using a 21 CFR Part 11-compliant electronic 
data capture system. The data system includes password protection and internal quality checks, 
such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate. Clinical data will be entered directly from the source documents.
12.1.8.2 Study Records Retention 
Study documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region, or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the study medication. These documents should be 
retained for a longer period, however, if required by local regulations. No records will be 
destroyed without the written consent of the Sponsor, if applicable. It is the responsibility of the 
Sponsor to inform the investigator when these documents no longer need to be retained.
12.1.9 Protocol Deviations 
A protocol deviation is a departure from the study protocol and/or study related documents. The 
departure may be either on the part of the site or the patient and identified as site or patient 
deviations. As a result of deviations, corrective actions are to be developed by the site and 
implemented promptly.
All important deviations related to study inclusion or exclusion criteria, conduct of the trial, 
patient management or patient assessment should be addressed in study source documents and 
reported to the sponsor. Protocol deviations must be submitted to the local or central IRB 
according to their guidelines. The site PI/study staff is responsible for knowing and adhering to 
their IRB requirements.
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Protocol waivers are not allowed. If a patient's eligibility is in question, please contact the 
sponsor.
12.1.10
Publication and Data Sharing Policy
Not applicable.
12.1.11
Conflict of Interest Policy
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and 
conduct of this trial. The Sponsor has established policies and procedures for all study group 
members to disclose all conflicts of interest and will establish a mechanism for the management 
of all reported dualities of interest.
12.2
Additional Considerations
12.2.1 Finance and Insurance
12.2.1.1 Finance:
The trial is financed by the Sponsor as detailed in the financial agreement between the Sponsor 
and the investigator/institution.
12.2.1.2 Insurance:
The trial will be covered in accordance with local requirements. Insurance coverage will be 
provided by the Sponsor. In case of any damage or inquiry occurring to a patient in association 
with the IP or the participation in this trial, the Sponsor will contact the insurance company that 
covers the liability of the Sponsor, the investigator, and other persons involved in the trial, in 
compliance with the laws in the country where the trial takes place.
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13 PROTOCOL AMENDMENT HISTORY
Version
Date
Description of Changes
Brief Rationale
4.0

Removal of maintenance 
monthly instillations visits, 
replaced by telephone 
contacts for safety follow-up 
at months 8, 9, 10, 11, 12, 13, 
14, and 15 in sections 1.1, 1.2, 
1.3.2, 6.1, 8.1.3, 10.1.5, and 
10.1.6.

Additional study design 
rationale added to section 6.2: 
“Based on data from an 
ongoing Phase 3 trial in a 
similar indication, UTUC, 
monthly maintenance 
treatments do not appear to 
have a meaningful effect on 
durability of response in those 
patients who were CR at the 
3-month assessment (primary 
endpoint).”

Reference to monthly study 
drug instillations removed in 
sect. 8.1.3

Addition of the word 
“bladder” in sect. 8.5

Removal of pregnancy test at 
months 6, 9, and 12 in sect. 
10.1.6, 10.1.7, and 10.5.5

Additional reference added to 
section 13
Sponsor decision
Revised study design 
rationale
Sponsor decision
Due to oversight, the word 
“bladder” had been omitted.
Patients will have been off 
study drug for at least 4 
months
To support change study 
design  
Version
Date
Description of Changes
Brief Rationale
3.0 
20Jan2019
QoL questionnaire added as a 
Tertiary/Exploratory endpoints 
in Summary sect. 5 and sect. 
11.4.10
Sponsor decision
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Page 48 of 56


Version
Date
Description of Changes
Brief Rationale
Adjustments to the SoA in 
section 1.3.1
Several new abbreviations 
added to the abbreviations 
section
Updates to contact information 
in sect. 3
Screening period revised based 
on timing of eligibility biopsy, 
sect. 6.1 and 10.1.1
Additional instructions in case 
of symptomatic and 
asymptomatic UTI at 
treatment visits, sect. 8.5
Additional instructions on 
permissible study personnel 
for instillation of study drug 
10.1.2
Addition of QLQ-NMIBC24 
questionnaire at applicable 
study visits in sect. 10.1 and 
10.3.2
Update to sample size section 
11.2
Addition of an interim analysis
Minor typographical 
corrections and clarifications 
throughout the document
Additional reference added to 
sect. 
Addition of sect.15 Appendix 
1 QLQ-NMIBC24 sample
Clarification
To be consistent with 
protocol additions
New information
To be consistent with prior 
administrative letter
Clarification
Clarification
New study procedure
Clarification
Sponsor decision
NA
Reference for QLQ-
NMIBC24 validation 
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Version
Date
Description of Changes 
Brief Rationale
2.0
10AUG2018

Study Title: removal of “a 
chemoablation agent”  
replaced with “as primary 
chemoablative therapy”

Abbreviations moved to 
Section 2

Section 3 Key Roles and 
Study Contact 
Information added

Sect. 7.1: 
o Reduction of the 12-
week screening biopsy 
period requirement to 
6 weeks so as to 
shorten the period 
between diagnosis and 
the 3-month primary 
endpoint evaluation
o New definition of 
recurrence in inclusion 
criterion 4c
o Addition of inclusion 
criterion 7 requiring 
baseline minimum 
organ and bone 
marrow function blood 
levels 

Sect. 10.5.2: Addition of 
PK analysis in a subset of 
patients and the required 
collection timepoints at 
the enrollment visit. 

Sect. 11.4.5.6: Description 
of the PK profiling

Minor typographical 
corrections and 
clarifications throughout 
the document
To clarify that this treatment is 
being studied as first line 
therapy in lieu of TURBT
For ease of reference
Additional section
FDA request
FDA request
FDA request
FDA recommendation
FDA recommendation
NA
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14 REFERENCES
Anastasiadis A, Cordeiro E, Bus MT, Alivizatos G, de la Rosette JJ, de Reijke TM. Follow-
up procedures for non-muscle-invasive bladder cancer: an update. Expert Rev Anticancer 
Ther. 2012 Sep;12(9):1229-41. doi: 10.1586/era.12.98.
Audenet F, Traxer O, Bensalah K, Roupret M. Upper urinary tract instillations in the 
treatment of urothelial carcinomas: a review of technical constraints and outcomes. World J 
Urol 2013; 31(1):45-52.
Badalament, R.A. and Farah, R.N., "Treatment of Superficial Bladder Cancer With 
Intravesical Chemotherapy", Seminar in Surgical Oncology V. 13, p. 335-341, 1997
Barlogie B, Drewinko B. Lethal and cytokinetic effects of mitomycin C on cultured human 
colon cancer cells. Cancer Res. 1980 Jun;40(6):1973-80.
Blazeby J.M.,  et al.  “Validation and Reliability Testing of the EORTC QLQ-NMIBC24 
Questionnaire Module to Assess Patient-reported Outcomes in Non-Muscle Invasive Bladder 
Cancer." Eur Urol. 2014 Dec; 66(6): 1148–1156. doi: 10.1016/j.eururo.2014.02.034.
Bono, A. V., et al. "Chemoresection in Ta-T1 bladder cancer." European urology 29 (1996): 
385-390.
Bracken, R. Bruce, et al. "Role of intravesical mitomycin C in management of superficial 
bladder tumors." Urology 16.1 (1980): 11-15.
Brausi, M, et al. "Intravesical electromotive administration of drugs for treatment of 
superficial bladder cancer: a comparative phase II study." Urology 51.3 (1998): 506-509.
Brausi M., Collette L., Kurth K., van der Meijden A.P., Oosterlinck W., Witjes J.A. 
Variability in the recurrence rate at first follow-up cystoscopy after TUR in stage Ta T1 
transitional cell carcinoma of the bladder: a combined analysis of seven EORTC studies. Eur 
Urol. 2002. May; 41(5): 523–31.
Colombo, Renzo, et al. "Nerve and seminal sparing radical cystectomy with orthotopic 
urinary diversion for select patients with superficial bladder cancer: an innovative surgical 
approach." The Journal of urology 165.1 (2001): 51-55.
Dalton, J.T., Wientjes, M.G., and Badalament, R.A.," Pharmacokinetics of Intravesical 
Mitomycin C in Superficial Bladder Cancer", Bladder Research, V. 51, p. 5144-5152, 1991.
De Bruijn EA, Sleeboom HP, van Helsdingen PJ, van Oosterom AT, Tjaden UR, Maes RA. 
Pharmacodynamics and pharmacokinetics of intravesical mitomycin C upon different 
dwelling times. Int J Cancer. 1992 May 28;51(3):359-64.
Deb AA, Wilson SS, Rove KO, Kumar B, Koul S, Lim DD, Meacham RB, Koul HK. 
Potentiation of mitomycin C tumoricidal activity for transitional cell carcinoma by histone 
deacetylase inhibitors in vitro. J Urol. 2011 Dec;186(6):2426-33. doi: 
10.1016/j.juro.2011.07.107.
Eastham JA, Huffman JL. Technique of mitomycin C instillation in the treatment of upper 
urinary tract urothelial tumors. J Urol. 1993 Aug;150(2 Pt 1):324-5.
Giesbers A.A.G.M., Van Heldingen, P.J.R.O., and Kramer A.E.J., "Recirrence of Superficial 
Bladder Carcinoma after Intravesical Instillation of MMC- Comparison of Exposure Times", 
British Journal of Urology, V. 63, p. 176-179, 1989.
TC-BC-12 - UGN-102 - IND Clinical Trial Protocol
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Hall, M. Craig, et al. "Guideline for the management of nonmuscle invasive bladder cancer 
(stages Ta, T1, and Tis): 2007 update." The Journal of urology 178.6 (2007): 2314-2330.
Hamdy, F. C., et al. "Mitomycin‐C in Superficial Bladder Cancer. Is Long‐term Maintenance 
Therapy Worthwhile After Initial Treatment?." BJU International 71.2 (1993): 183-186.
Harrison, G. S. M., et al. "A Phase II Study of lntravesical Mitomycin C in the Treatment of 
Superficial Bladder Cancer." BJU International 55.6 (1983): 676-679.
Heney NM. Natural history of superficial bladder cancer. Prognostic features and long-term 
disease course. Urol Clin North Am. 1992;19:429–433.
Hetherington, J. W., et al. "Intravesical mitomycin C for the treatment of recurrent superficial 
bladder tumours." BJU International 59.3 (1987): 239-241.
Maffezzini, Massimo, et al. "Up-front intravesical chemotherapy for low stage, low grade 
recurrent bladder cancer." The Journal of urology 155.1 (1996): 91-93.
Miladi M, Peyromaure M, Zerbib M, Saïghi D, Debré B. The value of a second transurethral 
resection in evaluating patients with bladder tumours. Eur Urol. 2003 Mar;43(3):241-5.
Mishina, Teruo, et al. "Mitomycin C bladder instillation therapy for bladder tumors." The 
Journal of urology 114.2 (1975): 217-219.
Nozue M, Todoroki T, Fukao K. 5-fu dose-dependency in mtx/s-fu sequential therapy 
assessed by in-vitro assay using gastric-cancer cell-lines. Oncol Rep. 1995 Sep;2(5):737-40. 
(Nozue, 1995a).
Nozue, M., Nishida, M., Todoroki, T., Fukao, K., and Tanaka, M., "Selection of Three Out of 
24 Anti-cancer Agents in Poorly-differentiated Gastric Cancer Cell Lines, Evaluated by the 
AUC/ΔIC50 ratio", Anti-Cancer Drugs, V.  6. p. 291-302, 1995 (Nozue, 1995b).
O'Donoghue JP, Crew JP. Adjuvant topical treatment of upper urinary tract urothelial tumors. 
BJU Int. 2004 Sep;94(4):483-5.
Ost, Piet, et al. "Metastasis-directed therapy of regional and distant recurrences after curative 
treatment of prostate cancer: a systematic review of the literature." European urology 67.5 
(2015): 852-863.
Ozawa S, Sugiyama Y, Mitsuhashi Y, Kobayashi T, Inaba M. Cell killing action of cell cycle 
phase-non-specific antitumor agents is dependent on concentration--time product. Cancer 
Chemother Pharmacol 1988; 21(3):185-190.
Perry RR, Greaves BR, Rasberry U, Barranco SC. Effect of treatment duration and 
glutathione depletion on mitomycin C cytotoxicity in vitro. Cancer Res. 1992 Sep 
1;52(17):4608-12.
Sadeghi HM, Seitz B, Hayashi S, LaBree L, McDonnell PJ. In vitro effects of mitomycin-C 
on human keratocytes. J Refract Surg. 1998 Sep-Oct;14(5):534-40.
Schmittgen TD, Wientjes MG, Badalament RA, Au JL. Pharmacodynamics of mitomycin C 
in cultured human bladder tumors. Cancer Res. 1991 Aug 1;51(15):3849-56.
Serreta, V., "Optimizing intravesical chemotherapy in patient with non-muscle invasive 
bladder carcinoma" Archivio Italiano di Urologia e Andrologia, V. 80, 4, p.143-147, 2008.
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Slee PH, de Bruijn EA, Leeflang P, Kuppen PJ, van den Berg L, van Oosterom AT. 
Variations in exposure to mitomycin C in an in vitro colony-forming assay. Br J Cancer. 1986 
Dec;54(6):951-5.
Soloway, M. S. "Overview of treatment of superficial bladder cancer." Urology 26.4 Suppl 
(1985): 18-26.
Sylvester RJ, van der Meijden AP, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, et al. 
Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer 
using EORTC risk tables: A combined analysis of 2596 patients from seven EORTC trials. 
Eur Urol. 2006;49:466–5. discussion 75-7.
Walker MC, Masters JR, Parris CN, Hepburn PJ, English PJ. Intravesical chemotherapy: in 
vitro studies on the relationship between dose and cytotoxicity. Urol Res. 1986;14(3):137-40.
Wang AJ, Goldsmith ZG, Neisius A, Astroza GM, Oredein-McCoy O, Iqbal MW, Simmons 
WN, Madden JF, Preminger GM, Inman BA, Lipkin ME, Ferrandino MN. Increasing dwell 
time of mitomycin C in the upper tract with a reverse thermosensitive polymer. J Endourol. 
2013 Mar;27(3):288-93. doi: 10.1089/end.2012.0211.
UroGen Study TC-UT-03, A Phase 3 Multicenter Trial Evaluating the Efficacy and Safety of 
MitoGel™ (UGN-101) on Ablation of Upper Urinary Tract Urothelial Carcinoma  
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15 APPENDIX 1
15.1
EORTC QLQ – NMIBC24
Patients sometimes report that they have the following symptoms or problems. Please indicate 
the extent to which you have experienced these symptoms or problems during the past week. 
Please answer by circling the number that best applies to you.
During the past week:
Not at 
all
A little Quite a 
bit
Very 
much
31.
Have you had to urinate frequently during the day?
1
2
3
4
32.
Have you had to urinate frequently at night?
1
2
3
4
33.
When you felt the urge to pass urine,
did you have to hurry to get to the toilet?
1
2
3
4
34.
Was it difficult for you to get enough sleep, because you 
needed to get up frequently at night to urinate?
1
2
3
4
35.
Have you had difficulty going out of the house, because you 
needed to be close to a toilet?
1
2
3
4
36.
Have you had any unintentional release (leakage) of urine?
1
2
3
4
37.
Have you had pain or a burning feeling when urinating?
1
2
3
4
38.
Did you have a fever?
1
2
3
4
39.
Did you feel ill or unwell?
1
2
3
4
40.
Did you have trouble arranging your life around the 
repeated bladder treatment appointments (cystoscopies or 
instillations)?
1
2
3
4
41.
Did you worry about having repeated bladder treatments 
(cystoscopies or instillations)?
1
2
3
4
42.
Were you worried about your health in the future?
1
2
3
4
43.
Did you worry about the results of examinations and tests?
1
2
3
4
44.
Did you worry about possible future treatments?
1
2
3
4
45.
Did you have a bloated feeling in your abdomen?
1
2
3
4
46.
Have you had flatulence or gas?
1
2
3
4
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During the past 4 weeks:
Not at 
all
A little Quite a 
bit
Very 
much
47.
To what extent were you interested in sex?
1
2
3
4
48.
To what extent were you sexually active (with or without 
sexual intercourse)?
1
2
3
4
49.
For men only: Did you have difficulty gaining or 
maintaining an erection?
1
2
3
4
50.
For men only: Did you have ejaculation problems (e.g. dry 
ejaculation)?
1
2
3
4
Please answer the following 4 questions only if you have been 
sexually active during the past 4 weeks:
Not at 
all
A little Quite a 
bit
Very 
much
51.
Have you felt uncomfortable about being sexually intimate?
1
2
3
4
52.
Have you worried that you may contaminate your partner 
during sexual contact with the bladder treatment you have 
been receiving?
1
2
3
4
53.
To what extent was sex enjoyable for you?
1
2
3
4
54.
For Women only: did you have a dry vagina or other 
problems during intercourse?
1
2
3
4
© Copyright 1994 EORTC Quality of Life Study Group, All rights reserved.
ENGLISH
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Description of Change: 10.5.5 should read: A urine pregnancy test will be conducted in female
patients of childbearing potential at the screening Visit and at Study Visit 7. And the summary of
changes should say: Removal of pregnancy test at months 6, 9, and 12 in sect. 10.1.6, 10.1.7, and
10.5.5
Action Name
User Name
Title
Date
Created By
Shira Simis
QA Team Leader
13-Apr-2019
Review
Robert Kirshoff
S. Director Clinical Development
14-Apr-2019
Approve
Gilad Bernadsky
VP QA
15-Apr-2019
Approve
Elyse Seltzer
SVP Clinical Development, Medical Affairs & PV
15-Apr-2019
Approve
Jim Ottinger
SVP Regulatory Affairs
15-Apr-2019
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SAP_001.pdf: 
Statistical Analysis Plan: TC-BC-12 
 
