Conditions: Carcinoma, Transitional Cell Transitional Cell Carcinoma of Renal Pelvis
Keywords: TC-3 UTUC Ureteral Upper Tract Carcinoma Kidney Renal Gel Local Mitomycin C Prolonged Release Slow Release Kidney Sparing T1 T0 Low Grade Transitional Cell Carcinoma of Renal Pelvis TCC UGN-101
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 71
Healthy volunteers: no

Brief summary:
The study is investigating the ability of UroGen's UGN-101 to treat urothelial carcinoma tumors from the upper urinary tract.

Detailed description:
Trial TC-UT-03 is a prospective, open label, single-arm trial, designed to assess the efficacy, safety, and tolerability of treatment with UGN-101 instilled in the upper urinary system of patients with non-invasive low-grade (LG), Upper Tract Urothelial Carcinoma (UTUC).

Upon signing of informed consent, the patients will undergo a screening visit for eligibility evaluation. Eligible patients will be treated with UGN-101 once weekly for a total of 6 times; in a retrograde fashion. Patients who will demonstrate complete response (CR) will be treated with UGN-101 once monthly as a maintenance therapy for a total of 11 instillations or up to the first recurrence whichever comes first.

Five (5) weeks (± 1 w) following the last instillation, the Primary Disease Evaluation (PDE) Visit, during which safety and efficacy will be assessed, will take place. During this visit, the ablative effect of the UGN-101 will be assessed visually, by upper tract washed urine cytology, and if there are remaining tumors, by biopsy or brush biopsy if technically feasible.

Patient demonstrating CR at PDE will undergo monthly maintenance instillations of UGN-101 up to 11 months post PDE. Safety follow-up for these patients will be done until one month post last instillation or at the end of the follow-up period in FU visit 12, which is the earlier.

For patients who did not demonstrate Complete Response, to the extent that it is possible, all remaining tumors lesions will be biopsied. The patients shall undergo any additional surgical or other treatment the Principal Investigator (PI) decides deem necessary to remove remaining tumor.

An independent Data Monitoring Committee (DMC) was assigned to this trial. Accumulating safety, tolerability and efficacy data will be monitored periodically by the DMC according to a pre-specified process and frequency detailed in the DMC charter.

Arms:
arm 1: The Mitomycin C (MMC) concentration of UGN-101 to be used in this trial will be 4 mg MMC per 1 mL of TC-3 gel, maximum dose is 15ml. 6 once weekly intravesical instillations for the ablation treatment.

Interventions: intervention 1: UGN-101 instillations
Intervention descriptions: intervention 1: Treatment with UGN-101 once weekly for a total of 6 times; in a retrograde fashion. Patients who will demonstrate complete response (CR) will be treated with UGN-101 once monthly as a maintenance therapy for a total of 11 instillations or up to the first recurrence whichever comes first.

Protocol document:
SAP_004.pdf: 
Protocol No. TC-UT-03-P V6.0        UroGen Pharma Ltd. 
SAP 
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Template V1.8 
 
 
Statistical Analysis Plan 
UroGen Pharma Ltd.  
 
 
 
A Phase 3 Multicenter Study Evaluating the Efficacy and 
Safety of UGN-101 on 
Ablation of Upper Urinary Tract Urothelial Carcinoma 
 
 
 
Final/Amendment 1 
 
 
Final: 17 June 2019 
Amendment 1: 27 April 2020 


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Signature Page 
Written by: 
Amendment 1 Version: 
Signature: 
___________________________ 
Date: 
_______________________________ 
 
Lead Biostatistician 
  
 
Signature: 
___________________________ 
Date: 
_______________________________ 
 
Senior Reviewer 
 
 
 
Sponsor Signature: 
The undersigned hereby declare that they have examined the Statistical Analysis Plan 
document and agree to its form and content.  
Represented by: 
Signature: 
___________________________ 
Date: 
_______________________________ 
 
SVP Clinical Development 
UroGen Pharma Ltd. 
Signature: 
___________________________ 
Date: 
_______________________________ 
 
Sr. Director, Biostatistics 
UroGen Pharma Ltd. 


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Version History 
Version Number 
Date 
Revision 
1.8 
27 April 2017 
Final (Signed) 
2.0 
17 June 2019 
Final 
2.1 
27 April 2020 
Amendment 1 
 


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Table of Contents 
1 
INTRODUCTION ......................................................................................... 8 
1.1 
GENERAL ..................................................................................................... 8 
1.2 
STUDY DESIGN CONFIGURATION ........................................................... 8 
2 
CENTERS...................................................................................................... 9 
3 
STUDY OBJECTIVES ................................................................................... 9 
3.1 
SAFETY OBJECTIVE ................................................................................... 9 
3.2 
PRIMARY EFFICACY OBJECTIVE ............................................................. 9 
3.3 
KEY SECONDARY EFFICACY OBJECTIVE ................................................ 9 
3.4 
SECONDARY EFFICACY OBJECTIVES ...................................................... 9 
4 
TREATMENT GROUPS ............................................................................. 10 
5 
SAMPLE SIZE RATIONALE ...................................................................... 10 
6 
STUDY SCHEDULE ................................................................................... 11 
7 
ANALYSIS SETS ........................................................................................ 23 
7.1 
SAFETY ANALYSIS SET ........................................................................... 23 
7.2 
PHARMACOKINETIC (PK) SET .............................................................. 23 
7.3 
EFFICACY ANALYSIS SETS ...................................................................... 23 
7.3.1 
MAIN EFFICACY ANALYSIS SET ............................................................. 23 
7.3.2 
ADDITIONAL EFFICACY ANALYSIS SETS BASED ON LOCAL LAB 
OUTCOMES ............................................................................................................... 24 
7.3.3 
ADDITIONAL EFFICACY ANALYSIS SETS BASED ON CENTRAL LAB 
OUTCOMES ............................................................................................................... 26 
8 
DEFINITION OF ENDPOINTS .................................................................. 27 


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8.1 
SAFETY ENDPOINTS ................................................................................ 27 
8.2 
PHARMACOKINETIC (PK) ENDPOINTS ............................................... 27 
8.3 
PRIMARY EFFICACY ENDPOINT ............................................................ 28 
8.4 
KEY SECONDARY EFFICACY ENDPOINT .............................................. 29 
8.5 
SECONDARY EFFICACY ENDPOINT ...................................................... 30 
9 
DATA DERIVATION AND TRANSFORMATION .................................... 31 
10 
INTERIM ANALYSIS ................................................................................. 31 
11 
STATISTICAL ANALYSIS ......................................................................... 32 
11.1 
PATIENT DISPOSITION .......................................................................... 32 
11.2 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ....................... 33 
11.3 
PRE-TREATMENT MEDICATIONS ......................................................... 36 
11.4 
TREATMENT PROCEDURE ..................................................................... 37 
11.5 
EFFICACY ................................................................................................... 38 
11.5.1 PDE RESPONSE EVALUATION ............................................................... 38 
11.5.2 PRIMARY EFFICACY ANALYSIS ............................................................. 39 
11.5.3 KEY SECONDARY EFFICACY ANALYSIS ................................................ 39 
11.5.4 SECONDARY EFFICACY ANALYSIS ........................................................ 41 
11.5.5 TARGET TREATMENT AREA LESION MAPPING ................................. 42 
11.5.6 COVARIATE (SUBGROUP) ANALYSES .................................................. 42 
11.5.7 SENSITIVITY ANALYSIS .......................................................................... 44 
11.5.8 LONG-TERM EXTENDED FOLLOW-UP ................................................. 45 
11.6 
CYTOLOGY AND HISTOPATHOLOGY RESULTS .................................. 45 


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11.6.1 CYTOLOGY RESULTS ............................................................................... 45 
11.6.2 BIOPSY FOR HISTOPATHOLOGY RESULTS ......................................... 46 
11.7 
SAFETY ...................................................................................................... 47 
11.7.1 EXPOSURE ................................................................................................. 47 
11.7.2 DISPLAYS OF ADVERSE EVENTS ........................................................... 47 
11.7.3 LISTING OF DEATHS, OTHER SERIOUS AND CLINICALLY 
MEANINGFUL ADVERSE EVENTS ......................................................................... 52 
11.7.4 OTHER SAFETY DATA ............................................................................. 52 
11.8 
PK ANALYSIS ............................................................................................ 57 
12 
DATA LISTINGS ........................................................................................ 57 
13 
COMPUTER SOFTWARE ......................................................................... 58 
14 
CHANGE IN THE PLANNED ANALYSIS FROM PROTOCOL ................ 58 
15 
AMENDMENT 1 - SUMMRY OF CHANGES ................................................ 60 
 


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List of Abbreviations 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AUC 
Area Under Curve 
CBC 
Complete Blood Count 
CR 
Complete Response 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTU 
Computed Tomography-Urography  
DBP 
Diastolic Blood Pressure 
DMC 
Data Monitoring Committee  
FU 
Follow-Up 
HG 
High Grade 
HR 
Heart Rate 
ITT 
Intent-to-Treat 
LG 
Low Grade 
LOQ 
Limit of Quantitation  
mITT 
Modified Intent-to-Treat 
MMC 
Mitomycin C 
NIH 
National Institutes of Health 
PCS 
Potentially Clinically Significant 
PDE 
Primary Disease Evaluation 
PDECR 
Complete Responder at the PDE visit  
PG 
Performance Goal 
PK 
Pharmacokinetic 
PP 
Per Protocol 
RNU 
Radical Nephro-Ureterectomy  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SOC 
System Organ Class 
TCC 
Transitional Cell Carcinoma 
UPJ 
Uretero-Pelvic Junction 
URS 
Ureteroscopy  
UTUC 
Upper Tract Urothelial Carcinoma 
UUT 
Upper Urinary Tract 
VAS 
Visual Analog Scale 


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1 Introduction 
1.1 General 
Upper tract urothelial carcinomas (UTUCs) are malignant changes of the transitional 
urothelial cells lining of the upper urinary tract. The current gold standard of care for 
UTUCs patients with a normally functioning contra lateral kidney is radical nephro-
ureterectomy (RNU) with excision of bladder cuff. 
Urogen Pharma developed the investigational product for UTUCs patients that is 
presented in UGN-101 Kit comprising Mitomycin C (MMC) for injection drug 
product (the active component), and TC-3 Sterile Hydrogel. The proprietary gel (TC-
3), 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 exerts the chemical 
ablative effect. 
The main objective of this Phase III trial is to evaluate the efficacy and safety of 
UGN-101 on ablation of UTUC.  
This document is based on the protocol version V6.0 (dated 18 June 2018) and 
contains updates from the previous statistical analysis plan (SAP) signed version 
(V1.8). 
SAP Amendment is on the protocol version V6.0 (dated 18 June 2018) and includes 
revisions from the previous SAP signed version2.0 dated 17 June 2019. A summary 
of changes in SAP Amendment 1 is included in Section 15. 
1.2 Study Design Configuration 
This is a phase III, prospective, single-arm study designed to assess the efficacy, 
safety, and tolerability of treatment with UGN-101 instilled in the upper urinary 
system of patients with non-invasive low-grade, UTUC. 
Upon signing of informed consent, the patients will undergo a screening visit for 
eligibility evaluation. Eligible patients will be treated with UGN-101 once weekly for 
a total of 6 times in a retrograde fashion. Patients who demonstrate complete response 
(CR) will be treated with UGN-101 once monthly as maintenance. 
 
The primary efficacy endpoint is the rate of complete response (CR); i.e., a complete 
ablation of tumor lesions as a response to the chemotherapy treatment, which will be 
assessed during the primary disease evaluation (PDE) visit. The PDE will occur at the 


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pre-scheduled visit for endoscopic management treatment, set for 5 weeks following 
the last instillation (altogether, approximately 3 months from baseline). 
2 Centers 
This is a multicenter study, planning to include about 45-50 medical sites across the 
United States, Canada, and Israel. 
 
3 Study Objectives 
3.1 Safety Objective 
Safety objectives include: 
• Evaluation of safety and tolerability of the UGN-101 admixture in UTUC 
patients. 
• Assessment of the pharmacokinetics profile of Mitomycin C (MMC) in 
plasma of a sub-group of patients treated with UGN-101 admixture.  
3.2 Primary Efficacy Objective 
The study's primary efficacy objective is to evaluate the tumor ablative effect of 
UGN-101 admixture in the upper urinary tract (UUT) of patients with UTUC at PDE 
visit. 
3.3 Key Secondary Efficacy Objective 
The study's key secondary efficacy objective is to evaluate response durability at 12-
months follow-up for patients showing CR at PDE visit 
3.4 Secondary Efficacy Objectives 
The study's secondary efficacy objectives are 
• 
To evaluate the durability of tumor ablative effect of UGN-101 admixture in 
patients who demonstrated complete response (CR) at the Primary Disease 
Evaluation (PDE) Visit, 3, 6 and 9 months following the PDE visit.  
• 
To evaluate the overall clinical benefit to treatment with UGN-101 admixture. 
 


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4 Treatment Groups 
This is a single arm study where all eligible patients will be treated with 
investigational product - UGN-101. 
5 Sample Size Rationale 
Sample size determination was performed under the following assumptions: 
• 
The primary efficacy endpoint of the study is the Complete Response rate at the 
PDE Visit; 
• 
It is expected that the true CR rate following treatment with UGN-101 is 30% or 
more; 
• 
The primary analysis of the primary endpoint will aim to rule out a threshold rate 
of 15% using a two-tailed test for binomial proportion at two-sided Alpha = 0.05; 
i.e., 15% CR is the study’s performance goal (PG). 
Under these assumptions, a sample size of 74 evaluable patients will provide a power 
of 88.5% to demonstrate that the observed CR rate is superior to the PG of 15%. 
Assuming a lost to follow-up rate of about 10%, at total of at least 83 patients will 
participate in this study. 
 
 
 


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6 Study Schedule 
Table 1 Part I - All Patients - Up to PDE Visit 
Study Week† 
 
 
Wk 
(-)4-(-)1 
Treatment period 
 
 
Primary 
Disease 
Evaluation 
Wk 10 
(±1 w) 
Wk 0 
 
Wk 1  
(±3 d) 
Wk 2 
(±3 d) 
Wk 3  
(±3 d) 
Wk 4  
(±3 d) 
Wk 5  
(±3 d) 
Wk 6 
(±3 d) 
Wk 8 
(±3 d) 
Visit Number 
V0 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Visit Name 
Screening‡ 
Tx #1 
Tx #2 
Tx #3 
Tx #4 
Tx #5 
Tx #6 
Lab 1 
Lab 2 
PDE 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
General and Urothelial 
Carcinoma Medical 
History, Smoking 
X 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
Review 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
† Time windows for study visits: V2-V6 ±3 day; V9 ±1 week 
‡ Screening activities may be performed on separate days as long as they are completed within the screening period, before treatment starts. 


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Template V1.8 
Study Week† 
 
 
Wk 
(-)4-(-)1 
Treatment period 
 
 
Primary 
Disease 
Evaluation 
Wk 10 
(±1 w) 
Wk 0 
 
Wk 1  
(±3 d) 
Wk 2 
(±3 d) 
Wk 3  
(±3 d) 
Wk 4  
(±3 d) 
Wk 5  
(±3 d) 
Wk 6 
(±3 d) 
Wk 8 
(±3 d) 
Visit Number 
V0 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Visit Name 
Screening‡ 
Tx #1 
Tx #2 
Tx #3 
Tx #4 
Tx #5 
Tx #6 
Lab 1 
Lab 2 
PDE 
Eligibility criteria 
X 
X§ 
 
 
 
 
 
 
 
 
Full Physical Examination  
X 
 
 
 
 
 
 
 
 
X 
Urology oriented Physical 
Examination 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Vital signs♠ 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
CBC, liver and renal function, 
coagulation ** 
X 
X♣ 
X♣ 
X♣ 
X♣ 
X♣ 
X♣ 
X♣ 
coags 
not 
required 
X♣ 
coags 
not 
required 
X 
Urinalysis/dipstick 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
§ Investigator and sponsor confirmation of eligibility prior to instillation. Entry into the trial will be based on the local pathologist diagnosis. 
Tx = Treatment; d = day; Wk/w = week 
♠        Vital signs: Body temperature, blood pressure, heart rate, height and weight (screening) 
♣  
In case patient preformed all required blood test according to Appendix III up to 3 days prior to the instillation- no need to repeat; 


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Template V1.8 
Study Week† 
 
 
Wk 
(-)4-(-)1 
Treatment period 
 
 
Primary 
Disease 
Evaluation 
Wk 10 
(±1 w) 
Wk 0 
 
Wk 1  
(±3 d) 
Wk 2 
(±3 d) 
Wk 3  
(±3 d) 
Wk 4  
(±3 d) 
Wk 5  
(±3 d) 
Wk 6 
(±3 d) 
Wk 8 
(±3 d) 
Visit Number 
V0 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Visit Name 
Screening‡ 
Tx #1 
Tx #2 
Tx #3 
Tx #4 
Tx #5 
Tx #6 
Lab 1 
Lab 2 
PDE 
Urine culture 
X 
X†† 
X 
X 
X 
X 
X 
 
 
X 
CTU or MRI 
X# 
 
 
 
 
 
 
 
 
 
Biopsy for histopathology 
X§§ 
 
 
 
 
 
 
 
 
X*** 
Upper Urinary Tract 
Urine cytology-washing 
X 
 
 
 
 
 
 
 
 
X 
Pregnancy serum test ††† 
X  
X## 
X 
X 
X 
X 
X 
 
 
X 
 
††   
To be performed when UTI is suspected according to urinalysis results.  
#  
CTU to be repeated if done more than 3 months prior to first treatment. In the event that CTU is not applicable from any reason, an MRI should be performed instead 
Tx = Treatment; d = day; Wk/w = week; CBC = Complete Blood Count; CTU = Computerized Tomography (CT) Urogram; MRI = Magnetic Resonance Imaging 
§§  
Histopathology and cytology evidence of LG UTUC performed ≤2 months prior to V0 (or 3 months prior to the first instillation) is acceptable provided that the slides can be sent for central 
pathology evaluation. All Histopathology evaluations performed locally will be reviewed centrally.  
***  
Biopsy will be taken at PDE and any follow up visit when lesions are detected and recurrence is suspected. 
†††    Only for women of childbearing potential 
##       Only for women of childbearing potential and a positive pregnancy urine test 


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Template V1.8 
Study Week† 
 
 
Wk 
(-)4-(-)1 
Treatment period 
 
 
Primary 
Disease 
Evaluation 
Wk 10 
(±1 w) 
Wk 0 
 
Wk 1  
(±3 d) 
Wk 2 
(±3 d) 
Wk 3  
(±3 d) 
Wk 4  
(±3 d) 
Wk 5  
(±3 d) 
Wk 6 
(±3 d) 
Wk 8 
(±3 d) 
Visit Number 
V0 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Visit Name 
Screening‡ 
Tx #1 
Tx #2 
Tx #3 
Tx #4 
Tx #5 
Tx #6 
Lab 1 
Lab 2 
PDE 
Pregnancy urine test 
 
X  
X 
X 
X 
X 
X 
 
 
X 
Ureteroscopy (URS)+C 
arm 
X§§§ 
 
 
 
 
 
 
 
 
X 
Recording/ 
Photographing of UUT 
lesions number, size, 
appearance and location  
X 
 
 
 
 
 
 
 
 
X 
Volumetric estimation 
(retrograde pyelography 
and fluoroscopy) 3 
repetitions 
X 
 
 
 
 
 
 
 
 
 
 
§§§  URS to be repeated If done more than 2 months prior to V0, or in case it is not informative enough for the trial. In case URS cannot be performed, other method may be used for baseline 
lesion/s mapping 
Tx = Treatment; d = day; Wk/w = week 


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Template V1.8 
Study Week† 
 
 
Wk 
(-)4-(-)1 
Treatment period 
 
 
Primary 
Disease 
Evaluation 
Wk 10 
(±1 w) 
Wk 0 
 
Wk 1  
(±3 d) 
Wk 2 
(±3 d) 
Wk 3  
(±3 d) 
Wk 4  
(±3 d) 
Wk 5  
(±3 d) 
Wk 6 
(±3 d) 
Wk 8 
(±3 d) 
Visit Number 
V0 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Visit Name 
Screening‡ 
Tx #1 
Tx #2 
Tx #3 
Tx #4 
Tx #5 
Tx #6 
Lab 1 
Lab 2 
PDE 
Provide prescription for 
sodium bicarbonate, 
Prophylaxis antibiotic , 
anti- 
histaminic and 
diazepam(optional) and 
written instructions 
X 
 
 
 
 
 
 
 
 
 
Patient card, letter to GP, 
Guidance letter to patient 
X 
 
 
 
 
 
 
 
 
 
Fluoroscopy  
 
X 
X 
X 
X 
X 
X 
 
 
 
Cystoscopy for 
catheterization  
 
X 
X 
X 
X 
X 
X 
 
 
 
MitoGel™ (UGN-101) 
Admixture administration   
 
X 
X 
X 
X 
X 
X 
 
 
 
VAS for pain evaluation 
 
X 
X 
X 
X 
X 
X 
 
 
 


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Template V1.8 
Study Week† 
 
 
Wk 
(-)4-(-)1 
Treatment period 
 
 
Primary 
Disease 
Evaluation 
Wk 10 
(±1 w) 
Wk 0 
 
Wk 1  
(±3 d) 
Wk 2 
(±3 d) 
Wk 3  
(±3 d) 
Wk 4  
(±3 d) 
Wk 5  
(±3 d) 
Wk 6 
(±3 d) 
Wk 8 
(±3 d) 
Visit Number 
V0 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Visit Name 
Screening‡ 
Tx #1 
Tx #2 
Tx #3 
Tx #4 
Tx #5 
Tx #6 
Lab 1 
Lab 2 
PDE 
6 hours observation post 
treatment  
 
X 
 
 
 
 
 
 
 
 
1.3 gr × 3 of sodium 
bicarbonate (|The night before, 
morning of and 30 min  prior to 
treatment)  
 
X 
X 
X 
X 
X 
X 
 
 
 
MMC level (plasma) **** 
 
X †††† 
 
 
 
 
 
 
 
 
Phone reminder day prior 
to instillation: 
Bicarbonate, liquid 
limitation, diuretics,  
 
X 
X 
X 
X 
X 
X 
 
 
 
 
****  In 6 treated patients 
††††  Prior to instillation, 30min., 1, 2, 3, 4, 5, and 6 hours post instillation 


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Template V1.8 
Study Week† 
 
 
Wk 
(-)4-(-)1 
Treatment period 
 
 
Primary 
Disease 
Evaluation 
Wk 10 
(±1 w) 
Wk 0 
 
Wk 1  
(±3 d) 
Wk 2 
(±3 d) 
Wk 3  
(±3 d) 
Wk 4  
(±3 d) 
Wk 5  
(±3 d) 
Wk 6 
(±3 d) 
Wk 8 
(±3 d) 
Visit Number 
V0 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Visit Name 
Screening‡ 
Tx #1 
Tx #2 
Tx #3 
Tx #4 
Tx #5 
Tx #6 
Lab 1 
Lab 2 
PDE 
Supply questionnaire for 
24-32 h Post treatment 
telephone contact### 
 
X 
X 
X 
X 
X 
X 
 
 
 
24-32 h Post treatment 
telephone contact ### 
 
X 
X 
X 
X 
X 
X 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
 
 
X §§§§ 
 
 
 
 
 
 
 
###  For patients treated in retrograde fashion only 
§§§§ Review of unresolved AEs and recording of newly emerging AEs considered to be related to participation in the study 
Tx = Treatment; d = day; Wk/w = week 


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Table 2 Part II –Maintenance & Follow Up - Complete Response Patients 
Study Month***** 
Maintenance Treatment (±1 w) 
up to 
3 
Week
s post 
PDE 
 
FU1 
+3mo   
Post 
PDE 
(±2 w) 
 
 
FU2 
+6mo 
Post 
PDE 
(±2 w) 
 
 
 
FU 3 
+9mo 
Post 
PDE 
(±2 w) 
 
 
 
FU 4 
+12mo 
Post PDE 
 
 (±2 w) 
 
Visit Number 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
V19 
V20 
V21 
Visit Name 
Maint
. #1 
Maint
. #2 
Maint
. #3 
Maint
. #4 
Maint
. #5 
Maint
. #6 
Maint
. #7 
Maint
. #8 
Maint
. #9 
Maint
. #10 
Maint
. #11 
FU4 
Study 
Completion 
Urology oriented Physical 
Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC, liver and renal function, 
coagulation††††† 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
*****  Time windows for study visits V10, V12, V15, V18, V21 ±2 weeks. 
†††††  CBC, liver and renal function, coagulation tests to be performed before the instillation, see Appendix III 
Tx = Treatment; d = day; Wk/w = week; Maint = Maintenance; FU= Follow-up; CBC = Complete Blood Count 


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Template V1.8 
Study Month***** 
Maintenance Treatment (±1 w) 
up to 
3 
Week
s post 
PDE 
 
FU1 
+3mo   
Post 
PDE 
(±2 w) 
 
 
FU2 
+6mo 
Post 
PDE 
(±2 w) 
 
 
 
FU 3 
+9mo 
Post 
PDE 
(±2 w) 
 
 
 
FU 4 
+12mo 
Post PDE 
 
 (±2 w) 
 
Visit Number 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
V19 
V20 
V21 
Visit Name 
Maint
. #1 
Maint
. #2 
Maint
. #3 
Maint
. #4 
Maint
. #5 
Maint
. #6 
Maint
. #7 
Maint
. #8 
Maint
. #9 
Maint
. #10 
Maint
. #11 
FU4 
Study 
Completion 
Urinalysis/dipstick 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine culture##### 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CTU  Scan 
 
 
 
 
 
 
 
 
 
 
 
X§§§§§ 
Biopsy for histopathology****** 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Upper Urinary Tract Urine 
cytology-washing 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
##### To be performed when UTI is suspected according to urinalysis results 
§§§§§ At the 12 M FU Visit, CT scan should be obtained for all patients who continue to demonstrate CR 
****** Biopsy will be taken at PDE and any follow up visit when lesions are detected and recurrence is suspected. 


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Template V1.8 
Study Month***** 
Maintenance Treatment (±1 w) 
up to 
3 
Week
s post 
PDE 
 
FU1 
+3mo   
Post 
PDE 
(±2 w) 
 
 
FU2 
+6mo 
Post 
PDE 
(±2 w) 
 
 
 
FU 3 
+9mo 
Post 
PDE 
(±2 w) 
 
 
 
FU 4 
+12mo 
Post PDE 
 
 (±2 w) 
 
Visit Number 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
V19 
V20 
V21 
Visit Name 
Maint
. #1 
Maint
. #2 
Maint
. #3 
Maint
. #4 
Maint
. #5 
Maint
. #6 
Maint
. #7 
Maint
. #8 
Maint
. #9 
Maint
. #10 
Maint
. #11 
FU4 
Study 
Completion 
Pregnancy urine test †††††† 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy serum test ‡‡‡‡‡‡ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ureteroscopy (URS) 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Recording/Photographing of 
UUT lesions number, size, 
appearance and location 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Fluoroscopy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
††††††  Only for women of childbearing potential 
‡‡‡‡‡‡ Only for women of childbearing potential and a positive pregnancy urine test 


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Template V1.8 
Study Month***** 
Maintenance Treatment (±1 w) 
up to 
3 
Week
s post 
PDE 
 
FU1 
+3mo   
Post 
PDE 
(±2 w) 
 
 
FU2 
+6mo 
Post 
PDE 
(±2 w) 
 
 
 
FU 3 
+9mo 
Post 
PDE 
(±2 w) 
 
 
 
FU 4 
+12mo 
Post PDE 
 
 (±2 w) 
 
Visit Number 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
V19 
V20 
V21 
Visit Name 
Maint
. #1 
Maint
. #2 
Maint
. #3 
Maint
. #4 
Maint
. #5 
Maint
. #6 
Maint
. #7 
Maint
. #8 
Maint
. #9 
Maint
. #10 
Maint
. #11 
FU4 
Study 
Completion 
Cystoscopy for catheterization 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
MitoGel™ (UGN-101)Admixture 
instillation  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
1.3 g × 3 of sodium bicarbonate  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 


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Template V1.8 
Study Month***** 
Maintenance Treatment (±1 w) 
up to 
3 
Week
s post 
PDE 
 
FU1 
+3mo   
Post 
PDE 
(±2 w) 
 
 
FU2 
+6mo 
Post 
PDE 
(±2 w) 
 
 
 
FU 3 
+9mo 
Post 
PDE 
(±2 w) 
 
 
 
FU 4 
+12mo 
Post PDE 
 
 (±2 w) 
 
Visit Number 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
V19 
V20 
V21 
Visit Name 
Maint
. #1 
Maint
. #2 
Maint
. #3 
Maint
. #4 
Maint
. #5 
Maint
. #6 
Maint
. #7 
Maint
. #8 
Maint
. #9 
Maint
. #10 
Maint
. #11 
FU4 
Study 
Completion 
Phone reminder day prior to 
instillation: Bicarbonate, liquid 
limitation, diuretics 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Review of Disease Outcome and 
Complete Response Durability  
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Adverse Events /Concomitant 
Med. 
X 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
*****  Time windows for study visits V10, V12, V15, V18, V21 ±2 weeks. 


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Template V1.8 
7 Analysis Sets 
7.1 Safety Analysis Set 
The Safety analysis set will consist of all patients who enrolled in the study and 
received at least 1 instillation of UGN-101.   
Specifically, this set will include all patients for whom the Case Report Form (CRF) 
item "Was the Instillation performed" is marked as "Yes" at least once. 
7.2 Pharmacokinetic (PK) Set 
The pharmacokinetic (PK) set will consist of all patients who signed the consent for 
PK and have sufficient data for the determination of PK parameters.  
The PK data will be provided by the Sponsor as an external dataset. 
7.3 Efficacy Analysis Sets 
7.3.1 Main Efficacy Analysis Set 
7.3.1.1 Intent-to-Treat (ITT) Analysis Set  
The intent-to-treat (ITT) analysis set will consist of all patients enrolled in the study 
and have received at least one instillation of UGN-101. 
Therefore, the ITT analysis set is identical to the Safety analysis set. 
Treatment of Missing Values in ITT Analysis Set:  
ITT patients with no observed value on primary efficacy will be imputed "Failure" for 
the primary efficacy endpoint. Note that this only affects patients who dropped out 
from the study before the PDE evaluation. In other words, patients with indeterminate 
results at the PDE visit but found to be CR at subsequent visits will be considered as 
CR at PDE also and will not be imputed as “Failure” for the primary efficacy analysis 
based on the ITT analysis set. 
Note: Throughout this document, "indeterminate results" will refer to "undetermined" 
response recorded on the CRF or unavailable results. 
Treatment of missing values for the key secondary endpoint is detailed in Section 8.4. 


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Template V1.8 
7.3.2 Additional Efficacy Analysis Sets Based on Local Lab 
Outcomes 
7.3.2.1 Modified Intent-to-Treat (mITT) Analysis Set  
The modified intent-to-treat (mITT) analysis set will be a subset of the ITT analysis 
set who have a valid response evaluation at PDE and / or re-evaluation visit (i.e. 
provide a clinical result and are not indeterminate). Patients with indeterminate results 
at PDE but found to be CR at subsequent visits will be considered as CR at PDE also 
and will be included in the mITT analysis set. 
Treatment of Missing Values in mITT: Analysis Set:  
By the analysis set definition, no missing primary outcomes are possible. Thus, only 
observed primary endpoint values will be used.  
7.3.2.2 Per Protocol Analysis Set 1 (PP1) 
The Per Protocol analysis set 1 (PP1) is a subset of the mITT analysis set and will 
consist of all enrolled patients who received at least four (4) UGN-101 instillations. 
Patients who are identified as high grade (HG) by local lab at the PDE visit will be 
excluded from the PP1 analysis set. 
Treatment of Missing Values in PP1: Analysis Set:  
Only observed values will be used in PP1 analysis set; i.e. missing data will not be 
imputed. 
7.3.2.3 Per Protocol Analysis Set 2 (PP2) 
The Per Protocol analysis set 2 (PP2) is a subset of the PP1 analysis set and will 
consist of all enrolled patients who received a total of six (6) UGN-101 instillations, 
who do not have major protocol deviations that could potentially affect the study 
efficacy outcomes. The listing of major protocol deviations will be provided by the 
Sponsor prior to the database lock. 
Treatment of Missing Values in PP2 Analysis Set:  
Only observed values will be used in PP2 analysis set; i.e. missing data will not be 
imputed. 


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Template V1.8 
7.3.2.4 Complete Responder at the PDE Visit (PDECR) Analysis Set  
The complete responder at the PDE visit (PDECR) analysis set is a subset of the ITT 
analysis set  that will include all patients who are CR at the PDE visit based on the 
local laboratory evaluations (see the definition of CR at PDE in Section 8.3).  
Patients with UUT Cytology = 'Suspicious for High Grade Urothelial Carcinoma' at 
PDE visit from both local and central labs are excluded from PDECR. analysis set. 
Treatment of Missing Values in PDECR:  Analysis Set:  
The PDECR analysis set is used to analyze the durability of CR summarized as time-to 
recurrence and as recurrence incidence.  
 
Recurrence-free survival (or time to recurrence) at 12 month will be analyzed using 
Kaplan-Meier method. The censoring rule is provided in the following table: 
 
Status 
Date of censor/event 
Patients who discontinued 
prior to first follow-up visit 
after PDE evaluation 
Censored 
Date of PDE visit 
Patients who died without 
disease recurrence after 
PDE visit 
Censored 
Date of death 
Patients who had at least 
one follow-up visit and 
completed or discontinued 
without disease recurrence 
Censored 
Date of the last assessment 
Patients who recurred  
Event 
Date of recurrence 
 
Time to recurrence will be defined as date of censor or event – start study day for 
recurrence + 1. 
The start study day for time-to-recurrence is the study day (date) when patients had an 
actual CR response, i.e., the study day of the repeated evaluation for the patients with 
indeterminate results at PDE but found to be CR at repeated evaluation visit. 
 


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Template V1.8 
Recurrence incidence, which serves as a supportive efficacy analysis, will not have 
missing data imputed; i.e. only observed data will be used.  At the same time, patients 
with indeterminate results but found to be CR at subsequent visits will be considered 
as CR at the prior visits as well.  It should be noted that such cases are not considered 
imputation of missing data, as clinically their status is known (retrospectively).  
Additionally, a tipping point sensitivity analysis may be performed for each time 
point separately if indicated by the data. 
 
7.3.3 Additional Efficacy Analysis Sets Based on Central Lab 
Outcomes 
7.3.3.1 Central Modified Intent-to-Treat (Central - mITT) Analysis Set  
The central modified intent to treat (Central - mITT) analysis set is a subset of the ITT 
analysis set with confirmed LG UTUC at Screening by central lab and who have a 
PDE evaluation of response by the central lab.   
Treatment of Missing Values in Central – mITT Analysis Set:  
By the analysis set definition, no missing primary outcomes are possible. Thus, only 
observed values will be used. 
 
 


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Template V1.8 
8 Definition of Endpoints 
8.1 Safety Endpoints 
Safety endpoints will include: 
• Treatment-emergent adverse events (AEs) and serious AEs (SAEs) 
• AEs of special interest (AESIs) (see addendum of such AEs, prepared and 
appended prior to database lock) 
• Laboratory test results  
• Vital signs 
• Full physical examination and urology-oriented examination 
• Adverse events leading to discontinuation of study drug 
• Pain during the instillation procedure assessed by Visual Analog Scale (VAS) 
• Concomitant medications use 
8.2 Pharmacokinetic (PK) Endpoints 
The following PK parameters will be assessed: 
• Cmax — maximum plasma concentration 
• Tmax — time to maximum plasma concentration 
• AUC(0-t) — area under the plasma concentration-time curve from 0 to final 
time with a concentration ≥ limit of quantitation (LOQ)  
Area under the curve to the final sample with a concentration ≥ LOQ will be 
calculated using the linear trapezoidal method 
If data allows the following parameters will calculated as well: 
• λz— elimination rate constant 
The elimination rate constant, λz, will be calculated as the negative of the 
slope of the terminal log-linear segment of the plasma concentration-time 
curve. The slope will be determined from a plot of the natural log of the 
terminal plasma concentrations against time; at least 3 terminal plasma 
concentration time points, beginning with the final concentration ≥ LOQ and 
not including Cmax, will be selected for the determination of λz; the 
regression will have a coefficient of determination R² ≥ 0.9000. 
• Half-life (t½) — terminal half-life 
t½ = 0.693 / λz 


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Template V1.8 
• AUC(inf) — AUC extrapolated to infinity 
AUC(inf) = AUC(0-t) + C(last) / λz, 
 
where C(last) is the final concentration ≥ LOQ. 
 
8.3 Primary Efficacy Endpoint 
The primary efficacy endpoint is CR defined for each patient dichotomously at PDE 
visit (CRF form "Evaluation of Response (Target Area Lesions) (PDE)".  
The evaluation of response will be based on the local laboratory.  
In more details: 
• If "Evaluation of Response" at PDE visit is marked as "Complete Response" 
the CR is defined as 1 ("Success") 
• If "Evaluation of Response" at PDE visit is marked as "Partial Response" or 
"No Response" the CR is defined as 0 ("Failure") 
• If "Evaluation of Response" at PDE visit is marked as "HG Patient" 
o For ITT and mITT analysis sets, a patient is considered as non-CR 
("Failure") 
o For the per-protocol analysis sets, the patient will be excluded from the 
analysis  
• If "Evaluation of Response" at PDE visit is marked as "Undetermined" check 
the repeated evaluation (CRF form "Evaluation of Response (Target Area 
Lesions) (Repeated Evaluation)")  
o The repeated evaluation must be performed before the first 
maintenance treatment is done. If a patient was not re-evaluated before 
the first maintenance treatment or marked as “Undetermined”, the 
patient will be considered a failure (CR=0). 
Note: If re-evaluation and first maintenance are scheduled on the same 
date, the re-evaluation will always happen before the maintenance 
treatment. 
o If "Evaluation of Response" at re-evaluation visit is marked as 
"Complete Response" the CR is defined as 1 ("Success"),  
o If "Evaluation of Response" at re-evaluation visit is marked as "Partial 
Response" or "No Response" the CR is defined as 0 ("Failure") 


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Template V1.8 
o If "Evaluation of Response" at re-evaluation visit is marked as "HG 
Patient," the CR is defined dependent on the analysis set, as detailed 
above. 
o If patient response is “Undetermined” or missing at PDE visit but the 
patient arrived to a later study follow-up visit (prior to receiving any 
maintenance treatments), the response determined at that follow-up 
visit will be imputed backward to the PDE visit. 
For patients with UUT Cytology = 'Suspicious for High Grade Urothelial 
Carcinoma' from both local and central labs CR is defined as 0 ("Failure"). 
Primary endpoint will be considered missing only if a patient discontinues the 
study before achieving the PDE visit. Treatment of indeterminate results is 
addressed in Section 7. 
8.4 Key Secondary Efficacy Endpoint 
Long-term durability of CR is defined only for patients who achieved CR at PDE 
visit. Thus, long-term durability will be analyzed using PDECR analysis set.   Long-
term durability of CR will be defined in two ways: 
1. Continuously: Duration of CR or time-to recurrence since the PDE visit (i.e. 
time in days from the visit at which CR was determined until recurrence or 
censoring).  The analysis for this endpoint will serve as the primary analysis to 
assess and describe the long-term durability endpoint. 
2. Dichotomously: "Success" if CR was still present at 12 months post PDE visit 
(at follow-up visit 4), and "Failure" otherwise.  The analysis for this endpoint 
will serve as a supportive approach to describe the long-term durability 
endpoint, but will be the endpoint considered for the hypothesis testing for the 
key secondary endpoint as defined in the protocol. 
The dichotomous endpoint is defined based on the CRF form "Complete Response 
Durability Assessment".  
The evaluation of the patient for CR durability will be based on local laboratory 
results. 
Although the key secondary endpoint for recurrence incidence is defined for the 12-
month visit, the following definition for the recurrence incidence will be applied to all 
time points separately (3, 6, 9, 12 months follow-up, and all unscheduled visits). 


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Template V1.8 
• If "Complete Response Durability Assessment" at any follow-up visit is 
marked as "Urothelial carcinoma recurrence at the target area" or "Urothelial 
carcinoma progression at the target area" (at least once), all subsequent 
follow-up visits are defined as 0 ("Failure"/recurrence event). 
• If "Complete Response Durability Assessment" at any follow-up visit is 
marked as "Durable complete response at target area," all previous follow-up 
visits with missing assessment of durability of CR or indeterminate response 
are defined as CR (“Success”/no recurrence). 
• If "Complete Response Durability Assessment" at follow-up visit 4 is 
indeterminate (i.e. marked as "Undetermined" on CRF or not evaluated) check 
the repeated evaluation (unscheduled visit) 
 If "Complete Response Durability Assessment" at re-evaluation visit is 
marked as "Complete Response" (i.e. at the target area) the long-term 
durability of CR is defined as 1 ("Success"/no recurrence). 
 Otherwise, the measure is not valid; i.e. is considered missing for 
analysis. 
 
8.5 Secondary Efficacy Endpoint 
Durability of CR for each follow-up time point separately is defined in the preceding 
section. 
Clinical Benefit for Patients with Partial Response at PDE Visit 
Clinical benefit endpoint will be analyzed using the ITT analysis set including 
patients who achieved partial response at PDE visit. 
The clinical benefit endpoint is evaluated by the following: 
• Originally planned treatment (CRF form "Planned UTUC Treatment prior to 
Study (Screening)") 
• Whether the planned treatment changed (the CRF item "Has the UTUC 
treatment plan for the target lesions, above the uretero-pelvic junction (UPJ), 
changed compared to planed treatment prior to study?" 
• Actual treatment (the CRF item "If ‘Yes’, please specify current treatment 
plan"). 
 


