A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Multi-Center Single Dose Study to Evaluate the Safety and Effectiveness of URG101 Compared With the Individual Components Lidocaine and Heparin in Subjects With Interstitial Cystitis/Bladder Pain Syndrome
Phase: PHASE2
Conditions: Interstitial Cystitis, Bladder Pain Syndrome
Sponsor: Urigen

 
 
 
ClinicalTrials.gov ID: NCT02591199 
 
A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Multi-Center Single Dose Study to 
Evaluate the Safety and Effectiveness of URG101 Compared with the Individual Components 
Lidocaine and Heparin in Subjects with Interstitial Cystitis/Bladder Pain Syndrome 
(URG101-105, the ENGAGE-24 Study) 
 
Clinical Protocol Version 5.0: 18-Apr-2017 

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Urigen N.A., Inc. 
 
 
Clinical Protocol  
Protocol:  URG101-105 (ENGAGE-24) 
 
 
Version 5.0, 18 April 2017 
Page  1 
1.0 
TITLE PAGE 
URG101 
CLINICAL PROTOCOL 
A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Multi-Center Single Dose Study to 
Evaluate the Safety and Effectiveness of URG101 Compared with the Individual Components 
Lidocaine and Heparin in Subjects with Interstitial Cystitis/Bladder Pain Syndrome (the 
ENGAGE-24 Study). 
(Protocol URG101-105, the ENGAGE-24 Study) 
Sponsor: 
Urigen N.A., Inc. 
675 US Hwy 1, STE B206 
North Brunswick, NJ 08902 USA 
 
Sponsor Contact: 
 
 
 
Investigational 
Product: 
URG101 (Alkalinized lidocaine and heparin) 
 
 
Clinical Phase: 
2a 
 
 
Approval Date/Version: 18 April 2017; Version 5.0 
 
 
Confidentiality 
Statement: 
This protocol is a confidential communication and is the property of 
Urigen N.A., Inc.  Acceptance implies an agreement not to disclose 
the information contained herein that is not otherwise publicly 
available, except for use by an institutional review board (IRB) for 
the purpose of obtaining approval to conduct the study.  The IRB is 
requested and expected to maintain confidentiality.  This document 
may not be used or published in whole or in part without the 
consent of Urigen N.A., Inc. 
 

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Clinical Protocol  
Protocol:  URG101-105 (ENGAGE-24) 
 
 
Version 5.0, 18 April 2017 
Page 2 
2.0 
CLINICAL PROTOCOL SYNOPSIS 
Name of Sponsor: 
Name of Product: 
Urigen N.A., Inc. 
URG101 
Protocol Title: 
A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Multi-Center Single 
Dose Study to Evaluate the Safety and Effectiveness of URG101 Compared with the 
Individual Components Lidocaine and Heparin in Subjects with Interstitial 
Cystitis/Bladder Pain Syndrome (Protocol URG101-105, the ENGAGE-24 Study) 
Clinical Phase  
2a 
Objectives: 
Primary Objective: 
1. To evaluate the change in sum of bladder pain intensity differences from baseline 
to 12 hours (SPID-12) after administration of URG101 compared with the SPID-
12 after administration of lidocaine alone, heparin alone, and placebo as 
determined by using the 11-point NRS for bladder pain.  
Secondary Objectives: 
1. To evaluate the change in bladder pain from baseline to 24 hours, using the sum 
of pain intensity differences (SPID-24) at defined time points, after 
administration of  intravesical URG101 compared with alkalinized Lidocaine 
Hydrochloride Injection (20 mg/mL) alone, alkalinized Heparin Sodium 
Injection (5,000 USPU/mL) alone, and placebo 
) 
2. To evaluate the change in urgency from baseline to 12 and 24 hours, using the 
sum of urgency intensity differences (SUID) at defined time points,  after 
administration of  URG101 compared with alkalinized Lidocaine Hydrochloride 
Injection 
(20 
mg/mL) 
alone, 
alkalinized 
Heparin 
Sodium 
Injection (5,000 USPU/mL) alone, and placebo (
)  
3. To evaluate the absolute and percentage change in bladder pain and urgency 
intensity differences at 1, 12, and 24 hours after administration of URG101 
compared with alkalinized Lidocaine Hydrochloride Injection USP (20 mg/mL) 
alone, alkalinized Heparin Sodium Injection USP (5,000 USPU/mL) alone, and 
placebo (
) 
4. To evaluate the improvement of symptoms after treatment with URG101, 
measured using the Patient Global Assessment (question number 3) compared 
with alkalinized Lidocaine Hydrochloride Injection (20 mg/mL) alone, 
alkalinized Heparin Sodium Injection (5,000 USPU/mL) alone, and placebo 
(
) at 1, 12, and 24 hours after treatment 
5. To evaluate the time to first administration of rescue medication for pain after 
treatment with URG101 compared to alkalinized Lidocaine Hydrochloride 
Injection (20 mg/mL) alone, alkalinized Heparin Sodium Injection (5,000 
USPU/mL) alone, and placebo 
) 
6. To investigate the relationship of plasma lidocaine concentrations at 1 hour after 
study drug administration to bladder pain and urgency at 1 hour, and from 
baseline to 12 and 24 hours, using the sum of pain and urgency intensity 
differences at defined time points, after administration of URG101 compared 
with alkalinized Lidocaine Hydrochloride Injection (20 mg/mL) alone, 
alkalinized Heparin Sodium Injection (5,000 USPU/mL) alone, and placebo 
) 
7. To evaluate the safety and tolerability of intravesical administration of URG101 
Study Design: 
This is a Phase 2a, prospective, randomized, double-blind, placebo-controlled, 

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Clinical Protocol  
Protocol:  URG101-105 
 
CLINICAL PROTOCOL SYNOPSIS (continued) 
 
Version 5.0, 18 April 2017 
Page 3 
multicenter, single-dose, pharmacokinetic study designed to test the efficacy and 
safety of  the combination product (URG101) versus its alkalinized individual 
components (Heparin Sodium and Lidocaine Hydrochloride ) and placebo 
).  A maximum of 300 subjects will be enrolled in Study URG101-
105. 
In this study, alkalinized Lidocaine Hydrochloride Injection (20 mg/mL) and 
alkalinized Heparin Sodium Injection (5,000 USPU/mL) will be subsequently 
referred to by the drug names Lidocaine and Heparin. 
Eligible subjects exhibiting interstitial cystitis symptoms who have signed informed 
consent, will be screened and provisionally enrolled for intravesical treatment.  
Treatment may occur on the day of the Screening Visit (Visit 1) or any following day 
up to 1 week (Baseline and Drug Administration Visit 1a).  If drug administration 
occurs on same day as screening then all assessments in Visit 1 and Visit 1a will be 
combined.  If screening (V1), and baseline and drug administration (V1a) do not 
occur on same day, urine pregnancy test for women of childbearing potential and 
urine screen for drugs of abuse must be performed at both visits (V1 and V1a).  
Confirmation of symptom severity must be obtained before randomization: minimum 
pain score of 5 on the 11-point numerical rating scale [NRS] at Screening and 
15 minutes (± 5 minutes) after voiding prior to study drug administration.  Subjects 
will become fully enrolled upon receipt of acceptable qualifying laboratory 
evaluations (obtained via dipstick) and clinical assessments obtained before 
randomization.   
At the Screening Visit (V1), the following will be completed: medical history and 
demographics; medication history; the Pelvic Pain and Urgency/Frequency (PUF) 
questionnaire; 11-point NRS for bladder pain and urgency; a physical examination, 
including a pelvic examination to confirm lower urinary tract tenderness; vital signs; 
blood and urine samples for safety laboratory assessments (including urine hematuria 
analysis); urine pregnancy test for women of childbearing potential; urine screen for 
drugs of abuse; and concomitant medications. (Note: results from a pelvic 
examination performed within 7 days prior to the Screening Visit (V1) may replace a 
V1 pelvic examination.) 
 
 
 
 
 
 
 
 
On the day of study drug administration (V1a), subjects will be randomized 
(2:1:2:1); 
URG101:placebo:lidocaine:heparin) 
and 
will 
receive 
a 
single 
administration of one of four intravesical treatments in a blinded fashion, based on 
random assignment: 
1. Combination product, URG101 (buffered heparin-lidocaine)  
2. Placebo: 
  
3. Lidocaine: 
 
4. Heparin: 
 
Subjects will be monitored for 2 hours in the clinic after study drug administration.  

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Clinical Protocol  
Protocol:  URG101-105 
 
CLINICAL PROTOCOL SYNOPSIS (continued) 
 
Version 5.0, 18 April 2017 
Page 4 
Subjects will maintain a urination log and symptom diary after discharge and will 
return to the clinic the following day to complete the in-clinic study procedures and 
collection of the study diary. 
The following will be completed according to the schedule of assessments over a 
24-hour period after study drug administration: the 11-point NRS for bladder pain 
and urgency; the PORIS questionnaire; vital signs assessments; blood samples for 
safety laboratory assessments, i.e. blood coagulation (prothrombin time [INR] and 
activated partial thromboplastin time [aPTT]), and plasma lidocaine concentrations; 
adverse events; and concomitant medication assessments.   
Subjects will be contacted within 48 to 72 hours after the last study treatment to 
follow-up on any ongoing adverse events after the last clinic visit. 
The clinical study will plan to randomize 180 subjects.  After 90 (50%) subjects have 
been enrolled and treated, the IDMC will examine the conditional power and 
determine if a modification to the sample size is required to yield an overall power of 
90%.  An adjustment to the type 1 error rate will not be necessary if the conditional 
power is >39% at the interim assessment.   
The IDMC will consist of 3 members: 1 physician expert in IC/BPS, 1 expert in 
clinical development, and a biostatistician. None of the IDMC members will be 
associated with study personnel; all communication between the IDMC and study 
personnel will be pre-defined and governed by the IDMC charter. The IDMC will 
have access to unblinded pain scores to perform their ranking of the pain endpoints 
and for assessment of conditional power. 
 
Estimated Number of 
Subjects:  
A target of 180 subjects subject to adjustment by the IDMC.  A maximum of 300 
subjects will be enrolled in Study URG101-105. 
Number of Study Sites:  
Up to 30 sites in the United States and Canada 
Subject Population:  
Adult subjects, aged ≥ 18 years, with Interstitial Cystitis who have moderate–to-
severe symptoms of pain and/or urgency of bladder origin for at least 9 months, not 
currently taking narcotic pain medications, meeting the minimum screening scores.  
Study Drug, Dose, 
Formulation, Method of 
Administration: 
URG101:  buffered lidocaine and heparin, instillation via urethral catheter.  URG101 
treatment comprises the following:  
• 
18 mL containing Heparin Sodium 
 
 
 
 
 
 
Placebo treatment comprises the following: 
• 
18 mL 
 
Heparin treatment comprises the following: 
• 
12 mL Heparin Sodium 
, plus 6 mL 
3X 
 buffer 
 
Alkalinized Lidocaine treatment comprises the following: 
• 
12 mL Lidocaine HCl (
), plus 6 mL 3X 
 buffer 
 
Criteria for Evaluation: 
Primary Endpoint:  
1. 
A measure of the sum of bladder pain intensity differences from baseline to 

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Clinical Protocol  
Protocol:  URG101-105 
 
CLINICAL PROTOCOL SYNOPSIS (continued) 
 
Version 5.0, 18 April 2017 
Page 5 
12 hours (SPID-12) after administration of URG101 compared with the SPID-
12 after administration of lidocaine alone, heparin alone, and placebo as 
determined by using the 11-point NRS for bladder pain 
 
Secondary Endpoints:  
1. 
The sum of bladder pain intensity differences from baseline to 24 hours  
(SPID-24) after administration  of URG101 compared with lidocaine alone, 
heparin alone, and placebo as determined by using the 11-point bladder pain 
NRS 
2. 
The sum of urgency intensity differences from baseline to 12 and 24 hours 
(SUID-12 and SUID-24) after administration of URG101 compared with 
lidocaine alone, heparin alone, and placebo using the 11-point urgency NRS 
3. 
Absolute and percentage change in bladder pain from baseline to 1, 12, and 
24 hours after administration of URG101 compared with lidocaine alone, 
heparin alone, and placebo as determined by using the 11-point NRS for 
bladder pain 
4. 
Absolute and percentage change in urgency intensity from baseline to 1, 12, and 
24 hours after administration of URG101 compared with lidocaine alone, 
heparin alone, and placebo using the 11-point urgency NRS   
5. Patient Global Assessment:  Comparison of the percentage of subjects achieving 
≥ 50% improvement in the PORIS questionnaire(Question 3), from baseline to 1, 
12, and 24 hours after administration of URG101, lidocaine alone, heparin alone, 
and placebo 
6.  Time to first administration of rescue medication for pain after treatment with 
URG101 compared to alkalinized Lidocaine Hydrochloride Injection (20 
mg/mL) alone, alkalinized Heparin Sodium Injection (5,000 USPU/mL) alone, 
and placebo 
) 
7. To evaluate the safety and tolerability of intravesical administration of URG101 
 
Pharmacokinetic Endpoints:  
1. 
Comparison of plasma lidocaine concentrations at 1 hour post treatment with 
absolute and percentage change in pain using the 11-point NRS for bladder pain 
at 1, 12 and 24 hours after administration of URG101, lidocaine alone, heparin 
alone, and placebo 
2. Comparison of plasma lidocaine concentrations at 1 hour post treatment with 
absolute and percentage change in urgency using the 11-point NRS for urgency, 
at 1, 12 and 24 hours after administration of URG101, lidocaine alone, heparin 
alone, and placebo 
3. Comparison of plasma lidocaine concentrations at 1 hour post treatment with 
the sum of bladder pain intensity differences from baseline to 12 and 24 hours 
(SPID-12 and SPID-24) after administration of URG101 compared with 
lidocaine alone, heparin alone, and placebo as determined by using the 11-point 
bladder pain NRS 
4. Comparison of plasma lidocaine concentrations at 1 hour post treatment with 
the sum of urgency intensity differences from baseline to 12 and 24 hours 
(SUID-12 and SUID-24) after administration of URG101compared with 
lidocaine alone, heparin alone, and placebo as determined by using the 11-point 
urgency NRS 
 
Safety Endpoints: 
1. 
Change from baseline in INR at 1 hour after study drug administration 

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Clinical Protocol  
Protocol:  URG101-105 
 
CLINICAL PROTOCOL SYNOPSIS (continued) 
 
Version 5.0, 18 April 2017 
Page 6 
2. 
Change from baseline in aPTT at the 1-hour post-study-drug time point 
3. 
Adverse events 
 
Pharmacokinetics: 
Samples for peak plasma lidocaine concentrations will be collected at baseline and at 
1 hour after study drug administration.   
 