 Study Title: 
A Phase 2b, Single-Arm, Multicenter Trial to Evaluate the 
Efficacy and Safety of UGN-102 as Primary Chemoablative 
Therapy in Patients with Low Grade (LG) Non-Muscle-Invasive 
Bladder Cancer (NMIBC) at Intermediate Risk of Recurrence 
Study Number: 
TC-BC-12 
Study Phase:  
2b 
Sponsor: 
UroGen Pharma 
499 Park Avenue, Suite 1200 
New York, NY 10022 
Version  
Final 
NCT #: 
NCT03558503 
Date: 
24 July 2020 
 
Confidentiality Statement 
This document contains confidential and proprietary information, and is not to 
be distributed to any third party. 
 
 
 


UGN-102 
UroGen Pharm 
Statistical Analysis Plan: TC-BC-12 
24 July 2020 
 
 
 
 
Confidential 
Page 2 of 46 
1 TABLE OF CONTENTS 
1 
TABLE OF CONTENTS .........................................................................................................2 
LIST OF TABLES ...........................................................................................................................4 
LIST OF APPENDICES ..................................................................................................................5 
2 
SIGNATURE PAGE ................................................................................................................6 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS...........................................7 
4 
INTRODUCTION ....................................................................................................................9 
5 
TRIAL OBJECTIVES ..............................................................................................................9 
5.1 
Primary Objective ................................................................................................................9 
5.2 
Secondary Objectives...........................................................................................................9 
5.3 
Tertiary Objective ................................................................................................................9 
5.4 
Exploratory Objective ..........................................................................................................9 
6 
STUDY DESIGN CONSIDERATIONS ..................................................................................9 
6.1 
Study Design ........................................................................................................................9 
6.1.1 
Study Schema...............................................................................................................11 
6.2 
Statistical Hypotheses ........................................................................................................11 
6.3 
Sample Size Determination................................................................................................11 
6.4 
Efficacy Measures ..............................................................................................................12 
6.5 
Safety Measures .................................................................................................................12 
6.6 
Pharmacokinetic Parameters ..............................................................................................12 
7 
STUDY POPULATIONS .......................................................................................................13 
7.1 
Analysis Populations ..........................................................................................................13 
7.1.1 
Intent-to-Treat (ITT) Analysis Set (Safety Analysis Set) ............................................13 
7.1.2 
Modified ITT (mITT) Analysis Set .............................................................................13 
7.1.3 
Per Protocol (PP) Analysis Set ....................................................................................13 
7.1.4 
CR at Primary Outcome Analysis Set ..........................................................................13 
7.1.5 
PK Analysis Set ...........................................................................................................13 
8 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE PROTOCOL .........14 
9 
OVERALL STATISTICAL CONSIDERATIONS ................................................................14 
9.1 
General Conventions ..........................................................................................................14 
9.2 
Reference Date ...................................................................................................................15 
9.3 
Study Day for Safety Measures .........................................................................................15 


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9.4 
Study Day for Efficacy ......................................................................................................15 
9.5 
Calculation of Duration......................................................................................................15 
9.6 
Baseline definition .............................................................................................................15 
9.7 
Handling of Missing Data ..................................................................................................16 
9.8 
Interim Analysis .................................................................................................................16 
9.9 
Pooling Strategy for Study Sites ........................................................................................16 
10 STATISTICAL ANALYSIS METHODS ..............................................................................16 
10.1 
Patient Disposition .............................................................................................................16 
10.2 
Demographics and Baseline Characteristics ......................................................................18 
10.3 
Medical History .................................................................................................................18 
10.4 
Prior and Concomitant Medications ..................................................................................18 
10.5 
Prior and Concomitant Surgical Procedures ......................................................................19 
10.6 
Analysis of Pharmacokinetics ............................................................................................19 
10.7 
Treatment Exposure ...........................................................................................................19 
10.8 
Protocol Deviations ............................................................................................................20 
10.9 
Delayed or Missed Study Visits Due to COVID-19 ..........................................................20 
11 EFFICACY PARAMETERS ..................................................................................................20 
11.1 
Primary Analysis ................................................................................................................20 
11.2 
Supportive Analysis ...........................................................................................................21 
11.3 
Secondary Analysis ............................................................................................................21 
11.3.1 
Durable Complete Response ........................................................................................21 
11.3.1.1 
Impact of COVID-19 Situation on Analysis of Durability ....................................22 
11.3.2 
Duration of Response ...................................................................................................23 
11.3.2.1 
Impact of COVID-19 Situation on DOR Analysis ................................................24 
11.3.3 
Pathological Evaluation ...............................................................................................24 
11.3.3.1 
Impact of COVID-19 on Pathological Evaluation .................................................24 
11.4 
Other Efficacy Analysis .....................................................................................................25 
11.4.1 
Disease-free Survival (DFS) ........................................................................................25 
11.4.1.1 
Impact of COVID-19 Situation on DFS Analysis .................................................25 
11.4.2 
Time to Recurrence (TTR)...........................................................................................25 
11.4.2.1 
Impact of COVID-19 Situation on TTR Analysis .................................................26 
11.5 
Exploratory Analyses .........................................................................................................26 


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24 July 2020 
 
 
 
 
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Page 4 of 46 
11.5.1 
Impact of COVID-19 on QLQ Analysis ......................................................................28 
11.6 
Interim Analysis .................................................................................................................28 
11.7 
Subgroup Analyses ............................................................................................................28 
12 SAFETY AND TOLERABILITY ..........................................................................................29 
12.1 
Adverse Events ..................................................................................................................29 
12.1.1 
General Definitions and Conventions for AEs ............................................................29 
12.1.2 
Overall Summary of AEs .............................................................................................29 
12.1.3 
Summary of AEs by SOC and PT................................................................................30 
12.1.4 
Summary of AEs by PT ...............................................................................................31 
12.1.5 
Summary of AEs by SOC, PT, and Age ......................................................................31 
12.1.6 
Summary of AEs by SOC, PT, and Sex.......................................................................31 
12.1.7 
Adverse Event of Special Interest ................................................................................31 
12.2 
Laboratory Assessments ....................................................................................................32 
12.2.1 
Impact of COVID-19 on Laboratory Assessment .......................................................33 
12.2.2 
Potentially Clinically Significant Laboratory Values ..................................................34 
12.2.3 
Abnormal Liver Function Tests ...................................................................................34 
12.3 
Vital Signs ..........................................................................................................................35 
12.3.1 
Measurements of Vital Signs .......................................................................................35 
12.3.2 
Impact of COVID-19 on Vital Signs ...........................................................................35 
12.3.3 
Potentially Clinically Significant Vital Sign Abnormalities ........................................35 
12.3.4 
Physical Examination...................................................................................................36 
12.4 
Urology-Oriented Physical Examination ...........................................................................36 
12.5 
MMC Levels (Pharmacokinetics) Profiling .......................................................................37 
13 REFERENCES .......................................................................................................................38 
14 APPENDICES ........................................................................................................................39 
 
LIST OF TABLES 
Table 1.  
Assignments for Event and Censoring Dates for DOR Analysis ..........................23 
Table 2.  
Assignments for Event and Censoring Dates for DFS Analysis ............................25 
Table 3.  
Assignments for Event and Censoring Dates for TTR Analysis ...........................26 
Table 4.  
Scoring 11 Domains of QLQ-NMIBC24 ...............................................................27 
Table 5.  
Laboratory Parameters ...........................................................................................33 
Table 6.  
PCS Laboratory Criteria ........................................................................................34 


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UroGen Pharm 
Statistical Analysis Plan: TC-BC-12 
24 July 2020 
 
 
 
 
Confidential 
Page 5 of 46 
Table 7.  
Liver Function Tests Criteria .................................................................................35 
Table 8.  
Vital Signs PCS Criteria ........................................................................................36 
Table 9.  
Physical Examination.............................................................................................36 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Activities: Screening to 3-MONTH Visit ..........................................39 
Appendix 2 
Schedule of Activities: Complete Responder at 3-MONTH Visit: Visit 8 to End of 
Study ......................................................................................................................40 
Appendix 3 
Imputation Rules for Missing or Partial Dates for AEs and Medical History .......41 
Appendix 4 
Imputation Rules for Missing or Partial Dates for Prior and Concomitant 
Medications and Surgical Procedures ....................................................................42 
Appendix 5 
Laboratory CTCAE Grade Version 5.0 Criteria ....................................................43 
Appendix 6 
QLQ – NMIBC24 ..................................................................................................45 
 
 


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Statistical Analysis Plan: TC-BC-12 
24 July 2020 
 
 
 
 
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2 SIGNATURE PAGE 
Study Title: 
A Phase 2b, Single-Arm, Multicenter Trial to Evaluate the 
Efficacy and Safety of UGN-102 as Primary Chemoablative 
Therapy in Patients with Low Grade (LG) Non-Muscle-Invasive 
Bladder Cancer (NMIBC) at Intermediate Risk of Recurrence 
Study Number: 
TC-BC-12 
  
 
Prepared by: 
 
Date:_______________ 
                    Hung Lam, PhD 
                    Principal Statistician I 
                    MMS Holdings, Inc. 
 