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Template V1.8 
9 Data Derivation and Transformation 
Data not originally part of the CRF will be derived as follows: 
• Age (years) = [Date of Informed Consent – Date of Birth] / 365.25 
• BMI = Weight (kg) / Height (m)2 
• Temperature [F°] = (9/5) × Temperature [C°] + 32 
• Coding of Adverse Events will be done using MedDRA version 19.1. 
• Coding of Concomitant Medication will be done using the WHODrug 
Dictionary (version September 2016). 
• Baseline refers to the last available observation prior to initiation of treatment 
(including at the treatment 1 visit but prior to treatment) unless noted 
otherwise. 
• Severity of adverse events was coded by sites using NIH CTCAE version 
4.03. 
• Abnormal laboratory results will be coded using NIH CTCAE version 5.0. 
 
10 Interim Analysis 
An independent Data Monitoring Committee (DMC) is assigned for this study. 
Accumulated safety, tolerability, and efficacy data will be monitored periodically by 
the DMC according to the schedule and scope defined in the DMC charter. The DMC 
is established according to the FDA’s Guidance (Guidance for Clinical Trial 
Sponsors: Establishment and Operation of Clinical Trial Data Monitoring 
Committees; 2006). 
A futility analysis will be conducted after N = 20 evaluable patients have provided 
primary efficacy data. Results of the analysis will be provided to the DMC. The DMC 
will forward its recommendations following DMC meetings to the steering committee 
who will than make the final determination on study continuation. 
An interim clinical study report including efficacy and safety analysis results will be 
prepared using an early data cut-off.  At the time of this early data cut-off, all patients 
would have completed the treatment period and most would have completed the 
maintenance phase. 


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Template V1.8 
11 Statistical Analysis 
All descriptive statistics will be provided by visit (if relevant) and overall.  
Numerical variables will be tabulated using mean, standard deviation, minimum, 
median, maximum and number of observations.  Categorical variables will be 
tabulated using number of observations and percentages. Time-to variables will be 
analyzed using Kaplan-Meier method and descriptive statistics as appropriate. 
11.1 Patient Disposition 
The following will be provided:  
• Number and percentage of patients in each of the analysis sets by site and 
overall. Only sites with patients which received treatment will be included in 
this summary. That is, the table will be based on the Safety analysis set. 
Percentages will be calculated out of number of patients in Safety analysis set 
for each site. 
• Listing of enrolled patients excluded from each analysis set along with reason 
for exclusion. 
• Frequency distribution of enrolled patients excluded from each analysis set by 
reason for exclusion. 
• Frequency distribution of reason for screen failure (based on patient eligibility 
by site investigator, or on patient eligibility by the sponsor, in case that that 
patient was eligible by the investigator). 
• Summary of patient disposition table, including frequency distribution of 
screened, enrolled, treated and not treated, per-protocol study completion 
(based on study termination CRF form), ongoing within the study (i.e. all 
patients who have not completed the study termination CRF form), study early 
termination (i.e. patients who did not complete study per-protocol according to 
the study termination CRF form), treatment early termination (based on 
treatment early termination CRF form) and patients with partial maintenance 
treatment (i.e. began but not completed maintenance period; PDECR analysis 
set). 
• By-patient listing of early treatment termination, including the screening 
number, number of instillations received, time since enrollment (days) and 
reason for termination (Safety analysis set). 


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Template V1.8 
• By-patient listing of maintenance early treatment termination, including the 
screening number, number of maintenance instillations received, time since 
PDE visit (days) and reason for termination (PDECR analysis set). 
• By-patient listing of early study termination, including the screening number, 
time since enrollment (days) and reason for study termination (Safety analysis 
set). 
• By-patient listing of all protocol deviations (Safety analysis set) 
• Frequency distribution of protocol deviations by the following types: study 
eligibility, study conduct and patient management, and severity (major / 
minor). 
• By-patient listing of screen failures including reason for screen failure. 
 
11.2 Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized using the ITT analysis 
set. 
Descriptive statistics will be provided for the following: 
Demographic characteristics  
• Summary of baseline characteristics including, Age and Age groups (<65, 65-
74 and ≥75 years), Sex, Race, Height, Weight, BMI and BMI groups (≤30 and 
>30 kg/m2). 
• Number and percent of patients who are never, current or past smokers. 
 
 


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Template V1.8 
General Medical History, Prior (Past) and Concomitant Medications 
• Number and percent of patients who have any known medical conditions, by 
MedDRA V19.1 System Organ Class (SOC) and by preferred term (PT) in 
descending frequency order within each SOC. 
A patient with multiple conditions will be counted once per SOC/PT 
combination.   
• Frequency distribution of patient’s number of kidneys. 
• By-patient listing of patient’s number of kidneys. 
• By-patient listing of general medical history including patient screening 
number, reported term for the medical history, MedDRA term, SOC, Start 
Date, End Date or whether ongoing, and whether the patient received therapy 
for this medical condition.  
• Frequency distribution of concomitant medications not related to urothelial 
carcinoma (i.e. not marked as “past and concurrent urothelial carcinoma 
medical history” on the “Past and Concomitant Therapies” CRF form and with 
end date after start of treatment), by WHODrug dictionary (version September 
2016) ATC class and medication name. Summary results will be presented in 
descending order of frequency.  
• Frequency distribution of any prior or concomitant medications related to 
urothelial carcinoma medical history (irrespective of dates of start or end). 
• Frequency distribution of prior procedures and surgeries according to the same 
classifications as the previous two bullets regarding medications. 
Prior (past) and concomitant medications (as collected on the Past and Concomitant 
Therapies CRF form) will be presented in two by-patient listings: 
(1) By-patient listing of all medications where the CRF item "indication related 
to" is not answered by "Past and Concurrent Urothelial Carcinoma medical 
history, record number". 
This listing will include: Screening number, medication generic name or 
therapy, dose, start date, end date, whether ongoing, indication, and 
“indication related to". 
(2) By-patient listing of all medications where the CRF item "indication related 
to" is answered by "Past and Concurrent Urothelial Carcinoma medical 
history, record number". 


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This listing will include: Screening number, medication generic name or 
therapy, frequency, start date, end date, whether ongoing, indication, and 
urothelial carcinoma treatment. 
By-patient listing of all prior and concomitant procedures and surgeries (i.e. all non-
medication therapies collected on the Past and Concomitant Therapies CRF form).  
Past and Concurrent Urothelial Carcinoma Medical History (Screening, pre-
debulking) 
Number of Past Episodes Definition: 
If a patient has several records with the same start date (for example, one record in 
upper tract and another record in bladder), these records will be counted as a single 
episode. If there are both current and past episodes with the same start date, the 
episodes are considered as a current episode and will not be counted as a past episode. 
An episode is considered as an "Upper Urinary Tract Episode" if it has at least one 
record in the UUT. 
• Summary of past urothelial carcinoma, including frequency distribution for the 
number of any past episodes and UUT past episodes obtained per patient (not 
including the current episode). 
Number of Papillary Lesions 
• Summary of Papillary Lesions for the current upper urinary tract episode with 
at least one lesion located above UPJ, including descriptive statistics for: 
o Number of papillary lesions 
If more than 1 episode in the same location (above the UPJ or below 
the UPJ) was marked as current episode, the number of lesions, 
diameter of largest tumor and the tumor burden within the location will 
be calculated according to the largest record available for each of these 
parameters. 
o Diameter of the largest papillary tumor for the current UUT episode 
(mm) 
If more than one UUT record within the current episode exists, the 
Largest Papillary Tumor Largest Diameter is defined as the maximum 
over all reported largest diameter (located either above or below UPJ). 
o Total tumor burden of the current UUT episode (mm) 


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 For each patient, if more than one UUT record within the 
current episode exists, the tumor burden is defined as the sum 
of all tumor burdens reported in the upper urinary tract (above 
UPJ or below UPJ). 
 If at least one tumor burden in the UUT current episode (above 
UPJ or below UPJ) is missing, the total tumor burden of this 
episode will be considered missing. 
o Whether tumor is unreachable by laser 
Notes: 
(1) The total N in this table counts the number of current UUT episodes with at 
least one lesion above the UPJ.  
(2) For each patient, the number of lesions is defined as the sum of papillary 
lesions (in the current UUT episode) found above the UPJ and below the UPJ. 
Only the treated side (either left or right) will be considered in this analysis. 
The information about the treated side appears in the CRF form "Target 
Treatment Area Lesion Mapping – Information."  
(3) Bladder lesions (if any exist) will be ignored in this analysis. 
Target Treatment Area Lesion Mapping - Information  
Number of papillary lesions, Largest diameter and Tumor Burden post debulking 
procedure will also be summarized. 
ECOG & Karnofsky Scores at Screening 
• Frequency distribution of ECOG performance status. 
• Frequency distribution of Karnofsky performance status. 
11.3 Pre-Treatment Medications 
This analysis will be done using ITT and PDECR analysis sets.  
This analysis will be done separately for  
a) Main treatment period of 6 instillations 
b) Maintenance period of additional 11 instillations 
 
• Frequency distribution of patients who consume 1.3 gr bicarbonate, by 
treatment visit and time point (the compliant answer is "Yes"). 


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The table will also present the rate of patients who are 100% and at least 80% 
compliant with the pre-treatment requirement (where compliance is defined as 
taking all 3 pre-treatment doses for a given treatment).  
• Frequency distribution of patients who receive a prophylactic antibiotic (the 
compliant answer is "Yes"). 
• The table will also present the rate of patients who are 100% and at least 80% 
compliant with the pre-treatment requirement (where compliance is defined as 
taking all 3 pre-treatment doses for a given treatment).  
 
In addition, for the main treatment period by-item compliance will be defined as 
follows: 
By-item compliance: 
For each of the above items and for each patient, compliance percentage will be 
calculated as the number of doses of bicarbonate or antibiotic taken out of the total 
number of doses expected for each patient based on the number of treatments the 
patient received (i.e. out of the number of treatments among patients in the analysis 
set).   
Descriptive statistics of the compliance percentage will be presented. 
11.4 Treatment Procedure 
This analysis will be done using ITT and PDECR analysis sets.  
This analysis will be done separately for  
a) Main treatment period of 6 instillations using ITT analysis set 
b) Maintenance period of additional 11 instillations using PDECR analysis set  
 
The following will be presented: 
• Frequency distribution of mode of planned Instillation administration 
(identified based on CRF form "Pyelography and Planned Mode of 
Installation") (only for ITT analysis set) 
• Descriptive statistics of the number of instillations performed per patient 
(derived based on CRF item "Was the instillation performed" is marked as 
"Yes"). 


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Note:  Information from unscheduled visits will be included. If treatment was done 
before the date of PDE, the unscheduled visit with a visit date prior to PDE visit will 
be counted as part of the main treatment period; otherwise, it will be counted as part 
of the maintenance period.  
• Frequency distribution of the number of patients with actual volume different 
than planned. 
Note: Volume actually instilled is considered to be different if at least one 
reason for actual volume being different from the planned volume was 
fulfilled on the CRF.  
• By-patient listing of all instillations where there is a difference between the 
planned and the actual volume instilled (including number of days since first 
treatment). 
• By-patient listing of all instillations where ureteral catheter was not inserted, 
including the reason (A single J in-dwelling ureteral catheter is already 
inserted / Nephrostomy tube / Other). 
• Frequency distribution of ureteral catheter diameter used (7 Fr / 5 Fr / Other). 
Exploratory analysis evaluating the effect of catheter size and diameter may be 
performed specifically for AESIs in the renal urinary SOC (see addendum to 
SAP with list of these AEs). 
• Number and percentage of patients for whom general anesthesia was given, 
out of patients receiving treatment anytime and by visit during treatment and 
maintenance periods (separately).  
 
11.5 Efficacy 
11.5.1 PDE Response Evaluation 
Frequency distribution of patient response at PDE (or repeated evaluation) will be 
presented based on local and central laboratory results. Local laboratory results will 
be presented based on the ITT analysis set and central laboratory results will be 
presented based on the Central – mITT analysis set. 
 
 


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11.5.2 Primary Efficacy Analysis 
Primary efficacy analysis will be done using the ITT analysis set. 
The primary efficacy analysis will test the following hypotheses: 
H0: CR rate at PDE ≤ 15%  
H1: CR rate at PDE > 15%. 
Testing will be done by using an exact binomial two-sided hypothesis testing, with 
two-sided α= 0.05. (Note that this is identical to the one-sided test with α=0.025).  
Assuming the sample includes 74 evaluable patients (the sample size planned in the 
protocol) the decision rule is: Reject the null hypothesis above if the number of CRs 
in the sample is at least 18.   
If the number of evaluable patients will not be 74, the rejection area will be updated 
accordingly, using the same statistical methodology. 
The following will be presented as a part of Primary efficacy analysis: 
Number and percent of patients who are complete responders at PDE, along with 95% 
exact confidence interval, and exact binomial hypothesis testing p-value. 
A sensitivity analysis will be performed to evaluate the robustness of the primary 
efficacy results using different assumptions for handling missing values and repeating 
the primary analysis on different analysis sets. Sensitivity analysis is detailed in 
Section 11.5.7.1. 
 
11.5.3 Key Secondary Efficacy Analysis 
The key secondary endpoint, durability of CR at 12 month, will be analyzed based on 
the PDECR analysis set.  
The key secondary efficacy analysis for the dichotomous endpoint will test the 
following hypotheses using exact binomial test and PDECR analysis set: 
H0: Durable CR at 12-months ≤ 40%  
H1: Durable CR at 12-months > 40%. 
where durable CR at 12-months is defined as percentage of patients in PDECR analysis 
set who are CR at 12 months. Success for this endpoint will be declared if the lower 
bound of the exact binomial 95% confidence interval for recurrence-free rate at 12 
months is above 40%.  


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Recurrence-free survival rate at 12 month (continuous key secondary endpoint) 
defined as the probability of maintaining CR (i.e. remaining recurrence free) at 12 
month. This will be estimated using Kaplan-Meier method. The standard error and 
95% confidence interval of the estimate will be calculated using Greenwood’s 
method.  
In addition, the following will be presented: 
• Summary of events and censoring 
• Quartiles and median recurrence-free survival with the corresponding 95% 
confidence interval. 
• Kaplan-Meier survival plot 
• Life table from the Kaplan-Meier analysis, including monthly time point (0-
12), number of patients at risk, number recurred and censored patients, 
estimated survival probability along with 95% confidence intervals.   
• Descriptive statistics (mean, standard deviation, median, 1st and 3rd quartile, 
minimum, and maximum) for time (months) to recurrence computed as 
[Recurrence date – CR response date + 1]/30.4375 
 
Additional summary results: 
• Descriptive statistics (mean, standard deviation, median, 1st and 3rd quartile, 
minimum, and maximum) for duration of follow-up post PDE visit computed 
as [End of study date – CR response date + 1]/30.4375. This analysis will be 
based on PDECR analysis set. 
• Descriptive statistics (mean, standard deviation, median, 1st and 3rd quartile, 
minimum, and maximum) for duration of study follow-up computed as [End 
of study date – first dose date + 1]/30.4375.  This analysis will be based on 
ITT analysis set. 
 
The analysis using dichotomous durability of CR will include: 
• Frequency distribution of dichotomous observed long-term durability of CR, 
along with a two-sided 95% exact binomial confidence interval. 
 


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A sensitivity tipping point analysis may be performed  to evaluate the robustness of 
the dichotomous key secondary efficacy results if indicated by the data, as detailed in 
Section 11.5.7.3￼.  
11.5.4 Secondary Efficacy Analysis 
The first secondary endpoint—durability of CR at target area — will be analyzed 
using the PDECR analysis set. 
Durability of CR 
The following will be presented: 
• Frequency distribution of patient response evaluation at follow-up visits based 
on observed local and central laboratory results. If there is more than 1 
response by central laboratory within an analysis visit, the results from the 
same visit as the local laboratory analysis will be used. In other words, the 
selection of the analysis visits for the central laboratory results is based on the 
local laboratory results. 
• Frequency distribution of dichotomous durability of CR at 3, 6 and 9 months 
post PDE (FU visits 1, 2 and 3), along with 95% exact confidence interval. 
• Sensitivity tipping point analysis may be performed for dichotomous 
durability of CR for each time point separately, if indicated by the data. 
 
Clinical Benefit for Patients with Partial Response at PDE Visit 
The second secondary endpoint—Clinical Benefit—will be presented using ITT 
analysis set. 
• By-patient listing of all patients who are partial response at PDE visit 
including patient ID, site, number of instillations received within the treatment 
period, planned UTUC treatment at screening, whether this treatment was 
changed, current treatment plan (if was changed). 
• By-patient listing of the reason patients who were considered ineligible for 
endoscopic resection, included within the listing of Upper Tract Urothelial 
Carcinoma Treatments. These cases will be recorded in the Comments CRF 
form and will be filtered by the Sponsor based on investigators reports and/or 
via review of the patients’ medical records. 
 


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11.5.5 Target Treatment Area Lesion Mapping  
Target treatment area location mapping analysis will be done using ITT analysis set.  
 
Target Treatment Area Lesion Mapping - Information  
Summary of papillary lesions information, presented by visit and including the 
following (on a patient level): total number of papillary lesions, largest lesion 
diameter (mm), total tumor burden (as defined in Section 11.2). 
 
11.5.6 Covariate (Subgroup) Analyses 
These analyses will be performed to examine the effect of the following covariates on 
the primary and key secondary (continuous) endpoints. No p-values will be reported. 
i. 
For the primary endpoint the covariate analysis will be done using ITT 
analysis set. 
ii. 
For the key secondary endpoint (dichotomous and continuous) the covariate 
analysis will be performed using PDECR analysis set. 
The following covariates (subgroups) will be examined.   
• Age (years): <65, 65-74 and ≥75. 
• Gender 
• BMI (≤30 kg/m2 and >30 kg/m2) 
• Country (US/Israel) 
• Site - If many sites will include a small number of patients, the analysis will be 
done descriptively  
• Largest Diameter (pre- and post-debulking) at Screening  
Largest diameter is defined as the maximum within a patient over all 
diameters of papillary lesions reported in the CRF Urothelial Carcinoma 
Medical History CRF form (for pre-debulking) and in "Target Treatment Area 
Lesion Mapping – Information (Screening)" CRF for post-debulking. The 
largest diameter will be divided into 2 categories:  ≤ 1cm and > 1 cm. 
• Number of papillary lesions (pre- and post-debulking) at Screening 
Number of papillary lesions is defined as the total number of lesions reported 
per patient in the CRF "Target Urothelial Carcinoma Medical History CRF 
form (for pre-debulking) and for post-debulking in CRF "Target Treatment 
Area Lesion Mapping – Information (Screening)". The number of papillary 


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lesions will be divided into 2 categories:  a single lesion and more than 1 
lesion. 
• Number of previous upper urinary tract (UUT) episodes (zero versus at least 
one) based on Urothelial Carcinoma Medical History form. 
• Tumor Burden (pre- and post-debulking) at Screening 
Tumor burden is calculated per patient as the sum over all lesions largest 
diameters of papillary lesions in the CRF "Target Urothelial Carcinoma 
Medical History CRF form (for pre-debulking) and in CRF "Target Treatment 
Area Lesion Mapping – Information (Screening)" for post-debulking. If at 
least one of lesion largest diameters within a patient is missing (was not 
measurable or unknown) the tumor burden of the patient will be considered 
missing. 
Tumor burden will be divided into two levels based on sample median value. 
• Number of treatment/maintenance instillations received. 
o Number of treatments will also be divided into two categories: 6 
treatments (full per-protocol course) and less than 6 treatments (partial 
course).  
• Whether tumor is unreachable by laser (Yes / No) 
Pre-debulking observations are based on Urothelial Carcinoma Medical History CRF 
form and post-debulking observations are based on Target Treatment Area Lesion 
Mapping CRF form. 
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. 
 
Frequency and percentage of durable CR (dichotomous key secondary endpoint) will 
be presented at 12 month time point, and separately at 3, 6, and 9–month time points 
along with the exact binomial 95% confidence interval for each of the above 
covariates (subgroups) using the PDECR analysis set.  The summary for 12-month 
time point will also be displayed by a forest plot. 
 


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11.5.7 Sensitivity Analysis  
Sensitivity analysis will be performed for the primary and the key secondary 
endpoints.  
11.5.7.1 Primary Related Analysis  
The primary analysis will be repeated using different analysis sets — mITT, PP1, PP2 
and Central-mITT. No p values will be generated. The results will also be displayed 
by a forest plot.  
11.5.7.2 Primary Endpoint Missing Values Sensitivity Analysis  
For the primary analysis, patients who do not have a PDE visit (early study 
termination) for any reason, will be treated as Failures (which is the "worst case" 
imputation scenario). Sensitivity analysis will be done to examine the results if 
alternative imputation scenarios are used. Specifically, the tipping point imputation 
may be applied if indicated by the data.   
This analysis will start by imputing all missing patients (early terminations) as 
"Success" (or Complete Responders). Then, at each step, the number of imputed 
"Successes" will be reduced by one and the number of imputed "Failures" will be 
increased by 1, until the case where all missing values are imputed as "Failure" 
(which is equivalent to the primary analysis). For each imputation scenario, exact 
binomial hypothesis testing p-value and 95% confidence interval will be reported. 
The summary presentation of tipping point analysis will include the best case 
scenario, worst case scenario and the tipping point from statistically significant to 
statistically non-significant results. 
It should be noted that multiple imputation will not be performed as in the case of a 
binary endpoint tipping point analysis addresses all possible scenarios.  
11.5.7.3   Dichotomous Key Secondary Endpoint Missing Values Sensitivity 
Analysis  
For the dichotomous key secondary analysis, patients who did not complete the last 
FU visit and have no prior recurrence are not imputed.  A sensitivity analysis will be 
done to examine the robustness of results if alternative imputation scenarios are used. 
Specifically, the tipping point imputation may be applied if indicated by the data.  


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This analysis will start by imputing all missing patients (early terminations) as 
"Success" (or CR). Then, at each step, the number of imputed "Success" will be 
reduced by one and the number of imputed "Failure" will be increased by 1, until the 
case where all missing values are imputed as "Failure" (which is equivalent to the 
primary analysis). For each imputation scenario, exact binomial hypothesis testing p-
value and 95% confidence interval will be reported. 
The summary presentation of tipping point analysis will include the best case 
scenario, worst case scenario and the tipping point from statistically significant to 
statistically non-significant results. 
 
11.5.8 Long-Term Extended Follow-Up  
Following the FDA request, patients with CR at PDE will be followed-up beyond the 
initial 12 months planned in the protocol for data of bladder urothelial carcinoma 
occurrence/recurrence and upper tract urothelial carcinoma recurrence, progression, 
and occurrence of invasive disease and radical nephroureterectomy. These data will 
be presented and summarized descriptively. 
 
11.6 Cytology and Histopathology Results 
11.6.1 Cytology Results 
CRF form "UUT Cytology- Local Lab Results (Screening / PDE / FU / unscheduled)" 
• Frequency distribution of the classification tool used in local laboratory, by visit. 
(Paris Classification (New), Bethesda Classification (Older), Other) 
• Frequency distribution of diagnosis, by visit 
Note that the two tools will be combined into a single output. The combination is 
done based on the following: 


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Table 3 Cytology Paris and Bethesda Classifications Combined Results 
Combined cytology results 
According to on Paris 
Classification 
According to 
Bethesda 
Classification 
Non-
diagnostic/Unsatisfactory 
Non-
diagnostic/Unsatisfactory 
 
Negative for High Grade 
Urothelial Carcinoma 
(NHGUC) or Epithelial cell 
abnormality 
Negative for High Grade 
Urothelial Carcinoma 
(NHGUC) 
Negative for 
epithelial cell 
abnormality 
Atypical Urothelial Cells  
Atypical Urothelial Cells 
(AUC) 
Atypical urothelial 
cells 
Suspicious for High Grade 
Urothelial Carcinoma 
(SHGUC) 
Suspicious for High Grade 
Urothelial Carcinoma 
(SHGUC) 
 
High Grade Urothelial 
Carcinoma (HGUC) 
High Grade Urothelial 
Carcinoma (HGUC) 
High-grade 
urothelial 
carcinoma 
Low Grade Urothelial 
Neoplasm (LGUN) 
Low Grade Urothelial 
Neoplasm (LGUN) 
Low-grade 
urothelial 
carcinoma 
Other/ Adenocarcinoma 
Other: Primary and 
secondary malignancies and 
Miscellaneous lesions 
1) Other, Any 
molecular Findings 
+ 2) 
Adenocarcinoma 
 
CRF form "UUT Cytology- Central Lab Results (Screening / PDE / FU)" 
• Frequency distribution of test results, by visit   
Local versus Central Diagnosis 
• By-patient listing of discrepancies between local and central diagnosis results and 
patient response based on local and central laboratory (ITT analysis set) 
 
11.6.2 Biopsy for Histopathology Results 
Biopsy for Histopathology- Local laboratory results (Screening / PDE / FU) 
• Frequency distribution of Histology Results, by visit  
If more than one option is chosen it will be defined as a separate category. 
Biopsy for Histopathology- Central laboratory results (Screening / PDE / FU) 
• Frequency distribution of Histology Results, by visit 
If more than one option is chosen it will be defined as a separate category 
Local versus Central Diagnosis 
• By-patient listing of discrepancies between local and central diagnosis results and 
patient response based on local and central laboratory (ITT analysis set) 


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11.7 Safety 
All safety analyses will be performed on the safety analysis set. 
The following will be provided:  
11.7.1 Exposure 
• Descriptive statistics of the volume (mL) of UGN-101 and Mitomycin to be 
instilled (auto-calculated in the CRF at Screening) (CRF form "Pyelography 
and Planned Mode of Installation"), or actually calculated and instilled at other 
visits. The table will also include the total UGN-101 volume instilled (per 
patient) over the course of participation (treatment and maintenance), to 
address the drug exposure.  
• Frequency distribution for the number of treatment and maintenance 
instillations performed. 
• Descriptive statistics for the length of exposure to study treatment (days) from 
the first instillation received. 
11.7.2 Displays of Adverse Events 
Summary of Adverse Events (AEs), including the incidence of all AEs, treatment 
emergent AEs, serious AEs (SAEs), serious adverse reactions (SAR; i.e. SAEs 
that are possibly, probably or definitely related to study drug), suspected 
unexpected serious adverse reaction (SUSAR) as determined based on Sponsor 
SAE reporting where event was both related and unexpected (expected AEs are 
listed in the Investigator’s Brochure), AEs leading to treatment discontinuation, 
study drug or procedure related AEs leading to treatment discontinuation, AEs 
leading to death, drug related AEs, procedure related AEs, procedure related 
SAEs, drug or procedure related AEs, drug or procedure related SAEs. 
 
AEs leading to treatment discontinuation are considered as such when the action 
taken is marked as ‘drug permanently discontinued’ or was marked as terminated 
from treatment due to this AE.  An AE is considered related to study drug or study 
procedure when indicated in CRF to be possibly, probably or definitely related.  
Treatment emergent AEs are those occurring on or after the first day of study 
treatment.  AEs with missing start date (both month and year) will be considered 
treatment emergent, unless the non-missing year indicates prior year before the 


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first dose date.  Partial AE start dates (i.e., missing day) will be imputed as the 1st 
of the month. Partial AE end dates (i.e., missing day) will be imputed as the end of 
the month. 
All Adverse Events 
Tables specified below will be presented by:  
(1) MedDRA V19.1 System Organ Class (SOC) and preferred term (PT) 
(2) MedDRA V19.1 PT 
• Incidence of patients with treatment emergent adverse events by maximal 
severity. The table will be presented in the descending frequency order.  
• Incidence of patients with treatment emergent adverse events by maximal 
relationship to study drug or procedure. The table will be presented in the 
descending frequency order.  
• Incidence of patients with treatment emergent adverse events by maximal 
relationship to study drug. The table will be presented in the descending 
frequency order.  
• Incidence of patients with treatment emergent adverse events by maximal 
relationship to study procedure. The table will be presented in the descending 
frequency order.  
• Incidence of patients with all grade and grade 3 or 4 adverse events. 
• Summary of adverse events reported in >=10% (any grade) or >=5% (grade 
3/4) of patients. 
• Descriptive statistics of time to first AE leading to treatment interruption 
(temporary discontinuation) or treatment discontinuation (permanent 
discontinuation), as well as time to any treatment interruption and days from 
last treatment prior to the onset of the treatment discontinuation or any dose 
interruption (per event). 
• Incidence of patients with treatment emergent adverse events leading to 
treatment discontinuation. The table will be presented in the descending 
frequency order. 
• Incidence of patients with treatment emergent adverse events leading to death. 
The table will be presented in the descending frequency order. 
• Number and percentage of patients with at least one AE by the following 
subgroups: Age group, sex, BMI group, renal function (baseline eGFR, <35, 


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35-45, 45-60, ≥60), center, number of kidneys, success on primary endpoint 
(CR at PDE), tumor debulking at baseline (at least one upper urinary tract 
episode was treated and marked as current based on Past and Concurrent 
Urothelial Carcinoma Medical History CRF form) and catheter size 
(categorized by percentage of treatments with 7 Fr used: 0%, 0%-50%, 50%-
100%, 100%). 
Serious Adverse Events 
Tables specified below will be presented by  
(1) MedDRA V19.1 SOC and PT 
(2) MedDRA V19.1 PT 
• Incidence of patients with treatment emergent serious adverse events maximal 
severity. The table will be presented in the descending frequency order.  
• Incidence of patients with treatment emergent adverse events by maximal 
relationship to study drug or procedure. The table will be presented in the 
descending frequency order.  
• Incidence of patients with treatment emergent serious adverse events by 
maximal relationship to study drug. The table will be presented in the 
descending frequency order.  
• Incidence of patients with treatment emergent serious adverse events by 
maximal relationship to study procedure. The table will be presented in the 
descending frequency order.  
• Descriptive statistics of time to first SAE leading to treatment interruption 
(temporary discontinuation) or treatment discontinuation (permanent 
discontinuation), as well as time to any treatment interruption and days from 
last treatment prior to the onset of the treatment discontinuation or any dose 
interruption (per event). 
• Number and percentage of patients with at least one SAE by the following 
subgroups: Age group, sex, BMI group, renal function (baseline eGFR, <35, 
35-45, 45-60, ≥60), center, number of kidneys, success on primary endpoint 
(CR at PDE), tumor debulking at baseline (at least one upper urinary tract 
episode was treated and marked as current) and catheter size (categorized by 
percentage of treatments with 7 Fr used: 0%, 0%-50%, 50%-100%, 100%). 


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Adverse Events of Special Interest (AESI)  
A list of AESIs to be included in the tables described below will be provided by 
the Sponsor as an addendum to the SAP following their review and comparison to 
the criteria of such events as outlined in the study protocol.  
• Summary table of all AESIs, presented in same way as the overall AE 
summary table. 
The tables specified below will be presented by MedDRA V19.1 SOC and PT: 
• Incidence of patients with all treatment emergent AESIs by maximal severity. 
The table will be presented in the descending frequency.  
• Incidence of patients with treatment emergent AESIs by relationship to study 
drug. The table will be presented in the descending frequency.  
• Summary of duration of stent for patients with adverse events of Urinary Tract 
Obstruction 
• Incidence of patients with treatment emergent serious AESIs. The table will be 
presented in the descending frequency.  
• Descriptive statistics for the onset of all treatment emergent and time to onset 
of first occurrence of treatment emergent AESIs in the Renal Urinary SOC by 
Preferred Term, including time from first instillation to start of AE , time from 
last treatment prior to the onset of the AE and number of instillations prior to 
AE. 
• Number and percentage of patients with at least one AESI in the Renal 
Urinary SOC by the following subgroups: Age group, sex, BMI group, renal 
function (baseline eGFR, <35, 35-45, 45-60, ≥60), center, number of kidneys, 
success on primary endpoint (CR at PDE), tumor debulking at baseline (at 
least one upper urinary tract episode was treated and marked as current) and 
catheter size (categorized by percentage of treatments with 7 Fr used: 0%, 0%-
50%, 50%-100%, 100%). 
• Incidence of patients with treatment emergent AESIs in the Renal Urinary 
SOC by whether resolved, resolved with sequalae or ongoing. 
• Number of instillations prior to onset of urinary obstruction adverse events 
with no documented resolution or resolved with sequelae. 
• Incidence of patients with treatment emergent serious AESIs in the Renal 
Urinary SOC. The table will be presented in the descending frequency.  


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TC-UT-03 Phase III SAP V2.1_FINALPage 51 of 63 
Template V1.8 
• Descriptive statistics for the onset of serious treatment emergent AESIs in the 
Renal Urinary SOC by Preferred Term, including time from first instillation to 
start of AE, time from last treatment prior to the onset of the AE and number 
of instillations prior to AE. 
• Number and percentage of patients with at least one serious AESIs in the 
Renal Urinary SOC by the following subgroups: Age group, sex, BMI group, 
renal function (baseline eGFR, <35, 35-45, 45-60, ≥60), center, number of 
kidneys, success on primary endpoint (CR at PDE), tumor debulking at 
baseline (at least one upper urinary tract episode was treated and marked as 
current) and catheter size (categorized by percentage of treatments with 7 Fr 
used: 0%, 0%-50%, 50%-100%, 100%). 
• Summary table of urinary tract narrowing events, including frequencies of 
narrowing events, patients experiencing pain, hydronephrosis identified, urine 
flow compromised, interventions performed as well as frequency of each of 
the interventions. 
Treatment-Emergent Adverse Events Listings 
• Listing of all AEs including Screening Number, AE description, mandatory 
treatment discontinuation, start date, stop date, frequency, severity grade, 
action taken, whether serious or not, whether SUSAR or not, action taken with 
study treatment, other actions taken to treat the event, relationship to study 
drug, relationship to the study procedure, specify related procedure, outcome, 
was patient terminated from Treatment due to this AE? 
• Listing of all Serious Adverse Events as described in the previous bullet. 
• Listing of all AEs leading to dose reduction, temporary or permanent 
discontinuation of study treatment or maintenance treatment. AE leading to 
permanent discontinuation is defined as AEs with "Action Taken with Study 
Treatment" marked as "permanently discontinued" AND AEs with "was 
patient terminated from Treatment due to this AE?" marked as "yes". This 
listing will include the information specified above as well as the number of 
treatment instillations received, the number of maintenance instillations 
received and the time to event (in days).  
• Listing of AESIs including SOC, PT, severity, relationship and if it led to 
discontinuation of treatment. 


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Template V1.8 
11.7.3 Listing of Deaths, Other Serious and Clinically Meaningful 
Adverse Events 
• A listing of all deaths, including site, number of instillations received, cause of 
death, autopsy, circumstances description, whether associated with an AE, if 
yes what AE, time from start of first exposure and time from last exposure 
 
11.7.4 Other Safety Data 
All analyses (not including shift tables) specified below will be done separately for  
a) Baseline, Main treatment period of 6 instillation, Lab 1 and Lab 2 visits (for 
CBC, renal and liver function tests), the PDE visit and re-evaluation visits if 
relevant. 
b) All the remaining visits (Maintenance and follow-up visits) 
11.7.4.1 Laboratory Results 
Hematology - Complete Blood Count  
• Descriptive statistics of hematology results, including change from baseline, 
by visit. 
• Frequency distribution of hematology results (within normal range / not 
clinically significant / clinically significant) by test and visit. 
• Toxicity score shift table for key hematologic parameters from Baseline to the 
worst post-baseline result. The results will be coded based on CTCAE V5.0 
into Grade 0 to Grade 4. 
(1) From Baseline to PDE visit. 
(2) From Baseline to the worst condition observed during the treatment 
period. 
(3) From Baseline to Study Completion visit 
Renal and Liver Function 
• Descriptive statistics of renal and liver function results, including change from 
baseline, by visit. 
• Descriptive statistics for creatinine and eGFR by visit for patients with Renal 
Urinary AESIs. 


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Template V1.8 
• Descriptive statistics for creatinine and eGFR Tests before and after onset of 
Urinary Obstruction adverse events with no documented resolution or resolved 
with sequelae. 
• Frequency distribution of results (within normal range / not clinically 
significant / clinically significant) by test and visit. 
• Frequency distribution of creatinine and eGFR by visit for patients with Renal 
Urinary AESIs. 
• Frequency distribution of creatinine and eGFR by visit for patients with single 
kidney. 
• Toxicity score shift table for key renal and liver test from Baseline to the worst 
post-baseline result. The results will be coded based on CTCAE V5.0 into 
Grade 0 to Grade 4. 
(1) From Baseline to PDE visit. 
(2) From Baseline to the worst condition obtained during the treatment 
period. 
(3) From Baseline to Study Completion visit 
• Toxicity grade shift from baseline to PDE visit for creatinine and eGFR for 
patients with Renal Urinary AESIs. 
• Toxicity grade shift from baseline to the worst value obtained during the 
treatment period for creatinine and eGFR for patients with Renal Urinary 
AESIs. 
• Toxicity grade shift from baseline to study completion visit for creatinine and 
eGFR for patients with Renal Urinary AESIs. 
• Spaghetti plots for eGFR (one line per patient) 
Coagulation Tests 
• Descriptive statistics of coagulation test results, including change from 
baseline, by visit. 
• Frequency distribution of results (within normal range / not clinically 
significant / clinically significant) by test and visit 
Urinalysis/ Dipstick 
• Descriptive statistics of numeric results (pH and specific gravity only), 
including change from baseline, by visit. 


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Template V1.8 
• Frequency distribution of Normal (Negative) / Abnormal (Positive) not 
clinically significant / (Positive) Abnormal Clinically Significant results by 
test and visit 
If normal ranges are applicable, the frequencies will be provided by clinically 
significant within normal range / not clinically significant / clinically 
significant  
• By-patient listing of urinalysis parameter results, including visit, normal / 
abnormal (including clinical significance) 
Urine Culture  
• Frequency distribution of urine culture result by visit 
Potentially Clinically Significant (PCS) Results 
• Frequency of patients meeting criteria for potentially clinically significant 
(PCS) results, defined as follows: 
Lab Parameter 
Conventional 
Unit 
Lower Limit 
Upper Limit 
Biochemistry 
Creatinine 
mg/dL 
> 2.2 
ALT 
U/L 
 
> 3 x upper limit of normal 
AST 
U/L 
 
> 3 x upper limit of normal 
Total Bilirubin 
mg/dL 
 
> 1.5 x upper limit of normal 
Gamma glutamyl-
transferase 
U/L 
 
> 2.5 x upper limit of normal 
INR 
ratio 
 
> 1.5 
Potassium 
mEq/L 
< 3.0  
> 5.5 
Sodium 
mEq/L 
≤ 130  
> 150 
Hematology 
Hemoglobin 
g/dL 
<0.8 x lower limit of normal and 
>20% decrease from baseline 
>1.3 x upper limit of normal and 
>30% increase from baseline 
Leukocytes 
x103/µL 
≤ 2.8 
≥ 16.0 
Lymphocytes 
x103/µL 
< 0.5   
> 20 
Neutrophils 
x103/µL 
< 1.0 
 
Platelets 
x103/µL 
< 75 
≥ 700 
 
• Abnormal Liver Function Test Results: Frequency of patients meeting the 
criteria for abnormal liver function tests (LFTs) at any time post-baseline by 
treatment group according to the following criteria: 
o ALT > 3 x upper limit of normal 


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o ALT > 5 x upper limit of normal 
o ALT > 10 x upper limit of normal 
o AST > 3 x upper limit of normal 
o AST > 5 x upper limit of normal 
o AST > 10 x upper limit of normal 
o ALT OR AST > 3 x upper limit of normal AND Total bilirubin > 2 x 
upper limit of normal without findings of cholestasis (i.e. serum 
alkaline phosphatase activity less than 2× the upper limit of normal) 
11.7.4.2 Vital Signs 
• Frequency distribution of the following heart rate (HR, bpm) results, by visit 
and overall 
(1) High 
 if HR ≥ 120 bpm 
 if HR ≥ 120 bpm or there was an increase of at least 15 points 
on HR from baseline 
(2) Low 
 if HR ≤ 50 bpm 
 if HR ≤ 50 bpm or there was a reduction of at least 15 points on 
HR from baseline 
The “total” will present any post-baseline visit. 
• Frequency distribution of the following systolic blood pressure (SBP, mmHg) 
results, by visit and overall 
(1) High 
 if SBP ≥ 180 mmHg 
 if SBP ≥ 180 mmHg or there was an increase of at least 20 
points on SBP from baseline 
(2) Low 
 if SBP < 90 mmHg 
 if SBP < 90 mmHg or there was a reduction of at least 20 
points on SBP from baseline 
The “total” will present any post-baseline visit. 
• Frequency distribution of the following diastolic blood pressure (DBP, 
mmHg) results, by visit and overall 


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(1) High 
 if DBP ≥ 105 mmHg 
 if DBP ≥ 105 mmHg or there was an increase of at least 15 
points on DBP from baseline 
(2) Low 
 if DBP < 50 mmHg 
 if DBP < 50 mmHg or there was a reduction of at least 15 
points on DBP from baseline 
The “total” will present any post-baseline visit. 
 
• By-patient listing of all vital signs results, by visit 
• By-patient listing of clinically significant abnormal vital signs results, by visit 
11.7.4.3 Physical and Urology Oriented Examination 
General Physical Examination  
• By-patient listing of all general physical examinations results, by visit 
• By-patient listing of clinically significant abnormal physical examinations 
results, by visit 
11.7.4.4 Urology Oriented Examination 
• By-patient listing of all urology oriented examination results, by visit 
• By-patient listing of clinically significant abnormal urology oriented 
examination results, by visit 
11.7.4.5 Post-Treatment Urination 
Descriptive statistics by instillation for the following 
• Time to first urination and to first clear urination post treatment (no purple 
color), as collected after each Treatment during the Telephone Contact 
11.7.4.6 Pain during Instillation 
• Descriptive statistics of degree of pain, VAS, experienced by patients during 
the instillation, by visit  


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Template V1.8 
11.7.4.7 CTU/MRI  
• Summary of CTU/MRI results at screening and study completion 
• By-patient listing of CTU/MRI results 
 
11.8 PK Analysis 
PK analysis will be performed using the PK analysis set.  
Actual blood sampling times will be used in all PK analyses. Per protocol times will 
be used to calculate mean plasma concentrations for tabular and graphical displays. 
Spaghetti graphs of plasma concentrations and average over all patients will be 
presented on original and semi-logarithmic scale. 
 