Efficacy: 
• 
11-point (i.e., 0 to 10) NRS bladder pain (numerical rating scale) 
• 
11-point (i.e., 0 to 10) NRS urge (urgency intensity) to urinate (numerical rating 
scale) 
• 
PORIS questionnaire 
 
Safety: 
The following safety parameters will be evaluated: 
• 
Clinical laboratory tests 
• 
Vital sign measurements 
• 
Physical examination 
• 
Incidence of adverse events, serious adverse events 
• 
INR and aPTT 
 
Follow-up will occur for subjects with clinically significant, study drug–related 
abnormalities at the conclusion of the study termination visit, based on the 
investigators discretion. 
Statistical Methods: 
Sample Size Estimate 
Sample size estimates were based on a pilot trial of heparin-lidocaine versus lidocaine 
alone and a prior two-arm study of URG101 versus placebo.  The primary efficacy 
endpoint is SPID-12.  The sample size calculation is based on a one-way analysis of 
variance, comparing SPID-12 from four treatment groups.  A target sample size of 
180 subjects to be allocated unequally among the four treatment groups as follows: 
URG101:placebo:lidocaine: heparin at 2:1:2:1 (60 subjects per group and 30 subjects 
per group).  This sample size  is sufficient to achieve 90% power to detect a 
difference between the URG101 and lidocaine groups assuming a treatment effect 
size of 0.60. The study will also have 90% power to detect a difference between the 
URG101 and each of the placebo and heparin groups assuming an effect size for 
these comparisons of 0.75.  Once 90 subjects have been enrolled, a blinded interim 
analysis will take place; and, if required, the number of subjects for the study 
increased to a maximum of 300 subjects. 
 
Description of Analysis Sets: 
All analyses of the efficacy of URG101 will be performed on the ITT set, which will 
include all randomized subjects from the investigative phase of the study who 
receive study drug.  These efficacy analyses will compare the treatment groups on 
the basis of randomized treatment, regardless of the treatment actually received.  
Primary efficacy and key secondary efficacy analyses will also be conducted on a per 
protocol set, which will include all subjects in the ITT set who sufficiently comply 
with the protocol. 
 
Safety analyses will be based on the safety analysis set which will include all 
subjects who receive at least one dose of study drug and have at least one post dose 
safety assessment in both phases of the study.  Safety summaries will be produced 
based on study treatment actually received. 

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Clinical Protocol  
Protocol:  URG101-105 
 
CLINICAL PROTOCOL SYNOPSIS (continued) 
 
Version 5.0, 18 April 2017 
Page 7 
 
Primary Efficacy Determination: 
The primary efficacy endpoint will be compared between the URG101 and the 
lidocaine, heparin, and placebo groups using an analysis of covariance model which 
will include factors for treatment and baseline pain values.  Pairwise comparisons of 
least squares means between URG101 and each of the other treatment arms will be 
performed.  If the p-value associated with these comparisons is < 0.05 in favor of 
URG101, the primary aim of the trial will be confirmed.  
 
Missing data for efficacy values will be imputed by the last observation carried 
forward method. 
 
Secondary Efficacy Determinations: 
Analyses of secondary endpoints relating to changes in the NRSs for pain and 
urgency will be performed using analysis of covariance models similar to that used 
for the primary efficacy endpoint.  Nonparametric methodology in exploratory 
analyses may be used to supplement the parametric analyses. 
 
Treatment group comparisons relative to improvement on the PORIS questionnaire, 
(Question 3), will be made with standard contingency table techniques. 
 
Pharmacokinetic Determinations: 
A comparison of pain and urgency assessments as measured by 11-point NRS to 
plasma lidocaine concentrations at 1 hour after study drug administration will be 
made for the PK set. 
 
 
 
 
Safety Determinations: 
All safety analyses will be performed on the safety analysis set.  
 
The change in INR and aPTT at baseline and 1 hour will be compared for the various 
treatment groups using descriptive statistics. 
 
Other Determinations: 
Demographic and disposition data, randomization, drug administration, medical 
history, prior and concomitant medications, adverse events, clinical laboratory 
measurements, vital signs, physical examination findings, and all other safety data 
will be listed by subject and time point.   
Descriptive statistics will be tabulated for change from baseline in the vital signs. 
In addition to clinical and laboratory assessments, subject safety will be monitored 
by recording adverse events and serious adverse events throughout the study.  Any 
pregnancy that occurs during the study will be promptly reported to the sponsor, but  
will not be considered a serious adverse event.  Treatment-emergent adverse events 
will be summarized by type, frequency, severity, relationship to study drug, and 
number of subjects per treatment.  Adverse events will be coded according to the 
Medical Dictionary for Regulatory Activities. 
 
Duration of Treatment: 
Each study subject will receive a single dose of URG101, placebo (
 
), alkalinized Lidocaine, or alkalinized Heparin by random assignment.  The 
randomization ratio will be 2:1:2:1, respectively.  
 

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Clinical Protocol  
Protocol:  URG101-105 (ENGAGE-24) 
 
 
Version 5.0, 18 April 2017 
Page 8 
3.0 
TABLE OF CONTENTS  
Page 
 
1.0 
TITLE PAGE................................................................................................................................................. 1 
2.0 
CLINICAL PROTOCOL SYNOPSIS ......................................................................................................... 2 
3.0 
TABLE OF CONTENTS .............................................................................................................................. 8 
3.1 
LIST OF IN-TEXT TABLES ........................................................................................................................ 11 
3.2 
LIST OF APPENDICES ............................................................................................................................... 12 
4.0 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .......................................................... 13 
5.0 
ETHICS ........................................................................................................................................................ 14 
5.1 
INFORMED CONSENT ............................................................................................................................... 14 
6.0 
INVESTIGATORS AND STUDY PERSONNEL .................................................................................... 16 
7.0 
INTRODUCTION ....................................................................................................................................... 17 
7.1 
BACKGROUND ........................................................................................................................................... 17 
7.2 
URG101 ........................................................................................................................................................ 20 
7.3 
CLINICAL EXPERIENCE WITH URG101 ................................................................................................ 20 
7.4 
RISKS AND BENEFITS .............................................................................................................................. 21 
7.5 
STUDY RATIONALE .................................................................................................................................. 22 
7.5.1 
Rationale for Dose .......................................................................................................................... 22 
7.5.2 
Rationale for Single Dose ............................................................................................................... 23 
7.5.3 
Rationale for Study Endpoint .......................................................................................................... 23 
8.0 
STUDY OBJECTIVES ............................................................................................................................... 25 
8.1 
PRIMARY OBJECTIVE .............................................................................................................................. 25 
8.2 
SECONDARY OBJECTIVES ...................................................................................................................... 25 
9.0 
INVESTIGATIONAL PLAN ..................................................................................................................... 27 
9.1 
OVERALL STUDY DESIGN AND PLAN ................................................................................................. 27 
9.1.1 
Screening (Visit 1) .......................................................................................................................... 28 
9.1.2 
Baseline and Single-Dose Administration (Visit 1a) ...................................................................... 29 
9.1.3 
Home Assessment ........................................................................................................................... 30 
9.1.4 
24-Hour Follow-up Visit (Visit 2) .................................................................................................. 31 
9.1.5 
End-of Study Follow-up .................................................................................................................. 32 
9.1.6 
Run-in Study Analysis .................................................................................................................... 32 
9.2 
DISCUSSION OF STUDY DESIGN INCLUDING CHOICE OF CONTROL GROUPS .......................... 32 
9.3 
SELECTION OF STUDY POPULATION ................................................................................................... 33 
9.3.1 
Inclusion Criteria ............................................................................................................................ 33 
9.3.2 
Exclusion Criteria ........................................................................................................................... 34 

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Clinical Protocol  
Protocol:  URG101-105(ENGAGE-24) 
 
TABLE OF CONTENTS (continued) 
 
Page 
 
 
Version 5.0, 18 April 2017 
Page 9 
9.3.3 
Removal of Subjects from Therapy or Assessment ........................................................................ 37 
9.4 
TREATMENTS ............................................................................................................................................ 39 
9.4.1 
Treatments Administered ................................................................................................................ 39 
9.4.2 
Identity and Storage of Investigational Products ............................................................................ 40 
9.4.3 
Labeling of Investigational Products .............................................................................................. 40 
9.4.4 
Storage Conditions .......................................................................................................................... 40 
9.4.5 
Method of Assigning Subjects to Treatment Groups ...................................................................... 41 
9.4.6 
Prior and Concomitant Therapy ...................................................................................................... 41 
9.4.7 
Treatment Compliance .................................................................................................................... 42 
9.4.8 
Drug Supplies and Accountability .................................................................................................. 42 
9.5 
STUDY ASSESSMENTS ............................................................................................................................. 44 
9.5.1 
Screening and Baseline Assessments .............................................................................................. 44 
9.5.2 
Efficacy Assessments ...................................................................................................................... 51 
9.5.3 
Pharmacokinetic Assessments ........................................................................................................ 53 
9.5.4 
Schedule of Assessments ................................................................................................................ 53 
9.5.5 
Appropriateness of Measurements .................................................................................................. 55 
9.5.6 
Reporting of Serious Adverse Events, Pregnancy, and Other Events of Interest ............................ 55 
9.5.7 
Completion and Discontinuation of Subjects .................................................................................. 58 
9.6 
DATA QUALITY ASSURANCE ................................................................................................................ 59 
9.6.1 
Monitoring ...................................................................................................................................... 59 
9.6.2 
Investigator’s Responsibility ........................................................................................................... 59 
9.7 
STATISTICAL METHODS ......................................................................................................................... 59 
9.7.1 
Statistical and Analytical Plans ....................................................................................................... 59 
9.7.2 
Handling of Missing Data ............................................................................................................... 67 
9.7.3 
Determination of Sample Size ........................................................................................................ 67 
9.7.4 
Interim Analysis .............................................................................................................................. 68 
9.7.5 
Other Statistical and Analytical Issues ............................................................................................ 73 
9.7.6 
Procedure for Revising the Statistical Analysis Plan ...................................................................... 73 
10.0 
ADMINISTRATIVE PROCEDURES AND INSTRUCTIONS .............................................................. 74 
10.1 
CHANGES TO THE PROTOCOL ............................................................................................................... 74 
10.2 
ADHERENCE TO THE PROTOCOL .......................................................................................................... 74 
10.3 
MONITORING PROCEDURES .................................................................................................................. 74 
10.4 
RECORDING OF DATA ............................................................................................................................. 76 
10.5 
IDENTIFICATION OF SOURCE DATA .................................................................................................... 76 

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Clinical Protocol  
Protocol:  URG101-105(ENGAGE-24) 
 
TABLE OF CONTENTS (continued) 
 
Page 
 
 
Version 5.0, 18 April 2017 
Page 10 
10.6 
RETENTION OF RECORDS ....................................................................................................................... 76 
10.7 
AUDITING PROCEDURES AND INSPECTION ....................................................................................... 76 
10.8 
REPORTING AND PUBLICATION OF RESULTS ................................................................................... 77 
10.9 
DISCLOSURE AND CONFIDENTIALITY ................................................................................................ 77 
10.10 
DISCONTINUATION OF STUDY .............................................................................................................. 77 
11.0 
REFERENCE LIST .................................................................................................................................... 79 
12.0 
APPENDICES ............................................................................................................................................. 82 
 
 
 

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Clinical Protocol  
Protocol:  URG101-105 (ENGAGE-24) 
 
 
Version 5.0, 18 April 2017 
Page 11 
3.1 
LIST OF IN-TEXT TABLES 
Page 
 
Table 1. 
Prohibited Concomitant Medications and Restrictions .......................................................................... 42 
Table 2. 
Clinical Laboratory Tests ....................................................................................................................... 47 
Table 3. 
Assessment of Causality of AEs ............................................................................................................ 50 
Table 4. 
Schedule of Assessments ....................................................................................................................... 54 
 

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Clinical Protocol  
Protocol:  URG101-105 (ENGAGE-24) 
 
 
Version 5.0, 18 April 2017 
Page 12 
3.2 
LIST OF APPENDICES 
Appendix 1: Pelvic Pain and Urgency/Frequency Questionnaire ............................................................................... 83 
Appendix 2: Guideline Script for Pelvic Pain and Urgency/Frequency Questionnaire .............................................. 84 
Appendix 3: 11-Point Bladder Pain and Urgency Scales ............................................................................................ 85 
Appendix 4: Guideline Script for 11-Point Bladder Pain and Urgency Scales ........................................................... 86 
Appendix 5: PORIS Questionnaire ............................................................................................................................. 87 
Appendix 6: Guideline Script for PORIS Questionnaire ............................................................................................ 88 
Appendix 7: Protocol Signature Pages ........................................................................................................................ 89 
 
 

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Clinical Protocol  
Protocol:  URG101-105 (ENGAGE-24) 
 