 
Reviewed by:  
 
Date: _______________ 
Harry Haber, MPH 
Principal Statistician I 
MMS Holdings, Inc. 
 
 
Approved by:  
 
Date: _______________ 
Soumi Lahiri, PhD 
Sr. Director, Biostatistics 
UroGen Pharm, Inc. 
 
 
Approved by:  
 
Date: _______________ 
Sunil Raju, MD 
Sr. Director, Clinical Development & Pharmacovigilance 
UroGen Pharm, Inc. 
 
 
Approved by: 
 
Date: _______________ 
Elyse Seltzer, MD 
SVP Clinical Development 
                      UroGen Pharma Inc. 
DocuSign Envelope ID: 4E472893-1B72-4C1E-9667-0A405252A60E
7/27/2020
7/27/2020
7/27/2020
7/27/2020
7/27/2020


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UroGen Pharm 
Statistical Analysis Plan: TC-BC-12 
24 July 2020 
 
 
 
 
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3 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic class 
AUC 
area under the time-concentration curve 
BMI 
body mass index 
CI 
confidence interval 
CDISC 
clinical data interchange standards consortium 
Cmax 
maximum plasma drug concentration 
COVID-19 
coronavirus disease 2019 
CR 
complete response 
CTCAE 
common terminology criteria for adverse events 
DBL 
direct bilirubin 
DBP 
diastolic blood pressure 
DCR 
durable complete response 
DFS 
disease-free survival 
DOR 
duration of CR 
eCRF 
electronic case report form 
EOS 
end of study 
HRQoL 
health related quality of life 
IP 
investigational product 
ITT 
intent-to-treat 
LFT 
liver function test 
LG 
low grade 
LLN 
lower limit of the normal range 
LOCB 
last observation carried backward 


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LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
MMC 
Mitomycin C 
NMIBC 
non-muscle-invasive bladder cancer 
PCS 
potentially clinically significant 
PK 
pharmacokinetic 
PP 
per protocol 
PT 
preferred term 
QLQ-NMIBC24 
24-item survey to assess quality of life for patients with NMIBC 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Statistical analysis system 
SBP 
systolic blood pressure 
SMQ 
standardized MedDRA queries 
SOA 
schedule of activities 
SOC 
system organ class 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
TLFs 
tables, listings, figures 
tmax 
time to maximum plasma concentration 
TTR 
time to recurrence 
ULN 
upper limit of the normal range 
 
 
 


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4 INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the framework for the reporting, 
summarization, and statistical analysis methodology of the safety and efficacy parameters 
measured throughout the study.  It is based on Protocol TC-BC-12 version 5.0 dated 15 April 
2019. 
5 TRIAL OBJECTIVES 
5.1 
Primary Objective 
To evaluate the tumor ablative effect of UGN-102 in patients with Low Grade (LG) 
Non-Muscle-Invasive Bladder Cancer (NMIBC). 
5.2 
Secondary Objectives 
 To evaluate the durability of response in patients with LG NMIBC who achieve Complete 
Response (CR) at the 3-MONTH Visit. 
 To evaluate the safety and tolerability of intravesical UGN-102 instillations in patients with 
LG NMIBC. 
5.3 
Tertiary Objective 
To assess the pharmacokinetic (PK) profile of the first Mitomycin C (MMC) instillation in 6 
patients. 
5.4 
Exploratory Objective 
To examine patient reported outcome of health-related quality of life (HRQoL) as compared to 
baseline. 
6 STUDY DESIGN CONSIDERATIONS 
6.1 
Study Design 
This study is a prospective, proof-of-concept, open-label, single-arm, multicenter Phase 2b trial 
designed to assess the efficacy and safety of UGN-102 treatment instilled in patients diagnosed 
with LG NMIBC, including newly-diagnosed patients, and determined to have intermediate risk 
of progression, defined as 1 or 2 of the following: multiple tumors, tumors >3 cm, or recurrence 
(≥1 occurrence of LG NMIBC within 1 year of the current diagnosis).  Eligible patients will be 
treated with 6 weekly instillations of UGN-102. 
Upon signing of informed consent, the patients will undergo a Screening Visit for an eligibility 
evaluation.  The screening period is 2 weeks if the patient’s cold cup biopsy to confirm LG 
tumor is historic (taken within 6 weeks of the screening visit) or 4 weeks if the patient’s cold cup 
biopsy to confirm LG tumor is current (taken at the screening visit).  


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Starting at the Baseline Visit (Day 1), eligible patients will be treated with UGN-102 once 
weekly for a total of 6 doses; the UGN-102 concentration to be used in this trial will be 1.33 mg 
MMC per 1 mL. The volume of UGN-102 to be instilled will be 56 mL (75 mg of MMC). 
The ablative effect of UGN-102 will be evaluated at the 3-month assessment, which will take 
place 5 weeks ±1 week after the last weekly instillation (3 months after initiation of treatment).  
Response will be determined based on visual evaluation by cystoscopy (appearance, number, and 
size of the lesions) and, if there are remaining lesions, by histopathology of the remaining 
lesions.  CR is defined as having no detectable disease and will be assessed visually during 
cystoscopy and also upon urine cytology.  In the event that the investigator is not sure, and there 
is suspect tissue, a small biopsy will be taken from the suspect tissue to confirm CR in addition 
to cystoscopy and urine cytology. Patients who achieve a CR will continue to have monthly 
telephone contacts to document any adverse events and changes in concomitant mediations and 
will be assessed at 6, 9, and 12 months after the first instillation of UGN-102 for evidence of 
disease recurrence.  The group of patients considered to be non-responders (non-CR) will 
discontinue the study and continue with standard of care according to their treating physician. 
Safety will be determined based on physical examination, laboratory assessments, and a review 
of adverse events (AEs) including adverse events of special interest (AESIs). All safety data will 
be reviewed on an ongoing basis, and qualified per National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE) as Grade 3 or 4. 


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6.1.1 
Study Schema 
 
LG = low grade; NMIBC = non-muscle-invasive bladder cancer 
 
Schedule of activities for Screening to the 3-MONTH Visit and for CRs at the 3-MONTH Visit: 
Visit 8 to end of study (EOS) are shown in Appendix 1 and Appendix 2, respectively. 
6.2 
Statistical Hypotheses 
No formal hypotheses will be tested. 
6.3 
Sample Size Determination 
Approximately 66 patients will enter the study, with 60 expected to complete, assuming 10% 
dropout rate. Given the patient population under study, i.e., those at intermediate risk of 
recurrence, a more conservative CR rate than previous studies of UGN-102 in the treatment of 
LG NMIBC has been assumed.  The primary objective will be successfully achieved if complete 
responses from 36 out of 60 patients with CR rate of 60% will be observed, which would yield a 
95% confidence interval of (46.5%, 72.4%) based on the exact (Clopper-Pearson) binomial 
distribution. 


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6.4 
Efficacy Measures 
There are 2 efficacy measures. The first one corresponds to primary objective. The second one 
corresponds to the secondary efficacy objective (refer to Protocol Section 5).  
1. CR rate at the 3-MONTH defined as the proportion of patients with CR at the 3-MONTH 
Visit using the ITT Analysis Set 
2. Durable CR (DCR) rate at 6, 9, and 12 months after the first instillation of UGN-102.  DCR 
rate is defined as the percentage of patients who continue to display CR at Study Visits 10, 
13, and 16, respectively, after achieving a CR at the 3-MONTH using the 3-MONTHCR 
Analysis Set. 
6.5 
Safety Measures 
The safety of intravesical UGN-102 instillations will be assessed by the following: 
 Evaluation (frequency, seriousness, and severity) of treatment emergent AEs and 
treatment-emergent AESIs. 
AESIs are defined as:  
 Overdose of an IP 
 Suspected abuse/misuse of IP 
 Inadvertent or accidental exposure to IP 
 Medication error involving IP (with or without patient/patient exposure to the 
Sponsor medicinal product 
 Identified significant safety issue either from an individual case report or review 
of aggregate data 
 Allergic reaction to MMC 
 Unexpected adverse drug reaction 
 Voiding interruption due to urethral/penile edema (unrelated to prostatic 
hypertrophy 
 Indication of bone marrow suppression 
 Lower urinary tract symptoms 
 Changes from baseline in laboratory values and incidence of measurements defined as 
potentially clinically significant (PCS) 
 Changes in physical examination findings (including urology-oriented physical 
examination) 
 Changes from baseline in vital sign values and incidence of measurements defined as 
PCS changes 
6.6 
Pharmacokinetic Parameters 
The pharmacokinetic (PK) profile of the first MMC instillation during the 6 hours following the 
first administration of UGN-102 will be based on PK sampling at 0 (pre-instillation), 0.5, 1, 2, 3, 
4, 5, and 6 hours post instillation.  PK will be performed with just 6 patients who provide 
informed consent for PK testing.  The following PK parameters will be provided:  


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 AUC0-6 – Area under the concentration-time curve from time zero to 6 hours 
post-instillation on Day 1, calculated using the linear trapezoidal rule 
 Cmax – Observed maximum plasma concentration. 
 tmax – Time to reach maximum plasma concentration. 
7 STUDY POPULATIONS 
7.1 
Analysis Populations 
7.1.1 
Intent-to-Treat (ITT) Analysis Set (Safety Analysis Set)  
The ITT analysis set (Safety analysis set), hereafter referred to as ITT analysis set, will consist of 
all patients who have been enrolled into the trial and who have received any instillation of UGN-
102 preparation.  ITT analysis set, which will include all data captured in the database for these 
patients, will serve for all efficacy and safety analyses. With respect to safety displays, a footnote 
will be added to emphasize ITT and Safety analysis sets are identical for this study. 
7.1.2 
Modified ITT (mITT) Analysis Set 
The mITT analysis set will consist of all patients who have been enrolled into the trial, who have 
a confirmed diagnosis of LG NMIBC based on the local pathology reading, who received at least 
1 instillation of UGN-102 preparation, and who have undergone the 3-MONTH Visit (since it is 
the first visit for the outcome evaluation).  This analysis set will serve as the supportive analysis 
set for the primary efficacy endpoint analysis. 
7.1.3 
Per Protocol (PP) Analysis Set 
The PP analysis set will consist of all patients who have been enrolled into the trial, who have a 
confirmed diagnosis of LG NMIBC based on the local pathology reading, who received all 6 
weekly instillations of UGN-102 preparation, have undergone the 3-MONTH Visit, and do not 
have any major protocol deviations that are deemed to affect efficacy outcomes.  This analysis 
set, which will include all data captured in the database for these patients, will serve as the 
supportive analysis set for the primary efficacy endpoint analysis. 
7.1.4 
CR at Primary Outcome Analysis Set 
The CR at 3-MONTH Visit (3-MONTHCR) analysis set will consist of all patients who achieved 
CR at the 3-MONTH Visit (Study Visit 7).  This analysis set, which will include all data 
captured in the database for these patients, will serve as the primary analysis set for the 
secondary efficacy endpoint analysis. 
7.1.5 
PK Analysis Set 
The PK analysis set will consist of all patients who consent to provide blood samples for PK 
analysis and have at least one plasma sample for evaluation of PK properties of MMC following 
an initial instillation of UGN-102.  