Pharmacokinetic parameters for MMC will be calculated using non-compartmental 
analysis (directly from the by-patient profile). Only plasma concentrations equal to or 
greater than the validated lower limit (LOQ) of the assay will be used in the PK 
analysis. For the PK analysis, plasma concentrations < LOQ that occur from pre-dose 
to the first concentration ≥ LOQ will be taken as 0 and those that occur thereafter will 
be taken as missing.  
The elimination rate constant, λz, will be calculated as the negative of the slope of the 
terminal log-linear segment of the plasma concentration-time curve. The slope will be 
determined from a plot of the natural log of the terminal plasma concentrations 
against time; at least 3 terminal plasma concentration time points, beginning with the 
final concentration ≥ LOQ and not including Cmax, will be selected for the 
determination of λz; the regression will have R2 ≥ 0.90. 
 
• Descriptive statistics of plasma concentration by time will be presented. 
• Descriptive statistics of PK parameters will be presented. 
• Spaghetti graphs of plasma concentrations and average over all patients will 
be presented on original and semi-logarithmic scale. 
12 Data Listings 
Data listings will be provided for all data available from the CRF.  


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Template V1.8 
13 Computer Software 
All statistical analyses will be carried out using SAS® Version 9.4 or higher under 
Windows® 2016 Terminal. 
14 Change in the Planned Analysis from Protocol 
The following changes from the protocol have been made in this statistical analysis 
plan, organized according to the section numbering of the protocol: 
Protocol Section18 Statistical Methodology: 
• Protocol Section 18 includes hierarchical testing of hypotheses. This approach 
was revised and it is not included in the SAP. 
• The protocol proposed to “avoid operational bias by providing the access to 
cumulative ongoing trial data to an independent body only.”  In practice this did 
not occur. 
18.4 Analysis Sets: 
• Local Modified Intent-to-Treat (mITT) analysis set defined in the protocol was 
renamed as mITT analysis set in SAP and there is no reference in mITT 
analysis set definition to ‘confirmed LG UTUC at Screening.’ 
18.4.4 Per Protocol (PP) analysis set 1 was defined in the SAP as a subset of the 
mITT analysis set in SAP while in the Protocol it was defined as a subset of the local 
mITT analysis set. 
18.4.5 Per Protocol (PP) analysis set 2 was defined as a subset of the PP1 analysis set 
in SAP while in the protocol it was defined as a subset of the local mITT analysis 
set. 
18.4.6 PDECR analysis population definition was updated to exclude patients with 
UUT Cytology = 'Suspicious for High Grade Urothelial Carcinoma' at PDE visit 
from both local and central labs 
18.6 Demographic and Baseline Characteristics: Analysis set was changed from 
Safety to ITT. 
18.7.1 Primary Efficacy Analyses: ‘Necessary follow-up’ was renamed as ‘repeated 
evaluation’ in SAP in accordance with CRF. 
18.7.2 Sensitivity Analysis for the Principal Analysis of the Primary Endpoint: Local 
diagnosis was changed from local mITT analysis set (Protocol) to mITT analysis 
set (SAP). 


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18.8.1 Adverse Events: Breakdown of AEs and SAEs by volume of instillation were 
proposed in the protocol but not included in the final SAP. 
18.8.2 Safety Laboratory Tests: Protocol included individual patients’ listings of PCS 
measurements which are not included in SAP. 
18.8.5 Tolerability Assessments: The protocol proposed: ‘The time to withdrawal due 
to adverse events and overall discontinuation rate, starting from first trial 
instillation censored by the date of the PDE visit, will be presented using Kaplan-
Meier curves.’  This analysis is not included in the SAP. 
18.8.6 Use of Concomitant Medications: 
• Pre and post instillation concomitant medications changed to related and not 
related to urothelial carcinoma concomitant medications in SAP 
• Prohibited Medications summary is not included in SAP 
 


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Template V1.8 
15 Amendment 1 - Summary of Changes 
Section 
Revisions 
7.3.2.4 
A table summarizing censoring rule was included. 
Time-to-recurrence derivation formula was included. 
The rule for the start day of time to recurrence is added. 
A new rule for PDECR exclusion based on UUT local and central 
labs was added. 
8.3  
Added for CR=Failure based on UUT Local and Central Lab 
8.4 
’Indeterminate response’ is added in the following statement: If 
"Complete Response Durability Assessment" at any follow-up 
visit is marked as "Durable complete response at target area," all 
previous follow-up visits with missing assessment of durability of 
CR or indeterminate response are defined as CR (“Success”/no 
recurrence. 
 
Revised text for duration of response continuous endpoint: “The 
analysis for this endpoint will serve as the primary analysis to 
assess and describe the long-term durability endpoint.” 
 
Revised text for duration of response dichotomous endpoint: “The 
analysis for this endpoint will serve as a supportive approach to 
describe the long-term durability endpoint, but will be the 
endpoint considered for the hypothesis testing for the key 
secondary endpoint as defined in the protocol.” 
 
The paragraph describing censoring rules was removed as the 
rules were included in Section 7.3.2.4 
10 
The statement regarding no interim analysis is planned was 
removed and statements about analyses for the interim clinical 
study report based on an early data cut-off was added. 
11.2 
The definition for the number of past episodes derivation was 
clarified. 


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Template V1.8 
Section 
Revisions 
11.4 
Added reporting requirement for number and percentage of 
patients for whom general anesthesia was given, out of patients 
receiving treatment any time during treatment and maintenance 
periods. 
11.5.3 
Key secondary endpoint definitions and planned analyses were 
clarified to indicate the hypothesis testing will be performed using 
the dichotomous endpoint using exact binomial test. 
Results for key secondary dichotomous endpoints are to be 
presented as frequency distribution of dichotomous observed 
long-term durability of CR, along with a two-sided 95% exact 
binomial confidence interval. 
Additional analyses for duration for study follow-up and duration 
of follow-up post CR. 
Added clarification: the standard error and 95% confidence 
interval of the estimate will be calculated using Greenwood’s 
method. 
Added requirement for reporting:  
• summary of events and censoring 
• time (months) to recurrence computed as [Recurrence date 
– CR response date + 1]/30.4375 
• duration of follow-up post PDE visit computed as [End of 
study date – CR response date + 1]/30.4375 
• duration of study follow-up computed as [End of study 
date – first dose date + 1]/30.4375. 
11.5.4 
Rules for selection of the observed results from central laboratory 
based on availability of local labs results were added.  
The following analysis was removed: “Based on the Kaplan-
Meier curve, the recurrence-free rates at 3, 6, 9 months post PDE 
will be estimated along with the 95% confidence intervals.” 


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Template V1.8 
Section 
Revisions 
11.5.6 
Included clarification: no p-values will be reported for subgroup 
analyses. 
Added requirement to present subgroup analyses results using 
forest plots. 
Subgroup analyses for continuous secondary endpoint using 
Kaplan-Meier analysis were removed. 
11.5.7.1 
Included clarification: no p-values will be reported. 
Added requirement to present results using forest plot. 
11.5.7.3 
Clarified this sensitivity analysis may be performed based on 
observed results. 
11.7.2 
Added data handling rules for partial AE start/stop dates 
 
Removed references to adverse events leading to study 
discontinuation as data was not collected in the CRF. 
 
Added summary of adverse events for all grades and grade 3/4 
and summary of adverse events reported in >=10% (any grade) or 
>=5% (grade 3/4) of patients. 
 
AESI: Added summary of duration of stent for patients with 
adverse events of Urinary Tract Obstruction and summary for 
number of instillations prior to onset of urinary obstruction 
adverse events with no documented resolution or resolved with 
sequelae. 


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Template V1.8 
Section 
Revisions 
11.7.4.1 
Added analyses: 
• Descriptive statistics for creatinine and eGFR by visit for 
patients with Renal Urinary AESIs. 
• Descriptive statistics for creatinine and eGFR by visit for 
patients with single kidney. 
• Descriptive statistics for creatinine and eGFR Tests before 
and after onset of Urinary Obstruction adverse events with 
no documented resolution or resolved with sequelae. 
• Frequency distribution of creatinine and eGFR by visit for 
patients with Renal Urinary AESIs. 
• Frequency distribution of creatinine and eGFR by visit for 
patients with single kidney. 
• Toxicity grade shift from baseline to PDE visit for 
creatinine and eGFR for patients with Renal Urinary 
AESIs. 
• Toxicity grade shift from baseline to the worst value 
obtained during the treatment period for creatinine and 
eGFR for patients with Renal Urinary AESIs. 
• Toxicity grade shift from baseline to study completion 
visit for creatinine and eGFR for patients with Renal 
Urinary AESIs. 
14 
Administrative changes. 
 

Prot_003.pdf: 
Confidential
Trial Title:
A Phase 3 Multicenter Trial Evaluating the Efficacy and Safety of 
MitoGel™ (UGN-101) on Ablation of Upper Urinary Tract 
Urothelial Carcinoma
Protocol ID: TC-UT-03-P
Country: USA
1. Statement of Compliance
The trial will be conducted in accordance with the International Conference on 
Harmonization guidelines for Good Clinical Practice (ICH E6), the Code of Federal 
Regulations on the Protection of Human Patients (21 CFR Part 50), and the Clinical Terms of 
Award.  All personnel involved in the conduct of this trial have completed human patients’ 
protection training.
2. Confidentiality Statement
The information in this document contains trade secrets and commercial information that 
are privileged or confidential and may not be disclosed unless such disclosure is required by 
applicable law or regulations. In any event, persons to whom the information is disclosed must 
be informed that the information is privileged or confidential and may not be further disclosed 
by them. These restrictions on disclosure will apply equally to all future information supplied to 
you that is indicated as privileged or confidential
A Ph-3 Multicenter Trial Evaluating the Efficacy
and Safety of MitoGel™ - US, IL
Document Number: CLP-0002344
Document Version: 6.0
Effective Date: 18-Jun-2018
Document State: Effective (Controlled)
Page 1 of 130


Confidential
3. Investigator’s Statement and Signature Page
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all stipulations 
of the protocol, including all statements regarding confidentiality, and according to local legal 
and regulatory requirements and applicable US federal regulations, local regulations and ICH 
guidelines.
Principal Site Investigator:
Principal Site Investigator:
_________________ ___________________ __________________ ______________
Name/Title
Site name
Signature
Date
A Ph-3 Multicenter Trial Evaluating the Efficacy
and Safety of MitoGel™ - US, IL
Document Number: CLP-0002344
Document Version: 6.0
Effective Date: 18-Jun-2018
Document State: Effective (Controlled)
Page 2 of 130


Confidential
Table of Contents
1.
Statement of Compliance
1
2.
Confidentiality Statement
1
3.
Investigator’s Statement and Signature Page
2
4.
Abbreviation List
6
5.
Protocol Synopsis
8
6.
Key Roles and Contact Information
17
7.
Introduction and Background
18
7.1.
Upper tract urothelial carcinoma (UTUC)
18
7.2.
Current treatment:
18
7.3.
Investigational Product: MitoGel™ (TC-3 and MMC)
21
7.4.
Justification of Trial Design
24
7.5.
Potential Risks and Benefits
26
8.
Trial Objectives
27
8.1.
Safety
27
8.2.
Primary Efficacy
28
8.3.
Key Secondary Efficacy
28
8.4.
Secondary Efficacy
28
9.
Trial Endpoints
28
9.1.
Safety Endpoints
28
9.2.
Efficacy Endpoints
28
9.3.
Trial Design
30
9.4.
Evaluation plan at PDE
32
9.5.
Evaluation plan at follow-up
33
9.6.
Central Lab Pathologist
34
10.
Trial Population and Eligibility Criteria
34
10.1.
Inclusion Criteria
34
10.2.
Exclusion Criteria
36
11.
Investigational product (IP) - MitoGel™ Kit
38
11.1.
MitoGel™ Kit Packaging and Labeling
38
11.2.
Investigational Product Acquisition, Dispatch, and Storage
41
11.3.
MitoGelTM Admixture Dosage, Preparation, Dispensing and Administration
43
11.4.
IP Accountability
46
11.5.
Replacement of Unusable MitoGel™ Kits
47
11.6.
Assessment of IP compliance
47
11.7.
Destruction of IP
47
12.
Safety Evaluation
48
12.1.
Safety Assessment Prior and During the Treatment Period:
48
12.2.
Telephone Contact 24–32 Hours Post-treatment
49
12.3.
VAS Questionnaire - Pain Assessment During Treatment
49
12.4.
Tests for Assessment of Safety
49
13.
Trial Conduct and Procedures
50
13.1.
Patient Eligibility Review and Enrolment to the Trial
50
13.2.
Screening Visit (V0): -4 to -1 weeks
51
13.3.
Treatment Visits
54
13.4.
LAB 1 (V7) & LAB 2 (V8):
63
13.5.
Primary Disease Evaluation Visit (PDE, V9)
64
13.6.
CR Patients Maintenance Instillations (Maintenance Visits)
65
13.7.
Follow-up Visits (V12, V15, V18, V21)
65
13.8.
Unscheduled Visit
66
13.9.
Treatment Discontinuation
66
A Ph-3 Multicenter Trial Evaluating the Efficacy
and Safety of MitoGel™ - US, IL
Document Number: CLP-0002344
Document Version: 6.0
Effective Date: 18-Jun-2018
Document State: Effective (Controlled)
Page 3 of 130


Confidential
14.
Schedule of Events
68
14.1.
Part I - All Patients - Up to PDE Visit
68
15.
Evaluation of Response
75
15.1.
Tumor Measurements and Classification of Partial Response (PR)
75
15.2.
Assessment of UC Tumor Progression
76
15.3.
Assessment of UC Tumor Recurrence
76
15.4.
Pathological Evaluation:
77
16.
Trial Flow-Chart Per Patient
78
17.
Patients Withdrawal From Treatment or/and Follow Up, and Trial Completion
79
17.1.
Criteria for Patient withdrawal from MitoGel Treatment:
79
17.2.
Definition of Trial Completion
81
17.3.
Replacement of Individual Patients
81
18.
Statistical Methodology
81
18.1.
Significance Level
82
18.2.
Sample Size Rationale
82
18.3.
Futility Analysis
83
18.4.
Analysis Sets
83
18.5.
Patient Disposition
85
18.6.
Demographic and Baseline Characteristics
85
18.7.
Efficacy Analyses
85
18.8.
Evaluation of Safety
88
19.
Management of Adverse Events
91
19.1.
Definitions
91
19.2.
Reporting procedures
93
19.3.
Data Monitoring Committee (DMC)
97
20.
Concomitant Medications
98
21.
Ethical Considerations and Confidentiality
98
21.1.
Informed Consent
98
21.2.
Ethics Committee and Competent Authorities
99
22.
Quality Control and Quality Assurance:
100
22.1.
Source Documentation
100
22.2.
Record Retention
101
22.3.
Clinical Monitoring
101
22.4.
Protocol Deviations
102
22.5.
Audit and Inspection
102
23.
Trial Systems
103
23.1.
Data Collection and Management Responsibilities
103
23.2.
Procedures & Timelines for Data Capturing
103
23.3.
Acknowledgment of MitoGel™ Kit Shipment Receipt
105
23.4.
 System for Images Upload
105
24.
Trial Completion/Termination
105
24.1.
Trial Completion
105
24.2.
Trial Termination
105
25.
Changes in the Conduct of the Trial:
106
25.1.
Protocol Amendments
106
26.
Study Leadership
106
27.
Administrative and Regulatory Details
107
27.1.
Registration of Clinical Studies and Disclosure of Results
107
27.2.
Ownership of Data
107
27.3.
Conflict of Interest Policy
107
27.4.
Final Report and Publication of the Results
107
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27.5.
Finance and Insurance
108
28.
Bibliography:
109
Appendix I: Clinical Evaluation
116
Appendix II: Vital Signs
117
Appendix III: Required Lab Tests
118
Appendix IV: Questions 24–32 hours Post Treatment Visit
119
Appendix V: Karnofsky & ECOG Scores (Oken et al, 1982)
120
Appendix VI:  Recommended Antimicrobial Prophylaxis for Urologic Procedure
121
Appendix VII: Collection and Handling of Plasma Samples for MMC Pharmacokinetics 122
Appendix VIII: CTACAE 4.03 Severity Grades, and Allergic Reaction Grades
123
Appendix IX: Protocol Amendment Version 6.0 – Summary of Changes
124
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4. Abbreviation List 
ADL
Activities of Daily Living
ADR
Adverse drug reaction
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
BCG
Bacille de Calmette et Guérin
CBC
Complete Blood Count
CFR
Code of Federal Regulations
CI
Confidence Interval
CIS
Carcinoma In Situ
CR
Complete response
CRF
Case Report Form
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee
EC
Ethical Committee
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic Data Capturing system
eGFR
Estimated Glomerular Filtration Rate
FDA
Food and Drug Administration
FU
Follow Up
FPI
First Patient In
g
Gram
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HG
High Grade
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IFP
Instructions for Pharmacy
IFU
Instructions for Use
IP
Investigational Product
IRB
Institutional Review Board
LG
Low Grade
LPO
Last Patient Out
mg
Milligram
mL
Milliliter
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mITT
Modified Intent-to-Treat
MitoGel™
MitoGel™ Admixture, of TC-3 Hydrogel Mixed with 
Mitomycin C, using the Kit’s components
MMC
Mitomycin C
NCI
National Cancer Institute
NDD
No detectable Disease
NMIBC
Non Muscle Invasive Bladder Cancer
NR
No Response
NSP
Nephron-Sparing Procedures
ORR
Objective Response Rate
PCS
Potentially Clinically Significant
PDE
Primary Disease Evaluation
PG
Performance goal
PK
Pharmacokinetics
PQC
product quality complaint 
PR
Partial Response
PP
Per Protocol
RNU
Radical nephro-ureterectomy
SAE
Serious Adverse Event
SE
Safety Evaluation
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
SOC
Standard of Care
SUSAR
Suspected Unexpected Serious Adverse Events 
Response
TC-3
TC-3 Sterile Hydrogel by UroGen Pharma Ltd.
TEAE
Treatment Emergent Adverse Events
TNM
Tumor Node Metastases
TURBT
Transurethral Resection of Bladder Tumor
UADR
Unexpected Adverse Drug Reaction
UC
Urothelial carcinoma
ULN
Upper limit of normal
URS
Ureteroscopy
UPJ
Ureteropelvic Junction
UUT
Upper Urinary Tract
UTI
Urinary tract infection
UTUC
Upper Tract Urothelial Carcinoma
WFI
Water for Injection
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5. Protocol Synopsis
Trial Title
A Phase 3 Multicenter Trial Evaluating the Efficacy 
and Safety of MitoGel™ (UGN-101) on Ablation of 
Upper Urinary Tract Urothelial Carcinoma  
Protocol 
Number
TC-UT-03
Clinical Phase
Phase III and Phase IIIb 
Investigationa
l Product
MitoGel™ Kit 
Route of 
Delivery
Instillation to the Upper Urinary Tract (UUT) 
Indication
Treatment for Upper Tract Urothelial Carcinoma (UTUC)
Sponsor
UroGen Pharma Ltd.
9 Ha’Ta’asiya St., Ra’anana, Israel
Trial Centers
Approximately 45 medical centers across the United States, Canada, Europe 
and Israel.
Safety: 

To evaluate the safety and tolerability of the MitoGel™ Admixture in 
UTUC patients.

To assess the pharmacokinetics profile of Mitomycin C (MMC) in 
plasma of a sub-group of patients treated with MitoGel™ Admixture.
Primary Efficacy Objectives:
To evaluate the tumor ablative effect of MitoGel™ Admixture in the UUT 
of patients with UTUC at PDE visit.
Key Secondary Efficacy Objectives:
To evaluate response durability at 12 months for patients showing CR at 
PDE. 
Trial 
Objectives:
Secondary Efficacy Objectives:

To evaluate the durability of tumor ablative effect of MitoGel™ 
Admixture in patients who demonstrated complete response (CR) at the 
Primary Disease Evaluation (PDE) Visit, 3, 6 and 9 months following 
the PDE visit.

To evaluate the overall clinical benefit to the treatment with MitoGel™ 
admixture
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Safety 
Endpoints
Study's safety endpoints include:

Frequency (number of events) and incidence (number of patients) of 
adverse events.

Changes from baseline in laboratory values and incidence of 
measurements defined as Potentially Clinically Significant (PCS).

Changes from baseline in vital signs assessments values and incidence of 
measurements of Potential Clinical Significance (PCS).

Clinically relevant Physical examinations findings.

Changes in concomitant medications (type or dose) from baseline.
In addition, pharmacokinetic (PK) profile of the first MMC instillation in the 
blood will be examined for the first six patients.  In addition, 
pharmacokinetic (PK) profile of the first MMC instillation in the blood will 
be examined for the first six patients.
Efficacy 
Endpoints
Primary Efficacy Endpoint:
Complete Response (CR) defined dichotomously as "Success" if CR was 
confirmed at the end of the treatment period (PDE Visit), and "Failure" 
otherwise.
Key Secondary Efficacy Endpoint:
Long term durability of CR:  This endpoint is defined only for those patients 
demonstrating CR at PDE visit. The endpoint is defined dichotomously as 
"Success" if CR was obtained at follow-up Visit 4 (12 months post PDE 
visit), and "Failure" otherwise. 
Secondary Efficacy Endpoint 

Durability of CR defined dichotomously as "Success" if CR was 
achieved at PDE visit and remained at follow-up Visit 1, Visit 2 and 
Visit 3 (3, 6 and 9 months post PDE), and "Failure" otherwise.  This 
endpoint is defined only for those patients demonstrating CR at PDE 
visit.

Partial response at PDE visit will be defined dichotomously, similarly to 
the primary efficacy endpoint. For subjects with partial response at PDE 
visit, originally planned and actual treatments will be compared.
Trial Design
Trial TC-UT-03 is a prospective, open label, single-arm trial, designed to assess the efficacy, 
safety, and tolerability of treatment with MitoGel™ instilled in the upper urinary tract of 
patients with non-invasive low-grade (LG), UTUC.
Upon signing of informed consent, the patients will undergo a screening visit for eligibility 
evaluation. Eligible patients will be treated with MitoGel™ once weekly for a total of 6 times; 
in a retrograde fashion. Patients who demonstrate CR (based on the central lab evaluation and 
URS) will be treated with MitoGel™ once monthly as a maintenance therapy for a total of 11 
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instillations or up to the first recurrence, whichever comes first.  
Instillation through a nephrostomy tube may be an option if necessary upon advising with the 
principle coordinating investigator. 
Determination of the eligibility of all patients and admission into the trial will be decided upon 
a case-by-case basis in consultation with the trial principal coordinating investigator Dr. Seth 
Lerner 
.  The sponsor will send a final approval for patient enrollment to 
the site. 
General description of trial visits
Visit
Timeline
Screening (V0)
Up to 4 weeks prior to treatment
Instillations 1-6 (V1-V6)
Once weekly for 6 weeks
Safety Labs (V7-V8)
One week and 3 weeks post last instillation
Primary disease evaluation (PDE) 
(V9)
5±1 weeks following the last instillation visit
Maintenance Instillations (V10-V20)
Within 2-3 weeks following PDE visit, 11 monthly 
administration of MitoGelTM 
Follow up visits (FU 1-4) (V12, 
V15, V18, V21)
3, 6, 9, and 12 months following the PDE visit.  
Investigational product: The MMC concentration of MitoGel™ to be used in this trial will 
be 4 mg MMC per 1 mL of TC-3 gel.  The volume of the MitoGel™ to be instilled into the 
patient pyelocalyceal system will be individualized and will be based on volumetric 
measurements of the pyelocalyceal system using pyelography (average of 3 measurements) 
and will not exceed 15 mL (a maximum dose of 60 mg).  The pyelography procedure can be 
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done at any time before the first treatment.   The volume of MitoGel™ instilled will be 100% 
of the measured pyelocalyceal volume or 15 mL (whichever is lower). 
Instillations process: Prior to every instillation the patient will be prescribed with sodium 
bicarbonate and will be instructed to consume 1.3 g of sodium bicarbonate the night prior to 
treatment, the morning of, and 30 min. prior to the treatment the patient will be also prescribed 
with a prophylaxis antibiotic to be taken to cover each treatment according to the AUA 
antimicrobial prophylaxis recommendations. 
Prophylactic anti-allergic treatment will be given per PI discretion.  Recommended regimen–
Anti-histaminic agents to be taken the day before instillation, on the day of instillation and 1-3 
days after the instillation.  Changes in such regimen may occur per the site principal 
investigator medical judgment.
Diazepam (5-10 mg) (or any other relaxation pill) will be given before instillations according 
to the PI discretion to reduce the anxiety. 
PK evaluation will take place in a subset of patient (N=6) who provided an informed consent. 
Blood samples will be collected at 0 (pre-dose) and 30 min, 1, 2, 3, 4, 5, and 6 hours post first 
MitoGel™ instillation.
Patients’ safety will be monitored through the entire study by recording Adverse Events (AEs) 
throughout the study by: 

Frequency (number of events) and incidence (number of patients) of adverse events

Changes from baseline in laboratory values and incidence of measurements defined as 
Potentially Clinically Significant (PCS).

Changes from baseline in vital signs assessments values and incidence of measurements of 
Potential Clinical Significance (PCS).

Clinically relevant Physical examinations findings 
Five (5) weeks (± 1 w) following the last treatment, the PDE Visit, during which safety and 
efficacy will be assessed, will take place.  During this visit, UT wash urine cytology will be 
carried out followed by URS which enables to assess visually the ablative effect of the 
MitoGel™.  In case of remaining lesions, biopsy or brush biopsy shall be taken if applicable. 
Patient demonstrating CR at PDE will undergo monthly maintenance instillations of 
MitoGel™ up to 11 months post PDE.  Safety follow-up for these patients will be done until 
one month post last instillation or at the end of the follow-up period in FU visit 12, which is 
the earlier. 
For patients who did not demonstrate Complete Response, to the extent that it is possible, all 
remaining tumors lesions will be biopsied.  Based upon PI discretion the patients shall 
undergo any additional surgical or other treatment which might be deemed necessary to the 
patient health.  The tumor lesion location, size and grade, as well as the surgical procedure or 
treatment provided to treat the remaining disease will be documented.
Efficacy will be assessed by the rate of CR at PDE, i.e., 5 weeks (±1 week) after last 
MitoGel™ treatment.  The durability of response will be assessed primarily by the rate of CR 
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at 3 months after PDE and then every 3 months up to a one year post PDE visit. 
During the FU period, disease recurrence and or progression, the type of intervention, and 
histopathological (where applicable) will be recorded.
DMC-An independent Data Monitoring Committee (DMC) has been assigned to this trial. 
Accumulating safety, tolerability and efficacy data will be monitored periodically by the DMC 
according to a pre-specified process and frequency detailed in the DMC charter.
In addition, a steering committee has been assigned to this trial. In case need arises, Ad hoc 
DMC meetings will be initiated by the steering committee. 
Every effort will be made to reach a consensus within the Data Monitoring Committee and 
with the principal coordinating investigator. In case of disagreement on recommended 
modifications to the protocol, the Steering Committee will make the final decision.
Follow up data will be collected up to 3 years from PDE visit for all patients to evaluate 
long term safety and efficacy of the investigational product.
Number of 
Patients
74 patients
Planned trial 
period
FPI to Last Patient Out (LPO):  Approximately 34 months;
Treatment 
and follow up 
duration per 
patient
Total: Approximately 14-16 months, per patient: 
1-3 weeks screening period, 6 weeks treatment period, 5 weeks post-
treatment to PDE, up to 12 months Follow Up (FU) period from the PDE 
including a maintenance therapy of a single instillation once monthly up to 
11 months FU.
Trial 
population
Adults patients with LG, non-invasive UTUC in renal pelvis and calyces 
above the UPJ (Ureteropelvic Junction)
Inclusion 
Criteria:
1. Patient has signed Informed Consent Form and is willing and able to 
comply with all requirements of the protocol.
2. Patient is at least 18 years of age.
3. Naive or recurrent patients with LG, non-invasive UTUC in the 
pyelocalyceal system.
4. Patient has at least one (1) measurable papillary LG tumor, evaluated 
visually, ≤ 15 mm. The largest lesion should not exceed 15mm.
5. Biopsy taken from one or more tumors located above the ureteropelvic 
junction (UPJ) showing LG urothelial carcinoma. Diagnosed not more 
than 2 months prior to the screening.
6. Patient should have at least one remaining papillary LG tumor evaluated 
visually with a diameter of at least 5 mm.
7. Wash urine cytology sampled from the pyelocalyceal system 
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documenting the absence of HG urothelial cancer, diagnosed not more 
than 2 months prior to the screening. 
8. Patients with bilateral LG UTUC may be enrolled if at least one side 
meets the inclusion criteria for the trial and if the other kidney does not 
require further treatments (The other kidney can be treated prior to the 
beginning of the study).§  
9. Patients with ECOG (Eastern Cooperative Oncology Group) 
performance status <3 (with Karnofsky >40).
10. Patients with life expectancy greater than 24 months at time of 
screening.
11. Patients must have adequate organ and bone marrow function as 
determined by routine laboratory tests as below: Patients must have 
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 × institutional ULN, and
Estimated glomerular filtration rate (eGFR) ≥30 mL/min. 
In rare instances, the Principal Investigator may enroll patients whose 
laboratory screening values do not conform exactly to the levels 
outlined above but who, in the judgement of the local PI, the DMC 
and the coordinating PI can be safely and ethically treated on 
protocol.    
12. Patient has no active urinary tract infection (UTI) as confirmed by urine 
culture or urinalysis*.
13. Female Patients of childbearing potential**, must have a negative serum 
pregnancy test at screening and must agree to use two acceptable & 
effective methods of contraception***, until 6 months post treatment. 
14. All sexually active male patients must agree to use a condom during 
intercourse, for at least 48 hours post each instillation.
15. Male patients who have a partner that is a female of childbearing 
potential must agree to use two acceptable & effective methods of 
contraception until 6 months post treatment. 
16. Patients must not have any other medical condition(s) that make(s) their 
participation in the study unadvisable in the opinion of the investigator.
(§ *; **; ***;   see end of Exclusion Criteria)
Exclusion 
1. Patient received BCG treatment for UC during the 6 months prior to 
Visit 1.
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Criteria:
2. The patient has untreated concurrent urothelial cancer in other locations 
other than the target area (unless treated during screening). 
3. Carcinoma in situ (CIS) in the past in the urinary tract.  
4. Patient has a history of invasive urothelial carcinoma during the past 5 
(Five) years. 
5. Patient has a history of high grade papillary urothelial carcinoma in the 
urinary tract during the past 2 (Two) years.   
6. Patient is actively being treated or intends to be treated with systemic 
chemotherapy during the duration of the trial. 
7. Any other malignancy diagnosed within 2 years of trial entry with the 
exception of:
a. Basal or squamous cell skin cancers, or 
b. Noninvasive cancer of the cervix, or 
c. Any other cancer deemed to be of low-risk for progression or patient 
morbidity during trial period.
8. Patient with urinary obstruction in a case of retrograde administration or 
administration not feasible via nephrostomy tube. 
9. Inability to deliver the investigational drug to the pyelocalyceal system. 
10. Patient has any other medical or mental condition(s) that make(s) his/her 
participation in the trial unadvisable in the opinion of the treating 
urologist. 
11. Patient has contraindication to MMC treatment, or known sensitivity to 
MMC.
12. Patient has an intractable bleeding disorder (e.g., coagulation factors 
deficiencies, Von Willebrand Disease).
13. Patient is currently receiving any other investigational agents or has 
participated in a research protocol involving administration of an 
investigational product within the past 30 days prior to Visit 1.
14. Patient previously treated with MitoGel™ for UTUC.
15. Pregnant (positive serum pregnancy test), planning to become pregnant 
during the trial period, breast-feeding, or of childbearing potential and 
not practicing reliable contraception***.
16. Patient is non-responder to Mitomycin C as a chemical ablation agent for 
urothelial carcinoma. This criterion relevant only to patient who already 
participated in another UroGen’s studies or any other relevant studies 
with chemical ablation efficacy endpoint.  
§  If both upper tracts meet inclusion criteria, the treating urologist in 
consultation with the sponsor can decide which side is to be treated 
within the trial. The other side should be treated as per standard of care, 
however if the other kidney treatment includes an intravesical 
instillations, the patient is not eligible. In any case, the other kidney must 
be free of cancer before the first instillation on the side to be treated in 
the clinical trial.
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*
In case of a symptomatic UTI the patient will be treated with a full 
course of antibiotics, and the instillation will be postponed until 
resolution. In the case of asymptomatic bacteriuria, the use of 
prophylactic antibiotics and postponement of the treatment is left to the 
discretion of the PI.
** Women of non-childbearing potential: 
1.
At least 12 months since the last menses, or
2.
Without uterus and/or both ovaries, or
3.
Has been surgically sterile for at least 6 months prior to trial drug 
administration.
***
Acceptable methods of birth control which are considered to have a 
low failure rate (i.e., less than 1% per year) when used consistently and 
correctly, such as implants, injectable, combined (estrogen/progesterone) 
oral contraceptives, intrauterine devices (IUDs-only hormonal), condoms 
with spermicide, sexual abstinence or vasectomized partner.
Statistical 
Methodology
Approximately 83 patients will be recruited to provide at least 74 evaluable 
patients. While no interim efficacy analysis is planned:

A futility analysis is planned after 20 subjects have reached PDE,

The DMC will periodically review safety and efficacy data and will, if 
appropriate, recommend earlier submission to FDA in the case where it 
has concluded that safety and efficacy have been demonstrated. If this 
were to occur, the study would nevertheless continue while FDA 
evaluates the data provided. 
Sample Size Rationale: 
A total of approximately 83 subjects are planned to provide at least 74 who 
are evaluable that will provide 88.5% power to demonstrate the 
hypothesized CR rate of 30% is higher than the performance goal of 15%.  
Power is estimated using an exact binomial hypothesis testing with two-
sided Alpha=0.05.
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Primary Efficacy Analysis:
The primary efficacy analysis will test the following hypotheses in ITT, 
using an exact binomial hypothesis testing:
H0: CRrate ≤15% 
H1: CRrate >15% 
Key Secondary Efficacy Analysis:
The key secondary efficacy analysis will test the following hypotheses in the 
CR analysis set of subjects demonstrating CR at PDE, using exact binomial 
testing:
H0: Durable CR at 12-months ≤ 40%
H1: Durable CR at 12 months > 40%
In addition, durability of CR will be analyzed continuously using Kaplan-
Meier curve.
Interim Analysis
A futility analysis will be conducted after N = 20 evaluable subjects have 
provided primary efficacy data.  Results of the analysis will be provided to 
the DMC.  The DMC will forward its recommendations following DMC 
meetings to the steering committee, which will than make the final 
determination on trial continuation.
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6. Key Roles and Contact Information
Sponsor
UroGen Pharma Ltd.
9 Ha’Ta’asiya., POB 2397 
Ra’anana, 4365405, Israel
info@urogen.com
Tel: +972-9-770-7600
Fax: +972-77-4171410
Trial Manager
 
Medical Monitor /
Pharmacovigilance Officer
Medical Director
Quality Assurance
 
Principal Coordinating 
Investigator
Dr. Seth Paul Lerner
Site: Baylor College of Medicine M.C.
Houston, Texas  77030, USA
Office Phone: 
Data Management & Statistics
Tel:
Primary Central Pathology and 
Cytology Reviewer
 
 
Phone: 
Secondary Central Pathology and 
Cytology Reviewer
 
Phone: 
Fax:  
Pharmacokinetics Central Lab
Tel: 
Study Logistics:
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7. Introduction and Background 
7.1.
Upper tract urothelial carcinoma (UTUC)
Upper tract urothelial carcinomas (UTUCs) are malignant changes of the transitional 
urothelial cells lining of the upper urinary tract.  UTUC are uncommon and account for only 
5%–10% of urothelial carcinomas (UCs) [Browne, 2005; Rouprêt, 2013; Hurwitz, 2014], and 
the estimated annual incidence of UTUCs in western countries is about two new cases per 
100,000 inhabitants.  UTUC is found in the renal pelvis (in about two-thirds of the cases) and 
the ureter (in about one-third of the cases) [Jarrard, 2012].  Concurrent bladder cancer is present 
in approximately 17% of cases of UTUC.  In 22%–47% of UTUC patients, recurrence occurs in 
the bladder, whereas recurrence in the contralateral upper tract is observed in 2%–6% [Rouprêt, 
2013].
About 60% of UTUCs are invasive at diagnosis, with a peak incidence in people in their 
70s and 80s, and prevalence is 3 times higher in men than in women. [Rouprêt, 2013].
The most common symptom of UTUC is microscopic or gross hematuria (70%–80%), 
while flank pain occurs in 20%–40% of cases, and a lumbar mass is present in 10%–20% [Hall, 
1998: Rouprêt, 2013].  
Screening and diagnosis of UTUC consists of upper tract urinary cytology, various imaging 
assessment methods, and ureteroscopy [Grossfeld, 2001, Rouprêt, 2013, Hurwitz 2014].  
Urinary cytology correlates with the presence of urothelial carcinoma, but does not accurately 
predict the stage or grade of these respective tumors [Messer, 2011; Sverrisson, 2014].  Flexible 
ureteroscopy can assess the tumor, obtain tumor biopsy, and determine tumor grade in 95% of 
cases [Tavora, 2009; Rouprêt, 2013].   Multi-Detector Computed Tomographic Urography 
(MDCTU) is the gold standard for exploration of the upper urinary tract and has high sensitivity 
in the detection of small renal lesions [Scolieri, 2000]. 
7.2.
Current treatment:
7.2.1.
Surgical treatment
Radical nephro-ureterectomy (RNU) with excision of bladder cuff (through either open or 
laparoscopic access) is the gold standard of care for upper tract urothelial cancer in patients 
with a normally functioning contralateral kidney [Lughezzani, 2010; Rouprêt, 2011; Cutress, 
2012; Rouprêt, 2013].  RNU is indicated in cases of:
Upper ureteral and renal pelvic tumors,
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Infiltrating tumor on imaging,
High-grade tumor, and
Multifocality (with two functional kidneys).
7.2.2.
Nephron-Sparing Procedures (NSP) 
Conservative surgery, or first-line nephron-sparing procedures (NSP) for low-risk UTUCs 
allows preservation of the upper urinary and renal unit while sparing the patient the morbidity 
associated with open radical surgery. Conservative management of UTUCs can be considered 
in imperative cases (renal insufficiency or solitary functional kidney) or in elective cases (when 
the contralateral kidney is functional) for LG, low-stage tumors [O’Malley, 2009; Volanis, 
2012; Cutress, 2012; Rouprêt, 2014].  Combining ureteroscopic biopsy grade, diagnostic 
imaging findings, and urinary cytology may help decision making on radical RNU versus NSP 
[Rouprêt, 2011; Rouprêt, 2014].  Recent recommendations have established selection criteria 
for NSP (i.e., LG biopsy, unifocal tumor <1 cm in diameter, complete resection possible, no 
evidence of parenchymal invasion on imagery, patients informed of and committed to the need 
for closer surveillance).  Advances in imaging techniques, practice of systematic ureteroscopic 
biopsies, and development of preoperative prediction tools also allow for a better selection of 
candidates who would benefit from NSP [Colin, 2013].  Disease recurrence has been shown to 
be common after NSP (ranging between 26%–90%), which mandates a regular, close, lifelong 
follow-up of the upper urinary tract [Pak, 2009; Cutress, 2012; Colin, 2013; Kalaitzis, 2013].  
The challenge of high recurrence rate and the (low) potential for progression following NSP 
often requires patients to undergo multiple resection procedures.  Thus, in addition to clinical 
characteristics, the motivation, comprehension, and compliance of the patients are required 
[Cutress, 2012; Colin, 2013; Kalaitzis, 2013; Rouprêt, 2007; Rouprêt, 2013].  Nevertheless, as 
clinical stage and tumor grade are prognostic factors for recurrence and survival [Rouprêt, 
2007], choosing the correct patient population for this treatment will increase the chances of 
treatment success and reduce the risk.
In a retrospective review of a cohort of 57 patients treated conservatively and followed for 
a minimum of 2 years, the recurrence rate was 89.5%, with a mean of 5.5 recurrences per 
patient [Pak, 2009; Park, 2013). The average number of procedures per patient was 10.1, over a 
range of 5 to 41 months.  The most conservative estimate of overall survival for UTUC treated 
with the current paradigm is 35%, for a cohort with an average age of 74 years with 35 months 
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of follow-up, with progression of the UTUC as the cause of death in approximately 50% of the 
patients [Krambeck, 2007).  There are few reports that have evaluated the quality of life (QOL) 
in patients with UTUC, but it is apparent that patients with non-muscle invasive bladder cancer 
who were undergoing repeated transurethral resections had lower general health perceptions 
than normal cohorts [Yoshimura, 2005).  It seems that in patients with LG, small-sized tumors 
have equal endpoints following endoscopic treatment as compared to RNU, with the advantages 
of minimal morbidity and preservation of renal parenchyma following endoscopic management 
[Singh, 2011; Rouprêt, 2013].  To date, however, only a few studies have reported long-term 
endpoints after NSP in UTUCs and strong data are lacking to assess definitively the cancer 
control allowed by this therapeutic strategy [Colin, 2013].  As it seems that a tumor-free status 
can be achieved only rarely, therapy for urothelial cancer in the upper urinary tract represents a 
significant unmet medical need [Volanis, 2012; Grasso, 2012; Kalaitzis, 2013].
7.2.3.
Chemotherapy
Transitional cell tumors of both the upper and lower urinary tract are considered to be 
chemo-sensitive tumors.  Intravesical Mitomycin C (MMC) therapy for lower urinary tract 
(bladder) transitional cell carcinoma has been used for more than two decades, as adjuvant 
therapy.  Its use in upper tract (renal pelvis and ureter) transitional cell carcinoma has showed 
promise in terms of both efficacy and safety, but the number of published studies is limited, due 
to low incidence and prevalence of this type of tumor [Keeley, 1997]. 
A variety of adjuvant topical chemotherapy studies demonstrated ability to reduce the risk 
of tumor recurrence in the UUT and in the bladder following UTUC operative treatments (both 
RNU and NSP).  The optimal use of adjuvant chemotherapy, using MMC, Bacillus Calmette-
Guérin vaccine (BCG), or cisplatin, is not defined yet [Elliott, 1996; Martinez-Pineiro, 1996; 
Sakamoto, 2001; Matin, 2010; O'brien, 2011; Kim, 2013; Rouprêt, 2013].  In addition, only a 
few neo-adjuvant systemic chemotherapy studies have been published to date, and they 
demonstrated some complete response (chemical ablation), a significant rate of down-staging, 
and significantly higher survival rates than surgery without neo-adjuvant chemotherapy [Matin 
2010, Rouprêt 2013, Porten 2014].  Thus, the cumulative data provide justification for the 
additional clinical trials using improved adjuvant and neo-adjuvant chemotherapy strategies 
[Rouprêt, 2013; Audenet, 2013b]. 
Difficulties in administering and maintaining MMC or other topical chemotherapeutic 
agents for sufficient time to the upper tract have limited their use for chemo-ablative purpose in 
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patients with UTUC [O'Donoghue, 2004].  The improved efficacy of MMC following the 
increase in exposure time was established by numerous in-vitro models, in-vivo clinical studies, 
and computer simulations [De Bruijn, 1992; Sadeghi, 1998; Au, 2002].  Therefore, providing a 
means to prolong the duration of MMC intravesical treatment is imperative for enhancing the 
anti-tumor effect of the instilled MMC. 
Mitomycin C is inactivated by acid urine (Au et al. 2001). Therefore, the patients in this 
study will receive 1.3 gr of sodium bicarbonate 3 times prior to every instillation for 
alkalization of urine.
7.3.
Investigational Product: MitoGel™ (TC-3 and MMC)
The investigational product is presented in MitoGel™ Kit comprising MMC for injection 
drug product (the active component), and TC-3 Sterile Hydrogel.
MitoGel™ is initially prepared as a cooled liquid preparation; as a reverse thermal 
hydrogel, MitoGel™ subsequently solidifies at body temperature at the site of instillation in 
vivo, leading to the formation of a MMC containing gel-depot.  As a result, the MitoGel™ 
provides prolonged exposure of UTUC tumors to MMC.  Accordingly, MitoGel™ is 
envisioned to act as a chemoablative therapeutic product in the setting of UTUC.  Studies 
reported in the literature indicate a direct correlation between anti-tumor activity and instilled 
MMC concentration and dwelling (exposure) time on treatment effectiveness [Deb, 2001; 
Eastham, 1993; Schmittgen, 1991; Wang, 2013]. 
Prolongation of the MMC exposure time is expected to increase the drug efficacy over time 
while maintaining similar or lower systemic peak exposure, and therefore a good safety profile 
is expected.  In-vitro models, in-vivo studies, clinical trials, and computer simulations have 
shown that enhancement of MMC activity may be achieved by increasing MMC dwelling time 
and drug concentration in the target tissue [Barlogie, 1980; De Bruijn, 1992; Nozue, 1995; 
Ozawa, 1998; Perry, 1992; Sadeghi, 1998; Schmittgen, 1991; Slee, 1986; Walker, 1986]. 
Furthermore, owing to the nature of the TC-3 component of the MitoGel™, mixing with 
the drug and instillation via a standard ureteral catheter is relatively straightforward, as the 
unique thermo-sensitive properties enable it to convert from a liquid state when chilled, 
throughout the mixing with the drug and the instillation, into a semi-solid gel at body 
temperature inside the target organ.
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Following instillation of MitoGel™, MMC is efficiently released from TC-3 when the 
gel is dissolved by the urine [TheraCoat, 2014a, Report No. TAS-4M-P-A-133, Rev 3].  
Preliminary studies provide in-vitro and in-vivo data that support the use of this formulation of 
sustained-release MMC.  The release profile of MMC from MitoGel™ was evaluated in in-
vitro studies.  
 