 
Version 5.0, 18 April 2017 
Page 13 
4.0 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
adverse event 
aPTT 
activated partial thromboplastin time 
AUC 
area under the concentration-time curve 
β-hCG 
beta human chorionic gonadotropin 
BPS 
bladder pain syndrome 
CRA 
clinical research associate 
CRF 
case report form 
DMSO 
dimethyl sulfoxide 
ECG 
electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HCl 
hydrochloride 
IC 
interstitial cystitis 
IC/BPS 
Interstitial cystitis/bladder pain syndrome 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
INR 
international normalized ratio 
IRB 
institutional review board 
IxRS 
interactive voice or web response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
NRS 
numerical rating scale 
PORIS 
Patient Overall Rating of Improvement of Symptoms  
PT 
prothrombin time 
PUF 
Pelvic Pain and Urgency/Frequency 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
SPID-12 
sum of pain intensity differences from baseline to 12 hours 
SPID-24 
sum of pain intensity differences from baseline to 24 hours 
SUID-12 
sum of urgency intensity differences from baseline to 12 hours 
SUID-24 
sum of urgency intensity differences from baseline to 24 hours 
TEAE 
treatment emergent adverse event 
USP 
United States Pharmacopeia 
WBC 
white blood cell 
 
 

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Clinical Protocol  
Protocol:  URG101-105 (ENGAGE-24) 
 
 
Version 5.0, 18 April 2017 
Page 14 
5.0 
ETHICS 
This study will be conducted in compliance with the following: the protocol; Food 
and Drug Administration (FDA) regulations;  International Conference on 
Harmonisation (ICH) E6, Guideline for Good Clinical Practice; and all other 
applicable local laws and regulatory requirements.  Each study site will seek approval 
by an institutional review board (IRB) or according to regional requirements.  The 
IRB will evaluate the ethical, scientific and medical appropriateness of the study.  
Furthermore, in preparing and handling case report forms (CRFs), the investigator, 
subinvestigator, and the site staff will take measures to ensure adequate care in 
protecting subject privacy.  To this end, a subject number and subject identification 
code will be used to identify each subject. 
5.1 
INFORMED CONSENT 
All subjects will have the purpose of the study, study interventions and evaluations, 
and the potential risks and benefits of participation explained to them and any 
questions will be answered.  If a subject consents to participation in this study, the 
subject will review and sign the informed consent form (ICF). 
Written informed consent will be obtained from all subjects (or their guardian or legal 
representative, as applicable for local laws).  Consent will be documented on a 
written ICF.  The ICF will be approved by the same IRB that approves this protocol.  
Each ICF will comply with the following: the FDA regulations in Title 21 Code of 
Federal Regulations, Part 50; ICH; Good Clinical Practice (GCP); and local 
regulatory requirements.  The investigator agrees to obtain approval from the sponsor 
of any written ICF used in the study, prior to submission to the IRB. 
Investigators may discuss study availability and the possibility for entry with a 
potential subject without first obtaining informed consent.  However, informed 
consent must be obtained and documented prior to initiation of any procedures that 
are performed solely for the purpose of determining eligibility for this study, 
including withdrawal from current medication(s). 
Once appropriate essential information has been provided and fully explained in 
layman’s language to the subject by the investigator or by a qualified designee, the 
IRB-approved written ICF will be signed and dated by both the subject and the person 

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obtaining consent (investigator or designee), as well as by any other parties required 
by the IRB.  The subject will receive a copy of the signed ICF; the original will be 
kept on file by the investigator. 

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6.0 
INVESTIGATORS AND STUDY PERSONNEL 
This study will be conducted by qualified investigators under the sponsorship of 
Urigen N.A, Inc. (Urigen), at approximately 30 investigational sites in the United 
States and Canada. 
The name and telephone and fax numbers of the medical monitor and other contact 
personnel at the sponsor and of the contract research organization(s) are included in 
the Investigator Study Files provided to each site. 

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7.0 
INTRODUCTION 
7.1 
BACKGROUND 
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a disease considered rare as 
late as 1990.  The hallmarks of the disease are frequency and urgency of urination, 
and bladder pain of simply pelvic origin.  As knowledge of the disease and its 
symptomology increase, the reported prevalence increases.  In 1990 it was thought 
that 60,000 to 80,000 women in the United States had IC1.  In 1997, it was thought to 
be approximately 500,000 to 1,000,0004.  Estimates as high as one in four women can 
be made when utilizing a questionnaire that encompasses a more complete battery of 
IC symptoms1,7.  This increase in reported prevalence is primarily due to a change in 
awareness of the disease.  Traditionally, IC was diagnosed only in severe patients 
with a destroyed bladder, and considered to be relatively rare.  It is currently widely 
accepted that IC includes many patients with mild, intermittent, and severe forms of 
the disease7,8.  Most patients with IC have low-grade bladder symptoms (3 on a scale 
of 0 to 10) punctuated by intense flares of 8 to 10 out of 10 that last from 3 days to 
3 weeks and may occur infrequently or as often as five to eight times per year.  These 
flares are often incorrectly diagnosed.   
Currently, since many of these IC flares are misdiagnosed as urinary infections in 
women and often as prostatitis in men, several billion dollars in treatments are 
inappropriately prescribed to these patients that offer no relief. 
For the unfortunate patient with severe disease living daily with pain scores of 8, 9, or 
10 out of 10, there is little or no relief or effective therapy available to relieve these 
intense symptom flares.  Drugs such as pyridium and urelle offer minimal urinary 
analgesia.  Anticholinergic and antimuscarinic compounds have limited or no success 
in the treatment of pain in IC/BPS.   
Opiates have been utilized but have limited success and are not optimum drugs to 
employ.  Because opiates can, in time, upregulate sensory nerves due to dependency, 
the patient’s pain will become resistant relatively quickly as tolerance to the drug 
grows; the patient will become addicted to the medications.  In addition, opiates can 
significantly impair a patient’s mental faculties, and overall functioning will be 
markedly affected.  Neural stimulators such as Interstim® might help temporarily with 
frequency and urgency, but have little or no activity on small unmyelinated C fibers 

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(pain fibers) because they do not originate in the sacral nerves being stimulated.  
Patients who are considered to be surviving this disease have a quality of life reported 
to be worse than that of dialysis patients and unfortunately many have committed 
suicide16. 
There are currently two FDA-approved therapies for the symptoms of bladder pain of 
IC: oral Elmiron® capsules (pentosan polysulfate sodium) and intravesical 
RIMSO®-50 and its generics (50% dimethyl sulfoxide [DMSO]).   
Elmiron is a synthetic heparinoid-like molecule that is thought to work by 
augmenting the mucus layer with heparin and, thus may provide a physicochemical 
barrier to the penetration of the urinary solutes to the bladder wall21.  According to the 
product label, the efficacy of Elmiron was evaluable at 3 months, with 38% of 
patients achieving greater than 50% improvement in bladder pain versus 18% for 
placebo-treated patients.  In a dose-ranging study of Elmiron, Nickel et al.1 observed 
a response rate of about 20% at 1 month of treatment that increased to approximately 
60% at 8 months, resulting in their conclusion that chronic duration of therapy is 
more important than dosage.  
Intravesical treatment with RIMSO-50 (50% DMSO) was approved by the FDA in 
1978 for symptomatic treatment of IC.  Its exact mechanism of action is unclear, and 
six to eight weekly bladder instillations are required.  After each instillation, patients 
exhibit an unpleasant garlic-like odor, and the majority of patients complain of 
significant discomfort both during and after each treatment (RIMSO-50 product 
label).  Perez-Marrero et al.11 conducted a placebo-controlled study of 50% DMSO 
for IC, during which subjects received intravesical instillations of study drug or saline 
placebo every 2 weeks for two sessions of four treatments each.  A total of 53% of 
DMSO treated patients exhibited “marked improvement” versus 18% for placebo 
treated patients.  Nevertheless, most urologists view current IC treatment options as 
unsatisfactory, as exemplified by the Mayer et al.2 statement: “Effective medical 
treatment for patients with moderate to severe IC remains elusive.” 
Buffered lidocaine-heparin (intravesical instillation) URG 101, is proposed as an 
investigational new drug for the treatment of pelvic pain and urgency of bladder 
origin.  All components of the investigational solution are currently FDA approved 
for other indications.  Lidocaine Hydrochloride (HCl) is a local anesthesia for pain 
control during surgical procedures and for topical applications.  Heparin sodium is an 

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anticoagulant for the prevention and treatment of thrombotic conditions such as 
pulmonary embolism and arteriovenous thrombosis.  The proposed use of buffered 
lidocaine-heparin is based on both open-label clinical experience12,13, and on Urigen’s 
double-blind placebo-controlled study, URG101-101, in subjects with symptoms of 
pelvic pain and urgency.  In this study, subjects experienced immediate symptom 
relief; improvement in urgency for drug versus placebo achieved statistical 
significance (p = 0.006) and trended to improvement in pain (p = 0.093).  A recent, 
multisite, double-blind study using a single dose of URG101 versus  placebo showed 
a significant reduction in pain and urgency (p = 0.03)20. 
URG101 (alkalinized lidocaine-heparin) is a combination therapy for relief of 
symptoms of pain and urgency associated with interstitial cystitis/bladder pain 
syndrome.  The formulation is instilled directly into the bladder, with the lidocaine 
modulating bladder neural hyperactivity that is often associated with bladder pain and 
urgency, urge, and muscle spasms.  Heparin (chemically similar to Elmiron, which is 
approved for IC) augments natural heparinoids on the surface of the urothelium to 
limit urinary potassium and other urinary toxins from penetrating to the underlying 
tissues.  
Since the two FDA-approved therapeutics, RIMSO-50 and Elmiron, require chronic 
administration for any benefit to develop, there is no treatment for pain other than 
narcotics.  Consequently, alkalinized lidocaine-heparin provides relief over both a 
short-term and medium-term time period, for which there is no current  
FDA-approved therapy.  URG101 offers the first relief that is effective and that 
downregulates sensory nerves without rebound13.  
We propose that URG101 will meet a serious need in this patient population for the 
following reasons:  (1) the millions of people afflicted with IC; (2) no effective 
therapy for severe symptom flares; (3) reduced quality of life; (4) the wasted use of 
antibiotics to treat nonexistent infections; and (5) very real suicide threat in patients 
with severe symptoms. 

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7.2 
URG101 
The individual components of this combination therapy, Lidocaine HCl and heparin 
sodium, are FDA-approved products for use as a local anesthetic and an 
anticoagulant, respectively.  It was demonstrated that when these components were 
mixed together and buffered by the addition of sodium bicarbonate, the resultant 
solution reduced symptoms of pelvic pain and urgency upon instillation into a 
subject’s bladder12.  Most subjects exhibit both an acute benefit as well as sustained 
benefit from single and multiple treatments13,20.  This multimodal therapy achieves 
acute benefit for subjects who have no standard acute treatment for pelvic pain and 
urgency of bladder origin.  
The rationale for this combination therapy is twofold.  Lidocaine, a local anesthetic, 
traverses the urothelium when uncharged at alkaline pH, reversing the local neural 
hyperactivity of the bladder neurons and, thereby reducing the sensations of pain and 
urge, and also reducing muscle spasms.  Heparin, a glycosaminoglycan, augments 
natural heparinoids that may be deficient on the surface of the urothelium.  
Heparinoids are part of the mucus layer of the urothelium and help to limit urinary 
solutes such as urea and potassium from penetrating to the underlying tissues thereby 
preventing pain, tissue inflammation, and muscle spasms21. 
7.3 
CLINICAL EXPERIENCE WITH URG101 
Previously, URG101 was studied in open-label clinical studies at the University of 
California – San Diego13 and in a controlled Phase 2 multicenter trial sponsored by 
Urigen.  These studies demonstrated that URG101 was safe and well tolerated.  No 
serious adverse events (SAEs) or unexpected adverse events (AEs) or significant 
changes in blood coagulation were observed, demonstrating that heparin in the 
bladder does not appreciably enter into systemic circulation.   
 
 
 
  
 
  
 
 
  

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In the URG101-104 study, a multicenter, single-dose, cross-over, double-blind, 
placebo-controlled study, followed by one open label treatment, a total of 28 subjects 
were enrolled20.  The study was terminated early due to a recall of heparin with no 
suitable replacement, and the planned interim analysis became the final unblinded 
analysis.  Statistical significance was achieved for the primary endpoint (i.e., average 
percentage change in pain from 0.5 to 12 hours), was 42% on URG101 compared 
with 21% on placebo (p = 0.03).  Similar results were seen with the secondary 
endpoints of ≥ 50% overall improvement (p = 0.01) and average percentage change in 
pain plus urge and urge alone (p = 0.03). 
7.4 
RISKS AND BENEFITS 
The study drug components (Lidocaine Hydrochloride and Heparin Sodium) both 
have extensive previous human experience since their United States approvals in 
1948 and 1939, respectively.  Additionally, both of these drugs are normally 
administered via parenteral injection, whereas intravesical alkalinized lidocaine-
heparin is administered into the lumen of the bladder and only comes into contact 
with the urothelium.  
Lidocaine is a well-characterized small molecule drug used for local anesthesia.  The 
uncharged form of lidocaine is able to traverse membranes and enter into systemic 
circulation.  AEs are primarily dose-related upon reaching a 6-µg/mL serum lidocaine 
concentration.  The maximum recommended intravenous dose for adults is 300 mg, 
which is well above the 200 mg lidocaine dose in URG101.  Additionally, 
intravenous lidocaine is also a class I antiarrhythmic and is often used simultaneously 
with intravenous heparin in the acute care setting after myocardial infarction.  
Heparin (a large, naturally sulfated polysaccharide) is an intravenous anticoagulant 
used for the prophylaxis and treatment of arterial or venous thrombosis and 
coagulopathies.  Heparin’s large size prevents it from being absorbed across epithelial 
surfaces.  
The previous human experience of intravesical buffered lidocaine-heparin in the 
URG101-101 study involved 43 subjects on active drug.  The intravesical instillation 
of buffered lidocaine-heparin (160 mg lidocaine, 40,000 units heparin, pH 7.8) did 
not alter the prothrombin time (PT) and activated partial thromboplastin time (aPTT) 
of these subjects, consistent with the heparin component not entering systemic 
circulation.  Monitoring of serum lidocaine concentrations at 1 hour demonstrated 