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8 CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE 
PROTOCOL 
1. Definition for Per Protocol analysis set is modified to exclude any patients who have any 
major protocol deviations that are deemed to affect efficacy outcomes. 
2. Analysis of CR at the 3-MONTH visit using mITT analysis set will be performed as an 
additional supportive analysis.  
3. Addition of Kaplan-Meier analysis for DOR, DFS, and TTR. Addition of sensitivity analyses 
for DOR, DFS, and TTR to address delayed or missed efficacy visits due to COVID-19. 
4. Some patients had disruptions to their visit schedules due to COVID-19 situation after 
completing their 3-MONTH visit. All missed / delayed study visits following the 3-MONTH 
Visit will be summarized. All protocol deviations due to visits outside the protocol window 
will be recorded and summarized. Appropriate changes will be made those analyses which 
are typically summarized by scheduled visits (e.g. laboratory measures, vital signs, QOL 
etc.). 
9 OVERALL STATISTICAL CONSIDERATIONS 
9.1 
General Conventions 
Data will be listed and summarized according to Clinical Data Interchange Standards 
Consortium (CDISC) standards. SAS software will be used to perform all data analyses, generate 
tables, figures, and listings. 
All measured variables and derived parameters will be listed individually and, if appropriate, 
tabulated using descriptive statistics.  For categorical variables, summary tables will be provided 
giving sample size, absolute and relative frequency, and 95% confidence interval (CI) for 
proportions using exact approach.  For continuous variables, summary tables will be provided 
giving sample size, arithmetic mean, standard deviation, coefficient of variation (if appropriate), 
median, minimum and maximum, percentiles. For variables with non-normal distribution, 
medians and interquartile range will be calculated, and the appropriate non-parametric tests will 
be applied.  
Change from baseline for a measured variable at a particular post-baseline time point will be 
computed as the value at the post-baseline time point minus the baseline value. If either the 
baseline or visit value is missing, the change from baseline is set to missing as well. 
Generally, only pre-specified planned times will be used in the summaries, statistical analyses 
and calculations of any derived parameters of safety data; unscheduled readings will be listed. 
Summaries of safety data will include data from unscheduled visits only in sections labelled 
“worst case on-therapy”.  
Percentages will be displayed with one decimal place and percentages for zero counts will be 
omitted from the presented results. 


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Day 1 will be defined as the first date on which UGN-102 was administered. Positive study days 
will be counted forward from Day 1.  Day -1 will be the date immediately preceding Day 1, and 
negative study days will be counted backward from Day 1. 
Deviations from the analyses in the SAP will be identified in the CSR. 
9.2 
Reference Date 
There are three reference dates: 
 Informed consent date will be used as a reference date for calculating age. 
 The primary efficacy endpoint reference date is the primary disease assessment at the 
3-MONTH visit, and will be used to calculate duration of CR. 
 The safety and other efficacy reference date is the treatment start date, and will be used to 
calculate study day for safety and efficacy measures.   
9.3 
Study Day for Safety Measures 
If the date of interest occurs on or after the safety reference date then the safety study day will be 
calculated as (date of interest - safety reference date) + 1.  If the date of interest occurs before the 
safety reference date then the safety study day will be calculated as (date of interest – safety 
reference date).  There is no safety study day 0.  
9.4 
Study Day for Efficacy 
Same as study day for safety measures (Section 9.3), since the safety and efficacy reference dates 
are the same for this study.  
9.5 
Calculation of Duration 
Durations (e.g. duration of adverse event, duration of response, etc.) will be calculated as stop 
date minus start date plus one. 
When reporting time to event durations (e.g., DOR, DFS, TTR) for efficacy and safety measures 
in months, divide the number of days by 30.4375; to report in weeks divide the number of days 
by 7; to report in years divide the number of days by 365.25.   
The algorithm below will be used to compute integer age accounting for the actual number of 
days in months or years between date of birth (date1) and informed consent date (date2) 
intck('year', date1, date2+1) - ( month(date2+1)<month(date1) or 
(month(date2+1)=month(daste1) and day(date2+1)<day(date1)) ) 
9.6 
Baseline definition 
Baseline will be defined as the most recent non-missing value prior to the first instillation of 
UGN-102.   


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Parameter  
Baseline Days Collected 
Baseline To Be Used 
in Analysis / 
Summaries 
Day -2 
Day -1 
Day 1 
Safety : 
 
 
 
 
Laboratory 
 
X 
 
Day -1 
Vital Signs  
 
 
X 
Day 11 
1. Use the mean of replicate assessments at any given time point as the value for 
that time point in all summaries, figures and statistical analyses. 
 
9.7 
Handling of Missing Data 
Imputation rules for partial or missing start/stop date for AEs and medical history are detailed in 
Appendix 3. Imputations done for partial or missing start/stop dates will only be used to classify 
events as treatment-emergent, while the listings will display the dates as collected on the case 
report form.  For these date imputations, an estimated study day will be determined based on the 
imputation rules and will be flagged as such in the listings. 
Imputation rules for partial or missing start/stop date for prior and concomitant medications and 
surgical procedures are detailed in Appendix 4. Imputations done for partial or missing start/stop 
dates will only be used to classify medications or surgical procedures as concomitant, while the 
listings will display the dates as collected on the case report form. 
Other than above and the specific rules for imputing missing disease assessment for durable CR 
as described in Section 11.3.1, no imputation of missing data will be performed. 
9.8 
Interim Analysis 
The purpose of the interim analysis is to obtain interim complete response (CR) and 
non-complete response data for informational purposes. The trial will not be stopped as a result 
of this analysis.  Details of the interim analysis will be described in a separate interim analysis 
plan. 
9.9 
Pooling Strategy for Study Sites 
Data will be pooled across all study sites. 
10 STATISTICAL ANALYSIS METHODS 
10.1 Patient Disposition 
The number and percentages of patients for each analysis set (ITT, mITT, PP, 3-MONTHCR, and 
PK) will be summarized.  For computing percentages, the denominator will be the number of 
patients in the ITT analysis set. 
Patient disposition will be summarized for the following study periods: 
 Screening Period: 


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The following patient disposition as recorded on the Inclusion/Exclusion Criteria and 
Enrollment eCRF will be tabulated using the number and percentages of patients: 
 Screened  
 Screen failures 
 Primary reasons for screen failure comprise failed to meet the inclusion/exclusion 
criteria, consent withdrawn, adverse event/death and other 
For computing percentages, the denominator will be the number of patients screened. 
 Treatment Period: 
The following patient disposition as recorded on the 1-6 Weeks Treatment Early Termination 
eCRF will be tabulated using the number and percentages of patients: 
 Completed treatment 
 Discontinued treatment 
 Primary reasons for discontinuation of treatment comprises adverse event, consent 
withdrawal, investigator discretion, pregnancy, noncompliance, lost to follow-up, death 
and other   
For computing percentages, the denominator will be the number of patients in the ITT 
analysis set. 
 End of Study: 
The following patient disposition as recorded on the Study Completion eCRF will be 
tabulated using the number and percentages of patients by non-CR, CR, and Total (non-CR 
and CR combined): 
 Completed study 
 Discontinued study 
 Primary reasons for discontinuation of study comprises adverse event, consent 
withdrawn, investigator discretion, pregnancy, noncompliance, lost to follow-up, death 
and other 
Non-CR completers are patients who completed the end of study at the 3-MONTH visit as 
dictated by the protocol.  CR completers are patients who completed the follow-up period or 
had recurrence at 6 or 9 months after the first instillation of UGN-102 as recorded on eCRF.  
For computing percentages, the denominator will be the number of non-CR patients, CR 
patients, and all patients in the ITT analysis set for the respective column.  
A data listing of patient disposition will be provided. 
Duration of Follow-up 
Descriptive statistics (mean, standard deviation, median, 1st and 3rd quartile, minimum, and 
maximum) for duration, expressed in months, of study follow-up computed as  
[End of study date – first dose date + 1]/30.4375.  This analysis will be based on ITT and 
3-MONTHCR analysis sets. 


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10.2 Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized using the ITT analysis set.  
Continuous variables such as age, BMI, weight, and height will be summarized using 
descriptive statistics (n, mean, standard deviation, and median, minimum, maximum). 
Categorical variables including but not limited to age group (<65, 65 to <75, ≥75 years), BMI 
category (<30 kg/m2, ≥30 kg/m2), sex, race, ethnicity, treatment course (full course - 6 
instillations, partial course <6 instillations) , tumor size (≤3 cm, >3 cm), tumor type, visual 
appearance of the lesions, and previous LG NMIBC episodes within 1 year of the current diagnosis 
(Yes, No) will be summarized using counts and percentages.  
 
10.3 Medical History 
Medical history reported terms will be coded to a SOC and PT using the most recent version of the 
Medical Dictionary for Regulatory Activities (MedDRA) dictionary version 21.0 or later.  
Number and percent of patients reporting any medical history by SOC and PT for the ITT 
analysis set will be provided.  A patient with multiple medical conditions will be counted once 
per SOC and PT.  For computing percentages, the denominator will be the number of patients 
in the ITT analysis Set.  The summary table will be sorted by descending order of frequency of 
SOC (then alphabetically for ties), then by descending order of frequency of PT within each 
SOC (then alphabetically for ties). 
10.4 Prior and Concomitant Medications 
All medications will be coded using the World Health Organization Drug Dictionary, March 1, 
2018 version or later.  The Anatomical Therapeutic Class (ATC) Level 3 and preferred name will 
be used to list and summarize the data.  Analysis of prior and concomitant medications use will 
be performed in the following manner:     
 Pre-instillation (prior) medications use: Medications that were administered prior to the 
first instillation of UGN-102, regardless if stopped after the first instillation, will be included 
for the summary of prior medications.  The number and percentage of patients reporting the 
use of prior medications by ATC Level 3 and preferred name will be summarized for the ITT 
analysis set.  For computing percentages, the denominator will be the number of patients in 
the ITT analysis set.  
 Concomitant medications use: Concomitant medications that were administered following 
the first instillation of UGN-102 through end of study regardless if concomitant medication 
initiation was before or after the first instillation will be included for the summary of 
concomitant medications.  The number and percentage of patients reporting the use of 
concomitant medications by ATC Level 3 and preferred name will be summarized for the 
ITT analysis set.  For computing percentages, the denominator will be the number of patients 
in the ITT analysis Set. 
All prior and concomitant medications will be included in a data listing. 


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10.5 Prior and Concomitant Surgical Procedures 
All surgical procedures will be coded to a SOC and PT using the most recent version of the 
MedDRA dictionary version 21.0 or later.  Prior and concomitant surgical procedures will be 
summarized similar to that described for prior and concomitant medication use in Section 10.4. 
In addition, incidence of prior TURBT interventions will be summarized.  
All prior and concomitant surgical procedures will be included in a data listing. 
10.6 Analysis of Pharmacokinetics 
The plasma concentration versus time profiles collected for MMC will be summarized using 
descriptive statistics for predose, and 0.5, 1, 2, 3, 4, 5, and 6 hours after the first instillation of 
UGN-102 for patients in the PK analysis set.  The following statistics will be calculated for 
plasma concentrations at each time point: arithmetic mean, standard deviation and coefficient of 
variation, geometric mean, minimum, median, maximum value and number of measurements.  
When calculating the descriptive statistics for the plasma concentration data, values for data 
points below the lower limit of quantitation will be set to zero.   
The pharmacokinetic PK analysis will be performed using a non-compartmental analysis to 
determine MMC Cmax, tmax, and AUC0-6, where Cmax is the observed maximum plasma 
concentration, tmax is the time Cmax occurs, and AUC0-6 is the area under the plasma 
concentration-time profile from time 0 to 6 hours after the first instillation of UGN-102.  When 
available, actual sampling and dose times, rather than scheduled times, will be used for all 
computations. 
10.7 Treatment Exposure 
Treatment exposure will be categorized as follows:   
 1 instillation of UGN-102 
 2 instillations of UGN-102 
 3 instillations of UGN-102 
 4 instillations of UGN-102 
 5 instillations of UGN-102 
 6 instillations of UGN-102 
Categorical treatment exposure will be summarized using patient counts and percentages.  For 
computing percentages, the denominator will be the number of patients in the ITT analysis set. 
Descriptive statistics of UGN-102 volume (mL) and mitomycin C dose (mg) instilled at week 1 
through week 6 will be presented for the ITT analysis set.  Mitomycin C dose in mg will be 
calculated as 1.33 mg/mL concentration of mitomycin C times volume of UGN-102 (mL) 
instilled at week 1 through week 6. 
A data listing of treatment exposure will be presented. 