 
.  The results of safety and performance tests 
reveal that TC-3 is biocompatible, poses no deleterious effect on the urothelium and does not 
obstruct ureters or urethra upon instillation and the subsequent solidification of the gel.  
Preclinical studies 
 demonstrating low MMC plasma levels, well below the 
toxicity level, support the systemic safety of upper-tract instillation of MitoGel™.  In a GLP 
toxicology study (
), six weekly instillations of  mL MitoGel™ to the upper 
urinary tract of 
 at a total MMC dose of up to 
 mg MMC (concentration of  
mg/mL) were not associated with any mortality, clinical findings, changes in body weights, 
ECG intervals or meaningful changes hematologic, coagulation, serum chemistry , urinalysis or 
urine chemistry endpoints, at any collection interval, up to and including the 4 weeks recovery 
period at the end of the instillation period. 
Analysis of plasma samples found that following retrograde instillation of MitoGel™, 
systemic exposure (AUC0-10hr) and Cmax values of MMC increased with increasing dose in an 
approximately dose proportional manner on Days 1 (1st instillation) and 36 (last instillation).  It 
should be noted that systemic exposure levels were significantly below report levels known to 
cause myelosuppression (threshold of 400 ng/mL).
Macroscopic findings in the ureter of mild to moderate swelling/thickening and/or 
irregular surface were noted at necropsy following the last instillation in a dose dependent 
pattern. These corresponded to microscopic findings of edema and/or urothelial vacuolation. 
Four weeks following the last instillation, findings of mild swelling/thickening of the ureter 
were rare. 
Microscopic findings noted in the kidney were confined to the pelvis, involving the 
urothelium and submucosa. These findings included urothelial vacuolation, urothelial 
hypertrophy, and erosion; while edema, mixed leukocyte infiltrates, and hemorrhage were 
primarily found in the submucosa. Similar microscopic findings were noted mostly in the 
proximal ureter. The findings were similar in nature to the findings described in the literature 
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for intravesicular MMC treatment.  Microscopic findings trended towards resolution over the 
recovery period, with decreased severity and incidence after the recovery phase.  The 
microscopic findings were considered to be non-adverse, given the generally limited severity, 
the progression towards recovery, the lack of associated clinical or clinical pathology findings, 
the lack of systemic changes, and the localized nature of the microscopic findings.
Based upon the results of this study, six weekly repeated administrations of MitoGel at a 
concentration of  mg/mL (
 mg MMC) was found to produce no adverse effects.  Taken 
together, TC-3 Sterile Hydrogel appears to provide a safe drug retention and delivery system 
for MMC in the upper urinary tract. 
While MMC has been studied extensively and is routinely used in clinical practice for 
intracavital (as well as systemic) administration, the human experience with MitoGel™ is 
limited.  As of July 2016, MitoGel™ has been used as compassionate use treatment in 18 
patients for whom the remaining treatment alternative was removal of the affected kidney.  Out 
of 18 recruited patients, 14 were classified as LG.  To date, of the 14 LG UTUC patients (our 
target patient population for the pivotal trial), we noticed the following results:
•
Eleven patients completed the 6 weekly instillations (the anticipated protocol in the 
planned pivotal trial)
•
10 patients were evaluable (one patient was only partially evaluable)
•
Of these 10 patients, all patients have responded; 7 having reported complete responses 
(CR) and 3 with partial responses (PR)
•
2 out of the 3 PR’s were treated with low MMC concentration formulation of MitoGel
•
Response durability evaluation is ongoing and encouraging
The most commonly reported adverse events by patients was flank pain (n=6) or ”fullness” 
sensation (5 patients) during the instillation procedure or during the period immediately 
following the instillation.   These adverse events are believed to be associated with the 
instillation of the gel or insertion of the ureter catheter, and were generally mild or moderate 
and resolved without treatment.  Three patients had acute Pyelonephritis (one of them with 
aggravation of chronic renal failure) which resolved following IV antibiotics. This event is a 
known and accepted AE in cases of upper tract manipulations. Other events reported which are 
believed to be related, or partially related to the MMC component of the investigational product 
is allergic reaction to Mitomycin, involving palmar and arm rash and pruritus (n=1), and cheek 
blush and swelling (n=1) and post instillation short single or recurrent febrile event (n=3), 
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Nausea was reported in four patients and can be related either to upper tract manipulations or to 
MMC itself. In addition, pancytopenia was evident in two patients: The first being an elderly 
previously polycythemic patient who received Hydrae (a myelosuppressant) concomitantly with 
the investigational product and the second patient underwent the following in the same 
treatment session: TURBT, immediate MMC instillation to the bladder and upper tract 
instillation with MitoGel which probably led to enhanced systemic absorption of MMC. 
Weakness, fatigue and dizziness could also be related to MMC component of MitoGel as well 
as a single case of bladder inflammation and upper tract inflammation. Both of which 
completely resolved.
MMC mixed with TC-3 has also been studied as an ablative intravesical treatment in Non-
Muscle Invasive Bladder Cancer (NMIBC).  While the different anatomy of the UUT may pose 
new challenges, the clinical data from the bladder instillations is relevant to support safety and 
efficacy of MMC in the upper tract, as it consists of a similar epithelial tissue and can provide 
some information with regard to the expected adverse events 
7.4.
Justification of Trial Design 
The present trial is designed to evaluate the efficacy and safety of MitoGel™ administered 
to the UUT in patients with LG-UTUC. 
Only a few trials were performed with chemotherapy and endoscopic management in 
UTUC, and the trials differed one from each other in eligibility criteria, treatment specificities 
and results [Cutress, 2012; Ristau, 2012; Audenet, 2013a]. However, it can be collectively 
concluded that favorable population that benefit from elective endoscopic management have 
non-invasive LG disease characteristics [Cutress, 2012; Rouprêt, 2013]. Therefore, we chose to 
have naive or recurrent patients with LG, non-invasive UTUC, as the target population for this 
trial. 
There are only few publications on instillation of MMC as either adjuvant or neo-adjuvant 
therapy in the upper urinary tract [Hellenthal, 2009; O'Brien, 2011].  In the literature, the total 
dose for MMC instillation in the UUT ranges from 20 to 60 mg (with concentrations generally 
ranging from 1-2 mg/mL) [Keeley, 1997; Nepple, 2009; Aboumarzouk, 2013; Wang, 2013; 
Hurwitz, 2014]. 
More data is available on instillation of MMC as adjuvant therapy for urothelial cancer of 
the bladder. Given the similarity of the disease and urothelial lining throughout the urinary 
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tract, the experience with MMC in the bladder is informative and can be used to determine the 
concentration of instillation in the UUT. 
The FDA has granted an orphan designation for MitoGel for “treatment of upper tract 
urothelial carcinoma (UTUC)”.  To date, UroGen have conducted over 250 instillations in the 
upper tract of 
, at three dose concentrations i.e., mg, mg and mg per mL, of the 
product in a GLP toxicology study evaluating the safety of the MitoGel™, simulating the 
intended regimen in the clinic at higher concentration, with each 
 undergo 6 weekly 
instillations. This GLP regulated toxicity study was conducted in support of the IND 
submission to the agency.
The study concluded that even at the high concentration used, which are double than the 
one proposed in the clinical settings ( mg of MMC per mL of gel in the GLP study vs. 4mg of 
MMC per mL of gel in the human study) no toxicity has been observed (systemic or local). 
The dose selected for the UTUC patients in the phase 3 study is 4mg of MMC per mL of 
gel, to allow a safety margin, which was accepted by the FDA during pre-IND discussions. 
This safety data together with the clinical experience of using MitoGel™ in human 
subjects (over 60 instillations in 18 subjects collected from the Expanded Access Program) was 
found acceptable by the FDA in order to move forward with this study.
In the current trial, the total dose to be instilled in patients will not exceed 60 mg MMC.  
The concentration of MMC in MitoGel™ will be 4 mg MMC/1 mL TC-3.  This is similar to the 
dosage of MMC used for intravesical instillations and in post/peri-operative instillations in the 
UUT [Mohamed, 2011 (Smith's Textbook of Endourology, 2011 see page 291)].  Due to the 
inter-individual variability in the anatomy and volume of renal pelvis and calyces, the volume 
of the MitoGel™ for the instillation will be determined for each patient individually by the 
investigator.  This will be based on volumetric estimation using retrograde pyelography for 
injecting the contrast agent (maximal volume required to fill the pyelocalyceal space).  Based 
on clinical experience from the Expanded Access Program treatment in UTUC patients, it is 
estimated that between 5 and 15 mL of MitoGel™ should be sufficient for filling and even 
distribution of the gel within the renal pelvis and calyces. 
7.4.1.
Justification of single arm
This treatment protocol addresses an unmet medical need for an orphan indication. The 
standard treatment for UTUC requires either nephroureterectomy or endoscopic surgical 
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resection. In this protocol the utilizing of a primarily non-surgical approach to the management 
of UTUC is explored.  In pre-IND discussions, the FDA has agreed with the single arm design 
of this trial. There is no comparable non-surgical “ablative” therapy to which MitoGel™ can be 
compared.  In addition, MitoGel™ is indicated as a nephron sparing approach for patients who 
are currently candidates for RNU, therefore, neither equivalent control nor placebo arms are 
applicable or may be considered due to unethical reasons.
7.4.2.
Justification of the trial primary endpoint 
The primary efficacy endpoint is the rate of complete response (CR); i.e., a complete 
ablation of tumor lesions as a response to the chemotherapy treatment, which will be assessed 
during the primary disease evaluation (PDE) Visit. The PDE will occur at the pre-scheduled 
visit for endoscopic management treatment, set for 5 weeks following the last instillation 
(altogether, approximately 3 months from baseline). As tumors are not expected to disappear 
spontaneously, response can be attributed to the treatment, making the rate of CR an 
appropriate endpoint for a trial lacking a placebo control arm.  For confirmation of therapeutic 
benefit, durability of ablation at 3 months post PDE has been chosen as a secondary endpoint. 
This time-point was chosen because recurrence within 3 months post-surgical removal of 
bladder lesions has been previously associated with the efficiency of the surgical procedure 
indicative of incomplete removal of the lesions rather than true recurrence. Therefore, a 
“second look” (clinical evaluation) at 3 months post Transurethral Resection of Bladder Tumor 
(TURBT), for example, is recommended in the guidelines [Kapoor, 2013; Rouprêt, 2013]. 
Durable CR at Month 3 post PDE in this trial will be taken to indicate a complete ablation of 
the tumor(s) and is thus expected to be indicative of the efficiency of the new treatment offered 
and a confirmation of efficacy.  Accumulating evidence of recurrence rate and of time for 
recurrence post retrograde management varies significantly between different publications 
[Kapoor, 2013; Rouprêt, 2013]. In this trial, we will follow recurrence rate and time for 12 
months post PDE, as exploratory endpoints. 
7.5.
Potential Risks and Benefits
7.5.1.
Potential risks
Toxicity associated with systemic absorption 
Although literature review did not demonstrate any side effects associated with the 
systemic absorption when MMC was administered topically, bone marrow toxicity 
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(thrombocytopenia and leukopenia) and renal toxicity are considered possible risks for the 
patients.  The CBC, renal, and liver blood function will be checked regularly during the trial.
Allergic Response to MMC
MMC (Kyowa) bladder instillations have been shown to cause allergic reactions in various 
toxicities 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.  Allergic response 
will be closely monitored during the trial.
Cystitis
Cystitis and other bladder irritation symptoms secondary to UUT instillation of MMC may 
develop.   Urine tests, including urine culture and urinalysis, will be checked regularly during 
the trial.
UTI and Pyelonephritis
Aiming to minimize the risk for Urinary Tract Infections (UTI), especially Acute 
Pyelonephritis, anti-microbial prophylaxis should be prescribed according to the AUA Best 
Practice Policy Statement on Urologic Surgery Antimicrobial Prophylaxis (See Appendix VI);
Onset of renal insufficiency or deterioration of renal function
Although uncommon, treatment may cause impairment of renal function. Renal functions 
test will be checked regularly during the trial.
7.5.2.
Potential benefits
This trial is potentially beneficial in several aspects:
It will evaluate a new mode of UTUC treatment, MitoGel™ for local therapy, that may 
prevail the drawbacks of the current UTUC topical treatment, 
It may entail good safety profile of MitoGel™ in UTUC patients.
8. Trial Objectives
8.1. Safety
To evaluate the safety and tolerability of the MitoGel™ Admixture in UTUC patients.
To assess the pharmacokinetics profile of Mitomycin C (MMC) in plasma of a sub-
group of patients treated with MitoGel™ Admixture. 
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8.2. Primary Efficacy
To evaluate the tumor ablative effect of MitoGel™ Admixture in UTUC patients at PDE 
visit.
8.3. Key Secondary Efficacy
To evaluate response durability at 12-months follow-up for subjects showing CR at PDE 
visit
8.4. Secondary Efficacy 
To evaluate the durability of tumor ablative effect of MitoGel™ Admixture in patients 
who demonstrated complete response (CR) at the Primary Disease Evaluation (PDE) 
Visit, 3, 6 and 9 months following the PDE visit. 
To evaluate the overall clinical benefit to treatment with MitoGel™ admixture
9. Trial Endpoints
9.1.
Safety Endpoints
Study's safety endpoints include:
Adverse events and serious adverse events occurring at any time during the study,
Laboratory tests,
Physical and urology oriented examinations, 
Vital signs.
In addition, pharmacokinetic (PK) profile of the first MMC instillation in the blood will be 
examined for the first six patients.
9.2.
Efficacy Endpoints
9.2.1.
Primary Efficacy Endpoint
Study's primary endpoint is Complete Response (CR) at the end of the treatment period 
(PDE Visit). CR is defined dichotomously as "Success" if CR was confirmed at PDE visit (or 
relevant follow-up; see Figure 1 below), and "Failure" otherwise.
There are a number of diagnostic scenarios for CR, which are described in the following figure. 
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9.2.3.
Secondary Efficacy Endpoints

Durability of CR defined dichotomously as "Success" if CR was achieved at PDE visit 
and remained at follow-up Visit 1, Visit 2 and Visit 3 (3, 6 and 9  months post PDE 
visit), and "Failure" otherwise.
This endpoint is defined only for those patients demonstrating CR at PDE visit.

Partial response at PDE visit will be defined dichotomously, similarly to the primary 
efficacy endpoint. For subjects with partial response at PDE visit, originally planned and 
actual treatments will be compared.
9.3.
Trial Design 
The current trial is a prospective, open-label, single-arm phase III trial, designed to assess 
efficacy tolerability and safety of MitoGel™ treatment administered to the upper urinary tract. 
Upon signing of informed consent, the patients will undergo a screening visit for eligibility 
evaluation. Eligible patients with confirmed LG non-invasive UTUC will be treated with 6 
once-weekly instillations of MitoGel™ in a retrograde fashion.  Instillation through a 
nephrostomy tube may be an option, if necessary upon advising with the principle coordinating 
investigator. 
Determination of the eligibility of the entire patients and admission into the trial will be 
decided upon a case-by-case basis in consultation with the trial principle coordinating 
investigator (Dr. Seth Lerner). Patient relevant data will be sent by email to the Sponsor and 
images will be uploaded to a secure portal (
). The patient’s medical history, 
concomitant medications, pyelography imaging of the pyelocalyceal system anatomy, URS 
photos when available, local pathology and cytology results and all other relevant clinical 
records will be sent in un-identified manner. The entire patient information should be sent to 
the Sponsor no later than 7 working days from the screening visit and earlier if possible. 
The final eligibility will be approved by email from the sponsor to the site. 
MitoGel™ Admixture concentration to be used in this trial will be 4mg MMC per 1mL of 
TC-3 gel.
The volume of the MitoGel™ Admixture to be instilled will be individualized, based on 
the volumetric estimation of the pyelocalyceal space using retrograde (antegrade if required) 
pyelography.  To increase accuracy, an average of three (3) measurements will be the reference 
in case the number contains decimal fraction it should be round to the closest whole number. 
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The pyelography procedure can be done at any time before the first instillation and in 
accordance with the method of administration selected by the investigator. The measurements 
will be documented in each patient’s study file and the volume required to fill the UUT will be 
recorded. 
Prior to every instillation, the treating investigator/designee must review the pyelocalyceal 
volume measurement recorded in the patient file and complete the designated MitoGel 
administration form which is provided by UroGen, with the required volume for instillation. 
The volume will be verified by site team observer. Both treating urologist and the observer will 
sign the administration form, thus confirming the correct volume will be instilled. 
Thereafter, the treating investigator/designee will withdraw the exact volume required into 
the syringe. 
Once instillation is completed, the investigator /designee who performed the instillation 
will complete the actual volume instilled and sign the administration form. The administration 
form will be filed in the study patient file. These steps will be repeated at each administration.  
Administration of MitoGelTM Admixture to the upper urinary tract shall be carried out 
while the patient is in Trendelenburg position and lies down on the side that is being treated to 
the extent that it is possible.
Patients should remain in the clinic/hospital for at least 6 hours observation period 
following the first instillation procedure.  
Placement of a ureteral catheter for instillation of MitoGel™ should be performed as 
follow: 1. Cystoscopy should be performed in order to obtain screening of the urethra and the 
bladder for abnormal findings, 2. advance guidewire through the cystoscope working channel 
via the ureter to the renal pelvis, 3. anchor the guidewire in the renal pelvis and remove the 
cystoscope, 4. advance the ureteral catheter over the guidewire to the preferable location in the 
renal pelvis and take photos to document the location of the catheter tip.  Preferable location 
will be considered as the place where the flow from the catheter tip of the investigational 
product will enable best coverage of MitoGelTM in the renal pelvis and the calyces. Fluoroscopy 
should be used to ensure proper placement of the catheter within the renal pelvis prior to 
instillation. 
The ablative effect of the MitoGel™ will be evaluated at the pre-scheduled ureteroscopy 
(URS) (on PDE visit), performed 5 weeks after the last instillation.  Response will be 
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determined based on upper tract wash urine cytology followed by visual evaluation using 
video-ureteroscopy (appearance, number, size, and location of the lesions), and histopathology 
of remaining lesions.  A biopsy shall be performed for all remaining lesions where it is 
technically feasible. Cytology and histophathology slides will be reviewed by the local and the 
central pathology lab. The determination of degree of response and durability of complete 
response for trial analysis purposes will be based on the local lab readings. 
An independent Data Monitoring Committee (DMC) is assigned for this trial. Accumulated 
safety, tolerability, and efficacy data will be monitored periodically by the DMC according to 
the schedule and scope defined in the DMC charter. The DMC is established according to the 
FDA’s Guidance (Guidance for Clinical Trial Sponsors: Establishment and Operation of 
Clinical Trial Data Monitoring Committees; 2006).
A trial steering committee is also assigned for this trial. In case of need the steering 
committee will initiate Ad hoc DMC meetings, and will review the DMC recommendations.
A futility analysis will be conducted after N = 20 evaluable subjects have provided primary 
efficacy data. Results of the analysis will be provided to the data monitoring committee (DMC). 
The DMC will forward to the steering committee its recommendations and the steering 
committee will make the final determination regarding trial continuation. The accumulated 
study data at this stage will be shared with the FDA for the decision of study continuation 
and/or adaptation. Study will continue to enroll subjects as per study plan while discussions 
Agency is taking place.    
Safety will be determined based on physical examination, blood tests, vital signs, and a 
record of AEs. Any unexpected AE related to MitoGel™ and qualified per National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) as grade 3 or 4 
will be evaluated by the sponsor medical team and steering committee, see AE grading 
terminology in Appendix VIII: CTACAE 4.03 Severity Grades, and Allergic Reaction Grades. 
9.4.
Evaluation plan at PDE  
Tumor response to treatment will be evaluated during the PDE visit occurring 5 weeks 
after the last treatment. Please refer to Section 15 for a detailed description of response 
evaluation criteria:  
Complete Response (CR) is defined as No Detectable Disease (NDD) and will be 
assessed visually during ureteroscopy (URS) and by upper tract washing urine cytology.
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9.4.1.
CR Patients Maintenance Instillations (Maintenance Visits)
A maintenance treatment will start immediately after the local lab confirms that patient's 
cytology is negative for cancer, and no longer than 2-3 weeks post PDE, unless there is 
a medical condition which require to postpone the treatment. In these cases, the first 
maintenance instillation should be delayed until recovery. 
Maintenance Regimen- MitoGel™ Admixture will be given once monthly (±2 week) 
until one month prior to last FU visit within the study (i.e., until Month 11 post PDE).  
Safety assessment – During maintenance treatment at each instillation the patients will 
have performed in the hospital local lab, safety lab tests, physical examination and vital 
signs per protocol (see Appendix I - Appendix III).  For patients who drop out of the 
study safety will be assessed according to the SOC.
9.5.
Evaluation plan at follow-up 
Patients will be followed-up for twelve months (12) or until disease recurrent or 
progression. 
Patient will be given the maintenance treatment with the study IP during the follow-up 
period, meaning that the same safety assessment will be done as written in the above 
section. 
Three (3) months after PDE, the first follow-up (FU) visit will be conducted. During this 
visit, follow-up data on disease outcome will be collected.  
Additional follow-up data on disease outcome will be collected for up to 12 months 
after PDE.
Follow up data may be collected up to 3 years from PDE visit for all patients to 
evaluate long term safety and efficacy of the investigational product.
Disease outcome to be recorded will include the following: 
o Recurrence. 
o Progression defined as either change in stage according to the Tumor-Node-
Metastases (TNM) classification, or grade according to the 2004 WHO classification 
of tumors.
Any intervention conducted to treat the UTUC will be recorded.
AEs will be recorded according to the rules described in Section 19. 
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9.6.
Central Lab Pathologist 
Biopsy and UUT cytology slides will be sent to the central lab pathologist at the screening 
visit. Biopsy slides from PDE and FU visits will be sent to the central lab pathologist 
according to the findings of this visit. Cytology slides will be sent to the central lab in any 
of the above visits. 
9.6.1.
General Process & Timelines 
In case of low grade patient by local pathologist, and confirmation of eligibility by the 
investigator, biopsy and cytology slides should be shipped to the central lab no longer 
than 14 working days following the screening visit and after the site has received the 
eligibility confirmation by the Sponsor. 
Central lab results are expected to be emailed to the site and UroGen within no longer 
than 4 working days.
The central lab should send the slides back to the site within 3 weeks of receipt.
In case of contradiction between local diagnosis and central lab diagnosis, here are 
the steps to be taken:
1. Study coordinator to forward the central lab report to the local pathologist 
requesting repeated review.
2. Central lab findings provided to both physician and local pathologist
3. Any change in physician diagnosis or treatment as a result of central lab findings 
will be recorded. At the same time, primary analysis will be based on initial 
determination based on site’s local lab. 
In any case it is at the local PI judgment if to treat the patient within the study 
10. Trial Population and Eligibility Criteria 
Patients with LG, non-invasive UTUC lesions in the renal pelvis and calyces above the 
UPJ as determined by local lab.
10.1. Inclusion Criteria
1. Patient has signed Informed Consent Form and is willing and able to comply with all 
requirements of the protocol.
2. Patient is at least 18 years of age.
3. Naive or recurrent patients with LG, non-invasive UTUC in the pyelocalyceal system.
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4. Patient has at least one (1) measurable papillary LG tumor, evaluated visually, ≤ 15 mm. 
The largest lesion should not exceed 15mm.
5. Biopsy taken from one or more tumors located above the ureteropelvic junction (UPJ) 
showing LG urothelial carcinoma. Diagnosed not more than 2 months prior to the 
screening.
6. Patient should have at least one remaining papillary LG tumor evaluated visually with a 
diameter of at least 5 mm.
7. Wash urine cytology sampled from the pyelocalyceal system documenting the absence of 
HG urothelial cancer, diagnosed not more than 2 months prior to the screening 
8. Patients with bilateral LG UTUC may be enrolled if at least one side meets the inclusion 
criteria for the trial and if the other kidney does not require further treatments (The other 
kidney can be treated prior to the beginning of the study).§  
9. Patients with ECOG (Eastern Cooperative Oncology Group) performance status <3 (with 
Karnofsky >40).
10. Patients with life expectancy greater than 24 months at time of screening.
11. Patients must have 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 × institutional ULN, 
Estimated glomerular filtration rate (eGFR) ≥30 mL/min, and
In rare instances, the Principal Investigator may enroll patients whose laboratory 
screening values do not conform exactly to the levels outlined above but who, in the 
judgement of the local PI, the DMC and the coordinating PI, can be safely and ethically 
treated on protocol.    
12. Patient has no active urinary tract infection (UTI) as confirmed by urine culture or 
urinalysis*.
13. Female Patients of childbearing potential**, must have a negative serum pregnancy test at 
screening and must agree to use two acceptable & effective methods of contraception***, 
until 6 months post treatment. 
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14. All sexually active male patients must agree to use a condom during intercourse, for at least 
48 hours post each instillation.
15. Male patients who have a partner that is a female of childbearing potential must agree to 
use two acceptable & effective methods of contraception until 6 months post treatment. 
16. Patients must not have any other medical condition(s) that make(s) their participation in the 
study unadvisable in the opinion of the investigator.
(§ *; **; ***;   see end of Exclusion Criteria)
10.2. Exclusion Criteria
1.
Patient received BCG treatment for UC during the 6 months prior to Visit 1.
2. The patient has untreated concurrent urothelial cancer in other locations other than the 
target area (unless treated during screening) 
3. Carcinoma in situ (CIS) in the past in the urinary tract.  
4. Patient has a history of invasive urothelial carcinoma during the past 5 (Five) years. 
5. Patient has a history of high grade papillary urothelial carcinoma in the urinary tract during 
the past 2 (Two) years.     
6. Patient is actively being treated or intends to be treated with systemic chemotherapy during 
the duration of the trial. 
7. Any other malignancy diagnosed within 2 years of trial entry with the exception of:
a. Basal or squamous cell skin cancers, or 
b. Noninvasive cancer of the cervix, or 
c. Any other cancer deemed to be of low-risk for progression or patient morbidity during 
trial period.
8. Patient with urinary obstruction in a case of retrograde administration or administration not 
feasible via nephrostomy tube. 
9. Inability to deliver the investigational drug to the pyelocalyceal system. 
10. Patient has any other medical or mental condition(s) that make(s) his/her participation in 
the trial unadvisable in the opinion of the treating urologist. 
11. Patient has contraindication to MMC treatment, or known sensitivity to MMC
12. Patient has an intractable bleeding disorder (e.g., coagulation factors deficiencies, Von 
Willebrand Disease).
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13. Patient is currently receiving any other investigational agents or has participated in a 
research protocol involving administration of an investigational product within the past 30 
days prior to Visit 1.
14. Patient previously treated with MitoGel™ for UTUC.
15. Pregnant (positive serum pregnancy test), planning to become pregnant during the trial 
period, breast-feeding, or of childbearing potential and not practicing reliable 
contraception***.
16. Patient is non-responder to Mitomycin C as a chemical ablation agent for urothelial 
carcinoma. This criterion relevant only to patient who already participated in another 
UroGen’s studies or any other relevant studies with chemical ablation efficacy endpoint.    
§  If both upper tracts meet inclusion criteria, the treating urologist in consultation with the 
sponsor can decide which side is to be treated within the trial. The other side should be 
treated as per standard of care, however if the other kidney treatment includes an 
intravesical instillations, the patient is not eligible. In any case, the other kidney must be 
free of cancer before the first instillation on the side to be treated in the clinical trial.
*
In case of a symptomatic UTI the patient will be treated with full course of antibiotics and 
the instillation will be postponed until resolution. In the case of asymptomatic bacteriuria, 
the use of prophylactic antibiotics and postponement of the treatment is left to the discretion 
of the PI. 
** Women of non-childbearing potential: 
4. At least 12 months since the last menses, or
5. Without uterus and/or both ovaries, or
6. Has been surgically sterile for at least 6 months prior to trial drug administration.
***Acceptable methods of birth control which are considered to have a low failure rate (i.e., 
less than 1% per year) when used consistently and correctly, such as implants, injectable, 
combined (estrogen/progesterone) oral contraceptives, intrauterine devices (IUDs-only 
hormonal), condoms with spermicide, sexual abstinence or vasectomized partner.
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11. Investigational product (IP) - MitoGel™ Kit
Detailed information about the investigational product is found in the investigator 
brochure. 
11.1. MitoGel™ Kit Packaging and Labeling
All clinical supplies will be packaged (Figure 2), labeled (Figure 3-Figure 5:) and shipped 
in compliance with cGMP and GDP.  All trial provided IP will be appropriately documented 
(i.e., batch records, Certificate of Analysis, etc.).
11.1.1. MitoGel™ Kit
The MitoGel™ Kit contains the following components (Table 1):
Table 1
MitoGel™ Kit components
Component
Quantity (per Kit)
Function
Mitomycin for Injection, USP 
(vial) *
2  40-mg vials 
Active Ingredient
TC-3 Sterile Hydrogel (vial) 
1  20-mL vial
Sustained release medium
Blank MitoGel™ Admixture 
Labels 
5
Once Admixture ready to be 
completed and affixed on the: 
Vial, Protective Bag, pharmacy 
book, patient study file
Light Protective Bag
1
Protects MitoGel from light
MitoGel™ Admixture Syringe 
Label
1
To be affixed on the syringe at 
the treatment area. 
Instructions for Pharmacy (IFP) 
1
Instructions for MitoGel 
Admixture Preparation.
* USP = United States Pharmacopeia; The MMC is provided as a dry lyophilized powder.  
** The 20 mL of “TC-3 Sterile Hydrogel” is provided in a 25-mL glass vial.
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Figure 2: Sample of the Kit Box
Caution: New Drug-Limited by Federal (or United States) Law to Investigational Use
MitoGel™ Kit
UroGen Pharma Ltd., 9 Ha’Ta’asiya St., Ra’anana, Israel. Tel: +972-77-4171412
For instillation to the upper urinary tracts 
Each Kit contains 
Component
Manufactured by
Quantity per Kit
Mitomycin for Injection, USP (vial)
 for UroGen Pharma  Ltd.
2 x 40 mg vials
TC-3 Sterile Hydrogel (vial) 
 for UroGen Pharma  Ltd. 
1 x 20 mL  vial
Labels
 for UroGen Pharma  Ltd.
5
Preparation Leaflet
 for UroGen Pharma  Ltd.
1
Rx only 
Storage: Retain the vials in the carton until use.  Store the kit at 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).
Once prepared as MitoGel™ Admixture, keep in the vial at room temperature and protected from light. 
Use the Instructions for Pharmacist leaflet while preparing the MitoGel™ Admixture.
Packed for: UroGen Pharma Ltd.
Packed by: 
 Tel: 
Kit Batch Number:                                      Mfg Date:
Kit serial Number: 
* Format presentation. Data will be updated according to batches manufactured.
Figure 3: MitoGel Kit Label Format
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Caution: New Drug-Limited by Federal (or United States) Law to Investigational Use
Mitomycin for Injection, USP, 40 mg, for instillation to the upper urinary tracts 
when used in MitoGel™ Admixture 
Rx only
Storage: Retain the vial in the carton. Store dry powder at 25°C (77°F), excursion permitted between 15°C 
(59°F) and 30°C (86°F), protected from light.  Avoid excessive heat (over 40°C, 104°F).
Mfd for: UroGen Pharma Ltd. 9 Ha’Ta’asiya St. Ra’anana, Israel. 
Tel: +972-77-4171412
Mfd by:
Tel: 
Batch Number: 
Mfg. Date:    MMMYYYY
Figure 4:  Mitomycin for Injection, USP Label
Caution: New Drug-Limited by Federal (or United States) Law to Investigational Use
TC-3 Sterile Hydrogel for instillation to the upper urinary tracts when used in 
MitoGel™ Admixture
Volume: 20mL
Storage:
Store at 25°C (77°F), excursion permi
 
 
 
 
 
 (86°F).  Avoid 
excessive heat (over 40°C, 104°F).
Ingredients:
Poloxamer P407, hydroxypropyl methylcellulose, polyethylene glycol 400, water for injection.
Mfd for: UroGen Pharma Ltd. 9 Ha’Ta’asiya St. Ra’anana, Israel.
Tel: +972-77-4171412
Mfd by: 
Tel: 
Batch Number: 
Mfg. Date:    MMMYYYY
Figure 5: TC-3 Sterile Hydrogel Label
The components of the MitoGel™ Kit are produced under aseptic conditions and according 
to current Good Manufacturing Practice (GMP) (European Commission, May 2003 Guidelines) 
and FDA “Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing —  
Current Good Manufacturing Practice”, September 2004.
The MitoGel™ Kit lots used in this trial are tested and their release is supervised and 
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approved by the UroGen QA Department.
11.2.Investigational Product Acquisition, Dispatch, and Storage 
11.2.1. Initial Supply
Initial clinical supply shipment will be sent automatically to sites in which the study was 
approved by their CA/IRB/EC, when the first patient at the site has been enrolled. 
11.2.2. Shipment of Clinical Supplies
The Sponsor/designee will notify the Principal Investigator prior to shipment of drug 
supplies and other related clinical supplies regarding the anticipated date of their arrival at the 
pharmacy.  Shipment will be sent directly to the delegated personnel at the pharmacy. 
All shipped clinical supplies will be appropriately documented to ensure proper handling in 
case of emergency.  
Shipment will be sent under controlled conditions. Transportation temperature will be 
monitored and recorded by temperature-monitoring devices loggers.
Each shipment of clinical supplies for the trial will contain a certificate of analysis and a 
shipment certificate detailing the content of shipment.  
The pharmacist or study coordinator (in case of ancillary clinical supplies required for 
MitoGel instillation procedure) who receive the shipment will review the shipment items 
against the shipping certificate supplied to assure adequacy of shipment.  In addition, the 
temperature logger will be read and the output will be printed for the pharmacy's records, 
assuring the shipment has arrived in good condition according to requirements.  If all is OK, 
he/she will confirm receipt in the eCRF system
11.2.3. MitoGelTM Kit Storage and Handling 
The MitoGel™ Kit must be stored under controlled conditions and in accordance with 
applicable regulatory requirement(s) for cytotoxic substances.
Retain the vials in the carton until use. Store the kit at 15-25°C (59-77°F). Avoid excessive 
heat (over 40°C, or 104°F). Once prepared as MitoGelTM Admixture, keep in the vial at room 
temperature and protect from light.
The clinical supplies storage area at the site must be monitored by the site staff for 
temperature consistency with the above instructions.  Documentation of temperature monitoring 
should be maintained at all times until study closure.
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11.2.4. MitoGel™ Admixture Stability and Handling
Store the vial at 15-250C (59-770F). One hour before administration place in refrigerator, or 
in any other cooling apparatus at 2-80C (35-460F) to liquefy the MitoGel™ Admixture for the 
instillation.   Keep protected from light. Avoid exposure to excessive heat (over 40°C, or 
104°F)
The MitoGel should be instilled up to 9hrs from end of preparation.
11.2.5. Clinical Supplies Quality Complaint Handling Procedure
A product quality complaint (PQC) is defined as any suspicion of a product defect related 
to manufacturing, labeling, or packaging, i.e., any dissatisfaction related to the identity, quality, 
quantity, durability, or reliability of a product, including but not limited to its labeling or 
packaging integrity.  
The impacted MitoGelTM Kit or ancillary supplies must be marked “not for use” and 
quarantined during investigation and until a decision has been made by the sponsor regarding 
the drug’s validity.  In case of MitoGel, the quarantined kits should be kept at the required 
temperature to allow future use if approval is received by quality assurance personnel of the 
sponsor.  Reporting must be done upon first awareness, and the site should await the sponsor's 
written decision regarding the drug's validity prior to drug dispensing. 
PQC forms will be supplied to the site and pharmacy at trial start. In case of any 
temperature deviation, either during transport or storage at the pharmacy, or any problem (as 
specified above) with supplied clinical ancillary supplies (injector, catheters etc.), it is the site 
investigator's responsibility to assure the completed PQC is sent to the sponsor via email/fax 
immediately, to allow proper monitoring of complaints relating first, to patients safety, 
monitoring of site's supplies inventory. 
Any PQC written report must be reported immediately to the site CRA & Sponsor by email:
ATTN:  Quality Assurance
Following review of the quality complaint form, the sponsor will send written approval to 
allow the use of the affected Kit/s, or request for kit destruction. In case a kit should be 
destroyed, it will be disabled in the system by the site pharmacist or sponsor, and will not be 
available for dispensing. 
Product quality complaints may have an impact on the safety and efficacy of the product.  
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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.
11.3. MitoGelTM Admixture Dosage, Preparation, Dispensing and Administration
11.3.1. Dosage Determination 
MitoGel TM Admixture dose will depend on the patient's pelvicalyceal volume.
MitoGel TM Admixture concentration will be 4mg/mL (4mg MMC in 1 mL of TC-3). 
Enrolled patients will receive 6 weekly instillations given in a retrograde fashion.
CR patients will undergo additional, monthly maintenance instillations of the same 
concentration, up to 12 months following PDE visit. 
The volume of the MitoGel™ Admixture to be administered and thus, the final dose, will 
be individualized and will be based on volumetric measurements of the pyelocalyceal system 
using pyelography.  For better accuracy, the volumetric measurement should be repeated 3 
times. The volume of MitoGel™ Admixture instilled will be 100% of the measured 
pyelocalyceal system volume: average of the three measurements.  The average of the three 
measurements is the instillation volume. In case the number contains decimal fraction, please 
round it as follows:
≥0.5 - round it up to the closest whole number. 
<0.5 - round it down to the closest whole number.   
The administered volume should be identical to the mean measured volume and will not 
exceed 15 mL (a maximum total dose of 60 mg MMC), whichever is lower (For detailed 
instillation instructions please refer to the IFU). 
The volumetric measurements should be documented in the source data and the CRF
11.3.2. MitoGelTM Kit Dispensing
The investigator or coordinator will be responsible for notifying the responsible person in 
the pharmacy ahead of time of the participants scheduled instillation visit. 
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Prior to every treatment, investigator/coordinator will dispense MitoGel Kit in the EDC 
system (
), obtaining the number of MitoGel kit to be withdrawn from the pharmacy 
stock.
Withdraw of MitoGel TM Kit from inventory for the preparation of the MitoGel TM 
Admixture will be done only after the investigator has provided designated prescription with 
patient details according to the trial specific supplied prescription, and supplied MitoGel kit 
number.
In clinical sites using their own systems for ordering MitoGel Admixture (instead of 
UroGen supplied prescriptions for the trial) the drug order wording MUST be: 
"Please dispense 1 vial of 4mg/ml MitoGel Admixture, according to the IFP" OR
"Please dispense at least 17ml of 4mg/ml MitoGel Admixture, according to the IFP" OR
In sites where the inclusion of exact volume is mandatory in the drug order the wording 
will be: "Please dispense 17ml of 4mg/ml MitoGel Admixture".
The maximal volume to be administered to a patient is 15ml. The drug order should 
NOT request 15ml of MitoGel since the adjustment for the individualized volume will be 
done by the clinical team at the treatment center. 
  The MitoGel™ Admixture will be dispensed only to authorized site trial personnel. 
Dispensing must be documented in the study accountability log. 
In case the instillation has been cancelled the pharmacist must document in the study 
accountability log that the Admixture was prepared but not dispensed to the patient. 
In case the instillation was cancelled after MitoGel™ Admixture was dispensed, it is the 
investigator responsibility to notify the pharmacy about the cancellation.  
Returned MitoGel™ Admixture must not be dispensed again, even to the same patient, and 
must be destroyed.  MitoGel™ Admixture may not be relabeled or reassigned for use to other 
patients.
In case MitoGel kit was dispensed in the EDC system but eventually was not opened/not 
used, and kit was kept at required storage conditions at the pharmacy, the MitoGel kit may be 
returned to the site stock but ONLY after coordination with Sponsor/Designee.
11.3.3. Preparation
MitoGel™ Admixture will be prepared according to the Instructions For Pharmacy (IFP) 
document provided in the MitoGel™ Kit.
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When not using the trial-supplied labels, the MitoGelTM Admixture Vial label should 
contain at the minimum the following information:

<Trial Identifier, preferably TC-UT-03-P>

<Subject Identifier, preferably subject enrollment ID>

"MitoGelTM Admixture 4mg/ml (Mitomycin C 4mg per 1mL)

Kit Batch Number ___________

"For instillation to the upper urinary tract"

"Note: Maximum patient dose is 15mL (60mg)

"Storage: Store up to 8 hours at room temperature protected from light” 

"Caution: New Drug-Limited by Federal (or United States) Law to Investigational 
Use" 

Prep. Date:

Exp. Date and Time:
MitoGelTM Admixture Syringe label
Admixture label for the syringe is provided within the MitoGel kit. It must be used. The 
pharmacists can either complete or not complete it, but it must be sent to the site along with the 
Admixture vial. If not completed by the pharmacist, the syringe admixture label should be 
completed by the person withdrawing admixture from the vial into the syringe and affixed onto 
the syringe, prior to treatment. 
11.3.4. IP Administration
MitoGel™ Admixture will be administered by study authorized person as documented in 
the delegation log and only after proper training was given regarding the instillation procedure. 
The pharmacy will dispense a 17-20 mL MitoGel™ Admixture for every instillation 
regardless of the individual volume required. Prior to every instillation, the treating 
investigator/designee must review the pyelocalyceal volume measurement recorded in the 
patient file and complete the designated MitoGel administration form which is provided by 
UroGen, with the required volume for instillation. The volume will be verified by site team 
observer. Both treating investigator/designee and observer will sign the administration form, 
thus confirming the correct volume will be instilled. 
Thereafter the treating investigator/designee will withdraw the exact volume required into 
the syringe. 
Once instillation is over, the treating investigator or designee who performed the 
instillation must complete the actual volume instilled and sign the administration form. The 
administration form must be filed in the study patient file. These steps MUST be repeated at 
each instillation.
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The Admixture will be instilled in a retrograde fashion via ureter catheter. In exceptional 
cases after approval by the trial coordinating PI, instillation through a nephrostomy tube may be 
conducted.
Due to the viscose nature of the Admixture the instillation must be done using the 
designated Injector Device supplied by UroGen.  For detailed instillation instructions please 
refer to the Instructions for Use (IFU) document as well as UroGen’s Injector Device 
Instructions for Use Manuel.
11.3.5. IP Instillation Schedule
MitoGel™ Admixture will be administered for therapy in the pyelocalyceal system as 6 
once-a-week, consecutive instillations, at Weeks 1, 2, 3, 4, 5, and 6.  Drug administration will 
be documented in the patient file, Case Report Forms (CRFs), and in the Drug Administration 
Records. For CR patients, additional instillations will be administered until 11M FU visit or 
until tumors' recurrence.
11.4. IP Accountability
The investigator is responsible for ensuring that all MitoGel™ Kits received at the site are 
inventoried and accounted for throughout the trial.  The MitoGel™ Kit should be dispensed 
under the supervision of the investigator or a qualified member of the investigational staff, or 
by a hospital/clinic pharmacist. The dispensing of a MitoGel™ Admixture to a patient will be 
documented in the pharmacy drug accountability form or electronic drug accountability logs.
The MitoGel™ Kit must be handled in strict accordance with the protocol and the 
container label, and must be stored at the site’s secure drug room or Pharmacy at a limited-
access area under appropriate storage conditions.  
Unused MitoGel™ Kits must be available for verification by the sponsor’s site monitor 
during on-site monitoring visits.  The return to the sponsor of unused or expired MitoGel™ Kits 
will be documented on the drug return form. Destruction of unused MitoGel Kits may be done 
on-site following written approval by the sponsor. Destruction must be documented in the "IP 
destruction form".
Used (Empty) MitoGel TM vial or kit boxes should be discarded after use and will not be 
reviewed by the sponsor’s site monitor.
The investigator agrees to neither dispense the trial drug from, nor store it at, any site other 
than the trial sites agreed upon with the sponsor.
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11.5. Replacement of Unusable MitoGel™ Kits
Unusable MitoGel™ Kits will be marked “not for use” in pen over the label and stored 
separately from usable MitoGel™ Kits. 
In addition, unusable kits will be disabled in the EDC. Disabling of the kit will trigger 
shipment of replacement kit, in case kits are scarce at site. 
Site should also notify of the need for additional MitoGel kits to the site CRA and email 
the sponsor's operations: 
.  
11.6. Assessment of IP compliance
At each treatment visit the actual dose administered will be documented in the 
Administration Form, which will be filed at the study file, and data recorded in the CRF, thus 
allowing monitoring of IP compliance.  
11.6.1. Assessment of the other treatment related drugs compliance
At each treatment visit, the site team will check the compliance of the patients taking the 
bicarbonate and antibiotics and results will be recorded in the patient’s file and in the CRF. The 
sites are requested to document the bicarbonate compliance on the supplied compliance log.  
Anti-histaminic drugs and relaxants are prescribed at the investigator's discretion therefore 
the data will be reviewed but not assessed for compliance.
11.7. Destruction of IP
Used MitoGel™ Kit vials should be discarded locally according to local institution 
guidelines for cytotoxic waste destruction.
Unused MitoGel™ Kits must be available for verification by the sponsor’s site monitor 
during on-site monitoring visits and will not be destroyed prior to Sponsor approval.  Once 
destruction is approved, site will destroy the kit locally and will document it in the destruction 
form and accountability log.
MitoGel™ Admixture vial and used syringe will be discarded at the clinic/urology 
department according to local institution guidelines for cytotoxic waste destruction
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12. Safety Evaluation 
12.1. Safety Assessment Prior and During the Treatment Period:
12.1.1. Adverse Event Collection
The patient's condition will be monitored throughout the study.  At each visit, adverse 
events (AEs) will be elicited using a standard non-leading question, such as “How have 
you felt since the last visit?”  In addition, any AE signs or symptoms that are observed 
will be documented;
The AE/safety assessment will be conducted by the investigator or qualified clinical 
staff.  The Investigator or qualified clinical staff will record the AEs on the Adverse 
Event Log provided in each patient’s chart and CRF;
The study period for AEs collection is defined from the ICF signature and up to 30 days 
following the last administration of investigational product unless the AE is suspected to 
be related to the study treatment, in such case the AE should be reported regardless to 
the timelines of the reporting period (refer to section 19.2);
All AEs will be collected as follows:
o
The patients’ response to questions about their health,
o
Symptoms spontaneously reported by the patient to be recorded in the CRF,
o
Clinically relevant changes and abnormalities observed by the Investigator (e.g., 
local and systemic tolerability, clinically significant laboratory measurements 
confirmed by repeated measurement, vital signs, results of physical examinations);
If an AE worsens in intensity, it should be recorded as a new AE.  If an AE gets milder 
in intensity, it continues as the first report until the patient is recovered.
12.1.2. Action Taken and Follow-up of AEs
AEs requiring intervention must be treated according to the standard care procedures to 
protect the health and well-being of the patient.  Appropriate resuscitation equipment and 
medicines must be available to ensure the treatment of an emergency situation.
Treatment due to an AE will be recorded as concomitant medication.
12.1.3. Follow-up of AEs
The investigator will follow up on each AE until it is resolved, until the medical condition 
of the patient is stable, or until the AE is otherwise explained by the PI.  All relevant follow-up 
information will be reported to the sponsor.  The outcome of an AE will be classified as 
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recovered, recovered with sequelae, not yet recovered, or death.
Adverse events will be reported according to Section 19- "Management of Adverse 
events".
12.2. Telephone Contact 24–32 Hours Post-treatment 
For patients treated via retrograde fashion only: 
 After each instillation in the treatment period, the patient will be given a questionnaire 
with the questions, and will be notified that the site will contact him/her the day after to collect 
the answers. Questions are: 

How long after the treatment did you have your first urination?  

How long after the treatment was the urine clear (no purple color) for the first time?
Twenty-four (24) to 32 hours post each instillation, the patient will be contacted (via 
telephone) and information for the questionnaire will be collected answers will be completed 
and form will be signed by the site.  At this point, any spontaneously reported adverse events 
will also be recorded.  If necessary, a patient may be summoned for an unscheduled visit to 
follow up on any post treatment adverse event that requires clinical evaluation or follow-up. 
See Appendix IV.
12.3. VAS Questionnaire - Pain Assessment During Treatment  
Following each of the instillations 1-6 the patients will be requested to mark the degree of 
pain they felt during the IP instillation (and not during catheter insertion), in a VAS 
questionnaire 0-10 (100mm scale).   The study coordinator than will measure with cm ruler 
from left to right and document the degree of pain in the patients' file and CRF [Wewers ME, 
Lowe NK, 1990]. 
12.4. Tests for Assessment of Safety
12.4.1. Pregnancy Test
A pregnancy urine test will be conducted in female participants of childbearing potential in 
each of the study visit.  If positive, a pregnancy blood test will be performed to verify.   A 
female is considered of childbearing potential unless she is:  
At least 12 months since the last menstrual bleeding; or
Without a uterus and/or both ovaries; or
Has been surgically sterile for at least 6 months prior to trial drug administration.
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12.4.2. Clinical Evaluation
At the specified visits, a full physical exam or urology-oriented physical exam 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.  Vital signs (including 
heart rate and blood pressure, temperature, and respiration rate) will be taken See Appendix I 
& Appendix II.
12.4.3. Laboratory Assessments
All general blood and urine specimens will be analyzed by Local lab (Appendix III for the 
listing of tests). Blood samples for analysis of plasma level of Mitomycin (Pharmacokinetics) 
will be sent to the central PK lab (Appendix VII: Collection and Handling of Plasma Samples 
for MMC Pharmacokinetics).
13. Trial Conduct and Procedures
Pre-Screening stage- this stage in aiming to eliminate the screening of patients without the 
potential to meet the study criteria due to some complexity of their situation which can affect 
their compliance, and also to improve the adherence to the protocol procedures and timelines. 
This stage is very important due to the complexity of this protocol. The sites will be given a 
pre-screening questionnaire which they should fill-in in a timely manner and send it to the 
sponsor prior the consenting process. 
13.1. Patient Eligibility Review and Enrolment to the Trial 
Every patient must first sign the informed consent.
In order to obtain screening number, the site will need to register the patient in the 
electronic CRF (eCRF). 
Soon after patient registration, the site will email to the site CRA and UroGen personnel 
 and 
 the de-identified source documents accompanied by 
completed submission form, no later than 7 working days after the screening visit. In 
addition, site will upload the Pyelography/CT/MRI images relevant for taking the 
eligibility decision to the secure 
.  The documents and images must be 
patient de-identified (with no personal patient identifiers) prior to upload.
Prior to the first instillation on Visit 1 (V1), patient eligibility to the trial must be 
confirmed by the sponsor. The sponsor will consult with the trial principle coordinating 
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investigator (Dr. Seth Lerner) on a case by case basis and will notify the site investigator 
via email about the patient's eligibility. 
Upon eligibility approval, the site will record the approval in the eCRF and will perform 
patient enrollment. Patient enrollment number will be given automatically by the CRF. 
Enrollment of patient into the trial must occur prior to the day of first instillation 
to allow enough time for kit dispensing via the EDC and preparation of the IP.  
Refer to section 23.2 for patient registration, and enrolment procedures.
13.2. Screening Visit (V0): -4 to -1 weeks
Following the informed consent process and mutual signatures on the ICF, potential 
patients will undergo the following screening procedures:
Review of eligibility criteria and determination of the patient’s eligibility based on 
patient file and medical history;
Medical history - Including specific information regarding previous recurrences of 
urothelial carcinoma in the bladder, urethra, ureter and in the UUT; including 
information about the Tumor stage, grade, morphology etc. (according to the 
documentation level in the CRF.); 
The following documentation is required only for enrolled patients.  Default Planned 
UTUC Treatment Documentation had the patient not been enrolled in the trail;
Smoking history documentation (current smoker? Number of years, cigarettes per day, 
smoking stop date);
CTU - In the event that a CTU from the last 3 months is not available, or the one that is 
available does not reflect the current disease episode, or in the event that the investigator 
believes that an updated CTU in the screening will lead to a better tumor evaluation due 
to a patient’s specific anatomy a new one should be obtained during the screening 
period; in the event that CTU is not applicable for any reason, an MRI should be 
performed instead.  
Concomitant medication – All ongoing medications/therapies, including prior 
therapies & procedures given for the previous urothelial carcinomas;
General physical exam, urology oriented physical exam, vital signs measurements 
(Appendix I & Appendix II);
Blood tests (Appendix III);  
Urinalysis and Urine Culture to rule out UTI
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Pregnancy serum test (for women with childbearing potential Appendix III);
Upper tract wash urine cytology - The upper tract wash urine cytology can be 
collected using ureteroscope or ureteral catheter (wash), before any biopsy or topical 
treatment was done.
Biopsy for histopathology - should be performed prior to recording tumor size and 
location. 
UUT urine cytology and biopsy need not be repeated if done within the past 2 months 
(or 3 months prior to the first instillation), provided the records can be made available 
for the trial and the slides can be reviewed by the trial central pathology service.  In 
this case, patients should be scheduled for a Screening Visit, during which URS for 
lesions mapping (when it was not documented properly within 8 weeks to the 
screening), and documentation as well as pyelography and volumetric estimation will 
be performed as described above (if not done as part of the SOC before the screening).
In the event that a patient has undergone surgical procedure in which the lesions 
were partially removed (i.e. de-bulking), the surgical procedure should be documented 
in the patient's medical history record; 
Diagnostic URS with C-ARM pyelography in order to demonstrate the pyelocalyceal 
system, by two views: 1. Superior view; 2. Oblique view in order to reveal hidden calyx 
/ baseline UUT lesion assessment and videotape/photography record (if not done within 
past 2 months or if the documentation wasn’t done according to the protocol 
requirements): 
o Number, location (upper calyx, middle calyx, lower calyx, renal pelvis, UPJ), size by 
visual estimation (the longest diameter); the measurement shall be performed post 
biopsy.  
o Lesion appearance (visually described as papillary, solid, nodular, or sessile).  
Information must be recorded in the worksheet "UUT Lesion Documentation Form" 
provided by the Sponsor.
o In case URS needs to be repeated at screening but the investigator does not wish to 
repeat the test due to medical considerations (e.g., general anesthesia), a CTU can be 
performed instead if this test can reflect the tumors status for the specific patient (e.g., 
tumors is bigger than 4mm) 
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Pyelography for assessment of the upper tract anatomy and volume measurement: The 
volumetric measurements of the “Pyelocalyceal System” (PS) should be performed 
under fluoroscopy and be documented. The “Contrast Agent admixture 20%” (CA) shall 
be injected to the PS, until the CA start to flow backwards below the UPJ. The estimated 
total volume to be injected may vary due to patient’s PS anatomy. The volumetric 
measurements shall be repeated three times followed by mean calculation of the CA 
injected to the PS.  MitoGel™ volume to be instilled to the PS shall be 100% of the 
measured PS or 15mL, whichever is lower. The volumetric measurement should be 
documented in the source data and the CRF;
If a single J in-dwelling ureteral catheter is to be used for instillation, catheterization can 
be done at any time during the screening period prior to treatment.  In case that single J 
catheter remained in the pyelocalyceal system, reduce from the measurable volume 1 
mL IP (dead volume) which is left in the catheter (e.g., measured volume is 11 mL the 
volume to be injected is 10mL).  Following the instillation, the single J catheter should 
be flushed with 1.5mL of WFI in order to keep the catheter shaft open.
The decision on whether to enroll patient into the trial will be based on the histopathology 
and cytopathology results obtained from the local institutional pathologist; however, all 
biopsies and urine cytology obtained at Screening/baseline (or earlier if within 2 months of 
screening) and at PDE will be reviewed again centrally.  The results of the central reading will 
be used as a sensitivity analysis.
The sponsor highly recommends to wait for the central review prior the beginning of any 
treatment administration to have a better confidence that the patient is having LG disease. 
Once all eligibility criteria have been confirmed, the patient will be registered into the 
trial by receiving an enrollment number.  This should take place prior to treatment with 
sufficient lead-time to allow for preparation of the IP by the pharmacy;
Patient should be prescribed with sodium bicarbonate in advance and should be given 
written instructions to consume 1.3 g of Sodium Bicarbonate the night before 
instillation, the morning of, and 30 min (total of 3.9 g) prior to the instillation, in case 
that patient is planned to be anesthetized, bicarbonate may not be taken 30 minutes prior 
to the treatment.  If patient is enrolled, a reminder phone contact to the patient should be 
done the day before the instillation;  
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Aiming to minimize the risk for Urinary Tract Infections (UTI), especially Acute 
Pyelonephritis, anti-microbial prophylaxis (e.g., Ciprofloxacin) should be prescribed 
according to the AUA Best Practice Policy Statement on Urologic Surgery 
Antimicrobial Prophylaxis (See Appendix VI:  Recommended Antimicrobial 
Prophylaxis for Urologic Procedure);
Prophylactic anti-allergic treatment – Anti-histaminic agents to be taken the day before 
instillation, on the day of instillation and up to three days after the instillation; this 
treatment will be at the investigator's discretion.
It is recommended to allow the patients using a relaxing pill such a diazepam 5-10 mg 
(or any other relaxation pill) to reduce the anxiety before each of the instillations; 
Patient should be given patient guidance letter for UUT MMC-TC-3 Gel instillation. 
Patient should be provided with a patient card with treatment information and 
investigator details to be contacted in case of an emergency;
Patient should be provided with a letter notifying his general physician about his 
participation in the study.
13.3. Treatment Visits 
The pharmacy should be notified ahead of time regarding the required preparation of 
MitoGel™. Prescription signed by the investigator must be provided ahead.  
13.3.1. General Instructions for Instillation Visits 
In the first part of the study, all enrolled patients will undergo six (6) weekly UUT 
instillations - (± 3 day).
Prior to MitoGel™ administration, except the first treatment, the treating investigator 
MUST review the last patient’s safety lab results to determine if the instillation can be 
performed as planned. The review must be documented in the patient medical file prior 
to study treatment.
Following are the threshold parameters for acceptable laboratory values prior to each 
treatment*, blood tests will be performed according to Appendix III.  These tests must 
be done no longer than 3 days prior to the instillation and can be done also in the 
patient’s local clinic** if not feasible to have them done within short time period in the 
hospital: 
o
Absolute neutrophil count ≥1,000/μL (≥1.0×109/L),
o
Platelets ≥80,000/μL (≥80×109/L)
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o
AST (SGOT)/ALT (SGPT) ≤5 × upper limit of normal (ULN)
o
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.
* The results of these specific test must be reviewed prior to each treatment. 
Exception in Visit 1: Tests should be taken but results may be reviewed after the 
treatment.
If laboratory parameters do not conform to the detailed above, treatment will be 
postponed until laboratory values improve, for up to 4 weeks.
In the event of urinary tract infection or another safety reason which causes the PI 
to postpone a treatment, the treatment will be postponed until the event is resolved 
and not over 4 weeks; In case treatment has been delayed beyond 4w due to ADR 
(adverse drug reaction) study treatment will be discontinued permanently however 
study follow-up will be continued. 
Volume of MitoGel™ Admixture to be instilled (see Screening [V0] for details) – 
o The volume to be instilled will be based on estimation of the pyelocalyceal space 
conducted during the screening / prior to treatment initiation. 
o The volume of contrast agent required to fill the pyelocalyceal space (without causing 
distention) shall be measured.
o To increase accuracy, an average of three (3) measurements should be carried out.  In 
case the number contains decimal fraction, please round it as follows:
≥0.5 - round it up to the closest whole number. 
<0.5 - round it down to the closest whole number.  
o Repeated volumetric measurements may be performed prior to each instillation, at the 
discretion of the treating investigator. 
o The volume of MitoGel™ instilled will be 100% of the estimated pyelocalyceal 
volume or 15 mL (whichever is lower); all the measurement procedure and each of 
the three (3) measurement must be recorded in the patient’s source document and in 
the CRF. 
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Sodium Bicarbonate:  The Patient will be given 1.3 g Sodium bicarbonate tablets AND 
written instructions/dosing diary to consume 1.3 g of Sodium Bicarbonate orally, the 
night before the instillation, the morning of instillation, and 30 minutes prior to the 
instillation procedure (total of 3.9 g); in case that patient is planned to be anesthetized, 
bicarbonate might not be taken 30 minutes prior to the treatment.   
Diuretics:  It is preferred that diuretics not be taken the night before and prior to the 
instillation.  If a patient is on diuretic medications, the PI should determine, based on 
his/her clinical judgment whether the medication can be skipped prior to the instillations 
as recommended above and should advise the patient on the diuretics use during the 
study; 
Pre-instillation drinking:  General guidelines for drinking instruction pre- and post-
instillation are included below.  The need for de-hydration will be decided by the 
physician based upon the clinical guidelines mentioned herein:
o To the extent that it is possible, drinking should be avoided in the 4-6 hours prior to 
the instillation. 
Post instillation drinking should be limited. A recommended drinking schedule 
follows:
o 0-2 hours post instillation: refrain from drinking any liquid; 
o 2-4 hours post instillation: 1 cup of water every 2 hours;
o 4 hours post instillation: resume normal liquids consumption ;
o Following instillation, the patient will be carefully monitored for urine output and 
clinical symptoms, which might indicate urinary obstruction. Special caution should 
be taken in single kidney patients. Pre and post-Instillation Patient’s Instructions will 
be provided to the patient prior to the first instillation (Patient Guidance Letter).
Prophylactic antibiotics:  Aiming to minimize the risk for Urinary Tract Infections 
(UTI), especially Acute Pyelonephritis, anti-microbial prophylaxis will be prescribed 
(e.g., Ciprofloxacin) according to the AUA Best Practice Policy Statement on Urologic 
Surgery Antimicrobial Prophylaxis (See Appendix VI);
Prophylactic anti-allergic treatment – Prophylactic anti-allergic treatment will be 
given per PI discretion. Recommended regimen–Anti-histaminic agents to be taken the 
day before instillation, on the day of instillation and 1-3 days post instillation. 
Diazepam (5-10 mg) (or any other relaxation pill) will be given before instillations 
according to the PI discretion to reduce the anxiety. 
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Local ointment for protection of skin - Use of local ointment prior to instillation for 
reduction of local irritation around the genitalia;
Special precautions should be taken with females; the woman shall be instructed to 
carefully wash the genitalia following each urination during the day of instillation 
followed by using local ointment on the genitalia.
13.3.2. Treatments as Needed
Management of dysuria - Local and systemic analgesics administration; 
Management of other lower urinary tract symptoms (LUTS) such as Frequency/ 
urgency/incontinence - Use of anticholinergic agents if not contraindicated;
Diazepam 5-10 mg (or any other relaxation pill) as an optional therapy, to reduce 
anxiety before each instillation. To be given an hour before. The patient should be 
cautioned of driving on that day. 
13.3.3. Instillation Procedure 
For the instillation procedure the site should first verify they have Protocol TC-UT-03-P 
ancillaries, Injector device, and IFU manual. 
MitoGelTM Admixture must be instilled by study authorized person as documented in 
the delegation log and only after proper training was given regarding the instillation 
procedure. 

For instillation, a 7–8 Fr ureter catheter supplied by UroGen shall be used. In situations 
where it is technically challenging to pass the 7Fr catheter, a 5Fr Ureteral Catheter with 
molded Luer-Lock port may be used.
Due to the viscose nature of the MitoGelTM Admixture the instillation must be done 
using the designated Injector device supplied by UroGen.  Please refer to the UroGen’s 
Injector Device Instructions for Use Manuel for detailed instillation instructions.
Instillation volume of MitoGel™ Admixture/Administration Form: The pharmacy will 
dispense a 17-20 mL MitoGel™ Admixture for every instillation regardless of the 
individual volume required.
Prior to every instillation, the investigator must review the pyelocalyceal volume 
measurement done for that patient. A repeated volumetric measurements may be 
performed prior to each instillation, at the discretion of the treating investigator. 
The investigator must withdraw the exact volume required into the syringe, and 
document the required volume in the supplied Administration Form.  The required 
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volume information and syringe filling should be completed in the Administration 
Form, and confirmed by additional trial authorized personnel who should be 
present at that time.  Both must sign the Administration Form before instillation 
begins. Once instillation is over, the investigator or designee who performed the 
instillation must complete the actual volume instilled and sign the Administration 
Form. The Administration Form must be filed in the study patient file.
To obtain better dispersing of MitoGel™ Admixture in the pyelocalyceal system, the 
patient should be in Trendelenburg Position (if possible) lying down on the side that 
should be treated.
In cases where Trendelenburg Position can't be obtained, the patient should lie down (if 
possible) on the side that should be treated. 
The following procedures should be conducted during all instillations: 
Prior to MitoGelTM administration, cystoscopy should be performed (SOC) to obtain 
screening of the urethra and the bladder for abnormal findings. 
Pyelography- Prior to every instillation pyelography with contrast agent shall be 
performed to demonstrate pyelocalyceal system for abnormal findings and to verify that 
the catheter tip, is located above the UPJ for proper instillation to the renal pelvis.  The 
technique for an office-based approach for placement of ureteral catheter has been 
previously described (Nepple, 2009).   If a single J catheter is being used, the insertion 
of the catheter can be done prior to the treatment visit under pyelography (see above). 
Placement of guidewire and ureteral catheter shall be performed under fluoroscopy.
Advance guidewire through the cystoscope working channel via the ureter to the renal 
pelvis.
Anchor the guidewire in the renal pelvis and remove the cystoscope.
Advance the ureteral catheter over the guidewire to the preferable location in the renal 
pelvis and take photos to document the location of the catheter tip.  Preferable location 
will be considered as the place where the flow from the catheter tip of the 
investigational product will enable best coverage of the renal pelvis and the calyces.
MitoGel™ Admixture administration shall be according to individual dose/volume 
(Installation instructions-to be provided in the study manual); 
The same documentation is required also for patients administered through a 
nephrostomy tube: 
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In case of instillation via nephrostomy tube – the nephrostomy tube types allowed 
are Silicon or Simplastic.
Latex is not allowed, due to fear of rupture.
At the end of the instillation the catheter must be washed with 2 cc of saline, to 
remove remaining MitoGel™ Admixture.  Prior to patient leaving the clinic the site 
staff must verify that the patient urinates via the nephrostomy tube, by watching 
the urinary bag filling.
13.3.4. Instillation #1 Visit Procedures (V1):
The following procedures should be conducted prior to 1st instillation:
It is recommended to perform the first instillation in the OR under sedation. 
Patient reminder phone call shall be done a day before the treatment regarding antibiotic 
treatment, bicarbonate, antihistamine (if applicable) and limited drinking and diuretics; 
Confirmation of patient's eligibility; 
Confirmation that the safety labs results are available. 
Confirmation of limited drinking and/diuretics as per need;
Safety assessment, see Section 13.3.6;
On treatment day - Verification of consumption of oral dose of 1.3 g of sodium 
bicarbonate the night before the instillation, at the morning of and 30 minutes prior to 
the instillation procedure; Completion of bicarbonate compliance log. In case that 
patient is planned to be anesthetized, bicarbonate should not be taken 30 minutes prior 
to the treatment.  
Verification /administration of prophylactic anti-biotic treatment
Verification of consumption of oral dose of prophylactic anti-allergic treatment (if 
applicable).  The anti-histaminic agents should be consumed the day before instillation, 
on the day of instillation and 1 to 3 days following the instillation.
Pre-Dose MMC PK blood draw (when applicable; See PK instructions, Appendix VII: 
Collection and Handling of Plasma Samples for MMC Pharmacokinetics);
Evaluation and recording of AE and concomitant medications;
Urology oriented physical exam & vital signs measurements (Appendix II & Appendix 
III);
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Blood tests (Appendix III); In case patient preformed all required blood test according 
to Appendix III up to 3 days prior to the instillation- no need to repeat;
Urinalysis/dipstick;
Review of urine culture results from the Screening Visit;
If urine dip-stick is positive for pregnancy, serum pregnancy test should be performed. 
In this case, the instillation should be postponed until the serum pregnancy test results 
are available. If pregnancy test is positive, patient should be discontinued from study.
The following procedures should be conducted post instillation:
Recording of pain during the instillation procedure by the patient, by marking the score 
on the 0-10 scale VAS for pain*.
Following the first instillation, the patient should remain in the clinic/hospital for at 
least 6 hours for general observation; the patient will not be discharged before the first 
free urination. The medical team should document the patient assessment timely before 
leaving the clinic.
At the first treatment subset of patients (N=6) who gave informed consent, PK samples 
will be collected for MMC plasma level measurements; a notification will be sent to the 
study sites, when all the six specimens will be completed in order to stop offering the 
other patients this procedure. If from some reason, a sample from a patient will be 
destroyed, another patient will be picked to complete the quorum.
o MMC plasma level measurements:
The samples will be collected at 0 (pre-dose) and 30 min, 1, 2, 3, 4, 5, and 6 hours 
post instillation.  At each time point, 3 mL of blood will be collected to yield at least 
1.5–2 mL of plasm after centrifugation.  Altogether, a total of approximately 24 mL 
of blood will be collected for PK samples for each patient who signed an informed 
consent and contributed to this portion of the trial. The plasma samples will be 
analyzed by validated bioanalytical assay.
For detailed information, please refer to Appendix VII: Collection and Handling of 
Plasma Samples for MMC Pharmacokinetics;
Recording of AE post instillation;
* Local pain will be assessed by the Patient using a Visual Analogue Scale (VAS) provided by UroGen.
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Documentation of concomitant medications;
Telephone contact 24–32 hours post treatment (section 13.3.7);
Patient should be given or prescribed (not recommended) with 1.3 g Sodium 
bicarbonate tablets AND written instructions to consume 1.3 g of Sodium Bicarbonate 
the night before instillation, the morning of, and 30 min (total of 3.9 g) prior to the 
instillation; 
24-30 hour questionnaire should be provided; 
A reminder phone call to the patient should be done the day before treatment.
13.3.5. Instillations #2–#6 Visit Procedures (V2–V6):
The allowed visit window deviation is ±3 days. 
A reminder phone call to the patient should be done the day before the treatment 
regarding the following:
o
Confirmation that the safety labs results are available. 
o
Bicarbonate and antibiotic, antihistamine (if applicable) and limited drinking 
/diuretics uptake;
The following procedures should be conducted prior to every instillation:
Verification of consumption of oral dose of 1.3 g of sodium bicarbonate the night before 
the instillation, at the morning of and 30 minutes prior to the instillation procedure; In 
case that patient is planned to be anesthetized, bicarbonate should not be taken 30 
minutes prior to the treatment.  
Verification of consumption of oral dose of prophylactic anti-allergic treatment.  Where 
used, the anti-histaminic agents should be consumed the day before instillation, on the 
day of instillation and the day after the instillation.
Confirmation of limited drinking and/diuretics as per need,
Safety assessment, see Section 13.3.6;
Evaluation and recording of AEs and concomitant medications;
Urology oriented physical exam & vital signs measurements; 
Blood tests according to Appendix III; in case patient preformed all required blood test 
according to Appendix III up to 3 days prior to the instillation - no need to repeat;
Urinalysis/dipstick;
Urine Culture (only when applicable); 
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Urine test for pregnancy - when applicable;  
Serum pregnancy tests may be performed only if urine test is positive for pregnancy- 
results must be available before the next instillation. In the case that a serum pregnancy 
test is conducted, the instillation should be postponed until the serum pregnancy test 
results are available. If pregnancy test is positive, patient should be removed from study.
The following procedures should be conducted during the instillation:
Prior to IP administration, cystoscopy should be performed (SOC) to obtain screening of 
the urethra and the bladder for abnormal findings.
Cystoscopy for catheterization as described herein above followed by ureteral catheter 
placement under fluoroscopy in the preferable location in the renal pelvis;
MitoGel™ Admixture administration according to individual dose/volume; 
Patients will be requested to record VAS for pain to describe the degree of pain they felt 
during the instillation procedure. The patients will complete the VAS immediately after 
the procedure (only at visits 1-6).
The following procedures should be conducted post instillation:
Recording of AE post instillation;
24-32 hour questionnaire should be provided (only at visits 1-6);
Telephone contact 24–32 hours post treatment (section 13.3.7) (only at visits 1-6);
CBC (complete blood count), renal and liver function tests - Should be performed in 1st 
week and 3rd week following the 6th instillation. This blood test can be performed also in 
the patient's local clinic. Results should be recorded in the CRF.
13.3.6. Safety Assessment Prior and During the Treatment Period
In addition to general inquiry about patient's condition, prior to each instillation, the 
physician should query the patient specifically regarding pain, especially in the lower abdomen, 
flank, or urethra.  The physician should also inquire whether the patient has experienced 
symptoms suggestive of obstruction, urinary tract infection, or allergic reaction to MMC.  If 
symptoms of obstruction/UTI or allergy are backed up by physical/laboratory tests treatment 
will be postponed until symptom resolution.
In cases of allergic response to MMC, antihistamines with/without cortisone treatment may 
be administered at the physician's discretion.  Allergic response severity must be assessed 
according to CTCAE version 4.03 in Appendix VIII.
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Any unexpected AE related to MitoGel™ and qualified per National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) as grade 3 or 4 will be evaluated 
by the sponsor medical team and steering committee. In case of need, a DMC meeting will be 
gathered.
The following information about the AE must be included in the CRF: 
Reporting person details;
Adverse event and relevant clinical findings;
Time/date of onset;
Time/date of recovery;
Intensity/Severity (mild, moderate, severe, life threatening, lethal);
Action taken on study drug;
Other actions taken to treat the event;
Toxicity Grade according to CTCAE 4.03 (Investigator to designate);
Causality: relationship to study drug (Investigator to designate);
Seriousness of the AE;
The study period for AEs collection is defined as 30 days following the last 
administration of trial treatment unless the AE is unexpected and suspected to be related 
to the study treatment, in such case the AE should be reported regardless to the scope of 
reporting period.  
13.3.7. Telephone Contact 24–32 Hours Post-treatment (visits 1-6)
After each instillation, the patient will be given a questionnaire and requested to capture 
his/her post-treatment experience:  first urination time, and remnant of gel in the urine 
(Appendix IV).  Twenty-four (24 to 32 hours post each instillation, the patient will be 
contacted (via telephone) and answers for the questionnaire will be collected, and the 
questionnaire will be returned at the next visit.  At this point, any spontaneously 
reported adverse events will also be recorded.  If necessary, a patient may be called for 
an unscheduled visit to follow up on any post-treatment adverse event that requires 
clinical evaluation or follow-up.
13.4.  LAB 1 (V7) & LAB 2 (V8):
One week and 3 weeks following the last of the weekly instillations, CBC (complete blood 
count), renal and liver function tests will be done for safety control. A deviation window of ± 
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3d is allowed. 
These tests may be done in lab which is external to the hospital. In case of use of an 
external lab, the external lab's quality assurance documentation, normal ranges and CV of head 
lab must be collected by the site.
13.5. Primary Disease Evaluation Visit (PDE, V9)
5 weeks (± 1 week) Post last instillation. 
Following completion of the instillation treatment series, a 5-week ± 1 week healing period 
prior to evaluation of treatment response and, if needed, performance of ureteroscopic resection 
of remaining UTUC lesions.  At the PDE visit, the following activities will be performed: 

Review and recording of AEs and concomitant medication; 

Full physical examination and vital signs measurements (Appendix I and Appendix II);

Blood tests and urinalysis (Appendix III);

Urine culture (only when applicable);

Pregnancy tests (for women with childbearing potential; Appendix III); 

Upper tract urine cytology (Appendix III) - The upper tract urine must be collected using 
a catheter (wash), before any biopsy or topical treatment was done.