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that the serum lidocaine concentrations were < 1.0 µg/mL for most subjects (32 of 
43), with only 11 subjects with serum lidocaine concentrations > 1.0 µg/mL, and the 
highest concentration of 1.5 µg/mL.  In the URG101-104 study serum levels of 
lidocaine ranged from 0.24 to 2.0 µg/mL, with an average of 0.51 µg/mL, and neither 
the aPTT nor the PT was altered in any subject20.  These serum lidocaine 
concentrations are well below the toxic 6-µg/mL concentration for lidocaine and 
changes in bleeding parameters have not been seen; therefore, the lidocaine and 
heparin in URG101 do not pose an unacceptable safety risk.  
In summary, buffered lidocaine-heparin provides relief of bladder pain and urgency 
over both short-term and medium-term time periods, for which there is no currently 
FDA-approved therapy, and thus may be beneficial for individuals with chronic 
pelvic pain of bladder origin. 
7.5 
STUDY RATIONALE 
7.5.1 
Rationale for Dose 
Intravesically administered heparin is safe because it is a large molecule, will not 
penetrate the bladder epithelium, and will not be observed systemically; therefore, it 
is in essence, a topical therapy.  This was substantiated by the two Phase 2 clinical 
trials previously conducted by Urigen.  A total of 90 subjects received a dose of 
40,000 units of heparin, and 28 subjects received a total of 51 exposures to 
50,000 units of heparin.  Plasma INR and aPTT were unchanged after administration 
of drug in all subjects.  In extensive experience at University of California – San 
Diego, the higher doses of heparin were more effective than the lower doses.   
Unlike intravesically instilled heparin, lidocaine has potential toxicity if the serum 
concentrations exceed 6 µg/mL.  In one reported trial17, up to 6 mg lidocaine 
(approximately 300 to 400 mg total dose) per kg of body weight was given to 
12 subjects.  Serum lidocaine concentrations were measured for 3 hours after 
administration.  The highest serum concentration observed was 1.7 µg/mL, which 
was well below the level where symptoms may occur.  In the Urigen Phase 2 studies, 
the highest lidocaine dose administered was 200 mg.  In all subjects receiving the 
drug, lidocaine concentrations were < 2.0 µg/mL which were well below the 
concentrations that are associated with safety issues.  In the Urigen URG101-104 
study, 50% of subjects experienced relief of symptoms (i.e., 50% reduction overall) 

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after a single administration of URG101 containing 50,000 units of heparin and 
200 mg lidocaine20.  The placebo arm showed only an 11% reduction in symptoms.  
These data revealed the greatest difference in relief of symptoms between drug and 
placebo for any therapeutic trial conducted in IC.  As a result of these data, 
50,000 units of heparin combined with 200 mg lidocaine is the proposed dose for the 
Phase 2a URG101-105 study since excellent efficacy is seen at this dose, along with 
very safe serum lidocaine concentrations, no changes in bleeding parameters, and no 
significant symptoms or toxicities. 
7.5.2 
Rationale for Single Dose 
The Urigen Study URG101-101 revealed a 51% placebo response rate.  This was seen 
throughout the study, with the exception of one study site.  This site enrolled subjects 
with severe IC/BPS, where the placebo response was 20% in keeping with prior 
studies with subjects with severe disease.  
 
 
 
 
 
  There is currently no 
effective therapy to relieve these intense symptom flares.   
It is proposed, therefore, to perform a single-dose study to document the effectiveness 
of URG101 in relieving the intense flare in subjects with IC. 
7.5.3 
Rationale for Study Endpoint 
Pain and urgency analog scales were used in the clinical trials that were the basis of 
the Elmiron approval and were reliable outcome measures16.  The global assessment 
of symptoms (also known as the Patient Overall Rating of Improvement in Symptoms 
[PORIS] questionnaire) was also part of the basis for the ultimate FDA approval of 
Elmiron for sale in the United States.  This endpoint was validated statistically19 and 
was found to be a sensitive and reliable outcome measure.  This endpoint was also 
used for several therapeutic trials conducted by the National Institute of Diabetes and 
Digestive and Kidney Diseases clinical trials collaborative group11.  Both the analog 
scales and the PORIS questionnaire were utilized in Study URG101-104 with 
successful outcomes.  For the proposed Phase 2a (Study URG101-105) clinical trial 
with URG101, the numerical rating scales (NRSs) for bladder pain will be employed 

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as the basis for the primary outcome measure, and the urgency NRS,  the PORIS 
questionnaire and frequency will be used for secondary endpoints.  Urination diaries 
will be collected for information purposes. 

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8.0 
STUDY OBJECTIVES 
8.1 
PRIMARY OBJECTIVE 
The primary objective of the study is as follows: 
1. To evaluate the change in sum of bladder pain intensity differences from baseline 
to 12 hours (SPID-12) after administration of URG101 compared with the SPID-
12 after administration of lidocaine alone, heparin alone, and placebo as 
determined by using the 11-point NRS for bladder pain.  The IDMC will establish 
the exact primary endpoint based on the data recorded during the run-in phase of 
the study. The SPID score that is not determined by the IDMC as the primary 
endpoint will be considered the first secondary endpoint. 
8.2 
SECONDARY OBJECTIVES 
The secondary objectives of the study are as follows: 
1. To evaluate the change in bladder pain from baseline to 24 hours, using the sum 
of pain intensity differences (SPID-24) at defined time points, after administration 
of  intravesical URG101 compared with alkalinized Lidocaine Hydrochloride 
Injection (20 mg/mL) alone, alkalinized Heparin Sodium Injection (5,000 
USPU/mL) alone, and placebo 
 
2. To evaluate the change in urgency from baseline to 12 and 24 hours, using the 
sum of urgency intensity differences (SUID) at defined time points, after 
administration of  URG101 compared with alkalinized Lidocaine Hydrochloride 
Injection 
(20 
mg/mL) 
alone, 
alkalinized 
Heparin 
Sodium 
Injection (5,000 USPU/mL) alone, and placebo 
 
3. To evaluate the absolute and percentage change in bladder pain and urgency 
intensity differences at 1, 12, and 24 hours after administration of URG101 
compared with alkalinized Lidocaine Hydrochloride Injection USP (20 mg/mL) 
alone, alkalinized Heparin Sodium Injection USP (5,000 USPU/mL) alone, and 
placebo (
) 
4. To evaluate the change in improvement of symptoms  using the Patient Global 
Assessment (question number 3) after treatment with URG101 compared with 
alkalinized Lidocaine Hydrochloride Injection (20 mg/mL) alone, alkalinized 

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Heparin Sodium Injection (5,000 USPU/mL) alone, and placebo (
 
) at 1, 12, and 24 hours 
5. To evaluate the time to first administration of rescue medication for pain after 
treatment with URG101 compared to alkalinized Lidocaine Hydrochloride 
Injection 
(20 
mg/mL) 
alone, 
alkalinized 
Heparin 
Sodium 
Injection 
(5,000 USPU/mL) alone, and placebo (
) 
6. To investigate the relationship of plasma lidocaine concentrations at 1 hour after 
study drug administration to bladder pain and urgency at 1 hour, and from 
baseline to 12 and 24 hours, using the sum of pain and urgency intensity 
differences at defined time points,  after treatment with URG101compared with 
alkalinized Lidocaine Hydrochloride Injection USP (20 mg/mL) alone, 
alkalinized Heparin Sodium Injection USP (5,000 USPU/mL) alone, and placebo 
(
) 
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9.0 
INVESTIGATIONAL PLAN 
9.1 
OVERALL STUDY DESIGN AND PLAN 
This is a phase 2a, prospective, randomized, double-blind, placebo-controlled, 
multicenter, single-dose, pharmacokinetic study designed to determine the efficacy 
and safety of the combination product (URG101) versus its alkalinized individual 
components (Heparin Sodium and Lidocaine Hydrochloride) and placebo 
 
. 
In this study, alkalinized Lidocaine Hydrochloride Injection (20 mg/mL) and 
alkalinized Heparin Sodium Injection (5,000 USP U/mL) will be subsequently 
referred to by the drug names alkalinized Lidocaine and alkalinized Heparin. 
Eligible subjects exhibiting interstitial cystitis symptoms who have signed informed 
consent, will be screened and provisionally enrolled for intravesical treatment.  
Treatment may occur on the day of the Screening Visit (Visit 1) or any following day 
up to 1 week (Baseline and Drug Administration, Visit 1a).  If drug administration 
occurs on same day as screening then all assessments in Visit 1 and Visit 1a will 
be combined.  Confirmation of symptom severity must be obtained before 
randomization: minimum pain score of 5 on the 11-point numerical rating scale 
[NRS] at Screening and 15 minutes (± 5 minutes) after voiding prior to study drug 
administration.  There is no minimum score requirement for the urgency NRS scales 
for patients to enter the study.  Subjects will become fully enrolled upon receipt of 
acceptable qualifying laboratory evaluations and clinical assessments obtained before 
randomization. 
On the day of study drug administration (V1a), subjects will be randomized (2:1:2:1; 
URG101:placebo:lidocaine:heparin) and will receive a single administration of one of 
four intravesical treatments in a blinded fashion, based on random assignment: 
1. URG101 (buffered lidocaine-heparin) 
2. Placebo: 
 
3. Lidocaine alone: 
 
4. Heparin alone: 
 

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During the study, subjects will be allowed to take their protocol-allowed medications 
at their ususal doses. Additionally, they may use only a short acting non-steroidal 
anti-inflammatory drugs (NSAIDs) as rescue medication, not sooner than 8 hours 
after receiving study medication and not within 6 hours prior to receiving study 
medication (Table 1). 
9.1.1 
Screening (Visit 1) 
The purpose of the Screening Visit is to obtain informed consent and to establish 
protocol eligibility.  Informed consent will be obtained after the study is fully 
explained to each subject and before the conduct of any screening procedures or 
assessments.  Procedures to be followed when obtaining informed consent are 
detailed in Section 5.1. 
At the Screening Visit (V1), the following will be completed:  
• medical history and demographics;  
• medication history;  
• the Pelvic Pain and Urgency/Frequency (PUF) questionnaire;  
• 11-point NRS for bladder pain and urgency;  
• a physical examination, including a pelvic examination (which may be 
performed without speculum) to confirm lower urinary tract tenderness and 
vital signs (i.e., systolic and diastolic blood pressure, heart rate, respiratory 
rate, and oral body temperature); Results from a pelvic examination 
performed within 7 days prior to the Screening Visit (V1) may replace a V1 
pelvic examination.; 
• blood and urine samples for safety laboratory assessments (including urine 
hematuria analysis);  
• urine pregnancy test for women of childbearing potential;  
• urine screen for drugs of abuse;  
• adverse events; 
• and concomitant medications. 
With the exception of qualifying results for hematuria, drugs of abuse and pregnancy, 
no other clinical laboratory results are required prior to randomization. 

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9.1.2 
Baseline and Single-Dose Administration (Visit 1a) 
Randomization will occur after receipt of adequate qualifying urinalysis test results 
for drugs of abuse, hematuria and pregnancy and completion of qualifying 
assessments as documented in Section 9.3.  Study drug administration may occur on 
the day of screening or on any following day up to 1 week after screening, depending 
on the qualifying day of dosing residual urine assessment and 11-point bladder pain 
and urgency analog scales, which are administered 15 minutes (± 5 minutes) after 
voiding just prior to administration of study drug. 
The following assessments will occur at the site prior to study drug administration 
(Table 4):   
• 
urine pregnancy test for women of childbearing potential (must be repeated at 
V1a if screening [V1] does not occur on the same day as baseline and drug 
administration [V1a]);  
• 
urine screen for drugs of abuse (must be repeated at V1a if screening [V1] 
does not occur on the same day as baseline and drug administration [V1a]);  
• 
 
 
 
 
  
• 
dispense urination log and symptom diary; 
• 
11-point NRS for bladder pain and urgency 
 
 prior to study drug administration [time 0]);  
• 
vital signs measurements (i.e., systolic and diastolic blood pressure, heart rate, 
respiratory rate, and oral body temperature).  Measurements will be obtained 
immediately prior to study drug administration (time 0);  
• 
blood sample collection for prothrombin time (INR) and activated partial 
thromboplastin time (aPTT) prior to the dose at time 0;  

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• 
blood sample collection for plasma lidocaine prior to the dose at time 0;  
• 
randomization;  
• 
catheter tolerance assessment; 
The following assessments will occur at the site after study drug administration 
(Table 4):   
• 
study drug administration via urethral catheter installation (the study 
medication should left indwelling for 45 minutes [but not less than 30 
minutes] before voiding); 
• 
11-point NRS for bladder pain and urgency 30 minutes (± 5 minutes), 1 hour 
(± 5 minutes), 2 hours (± 10 minutes) after study drug administration; 
• 
blood sample collection for prothrombin time (INR) and activated partial 
thromboplastin time (aPTT) at 1 hour (± 10 minutes) after study drug 
administration;  
• 
blood sample collection for plasma lidocaine at 1 hour (± 10 minutes) 
after study drug administration; 
• 
the 
PORIS 
questionnaire 
at 
1 
hour 
(± 15 minutes) 
after 
study drug administration;  
• 
vital signs measurements (i.e., systolic and diastolic blood pressure, heart rate, 
respiratory rate, and oral body temperature) will be obtained at 1 hour 
(± 15 minutes) after study drug administration;  
• 
concomitant medications;  
• 
and adverse events. 
9.1.3 
Home Assessment 
After instructions, the subjects will be discharged from the clinic and reminded to 

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return the next day for the optional 24 hour Follow-up Visit.  However, return of 
subject diaries including 24 hour assessments are mandatory. All assessments and 
their respective timing are provided in Table 4. The following assessments will occur 
>2 hours post study drug administration but before 24-hour Follow-up Visit (V2): 
• 
11-point NRS for bladder pain and urgency at 4 hours (± 30 minutes), 6 hours 
(± 30 minutes), 8 hours (± 30 minutes), 10 hours (± 30 minutes), and 12 hours 
(± 30 minutes) (only during times the subject is awake); 
• 
the PORIS questionnaire at 12 hours after study drug administration or before 
the subject goes to bed for the evening; 
• 
urination log; 
• 
adverse event reporting; 
• 
and concomitant medications. 
9.1.4 
24-Hour Follow-up Visit (Visit 2; Optional) 
Approximately 24 hours after study drug administration, the subjects will return to 
the clinic for end-of-study assessments.  The following assessments will occur: 
• 
subject’s diary collection is mandatory to evaluate the efficacy of URG101; 
• 
11-point NRS for bladder pain and urgency at 24 hours (± 2 hours) is 
mandatory to be completed and returned; 
• 
the 
PORIS 
questionnaire 
at 
24 
hours 
(± 2 hours) 
after 
study drug administration is mandatory to be completed and returned; 
• 
vital 
signs 
measurements 
at 
24 
hours 
(± 2 
hours) 
after 
study drug administration (i.e., systolic and diastolic blood pressure, heart 
rate, respiratory rate, and oral body temperature) is optional; 
• 
and recording of any adverse events or concomitant medications is 
mandatory to be collected and returned for safety evaluation.  