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10.8 Protocol Deviations 
Reported protocol deviations will be categorized to a deviation category, either as major or 
minor; and mapped to a deviation term.  Patients having protocol deviations will be summarized 
using counts and percentages by deviation category and coded deviation term for the ITT 
analysis set.  Patients will be only counted once within each deviation category and coded 
deviation term.  For computing percentages, the denominator will be the number of patients in 
the ITT analysis set.  
Impact of COVID-19 Situation on Protocol Deviations 
Because some patients had disruptions to their visit schedules due to the COVID-19 after 
completing their 3-MONTH Visit, scheduled visits beyond the 3-MONTH Visit were delayed 
(outside the protocol window). All protocol deviations due to visits outside the protocol window 
will be recorded and summarized.  
10.9 Delayed or Missed Study Visits Due to COVID-19 
Any disruptions to study visits due to COVID 19 occurred after the 3-Month Visit. All missed / 
delayed study visits following the 3-MONTH Visit will be summarized for the 3-MONTHCR 
analysis set. Patients with missed study visit following the 3-MONTH Visit will be tabulated 
using frequency and percentages by study visit. A listing of patients reporting missed study visits 
due to COVID-19 will be presented.  
11 EFFICACY PARAMETERS 
11.1 Primary Analysis 
Assessment of CR and non-CR at the 3-MONTH Visit for patients who undergo treatment with 
intravesical UGN-102 (3 months after the first instillation of UGN-102).  CR and non-CR will be 
determined based on the following:  
 Cystoscopy 
 Biopsy of remaining lesions, if applicable 
 Voiding urine cytology 
The analysis of the primary endpoint will assess the CR rate defined as the proportion of patients 
with CR at the 3-MONTH Visit using the ITT analysis set.  A patient will be considered to have 
a CR at the 3-MONTH Visit if CR is recorded on the Evaluation of Response electronic case 
report form (eCRF).  The date of disease assessment associated to CR or non-CR will be 
determined using the date of cystoscopy, biopsy, or cytology, whichever occurs first.  If response 
cannot be evaluated for a patient at the 3-MONTH Visit, the patient will be considered as 
non-CR for the purpose of the analysis and will be included in the denominator. 
A test for binomial proportions (SAS PROC FREQ with binomial option) will be used to derive 
the exact two-sided 95% CI for the CR rate and non-CR rate using the Clopper-Pearson method. 
In addition, reasons for non-CR comprised “Indeterminate” and “Evidence of 


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Persistence/Worsening of Disease” will be tabulated using the number and percentages of 
patients.   
11.2 Supportive Analysis 
Sensitivity analyses for the primary endpoint similar to that described in Section 11.1 will be 
performed using the mITT analysis set and the PP analysis set. The results will also be displayed 
by a forest plot. 
11.3 Secondary Analysis 
11.3.1 
Durable Complete Response 
Assessment of durable CR (DCR) at 6, 9, and 12 months after the first instillation of UGN-102 
for patients who achieved CR at the 3-MONTH Visit will be based on the following: 
 Cystoscopy 
 Biopsy of remaining lesions, if applicable  
 Voiding urine cytology 
Two types of analyses will be performed to estimate the visit level durable CR rates. 
Analysis 1 
Point estimates and two-sided exact 95% binomial CIs [Clopper and Pearson 1934] for durable 
CR rates (i.e. proportion of patients who maintained CR) at 6, 9, and 12 months after the first 
instillation of UGN-102 (i.e. 3, 6, and 9 months post CR at the 3-MONTH Visit, respectively) 
will be presented. The denominator to calculate the proportion will include all patients who were 
CR at 3-month visit.  
Analysis 2 
The above analysis will be repeated using denominator with number of patients who reached at a 
follow-up visit (i.e. 3, 6, and 9 months post CR at the 3-MONTH Visit) with conclusive disease 
evaluation (i.e. either CR or recurrence). Patients who terminated the study early due to the 
reasons as per study termination page of the eCRF or patients who have indeterminate response 
(which are not confirmed by subsequent visits) will be excluded from the denominator.  
Illustrating cases of patients who would be excluded from the denominator for computing 
proportion of patients who maintained CR at months 6, 9, and 12.  
Case 
Exclusion from the denominator 
Month 6 Visit 
Month 9 Visit 
Month 12 Visit 
Patient A: discontinued due to AE 
prior to Month 9 visit 
No 
Yes 
Yes 
Patient B: had indeterminate 
response at Month 12 visit 
No 
No 
Yes 
Patient C: had recurrence response 
at Month 6 visit 
No 
No 
No 


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11.3.1.1 
Impact of COVID-19 Situation on Analysis of Durability 
Because some patients had disruptions to their visit schedules due to COVID-19 situation after 
completing their 3-MONTH Visit, scheduled visits beyond the 3-MONTH Visit were delayed 
(outside the protocol window) or missed. The CRF has been updated to record such efficacy data 
in unscheduled forms. In some cases, if the unscheduled visit was closer to the next scheduled 
visit (still outside the protocol defined window), investigator decided not to bring the patient 
until the following scheduled visits. For example, if a patient missed 6-month scheduled visit, 
had a delayed visit at 8 month, investigator may decide not to bring the patient for the 9-month 
scheduled visit, but to bring the patient in for the 12-month visit.  
The following rules will be used to impute missing or indeterminate visit level responses: 
Scheduled Visits (in Month) 
Converted Scheduled Visits (in days) 
3 months +/-2 weeks 
 Day 57 – Day 85 
6 months +/-2 weeks 
 Day 141 – Day 169  
9 months +/-2 weeks 
 Day 225 – Day 253 
12 months +/-2 weeks 
 Day 309 – Day 337 
1. If any recorded response is CR, then all previous missing or unknown scheduled visits 
responses are CR (Patient A). 
2. If any recorded response is RD, then all previous missing or unknown scheduled visits 
responses are RD (Patient B; Patient C) unless there is a previous CR response closer in time 
(days) to the scheduled visit in which case the visit response will be CR (Patient D). In the 
case of ties the scheduled visit will be RD (Patient E). 
3. Otherwise, responses will not be carried forward to scheduled visits that have not occurred 
(Patient C; Patient E) 
 
Visit  
Patient 
A 
Patient 
B 
Patient 
C 
Patient 
D 
Patient 
E 
3-MONTH Visit (Days 57- 85) 
CR 
CR 
CR 
CR 
CR 
Month 6 Visit (Days 141 -169) 
U/CR 
U/ RD 
U/RD 
CR 
CR 
Unscheduled Visit (Day 190) 
 
 
 
 
CR 
Unscheduled Visit (Day 220) 
 
 
 
CR 
 
Month 9 Visit (Days 225 – 253) 
CR 
RD 
RD 
CR 
RD 
Unscheduled Visit (Day 288) 
 
 
 
 
RD 
Unscheduled Visit (Day 300) 
 
 
RD 
 
 
Month 12 Visit (Days 309 – 337) 
 
 
 
RD 
 
RD=Recurrence disease; U=Unknown/Indeterminate; Red implicates imputed response.  


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In order to further explain ‘closer in time (days) to the scheduled visit’, the following variables 
are defined:  
a= Study day of the CR unscheduled visit 
b=Lower limit of next scheduled visit (days) 
c= Upper limit of the above scheduled visit (days) 
d= Study day of the following RD visit 
 
If (b-a) < (d-c) then the response at the scheduled visit will be CR; otherwise, RD.  
For example, Patient D has a CR response on Study Day 220, five days before the beginning of 
the Visit 9 window. This patient also has a RD response on study day 309 (say), 56 days (309-
253) after the end of the visit 9 window. Since the CR response is closer to the visit 9, the 
response will be CR. 
11.3.2 
Duration of Response 
Duration of CR (DOR) will be evaluated only for CR patients in the 3-MONTHCR analysis set.  
DOR is defined as time from the date of evidence of CR at the 3-MONTH Visit to the earliest 
date of recurrence as determined using the date of cystoscopy, biopsy, or cytology, whichever 
occurs first.  If a patient has not had an event (recurrence), DOR will be censored at the date of 
the last adequate disease assessment (i.e. assessment where visit level response is CR) or date of 
death. The rules for defining recurrence and censoring are described in Table 1.   
Table 1.  
Assignments for Event and Censoring Dates for DOR Analysis 
Situation 
Date of event/censoring 
Outcome 
Recurrence 
Date of visit when first 
recurrence was documented 
Event 
Death prior to recurrence 
Date of death 
Censored 
No disease assessment after the 
first determination of CR at 3-
Date of 3-MONTH assessment 
visit 
Censored 
Early discontinuation due to AE 
or any other reason 
Date of the last adequate 
assessment visit. 
Censored 
Response evaluation 
‘indeterminate’  
Date of last adequate 
assessment visit 
Censored  
Completed study without 
recurrence or death 
Date of last adequate 
assessment visit 
Censored 


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The distribution of DOR will be estimated using the Kaplan-Meier method. Median times to 
DOR, first and third quartiles along with 95% CI [Brookmeyer and Crowley 1982] will be 
estimated, if there are sufficient number of recurrences. A figure and listing of DOR time will 
also be provided. 
A supplementary table showing the details of the number at risk, number of events, and number 
censored with the event time will also be displayed. 
11.3.2.1 
Impact of COVID-19 Situation on DOR Analysis 
The following sensitivity analyses will be performed to address delayed visits under this 
situation. If a recurrence is observed after two or more missing disease assessments (i.e. after an 
extended period), then DOR will be censored at the last adequate assessment visit prior to 
recurrence. If a recurrence is observed after a single missing disease assessment, the actual date 
of recurrence will be used. There will be no change to rest of the event/censoring rules as defined 
in Table 1.  
Example (protocol defined schedule of disease assessments is every 3 months): A patient had 
the disease assessments at 3 months - 6 months - missing - missing - Recurrence. Then the DOR 
status of this patient will be censored and the censoring date will be the date of 6 month visit (if 
the patient had an adequate assessment at 6 month) or the date of 3 month visit (if the patient did 
not have an adequate assessment at 6 month).  
A patient will be identified as an extended loss to follow up if the patient did not have an 
adequate assessment during the time period of 196 days (6 months + 2 weeks) and then had a 
recurrence. 
The above sensitivity analysis will only be performed if there is at least one patient who is an 
extended lost to follow-up. 
11.3.3 
Pathological Evaluation 
Summary of pathological evaluation comprises number of lesions, visual appearance of the 
lesions, staging, grading, and urine cytology.  Frequency distribution of each classification by 
visit will be provided.   
11.3.3.1 
Impact of COVID-19 on Pathological Evaluation 
Because some patients had disruptions to their visit schedules due to COVID-19 situation after 
completing their 3-MONTH Visit, scheduled visits beyond the 3-MONTH Visit were delayed 
(outside the protocol window) or missed. The summary of pathological evaluation will only be 
presented at baseline, 3-MONTH, and end of study visit. 


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11.4 Other Efficacy Analysis 
11.4.1 
Disease-free Survival (DFS) 
Disease-free Survival (DFS) will be evaluated only for CR patients in the 3-MONTHCR analysis 
set. 
DFS is defined as the time from first dose to earliest date of disease recurrence as determined 
using the date of cystoscopy, biopsy, or cytology, or death from any cause, whichever occurs 
first. If a patient has not had an event (recurrence or death), DFS will be censored at the date of 
the last adequate disease assessment (i.e. assessment where visit level response is CR). The rules 
for defining event and censoring are described in Table 2. 
Table 2.  
Assignments for Event and Censoring Dates for DFS Analysis 
Situation 
Date of event/censoring 
Outcome 
Recurrence 
Date of visit when first 
recurrence was documented 
Event 
Death prior to recurrence 
Date of death 
Event 
No disease assessment after 
the first determination of CR 
Date of 3-MONTH 
assessment visit 
Censored 
Early discontinuation due to 
AE or any other reason 
Date of the last adequate 
assessment visit. 
Censored 
Response evaluation 
‘indeterminate’  
Date of last adequate 
assessment visit 
Censored  
Completed study without 
recurrence or death 
Date of last adequate 
assessment visit 
Censored 
The distribution of DFS will be estimated using the Kaplan-Meier method. Median times to DFS, 
first and third quartiles along with 95% CI [Brookmeyer and Crowley 1982] will be estimated, if 
there are sufficient number of recurrences or deaths. A figure and listing of DFS time will also be 
provided.  
A supplementary table showing the details of the number at risk, number of events, and number 
censored with the event time will also be displayed. 
11.4.1.1 
Impact of COVID-19 Situation on DFS Analysis 
A similar sensitivity analyses as of DOR will be performed by censoring extended loss to follow-
up patients. For details please see Section 11.3.2.  
11.4.2 
Time to Recurrence (TTR) 
Time to Recurrence (TTR) will be evaluated only for CR patients in the 3-MONTHCR analysis 
set. 
TTR is defined as the time from first dose to earliest date of disease recurrence as determined 
using the date of cystoscopy, biopsy, or cytology whichever occurs first. If a patient has not had 