UUT lesions status, i.e., number of lesions, lesion size, location and morphology of 
remaining lesions (if any) will be assessed visually during the URS and documented in the 
patient's file. Document the lesions in the UUT Lesion Documentation Form;

Biopsy or brush biopsy for histopathology for all remaining tumors if technically feasible;

Evaluation of response (Section 14)

Re-Evaluation of UTUC Treatment – Has UTUC treatment plan changed compared to 
prior entering the trial? N / Y, and planned treatment.
13.5.1. Complete Response (CR) patients

For patients who demonstrate Complete Response (CR) evaluated by visual inspection via 
URS upper tract urine cytology will be performed to confirm no residual disease (See 
Section 9.2.1) 

Patient demonstrating CR at PDE will undergo a maintenance MitoGel™ treatment (refer 
to section 11.3.5). 
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13.5.2. Non-CR patients

For patients who did not demonstrate CR, to the extent that it is possible, all remaining 
lesions will be biopsied. The patients shall undergo any additional surgical or other 
treatment the PI decides deem necessary to treat the patient.  The tumor location, size and 
grade, as well as the surgical procedure or treatment provided to treat the remaining 
disease will be documented; 

If no lesion was detected via URS, but the UUT urine cytology from the upper tract is 
equivocal positive, patient will be re-evaluated by urine cytology prior to the next 
scheduled maintenance treatment (~3 weeks after the original cytology test at the PDE) 
and prior to the instillation on that day. If the urine cytology is negative, the patient will 
be considered as a CR. If repeated cytology results are positive or equivocal, patient will 
be considered as not having CR (i.e., CR = “failure”; see Section 9.2.1)
13.6.
CR Patients Maintenance Instillations (Maintenance Visits)
A maintenance treatment will start immediately after the local lab confirms that patient's 
cytology is negative for cancer, and no longer than 3 weeks post PDE, unless there is a medical 
condition which requires postponing the treatment. In these cases, the first maintenance 
instillation should be delayed until recovery. 
Maintenance Regimen – MitoGel™ Admixture will be given once monthly (±1 week) 
until one month prior to last FU visit within the study (i.e., until Month 11 post PDE).  
Safety assessment – During maintenance treatment at each instillation the patients will 
have performed in the hospital local lab, safety lab tests, physical examination and vital 
signs per protocol (see Appendix I - Appendix II).  For patients who drop out of the 
study safety will be assessed according to the SOC.
13.7. Follow-up Visits (V12, V15, V18, V21)
Follow up visits for patients who demonstrate CR will be performed 3, 6, 9, and 12 months 
following the PDE:
Allowed visit window deviation for each of the FU visits is ±2 wks. 
The following activities will be performed: 
Review of unresolved AEs and recording of newly AEs (See Section 19 for management 
of AEs) 
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Physical examination & vital signs, and laboratory tests required the investigator think 
are required for the follow up on any unresolved AEs, should be conducted at the 
discretion of the investigator or according to the Standard of Care (SOC)
CTU (only in FU 12 months (V21)
Blood tests and urinalysis (Appendix III)
Pregnancy tests (for women with childbearing potential only)
Upper tract washing urine cytology at every Follow-up Visit (Appendix III).  The 
upper tract urine must be collected using catheter (wash), before any biopsy or topical 
treatment was done
Review of concomitant medications 
During FU period, patients will be followed-up for twelve months (12) or until disease 
recurrent or progression; however, during this period the following activities should be done: 
When done, histopathology results will be recorded in the patient's FU records,   
The presence of UUT lesions and status will be visually assessed during URS.  
Recurrence, progression (defined as increase in grade or stage), or durable CR (defined 
as NDD) will be determined for each patient 
Recurrence is to be confirmed by histopathology. To rule out recurrence biopsy of all 
visible lesions must be negative for urothelial carcinoma.
Recurrence for the analysis purpose will only count the direct recurrence of the original 
treated area, meaning the upper urinary tract above the UGJ.  Disease 
appearance/recurrence in other locations will be documented in the CRF, but will not be 
considered in this trial as a tumor recurrence. 
In case of disease progression in the UT during the follow-up period, the patient will be 
considered as a durable CR until the time of the progression findings.  In case of 
recurrence or progression assessed during the FU period, the patient will be considered 
as having completed the trial and will not be summoned for further follow-up visits.
13.8.
Unscheduled Visit
An unscheduled visit may be performed at any time during the trial if the investigator 
decides that the clinical state of the patient does not permit instillation of the IP, for assessment 
of safety, at the Patient's request, or as deemed necessary by the investigator.  The date, reason, 
and procedures done in unscheduled visit will be recorded in the patient's file and the CRF. 
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13.9.
Treatment Discontinuation 
Treatment discontinuation prior to PDE
If a patient discontinues during the treatment period or at any time prior to the PDE Visit, 
the patient to complete PDE visit within 4+/-1 week of last instillation and perform all 
assessments of the PDE visit (Section 13.4);
If the patient appears to have CR at PDE, patient should continue FU within the trial 
receiving the maintenance treatments should be considered as well; 
If patient agrees for FU within the trial or agrees to continue to share information regarding 
his/her disease status, information collected during the FU care of the patient should be 
recorded in the CRF.
Treatment Discontinuation during Maintenance 
If patient discontinues during the maintenance period or at any time after PDE visit, an 
unscheduled visit should be done (one month after the last installation treatment), in which 
following activities should be performed:
Full physical examination and vital signs measurements 
Blood tests and urinalysis
Pregnancy tests (for women with childbearing potential)
Review and recording of AEs and concomitant medication 
If patient agrees to continue to share information regarding his/her disease status, information 
collected during the FU care of the patient should be recorded in the CRF.
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14. Schedule of Events 
14.1.Part I - All Patients - Up to PDE Visit
Treatment period
Study Week†
Wk
(-)4-(-)1
Wk 0
Wk 1 
(±3 d)
Wk 2
(±3 d)
Wk 3 
(±3 d)
Wk 4 
(±3 d)
Wk 5 
(±3 d)
Wk 6
(±3 d)
Wk 8
(±3 d)
Primary Disease 
Evaluation
Wk 10
(±1 w)
Visit Number
V0
V1
V2
V3
V4
V5
V6
V7
V8
V9
Visit Name
Screening‡
Tx #1
Tx #2
Tx #3
Tx #4
Tx #5
Tx #6
Lab 1
Lab 2
PDE
Informed consent
X
Demographics
X
General and Urothelial 
Carcinoma Medical History, 
Smoking
X
Concomitant Medications 
Review
X
X
X
X
X
X
X
X
Eligibility criteria
X
X§
Full Physical Examination 
X
X
Urology oriented Physical 
Examination
X
X
X
X
X
X
X
X
Vital signs♠
X
X
X
X
X
X
X
X
†
Time windows for study visits: V2-V6 ±3 day; V9 ±1 week
‡
Screening activities may be performed on separate days as long as they are completed within the screening period, before treatment starts.
§
Investigator and sponsor confirmation of eligibility prior to instillation. Entry into the trial will be based on the local pathologist diagnosis.
♠
Vital signs: Body temperature, blood pressure, heart rate, height and weight (screening) 
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Treatment period
Study Week†
Wk
(-)4-(-)1
Wk 0
Wk 1 
(±3 d)
Wk 2
(±3 d)
Wk 3 
(±3 d)
Wk 4 
(±3 d)
Wk 5 
(±3 d)
Wk 6
(±3 d)
Wk 8
(±3 d)
Primary Disease 
Evaluation
Wk 10
(±1 w)
Visit Number
V0
V1
V2
V3
V4
V5
V6
V7
V8
V9
Visit Name
Screening‡
Tx #1
Tx #2
Tx #3
Tx #4
Tx #5
Tx #6
Lab 1
Lab 2
PDE
CBC, liver and renal function, 
coagulation **
X
X
X
X
X
X
X
X 
coagulation 
not required
X 
coagulation 
not required
X
Urinalysis/dipstick
X
X
X
X
X
X
X
X
Urine culture
X
X††
X††
X††
X††
X††
X††
X††
CTU or MRI
X‡‡
Biopsy for histopathology
X§§
X***
Upper Urinary Tract Urine 
cytology-washing
X§§
X
Pregnancy serum test †††
X 
X‡‡‡ 
X‡‡‡
X‡‡‡
X‡‡‡
X‡‡‡
X‡‡‡
X‡‡‡
Pregnancy urine test †††
X 
X
X
X
X
X
X
**       If done one week prior to screening, acceptable. Treatment period- To be performed before the instillation, see Appendix III
 
In case patient preformed all required blood test according to Appendix III up to 3 days prior to the instillation- no need to repeat;
††  
To be performed when UTI is suspected according to urinalysis results. 
‡‡
CTU to be repeated if done more than 3 months prior to first treatment. In the event that CTU is not applicable from any reason, an MRI should be performed instead
§§ 
Histopathology and cytology evidence of LG UTUC performed ≤2 months prior to V0 (or 3 months prior to the first instillation) is acceptable provided that the slides can be sent for central 
pathology evaluation. All Histopathology evaluations performed locally will be reviewed centrally. 
*** 
Biopsy will be taken at PDE and any follow up visit when lesions are detected and recurrence is suspected.
†††   Only for women of childbearing potential
‡‡‡   Only for women of childbearing potential and a positive pregnancy urine test
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Treatment period
Study Week†
Wk
(-)4-(-)1
Wk 0
Wk 1 
(±3 d)
Wk 2
(±3 d)
Wk 3 
(±3 d)
Wk 4 
(±3 d)
Wk 5 
(±3 d)
Wk 6
(±3 d)
Wk 8
(±3 d)
Primary Disease 
Evaluation
Wk 10
(±1 w)
Visit Number
V0
V1
V2
V3
V4
V5
V6
V7
V8
V9
Visit Name
Screening‡
Tx #1
Tx #2
Tx #3
Tx #4
Tx #5
Tx #6
Lab 1
Lab 2
PDE
Ureteroscopy (URS)+C arm
X§§§
X
Recording/ Photographing of 
UUT lesions number, size, 
appearance and location 
X
X
Volumetric estimation 
(retrograde pyelography and 
fluoroscopy) 3 repetitions
X
Provide prescription for 
sodium bicarbonate, 
Prophylaxis antibiotic, anti-
histaminic and 
diazepam(optional) and written 
instructions
X
Patient card, letter to GP, 
Guidance letter to patient
X
Fluoroscopy 
X
X
X
X
X
X
Cystoscopy for catheterization 
X
X
X
X
X
X
MitoGel™ Admixture 
administration  
X
X
X
X
X
X
§§§
URS to be repeated If done more than 2 months prior to V0, or in case it is not informative enough for the trial. In case URS cannot be performed, other method may be used for baseline lesion/s 
mapping
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Treatment period
Study Week†
Wk
(-)4-(-)1
Wk 0
Wk 1 
(±3 d)
Wk 2
(±3 d)
Wk 3 
(±3 d)
Wk 4 
(±3 d)
Wk 5 
(±3 d)
Wk 6
(±3 d)
Wk 8
(±3 d)
Primary Disease 
Evaluation
Wk 10
(±1 w)
Visit Number
V0
V1
V2
V3
V4
V5
V6
V7
V8
V9
Visit Name
Screening‡
Tx #1
Tx #2
Tx #3
Tx #4
Tx #5
Tx #6
Lab 1
Lab 2
PDE
VAS for pain evaluation
X
X
X
X
X
X
6 hours observation post 
treatment 
X
1.3 gr  3 of sodium 
bicarbonate (|The night before, 
morning of and 30 min. prior to 
treatment) 
X
X
X
X
X
X
MMC level (plasma) ****
X ††††
Phone reminder day prior to 
instillation: Bicarbonate, liquid 
limitation, diuretics, 
X
X
X
X
X
X
Supply questionnaire for 24-32 
h Post treatment telephone 
contact‡‡‡‡
X
X
X
X
X
X
24-32 h Post treatment 
telephone contact ‡‡‡‡
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X §§§§
**** In 6 treated patients
†††† Prior to instillation, 30min., 1, 2, 3, 4, 5, and 6 hours post instillation
‡‡‡‡
For patients treated in retrograde fashion only
§§§§ Review of unresolved AEs and recording of newly emerging AEs considered to be related to participation in the study (See Section 19)
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Part II –Maintenance & Follow Up - Complete Response Patients
Maintenance Treatment (±1 w)
Study Month*****
up to 3 
Weeks 
post 
PDE
FU1
+3mo  
Post 
PDE
(±2 w)
FU2
+6mo 
Post 
PDE
(±2 w)
FU 3
+9mo
Post 
PDE
(±2 w)
FU 4
+12mo
Post PDE
 (±2 w)
Visit Number
V10
V11
V12
V13
V14
V15
V16
V17
V18
V19
V20
V21
Visit Name
Maint. 
#1
Maint. 
#2
Maint. 
#3
Maint. 
#4
Maint. 
#5
Maint. 
#6
Maint. 
#7
Maint. 
#8
Maint. 
#9
Maint. 
#10
Maint. 
#11
FU4
Trial 
Completion
Urology oriented Physical Examination
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
CBC, liver and renal function, 
coagulation†††††
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis/dipstick
X
X
X
X
X
X
X
X
X
X
X
X
Urine culture‡‡‡‡‡
X
X
X
X
X
X
X
X
X
X
X
X
CTU Scan
X§§§§§
Biopsy for histopathology******
X
X
X
X
*****  Time windows for study visits V10, V12, V15, V18, V21 ±2 weeks.
†††††  CBC, liver and renal function, coagulation tests to be performed before the instillation, see Appendix III
‡‡‡‡‡ To be performed when UTI is suspected according to urinalysis results
§§§§§ At the 12 M FU Visit, CT scan should be obtained for all patients who continue to demonstrate CR
****** Biopsy will be taken at PDE and any follow up visit when lesions are detected and recurrence is suspected.
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Maintenance Treatment (±1 w)
Study Month*****
up to 3 
Weeks 
post 
PDE
FU1
+3mo  
Post 
PDE
(±2 w)
FU2
+6mo 
Post 
PDE
(±2 w)
FU 3
+9mo
Post 
PDE
(±2 w)
FU 4
+12mo
Post PDE
 (±2 w)
Visit Number
V10
V11
V12
V13
V14
V15
V16
V17
V18
V19
V20
V21
Visit Name
Maint. 
#1
Maint. 
#2
Maint. 
#3
Maint. 
#4
Maint. 
#5
Maint. 
#6
Maint. 
#7
Maint. 
#8
Maint. 
#9
Maint. 
#10
Maint. 
#11
FU4
Trial 
Completion
Upper Urinary Tract Urine cytology-
washing
X
X
X
X
Pregnancy urine test ††††††
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy serum test ‡‡‡‡‡‡
X
X
X
X
X
X
X
X
X
X
X
X
Ureteroscopy (URS)
X
X
X
X
Recording/Photographing of UUT 
lesions number, size, appearance and 
location
X
X
X
X
Fluoroscopy
X
X
X
X
X
X
X
X
X
X
X
Cystoscopy for catheterization
X
X
X
X
X
X
X
X
X
X
X
MitoGel™ Admixture instillation 
X
X
X
X
X
X
X
X
X
X
X
1.3 g  3 of sodium bicarbonate 
X
X
X
X
X
X
X
X
X
X
X
††††††  Only for women of childbearing potential
‡‡‡‡‡‡ Only for women of childbearing potential and a positive pregnancy urine test
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Maintenance Treatment (±1 w)
Study Month*****
up to 3 
Weeks 
post 
PDE
FU1
+3mo  
Post 
PDE
(±2 w)
FU2
+6mo 
Post 
PDE
(±2 w)
FU 3
+9mo
Post 
PDE
(±2 w)
FU 4
+12mo
Post PDE
 (±2 w)
Visit Number
V10
V11
V12
V13
V14
V15
V16
V17
V18
V19
V20
V21
Visit Name
Maint. 
#1
Maint. 
#2
Maint. 
#3
Maint. 
#4
Maint. 
#5
Maint. 
#6
Maint. 
#7
Maint. 
#8
Maint. 
#9
Maint. 
#10
Maint. 
#11
FU4
Trial 
Completion
Phone reminder day prior to 
instillation: Bicarbonate, liquid 
limitation, diuretics
X
X
X
X
X
X
X
X
X
X
X
Review of Disease Outcome and 
Complete Response Durability 
X
X
X
X
Adverse Events /Concomitant Med.
X
X
X 
X
X
X
X
X
X
X
X
X
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15. Evaluation of Response
Patient response will be evaluated according to the following criteria: 
Complete Response (CR):  A patient will be considered to have had CR if there is no 
detectable disease (NDD).  To determine NDD, the following conditions should be fulfilled 
(see also Figure 1 in Section 9.2.1)
1. If visual assessment (URS) indicates no remaining tumors the upper tract urine cytology 
must be negative;
2. If tumors are visible during URS, all remaining and accessible tumors should be biopsied.  
If the biopsied tumors are not viable upon histopathological evaluation and the cytology is 
negative, the patient should be considered to have had CR; 
3. In a case where the preferable treatment is RNU and its pathological evaluation indicates 
that no viable tumor(s) remained in the affected kidney (e.g., non-viable lesion), the 
patient will be considered CR retroactively. 
No Complete Response (NCR):  A patient will be considered to have had NCR if there is a 
residual disease. NCR should be determined only after pathology result was received from 
the pathology local lab.
Table 2  Response: Classification in possible scenarios (Assessed at PDE Visit) 
Visual Assessment via 
Video-URS
Biopsy (central lab)
Cytology (central lab)
CR Yes/No
Negative
NA
Negative
Yes (Success)
Negative
NA
Equivocal positive 
No*
Negative
NA
positive
No (Failure)
Positive
Positive
Negative
No (Failure)
Positive
Negative
Negative
Yes (Success)
*
Unless at next maintenance the upper tract urine cytology is negative 
15.1. Tumor Measurements and Classification of Partial Response (PR)
At Baseline, during the diagnostic ureteroscopy, the size of all measurable tumors for each 
patient will be estimated and recorded.  Each measurable lesion will be identified with a unique 
identifier number, and the morphology and location will be recorded on a diagram of the upper 
urinary tract provided in the chart and CRF.  Tumors size will be recorded in one dimension (the 
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longest diameter; mm).  Measurable tumors are defined as those for which a reasonable visual 
estimation can be obtained visually and photographically.  At PDE, the size of all measurable tumors 
identified at baseline, if still present, should be recorded, using the same identifier tumors number 
and location as recorded at baseline. PR is every change in the tumor size or number which is not CR 
or NR. 
15.2. Assessment of UC Tumor Progression 
Diagnosis of UC at the PDE visit with an increase in stage or grade compared to baseline will 
be tracked; however, as is explained below, it likely does not represent true progression for the 
following reasons:
1. Following RNU, a high rate (> 33%) of change in grade and stage of UC compared with the 
initial diagnostic biopsy has been reported [Smith, 2011).  This is likely due to the poor 
specimens usually obtained during initial diagnostic URS.  Therefore, if a patient diagnosed 
at Baseline with LG non-invasive UC and at the PDE with HG, or the tumor is found to be 
more invasive (stage increase); this more likely represents under grading/ under staging at 
the time of first diagnosis rather than true tumor progression;
2. The overall risk of progression for patients with LG papillary UC is about 5%.   A 12-week 
interval, during which the patient is exposed to MMC treatment, is not generally considered 
long enough for progression to occur in patients with non-invasive urothelial carcinoma;  
Upstaging/upgrading detected at the PDE visit will be recorded and the overall incidence will be 
compared with that reported in the literature. The progression of the initial disease during the FU 
period after the patient already achieved CR will be documented in the CRF. 
15.3. Assessment of UC Tumor Recurrence
Follow up will be conducted for patient who were defined as CR at PDE, or for patients for 
whom the investigator was uncertain of the final diagnosis and chose to continue to the next FU visit 
for re-assessment. 
Starting with the FU 1 visit (3 months post PDE visit), information regarding disease status 
based on Ureteroscopy, Upper tract washing urine cytology, and Biopsy, if needed, as well as 
intervention should be recorded.  For a patient to be defined as having recurrence complete 
documentation should be obtained and the following criteria should be met:
Visual confirmation of tumor presence; AND
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Positive biopsy for UC where it is technically feasible. 
Only recurrence in the treated area will be counted for the analysis as treatment failures. A new 
lesion within the renal pelvis be considered recurrent disease (meaning a disease recurrent in the 
UPJ and up). The appearance of urothelial carcinoma during the follow-up period in another 
area in the urinary system (the other kidney, ureter, bladder, and urethra) will be documented 
but will not be considered as a recurrence for the trial primary analysis.  
In a patient which during the trial period has a UC recurrence in the bladder and is required to 
undergo a TURBT, the surgery can be done during the FU period, and as long as his treatment 
doesn’t require intravesical instillations the patient can stay in the FU with the maintenance 
treatment for his UTUC disease.
If the recurrent bladder cancer in the FU period requires full course of intravesical treatment, it 
is the PI discretion whether to keep the patient in the FU period without the MitoGel 
maintenance treatment for the UT during the 6 weeks of the bladder instillations.   
If the recurrence is in the other kidney, and the patient requires immediate intervention, the FU 
period may be terminated for this patient and the durability will be calculated based on the 
existing data (depending also on the planned kidney surgery).  
15.4. Pathological Evaluation:  
Biopsies and upper tract washing urine cytology specimens obtained at baseline should be 
evaluated by the local institutional pathologist.  Patient's enrollment to the trial will be based on the 
local pathologists’ diagnosis. 
A central pathology service will be used for this trial.   Biopsy and urine cytology slides 
obtained either at Screening/Baseline, PDE and every FU visit, will be read by the central 
pathologist.  The diagnosis based on local reading will be considered the final one for the purpose of 
primary efficacy evaluation.
Note: Further details on the process will be provided in the Administrative Binder of the trial 
procedures. 
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17. Patients Withdrawal From Treatment or/and Follow Up, and Trial Completion
 A patient’s preterm withdrawal from the treatment or from the trial can take place at any stage 
prior to trial completion, and in any case, in which emerging adverse events are of such a nature that 
the risk/benefit ratio is unacceptable to the individual patient. 
17.1. Criteria for Patient withdrawal from MitoGel Treatment:
The single most important reason for premature discontinuation should be marked on the End of 
Treatment Form, under one of the following categories:
Adverse Event/Serious Adverse Event 
Mandatory criterion for discontinuation per protocol
Patient wishes to withdraw his/her consent for participation in the trial;
Patient's non-compliance with treatment or protocol requirements;
Patient lost to FU;
Pregnancy.
17.1.1. Discontinuation from MitoGel Treatment is mandated in the following event:
a. Grade 4 neutropenia lasting >5 days
b. Febrile neutropenia
c. Grade 4 thrombocytopenia
d. Grade 3 thrombocytopenia with hemorrhage
e. Dose delay of >4 weeks due to an adverse reaction 
f. Grade 3-4 non-infective cystitis
g. Grade 3-4 hematuria
h. Any grade of urinary system perforation 
i. Any Grade 4 non-hematologic toxicity EXCEPT:
I.
Grade 4 vomiting/diarrhea lasting <72 hours in the absence of maximal medical therapy
II.
Grade 4 laboratory abnormalities that can be readily corrected and do not result in 
hospitalization
Note: No dose modifications or delays are allowed in patients who do not tolerate MitoGel
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17.1.2. FU of Patients That Withdrew from MitoGel Treatment
For a patient who completes at least one instillation but withdraws from the treatment prior to 
the 6th instillation, the patient should be invited for an unscheduled visit in which all assessments 
scheduled for the PDE visit should be conducted.  If the patient is classified as CR., the patient will 
be asked to continue providing follow up data during FU visits, which are similar to the ones 
conducted under the standard of care.  Regardless, the site should explain to the patient the 
importance of continuing FU for disease management.
PDE will be performed 5 weeks (±1w) after last treatment, and all other FU procedures (safety 
and recurrence) will continue according to protocol.  The patient’s follow-up data will be collected in 
the trial database, upon completion of the trial (or an early withdrawal from the trial). In case of 
tumor recurrence, the patient's participation in the trial will be terminated. 
If a patient withdraws from the interventional portion of a trial and does not consent to continue 
FU or provide clinical outcome information, the investigator must not access for purposes related to 
the trial the patient's medical record or other confidential records requiring the patient's consent.  
However, an investigator may review trial data related to the patient collected prior to the patient's 
withdrawal from the trial for the purpose of clinical management of the patient, and may consult 
public records, such as those establishing survival status.
17.1.3. Patients Withdrawal from the Trial
A patient will be withdrawn from the trial for any of the following reasons:
Lost to follow-up;
Withdrawal of consent;
Sponsor terminates the study;
Death.
If a patient is lost to follow-up, any reasonable effort must be made by the trial site personnel to 
contact the patient and determine the reason for discontinuation/withdrawal. Attempts to contact the 
patient must be documented in the patient's file (at least 3 documented attempts).  If a FU visit was 
performed, relevant measures taken must be documented in the source document and entered into the 
CRF.
When a patient withdraws before completing the trial, the reason for withdrawal is to be 
documented in the source document and entered into the CRF.
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In case of death at any trial time point throughout the trial FU period, the cause of death will be 
reported to the Ethics Committee.
17.2. Definition of Trial Completion
A patient will be considered to have completed the trial in the following cases:
Patient was defined as PR or NR to treatment at PDE visit;
For patients with CR at PDE, FU will continue until one of the following occurs:
o
Recurrence of tumor has occurred,  
o
Patient has completed 12 months FU visit. 
17.3. Replacement of Individual Patients 
Patients who discontinued treatment will not be replaced.  Ineligible (screen-failures) patients, 
or patients who did not receive any study medication will be replaced. Screen failed patient can be 
re-screen if he meets the criteria later on the study period. Screen Failures Minimal Required Data
The minimal required CRF forms for screen failure patients are:
Demographics
Inclusion Criteria
Exclusion Criteria
Patient Eligibility by site investigator
Patient Eligibility by sponsor.  
18. Statistical Methodology
At least 74 evaluable patients meeting all inclusion and exclusion criteria with a confirmed 
diagnosis of LG UTUC will participate in this trial to provide 88.5% power to demonstrate efficacy 
(See Section 18.2).  Assuming a lost to follow-up rate of about 10%, approximately 83 subjects will 
participate in this trial. While no formal, interim analysis for stopping the trial for success is planned, 
the trial’s DMC will have continuous access to safety and efficacy data. This is meant to:
a.
Enable carrying out the following FDA suggestion: “The agency clarified that the sponsor 
does not have to wait until all patients have completed this additional follow up before 
submitting the application. The sponsor can submit an application once they believe they 
have demonstrated safety and efficacy of this product.” (PIND Nov, 2015 meeting minutes, 
p. 7).
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b. Avoid operational bias by providing the access to cumulative ongoing trial data to an 
independent body only.
The DMC will have the authority to decide whether the data is sufficiently indicative of safety and 
efficacy for submission to FDA even before the complete sample has been recruited and/or followed 
up.  At the same time, even if UroGen provides interim data to FDA at DMC’s recommendation, the 
study will continue to enroll subjects as per study plan while discussions with the FDA are taking 
place. 
It should be noted that MitoGel is intended for treating the entire upper urinary tract, not only a 
single marker lesion. Thus, subjects with multiple lesions will be included in the study and treatment 
will be considered successful only if all lesions disappear.
This study will test one primary and one key secondary efficacy endpoints. The former relates to CR 
at PDE visit while the latter assesses durability of CR at 12 months (for those demonstrating CR at 
PDE). To control Alpha for Type I Error, hypotheses will be tested hierarchically—primary first and 
key secondary, second—and only a significant result on the first test will enable conducting the 
second hypothesis test. Consequently, Alpha will be 0.05 two sided for both tests.
A formal Statistical Analysis Plan (SAP) will be developed and finalized prior to database lock. The 
SAP will supersede this statistical analysis section.
18.1. Significance Level 
The overall significance level for testing primary efficacy is 0.05, two sided. Since there is no 
formal interim analysis (DMC’s independent review of the data is described in Section 18), and 
Alpha is controlled for multiple testing hierarchically, Alpha for statistical testing will be 0.05, two 
sided. Non-confirmatory analyses will not control for multiple testing so that Alpha for significance 
in each will remain 0.05, two-sided.
18.2. Sample Size Rationale 
Sample size determination was performed under the following assumptions: 
The primary efficacy endpoint of the trial is the Complete Response (CR) rate at the PDE Visit;
It is expected that the true CR rate following treatment with MitoGel™ is 30% or more; 
The principal analysis of the primary endpoint will aim to rule out a threshold rate of 15% using 
a two-tailed exact test for binomial proportion at two-sided Alpha = 0.05; i.e., 15% CR is the 
study’s performance goal (PG).
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Under these assumptions, a sample of 74 evaluable patients will provide a power of 88.5% to 
demonstrate that the observed CR rate is superior to the PG of 15%.  Assuming a lost to follow-up 
rate of about 10%, at total of about 83 subjects will participate in this trial.
It should be noted that this trial is not powered for the key secondary endpoint.
18.3. Futility Analysis 
A futility analysis is planned for this trial after 20 evaluable subjects have provided primary 
efficacy data at the PDE visit or after as applicable24.  Since this interim analysis will be for futility 
only (i.e., it will not provide the option of stopping for success).  Alpha remains unaffected and need 
not be adjusted for multiplicity. 
Futility will be declared if the conditional power for success at the end of the trial given results 
at N = 20 is below 25% (i.e., less than 1 CR case out of 20).  It should be noted that the choice of 
futility analysis after 20 subjects was made based on: a) Company’s wanting to analyze the data as 
early as possible, so as not to conduct a larger trial that is futile and b) Error of Type II, Beta, at N = 
20 and the above rule for futility is 0.0; i.e. this futility analysis does not reduce overall study power. 
Results of the futility analysis will be presented in closed session to the DMC, which will make the 
final determination of trial continuation based on the statistical and clinical considerations.
18.4. Analysis Sets
18.4.1. Safety Analysis Set 
The safety analysis set will consist of all patients who enrolled in the trial and received at least 1 
instillation of MitoGel™ Admixture.  This analysis set, which will include all data captured in data 
base for these patients, will serve as the primary analysis set for safety assessment. Intent-to-Treat 
(ITT) Analysis Set (=safety analysis set).
This analysis set, which will include all data captured in the database for these patients, will 
serve as the primary analysis set for the primary efficacy analyses and inference.
24 Equivocal primary efficacy results at PDE visit (e.g., cytology = “equivocal”), will require follow-up testing for final 
determination of primary endpoint (see Section 9.2.1).
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
Treatment of Missing Values in ITT: 
ITT subjects with no observed value on primary efficacy will be imputed primary efficacy 
failures. Note that this only include patients who dropped from the study for any reason before the 
PDE evaluation. At the same time, sensitivity analyses will evaluate the robustness of results to 
different assumptions of missingness.
Treatment of missing values for the secondary endpoint detailed in Section18.7.2.
18.4.2. Local Modified Intent-to-Treat (mITT) Analysis Set 
The local modified intent to treat (local - mITT) analysis set will be a subset of ITT subjects with 
confirmed LG UTUC at Screening by local lab and who arrived to the PDE evaluation.  
Missing values: Only observed values will be used in local - mITT; i.e. missing data will not be 
imputed.
18.4.3. Central Modified Intent-to-Treat (mITT) Analysis Set 
The central modified intent to treat (Central - mITT) analysis set will be a subset of ITT subjects 
with confirmed LG UTUC at Screening by central lab and who arrived to the PDE evaluation and 
received the central lab diagnostic.  
Missing values: Only observed values will be used in central - mITT; i.e. missing data will not be 
imputed.
18.4.4. Per Protocol (PP) Analysis Set 1
The Per Protocol (PP) analysis set is a subset of the Local mITT Analysis Set and will consist of 
all enrolled patients who received at least 4 MitoGel™ Admixture instillations and have observed 
data on the primary efficacy endpoint. Patients who are identified as HG at the PDE visit will be 
excluded from the PP1 population.  This analysis set will include all data captured in database for 
this subpopulation.
18.4.5. Per Protocol (PP) Analysis Set 2
The Per Protocol (PP) analysis set is a subset of the Local mITT Analysis Set and will consist of 
all enrolled patients who received a total of 6 MitoGel™ Admixture instillations, who do not have 
major protocol violation, and have observed data on the primary efficacy endpoint.  Patients who are 
identified as HG at the PDE visit will be excluded from the PP2 population. This analysis set will 
include all data captured in database for this subpopulation.
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18.4.6. Complete Responders at the PDE Visit (PDECR) Analysis Set 
The PDECR analysis set is a subset of the ITT Analysis Set who had a Complete Response (CR) 
at the PDE Visit. 
18.5. Patient Disposition 
Subject disposition will be tabulated; the number of enrolled, exposed, prematurely terminated 
and completed subjects will be summarized separately according to treatment and by visit (where 
relevant).  A list of dropouts will be prepared including reason for discontinuation, and time of 
discontinuation. 
18.6. Demographic and Baseline Characteristics
Demographics and baseline data as well as disease prognostic factors, medical history, and prior 
medications will be summarized using the safety analysis set by descriptive statistics. For continuous 
variables, descriptive statistics (number [n], mean, standard deviation (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 separately if necessary. 
18.7. Efficacy Analyses
18.7.1. Primary Efficacy Analyses
The principal analysis of the primary endpoint will test the Complete Response (CR) rate 
defined as percent of patients with CR at the PDE Visit or necessary follow-up (See Section 9.2.1) 
using the ITT Analysis Set. Patients who did not demonstrate confirmed CR at PDE visit or 
necessary follow-up will be considered for the purpose of this analysis as treatment failures. 
The primary efficacy analysis will test the following hypotheses.
H0: CRrate ≤15% 
H1: CRrate >15% 
Testing will be done by using an exact binomial two-sided hypothesis testing, with two-sided Alpha 
= 0.05. (Note that this is in fact identical to the one-sided testing with Alpha=0.025). In addition, 
exact binomial 95% confidence interval about the observed CRrate will be provided.
It should be noted that FDA has made allowance for data assessed qualitatively by the DMC 
being submitted for the Agency’s evaluation (see Section 18) that, in FDA’s opinion, may be 
sufficient for demonstrating safety and efficacy of the product.
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18.7.2. Sensitivity Analysis for the Principal Analysis of the Primary Endpoint 
 The following analyses will be done to examine the robustness of the study's primary 
conclusion to inclusion criteria and differing patterns of missingness. The primary analysis described 
in the previous section will be repeated using
o
Local diagnosis in Local-mITT, PP1, PP2 populations
o
Central diagnosis in Central-mITT
In addition, two alternative imputation methodologies will be examined in the ITT population.
1.
Tipping point
In this analysis missing values on CR will be progressively imputed “failure” until such point 
when the CR rate is no longer significant; i.e. the 95% confidence interval about CR rate is no 
longer wholly above 15%. The point at which results are no longer significant will be defined 
as the “tipping point.” (Recall that missing subjects in ITT are imputed “failure” for the primary 
analysis, which is essentially a worst case analysis.)
2.
Multiple Imputation 
The missing response status will be imputed using the multiple imputation procedure (PROC 
MI in SAS®). Ten (10) imputed datasets will be created. The imputation model will use the 
following covariates: Sex, Age, number of papillary lesions at screening, the largest diameter 
at Screening, Tumor Burden and total number of episodes. 
18.7.3. Key Secondary Efficacy Analysis: Long Term Durability of CR 
The study’s key secondary endpoint is durable response at 12-month follow-up in the CR 
analysis set, which will test the following hypotheses:
H0: CR12-months ≤ 40%
H1: CR12-months > 40%
The key secondary endpoint will be tested by constructing a two-sided, 95%, Exact Binomial 
confidence interval about the rate of subjects in the CR analysis set continuing to show CR at 12 
months. We will declare success on this endpoint if the lower bound of the confidence interval is 
above 40%.
The key secondary endpoint will be tested on 12-month data, where missing data due to:
• Discontinuation due to AEs related or probably related to investigational therapy = “failure”
• Discontinuation or lost-to-follow-up for any other reason will not be imputed
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Since Alpha for multiple testing is controlled using the hierarchical method, there is no need to 
adjust Alpha for the key secondary endpoint.
Observed rate of CR at 12 months was selected because of its clinical meaningfulness. At the 
same time, the continuous durability of CR will also be analyzed by Kaplan Maier analysis. 
Durability will be defined from the time of the PDE visit where first CR is confirmed until the first 
visit where a patient do not meet the definition of CR. Patients who discontinued the study for any 
reason will be censored at their last assessment in which they had maintained a complete response.
18.7.4. Sensitivity Analysis for the Dichotomous Key Secondary Endpoint
For dichotomous key secondary analysis, patients who did not arrive the last FU visit and have 
no prior recurrence, are treated as Failures (which is the "worst case" imputation scenario). 
Sensitivity analysis will be done to examine the results if alternative imputation scenarios are used. 
Specifically, the tipping point imputation will be applied. 
 In this analysis we begin by imputing all missing subjects (early terminations) "Success" (or 
CR). Then, at each step, number of imputed "Successes" will reduce by one and number of imputed 
"Failures" will increase by 1, until the case where all missing values are imputed "Failure" (which is 
equivalent to the primary analysis). For each imputation scenario, exact binomial hypothesis testing 
p-value will be reported.
In addition, to the described above, analysis where only observed data is used will be done.
18.7.5. Secondary Efficacy Analyses
Secondary efficacy analyses will be conducted using all but the safety analysis sets.
Durable CR at 3, 6 and 9 months will be analyzed using the CR analysis set, so that the 
denominator for CR rate consists only of those subjects demonstrating CR at PDE. 
Durable CR at 3, 6 and 9 months will be analyzed by constructing a two-sided, 95%, exact 
binomial confidence interval about CR rate. Subjects whose data are missing at 3, 6 and 9 months 
due to AEs definitely or probably related to treatment will be imputed failures.  Subjects whose 
status of CR is missing at some FU visit, but the CR is confirmed at any further FU visit will be 
imputed CR (Success) backward. Data missing for other reasons will be excluded from the analysis.
For patients with PR at PDE visit, originally planned and actually received UTUC treatment 
will be compared.
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18.8. Evaluation of Safety 
Safety analyses will be descriptive and narrative in nature, with SAE's and AE's coded using 
MedDRA Version 19.0 or higher and tabulated by body system, preferred term, severity and relation 
to study drug and procedure. Descriptive statistics will be provided over time as appropriate.
18.8.1. Adverse Events
Adverse events will be recorded from the time a patient has signed the Informed Consent.  
Adverse Events (AEs) reported by the investigators will be coded according to the MedDRA 
dictionary. 
The following will be incorporated into the analysis of adverse events:

All analyses to be provided will include coded AEs;

Adverse events analyses will include only Treatment Emergent Adverse Events (TEAEs), 
namely, those events which started on the day of first trial IP administration or afterwards. 
Listings of both TEAEs and non-TEAES will be provided;

The incidence (no. of patients) and frequency (no. of events) of TEAEs will be provided 
when broken down by System Organ Class (SOC) and by Preferred Term (PT) according to 
MedDRA dictionary; 

Breakdowns of TEAEs by all AEs attributes will also be provided;

Breakdowns of TEAEs by age, sex and volume of instillation will also be provided;

The derived dictionary used in the analyses displaying the MedDRA System Organ Class 
(SOC), the Preferred Term (PT), and the AE Verbatim Term as specified by the 
Investigator, will be provided;

The incidence (no. of patients) and frequency (no. of events) of serious TEAEs will be 
provided when broken down by System Organ Class (SOC) and by Preferred Term (PT) 
according to MedDRA dictionary as well as by SAEs attributes and by age, sex, and volume 
of instillation.  SAEs will also be listed.
18.8.2. Safety Laboratory Tests
Analyses of safety laboratory data will be performed in the following manner:

Graphical presentation given in mean values + 2 standard errors of the mean of laboratory 
tests results by scheduled visits will be provided as well;
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
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 potentially clinically significant 
(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 lab values as well as the individual patient listing 
will be provided using the denominator which is the number of patients with at least one 
post-baseline administration of trial medication. Individual patients’ listings of PCS 
measurements will also be presented.
18.8.3. Vital Signs
Analyses of vital signs (blood pressure, pulse, temperature, and respiration rate) will be 
performed in the following manner:

Descriptive statistics of vital signs before first trial instillation and during trial as well as the 
changes from baseline by scheduled visit will be displayed;

The incidence (no. of patients) of potentially clinically significant (PCS) abnormal values 
will be summarized in a frequency table using the criteria defined by the Sponsor before 
first trial instillation. Please note that the denominator to be used for calculating percentages 
is the number of patients with at least one post-baseline evaluation. The incidence tables as 
well as the individual patient listing of vital signs of PCS will be reported.
18.8.4. Physical Examination
Any clinically relevant changes occurring from screening until the last trial visit will be 
recorded in the Adverse Event Sections of the CRF.
18.8.5. Tolerability Assessments
Tolerability analysis will be based on the number and percent of patients who failed to reach the 
PDE visit due to related adverse events (probably, definitely) and overall discontinuation rate.  The 
time to withdrawal due to adverse events and overall discontinuation rate, starting from first trial 
instillation censored by the date of the PDE visit, will be presented using Kaplan-Meier curves.
A similar analysis approach will be repeated for the FU1 and FU4 visits.
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18.8.6. Use of Concomitant Medications
The WHO drug dictionary will be used to classify medications verbatim for Concomitant 
Medication and Pre-Trial Medications.
Analysis of concomitant drug use will be performed in the following manner:
Pre-Instillation Concomitant Medications Use: Analyses will include coded medications that 
were initiated prior to first instillation, regardless if stopped after trial first instillation. An 
incidence table including patient counts (no. of patients) and percentages broken down by 
Medication Class and Preferred Term will be provided;
Concomitant Medications Use (Post-First Trial Instillation): Analyses will include only coded 
medications that were consumed following the first trial instillation, regardless if drug 
initiation date was before or after first trial instillation. An incidence table including patient 
counts (no. of patients) and percentages broken down by Medication Class and Preferred 
Term will be generated;
Prohibited Medications: systemic chemotherapy, intravesical chemotherapy (full course) and 
BCG, which is part of the exclusion criteria.
18.8.7. MMC Levels (Pharmacokinetics) Profiling
Pharmacokinetic (PK) profile during the 6 hours following the first administration of MitoGel™ 
will be based on PK sampling at 0, 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 MitoGel™ 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 
MitoGel™ 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, this data, combined with data emerging from other trials/compassionate use 
program may be used in population pharmacokinetic model development and analysis. 
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19. Management of Adverse Events
19.1. Definitions
19.1.1. Adverse Events
Adverse Event (AE): Any untoward medical occurrence in a patient or in a clinical trial patient 
administered a medicinal product and which does not necessarily have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory, physical exam, 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 adverse event shall be examined by a doctor as soon as possible, making whatever 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.  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.
Adverse Drug Reaction (ADR)/ Adverse Procedure Reaction: Any noxious and unintended 
responses to a medicinal product/procedure, related to any dose administered.  The phrase responses 
to a medicinal product/procedure, means that a causal relationship between a medicinal 
product/procedure, and an adverse event is at least a reasonable possibility, i.e., the relationship 
cannot be ruled out (“Note for Guidance on Good Clinical Practice” CPMP/ICH/135/95).  The 
definition also covers the medication errors and uses outside what is foreseen by the trial protocol, 
include misuse and abuse of the product. 
19.1.2. Serious Adverse Events 
A “serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose:
Results in death;
Is life-threatening;
Requires inpatient hospitalization or prolongation of existing hospitalization;
Results in persistent or significant disability/incapacity; or
Is a congenital anomaly/birth defect.
These characteristics/consequences have to be considered at the time of the event; some medical 
events may jeopardize the patient or may require an intervention to prevent one of above 
characteristics/consequences.  Such events (hereinafter referred to as an “important medical 
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events”) should also be considered as “serious” in accordance with the definition (“Note for 
Guidance on Good Clinical Practice” CPMP/ICH/135/95).
A “non-serious adverse event is an AE which does not meet the above criteria.
19.1.3. Suspected Unexpected Serious Adverse Reaction/Unexpected Adverse Drug 
Reaction (SUSAR /UADR):
UADR
An “Unexpected Adverse Drug Reaction” (UADR) is any noxious and unintended response that 
is related to the administration of an investigational product that has not been reported as expected in 
this protocol or the Investigator’s Brochure, either from previous clinical studies or the non-clinical 
studies.
SUSAR/SUADR
A “Suspected Unexpected Serious Adverse Reaction” is any UADR that at any dose also meet 
the criteria of SAE above. 
19.1.4. Causality
The investigator will determine the association between adverse event and treatment/procedure 
based on the following definitions:
Definitely Related
A clinical event, including laboratory test abnormalities, which follows the administration of a 
medicinal product, over a reasonable time period, but which cannot be explained by a concomitant 
illness or by other medicinal products.  The reaction must have already been observed for the 
suspected medicinal product.  The reaction must improve with “de-challenge” and reappear with “re-
challenge”.
Probably Related
A clinical event, including laboratory test abnormalities, which follows the administration of a 
medicinal product, over a reasonable time period, but which cannot be explained by a concomitant 
illness or by other medicinal products and the “de-challenge” response of which is clinically 
acceptable.  “Re-challenge” data are not necessary.
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Possibly Related
A clinical event, including laboratory test abnormalities, which follows the administration of a 
medicinal product, over a reasonable time period, but which could also be explained by a 
concomitant illness or by other medicinal products.  Information on suspension of the medicinal 
product may be missing or uncertain.
Not Related
A clinical event, including laboratory test abnormalities, where the duration of which, after 
administration of a medicinal product, makes the causal relationship improbable and where other 
medicinal products or pre-existing conditions offer plausible explanations.
19.1.5. AE Intensity 
The intensity of AE is to be graded by the investigator according to CTCAE 4.03 criteria, as 
outlined below:
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).
19.2. Reporting procedures
19.2.1. Instructions for Trial Personnel Regarding Patient Adverse Events 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.  
19.2.2. Events Requiring Immediate (24 hours) Reporting 
Expedited reporting to the sponsor is required in the following conditions:
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1. Any SAE & Follow up SAE report, if required;
2. Death of study patient; 
3. Pregnancy and outcome of the pregnancy;
The investigator must inform the relevant clinical research associate (CRA, Monitor) by phone 
about the above mentioned events AND notify via email the sponsor within 24 hours of becoming 
aware of the event. Sponsor contact: Email 
 with copies to 
. 
 Initial SAE/Death/Pregnancy must be recorded in the electronic Case Report Form (eCRF) 
within 24 hours of becoming aware of the event.  
In case event requires immediate reporting but the EDC system (eCRF) is not functioning, the 
site should use the relevant paper forms and email them to 
.  
The investigator should report the event to the local/central IRB/national EC, according to local 
requirements.
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected.  Pregnancy in a study subject is not considered an adverse event.  
However, the medical outcome of an elective or spontaneous abortion, stillbirth or congenital 
anomaly is considered a serious adverse event and must be reported to the sponsor.  In the event of 
pregnancy occurring in the partner of an enrolled subject, written informed consent for release of 
medical information from the partner must be obtained prior to the collection of any pregnancy-
specific information and the pregnancy will be followed to outcome.  
19.2.3. Special Reporting Situations 
Sponsor medicinal product that may require expedited reporting and/or safety evaluation 
include, but are not limited to:
1. Overdose of Investigational Product;
2. Suspected abuse/misuse of Investigational Product;
3. Inadvertent or accidental exposure to Investigational Product;
4. Medication error involving Investigational Product (with or without Patient/patient exposure 
to the sponsor medicinal product, e.g., name confusion).
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19.2.4. Events of special interest
1. Allergic reaction to MMC severity grade 3 or 4 on the CTCAE Scale V 4.03 (Appendix VIII: 
CTACAE 4.03 Severity Grades, and Allergic Reaction Grades);
2. Urosepsis;
3. Ureteral events, including stenosis, as well as symptoms suspicious of ureteral 
perforation/rupture – (prolonged localized abdominal or flank pain, abdominal 
tenderness/acute abdomen);
4. Any unexpected adverse drug reaction with severity grade of 3 or 4 on the CTCAE Scale V 
4.03 (Appendix VIII: CTACAE 4.03 Severity Grades, and Allergic Reaction 
GradesAppendix VIII);
5. Any level of urinary flow interruptions unrelated to enlarged prostate, e.g., Hesitancy ,
Interrupted urine stream, difficulty to urinate and urinary retention;
6. Onset of renal insufficiency or deterioration of renal function which occurred following 
treatment initiation;
7. Onset of hepatic insufficiency or deterioration of liver function which occurred following 
treatment initiation;
8. Any indication of bone marrow suppression:

Anemia: Acute decrease of HB of 2gr% and over or anemia severity grade 2 and over;

Neutropenia: New onset of Neutropenia grade 3 and over according to CTEAE version 
4.0;

Leukopenia: Acute onset of leukopenia grade 3 and over according to CTEAE version 4.0;

Thrombocytopenia: Acute decrease of thrombocyte count to below 50,000/µL;

And any change in myeloid cellularity which in the opinion of the local PI indicates of 
possible health risk to the patient.