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In the opinion of the Investigator, if the subject appears responsible to perform the 24 
hour assessments, correctly fill out the diary for all of the at home assessments, and 
the Investigator and the subject have made acceptable arrangements for the return of 
the diaries, answering of any follow up questions, and for the subject’s treatment and 
care after 24 hours, then Visit 2 may be considered an optional protocol visit to the 
clinic.  
 
9.1.5 
End-of Study Follow-up 
The site staff will call each subject within 48 to 72 hours of study drug administration 
to check on subject status and to ascertain AE and concomitant medication status. 
9.1.6 
Interim Study Analysis 
After recruitment and treatment of the first ~90 (50%) of the planned 180 subjects, 
the IDMC will examine the conditional power and determine if a modification to the 
sample size up to 300 subjects is required to yield an overall power of 90%.  An 
adjustment to the type 1 error rate will not be necessary if the conditional power is 
>39% at the interim assessment.   
The IDMC will consist of 3 members: 1 physician expert in IC/BPS, 1 expert in 
clinical development, and a biostatistician. None of the IDMC members will be 
associated with study personnel; all communication between the IDMC and study 
personnel will be pre-defined and governed by the IDMC charter. The IDMC will 
have access to unblinded pain scores to perform their assessment of conditional 
power. 
9.2 
DISCUSSION OF STUDY DESIGN INCLUDING CHOICE OF CONTROL 
GROUPS  
The URG101 drug product contains the active ingredients, heparin and lidocaine, 
buffered to a pH of 7.4 (± 0.2).  The anesthetic effect of lidocaine is anticipated to 
provide primary symptom relief of anesthetizing and “down-regulating” the bladder 
sensory nerves13,15,17,20.  Heparin is expected to potentiate this effect by coating the 
bladder epithelium and reducing the leak of additional potassium that would provoke 

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the nerves and initiate more symptoms.  It is unlikely that heparin alone could provide 
much in the way of relief since the bladder sensory nerves would still remain “up-
regulated” and volume sensitive even though the heparin would reduce the potassium 
leak.  In a clinical trial that evaluated intravesical heparin, there was only minimal 
benefit, and most of the benefit of chronically administered heparin was after many 
months of use18.  Therapeutic trials in this population are difficult to conduct due to 
recruitment issues.  It has been shown that it can take more than 3 years to accrue 
125 subjects with up to 10 active sites involved9.   
A practical solution is proposed to evaluate  the contribution of the components 
which is a four-arm study:  (1) combination product, URG101, heparin-lidocaine 
buffered to pH 7.4 (± 0.2); (2) placebo 
 pH 7.4 [± 0.2]); 
(3) lidocaine buffered to pH 7.4 ± 0.2; and (4) heparin buffered to pH 7.4 (± 0.2).  
Such a study would answer this critical question:  Does heparin potentiate the 
lidocaine effect and justify the combination of the drugs? 
Randomization will be used in this study to avoid bias in the assignment of subjects 
to treatment, to increase the likelihood that known and unknown subject attributes 
(e.g., demographics and baseline characteristics) are equal across treatment groups, 
and to ensure the validity of statistical comparisons across treatment groups.  
Blinding to treatment will be used to reduce potential bias during data collection and 
evaluation of endpoints. 
9.3 
SELECTION OF STUDY POPULATION 
An estimated 180 subjects will be randomized at approximately 30 sites.  A 
maximum of 300 subjects will be enrolled as determined by the IDMC. Subjects who 
do not meet all of the inclusion criteria or who meet any of the exclusion criteria will 
not be eligible to receive study drug. 
9.3.1 
Inclusion Criteria 
Subjects diagnosed with interstitial cystitis/bladder pain syndrome must meet all of 
the following criteria to participate in the study: 
1. Have provided written informed consent to participate in this trial  
2. Be male or female, ≥ 18 years of age 

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3. Have moderate-to-severe symptoms of bladder pain of bladder origin for at least 
9 months prior to the study 
4. May or may not have received a cystoscopy in association with their diagnosis of 
interstitial cystitis/bladder pain syndrome prior to or at time of screening   
5. Have a score of ≥ 15 and < 30 on the PUF questionnaire, completed at screening 
6. A minimum score of 5 is required on the 11-point bladder pain NRS 
7. Have been using a stable dose of hormone therapy for ≥ 3 months, if female and 
currently taking hormone therapy (postmenopausal women who have not been 
stabilized on a regimen of hormone replacement therapy within 3 months of 
screening will not be included) 
9.3.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from participating in 
the study: 
1. For females, have a positive pregnancy test at screening or be pregnant or 
lactating   
Note:  Females considered to be of child-bearing potential must commit to using a 
consistent and medically acceptable method of birth control for the duration of the 
study:  hormonal (i.e., oral, transdermal patch, implant, or injection) on a stable 
dose for at least 3 months prior to screening; double barrier (i.e., condom with 
spermicide or diaphragm with spermicide) consistently for at least 2 weeks prior 
to screening; and intrauterine device for at least 3 months prior to screening; or 
only have a partner who has been vasectomized for at least 6 months prior to 
screening or exclusively has same-sex partners.  Females considered to be of non-
childbearing potential include:  at least 1 year postmenopausal; surgically sterile 
(tubal ligation, bilateral oophorectomy, salpingectomy, of hysterectomy); 
congenitally sterile; diagnosed as infertile and not undergoing treatment to reverse 
infertility.  If male and sexually active, the patient is willing to commit to an 
acceptable method of birth control for the duration of the study or exclusively has 
same-sex partners. 
2. Have a known hypersensitivity to heparin or lidocaine 

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3. Have used any local anesthetic by any route within 24 hours prior to study drug 
administration, or used a lidocaine patch within 14 days prior to study drug 
administration 
4. Have used a tricyclic antidepressant, or a gamma-Aminobutyric acid (GABA) 
analogue (gabapentin or pregabalin), unless taking a stable dose of the medication 
for ≥ 3 weeks.  The stable dose of gabapentin may not exceed 1,200 mg per day, 
and the stable dose of pregabalin may not exceed 150 mg per day. 
5. Have used any pain medication within 6 hours prior to study drug administration 
6. Have used narcotics or medical marijuana ≤ 3 weeks prior to study entry (generic 
names:  fentanyl, hydrocodone, hydromorphone, levorphanol, medical marijuana, 
methadone, morphine, oxycodone, propoxyphene, tramadol).  Subjects who have 
received codeine within this time period may be admitted if the use is not chronic, 
and not within 6 hours of enrollment, such that they are not at risk for GI or opiate 
withdrawal symptoms that in the opinion of the investigator would impact the 
subject’s study participation due to their ability to follow the study protocol or 
bias study results. 
7. Have used prohibited drugs as determined by self-report, positive urine drug 
screen, or in the opinion of the investigator be under the influence of drugs 
affecting mentation precluding their ability to follow the study protocol or bias 
study results 
8. Have a known clinically significant abnormal laboratory test value defined by the 
investigator  (If a known clinically significant abnormal laboratory value exists, 
the investigator can request a waiver from the medical monitor.  The subject may 
not continue in the study without an approval waiver from the medical monitor)   
9. Have a neurogenic bladder or other disorder that, in the opinion of the 
investigator, may cause neurogenic bladder (including Parkinson’s disease, 
multiple sclerosis, epilepsy, myasthenia gravis, movement disorders, spinal cord 
damage) 
10. Have pain or a pain disorder that, in the opinion of the investigator, would make it 
difficult to discriminate pelvic pain of bladder origin from the other pain 
11. Have any of the following CNS conditions that in the opinion of the investigator 
would impact the subject’s study participation due to their ability to follow the 

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study protocol or bias study results, severe diagnosed: major depressive disorder, 
bipolar disorder, schizophrenia, general anxiety disorder, attention deficit 
disorder, obsessive compulsive disorder, or other major central nervous system 
disorder 
12. Have history of arrhythmias, conduction disturbances, or cardiac disease, or any 
coexisting medical condition that, in the opinion of the investigator, may be 
significant or interfere with study procedures or interpretation of study results 
13. Had bladder instillation therapy within 7 days prior to study entry or had a prior 
bladder instillation with heparin and lidocaine and did not respond 
14. Had dilatation (hydrodistention) of bladder within 3 months of study entry 
15. Evidence or suspected presence of cancer detected during cystoscopy prior to or 
at time of initial screening. 
16. Has received any investigational drug or device within 30 days prior to screening 
17. Is currently enrolled in another investigational drug or device study 
18. Is unwilling or unable to abide by the requirements of the study 
19. Have an actively bleeding lesion or area in the bladder as detected by dipstick 
urinalysis and investigator assessment, immediately prior to randomization 
(Section 9.5.1.5.  If the investigator determines that active bleeding is not 
occurring and that it is safe for the subject, the subject may continue in the study.) 
20. Have had any of the following:  
• 
Bacterial cystitis within 30 days as demonstrated by a positive urine culture 
(≥ 105 bacteria per mL) 
• 
History of pelvic irradiation or radiation cystitis 
• 
History or presence of uterine, cervical, pelvic, rectal, ovarian or vaginal 
cancer 
• 
History of benign or malignant bladder tumors 
• 
Current chemotherapy 
• 
History or presence of tuberculous cystitis 

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• 
History or presence of chemical cystitis, including that due to 
cyclophosphamide 
• 
History or presence of urinary schistosomiasis 
• 
Bladder or ureteral calculi 
• 
Clinically significant infectious vaginitis 
• 
Currently uncontrolled genital herpes 
• 
History or presence of urethral diverticulum 
• 
Presence of bladder fistulae 
• 
History of ketamine use 
Immediately prior to receiving treatment of study drug, subjects will be 
re-evaluated as follows:  Subjects will be asked to void; 15 minutes (± 5 minutes) 
after voiding, their urinary bladder volume will be measured to rule out diuresis by 
using an ultrasonic bladder scan or by inserting a catheter and collecting urine.  The 
11-point bladder pain NRS will also be administered at this time.  Subjects will be 
excluded based on the following criteria: 
• 
Score of < 5 on the 11-point bladder pain NRS (Note:  No minimum is needed for 
urgency NRS.) 
• 
 
 
 
 
• 
Significant urethral discomfort upon urethral catheterization 
9.3.3 
Removal of Subjects from Therapy or Assessment 
The investigator may withdraw the subject from the study at any time for safety or 
administrative reasons.  The subject may withdraw from the study at any time for any 
reason. 
9.3.3.1 
Entire Study or Treatment Arm(s) 
If Urigen terminates or suspends the study for safety or unanticipated other reasons, 

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prompt notification will be given to IRBs, and regulatory authorities in accordance 
with regulatory requirements. 
9.3.3.2 
Individual Center 
The investigator will notify Urigen promptly if the study is terminated by the 
investigator or the IRB at the site. 
9.3.3.3 
Individual Subject 
If a subject discontinues from the study prematurely, the reason must be fully 
evaluated and recorded appropriately in source documents and the CRF.  If the 
subject is being withdrawn because of an AE, that AE should be indicated as the 
reason for withdrawal. 
Any episodes of suicidal ideation or homicidal ideation will result in withdrawal from 
the study, based on the investigator’s discretion. 
All subjects have the right to withdraw at any point during treatment without 
prejudice.  The investigator can discontinue a subject’s participation in the study at 
any time if medically necessary.  In addition, subjects meeting the following criteria 
must be withdrawn from the study: 
1. Occurrence of any AE, intercurrent illness or abnormality in a laboratory 
assessment which, in the opinion of the investigator, warrants the subject’s 
permanent withdrawal from the study 
2. Treatment with a prohibited concomitant medication other than the use of 
appropriate medications for the treatment of AEs under direction of the 
investigator 
3. Subject noncompliance, defined as refusal or inability to adhere to the study 
schedule or procedures per the investigator’s discretion 
4. At the request of the subject, investigator, Urigen or designee, or regulatory 
authority 
5. Subject becomes pregnant 

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6. Subject is lost to follow-up 
The investigator will notify Urigen promptly when a subject is withdrawn. 
9.4 
TREATMENTS 
9.4.1 
Treatments Administered 
The study drugs will be blinded and assigned to each subject based on the 
randomization schedule.  The contents of each kit will be admixed immediately prior 
to administration by the investigator who will administer the drug to the patient at no 
colder than room temperature.  The following treatments will be administered as a 
single dose via urethral catheter: 
• 
URG101 treatment comprises the following:  
- 18 mL containing heparin sodium 
 
 Lidocaine HCl buffered to pH 7.4 (± 0.2) with 1X 
 
buffer, 
 
 
 
 
 
• 
Placebo treatment comprises the following: 
- 18 mL 1X 
 buffer (pH 7.4 [± 0.2]) 
• 
Heparin treatment comprises the following: 
- 12 mL Heparin Sodium 
 plus 6 mL 
3X 
 buffer (final mixture buffered to pH 7.4 [± 0.2]) 
• 
Lidocaine treatment comprises the following: 
- 12 mL Lidocaine HCl 
 plus 6 mL 3X 
 buffer 
(final mixture buffered to pH 7.4 [± 0.2]) 
Prior to administering drug each subject will empty their bladder.  Fifteen minutes 
later (± 5 minutes), the subject will complete the 11-point bladder pain NRS (requires 
a score of ≥ 5.0 to enter the trial and receive drug) and the 11-point urgency NRS 
(critical to administer 15 minutes (± 5 minutes) after voiding but no minimum score is 
required for study entry).  These NRS scores will be the baseline scores for pain and 

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urgency.  
 