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a recurrence, TTR will be censored at the date of the last adequate disease assessment (i.e. 
assessment where visit level response is CR). The rules for defining event and censoring are 
described in Table 3. 
Table 3.  
Assignments for Event and Censoring Dates for TTR Analysis 
Situation 
Date of event/censoring 
Outcome 
Recurrence 
Date of visit when first 
recurrence was documented 
Event 
Death prior to recurrence 
Date of death 
Censored 
Not related death 
Date of death 
Censored 
No disease assessment after 
the first determination of CR 
at 3-MONTH Visit 
Date of 3-MONTH 
assessment visit 
Censored 
Early discontinuation due to 
AE or any other reason 
Date of the last adequate 
assessment visit. 
Censored 
Response evaluation 
‘indeterminate’  
Date of last adequate 
assessment visit 
Censored  
The distribution of TTR will be estimated using the Kaplan-Meier method. Median times to 
TTR, first and third quartiles along with 95% CI [Brookmeyer and Crowley 1982] will be 
estimated, if there are sufficient number of recurrences or related deaths. A figure and listing of 
DFS time will also be provided.  
A supplementary table showing the details of the number at risk, number of events, and number 
censored with the event time will also be displayed. 
11.4.2.1 
Impact of COVID-19 Situation on TTR Analysis 
A similar sensitivity analyses as of DOR will be performed by censoring extended loss to 
follow-up patients. For details please see Section 11.3.2.  
11.5 Exploratory Analyses 
The EORTC QLQ-NMIBC24 is a self-reported 24-item NMIBC specific instrument that 
assesses 11 domains: 2 functional scales or single item (sexual function, sexual enjoyment), and 
9 symptom scales or single items (urinary symptoms, malaise, future worries, bloating and 
flatulence, male sexual problems, intravesical treatment issues, sexual intimacy, risk of 
contaminating partner, and female sexual problems). The QLQ-NMIBC24 questionnaire module 
is presented in Appendix 6. 
It will be administered at baseline/Day 1 and at 3-MONTH, 6 Month, 9 Month, and 12 Month or 
end of study visit. 
For the functional scales and symptom scales or single items, patients will be assessed as to how 
true each of the statements has been for them on a 4-point scale,  
1= not at all 


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2= a little  
3= quite a bit 
4= very much. 
For the functional scale and single item, a higher score reflects a more favorable level of 
functioning.  Conversely, symptom scales or single items a higher score represents low QoL.  
The scale score will be calculated with only those items for which all of the relevant questions 
have non-missing answers.  For example: The scale score for Urinary Symptoms can only be 
calculated if Questions 31-37 all were answered.   
All scoring information specific to the QLQ-NMIBC24 is presented in Table 4. The scoring 
method of this questionnaire will consist of a calculation of a raw score, followed by a linear 
transformation to standardize the raw score so that the scores range from 0 to 100.  Raw scores 
from the EORTC QLQ-NMIBC24 questionnaires will be transformed based on the scoring 
manual.  
Table 4.  
Scoring 11 Domains of QLQ-NMIBC24 
 
Scale 
Number 
of Items 
(n) 
Item 
Range* 
Item 
Numbers  
(I1, I2,…,In) 
Raw Score (RS) 
Symptom scales / items 
 
 
 
 
 
Urinary Symptoms 
US 
7 
3 
31- 37 
(I31 +…+ I37)/7 
Malaise 
MAL 
2 
3 
38, 39 
(I38 + I39)/2 
Intravesical treatment issues 
InV 
1 
3 
40 
I40 
Future worries 
FW 
4 
3 
41 - 44 
(I11+…+I44)/4 
Bloating and flatulence 
BAF 
2 
3 
45, 46 
(I45 + I46)/2 
Male sexual problems 
SXmen 
2 
3 
49, 50 
(I49 + I50)/2 
Sexual intimacy a 
SXI 
1 
3 
51 
I51 
Risk of contaminating partner a SXCP 
1 
3 
52 
I52 
Female sexual problems a 
SXfem 
1 
3 
54 
I54 
Functional scales / items 
 
 
 
 
 
Sexual function 
SX 
2 
3 
47, 48 
(I47 + I48)/2 
Sexual enjoyment a 
SXEN 
1 
3 
53 
I53 
* “Item range” is the difference between the possible maximum and the minimum response to 
individual items. All items are scored 1 to 4, giving range = 3. 
a Items 51 to 54 are conditional questions and must only be scored if these are applicable to the patient. 
Functional scales: Score= {1 - (RS-1)/range} × 100 
Symptom scales/items: Score= {(RS-1)/range} × 100 
Summary statistics will be provided for 11 domain scores at each assessment time for which 
there are adequate data. The change from baseline for 11 domain scores will be summarized with 
summary statistics at each assessment time for which there are adequate data. Analyses will be 
based on the ITT analysis set. A listing of the 11 domain scores values will be produced for each 
patient. 


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11.5.1 
Impact of COVID-19 on QLQ Analysis 
Scheduled visits during follow up, i.e. after the 3 month visit, were delayed or missed in some 
patients due to COVID-19. Therefore, at the time of final analysis, summary of QLQ score and 
change from baseline will be presented at baseline, 3-MONTH, End of Study visit, and 
worst-case post baseline (includes both scheduled and unscheduled assessments) as time points.   
Worst-case score for an individual scale is derived as follows: 
 For a symptom scale and single item, the worst-case score is the highest score. 
 For a functional scale and single item, the worst-case score is the highest score. 
11.6 Interim Analysis 
A separate Interim Analysis Plan was created.  The purpose of this interim analysis is to inform 
on the broader program. No decision directly related to this study was made from the results of 
this interim analysis. 
11.7 Subgroup Analyses 
The following subgroups will be explored in the analysis of key efficacy data provided 
subgroups have a minimum of 5 patients in each category, to result in meaningful analyses. 
 Age group (<75,  ≥75 years) 
 BMI category (<30 kg/m2, ≥30 kg/m2) 
 Sex (male, female) 
 Treatment course (full course - 6 instillations , partial course <6 instillations) 
 Tumor size (>3 cm, ≤3 cm) 
 Tumor (single, multiple) 
 Previous LG NMIBC episodes within 1 year of the current diagnosis (zero versus ≥ 1) 
based on Urothelial Carcinoma Medical History form. 
 In case of partial dates are reported for onset of LG NMIBC episodes, imputed 
dates based on the imputation rules described in Appendix 3 will be used. 
Number of days of previous LB NMIBC episode relative to the date of current 
diagnosis is calculated as 
DAYS = Date of current diagnosis – Date of onset of previous LB NMIBC +1. 
A previous onset of LB NMIBC occurring within a year of the current diagnosis 
when DAYS is less than 366. Date of current diagnosis is defined as the most 
recent date of LG NMIBC documented in the Urothelial Carcinoma Medical 
History form. 
The frequency and percentage of CR (primary endpoint) along with the exact 95%confidence 
interval will be presented for each of the above covariates (subgroups) using the ITT analysis set.  
The summary will also be displayed by a forest plot. 


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The frequency and percentage of durable CR (at 12 month or later) will be presented along with 
the exact 95% confidence interval for each of the above covariates (subgroups) using the 3-
MONTH CR analysis set.  The summary will also be displayed by a forest plot. 
12 SAFETY AND TOLERABILITY 
Summaries of AEs, serious adverse events (SAEs), laboratory assessments, vital signs, physical 
examination, urology-oriented physical examination, and concomitant medications will be 
presented for the ITT analysis set. ITT and Safety analysis sets are identical for this study.  
12.1 Adverse Events 
AEs will be recorded from the time a patient has signed the informed consent until end of study.  
Each verbatim AE term will be coded to a system organ class (SOC) and preferred term (PT) 
using the most recent version of the MedDRA dictionary version 21.0 or later. 
The intensity of an AE will be graded by the investigator according to CTCAE version 5.0 as 
follows: 
 Grade 1: Mild 
 Grade 2: Moderate 
 Grade 3: Severe or medically significant 
 Grade 4: Life-threatening consequences 
 Grade 5: Death related to AE (SAE) 
12.1.1 
General Definitions and Conventions for AEs 
Any AEs that occur on or after the day of first instillation of UGN-102 (Visit 1) will be defined as 
treatment-emergent AEs (TEAEs).  If the start date of an AE is incomplete or missing, the event 
will be assumed to be treatment emergent, unless the incomplete start date (month and/or year) or 
the stop date (complete or incomplete) clearly indicates that the event started before study Day 1. 
AE incidence will be presented as the number and percentage of patients with a specific AE. 
Percentages will be calculated as the number of patients with the AE divided by the number of 
patients in ITT analysis set.  
Unless otherwise specified, at each level of patient summarization (i.e. by SOC and PT), a 
patient will be counted only once. If there is more than one occurrence of an event, the event of 
the worst severity or the most causality category will be summarized. 
Summaries of AEs by SOC and PT will be sorted by descending order of frequency of SOC 
(then alphabetically for ties), then by descending order of frequency of PT within each SOC 
(then alphabetically for ties).  Summaries of AEs by PT will be sorted by descending order of 
frequency of PT, then alphabetically for ties.  
12.1.2 
Overall Summary of AEs 
An AE overview containing the number of unique patients and percentages will be provided for 
the following categories: 


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 Any AEs 
 Any serious AEs 
 Any TEAEs 
 Any study drug or procedure related TEAEs 
 Any study drug related TEAEs 
 Any procedure related TEAEs 
 Any TEAEs leading to treatment discontinuation 
 Any TEAEs leading to study discontinuation 
 Any study drug or procedure related TEAEs leading to treatment discontinuation 
 Any TEAEs by worst severity (mild, moderate, severe or medically significant, 
life-threatening, or death) 
 Any serious TEAEs 
 Any study drug or procedure related serious TEAEs 
 Any study drug related serious TEAEs 
 Any procedure related serious TEAEs 
 Any TEAEs leading to death 
 Any Treatment-emergent suspected unexpected adverse reactions (SUSAR) 
 TEAEs of special interest 
 Any Serious TEAEs by worst severity (mild, moderate, severe or medically significant, 
life-threatening, or death) 
12.1.3 
Summary of AEs by SOC and PT 
The following will be summarized by SOC and PT: 
 Incidence of TEAEs 
 Incidence of study drug or procedure related TEAEs  
 Incidence of study drug related TEAEs 
 Incidence of procedure related to TEAEs 
 Incidence of TEAEs leading to treatment discontinuation 
 Incidence of TEAEs leading to study discontinuation.  
 Incidence of study drug or procedure related to TEAEs leading to treatment 
discontinuation 
 Incidence of TEAEs by worst severity 
 Incidence of TEAEs by worst outcome 
 Incidence of Serious TEAEs 
 Incidence of study drug or procedure related serious TEAEs 
 Incidence of study drug related serious TEAEs 
 Incidence of procedure related serious TEAEs 
 Incidence of TEAEs leading to death 
 Incidence of treatment-emergent suspected unexpected adverse reactions (SUSAR) 
 Incidence of serious TEAEs by worst severity 
 Incidence of TEAEs of special interest 
 Incidence of TEAEs of special interest by worst outcome 


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Data listings of all AEs (including TEAEs and non-TEAEs), all serious AEs (including serious 
TEAEs and serious non-TEAEs), TEAE leading to treatment discontinuation, and TEAEs 
leading to death will be provided.  
12.1.4 
Summary of AEs by PT 
The following will be summarized by PT 
 Incidence of TEAEs 
 Incidence of study drug or procedure related TEAEs  
 Incidence of TEAEs leading to treatment discontinuation 
 Incidence of TEAEs by worst severity 
 Incidence of TEAEs by worst outcome 
 Incidence of Serious TEAEs 
 Incidence of study drug or procedure related serious TEAEs 
 Incidence of serious TEAEs by worst severity 
 Incidence of TEAEs of special interest 
 Incidence of TEAEs of special interest by worst outcome 
 
12.1.5 
Summary of AEs by SOC, PT, and Age  
The following will be summarized by SOC, PT, and age (<65 vs >=65): 
 Incidence of TEAEs 
 Incidence of serious TEAEs 
 
12.1.6 
Summary of AEs by SOC, PT, and Sex 
The following will be summarized by SOC, PT, and sex: 
 Incidence of TEAEs 
 Incidence of Serious TEAEs 
In addition, all deaths occurring any time from the time of informed consent to the clinical cut-
off date will be summarized based on the number and percentage of patients. This summary will 
classify patients by time of death relative to the last instillation of medication (> 30 days or  30 
days) and primary cause of death. 
 