Any of these Events of Special Interest that also meet criteria of Serious Adverse Event 
should be reported as such. 
19.2.5. Management of Anomalies in Laboratory Parameters
The investigator must review the patient's lab results and evaluate all anomalous laboratory values 
as clinically significant or not. Clinically significant results must be recorded as adverse events in the 
relevant section of the eCRF.
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19.2.6. Progression of Underlying Malignancy Disease:
Progression of underlying malignancy should not be reported as an adverse event if it is clearly 
consistent with the suspected progression of the underlying cancer, or other criteria as determined by 
protocol. Hospitalization due solely to the progression of underlying malignancy should NOT be 
reported as a serious adverse event.  Clinical symptoms of progression may be reported as adverse 
events if the symptom cannot be determined as exclusively due to the progression of the underlying 
malignancy, or does not fit the expected pattern of progression for the disease under trial.
19.2.7. Concomitant Illnesses and Pre-existing Conditions
Ongoing medical conditions and past cancer history other than urothelial carcinoma, and 
significant medical history up to 5 years back from screening must be collected and recorded in the 
eCRF. 
Concomitant illnesses (including signs/symptoms of a pre-existing pathological condition) that 
are present during or before the administration of a product under trial and which are manifested with 
the same severity, frequency, or duration after administration of the medicinal product under trial 
must be recorded in the relevant section of the eCRF.  However, cases which show an increase in the 
severity or duration of the concomitant illness or pre-existing condition must be reported as AEs.
19.2.8. Adverse Events Reporting Period

The investigator is required to collect AEs beginning with informed consent signature. 
This information is to be entered into the eCRF. 

All serious adverse events, and All AEs which are suspected to be related to the study 
treatment and/or procedures occurring during the trial period should be reported 
throughout a subject’s participation in the trial.

Adverse events will be collected up to 30 days post last  instillation or until resolution, 
and will be documented in the eCRF.

In case of non-complete response patients - All adverse events should be recorded up to 
the PDE Visit or until resolution (5 weeks after the last instillation).  

Progression of urothelial carcinoma disease should not be reported as an AE/SAE. 

Death due to any cause occurring during the trial period including follow up period will 
be reported.

Pregnancy should be reported at any time during the trial and during 6 months following 
last instillation (if site became aware of the pregnancy).
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The investigator should instruct each patient to report any subsequent event(s) that the patient, 
or the patient's personal physician, believes might reasonably be related to participation in this trial.  
The investigator should notify the trial sponsor of any death or any IP related adverse event.
19.2.9. Management of Adverse Events at Trial Conclusion
All unresolved adverse events should be followed by the investigator until the events are 
resolved, the patient is lost to follow-up, or the adverse event is otherwise explained.  
Unresolved IP/Procedure Related Adverse Event
All IP-related AEs shall be monitored until resolution and/or diagnosis or otherwise explained. 
Where a related adverse event is not resolved upon conclusion of the trial, the investigator will 
evaluate the need to continue follow-up.  All medicinal products taken during the trial to treat AEs or 
previous diagnoses must be recorded in the eCRF.
Unresolved Serious Adverse Events
SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject's participation in the study, must be followed until any of the following 
occurs:
1.
The event resolves;
2.
The event stabilizes;
3.
The event returns to baseline, if a baseline value/status is available;
4.
It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of 
due diligence with follow-up efforts).
19.3. Data Monitoring Committee (DMC)
An independent Data Monitoring Committee (DMC) will be appointed by the Sponsor 
The DMC will be responsible for safeguarding the interests of the patients by assessing the 
safety of the intervention during the trial, and for reviewing the overall conduct of the clinical trial.  
In addition, the DMC will have the responsibility to assess the efficacy data of the interim 
futility analysis and decide if stopping rules are met (see interim futility analysis in section 18).  The 
DMC will have access to the individual treatment - and will be able to merge these with the collected 
trial data while the trial is ongoing.
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Any unexpected AE related to MitoGel™ and qualified per National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE;  Appendix VIII: CTACAE 4.03 
Severity Grades, and Allergic Reaction Grades) as grade 3 or 4 will be evaluated by the sponsor 
medical team and steering committee. In case of need, a DMC meeting will be gathered.
The DMC charter is prepared to detail precise roles and responsibilities, meetings timelines and 
procedures and criteria for considering study discontinuation.
20. Concomitant Medications
The site should collect information and record in the eCRF all ongoing therapies, all past cancer 
therapies (including procedures), and other significant therapies taken within one month prior to 
screening.
Concomitant medications given to treat an adverse event must be recorded in the eCRF.
Concomitant medications must be recorded in the relevant section of the clinical data sheet and 
the CRF.  Refer to inclusion/exclusion criteria regarding excluded concomitant medication such as 
systemic chemotherapy, intravesical chemotherapy, and immunotherapy for cancer treatment 
including but not limited to BCG.
21. Ethical Considerations and Confidentiality
The trial will be performed in accordance with Food and Drug Administration (FDA) Good 
Clinical Practice (GCP) Regulations (Code of Federal Regulations [CFR] 21 parts 50, 56, and 312) 
and International Conference on Harmonization (ICH) GCP Guidelines (E6) and clinical safety data 
management (E2A).
21.1. Informed Consent
A properly executed, written informed consent form (ICF), in compliance with 21 CFR Part 50, 
must be obtained from each patient prior to enrollment and initiating screening evaluations required 
by this protocol.  A copy of the ICF planned for use will be reviewed by the sponsor (or designee) for 
acceptability and must be submitted by the Investigator, together with the protocol, to the appropriate 
IRB/EC for review and approval prior to the start of the trial.  Consent forms must be in a language 
fully comprehensible to the prospective patient.  The Investigator must provide the sponsor (or 
designee) with a copy of the IRB/EC letter approving the protocol and the ICF(s) before the trial 
drug supplies will be shipped and the trial can be initiated.
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The written consent form must be revised if new information becomes available during the trial 
that may be relevant to the Patient. Any revision(s) must be submitted to the appropriate IRB/EC for 
review and approval in advance of use.  It is the responsibility of the investigators or of any 
individuals appointed by them to obtain the informed consent of all patients, having given them 
sufficient information regarding the objectives, methods, expected benefits and foreseeable risks of 
the trial.  The investigators or such appointed workers must also inform participants that they shall 
not undergo any damages whatsoever should they choose not to take part in or to withdraw from the 
trial.
21.2. Ethics Committee and Competent Authorities
The sponsor shall provide the designated EC and the Competent Authorities with the trial 
protocol and any other related documents issued to the patient (Patient Information and ICF).  
Approval must be obtained from both the EC and the Competent Authorities before undertaking any 
procedures related to the trial and must be documented through an official communication to the 
investigator.  In the event that changes need to be made to the trial protocol during the course of the 
trial, the sponsor shall submit to the designated EC a request for amendment to the protocol, which 
must be approved following the procedures set forth in the regulations established by that EC.
The sponsor, according the law in force, will be responsible to report to the all the National 
Competent Authorities, where the investigation has commenced, any SAE related to the study drug, 
and any Investigational Product Failure that might lead to an SAE or new findings/updates in relation 
to those already reported. For the duration of the clinical trial, the trial sponsor shall submit to all the 
National Competent Authorities and to the relevant Ethics Committee(s) a list of serious adverse 
reactions observed over the course of the reporting period, and a report on the safety of the 
individuals involved in the clinical trial.  This will be done once a year or sooner if required by local 
regulations.
Sponsor reporting to the EC and National Competent authorities should be done as follows:
21.2.1. Fatal or Life-Threatening Unexpected ADRs
Regulatory agencies should be notified (e.g., by telephone, facsimile transmission, or in writing) 
as soon as possible but no later than 7 calendar days after first knowledge by the sponsor that a case 
qualifies, followed by as complete a report as possible within 8 additional calendar days. This report 
must include an assessment of the importance and implication of the findings, including relevant 
previous experience with the same or similar medicinal products.
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21.2.2. All Other Serious, Unexpected ADRs
Serious, unexpected reactions (ADRs) that are not fatal or life threatening must be filed as soon 
as possible but no later than 15 calendar days after first knowledge by the sponsor that the case meets 
the minimum criteria for expedited reporting.
21.2.3. Minimum Criteria for Reporting
Information for final description and evaluation of a case report may not be available within the 
required periods for reporting outlined above. Nevertheless, for regulatory purposes, initial reports 
should be submitted within the prescribed time as long as the following minimum criteria are met: 
1.
An identifiable patient;
2.
A suspect medicinal product; 
3.
An identifiable reporting source; 
4.
And an event or outcome that can be identified as serious and unexpected, and for which, in 
clinical investigation cases, there is a reasonable suspected causal relationship. 
Follow-up information should be actively sought and submitted as it becomes available. 
22. Quality Control and Quality Assurance:
22.1. Source Documentation
At a minimum, source documentation must be available for the following to confirm data 
collected in the CRF: Patient identification, eligibility, and trial identification; trial discussion and 
date of informed consent; dates of visits; results of safety and efficacy parameters as required by the 
protocol; record of all AEs and follow-up of AEs; concomitant medication; drug 
receipt/dispensing/return records; trial IP administration information; and date of trial completion 
and reason for early discontinuation of trial IP or withdrawal from the trial, if applicable. 
In addition, the author of an entry in the source documents should be identifiable.
At a minimum, the type and level of detail of source data available for a trial Patient should be 
consistent with that commonly recorded at the site as a basis for standard medical care.  Specific 
details required as source data for the trial will be reviewed with the investigator before the trial and 
will be described in the monitoring guidelines (or other equivalent document).
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22.2. Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all source 
documents that support the data collected from each patient, as well as all trial documents as 
specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical Trial, and all 
trial documents as specified by the applicable regulatory requirement(s).  The investigator/institution 
will take measures to prevent accidental or premature destruction of these documents.
Essential documents must be retained until at least 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 investigational product.  These documents will be retained for a longer period if 
required by the applicable regulatory requirements or by an agreement with the sponsor.  It is the 
responsibility of the sponsor to inform the investigator/institution as to when these documents no 
longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the trial records, custody must be transferred to a person who will accept 
the responsibility.  The sponsor must be notified in writing of the name and address of the new 
custodian.  Under no circumstance shall the investigator relocate or dispose of any trial documents 
before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this trial, the investigator must permit access to such reports.
22.3. Clinical Monitoring
The sponsor will perform on-site monitoring visits as frequently as necessary, depending of 
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 
subjects, to assure eligibility. The first post-initiation visit will be made as soon as possible 
(approximately two weeks) after enrollment has begun.  At these visits, the monitor will compare the 
data entered into the CRF 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 CRF 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. 
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Direct access to source documentation (medical records) must be allowed for verifying that the 
data recorded in the CRF are consistent with the original source data.  Findings from this review of 
CRFs 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. A separate clinical monitoring plan was put in place.
22.4. 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 subject, the investigator, or the study site staff.  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 managements 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 per their 
guidelines. The site PI/study staff is responsible for knowing and adhering to their IRB requirements. 
Protocol Deviations are not allowed.  If a subject's eligibility is in question, please contact the 
sponsor.
22.5. Audit and Inspection
Representatives of the sponsor's clinical quality assurance department may visit the site at any 
time during or after completion of the trial to conduct an audit of the trial in compliance with 
regulatory guidelines and company policy.  These audits will require access to all trial records, 
including source documents, for inspection and comparison with the CRFs.  Patient privacy must, 
however, be respected.  The investigator and staff are responsible for being present and available for 
consultation during routinely scheduled site audit visits conducted by the sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this trial in support of a 
regulatory submission. The investigator should immediately notify the sponsor if they have been 
contacted by a regulatory agency concerning an upcoming inspection.
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23.  Trial Systems
23.1. Data Collection and Management Responsibilities
The web based electronic data capturing (EDC) system (named 
) used for data 
collection in provided by 
.
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) 
and clinical laboratory data will be entered into 
, a 21 CFR Part 11 compliant data 
capturing system. 
The data system includes password protection and internal quality verification 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.
Passwords are personal and not to be shared.
Data management services will be provided by 
.  Data management 
plan will be in place.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site PI.  The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported according to ICH E6.  The site PI will login to the EDC and sign the 
patients' electronic Case Report Forms (eCRFs) after the database lock has achieved, thus confirming 
its content.
Data reported in the eCRF derived from source documents should be consistent with the source 
documents or the discrepancies should be explained and captured in a progress note and maintained 
in the participant’s official electronic study record. 
23.2. Procedures & Timelines for Data Capturing
1. Patient registration in the 
 system: Once patient signs informed consent, the site should 
register the patient in the system by completing the "Registration" eCRF form.  The next 
sequential screening number available at the site should be recorded, starting at 001.  The 
format of the screening number is 2 digits of the site number which is auto populated, followed 
by 'S', and 3 digits entered manually.  Example: 05 S 001 (Site 05 patient screening number 
001).
2. Patient enrollment number is given automatically by the 
 system.
In order to obtain enrollment number the following forms in the 'Screening' visit must be 
completed first:  Screening 'Visit date', Target Treatment Area Lesion Mapping' form, 'Target 
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Treatment Area Lesion Mapping Information' form, 'Patient Eligibility by Investigator" AND 
the 'Patient Eligibility by Sponsor" forms. 
3. To enroll a patient "Enrolment" tab should be selected from menu, data completed and 
submitted. The enrollment number will appear automatically.
The format of the enrollment number is 2 digits of the site number, followed by 'E', and 3 digits 
which represent the running number of enrolled patients across all sites.  Example: 05 E 010 
(site 05, patient enrollment number 010).
4. The minimum data required in the eCRF for patients considered screen failures are:

Registration - Informed consent

Demographics

Inclusion Criteria

Exclusion Criteria

Patient Eligibility by site investigator

Patient Eligibility by sponsor - This page will trigger the removal OR opening of the other 
forms in the screening visits and all other visits forms
5. The site investigator is responsible that the data from trial patients' visits will be recorded in 
eCRF no longer than 5 working days following the visit. Timelines may shorten during 
database clean-up and database lock period. 
6. Adverse event related queries must be resolved within 5 working days as well.
7. Initial report on subject's death, SAEs, SUSARs, and events of clinical interest must be 
reported in the eCRF within 24 hours.  Paper SAE /AE forms will be supplied to the site for 
completion in case of technical problem with the eCRF, not to delay the required immediate 
reporting.  
8. Queries relevant to subject's death, SAEs, SUSARs, and events of clinical interest must be 
resolved within 24 hours.
9. In case of delay in data recording/query resolution, the sites will receive email reminders 
reminding that data is to be completed.
10. An Interim Analysis is planned when 20 patients have performed PDE visit, for which all 
data must be clean and up to date at the time of analysis.
CRF data entry guidelines will be provided to all sites.
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23.3. Acknowledgment of MitoGel™ Kit Shipment Receipt
MitoGelTM Kit inventory will be managed via 
 web-based system.  MitoGelTM 
Kits shipments will be shipped to the authorized site pharmacist.  The pharmacist will receive a 
unique user name and password and should login to the system in order to confirm the receipt of 
shipments.  In case shipment was sent to the site but was not confirmed in the system, the specific 
kits belonging to this shipment would not appear in the site inventory and the MitoGelTM Kit 
belonging to this shipment will not be dispensed.  Therefore, the pharmacist should confirm 
shipments in the system as soon as they are received. 
23.4.
 System for Images Upload
The authorized site personnel will receive an email invitation with link to the website and will 
be requested to create account to the site. Personal username and password are required to access the 
 website. The sites are required to upload URS/CTU/MRI/Pyelography images 
performed during the following visits:

Screening

PDE visit

Follow up visits 1-4

Any unscheduled visit in which imaging was performed to determine eligibility, primary 
endpoint and secondary endpoint.
The 
 system is validated and in compliance with FDA requirements and has a 
feature enabling the removal of patient identifiers while uploading the images to the portal.
24. Trial Completion/Termination
24.1. Trial Completion
The trial is considered completed with the last visit for the last Patient participating in the trial. 
The final data from the investigational site will be sent to the sponsor (or designee) after completion 
of the final Patient visit at that site, in the period specified in the Clinical Trial Agreement.
24.2. Trial Termination
The sponsor reserves the right to close the investigational site or terminate the trial at any time 
for any reason at the sole discretion of the sponsor.  Investigational sites will be closed upon trial 
completion.  An investigational site is considered closed when all required documents and trial 
supplies have been collected and a site closure visit has been performed.
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The investigator may initiate site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of an investigational site by the sponsor or investigator may 
include but are not limited to:
1.
Failure of the investigator to comply with the protocol, the requirements of the IRB or local 
health authorities, the sponsor's procedures, or GCP guidelines;
2.
Inadequate recruitment of patients by the investigator;
3.
Discontinuation of further drug development.
25. Changes in the Conduct of the Trial:
25.1. Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor.  All protocol amendments must be issued by the sponsor, and signed and dated by the 
investigator.  Protocol amendments must not be implemented without prior IRB approval, or when 
the relevant competent authority has raised any grounds for non-acceptance, except when necessary 
to eliminate immediate hazards to the Patients, in which case the amendment must be promptly 
submitted to the IRB and relevant competent authority.  Documentation of amendment approval by 
the investigator and IRB must be provided to the sponsor or its designee.  When the change(s) 
involves only logistic or administrative aspects of the trial, the IRB (and IEC where required) only 
needs to be notified.
During the course of the trial, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor representative 
(see Contact Information page(s) provided separately).  Except in emergency situations, this contact 
should be made before implementing any departure from the protocol.  In all cases, contact with the 
sponsor must be made as soon as possible to discuss the situation and agree on an appropriate course 
of action.  The data recorded in the CRF and source documents will reflect any departure from the 
protocol, and the source documents will describe this departure and the circumstances requiring it.
26. Study Leadership
Steering committee and data monitoring committee (DMC) have been assigned for this trial. 
DMC charter was put in place. 
The Steering Committee will govern the conduct of the study. In case need arises, Ad hoc DMC 
meetings will be initiated by the steering committee. 
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Every effort will be made to reach a consensus within the DMC and with the principal 
coordinating investigator.  In case of disagreement on recommended modifications, the Steering 
Committee will make the final decision.
27. Administrative and Regulatory Details
27.1. Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by law.
27.2. Ownership of Data
All data is the property of the sponsor.
27.3. Conflict of Interest Policy 
The independence of this study from any actual or perceived influence 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 trial. The study leadership 
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.
27.4. Final Report and Publication of the Results 
Publication of the trial results in scientific literature is encouraged and the investigator shall be 
entitled, consistent with academic standards, to publish the results of the trial patient to the 
stipulations set forth in research contract.  The sponsor reserves the right to review any paper written 
utilizing data generated from the trial prior to such paper’s presentation or submission for publication 
purposes.  At least 90 (ninety) days prior to submitting or presenting a manuscript or other materials 
relating to the trial to a publisher, reviewer, or any third party, the investigator shall provide the 
sponsor a copy of all such manuscripts and materials, and allow the sponsor ninety (90) days to 
review and comment.  The investigator will give due consideration to the sponsor’s comments and 
should get prior in written consent from the sponsor to the content of any such publication.  The 
investigator further agrees to delay the publication for an additional 120 days, at the request of the 
sponsor, where the sponsor considers such delay necessary for the protection of its intellectual 
property rights. 
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a) If the trial is a part of a multi-center trial and the sponsor wishes to publicize a joint 
publication, which includes results of all sites, then the investigator shall not publicize the 
trial results before the first joint publication, unless such publication is not published within 
12 months from the completion of the trial at the trial center.
b) The sponsor can use, directly or indirectly, the name of the trial center and/or the investigator 
and/or any of the trial staff, in the sponsor's commercial publications. 
c) The sponsor undertakes that should it publicize the results of the trial, it shall publish the 
results in full and avoid quoting matters out of context.   
27.5.
Finance and Insurance 
27.5.1. Finance: 
The trial is financed by the sponsor as detailed in the financial agreement between the sponsor 
and the investigator/institution.
27.5.2. Insurance:
The trial will be covered in accordance to 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 investigational product or the participation in this trial the sponsor will contract the insurance 
company which 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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Appendix I: Clinical Evaluation
General physical Examination (V0, V9)
General Appearance
Cardiovascular system 
Respiratory
HEENT (head, eyes, ears, nose & throat) and neck 
Abdomen 
Extremities
Neurologic
Skin 
Other specify: ____________________________
Urology Oriented Examination (V0-V6)
Urethral meatus
Perineal skin and mucous membranes
Scrotum and Testes (for male patients)
Lymphadenopathy
Palmar erythema 
Rectal Examination  - Prostate (for male patients; Screening visit only)
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Appendix II: Vital Signs

Blood Pressure

Heart Rate

Body Temperature

Weight (only at screening)

Height (only at screening) 
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Appendix III: Required Lab Tests
The samples’ handling, packaging, and shipping details will be given in the site and central lab 
manual.  
Liver Function Tests * 
SGOT/AST
SGPT/ALT
GGT 
Alkaline phosphatase
Total Bilirubin
Direct Bilirubin 
Albumin
Total Protein
Renal Function Tests 
Creatinine
BUN or Urea Nitrogen
Uric acid
Sodium
Potassium
Phosphorus 
Calcium
Hematology Tests * 
Complete blood count, including red blood cell 
indices and white blood cell differential
Platelet count
Coagulation Tests 
Prothrombin Time (PT)
INR
Pregnancy Test **
Serum 
Urine dip stick for pregnancy
Urine Culture (at screening), on all other visits 
only if urinalysis if suspicious for UTI
Urine Cytology*** 
Upper Tract washing Urine Cytology 
Histology*** 
MMC Levels (6 Patients)**** 
Serum
Urinalysis 
Specific gravity 
pH 
Glucose
Urogilinogen
Bilirubin 
Blood 
Protein 
Nitrites Leukocyte Esterase
Microscopic examination 
Bacteriuria (if required)
WBC
*
The amount of blood required for hematology and biochemistry tests per visit is 15–20 cc.
**
The amount of blood required for pregnancy tests per visit is 5 cc.
Women of non-childbearing potential are defined as: 
a.
At least 12 months since the last menstrual bleeding, or
b. Without uterus and/or both ovaries, or
c.
Has been surgically sterile for at least 6 months prior to trial drug administration. 
*** Biopsy slides and urine cytology samples/slides will be sent to the central lab for central 
reading-a manual will be provided in separate to the pathology lab. 
****
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. Refer to Appendix VII.
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Appendix IV: Questions 24–32 hours Post Treatment Visit
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Appendix V: Karnofsky & ECOG Scores (Oken et al, 1982)
Performance Scales: Karnofsky & ECOG Scores
Karnofsky Status
Karnofsky 
Grade
ECOG 
Grade
ECOG Status
Normal, no complaints
100
0
Fully active, able to carry on all 
pre-disease performance without 
restriction
Able to carry on normal activities. 
Minor signs or symptoms of disease
90
1
Restricted in physically 
strenuous activity but 
ambulatory and able to carry out 
work of a light or sedentary 
nature, e.g., light house work, 
office work
Normal activity with effort
80
1
Restricted in physically 
strenuous activity but 
ambulatory and able to carry out 
work of a light or sedentary 
nature, e.g., light house work, 
office work
Care for self. Unable to carry on 
normal activity or to do active work
70
2
Ambulatory and capable of all 
self-care but unable to carry out 
any work activities. Up and 
about more than 50% of waking 
hours
Requires occasional assistance, but 
able to care for most of his needs
60
2
Ambulatory and capable of all 
self-care but unable to carry out 
any work activities. Up and 
about more than 50% of waking 
hours
Requires considerable assistance 
and frequent medical care
50
3
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking hours
Disabled. Requires special care and 
assistance
40
3
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking hours
Severely disabled. Hospitalization 
indicated though death no imminent
30
4
Completely disabled. Cannot 
carry on any self-care. Totally 
confined to bed or chair
Very sick. Hospitalization 
necessary. Active supportive 
treatment necessary
20
4
Completely disabled. Cannot 
carry on any self-care. Totally 
confined to bed or chair
Moribund
10
4
Completely disabled. Cannot 
carry on any self-care. Totally 
confined to bed or chair
Dead
0
5
Dead
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Appendix VI:  Recommended Antimicrobial Prophylaxis for Urologic Procedure
Taken from "Best Practice Statement on urologic surgery antimicrobial prophylaxis" 
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Appendix VII: Collection and Handling of Plasma Samples for MMC 
Pharmacokinetics 
Plasma MMC levels will be analyzed at 
.
Address: 
Instructions for plasma collection and handling are as follows:
CAUTION!  HANDLING OF THE SAMPLES SHOULD BE DONE WITH CAUTION 
ACCORDING TO THE INSTITUTE GUIDELINES FOR HANDLING CYTOTOXIC SAMPLES
1. Time points of plasma PK sampling: Time 0 (prior to instillation), 30min, 1, 2, 3, 4, 5 and 6 hr 
post instillation. For the sampling of 30 min. post treatment the deviation is ±5 minute. 
For sampling of 1-6 hours post treatment, allowed window is ±9 minutes.
2. Attention!  Mitomycin C is sensitive to light!! 
At each time point collect 3mL of blood into K2EDTA tube (supplied by UroGen) and place 
immediately in Ice (2-8°C) inside a closed cooling box protected from light. If the cooling box 
is unprotected from light, make sure to cover the collecting tubes with aluminum foil 
immediately after collection and then place them in ice.
3. Centrifuge the tubes immediately after collection. If this not possible, maintain the tubes prior to 
centrifugation in ice (2-80C) for no longer than 1 hour 
4. Use refrigerated centrifuge for plasma separation. Centrifuge at 3000 RPM for 10 min.
5. Transfer the plasma from each collecting tube using a disposable plastic pipette into 2  X  2mL 
Eppendorf tubes  (one will be shipped later to 
 central lab, the second will be left at the site 
as a backup)
6. Place the samples in a box protected from light (supplied by UroGen) 
7. Immediately store the box in -700C deep freeze.
8. The shipping of the samples to 
 central lab will be done in coordination with the CRA.
Labeling of Plasma Collecting Tubes and Eppendorf Tubes
Prior to each blood collection verify you have collecting tube and matching Eppendorf tubes of  the 
required time point.  Plasma labels Example: 
               Pre dose
         Post dose, time 0.5 hour
TC-UT-03  Plasma  MMC
 Pre-dose    Time: __ : __
Site / Pt. Number: __/__
Date: __/___/__
TC-UT-03 Plasma MMC
 PK: 0.5 h    Time: __ : __
Site / Pt. Number: __/__
Date: __/___/__
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Appendix VIII: CTACAE 4.03 Severity Grades, and Allergic Reaction Grades
Grades
Grade refers to the severity of the AE. The CTCAE
displays Grades 1 through 5 with unique clinical
descriptions of severity for each AE based on this
general guideline:
Grade 1 Mild; asymptomatic or mild symptoms; clinical 
or diagnostic observations only; intervention 
not
indicated.   
Grade 2 Moderate; minimal, local or
noninvasive intervention indicated;
limiting age-appropriate
instrumental ADL*.
Grade 3 Severe or medically significant but not 
immediately life-threatening; hospitalization or 
prolongation of
hospitalization indicated; disabling; limiting self 
care ADL**.
Grade 4
Life-threatening consequences; urgent 
intervention indicated.
Grade 5 Death related to AE.
Activities of Daily Living (ADL)
*  Instrumental ADL refer to 
preparing meals,
shopping for groceries or clothes, 
using the
telephone, managing money, etc.
** Self care ADL refer to bathing, 
dressing and
undressing, feeding self, using the 
toilet, taking medications, and not 
bedridden.
Source:
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf)
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Appendix IX: Protocol Amendment Version 6.0 – Summary of Changes
Note: Modified part is in Bold font
Section Updated
Protocol Version 5.0
Original Text
Protocol Version 6.0
Description of Change / New Text
Trial title
A Phase 3 Multicenter Trial Evaluating the 
Efficacy and Safety of MitoGel™ on Ablation of 
Upper Urinary Tract Urothelial Carcinoma  
UGN-101 was added: A Phase 3 Multicenter Trial Evaluating the Efficacy and 
Safety of MitoGel™ (UGN-101) on Ablation of Upper Urinary Tract Urothelial 
Carcinoma  
13.3.1.
General 
Instructions for 
Instillation Visits
"GFR ≥30"; "In the event that one or more of the 
above values are outside of the required limits, 
and the PI is confident that the treatment can be 
safely performed, he/she should contact UroGen 
Trial manager to obtain approval to proceed to 
treatment":
Deleted: 
In case of use of an external lab, the external lab's quality assurance documentation, 
normal ranges and CV of head lab must be collected by the site
Deleted: "GFR ≥30"; "In the event that one or more of the above values are 
outside of the required limits, and the PI is confident that the treatment can be 
safely performed, he/she should contact UroGen Trial manager to obtain approval 
to proceed to treatment"; 
Added " • 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"; " o
A repeated volumetric measurements may be performed 
prior to each instillation, at the discretion of the treating investigator"; 
• For all other patients, changes in creatinine should not result in GFR less 
than 30mL/min/1.73m2.
13.3.1 General 
Instructions for 
Instillation Visits
If parameters do not conform to the detailed 
above, treatment will be postponed until 
recuperation for up to 4 weeks.
Wording revised: If laboratory parameters do not conform to the detailed above, 
treatment will be postponed until laboratory values improve,  for up to 4 weeks.
13.3.1 General 
Instructions for 
Instillation Visits
Added: Repeated volumetric measurements may be performed prior to each 
instillation, at the discretion of the treating investigator.   
13.3.3. Instillation 
Procedure
" For instillation, a 7–8 Fr ureter catheter 
supplied by UroGen shall be used."; "Prior to 
every instillation, the investigator must review the 
pyelocalyceal volume measurement done for that 
patient, withdraw the exact volume required into 
the syringe…"
Added: " •For instillation, a 7–8 Fr ureter catheter supplied by UroGen shall be 
used. in situations where it is technically challenging to pass the Urogen 
provided 7Fr catheter, a 5Fr Ureteral Catheter with molded Luer-Lock port 
may be used."; Prior to every instillation, the investigator must review the 
pyelocalyceal volume measurement done for that patient. A repeated volumetric 
measurements may be performed prior to each instillation, at the discretion 
of the treating investigator. and The investigator must withdraw the exact 
volume required into the syringe…"
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Section Updated
Protocol Version 5.0
Original Text
Protocol Version 6.0
Description of Change / New Text
13.3.5.
Instillations #2–
#6 Visit Procedures (V2–
V6)
"CBC (complete blood count) - Should be 
performed in 1st week and 3rd week following the 
6th instillation. This blood test can be performed 
also in the patient's local clinic. The CBC results 
should be recorded in the CRF."
Updated: "CBC (complete blood count), renal and liver blood function and 
coagulation - Should be performed in 1st week and 3rd week following the 6th 
instillation. This blood test can be performed also in the patient's local clinic. The 
CBC, renal and liver blood function and coagulation results should be recorded 
in the CRF."
13.4 LAB 1 (V7) & LAB 
2 (V8):
" One week and 3 weeks following the last of the 
weekly instillations, complete blood count tests 
…"
Updated: " One week and 3 weeks following the last of the weekly instillations, 
CBC (complete blood count), renal and liver blood function and coagulation 
tests…"
13.9.
Treatment 
Discontinuation
Heading: "Treatment Discontinuation Visit"; " If 
a patient discontinues during the treatment period 
or at any time prior to the PDE Visit, an 
unscheduled visit should be done (one month after 
the last installation treatment) in which following 
activities should be performed: 
All assessments scheduled to be conducted during 
the PDE visit (Section 13.4);
If the patient appears to have CR, document if the 
patient agrees to continue FU within the trial;"
Updated: " Treatment discontinuation prior to PDE
If a patient discontinues during the treatment period or at any time prior to the 
PDE Visit, an unscheduled visit should be done (one month after the last 
installation treatment) in which the patient to complete PDE visit within 4+/-1 
week of last instillation following activities should be performed: and perform 
all
All assessments scheduled to be conducted during theof the PDE visit (Section 
13.4);
If the patient appears to have CR at PDE, document if the patient agreespatient 
should continue to continue FU within the trial receiving the maintenance 
treatments should be considered as well;"; Sub-heading was added: 
"Treatment Discontinuation during Maintenance"
14. Schedule of Events
14.1. Part I - All Patients 
- Up to PDE Visit
CBC, liver and renal function, coagulation, wk 6 
and wk 8 : "Only CBC" 
Updated: "Only CBC X" (X stand for CBC, liver and renal function, coagulation)
18. Statistical 
Methodology
Added: "A formal Statistical Analysis Plan (SAP) will be developed and 
finalized prior to database lock. The SAP will supersede this statistical 
analysis section."
18.4.1.
Safety Analysis 
Set
"...Intent-to-Treat (ITT) Analysis Set 
The intent to treat (ITT) analysis set will consist 
of all patients enrolled in the trial who have a 
confirmed diagnosis of LG UTUC by local 
pathology and have received at least one 
instillation of MitoGel™.";
 " ITT subjects with no observed value on primary 
efficacy will be imputed primary efficacy failures. 
At the same time, sensitivity analyses will 
evaluate the robustness of results to different 
Updated: " Intent-to-Treat (ITT) Analysis Set (=safety analysis set).
The intent to treat (ITT) analysis set will consist of all patients enrolled in the trial 
who have a confirmed diagnosis of LG UTUC by local pathology and have 
received at least one instillation of MitoGel™";
Updated: " ITT subjects with no observed value on primary efficacy will be 
imputed primary efficacy failures. Note that this only include patients who 
dropped from the study for any reason before the PDE evaluation. At the 
same time, sensitivity analyses will evaluate the robustness of results to different 
assumptions of missingness.
For the key secondary endpoint only observed data will be used.
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Section Updated
Protocol Version 5.0
Original Text
Protocol Version 6.0
Description of Change / New Text
assumptions of missingness.
For the key secondary endpoint only observed 
data will be used."
Treatment of missing values for the secondary endpoint detailed in Section 
18.7.2."
18.4.2.
Local Modified 
Intent-to-Treat (mITT) 
Analysis Set
Heading:" 18.4.2. Modified Intent-to-Treat 
(mITT) Analysis Set"; 
" The modified intent to treat (mITT) analysis set 
will be a subset of ITT subjects with confirmed 
LG UTUC at Screening by central lab."
Added:" 18.4.2. Local Modified Intent-to-Treat (mITT) Analysis Set";
" The local modified intent to treat (local - mITT) analysis set will be a subset of 
ITT subjects with confirmed LG UTUC at Screening by local lab and who 
arrived to the PDE evaluation. by central lab."
18.4.3.
Central 
Modified Intent-to-Treat 
(mITT) Analysis Set
Section was added:" The central modified intent to treat (Central - mITT) 
analysis set will be a subset of ITT subjects with confirmed LG UTUC at 
Screening by central lab and who arrived to the PDE evaluation and 
received the central lab diagnostic.  
Missing values: Only observed values will be used in central - mITT; i.e. 
missing data will not be imputed."
18.4.4.
Per Protocol 
(PP) Analysis Set 1
"18.4.3 Per Protocol (PP) Analysis Set 1";
" The Per Protocol (PP) analysis set is a subset of 
the mITT Analysis Set…"
Updated: "18.4.34 Per Protocol (PP) Analysis Set 1";
" The Per Protocol (PP) analysis set is a subset of the Local mITT Analysis 
Set…"
18.4.5.
Per Protocol 
(PP) Analysis Set 1
"18.4.4 Per Protocol (PP) Analysis Set 2";
" The Per Protocol (PP) analysis set is a subset of 
the mITT Analysis Set…"
Updated: "18.4.45 Per Protocol (PP) Analysis Set 2";
" The Per Protocol (PP) analysis set is a subset of the Local mITT Analysis 
Set…"
18.4.6.
Complete 
Responders at the PDE 
Visit (PDECR) Analysis 
Set
"18.4.5. Complete Responders at the PDE Visit 
(PDECR) Analysis Set"
"18.4.56 Complete Responders at the PDE Visit (PDECR) Analysis Set"
18.7.2.
Sensitivity 
Analysis for the 
Principal Analysis of the 
Primary Endpoint
" The primary analysis described in the previous 
section will be repeated using
o
Only observed data from ITT (i.e., 
excluding missing data imputed “failure”)
o
mITT population 
o
PP1 population
PP2 population"
Updated: " The primary analysis described in the previous section will be 
repeated using
o
Local diagnosis in Local-mITT, PP1, PP2 populations
o
Central diagnosis in Central-mITT
o
Only observed data from ITT (i.e., excluding missing data imputed 
“failure”)
o
mITT population 
o
PP1 population
o
PP2 population"
18.7.4.
Sensitivity 
Analysis for the 
Dichotomous Key 
Secondary Endpoint
Section was added: " For dichotomous key secondary analysis, patients who 
did not arrive the last FU visit and have no prior recurrence, are treated as 
Failures (which is the "worst case" imputation scenario). Sensitivity analysis 
will be done to examine the results if alternative imputation scenarios are 
A Ph-3 Multicenter Trial Evaluating the Efficacy and Safety of
MitoGel™ - US, IL
Document Number: CLP-0002344
Document Version: 6.0
Effective Date: 18-Jun-2018
Document State: Effective (Controlled)
Page 126 of 130




Confidential
Section Updated
Protocol Version 5.0
Original Text
Protocol Version 6.0
Description of Change / New Text
aware of the serious adverse event.  
Fax no. for events reporting: 
, 
Attn.:  
, QPPV.'
19.2.3.
Special 
Reporting Situations
" 19.2.3. Special Reporting Situations /Events of 
Clinical Interest"; " Safety events of interest on a 
sponsor medicinal product…"
Updated: " 19.2.3. Special Reporting Situations /Events of Clinical Interest "; 
"Safety events of interest onSponsor a sponsor medicinal product…"
19.2.4.
Events of 
special interest
" 19.2.4. In addition, the following adverse events 
are defined as “events of special interest”:"
Updated:" 19.2.4.In addition, the following adverse events are defined as 
“eEvents of special interest”:"; 
Added to bullet #8:"Any of these Events of Special Interest that also meet 
criteria of Serious Adverse Event should be reported as such. These events 
will be evaluated and reviewed by the Sponsor pharmacovigilance team."
19.2.4  Events of special 
interest
19.2.4 bullet 3
“Symptoms suspicious of ureteral perforation/rupture – 
(prolonged localized abdominal or flank pain, abdominal 
tenderness/acute abdomen);”
Revised 19.2.4 - bullet 3
Ureteral events, including stenosis, as well as symptoms suspicious of ureteral 
perforation/rupture – (prolonged localized abdominal or flank pain, abdominal 
tenderness/acute abdomen);
19.2.5- Management of 
Anomalies in Laboratory 
Parameters
The investigator must review the patient's lab results and 
evaluate the clinical meaning of all anomalous laboratory 
values based on the definition of standard values used by 
leading laboratories and CTCAE.  Each clinically 
significant anomaly must be fully reported.  “Clinically 
Significant” means any anomaly which, according to the 
investigator, represents a significant clinical problem, which 
requires medical attention or which otherwise falls under the 
definition of “Serious” adverse event.  When clinically 
advised, additional tests or evaluations should be carried out 
to determine the significance or etiology of an anomalous 
result or to monitor the course of an adverse event.  Any 
persistent anomalous value must be monitored at the 
investigator's discretion.  Clinically significant anomalous 
results must be recorded in the relevant section of the eCRF.
Revised: ‘The investigator must review the patient's lab results and evaluate all 
anomalous laboratory values as clinically significant or not. Clinically significant 
results must be recorded as adverse events in the relevant section of the eCRF”.
19.2.7.
Concomitant 
Illnesses and Pre-existing 
Conditions
Added:"Ongoing medical conditions and past cancer history other than 
urothelilal carcinoma, and significant medical history up to 5 years back 
from screening must be collected and recorded in the eCRF."
19.2.8.
Adverse Events 
Reporting Period
" The investigator is required to report all non-
serious adverse events/ occurring starting with 
Re-edited and updated: " • The investigator is required to report collect all non
serious adverse events/ occurringAEs starting beginning with informed consent 
A Ph-3 Multicenter Trial Evaluating the Efficacy and Safety of
MitoGel™ - US, IL
Document Number: CLP-0002344
Document Version: 6.0
Effective Date: 18-Jun-2018
Document State: Effective (Controlled)
Page 128 of 130


Confidential
Section Updated
Protocol Version 5.0
Original Text
Protocol Version 6.0
Description of Change / New Text
informed consent signing and up to 30 days post 
last instillation visit to the sponsor.  This 
information is to be entered into the eCRF.
•
In case of complete response patients 
continuing with maintenance treatments - Adverse 
events will be collected up to 30 days post last 
maintenance instillation and will be documented 
in the eCRF.
•
In case of non-complete response 
patients - All adverse events should be recorded 
up to the PDE Visit (5 weeks after the last 
instillation). 
•
All serious adverse events, all AEs which 
are suspected to be related to the study treatment 
and/or procedures occurring during the trial 
period should be reported at all times."
signing signature. and up to 30 days post last instillation visit to the sponsor.  
This information is to be entered into the eCRF. 
•
All serious adverse events, aand All AEs which are suspected to be 
related to the study treatment and/or procedures occurring during the trial 
period should be reported at all times.
•
In case of complete response patients continuing with maintenance 
treatments  Adverse events will be collected up to 30 days post last maintenance 
instillation or until resolution,  and will be documented in the eCRF.
•
In case of non-complete response patients - All adverse events should be 
recorded up to the PDE Visit or until resolution (5 weeks after the last 
instillation).  
All serious adverse events, all AEs which are suspected to be related to 
the study treatment and/or procedures occurring during the trial period should be 
reported at all times.
•
In case of complete response patients continuing with maintenance 
treatments  Adverse events will be collected up to 30 days post last maintenance 
instillation and will be documented in the eCRF.
•
In case of non complete response patients  All adverse events should be 
recorded up to the PDE Visit (5 weeks after the last instillation). 
•
All serious adverse events, all AEs which are suspected to be related to 
the study treatment and/or procedures occurring during the trial period should be 
reported at all times."
20.
Concomitant 
Medications
Added:" Concomitant medications given to treat a reported adverse event 
must be recorded in the eCRF."
Appendix III: Required 
Lab Tests
" Hematology Tests * 
•
Complete blood count, including red 
blood cell indices and white blood cell differential
Note: On visits where only CBC is required, it 
may be performed at the community but less 
recommendable.
•
Platelet count"
Deleted:" " Hematology Tests * 
•
Complete blood count, including red blood cell indices and white blood 
cell differential
Note: On visits where only CBC is required, it may be performed at the 
community but less recommendable.
•
Platelet count""
A Ph-3 Multicenter Trial Evaluating the Efficacy and Safety of
MitoGel™ - US, IL
Document Number: CLP-0002344
Document Version: 6.0
Effective Date: 18-Jun-2018
Document State: Effective (Controlled)
Page 129 of 130


Action Name
User Name
Title
Signature Date
Review
Director of Clinical Operations
29-May-2018 18:27 (GMT+2)
Review
VP QA
29-May-2018 18:49 (GMT+2)
Send for Approval
VP QA
29-May-2018 19:00 (GMT+2)
Send for Approval
VP QA
14-Jun-2018 15:31 (GMT+2)
Send for Approval
VP QA
14-Jun-2018 17:13 (GMT+2)
Send for Approval
VP QA
18-Jun-2018 13:40 (GMT+2)
Approve
VP Regulation
18-Jun-2018 14:52 (GMT+2)
Approve
Chief Scientific and Medical affairs 18-Jun-2018 15:23 (GMT+2)
Approve
SVP Clinical
18-Jun-2018 19:48 (GMT+2)
Approve
VP QA
18-Jun-2018 20:43 (GMT+2)
QA Approve Without Training
VP QA
18-Jun-2018 20:43 (GMT+2)
A Ph-3 Multicenter Trial Evaluating the Efficacy
and Safety of MitoGel™ - US, IL
Document Number: CLP-0002344
Document Version: 6.0
Effective Date: 18-Jun-2018
Document State: Effective (Controlled)
Page 130 of 130

ICF_001.pdf: 
 
18November2018 
 
Patient Consent Form, Version 7.0 
Page 1 of 19 
(Protocol TC-UT-03, Version 6.0) 
INFORMED CONSENT FORM 
AUTHORIZATION FOR ONCOLOGY RESEARCH  
 
TITLE: 
A Phase 3 Multicenter Trial Evaluating the Efficacy and Safety of 
MitoGel™ (UGN-101) on Ablation of Upper Urinary Tract 
Urothelial Carcinoma   
 
PROTOCOL NO.: 
TC-UT-03 
 
 
 
SPONSOR: 
UroGen Pharma Ltd 
 
INVESTIGATOR: 
Name 
 
Address 
 
City, State Zip 
 
Country 
 
SITE(S): 
Name 
 
Address 
 
City, State  Zip 
 
Country 
 
STUDY-RELATED 
PHONE NUMBER(S): 
Name 
 
Number(s) (24 hour required) 
 
 
INTRODUCTION  
You are invited to consider participating in a research study.  You were selected as a possible 
participant in this study because you have upper tract urothelial carcinoma (UTUC), and because 
you appear to meet the requirements for admission to this clinical trial. 
 