 
 
 
 
 
 
  The study medication is to be left indwelling for 45 minutes, with a 
minimum of 30 minutes, and after that may be voided by the subject.  The test 
instruments will then be administered at the intervals listed in the schedule of 
assessments (Table 4). 
9.4.2 
Identity and Storage of Investigational Products 
URG 101, Lidocaine HCl Injection, Heparin Sodium Injection, Placebo (1x 
 
) and diluent buffers (3X 
) will be prepared by a Good 
Manufacturing Practice compliant contract manufacturing organization and shipped 
to the designated responsible person at each site for oversight and preparation of the 
medications for patient treatments as described in the Study Procedures Manual.  A 
study drug preparation log and inventory accountability record of drug supplies will 
be kept at the clinical site or the pharmacy associated with the site.   
9.4.3 
Labeling of Investigational Products 
All study drug will be labeled in accordance with text that is in full compliance with 
FDA regulations.  
9.4.4 
Storage Conditions 
Drug kits will be stored at room temperature on-site in the clinic in an area accessible 
only to site staff.   
Temperature monitoring is required at the storage location to ensure that the study 
drug is maintained within an established temperature range of 15 to 25C.  The 
investigator or designee (or if regionally required, the head of the medical institution) 
is responsible for ensuring that the temperature is monitored throughout the total 
duration of the study and that records are maintained.  The temperature should be 
monitored continuously by using either an in-house–validated data acquisition 

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system, a mechanical recording device (such as a calibrated chart recorder), or 
manual means, so that minimum and maximum thermometric values over a specific 
time period can be recorded and retrieved as required. 
9.4.5 
Method of Assigning Subjects to Treatment Groups 
Subjects will be assigned to treatments based on a computer-generated, 
randomization scheme that will be reviewed and approved by an independent 
statistician.  The randomization scheme and identification for each subject will be 
included in the final clinical study report for this study. 
After the baseline period, subjects will be randomized to one of four treatment 
groups.  Each treatment group will receive either URG101, placebo, lidocaine, or 
heparin as a single dose.  The randomization ratio of the study is 2:1:2:1.  
Randomization will be performed centrally by an interactive web response system 
(IWRS).  The randomization schedule will be designed to randomly assign subjects to 
one of four treatment groups.  The IWRS will generate the randomized identification 
numbers.  At the time of randomization, the investigator or designee will use IWRS to 
register the subject information.  The IWRS will assign each subject a unique 6-digit 
randomization number.   
9.4.6 
Prior and Concomitant Therapy 
9.4.6.1 
Prohibited Medications 
Prohibited medications or therapies and restrictions for any drugs prior to receiving 
the double-blind study drug are provided in Table 1. 

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Table 1. 
Prohibited Concomitant Medications and Restrictions 
Medication or therapy 
Restrictions and timing with respect to 
study drug administration 
Local anesthetic via any route 
Within 24 hours  
Lidocaine patch 
Within 14 days  
Tricyclic antidepressants 
Prohibited unless the subject has been on a 
stable dose of the medication for ≥ 3 weeks  
Gabapentin 
Prohibited unless the subject has been on a 
stable dose ≤1200 mg daily for  ≥ 3 weeks 
Pregabalin 
Prohibited unless the subject has been on a 
stable dose ≤150 mg daily for ≥  3 weeks 
Any pain medication other than short 
acting NSAIDs 
Within 6 hours 
Short acting NSAIDs 
Within 6 hours but may be used as rescue 
medication 
8 
hours 
after 
study 
drug 
administration  
Narcotics or medical marijuana 
Within 3 weeks, except subjects on codeine 
may be admitted if use within this time 
period is not chronic and not within 6 hours 
of enrollment 
Illegal drugs 
Prohibited 
Bladder instillation therapy 
Within 7 days 
Investigational device or drug 
Within 30 days 
 
9.4.7 
Treatment Compliance 
All study drug administration will be performed at the clinical site.  Details of the 
study drug administration will be recorded on the CRF. 
9.4.8 
Drug Supplies and Accountability 
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator, or if regionally required, the head of the medical institution or the 
designated pharmacist, until the following documentation has been received by the 
sponsor: 
• A signed and dated confidentiality agreement 
• A copy of the final protocol signature page, signed and dated by both the sponsor 
and investigator 
• Written proof of approval of the protocol, the ICFs, and any other information 
provided to the subjects by the institutional review board (IRB) or independent 
ethics committee (IEC) for the institution where the study is to be conducted 

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• A copy of the IRB- or IEC-approved ICF and any other documentation provided to 
the subjects to be used in this study 
• The IRB or IEC membership list and statutes or Health and Human Services 
Assurance number 
• A copy of the certification and a table of the normal laboratory ranges for the 
reference laboratory conducting the clinical laboratory tests required by this 
protocol 
• An investigator-signed and dated Form FDA 1572, where applicable 
• Financial Disclosure form(s) for the investigator and all subinvestigators listed on 
Form FDA 1572, where applicable 
• A signed and dated curriculum vitae of the investigator including a copy of the 
investigator’s current medical license or medical registration number on the 
curriculum vitae 
• A signed and dated clinical trials agreement 
• A copy of the regulatory authority approval for the country in which the study is 
being conducted (if required), and the import license (if required) 
The investigator and the study staff, or if regionally required, the head of the medical 
institution or the designated pharmacist, will be responsible for the accountability of 
all study drugs and study supplies (dispensing, inventory, and record keeping) 
adherence to the sponsor’s instructions and adherence to GCP guidelines as well as 
local or regional requirements. 
Under no circumstances will the investigator allow the study drugs or study supplies 
to be used other than as directed by this protocol.  Study drugs and study supplies will 
not be dispensed to any individual who is not enrolled in the study. 

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The site must maintain an accurate and timely record of the following:  receipt of all 
study drugs and study supplies, dispensing of study drugs and study supplies to the 
subject, collection and reconciliation of unused study drugs and study supplies that 
are either returned by the subjects or shipped to the site but not dispensed to subjects, 
and return of reconciled study drugs and study supplies to the sponsor or (where 
applicable) destruction of reconciled study drugs and study supplies at the site.  This 
includes, but may not be limited to:  (a) documentation of receipt of study drugs and 
study supplies, (b) study drugs and study supplies dispensing and return reconciliation 
log(s), (c) study drugs and study supplies accountability log, (d) all shipping service 
receipts, (e) documentation of returns to the sponsor, and (f) certificates of destruction 
for any destruction of study drugs and study supplies that occurs at the site.  All forms 
will be provided by the sponsor.  Any comparable forms that the site wishes to use 
must be approved by the sponsor. 
The study drugs and study supplies and inventory records must be made available, 
upon request, for inspection by a designated representative of the sponsor or a 
representative of a health authority (e.g., the FDA).  Drug accountability will be 
reviewed during site visits and at the completion of the study. 
9.5 
STUDY ASSESSMENTS 
9.5.1 
Screening and Baseline Assessments 
Treatment may occur on the day of the Screening Visit (Visit 1) or any following day 
up to 1 week (Baseline and Drug Administration, Visit 1a).  If drug administration 
occurs on same day as screening then all assessments in Visit 1 and Visit 1a listed in 
Schedule of Assessments (Table 4) will be combined.   
9.5.1.1 
Demographics 
Subject demographic information will be collected at the Screening Visit.  
Demographic information includes date of birth (or age), sex, race, and ethnicity. 
9.5.1.2 
Medical History 
Medical and surgical history and current medical conditions will be recorded at the 
Screening Visit.  All relevant medical and surgical history must be recorded in the 

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CRF, including any record or history of cystoscopy and the diagnosis of IC/BPS. 
9.5.1.3 
Medication History 
All relevant medication history must be recorded in the CRF. 
9.5.1.4 
Physical and Pelvic Examination 
A comprehensive physical examination will be performed at the Screening Visit (V1).  
The physical examination will include evaluations of the following: general 
appearance; eyes, ears, nose, and throat; chest (including heart and lungs); abdomen 
(palpation and gastrointestinal sounds), extremities; and skin.  Weight and height will 
also be measured and will be recorded in the CRF. A pelvic examination will also be 
conducted which may be performed without speculum.  Results from a pelvic 
examination performed within 7 days prior to the Screening Visit (V1) may replace a 
V1 pelvic examination.  Documentation of the physical and pelvic examination 
results will be included in the source documentation.  Significant findings at the 
Screening Visit will be recorded in the CRF.   
9.5.1.5 
Urine Screening Tests 
A 30-mL urine sample will be collected and analyzed for pregnancy in women of 
childbearing potential, drug screen, and for standard urine analysis testing. 
The urine sample will be analyzed for hematuria by dipstick urinalysis.  If the urine 
dipstick is positive for blood, the investigator will evaluate the subject further before 
proceeding, (such as assessing the subject’s history to determine if the subject is 
menstruating, or performing a full urinalysis and if appropriate, a urine culture, to 
determine if the subject has a kidney or urinary tract infection, or cystoscopy prior to 
enrollment).  If the investigator determines that active bleeding is not occurring and 
that it is safe for the subject, the subject may continue in the study. 
9.5.1.6 
Catheter Tolerance 
All subjects will be catheterized with the hydrophilic ColoplastSpeediCath 8 Fr and 
12 Fr, respectively (for females and males).  Each subject will be assessed for the 
ability to tolerate the catheter after randomization into the study, based on the 

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investigator’s judgment.   
9.5.1.7 
 
 
 
 
 
 
 
 
 
 
9.5.1.8 
Pelvic Pain and Urgency/Frequency (PUF) Questionnaire 
Subjects will be asked to fill out the Pelvic Pain and Urgency/Frequency (PUF) 
Questionnaire, and it will be scored by the investigator.  Subjects must have a score 
of ≥ 15 and < 30 on the PUF questionnaire to qualify for the study. 
9.5.1.9 
Bladder Pain and Urgency 11-Point Numerical Rating Scales (NRS) 
As part of screening, subjects will be asked to fill out two sets of the 11-point bladder 
pain NRS and the 11-point urgency NRS, one at screening and one 15 minutes 
(± 5 minutes) after voiding just prior to study drug administration.  There is no 
minimum score requirement for the urgency NRS scales for patients to enter the 
study.  For the Pain NRS, both  the screening and
 pain NRS requires a score 
of ≥ 5.0 to enter the trial and receive study drug.   
9.5.1.10 
Safety Assessments 
Safety will be assessed by clinical laboratory tests (hematology, clinical chemistry, 
and urinalysis), vital signs measurements, and AE reporting. 
9.5.1.10.1 Clinical Laboratory Testing 
The local laboratory will be used for all laboratory testing required during the study 

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except for baseline and 1-hour plasma lidocaine, which will be analyzed by the 
central laboratory.  Reports from the laboratory should be filed with the source 
documents for each subject.  Samples will be obtained at the visits designated in 
Table 4.  Additional samples may be collected for further evaluation of safety as 
warranted by the investigator’s discretion.  The clinical laboratory tests performed 
during the study are provided in Table 2.  However, with the exception of qualifying 
results for hematuria, drugs of abuse and pregnancy, no other clinical laboratory 
results are required prior to randomization. 
Table 2. 
Clinical Laboratory Tests 
Hematology: 
Complete blood count (CBC): 
As defined by local laboratory 
Serum Chemistry: 
Alanine transaminase (ALT) 
Alkaline phosphatase (ALP) 
Aspartate transaminase (AST) 
Blood urea nitrogen (BUN)  
Calcium 
Creatinine  
γ-glutamyltransferase (GGT) 
Glucose 
Lactate dehydrogenase (LDH) 
Potassium 
Protein, total 
Sodium  
 
Dipstick Urinalysis: 
Color 
pH 
Specific gravity 
Blood/hemoglobin 
Leukocyte esterase 
Ketones 
Protein 
Additional Tests: 
Urine β-hCG for women of childbearing potential  
Urine drug screen 
INR and activated partial thromboplastin time 
Clean catch urine for bacterial culture if the urinalysis indicates:   
Plasma for lidocaine concentration 
β-hCG = beta human chorionic gonadotropin;  
 
 

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9.5.1.10.2 Vital Signs 
Vital sign measurements (i.e., systolic and diastolic blood pressure [mmHg], and 
pulse [beats per minute]) will be obtained at the visits designated on the schedule of 
assessments (Table 4).  Blood pressure and pulse will be measured after the subject 
has been sitting for 3 to 5 minutes.  All blood pressure measurements should be 
performed on the same arm, preferably by the same person. 
9.5.1.10.3 Adverse Events and Other Events of Interest 
An AE is any untoward medical occurrence in a subject who is administered an 
investigational product.  An AE does not necessarily have a causal relationship with 
the study drug. 
The criteria for identifying AEs include the following: 
• Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational 
product, whether or not considered related to the investigational product 
• Any new disease or exacerbation of an existing disease 
• Any deterioration in non–protocol-required measurements of a laboratory value or 
other clinical test (e.g., electrocardiogram [ECG] or x-ray) that results in 
symptoms, a change in treatment, or discontinuation of study drug 
• Recurrence of an intermittent medical condition (e.g., headache) not present 
pretreatment (baseline) 
• An abnormal laboratory test result should be considered an AE if the identified 
laboratory abnormality leads to any type of intervention, whether prescribed in the 
protocol or not, and after repeat confirmatory testing has been conducted 
A laboratory result should be considered by the investigator to be an AE if it includes 
the following: 
• Results in an intervention, based on medical evaluation (e.g., potassium 
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• Results in any out of range laboratory value that in the investigator’s judgment 
fulfills the definitions of an AE with regard to the subject’s medical profile 
All AEs observed during the study will be reported on the CRF.  All AEs, regardless 
of relationship to study drug or procedure, should be collected beginning from the 
time the subject signs the ICF through the last visit.  AEs reported prior to 
randomization will be termed medical history.  SAEs will not be considered medical 
history and will be collected for 72 hours after the last dose. 
Abnormal laboratory values should not be listed as separate AEs if the values are 
considered to be part of the clinical syndrome that is being reported as an AE.  Any 
laboratory abnormality considered to constitute an AE should be reported as an AE 
on the CRF. 
It is the responsibility of the investigator to review all laboratory findings in all 
subjects and determine if they constitute an AE.  Medical and scientific judgment 
should be exercised in deciding whether an isolated laboratory abnormality should be 
classified as an AE. 
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment. 
Assessing Severity of Adverse Events: 
AEs will be graded on a 3-point scale (mild, moderate, severe) and reported in the 
detail indicated on the CRF.  The definitions are as follows: 
Mild 
Discomfort noticed, but no disruption of normal daily activity 
Moderate 
Discomfort sufficient to reduce or affect normal daily activity 
Severe 
Incapacitating, with inability to work or to perform normal daily 
activity 
 
The criteria for assessing severity are different than those used for seriousness (see 
Section 9.5.1.10.3, Serious Adverse Events and Other Events of Interest for the 
definition of an SAE). 
 