12.1.7 
Adverse Event of Special Interest 
A comprehensive list of reported AE terms based on clinical review will be used to identify 
MedDRA PT terms for each of the AESI categories listed below. For some events several AE 
preferred terms may be ‘collapsed’. The list of terms to be used for each category of adverse 
events of interest may be based on the Safety Review Team (SRT) agreements in place at the 
time of reporting. The SRT agreements are based on a review of the MedDRA dictionary. 
The following categories of AE of special interest will be presented in table summary as 
permitted by data: 
 Overdose of an IP 


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 Suspected abuse/misuse of IP 
 Inadvertent or accidental exposure to IP 
 Medication error involving IP (with or without patient/patient exposure to the Sponsor 
medicinal product 
 Identified significant safety issue either from an individual case report or review of 
aggregate data 
 Allergic reaction to MMC  
 Voiding interruption due to urethral/penile edema (unrelated to prostatic hypertrophy) 
 Indication of bone marrow suppression 
 Lower urinary tract symptoms 
Additional AE of special interests may be identified through manual review of all AEs by PT 
prior to database lock.   
Summaries of the number and percentage of patients with these events will be provided by 
category and PT; and SOC and PT. The summary of event characteristics will also be provided, 
including number of patients with any event, number of events, number of patients with any 
event that is serious, number of patients with any event that is related to study treatment, the 
worst outcome of the event, maximum grade and the action taken for the event. The worst case 
approach will be applied at patient level for the event outcome, maximum grade and the action 
taken, i.e. a patient will only be counted once as the worst case from all the events that patient 
had. In addition, onset and duration of the first occurrences for each type of events will be 
summarized if data permits. 
Other safety analyses may be performed if deemed necessary during the data review. 
12.2 Laboratory Assessments 
Laboratory parameters of chemistry, hematology, and urinalysis will be collected at 
screening, baseline, Day 8, Day 15, Day 22, Day 29, Day 36, 3-MONTH Visit, 6 
Months, 9 Months, and at 12 Months. Laboratory results of chemistry and hematology 
will be graded according to laboratory CTCAE version 5.0 for each laboratory 
parameter defined in Appendix 5. Laboratory CTCAE grading has 5 levels (grade 0 to 
grade 4). 
Summaries of laboratory parameters will include chemistry and hematology using conventional 
units. 
A complete listing of chemistry, hematology, and urinalysis parameters is described in Table 5. 
 
 
 


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Table 5.  
Laboratory Parameters  
Chemistry 
Hematology 
Urinalysis 
Liver Function 
Tests: 
Aspartate 
aminotransferase 
Alanine 
aminotransferase 
Alkaline phosphatase 
Total bilirubin 
Direct bilirubin 
Albumin 
Total protein 
Kidney Function 
Tests: 
Creatinine 
Blood urea nitrogen 
Uric acid 
Sodium 
Potassium 
Phosphorus 
Calcium 
Bicarbonate 
Chloride 
Estimated glomerular 
filtration rate 
(calculated in 
electronic data 
capture) 
Red blood cell count 
Hemoglobin 
Hematocrit 
WBC count 
Neutrophils 
Neutrophils absolute 
Lymphocytes 
Lymphocytes absolute 
Monocytes 
Monocytes absolute 
Eosinophils 
Eosinophils absolute 
Basophils 
Basophils absolute 
Platelet count 
Mean corpuscular volume 
Mean corpuscular 
hemoglobin concentration 
Specific 
gravity 
pH 
Bilirubin 
Glucose 
Urobilinogen 
Ketones 
Blood 
Protein 
Nitrites 
Leukocyte 
Bacteriuria 
 
Patients having laboratory results that are outside the laboratory normal ranges, a complete 
laboratory test profile along with CTCAE grades and classification relative to the laboratory 
normal ranges for those patients will provided in a listing. 
12.2.1 
Impact of COVID-19 on Laboratory Assessment 
Due to some missing/delayed scheduled visits beyond the 3-MONTH Visit, at the time of final 
analysis, the summary of laboratory parameters will be presented at baseline, 3-MONTH, end of 
study, worst-case treatment-period, and worst-case post-baseline (includes both scheduled and 
unscheduled assessments) as time points.  Summaries of worst-case of observed lab values for a 
planned interval time point will be presented based on worst minimum and worst maximum lab 
values. 
Summaries of worst-case grade increase from baseline grade will be provided for all the lab tests 
that are gradable by CTCAE version 5.0. These summaries will display the number and 
percentage of subjects with a maximum post baseline grade increasing from their baseline grade. 
Any increase in grade from baseline will be summarized along with any increase to a maximum 
grade of 3 and any increase to a maximum grade of 4.  Missing baseline grade will be assumed 
as grade 0. For laboratory tests that are graded for both low and high values, summaries will be 
done separately and labeled by direction, e.g., sodium will be summarized as hyponatremia and 
hypernatremia. 
For lab tests that are not gradable by CTCAE version 5.0, summaries of worst-case changes from 
baseline with respect to normal range will be generated. Decreases to low, changes to normal or 


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no changes from baseline, and increases to high will be summarized at each planned time.  If a 
subject has a decrease to low and an increase to high during the same time interval, then the 
subject is counted in both the “Decrease to Low” categories and the “Increase to High” 
categories. 
12.2.2 
Potentially Clinically Significant Laboratory Values 
Patients with PCS laboratory values will be assessed via the incidence of patients meeting the 
PCS criteria by time point.  For computing percentages, the denominator will be the number of 
patients with a post-baseline value for the specific laboratory parameter, except for hemoglobin 
that requires patients with a baseline and a post-baseline value, and the respective time point.  
The PCS laboratory criteria are provided in Table 6. 
Table 6.  
PCS Laboratory Criteria  
Laboratory Parameter 
Conventional 
Unit 
Lower Limit 
Upper Limit 
Chemistry 
Creatinine 
mg/dL 
 
>2.2 
Sodium 
mEq/L 
≤130 
>150 
Potassium 
mEq/L 
<3.0 
>5.5 
Total bilirubin 
mg/dL 
 
>1.5 × ULN 
ALT 
U/L 
 
>3 × ULN 
AST 
U/L 
 
>3 × ULN 
GGT 
U/L 
 
>2.5 × ULN 
Hematology 
Hemoglobin 
g/dL 
<0.8 × LLN and 
>20% decrease 
from baseline 
>1.3 × ULN and 
>30% increase 
from baseline 
Leukocytes 
×103/µL 
≤ 2.8 
≥ 16.0 
Lymphocytes 
×103/µL 
<0.5   
>20 
Neutrophils 
×103/µL 
<1.0 
 
Platelets 
×103/µL 
<75 
≥700 
ALT = alanine aminotransferase; AST = aspartate aminotransferase;  
GGT = gamma-glutamyltransferase; PCS = potentially clinically significant; LLN=Lower 
limit of normal; ULN=Upper limit of normal  
12.2.3 
Abnormal Liver Function Tests 
The number and percentage of patients meeting criteria for abnormal liver function tests (LFTs) 
by time point will be summarized and listed by patient.  For computing percentages, the 
denominator will be the number of patients with a post-baseline value for the specific laboratory 


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24 July 2020 
 
 
 
 
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parameter and the respective time point.  Threshold values of interest for LFTs are provided in 
Table 7. 
Table 7.  
Liver Function Tests Criteria  
Parameter 
Criterion 
ALT 
>3×ULN; >5×ULN; >10×ULN 
AST 
>3×ULN; >5×ULN; >10×ULN 
ALT and TBL 
ALT 3×ULN and TBL >2×ULN 
AST and TBL 
AST 3×ULN and TBL >2×ULN 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; TBL = total bilirubin; ULN = upper limit 
of normal 
For a combined criterion to be fulfilled, all conditions have to be fulfilled by the same laboratory 
measurement. Only patients with newly occurring values (at least one post-baseline measurement 
and meeting the criterion but not meeting the criterion at baseline) will be counted. 
12.3 Vital Signs 
12.3.1 
Measurements of Vital Signs 
Systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse rate, respiration rate, 
temperature, and weight will be measured at baseline, Day 8, Day 15, Day 22, Day 29, Day 36, 
3-MONTH, 6 Months, 9 Months, and 12 Months/End of Study. 
12.3.2 
Impact of COVID-19 on Vital Signs 
Due to some missing/delayed scheduled visits beyond the 3-MONTH Visit, at the time of final 
analysis, the summary of vital signs will be presented at baseline, 3-MONTH, end of study, 
worst-case treatment-period, and worst-case post-baseline (includes both scheduled and 
unscheduled assessments) as time points. Summaries of worst-case of observed vital sign 
measurements for a planned interval time point will be presented based on worst minimum and 
worst maximum vital sign measurements. 
12.3.3 
Potentially Clinically Significant Vital Sign Abnormalities 
PCS criteria will be used to assess PCS vital sign abnormalities.  The incidence of patients 
meeting PCS criteria for pulse rate, SBP, and DBP at 3-MONTH, end of study, worst-case 
treatment-period, and worst-case post-baseline will be provided.  For computing percentages, the 
denominator will be the number of patients with a post-baseline value for the specific vital signs 
parameter and the respective time point.  The PCS criteria are shown in Table 8. 


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Table 8.  
Vital Signs PCS Criteria  
Parameter 
PCS Criterion 
Pulse rate 
≤50 bpm 
≤50 bpm and decrease of ≥15 bpm from Baseline 
≥120 bpm 
≥120 bpm and increase of ≥15 bpm from Baseline 
Systolic blood pressure 
≤90 mmHg 
≤90 mmHg and decrease of ≥20 mmHg from Baseline 
≥180 mmHg 
≥180 mmHg and increase of ≥20 mmHg from Baseline 
Diastolic blood pressure 
≤50 mmHg 
≤50 mmHg and decrease of ≥15 mmHg from Baseline 
≥105 mmHg 
≥105 mmHg and increase of ≥15 mmHg from Baseline 
12.3.4 
  Physical Examination 
Physical examination findings will be summarized at Baseline (Screening Visit) and at 12 
Months/End of Study.  The body system of physical examination to be summarized are listed in 
Table 9.  Each body system is assessed with the following examination findings: ‘normal’, 
‘abnormal – not clinically significant’, or ‘abnormal – clinically significant’.   
Shift tables for each body system, showing changes of examination findings from baseline to 
post-baseline.  For a specific body system, patients with both baseline and a post-baseline value 
will be included for shift summaries.  For computing percentages, the denominator will be the 
number of patients with a baseline and a post-baseline value for the specific body system. 
Table 9.  
Physical Examination  
Body System 
General appearance 
Cardiovascular system 
Respiratory system 
Head, eyes, ears, nose, throat, and neck 
Abdomen 
Extremities 
Neurologic system 
Skin 
12.4 Urology-Oriented Physical Examination 
Any clinically relevant changes occurring from Day 1 until the last trial visit will be recorded 
and summarized as part of adverse event data.  A listing of patients with abnormal 
urology-oriented physical examination findings either clinically significant or not clinically 
significant will be provided.   


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12.5 MMC Levels (Pharmacokinetics) Profiling 
The Pharmacokinetic (PK) profile of MMC during the 6 hours following the first instillation of 
UGN-102 will be based on PK sampling at 0 (pre-instillation), 0.5, 1, 2, 3, 4, 5, and 6 hours post 
instillation.  PK analysis will be performed using the PK analysis set.  Plasma concentration data, 
as well as PK parameters (Cmax, tmax, and AUC0-6) of MMC, will be provided using descriptive 
statistics. The PK parameters obtained, specifically Cmax, will be compared to the threshold of 
MMC plasma concentration (400 ng/mL) known to be associated with myelosuppression, as well 
as to the known PK profile of MMC obtained with different routes/methods of administration 
(e.g., intravesical instillation with water for injection). 
Additionally, these data, combined with data emerging from other trials, may be used in a 
population PK model development and analysis that will be described in a separate analysis plan. 
 
 


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13 REFERENCES 
BCG-Unresponsive Nonmuscle Invasive Bladder Cancer: Developing Drugs and Biologics for 
Treatment – Guidance for Industry 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM529600.pdf 
Clopper CJ and Pearson ES (1934).  The use of confidence or fiducial limits illustrated in the 
case of the binomial.  Biometrical, 26, 404-413. 
Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median Survival Time. 
Biometrics, 38, 29 - 41.    