Please take your time to make your decision.  It is important that you read and understand several 
general principles that apply to all who take part in our studies: 
a) Taking part in the study is entirely voluntary. 
b) Personal benefit to you may or may not result from taking part in the study, but 
knowledge gained from your participation may benefit others; 
c) You may decide not to participate in the study or you may decide to stop participating in 
the study at any time without 21penalty or loss of any benefits to which you are entitled. 
 
The purpose and nature of the study, possible benefits, risks, and discomforts, other options, your 
rights as a participant, and other information about the study are discussed below. Any new 
information discovered which might affect your decision to participate or remain in the study 
will be provided to you while you are a participant in this study.  You are urged to ask any 
questions you have about this study with members of the research team. You should take 


 
18November2018 
 
Patient Consent Form, Version 7.0 
Page 2 of 19 
(Protocol TC-UT-03, Version 6.0) 
whatever time you need to discuss the study with your physician and family.  The decision to 
participate or not to participate is yours.  If you decide to participate, please sign and date where 
indicated at the end of this form.   
 
The research study is being sponsored by UroGen. UroGen is called the Sponsor and 
[Site/Institution Name] is being paid by UroGen to conduct this study. [PI Name] is the primary 
investigator. 
 
The study will take place at [Site/Institution Name].  
 
WHY IS THE STUDY BEING DONE?  
The purpose of this study is to evaluate the effectiveness and safety of MitoGel on patients with 
UTUC. This research study is being done because this is a potentially beneficial new treatment 
for Low Grade UTUC.  
 
Mitomycin C (MMC) is FDA approved for other clinical indications and commercially available 
for the treatment of bladder cancer. UroGen’s MitoGel™ (a combination of MMC and TC-3 gel) 
has not been approved by the FDA and is not commercially available. The gel is designed to 
safely maintain the MMC within the body to treat the urinary tract urothelial carcinoma.  
 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY? 
Participants in the study are referred to as subjects. About 74 subjects will take part in this study 
worldwide; about [Number of Subjects] subjects will be recruited at this site. 
 
WHAT IS INVOLVED IN THE STUDY? 
If you take part in this study, you will have the following tests and procedures:  
 
You will receive 6 MitoGel instillations (treatments with the MitoGel) into upper urinary tract 
(specific area in the kidney) once per week for 6 weeks.  MitoGel for the treatment of upper tract 
urothelial carcinoma (UTUC) contains the drug Mitomycin C. The administration of MitoGel 
will be performed under fluoroscopy (medical imaging that shows a continuous x-ray image on a 
monitor) and cystoscopy (procedure to examine the lining of your bladder and the tube that 
carries urine out of your body) through a standard ureteral catheter. Your physician will review 
the details of the instillation procedure, which are similar to a cystoscopy.  
 
 
Entering this study will delay any other method of care for your situation by at least 3 months.  
 
Such delay is considered low risk in patient with low grade upper tract urothelial carcinoma. 
 
If the treatment succeeds, meaning, the tumor(s) disappeared after 6 instillations (Complete 
Response=CR), you will receive up to an additional 11 (eleven) maintenance instillations. 
 
This is a multi-center open label, single arm, safety and efficacy study. 


 
18November2018 
 
Patient Consent Form, Version 7.0 
Page 3 of 19 
(Protocol TC-UT-03, Version 6.0) 
• “Multi-center” means that this study will be done in approximately 40-50 medical centers 
across the US, Europe, Israel and Canada in approximately 74 individuals. 
• “Open label” means that everyone participating in this study will be treated with 
UroGen's MitoGel™ procedure. 
 
Your treating urologist within this trial will inform you of any new findings, during the course of 
your treatment that might affect your willingness to continue receiving this treatment. 
 
21A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identity you. At most, 
the Web site will include a summary of the results. You can search this Web site at any time.  
 
STUDY PARTICIPATION 
This study involving UroGen’s MitoGel™ procedure has 5 phases: 
 
Screening for eligibility 
1 to 4 weeks 
Treatments with UroGen’s MitoGel™ 
Once weekly for 6 weeks (Visits 1 through 6) 
Primary Disease Evaluation (PDE) 
Approximately 4 to 6 weeks after last treatment visit 
(Visit 9) 
MitoGel Maintenance Treatment 
Only for complete response (CR) patients- monthly, 
up to a total of 11 (Eleven) treatments 
 
Follow-up visits 
Approximately 3, 6, 9 and 12 months after the 
primary disease evaluation visit (Visits 12, 15, 18, 21)  
 
Total length of study: 16 months 
 
You can stop participating at any time.  However, if you decide to stop participating in the study, 
we encourage you to talk to the treating urologist and your primary physician first. 
 
If you decide to discontinue your participation, your urologist will discuss your options for 
continued care.  
 
Note:  You will be requested by signing this informed consent to allow your urologist to provide 
your relevant medical records to UroGen and to the coordinating investigator of this trial which 
is not your doctor for review of your eligibility to the trial. 
 
You will also be requested by signing this Informed Consent Form to allow sending of the 
biopsy and urine cytology slides/tissues taken prior to the trial which are relevant for eligibility 
and those taken during the trial, to central laboratory for a second reading. 
 
Your medical records and cytology/biopsy slides provided to UroGen and central lab, 
respectively will not contain your personal identification information (de-identified). 
 
SCREENING FOR ELIGIBILITY 


 
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Patient Consent Form, Version 7.0 
Page 4 of 19 
(Protocol TC-UT-03, Version 6.0) 
If you agree to participate in this study, the following may happen for participation up to 28 days 
before starting experimental treatment: 
 
• You must first consent to participate in this study 
• You will undergo a detailed evaluation.  This will include a collection of your medical 
history information, a physical examination, including a measurement of your vital signs, 
fulfillment of eligibility criteria, and a review of your current and past medications.  
• We will be collecting a urine sample for urinalysis and urine culture, which are all 
standard urine tests. 
• We will collect 20 ccs of blood (4 teaspoons) for routine testing, including kidney, liver, 
blood count, and coagulation tests. 
• If you are a woman of child bearing potential, 5ccs (1 teaspoon) blood will be drawn for a 
pregnancy test.  
 
Prior to Instillation (during the screening period):  
We will conduct a pyelography, which is an examination to assess the upper urinary tract, to 
determine the volume of MitoGel to be instilled in each visit. (Details below) 
 
During this examination, we will also conduct the following procedures, if they  
a) Have not already been completed for your care within the past two (2) months, and  
b) Records and slides are available for the study sponsor for review 
c) Or if it is not informative enough for the study requirement:   
 
• A biopsy of lesions within the upper tract 
• Upper tract urine cytology (a washing cytology) 
• A video recording or photography of the diagnostic ureteroscopy & upper urinary tract 
lesion assessment. (Under anesthesia) 
 
The volume of your kidney will be measured with a contrast agent (This is a commonly used 
substance that enhances the ability to see the specific parts inside the body during medical 
imaging), during the Ureteroscopy or during the first treatment through the ureter catheter. This 
measured volume will be the volume of the MitoGel you will receive each treatment. 
 
If you have not had a recent CTU (CT urography) scan within the past – Three (3)  months or if 
your doctor believes it is necessary to a better evaluation of your current disease, you will be 
required to repeat CTU scan. In the event that CTU cannot be performed due to any reason, an 
MRI should be performed instead. 
 
Medication: 
In order to facilitate the instillations, you will be prescribed with 1.3 g Sodium bicarbonate 
tablets (a type of salt), to help lower the acidity levels in your urine, as acidic urine can cause the 
fast breakdown of the Mitomycin C. These tablets are to be taken the night before each 
instillation, the morning of instillation, and again 30 minutes prior to each instillation procedure. 
 


 
18November2018 
 
Patient Consent Form, Version 7.0 
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(Protocol TC-UT-03, Version 6.0) 
In order to avoid allergic symptoms, you may be prescribed with prophylactic anti-allergic 
treatment –Anti-histaminic agents. These tablets are to be taken the day before instillation, on the 
day of instillation and the day after the instillation. 
 
It is preferred that diuretics not be taken the night before and prior to the instillation. If you are 
on diuretic medications, your doctor will determine whether the medication can be skipped prior 
to the instillations. 
 
To the extent that it is possible, drinking should be avoided in the 4-6 hours prior to the 
instillation.  
• Post instillation drinking should be limited. A recommended drinking schedule follows:  
• 0-2 hours post instillation: refrain from drinking any liquid  
• 2-4 hours post instillation: 1 cup of water every 2 hours  
• 4 hours post instillation: resume normal liquids consumption  
 
Following instillation, you will be carefully monitored for urine output and clinical symptoms, 
which might indicate urinary obstruction. 
 
Aiming to minimize the risk for Urinary Tract Infections (UTI), an antibiotic will be prescribed, 
as is normal for this kind of procedure. 
 
Your doctor might prescribe you with Diazepam, an anti-anxiety medication to be taken 1 hour 
prior to each instillation. 
 
You will be given separate written instructions for each of these steps, and will also receive a 
phone call from a member of the study team to remind you. 
 
Treatments with UroGen’s MitoGel™ 
You will have 6 treatments performed once weekly for 6 weeks. Each treatment will include 
MitoGel™ will contain 4 mg of Mitomycin C per 1 mL of TC-3 gel (4:1 ratio) which will be 
administered through an ureteral catheter into the upper urinary tract. The procedure will take 
approximately 30 minutes. After MitoGel™ administration (MitoGel injection will be performed 
under fluoroscopy and cystoscopy through a standard ureteral catheter as explained above)., the 
gel will form a reservoir in the renal pelvis, which will dissolve over several hours, delivering the 
drug to cover the surface during that time. 
 
Upon consultation with your urologist, in very rare cases, the catheter may be kept in place for 
the 6 weeks duration, instead of having new ones put in every week (and removed). Your care 
team will provide home care instructions. 
 
Instillation through a nephrostomy tube may be an option, if necessary. 
 
It may be required that an educational trainer from the sponsor will be present during some of the 
treatments to support the clinical team with the proper instructions of use.  
 


 
18November2018 
 
Patient Consent Form, Version 7.0 
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(Protocol TC-UT-03, Version 6.0) 
During the first instillation visit 
You will undergo a standard urology-oriented physical exam, including vital signs measurement, 
and we will collect information about your medications. We will collect 20 cc of blood (4 
teaspoons) for routine testing, including kidney, liver, blood count, and coagulation tests.  
 
• 
Urine will be collected for standard urologic assessment tests, including urinalysis, and 
urine culture. If you are a woman of child bearing potential, some of the urine will be 
used for a pregnancy test (If the urine test is positive, a blood (1 teaspoon) pregnancy test will 
be performed).  
 
If not done during screening, the volume of your kidney will be measured with a contrast agent 
through the ureter catheter. This measured volume will be the volume of the MitoGel you will 
receive each treatment 
 
After the treatment you will be provided with a Visual Analogue Scale (VAS) form and 
requested to mark the degree of pain during the instillation procedure on a scale of 0-10. You 
will also be given a Post-Treatment questionnaire to evaluate your post-treatment experience 
with the following questions: 
1. How long after the treatment did you have your first urination? 
2. How long after the treatment was the urine clear (no purple color) for the first time? 
 
Thereafter, 24 to 32 hours post treatment, you will be contacted via telephone to review the 
completed questionnaire. Please keep the completed questionnaire as it will be collected at the 
next visit. 
 
Following this first visit, we will monitor you for 6-23 hours after the instillation for observation, 
at the investigator’s discretion, to monitor for side effects. This initial treatment will be done in 
the clinic/office or in the operating room with anesthesia 
. 
If you allow, on the visit for the first instillation, for this, we will collect blood samples, to 
monitor the drug distribution (Pharmacokenetic assessment). PK will be performed with 
just 6 first patients who provide informed consent.  This will be done prior to instillation, 
thirty minutes after the instillations, and then again 1, 2, 3, 4, 5, and 6 hours post 
instillation. Each sample will require 5 mL of blood. Yes, I agree to the collection of 
serial blood samples during the first instillation visit. 
 
No, I do not agree to the collection of serial blood samples during the first instillation 
visit. 
 
 
Instillation Visits 2 through 6 
Prior to visits 2 through 6 -up to 3 days prior to treatment day, your blood (approximately 20 
mL) will be tested for safety evaluation (check your blood count, liver enzymes, kidney function, 
electrolytes and coagulation). 
 


 
18November2018 
 
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Page 7 of 19 
(Protocol TC-UT-03, Version 6.0) 
On treatment day the following procedures will be conducted: 
 
1. A standard urology-oriented physical examination, including a measurement of your 
vital signs, and a review of your current medications as well as any side effects.   
2. Urine will be collected for standard urologic assessment tests, including urinalysis 
and urine culture. 
3. If you are a woman of child bearing potential, a urine pregnancy test will be 
conducted.  If the urine test is positive, a blood pregnancy test will be performed. 
4. In case not all blood test were preformed prior to treatment – your blood (up to 20 
mL) will be tested according to missing test (blood count/ liver enzymes/ kidney 
function/ electrolytes / coagulation)..  
 
After each treatment, you will be requested to mark the degree of pain during the instillation 
procedure on a scale of 0-10. You will also be given a questionnaire to evaluate your post-
treatment experience with the following questions: 
1. How long after the treatment did you have your first urination? 
2. How long after the treatment was the urine clear (no purple color) for the first time? 
 
Thereafter, 24 to 32 hours post treatment, you will be contacted via telephone to review the 
completed questionnaire. Please keep the completed questionnaire as it will be collected at the 
next visit. 
 
If necessary, you may be called for an unscheduled visit to follow up on any post-treatment 
issues or problems that require clinical evaluation or follow-up. 
 
You will undergo safety evaluation after each instillation including adverse event rate and 
laboratory evaluation.  
 
In the event of a urinary tract infection or another safety reason which causes the investigator to 
postpone a treatment, the MitoGel treatment will be postponed until the event is resolved and not 
over 4 weeks; In case treatment has been delayed beyond 4 weeks due to adverse drug reaction 
MitoGel treatment will be stopped permanently, however, you will continue to follow up visits. 
 
Following Installation Visits 
One week, and again three weeks following the 6th installation, your blood (up to 20 mL/ 4 
teaspoons) will be tested (a CBC, liver function, renal function and coagulation will be taken).  If 
necessary, this can be done at your local clinic or doctor’s office. 
 
Primary Disease Evaluation Visit (PDE) 
 
About five weeks following the completion of treatment visits, you will be scheduled for an 
evaluation visit.  This will involve the following procedures: 
 
1. A full physical examination, including a urology oriented physical exam, vital signs 
measurements and a review of your current medications as well as any side effects.  


 
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(Protocol TC-UT-03, Version 6.0) 
2. Your blood will be tested to check your blood count, liver enzymes, kidney function, 
electrolytes and coagulation (4 teaspoon).  
3. Urine will be collected for urinalysis and urine culture. 
4. You will undergo Ureteroscopy evaluation under anesthesia to evaluate the area of 
treatment, which include an upper urinary tract cytology, and biopsy of lesions, if 
applicable.   
 
At the evaluation, if no detectable disease is found, you will be considered a Complete Response 
(CR) patient and continue with the study as described below.  You will receive up to an 
additional 11 (eleven) maintenance treatments. 
  
If you responded partially or did not respond to the treatment, you will be considered as a Non-
Complete Response and your participation in the study will be terminated.  
In the event that your cytology test results are equivocal, you will undergo re-cytology test after 
several weeks. This sentence apply also to each of the follow-up visits.   
 
Your urologist will discuss the results with you and will determine which standard of care 
treatment is best, and information about the disease will be collected.  
. 
Study continuation for Complete Response patients only: 
 
Maintenance Instillation Visits  
In the case that you are a complete response patient (no detectable disease on the PDE visit), you 
will be scheduled for monthly visits, during which MitoGel will be instilled as described in the 
visits above.  This will occur once per month (+- 2 week) for eleven months, (one month prior to 
last FU visit within the study - see below) or until tumor first recurrence.  
 
The following procedures will be conducted: 
• Standard urology-oriented physical examination 
• Your blood (approximately 20 mL) will be tested to check your blood count, liver 
enzymes, kidney function, electrolytes and coagulation and medication review. 
• Urine will be collected for standard urologic assessment tests, including urinalysis and 
urine culture.   
• Review of your current medications and adverse events, if any.   
 
The tests will be conducted while you are at the clinic for your monthly treatments. If the disease 
reoccurs, you will stop treatment in the study and your urologist will review your treatment 
options.  If you decide to stop study participation, you will be asked to perform a safety visit.   
 
Follow-up Visits  
During the time of the maintenance instillation visits, you will have an up to a 4 standard-of-care 
follow-up visits done every 3 months.   
 


 
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(Protocol TC-UT-03, Version 6.0) 
Three months after your evaluation visit, the first follow-up (FU) visit will be conducted. During 
this visit, follow-up data on your disease outcome will be collected. As per standard of care, you 
will undergo these follow-up visits every three months.  
 
These visits may include: 
1. A review of your current medications, vital signs and reporting of any adverse events.  
2. Endoscopy of the kidney (ureteroscopy under anesthesia) where the upper urinary 
tract will be examined and photographed to record number, size, appearance and 
location of tumors if any are present. This will also include a biopsy sample of the 
tumor, if lesions are detected. If present, the tumor(s) may be surgically ablated 
(destroyed)  
3. Upper urinary tract urine cytology will be performed to confirm the absence of 
cancer. 
 
The final follow up visit will happen 12 months after the post-instillation evaluation visit, or until 
tumor first recurrence, at which time, additional follow-up data on disease outcome will be 
collected. 
 
CTU Scan 
At the 4th follow up visit, we will obtain a final CTU scan. 
 
Note: In case of recurrence or progression at the original treated area, assessed during the 
follow-up period, you will be considered as having completed the trial and will not be summoned 
for further follow-up visits, but for a single termination visit for safety evaluation. 
 
FOLLOW-UP VISITS AND END OF STUDY PARTICIPATION 
 
Unscheduled Visit  
An unscheduled visit may be performed at any time during the trial if the investigator decides 
that the clinical state of the patient does not permit instillation of the IP, for assessment of safety, 
at the Patient's request, or as deemed necessary by the investigator. 
 
You should provide the trial urologist information about any medications you are taking.  In 
addition, if you are taking any over-the-counter drugs or herbal supplements which you have 
obtained from the drug store, grocery store, etc., this information should also be provided to the 
urologist. 
 
Withdrawal by investigator, physician, or sponsor 
The investigators may end your participation in this study for a number of reasons, such as if 
your safety and welfare are at risk, if you do not follow instructions or if you miss scheduled 
visits. The investigators or the study sponsor might also decide to stop the study at any time.  
 
The investigators, physicians or sponsors may stop the study or take you out of the study at any 
time should they judge that it is in your best interest to do so, if you experience a study-related 
injury, if you need additional or different medication, or if you do not comply with the study 


 
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plan. They may remove you from the study for various other administrative and medical reasons. 
They can do this without your consent. 
 
If you decide to stop being in the study or are removed from the study or the study is stopped the 
investigator will ask you to do a follow-up visit to complete an exit interview. The data collected 
about you up to the point of withdrawal will remain a part of the study and may not be removed 
from the study database. 
 
If you decide to stop receiving the study treatment prior the 6th instillation, the investigator will 
ask you to continue being in the study up to the PDE visit. In the event that you didn’t complete 
the study treatment, but have a Complete Response to the treatment, you will be advised to 
continue with the follow-up visits as long as possible even without having the study treatment, 
but in consultation with your study doctor it may be re-considered continuing with monthly 
instillations until 1-year follow-up or disease recurrence. The data collected about you up to the 
point of withdrawal will remain a part of the study and may not be removed from the study 
database.  
 
Note:  Your follow up data may be collected up to 3 years from PDE visit (visit 9) to evaluate 
long term safety and efficacy of the investigational product. 
 
WHAT ARE THE RISKS OF THE STUDY? 
For drug and device trials, there may be risks. These risks will be discussed with you by the 
research urologist.  
 
Each treatment may have possible adverse events. In the current treatment there might be 
Mitomycin C-related adverse events and Catheter insertion related adverse events. 
 
Many side effects go away shortly after treatment is stopped, but in some cases, side effects may 
be serious, long-lasting or permanent, and may even result in hospitalization. 
 
Inflammation causing narrowing in the ureters is   a common phenomenon, most of the cases 
resolve with or without intervention, for example placing a stent in the ureter. In some cases, the 
narrowing persists, or resolves with some residual damage. 
 
 
MMC+TC-3 Side Effects  
Based upon limited information regarding upper urinary tract irrigation with MMC+TC-3 (based 
on data from 22 compassionate treatments of upper tract urothelial carcinoma and the patients 
treated in the study so far): 
 
The following were reported more than once in the compassionate treatment series as probably or 
possibly related to study drug: 
• Allergic Reaction (n=2) 
• Dysuria (burning or painful urination) (n=2) 


 
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• Weakness/ Fatigue (n=4) 
• Fever/chills (n=2) 
• Aggravation of renal failure (n=2) 
• Blood line suppression (n=2) - decreased white blood cells (increases infection risk), red 
blood cells (increases fatigue risk), and platelets (increases bleeding and bruising risk) 
• Nausea (n=3)  
 
Catheter Insertion Related Side Effects 
Trauma to the bladder/ upper urinary tract creating: 
 
Common: 
Adverse events affecting the ureter  including, but not limited to inflammation of the ureter and 
narrowing of the ureter. 
 
Less Common or Rare: 
• Urinary tract infections resulting from the presence of a foreign body (the catheter) in the 
urinary tract  
 
• Urethral stenosis- narrowing of the urethra (passage from which urine leaves the bladder)  
 
• Urethral tear- due to traumatic insertion of the catheter  
 
• Ureteral perforation (tearing, breakage, or holes on the ureter) 
 
 
Mechanical Manipulations related Side effects (Including catheter Insertion and nephrostomy 
tube related side effects) 
 
Catheter insertion to the upper tract is well-practiced worldwide and widely used for many 
indications for example during kidney stones removal, the following are the known side effects 
of this procedure, including those evident in the upper urinary tract instillations  (as seen in the 
CUP described above: 
 
• Flank (between the ribs and the hip) pain (n=6) 
• Mild pressure/fullness at instillation site (n=4) 
• Acute Pyelonephritis (acute infection of the kidney)(n=3) 
• Asymptomatic Bacteriuria (n=2) 
• Macroscopic Hematuria (visible blood in urine)(n=2) 
 
Apart from the above- any adverse event mentioned in the information leaflet of mitomycin C 
may appear during the study. 
 


 
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Regarding Mitomycin C-related adverse events, please note: 
• Mytomicin C may cause burning sensation in the ureter, hand skin exfoliation (removal 
of dead skin cells), blood count changes, inflammation of the organ, soreness/pain in the 
area, soreness of the skin in the area around the openings of the urethra. 
 
• Mitomycin C can have also some side effects, including cystitis (bladder infection), 
frequent and / or painful urination, night-time urination or blood in the urine, allergic 
reactions in form of rashes or erythema (redness of the skin or painful itching) of a 
portion of the skin (i.e. palms and feet) or of the entire skin surface, contact dermatitis, 
generalized exanthemas (skin breakouts), skin peeling on the palms with/without 
generalized rash. 
 
Rare:  
• Blood line suppression - decreased white blood cells (increases infection risk), red blood 
cells (increases fatigue risk), and platelets (increases bleeding and bruising risk)  
• Death of cells of the urinary tract  
• Narrowed urethra (stenosis) Necrotizing severe cystitis (inflammation and dying of cells) 
are also very rare.  
• Cases of bladder shrinking with reduced bladder capacity have been described 
• Teratogenic effects (developmental disturbances) on embryo/foetus have been previously 
described.  
 
Previous studies using the MMC in association with TC-3 gel showed few side effects from 
the treatments which are related and expected to the treatments with MMC. Among the side 
effects have been found also urinary burning, urinary tract infections (UTI) and dysuria, which 
were resolved with or without any treatment. 
 
Anticipated TC-3 Gel Related Adverse Events: 
Common: 
• A sensation of bladder contractions due to the cold temperature of the instilled gel. 
• A sensation of upper urinary tract contractions due to the cold temperature of the instilled 
gel. 
 
• Rare:Upper urinary tract obstruction which occurred once due to violation of treatment 
instructions. 
 
Anticipated MitoGel-Related Phenomena (not an adverse event) 
• Purple colored urine 
• Urination of gel particles 
 
MMC+TC-3 may cause low blood cell counts (red blood cells, white blood cells, and/or 
platelets) that may require a transfusion, but this is very rare in local administration. 
Following are rare some side effects that were noticed during compassionate treatments:  


 
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• “Cool” flank sensation due to low temperature of instilled drug. 
•  narrowing of the ureter at location of the previously available tumor (Narrowing 
originated either from drug effect on the tissue or mechanical injury by rapidly inserted 
ureteral catheter). The event resolved following local treatment. 
•  Bladder inflammation and upper tract inflammation (due to treatment drug) 
• Enhanced frequency of urination (probably due to bladder irritation by the drug) 
• Hydronephrosis (distention of the kidney with urine as a result of obstruction of the 
outflow of urine) due to local edema caused by inflammation of the upper tract. 
 
 
Risks and side effects associated with Bicarbonate 
Sodium bicarbonate (baking soda) is generally well tolerated. However, high doses may cause 
headache, nausea or irritability. If any of these effects continue or become bothersome, inform 
your doctor. 
 
Risks and side effects associated with a biopsy  
Having biopsies performed in the upper urinary tract may cause pain, local bruising, bleeding, 
redness, swelling, and/or infection at the site of the biopsies.  An allergic reaction to the 
anesthetic may occur.  A scar may form at the biopsy site. 
 
Cytoscopy 
Cystoscopy is generally a safe procedure. Serious complications are rare. However, as with any 
surgery, there is the risk of infection, bleeding, and complications from the anesthesia. In all but 
the simplest procedures, antibiotics are used before the surgery to reduce the incidence of urinary 
tract infection. 
 
Side effects due to Blood Draws 
Blood draws may cause pain, bleeding, and/or bruising.  You may faint and/or develop an 
infection with redness and irritation of the vein at the site where blood is drawn.  Frequent blood 
collection may cause anemia (low red blood cell count), which may create a need for blood 
transfusions, but in this study the amount of blood drawn is limited and the risk for blood 
transfusion is extremely rare. 
 
This study involves exposure to radiation, and that exposure is increased the more often such 
tests are done. Radiation exposure at certain doses can potentially cause cancer. Any possible 
increase in cancer risk associated with participation in this study is within acceptable limits for 
human research subjects. 
 
Fluoroscopy 
Fluoroscopy involve the risks of radiation. Radiation-related risks associated with fluoroscopy 
include: 


 
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• Radiation-induced injuries to the skin and underlying tissues (“burns”), which occur 
shortly after the exposure, and 
• Radiation-induced cancers, which may occur 22sometime later in life. 
 
The probability that you will experience these effects from a fluoroscopic procedure is 
statistically very small.  
 
 
CT Scan Risks 
CT scans involve the risks of radiation (above) .In addition, if contrast material (iodine dye) is 
used, there is a slight risk of developing an allergic reaction, which may cause symptoms ranging 
from mild itching or a rash to severe difficulty breathing, shock, or rarely, death. The contrast 
material may also cause kidney problems, especially if you are dehydrated or have poor kidney 
function. The study doctors will ask you about any allergies or related conditions before the 
procedure. If you have any of these problems, you may not be allowed to have a CT scan. 
 
Having a CT scan may mean some added discomfort for you. In particular, you may be bothered 
by feelings of claustrophobia when placed inside the CT scanner, or by lying in one position for 
a long time. If contrast material is used, you may feel discomfort when it is injected. You may 
feel warm and flushed and get a metallic taste in your mouth. Rarely, the contrast material may 
cause nausea, vomiting or a headache. 
 
MRI Risks  
An MRI scan is a painless radiology technique that has the advantage of avoiding x-ray radiation 
exposure. There are no known side effects of an MRI scan. During the MRI scan, patient lies in a 
closed area inside the magnetic tube. Some patients can experience a claustrophobic sensation 
during the procedure. If you have history of claustrophobia please relate this to the treating 
urologist, as well as the radiology staff.  
If you have any metallic materials within the body please notify your treating urologist prior to 
the examination or inform the MRI staff. Metallic chips, materials, surgical clips, or foreign 
material (artificial joints, metallic bone plates, or prosthetic devices, etc.) can significantly distort 
the images obtained by the MRI scanner. If you have a heart pacemakers, metal implants, or 
metal chips or clips in or around the eyeballs you should not be scanned with an MRI because of 
the risk that the magnet may move the metal in these areas. If you have artificial heart valves, 
metallic ear implants, bullet fragments, and chemotherapy or insulin pumps you should not have 
MRI scanning. 
 
 
 
Reproductive Risks: 
You should not become pregnant or father a baby while on this study because the drugs in this 
study can affect an unborn baby. Women should not breastfeed a baby while on this study. 
Therefore, you need to use effective birth control while on this study.  You must use at least 2 
acceptable and effective methods of birth-control (like implants, injectable, combined 
estrogen/progesterone oral contraceptives and/or condoms with spermicide). 


 
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Unknown Risks to Women of Child Bearing Potential and Pregnant Women: The effects of 
the study medication on fertility or a fetus are not known. For this reason, if you believe that you 
are pregnant or have a chance of becoming pregnant you should not participate in this study. A 
urine pregnancy test will be performed before the start of study procedures. If you are pregnant, 
you will not be allowed to participate in the study. If you do participate in this study, you must 
use a medically effective form of birth control before entering the study, while participating in 
the study, and for at least 6 months after stopping the study. If you become pregnant during the 
study, tell the researchers right away.  
 
Unknown risks to infants: The side effects of the study medication on infants are also not 
known, therefore if you are currently breastfeeding you cannot participate in this study.  
 
Unknown risks and discomforts 
The experimental treatments may have side effects that no one knows about yet.  The researchers 
will let you know if they learn anything that might make you change your mind about 
participating in the study.  
 
As with any other new treatment this treatment may involve unpredictable risks to you 
 
ARE THERE ANY BENEFITS TO TAKING PART IN THE STUDY? 
 
You may or may not benefit from participation in this study. Treatment with the drug may help 
to control the disease, but there may be no benefits to you for receiving this treatment. 
 
The following are possible benefits from study treatment: 
 
- 
The tumors might disappear and subsequently no need for surgical removal would exist.  
- 
Additionally, in case of reduction of the number or size of the lesion(s) in comparison 
with baseline, the following surgical removal would be more limited; 
- 
A more efficient preventive effect of tumor recurrence might be proven. 
 
From what has been shown so far in the sponsor trials in urothelial carcinoma in the bladder, 
Mitomycin C appears to have a high potential for tumor removal, with more than 70% of the 
patients showing complete response to the treatment, and more than 80% of the patients showing 
either complete response or partial response. Moreover, the results suggest that the treatment 
appears to be generally safe and there has been no indication of a significant rise in risk related to 
the Mitomycin C dose used. 
 
The information generated by your participation may help future patients with Low Grade Upper 
Urinary Urothelial Carcinoma (UTUC). 
 
 
ALTERNATIVE TREATMENT 


 
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If you decide not to take part in this study, or if you withdraw from this study before it is 
completed, the following alternative procedures or courses of treatment are available: 
 
• There may be an opportunity to take part in other studies of investigational treatments, 
which your doctor will be happy to discuss with you.    
• You may be a candidate to undergo another approach of endoscopic management-like 
series of laser ablation or a kidney removal, partial or complete.   
• Alternatively, you may choose not to have any treatment directed at the cancer, but 
receive full supportive care, including treatment for pain and other symptoms of cancer.  
 
The risks, benefits and any questions you have regarding these other treatments will be explained 
to you by your doctor. 
 
FINANCIAL INFORMATION 
Any tests, procedures, and/or drugs that you may receive as part of this treatment will be without 
cost to you.  However, your insurance provider and/or you may be financially responsible for the 
cost of care and treatment of any complications resulting from the procedures and/or drugs, 
including hospitalization, nausea, vomiting, low blood cell counts, and dehydration.  Standard 
medical care that you receive under this treatment will be billed to your insurance provider 
and/or you in the ordinary manner.  Before receiving this treatment, you may ask about which 
parts of the treatment-related care may be provided without charge, which costs your insurance 
provider may pay for, and which costs may be your responsibility.  You may ask that a financial 
counselor be made available to you to talk about the costs of this treatment. 
 
UroGen will reimburse traveling expenses upon receipts and limited up to $50 per visit (higher 
reimbursed will be consider for exception cases)  
 
If you also participate in the PK trial, UroGen will reimbursed you $120 for your spent time.  
 
INJURE OR HURT  
If you are injured or harmed as a result of participating in the study and receive medical care 
through [Site Name/Institution] or any other health provider, you will be sent a bill for whatever 
medical care you receive.  All or part of your bill may be paid by your health insurance. If a 
Study patient suffers an illness or injury as a result of participating in this Study, the Sponsor 
shall reimburse the patient for the costs of diagnosis and treatment. The Sponsor, however, is not 
offering to reimburse for Study injuries that are caused by (i) Institution's negligence or willful 
misconduct or (ii) the natural progression of an underlying or pre-existing condition, unless 
participating in the study made such condition worse. The study sponsor is also not offering to 
pay for medical expenses that are covered by your insurance provider or if your injury was not 
caused by the study drug or a study procedure. 
 
CONFIDENTIALITY 
Your research records will be handled as confidentially as possible.  No individual identities will 
be used in any reports or publications resulting from this study.  In order to verify the study data, 


 
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the primary coordinating Investigator, clinical monitors authorized by the sponsor of this study 
and monitors from the Food and Drug Administration or the Institutional Review Board (IRB) 
may be allowed to see some specific records, including yours. This information may include 
personal identifying information about you (such as your name, race, date of birth, gender, city, 
and zip code), your medical history, treatment schedule, and the results of any of your tests, 
therapies, and/or procedures.  The purpose of collecting and sharing this information is to learn 
how the treatment procedures may affect the disease and any treatment-related side effects. 
 
 [Site Name/Institution] will take appropriate steps to keep your protected health information 
private and protected according to state and federal law.  However, there is no guarantee that 
your information will remain confidential, and it may be re-disclosed at some point. Federal 
agencies (such as the FDA, OHRP, or National Cancer Institute [NCI]), UroGen Pharma Ltd, 
and the IRB of Name of Institute where study will be performed might view or receive your 
record in order to collect data and/or meet legal, ethical, research, and safety-related obligations. 
In some situations, the FDA could be required to reveal the names of patients. 
 
You have the right to see and reproduce your records related to the treatment, and ask for 
corrections, for as long as this information is held by your doctor and/or [Site Name/Institution] 
where study will be performed.   
 
CONTACT INFORMATION 
If you have any other questions21, concerns or complaints about the study, your rights as a research 
subject or about an injury from the study, you may call the [Site Name] at [Contact Number(s)] 
between 8:00 am to 4:00 pm on weekdays and ask to speak to [PI/Contact Name].  During non-
office hours or on weekends, you may call the office and ask to be connected to the physician on 
call.  If you have any questions about your rights as a research subject 21or if you have questions, 
concerns, or complaints about the research,, you may contact IRC, an independent review research 
board.  They are available from time they are open, at phone number. 
 
 
  
 
RECORD OF INFORMATION PROVIDED 
 
I will be given a copy of this consent form to keep. 
 
SIGNATURES 


 
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PARTICIPATION IN RESEARCH IS VOLUNTARY.  I have the right to decline to participate or 
to withdraw at any point in this study without jeopardy to my medical care at the <<Name of 
Institute>> where study will be performed.   
 
If I wish to participate, I should sign below. 
 
 
_____________  
 ______________________________ 
__________________________  
Date 
Patient’s Signature 
Printed Name 
 
 
_____________  
 ______________________________ 
__________________________  
Date 
Person Obtaining Consent 
Printed Name 
 
 
_____________  
 ______________________________ 
__________________________  
Date 
PI Consent 
Printed Name 
 
 
CONSENT/AUTHORIZATION  
(Adult Patients Only) 
 
I understand the information in this consent form.  I have had a chance to read the consent 
form, or have had it read to me.  I have had a chance to think about it, ask questions, and talk 
about it with others as needed. I give the doctor permission to begin treatment.  By signing 
this consent form, I am not giving up any of my legal rights.  I will be given a signed copy of 
this consent document. 
 
 
_____________________________________________ 
_______________ 
SIGNATURE OF PATIENT 
DATE 
 
_____________________________________________ 
WITNESS TO CONSENT 
I was present during the explanation of the treatment to be performed under IND121922 
 
 
_____________________________________________ 
_______________ 
SIGNATURE OF WITNESS TO THE VERBAL  
DATE 
CONSENT PRESENTATION (OTHER THAN TREATING DOCTOR)
 
 
 
 
21PERSON OBTAINING CONSENT 


 
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I have discussed this treatment with the patient21 using language that is understandable and 
appropriate. 
 
I believe that I have fully informed this patient of the nature of this treatment and its possible 
benefits and risks and that the patient understood this explanation. 
 
 
_____________________________________________ 
_______________ 
SIGNATURE OF TREATING DOCTOR  
DATE 
OR PERSON AUTHORIZED TO OBTAIN CONSENT 
 
TRANSLATOR 
 
I have translated the above informed consent form as written (without additions or 
subtractions) into _____________________________ and assisted the people  
(Name of Language) 
obtaining and providing consent by translating all questions and responses during the consent 
process for this patient. 
 
 
 ____________________________  
________________________ 
_______________ 
NAME OF TRANSLATOR 
SIGNATURE OF TRANSLATOR 
DATE 
 
 Please check here if the translator was a member of the treating doctor's team.   
(If checked, a witness, other than the translator, must sign the witness line below.) 
 
 
_____________________________________________ 
_______________ 
SIGNATURE OF WITNESS TO THE VERBAL  
DATE 
TRANSLATION  (OTHER THAN TRANSLATOR,  
OR TREATING DOCTOR)