 

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The causal relationship of the study drug to an AE will be assessed as related or 
unrelated, as follows: 
Assessing Causality of Adverse Events: 
Table 3. 
Assessment of Causality of AEs 
Term 
Definition 
Definitely related 
The AE is clearly related to the investigational agent(s) or research 
intervention: the AE has a temporal relationship to the administration of the 
investigational agent(s) or research intervention and follows a known pattern 
of response, and no alternative cause is present.  
Probably related  
The AE is likely related to the investigational agent(s) or intervention: the AE 
has a temporal relationship to the administration of the investigational 
agent(s) or research intervention and follows a known or suspected pattern of 
response, but an alternative cause may be present.  
Possibly related 
The AE may be related to the investigational agent(s) or intervention: the AE 
has a temporal relationship to the administration of the investigational 
agent(s) or research intervention and follows a suspected pattern of response, 
but an alternative cause is present. 
Unrelated  
(or Not Related) 
The AE is clearly not related to the investigational agent(s) or intervention: 
the AE has no temporal relationship to the administration of the 
investigational agent(s) or research intervention, and follows no known or 
suspected pattern of response, and an alternative cause is present.  
AE = adverse event. 
 
 
 
9.5.1.10.4 Serious Adverse Events 
An SAE is any untoward medical occurrence that, at any dose, meets one of the 
following criteria: 
• Results in death  
• Is life-threatening (i.e., the subject was at immediate risk of death from the AE as 
it occurred; this does not include an event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect (in the child of a subject who was exposed 
to the study drug) 
 

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Other important medical events that may not be immediately life-threatening or result 
in death or hospitalization but, when based on appropriate medical judgment, may 
jeopardize the subject or may require intervention to prevent one of the outcomes in 
the definition of an SAE listed above should also be considered SAEs.  Medical and 
scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in such situations.  
Other events of interest include pregnancy or exposure to study drug through 
breastfeeding; AEs associated with study drug overdose, misuse, abuse, or medication 
error; and any treatment-emergent significant laboratory abnormality.  These events 
of interest are to be captured using the SAE procedures but are to be considered SAEs 
only if they meet one of the above criteria.  All AEs associated with events of interest 
are to be reported on the CRF whether or not they meet the criteria for SAEs. 
The following hospitalizations are not considered to be SAEs because there is no AE 
(i.e., there is no untoward medical occurrence) associated with the hospitalization: 
• Hospitalizations for respite care  
• Planned hospitalizations required by the protocol 
• Hospitalization planned before informed consent (where the condition requiring 
the hospitalization has not changed after study drug administration) 
• Hospitalization for administration of study drug or insertion of access for 
administration of study drug 
• Hospitalization for routine maintenance of a device (e.g., battery replacement) that 
was in place before study entry 
9.5.2 
Efficacy Assessments 
9.5.2.1 
11-Point Bladder Pain and Urgency Scales 
The 11-point bladder pain and urgency NRSs are provided in Appendix 3.  The 
11-point pain and urgency scales are two scales that are used to assess bladder pain, 
the primary endpoint of this study, and urinary urgency.  The subject will be asked to 
circle the number, from 0 to 10, that best describes the symptom the subject is feeling 
“right now.”  The 11-point bladder pain and urgency scales will be explained to the 

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subject by the investigator or designee prior to the subject completing the 
questionnaire.  Guideline scripts for the 11-point pain and urgency scales are 
provided in Appendix 4. 
9.5.2.2 
Patient Overall Rating of Improvement of Symptoms Questionnaire 
The PORIS questionnaire is provided in Appendix 5.  It comprises three questions 
that ask the subject to report the overall change in pain and urgency now as compared 
with before study drug administration.  The choices are the same for each symptom:  
worse, no better (0% improvement), slightly improved (25% improvement), 
moderately improved (50% improvement), greatly improved (75% improvement), 
and symptoms gone (100% improvement).  The PORIS questionnaire will be 
explained to each subject by the investigator or designee prior to the subject 
completing the questionnaire.  A guideline script for the PORIS questionnaire is 
provided in Appendix 6. 
9.5.2.3 
24-Hour Pain and Urgency Scale Diary and Urination Log 
Each subject will be provided with a set of pain and urgency questionnaires that use 
the 11-point NRSs that will be recorded by the subject at home after receiving the 
study medication, until going to bed.  Pain measurements will be recorded on-site up 
to 2 hours after study drug administration [at Time 0, 30 minutes (± 5 minutes) and 
1 hour (± 5 minutes), 2 hours(± 10 minutes)], and at home at 4 hours (± 30 minutes), 
6 hours (± 30 minutes), 8 hours (± 30 minutes), 10 hours (± 30 minutes), and 12 hours 
(± 30 minutes) while the subject is awake.  The last set of pain and urgency 
questionnaires will be completed at 24 hours, and may be completed at the clinic if 
the subject returns to the clinician’s office (Visit 2) at 24 hours (± 2 hours) after study 
drug administration or, at the Investigator’s discretion, will be completed at home and 
retuned to the clinic per the Investgator’s directions.  The site staff will ensure that the 
proper subject initials and numbers, and study drug administration time are recorded 
in each subject’s diary prior to dispensing them.  The diary also contains a urination 
log.  The diary will be explained to each subject by the investigator or designee prior 
to the subject recording any data in the diary.  Site staff will be tasked with placing 
phone calls to remind each subject to complete the diary at the assigned times, and if 
the subject has been given permission by the Investigator to not return for Visit 2 to 
confim the return of the completed subject diary and answer any follow up questions. 

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9.5.3 
Pharmacokinetic Assessments 
9.5.3.1 
Lidocaine Concentration 
A blood sample will be collected to determine the concentration of lidocaine in the 
peripheral blood.  An initial blood sample will be collected at baseline prior to study 
drug administration, and a second blood sample will be collected 1 hour 
(± 10 minutes) after administration of the study drug (i.e., 1 hour after instillation) to 
determine plasma lidocaine concentrations.   
9.5.4 
Schedule of Assessments 
The schedule of assessments for the study is provided in Table 4. 
 

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Table 4. 
Schedule of Assessments 
 
Procedure 
Visit 1 
Clinic 
Screening 
Visit 1a 
Clinic 
Baseline and Drug 
Administration 
Home 
Assessment 
Optional
Visit 2 
Clinic 
Follow-up 
telephone 
checkk 
 
Time after study drug administration 
0 - 2 hrs 
> 2 hrs 
24 hrs 
48 - 72 hrs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  

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9.5.5 
Appropriateness of Measurements 
All clinical assessments are standard measurements commonly used in studies of 
IC/BPS. 
The safety assessments to be performed in this study (including hematology analyses, 
blood chemistry tests, urinalysis, and assessment of AEs) are standard evaluations to 
ensure subject safety. 
9.5.6 
Reporting of Serious Adverse Events, Pregnancy, and Other Events of Interest 
9.5.6.1 
Reporting of Serious Adverse Events 
All SAEs, regardless of their relationship to study drug, must be reported on a 
completed SAE form by email or fax as soon as possible to 
  
 but should be reported no later than 
24 hours from the time the investigator becomes aware of the SAE. 
Any death or any life-threatening event should be reported immediately by telephone 
to 
  The 
immediate report should be followed up within 1 business day by emailing or faxing 
the completed SAE form. 
SAEs, regardless of causality assessment, must be collected through the last visit and 
up to 72 hours after drug administration.  All SAEs must be followed to resolution or, 
if resolution is unlikely, to stabilization.  Any SAE judged by the investigator to be 
related to the study treatment should be reported to the sponsor regardless of the 
length of time that has passed since study completion. 
For urgent safety issues, please ensure all appropriate medical care is administered 
to the subject, and contact the appropriate study team member listed in the 
Investigator Study File. 

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It is very important that the SAE form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality. 
Any follow-up information received about SAEs should be forwarded within 
1 business day of its receipt.  If the follow-up information changes the investigator’s 
assessment of causality, this should also be noted on the follow-up SAE form. 
Preliminary SAE reports should be followed as soon as possible by detailed 
descriptions of additional information including copies of hospital case reports, 
autopsy reports, and other documents, if requested by the sponsor. 
The investigator must notify the IRB of the occurrence of the SAE, in writing, if 
required by their institution.  A copy of this communication must be forwarded to the 
sponsor or the contract research organization to be filed in the sponsor’s Trial Master 
File. 
9.5.6.2 
Reporting of Pregnancy 
Any pregnancy in which the estimated date of conception is either before the last visit 
or within 30 days of study drug administration must be reported to Urigen. 
If an adverse outcome of a pregnancy is suspected to be related to study drug 
exposure, this should be reported, regardless of the length of time that has passed 
since the exposure to study treatment. 
A congenital anomaly, death during the perinatal period, an induced abortion, or a 
spontaneous abortion are considered to be an SAE and should be reported in the same 
time frame and in the same format as all other SAEs (see Section 9.5.6.1, Reporting 
of Serious Adverse Events). 
Pregnancies or exposure to study drug through breastfeeding must be reported by fax 
or email as soon as possible but no later than 1 business day from the date the 
investigator becomes aware of the pregnancy.  The contact information for the 
reporting of pregnancies and exposure to study drug through breastfeeding is 
provided in the investigator study file.  The Pregnancy Report Form must be used for 
reporting pregnancies.  All pregnancies must be followed to outcome, whenever 
possible.  The outcome of the pregnancy must be reported as soon as possible but no 

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later than 1 business day from the date the investigator becomes aware of the 
outcome. 
9.5.6.3 
Reporting of Other Events of Interest 
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE, 
MISUSE, ABUSE, OR MEDICATION ERROR 
AEs associated with study drug overdose, misuse, abuse, and medication error refer 
to AEs associated with uses of the study drug outside of that specified by the 
protocol.  Overdose, misuse, abuse, and medication error are defined as follows:  
Overdose 
Accidental or intentional use of the study drug in an amount 
higher than the protocol-defined dose  (If applicable, define the 
study-specific criteria for overdose that should be applied when 
determining whether an overdose occurred.) 
Misuse 
Intentional and inappropriate use of study drug not in accordance 
with the protocol 
Abuse 
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects 
Medication error 
Any unintentional event that causes or leads to inappropriate 
study drug use or subject harm while the study drug is in the 
control of site personnel or the subject 
All AEs associated with an overdose should be captured in the Adverse Event CRF.  
Adverse events associated with overdose, misuse, abuse, or medication error should 
be reported using the procedures detailed in Section 9.5.6.1, Reporting of Serious 
Adverse Events even if the AEs do not meet serious criteria.  Drug abuse is always to 
be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE 
form and in an expedited manner; however, the AE should be noted as nonserious on 
the SAE form and in the Adverse Event CRF. 
9.5.6.4 
Breaking the Blind 

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In the case of a medical emergency where the appropriate treatment of the subject 
requires knowledge of the study treatment given, the investigator may request that the 
medical monitor break the blind for an individual subject as described in the Study 
Procedures Manual.  In all such cases, the AE necessitating the emergency blind 
break will be handled as an SAE in accordance with the procedures indicated above.  
Any broken code will be clearly justified and documented.   
9.5.6.5 
Regulatory Reporting of Adverse Events 
AEs will be reported by the sponsor or a third party acting on behalf of the sponsor to 
regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements. 
9.5.7 
Completion and Discontinuation of Subjects 
A subject may elect to discontinue the study at any time for any reason without 
prejudice.  All subjects who discontinue the study are to complete the study’s Visit 2 
procedures and the follow-up phone call indicated in the schedule of assessments 
(Table 4) whenever possible. 
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other 
necessary measures for the subject.  A subject who has ceased to return for visits will 
be followed up by mail, phone, or other means to gather information such as the 
reason for failure to return, the status of treatment compliance, the presence or 
absence of AEs, and clinical courses of signs and symptoms.  This information will 
be recorded in the CRF. 
Subjects who discontinue early from the study will be discontinued for one of these 
primary reasons: AE(s), lost to follow-up, catheter intolerance, inadequate therapeutic 
effect, withdrawal of consent, pregnancy, study terminated, or other (to be specified).  
In addition to the primary reason, the subject may indicate one or more secondary 
reasons for discontinuation. 