14 APPENDICES 
Appendix 1 
Schedule of Activities: Screening to 3-MONTH Visit 
Procedures 
Screening 
Day -14 to 
Day -1 or  
Day -28 to  
Day -1§ 
Enrollment 
and Baseline 
Study Visit 1 
Day 1 
Study 
Visit 2 
Day 8 
-1/ +3 
days* 
Study 
Visit 3 
Day 15    
-1/ +3 
days* 
Study 
Visit 4 
Day 22 
-1/ +3 
days* 
Study 
Visit 5 
Day 29 
-1/ +3 
days* 
Study 
Visit 6 
 Day 36 
-1/ +3 
days* 
3-MONTH 
Study Visit 7 
5 weeks 
±1 week after last 
instillation (3 months 
post initiation)† 
Unscheduled 
Visit^ 
Informed consent 
X 
Inclusion/exclusion criteria 
X 
Demographics 
X 
Medical history 
X 
Administer study medication 
X 
X 
X 
X 
X 
X 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Directed physical examination‡ 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis# 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test 
X 
X 
Administer QlQ – NMIBC24 
 
X 
X 
X 
PK (in a subset of 6 patients) 
X 
Adverse event review 
and evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cystoscopy/urine cytology*** 
X 
X*** 
X 
Cold cup biopsy**** 
X 
CT Urogram***** 
X 
Complete eCRFs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
3-MONTH = Primary endpoint assessment; CT = computerized tomography; eCRF = electronic Case Report Form; Non-CR = nonresponder. 
§ The screening period is up to 14 days for patients that do not need a screening biopsy and up to 28 days for patients that need a screening biopsys (Refer to Section 1.0.1.1 of the protocol). 
* Windows are provided to accommodate patient logistics in scheduling. Instillations should not occur more frequently than 6 days apart. 
† Patients who discontinue before the 3-MONTH Visit or who are discontinued as Non-CR at the MONTH 3 Visit should have all assessments specified for the 3-MONTH Visit as their end-of 
study assessments. Patients discontinued as Non-CR will be managed according to best practice according to their treating physician (Refer to Section 10.2.2 of the protocol). 
^ If an unscheduled visit is required, assessments should be performed as appropriate to the needs of the visit, although safety assessments should be performed, if feasible. 
‡ Full physical examination at Screening; urology-oriented physical examination at Visits 1, 4, and 7 (Refer to Section 10.5.4: Table 5 of the protocol). 
#To include culture and sensitivity at Screening. 
** No cytology needed if results from a prior cytology within 6 weeks of screening are available) 
*** Biopsies may be needed at 3 months if any remaining lesions are visualized during cystoscopy (Refer to Sections10.2.1, 10.2.2) 
**** Cold cup biopsy performed only if not already performed within 6 weeks of screening 
***** Acceptable if performed within 6 months prior to Screening 


Appendix 2 
Schedule of Activities: Complete Responder at 3-MONTH Visit: Visit 8 to End of Study 
Procedures 
Study Visit 
8 
4 months 
post 
initiation 
±1 week 
Study Visit 
9 
5 months 
post 
initiation 
±1 week 
Study Visit 
10 
6 months 
post 
initiation 
±2 weeks 
Study Visit 
11 
7 months 
post 
initiation 
±1 week 
Study Visit 
12 
8 months 
post 
initiation 
±1 week 
Study Visit 
13 
9 months 
post 
initiation 
±2 weeks 
Study Visit 
14 
10 months 
post 
initiation 
±1 week 
Study Visit 
15 
11 months 
post 
initiation 
±1 week 
END OF 
STUDY 
Study Visit 16 
12 months 
post initiation 
±2 weeks 
Unscheduled 
Visit^ 
Concomitant medication 
review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Full physical 
examination 
  
  
  
  
  
  
X 
Vital signs 
  
  
X 
  
  
X 
  
  
X 
X 
Weight 
X 
Hematology 
  
  
X 
  
  
X 
  
  
X 
X 
Serum chemistry 
  
  
X 
  
  
X 
  
  
X 
X 
Urinalysis 
  
  
X 
  
  
X 
  
  
X 
X 
Administer  
QLQ - NMIBC24 
X 
 
 
X 
 
 
X 
X 
Adverse event review 
and evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cystoscopy/urine 
cytology§ 
X 
X 
X 
X 
Complete eCRFs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CR = Complete Response; eCRF = electronic Case Report Form. 
^ If an unscheduled visit is required, assessments should be performed as appropriate to the needs of the visit, although safety assessments should be performed, if feasible. 
§Any patient with evidence of disease recurrence post-CR will be documented as such, discontinued from the study, and should have all assessments specified for 
 the END OF STUDY Visit as their end-of-study assessments. Patients discontinued with disease recurrence will be managed according to best practice according to 
 their treating physician (Refer to Section 10.2.4 of the protocol). 
 
 
 


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Appendix 3 
Imputation Rules for Missing or Partial Dates for AEs and Medical History 
Date 
Situation 
Imputation Rule 
AE Start Date 
Only month and year are known and month 
and year are prior to first dose date  
Use the first day of the 
month 
Only month and year are known and month 
and year are the same as first dose date 
Use the first dose date 
Only month and year are known and month 
and year are after first dose date 
Use the first day of the 
month 
Only year is known and year is before first 
dose date 
Use Jan 1 of that year 
Only year is known and year is after first 
dose date 
Use Jan 1 of that year 
AE End Date 
Only month and year are known and month 
and year are prior to last dose date  
Use the last day of the 
month 
Only month and year are known and month 
and year are the same as last dose date 
Use the last dose date 
Only month and year are known and month 
and year are after last dose date 
Use the last day of the 
month 
Only year is known and year is before last 
dose date 
Use Dec 31 of that year 
The estimated stop date is before a 
complete or imputed AE start date 
Use the last day of the 
month of the AE start date 
AE = adverse event 
Note: The imputation of end date must be later than start date. 
 
 
 
 


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Appendix 4 
Imputation Rules for Missing or Partial Dates for Prior and Concomitant Medications and 
Surgical Procedures 
Imputation rules for missing or partial dates (D=day, M=month, Y=year, T=time) 
Parameter 
Missing 
Additional conditions 
Imputation Rule 
Start date  
D only 
M and Y same as M and Y of first dose of 
study drug 
Date of first dose of study drug 
M and/or Y not same as M and Y of first 
dose of study drug 
First day of month 
M and D 
Y same as Y of first dose of study drug 
Date of first dose of study drug 
Y not same as Y of first dose of study drug 
Use Jan 01 of Y 
M, D and Y 
None--date completely missing 
Date of first dose of study drug 
Stop date  
D only 
M and Y same as M and Y of last dose of 
study drug 
Date of last dose of study drug 
M and/or Y not same as M and Y of last dose 
of study drug 
Last day of month 
M and D 
Y same as Y of last dose of study drug 
Date of last dose of study drug 
Y not same as Y of last dose of study drug 
Use Dec 31 of Y 
M, D and Y 
None--date completely missing 
Date of last dose of study drug 
 
 
 


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Appendix 5 
Laboratory CTCAE Grade Version 5.0 Criteria 
Lab Parameter 
Conventional 
Unit 
CTCAE Grade v5.0 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
decreased (Anemia) 
g/dL 
≥LLN 
10 – <LLN 
8 – <10 
< 8 
 
Hemoglobin 
increased  
g/dL 
≤ULN 
>ULN – 2 + 
ULN 
>2 + ULN – 
4 + ULN 
>4 + ULN 
 
Hypoglycemia 
(Glucose decreased) 
mg/dL 
≥LLN 
55 – <LLN  
40 – <55  
30 – <40  
<30  
Glucose 
(hyperglycemia) 
mg/dL 
LLN – 
ULN 
>ULN – 
160 
>160 – 250 
>250 –500 
>500 
Albumin 
g/dL 
≥LLN 
<LLN – 3 
<3 – 2 
<2 
Life-threatening consequences; 
urgent intervention indicated 
Alkaline phosphatase 
 
≤ULN 
>ULN – 2.5 
× ULN 
>2.5 – 5.0 × 
ULN 
>5.0 – 20.0 
× ULN 
>20.0 × ULN 
Alanine 
aminotransferase 
increased 
U/L 
≤ULN 
>ULN – 
3 × ULN 
>3 × ULN – 
 5 × ULN 
>5 × ULN – 
20 × ULN 
> 20 × ULN 
Aspartate 
aminotransferase 
increased 
U/L 
≤ULN 
>ULN – 
3 × ULN 
>3 × ULN – 
 5 × ULN 
>5 × ULN – 
20 × ULN 
> 20 × ULN 
Blood bilirubin 
increased 
mg/dL 
≤ULN 
>ULN – 
1.5 × ULN 
>1.5 × ULN 
– 3 × ULN 
>3 × ULN – 
10 × ULN 
>10 × ULN 
Creatinine increased 
mg/dL 
≤ULN 
>ULN – 
1.5 × ULN 
>1.5 × ULN 
– 3 × ULN 
>3 × ULN – 
6 × ULN 
>6 × ULN 
Calcium 
(hypocalcemia) 
mg/dL 
LLN – 
ULN 
<LLN – 8.0 
<8.0 – 7.0 
<7.0 – 6.0 
<6.0 
Calcium 
(hypercalcemia) 
mg/dL 
LLN – 
ULN 
>ULN – 
11.5 
>11.5 – 12.5 
>12.5 – 
13.5 
>13.5 
Gamma-glutamyl 
transferase  increased 
U/L 
≤ULN 
>ULN – 2.5 
× ULN 
>2.5 × ULN 
– 5 × ULN 
>5 × ULN – 
20 × ULN 
> 20 × ULN 
Eosinophils increased 
×103/µL 
≤ULN 
>ULN and 
>Baseline 
 
 
 
Lymphocyte count 
decreased 
×103/µL 
≥LLN 
0.8 – < LLN 
0.5 – <0.8 
0.2 – <0.5 
<0.2 
Lymphocyte count 
increased 
×103/µL 
≤4  
 
>4 - 20 
>20 
 


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Neutrophil count 
decreased 
×103/µL 
≥LLN 
1.5 – <LLN 
1.0 – <1.5 
0.5 – <1.0 
<0.5 
Platelet count 
decreased 
×103/µL 
≥LLN 
75 – <LLN 
50 – <75 
25 – <50 
<25 
White blood cell 
decreased 
×103/µL 
≥LLN 
3.0 – <LLN 
2.0 – <3.0 
1.0 – <2.0 
<1.0 
White blood cell 
increased 
(eukocytosis) 
×103/µL 
≤100  
 
 
 
>100 
 
Hyperkalemia 
(Potassium increased) 
mEq/L 
≤ULN 
>ULN – 5.5  
>5.5 – 6.0  
>6.0 – 7.0  
>7.0  
Hypokalemia 
(Potassium decreased) 
mEq/L 
≥LLN 
3.0 – <LLN  
Symptomatic 
with 3.0 – 
 <LLN  
2.5 – <3.0  
<2.5  
Hypernatremia 
(Sodium increased) 
mEq/L 
≤ULN 
>ULN – 
150  
>150 – 155  
>155 – 160  
>160  
Hyponatremia 
(Sodium decreased) 
mEq/L 
≥LLN 
130 – <LLN   125 –  <130  
120 –  <125  <120  
Notes: ULN = upper limit of normal; LLN = lower limit of normal 
 
 
 


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24 July 2020 
 
 
 
 
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Appendix 6 
QLQ – NMIBC24 
 
Not at 
all 
A 
little 
Quite a 
bit 
Very 
much 
31. Have you had to urinate frequently during the day? 
1 
2 
3 
4 
32. Have you had to urinate frequently at night? 
1 
2 
3 
4 
33. When you felt the urge to pass urine, did you have to hurry to get to the toilet? 
1 
2 
3 
4 
34. Was it difficult for you to get enough sleep, because you needed to get up frequently at night to 
urinate? 
1 
2 
3 
4 
35. Have you had difficulty going out of the house, because you needed to be close to a toilet? 
1 
2 
3 
4 
36. Have you had any unintentional release (leakage) of urine? 
1 
2 
3 
4 
37. Have you had pain or a burning feeling when urinating? 
1 
2 
3 
4 
38. Did you have a fever? 
1 
2 
3 
4 
39. Did you feel ill or unwell? 
1 
2 
3 
4 
40. Did you have trouble arranging your life around the repeated bladder treatment 
appointments (cystoscopies or instillations)? 
1 
2 
3 
4 
41. Did you worry about having repeated bladder treatments (cystoscopies or instillations)? 
1 
2 
3 
4 
42. Were you worried about your health in the future? 
1 
2 
3 
4 
43. Did you worry about the results of examinations and tests? 
1 
2 
3 
4 
44. Did you worry about possible future treatments? 
1 
2 
3 
4 
45. Did you have a bloated feeling in your abdomen? 
1 
2 
3 
4 


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46. Have you had flatulence or gas? 
1 
2 
3 
4 
47. To what extent were you interested in sex? 
1 
2 
3 
4 
48. To what extent were you sexually active (with or without sexual intercourse)? 
1 
2 
3 
4 
49. For men only: Did you have difficulty gaining or maintaining an erection? 
1 
2 
3 
4 
50. For men only: Did you have ejaculation problems (e.g. dry ejaculation)? 
1 
2 
3 
4 
51. Have you felt uncomfortable about being sexually intimate? 
1 
2 
3 
4 
52. Have you worried that you may contaminate your partner during sexual contact with the bladder 
treatment you have been receiving? 
1 
2 
3 
4 
53. To what extent was sex enjoyable for you? 
1 
2 
3 
4 
54. For Women only: did you have a dry vagina or other problems during intercourse? 
1 
2 
3 
4