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9.6 
DATA QUALITY ASSURANCE 
9.6.1 
Monitoring 
The study will be monitored by designees of Urigen N.A., Inc. at all stages of study 
conduct, from inception to completion, in accordance with current GCP.  This 
monitoring will be in the form of site visits and other communication and will include 
review of original source documents and CRFs.  The monitor will notify the 
investigator prior to conducting any investigational site visit.  The frequency of these 
visits will depend upon the progress of the study, and will include monitoring to 
assess facilities and equipment, recruiting, record-keeping, protocol adherence, data 
collection, AE reporting, and other factors. 
9.6.2 
Investigator’s Responsibility 
The investigator will retain all study documents required to be maintained (1) for at 
least 2 years after the date a marketing application is approved for the drug for the 
indication for which it is being investigated, or (2) if no application is to be filed or if 
the application is not approved for such indication, until 2 years after the investigation 
is discontinued and the FDA is notified. 
9.7 
STATISTICAL METHODS 
All statistical analyses, except the interim analysis, will be performed after each study 
is completed, the database is locked and released, and randomization codes have been 
released.  Statistical analyses will be performed using SAS or other validated 
statistical software as required.  Details of the statistical analyses will be included in a 
separate statistical analysis plan (SAP). 
9.7.1 
Statistical and Analytical Plans 
The statistical analyses of study data are described in this section.  All hypothesis 
tests will be 2-sided and will use an alpha level of 0.05.  Additional details of the 
analytical plan will be provided in the SAP, which will be finalized before database 
lock. 
 

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9.7.1.1 
Primary Endpoint 
The primary endpoint for the investigative phase of the study is the sum of bladder 
pain intensity differences from baseline to 12 hours (SPID-12) after administration of 
URG101 compared with the SPID-12 after administration of lidocaine alone, heparin 
alone, and placebo as determined by using the 11-point NRS for bladder pain.   
9.7.1.2 
Secondary Endpoints 
The secondary endpoints of the study are: 
1. The sum of bladder pain intensity differences from baseline to 24 hours  
(SPID-24) after administration  of URG101 compared with lidocaine alone, 
heparin alone, and placebo as determined by using the 11-point bladder pain NRS 
2. The sum of urgency intensity differences from baseline to 12 and 24 hours 
(SUID-12 and SUID-24) after administration of URG101 compared with 
lidocaine alone, heparin alone, and placebo using the 11-point urgency NRS 
3. Absolute and percentage change in bladder pain from baseline to 1, 12, and 
24 hours after administration of URG101 compared with lidocaine alone, heparin 
alone, and placebo as determined by using the 11-point NRS for bladder pain 
4. Absolute and percentage change in urgency intensity from baseline to 1, 12, and 
24 hours after administration of URG101 compared with lidocaine alone, heparin 
alone, and placebo using the 11-point urgency NRS 
5. Patient Global Assessment:  Comparison of the percentage of subjects achieving 
≥ 50% improvement in the PORIS questionnaire, Question 3, from baseline to 
1 hour, 12 hours and 24 hours after administration of URG101, lidocaine alone, 
heparin alone, and placebo 
6. Time to first administration of rescue medication for pain after treatment with 
URG101 compared to alkalinized Lidocaine Hydrochloride Injection (20 mg/mL) 
alone, alkalinized Heparin Sodium Injection (5,000 USPU/mL) alone, and 
placebo 
) 
7. To evaluate the safety and tolerability of intravesical administration of URG101 
9.7.1.3 
Safety Endpoints 

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The safety endpoints of the study are: 
1. Change from baseline in INR at 1 hour after study drug administration. 
2. Change from baseline in aPTT at 1 hour after study drug administration. 
3. Adverse events 
9.7.1.4 
Pharmacokinetic Endpoints 
Samples for plasma lidocaine concentrations will be collected at baseline and at 
1 hour after study drug administration.  The pharmacokinetic endpoints of the study 
are: 
1. Comparison of plasma lidocaine concentrations at 1 hour post treatment with 
absolute and percentage change in pain using the 11-point bladder pain NRS, at 1, 
12 and 24 hours after administration of URG101, lidocaine alone, heparin alone, 
and placebo. 
2. Comparison of plasma lidocaine concentrations at 1 hour post treatment with 
absolute and percentage change in urgency using the 11-point urgency NRS, at 1, 
12 and 24 hours after administration of URG101, lidocaine alone, heparin alone, 
and placebo. 
3. Comparison of plasma lidocaine concentrations at 1 hour post treatment with the 
sum of bladder pain intensity differences from baseline to 12 and 24 hours (SPID-
12 and SPID-24) after administration of URG101 compared with lidocaine alone, 
heparin alone, and placebo as determined by using the 11-point bladder pain NRS. 
4. Comparison of plasma lidocaine concentrations at 1 hour post treatment with the 
sum of urgency intensity differences from baseline to 12 and 24 hours (SUID-12 
and SUID-24) after administration of URG101 compared with lidocaine alone, 
heparin alone, and placebo as determined by using the 11-point urgency NRS. 
 
9.7.1.5 
Definitions of Analysis Sets 
The safety analysis set will include all subjects who receive at least one dose of study 
drug and have at least one post dose safety assessment. 
The intent-to-treat set will include all randomized subjects who receive study drug. 

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The per protocol set will include all subjects who sufficiently comply with the 
protocol.  Details of the evaluability criteria will be determined before database lock 
and treatment unblinding. 
The pharmacokinetic (PK) set will include all subjects who receive at least one dose 
of study drug and have sufficient data to calculate PK parameters. 
9.7.1.6 
Subject Disposition 
Descriptive statistics will be utilized.  By-subject listings and summary tables will be 
provided. 
9.7.1.7 
Demographic and Baseline Characteristics 
Descriptive statistics will be utilized.  By-subject listings and summary tables will be 
provided. 
9.7.1.8 
Prior and Concomitant Therapy 
All investigator terms for medications recorded in the CRF will be coded to an  
11-digit code using the World Health Organization Drug Dictionary.  The number 
(percentage) of subjects who took prior and concomitant medications will be 
summarized on the safety analysis set by treatment group, Anatomical Therapeutic 
Chemical class, and World Health Organization Drug Dictionary preferred term.  
Prior medications will be defined as medications that stopped before the dose of study 
drug.  Concomitant medications will be defined as medications that (1) started before 
the dose of study drug and were continuing at the time of the dose of study drug, or 
(2) started on or after the date and time of the dose of study drug up to 72 hours after 
the subject’s last dose.  All medications will be presented in subject data listings. 
9.7.1.9 
Safety Analyses 
All safety analyses will be performed on the safety analysis set.  Safety data, 
presented by treatment group, will be summarized on an “as-treated” basis using 
descriptive statistics (e.g., n, mean, standard deviation, median, minimum, maximum 
for continuous variables; n [%] for categorical variables).  Safety variables will 
include physical examinations, treatment-emergent adverse events (TEAEs), clinical 

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laboratory parameters, vital signs.  Study Day 1 for all safety analyses will be defined 
as the date of the first dose of study drug. 
9.7.1.10 
Extent of Exposure 
By-subject listings and summary tables will be provided. 
9.7.1.11 
Adverse Events 
The AE verbatim descriptions (investigator terms from the CRF) will be classified 
into standardized medical terminology using the Medical Dictionary for Regulatory 
Activities (MedDRA).  Adverse events will be coded to the MedDRA lower level 
term closest to the verbatim term.  The linked MedDRA preferred term and primary 
system organ class (SOC) are also captured in the database. 
A TEAE is defined as an AE that emerges during treatment, having been absent at 
baseline and:  
● Reemerges during treatment, having been present before treatment (baseline) but 
stopped before treatment,  
or  
● Worsens in severity during treatment relative to the pretreatment state, when the 
AE is continuous. 
Adverse events will be summarized and listed for the safety analysis set.  Only those 
AEs that are treatment-emergent will be included in summary tables.  Summary 
tables will be by treatment group and overall.  The incidence (%) will be determined 
by calculating the number of subjects with at least 1 event and the percentage of 
subjects with TEAEs by SOC and by preferred term.  All AEs, treatment emergent or 
otherwise, will be presented in subject data listings. 
The incidence of TEAEs will be reported as the number (percentage) of subjects with 
TEAEs by SOC and preferred term.  A subject will be counted only once within a 
SOC and preferred term, even if the subject experiences more than one TEAE within 
a specific SOC and preferred term.  The number (percentage) of subjects with TEAEs 
will also be summarized by maximum severity (mild, moderate, or severe). 

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The number (percentage) of subjects with TEAEs will also be summarized by 
relationship to study drug (possibly related, probably related, and not related). 
The number (percentage) of subjects with treatment-related TEAEs will be 
summarized by SOC and preferred term.  Treatment-related TEAEs include those 
AEs considered by the investigator to be possibly or probably related to study 
treatment.  The number (percentage) of subjects with treatment-related TEAEs will 
also be summarized by maximum severity (mild, moderate, or severe). 
A subject data listing of all AEs leading to death will be provided.  Additionally, a 
subject data listing of all AEs leading to discontinuation from study drug will be 
provided. 
The number (percentage) of subjects with SAEs will be summarized by MedDRA 
SOC and preferred term for each treatment group.  A subject data listing of all SAEs 
will be provided. 
9.7.1.12 
Laboratory Values 
Summary statistics for changes from baseline and the incidence of treatment 
emergent abnormal values in coagulation measurements at 1 hour post drug 
administration will be provided.  
9.7.1.13 
Physical Examination, Pelvic Examination, and Vital Signs 
By-subject listings will be provided for physical examination and pelvic examination.  
Summary statistics for change from baseline and incidence of potentially clinically 
significant results in vital signs will be provided. 
9.7.1.14 
Efficacy Analyses 
All SPID endpoints will be calculated using Simpson’s trapezoidal rule.    SPID will 
be calculated as follows, where n is the total number of time points within the time 
period with non-missing imputed PID values:  

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If multiple scores are recorded at the same date and time, the most conservative PI 
scores (highest) will be used. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary Efficacy Analyses 
The primary efficacy analyses will be performed on the intent-to-treat set.  As a 
sensitivity analysis, the primary efficacy analysis will also be performed on the PP 
set.  Primary efficacy analyses will also be conducted on the per protocol set, which 
will include all subjects in the ITT set who sufficiently comply with the protocol. 
The primary efficacy endpoint will be compared between the URG101 group and the 
lidocaine, heparin, and placebo groups using an analysis of covariance model 
including factors for site and randomized treatment assignment; baseline pain will be 
added to the model as a covariate.  Pairwise comparisons of least squares means 
between URG 101 and the two active treatment arms, as well as the placebo arm, will 
be performed.  The probability values will be derived using the contrast statement 
from the model.  If the p-value associated with these comparisons is < 0.05 in favor of 
URG101, the primary aim of the trial will be confirmed. 

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Sites with small numbers of patients enrolled may be pooled for analysis. The method 
used to determine pooling will be specified in the statistical analysis plan and any 
pooling will be finalized and documented prior to database lock and unblinding. 
Secondary Efficacy Analyses 
Analyses of the secondary endpoints relating to changes in the pain and urgency NRS 
will be performed using analysis of covariance models similar to those used for the 
primary efficacy endpoint.  The ITT set will be used.  Nonparametric methodology in 
exploratory analyses may be used to supplement the parametric analyses. 
Treatment differences based on the PORIS questionnaire, Question 3, will be 
analyzed by pairwise Cochran-Mantel-Haenszel Tests based on ≥ 50% improvement 
of symptoms. 
Time to first pain medication use will be analyzed using Kaplan-Meier methodolgy. 
Log-rank tests will be used to compare the treament groups. 
9.7.1.15 
Safety Analyses 
All safety analyses will be performed on the safety analysis set.  
The change in INR and aPTT from baseline at 1 hour after study drug administration 
will be compared using descriptive statistics for the various treatment groups. 
9.7.1.16 
Pharmacokinetic Analyses 
Samples collected at baseline will be analyzed to determine if plasma lidocaine 
concentrations are detected prior to study drug administration.  A comparison of peak 
pain and urgency as measured by 11–point NRSs to plasma lidocaine levels at 1 hour 
after study drug administration will be made for the PK set. 

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9.7.2 
Handling of Missing Data 
9.7.2.1 
11-Point Bladder Pain and Urgency Scales 
For the 11-point numerical data, if subjects are administered any rescue pain 
medication, the pain score recorded immediately prior to receiving the rescue pain 
medication will be carried forward for 4 hours.  Data for subjects who withdraw will 
be imputed using the baseline observation carried forward method. The imputed 
dataset will be used to derive the SPID score. 
9.7.2.2 
24-Hour Symptom and Urination Diaries 
During the 24 hours after treatment, subjects are required to fill in their symptom 
diaries only while they are awake.  Missing data occurring will be imputed using 
LOCF methodology.  
If the number of missing data points in the 12-hour period after treatment 
administration is 6 or greater, then the subject is considered a major protocol violator 
and his or her data are excluded from the per protocol analysis.  If the number of 
missing data points in the first 6-hour period following treatment administration is 3 
or greater, then the subject is considered a major protocol violator and the subject’s 
data are excluded from the per protocol analysis. 
9.7.3 
Determination of Sample Size 
Sample size estimates were based on a pilot trial of heparin-lidocaine versus lidocaine 
alone and a prior two-arm study of URG101 versus placebo.  The primary efficacy 
endpoint is SPID-12.  The sample size calculation is based on a one-way analysis of 
variance, comparing SPID-12 from four treatment groups.  A target sample size of 
approximately 180 subjects allocated among the four treatment groups..  This sample 
size  will be  sufficient to achieve 90% power to detect a difference between the 
URG101 and components groups assuming a treatment effect size of 0.60.  Once 50% 
of the subjects (90) have been enrolled, an unblinded interim assessment will be 
performed.  The number of subjects for the study may be increased, based on the 
recommendation of the IDMC.  Overall, a maximum of 300 subjects will be enrolled 
in Study URG101-105. 

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9.7.4 
Interim Analysis 
Re-estimation of the Sample Size  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
The two possible types of interactions are defined as being either quantitative or 
qualitative.  A quantitative interaction exists where the relationship of the treatment 
groups are consistent across the sites, moving in the same direction, but at different 
magnitudes.  A qualitative interaction is much more serious and exists where one 
treatment group shows a positive effect of the study medication at certain sites, and 
the other sites show a negative effect of the same study treatment.  In most clinical 
studies, if an interaction is present between site and treatment, there will be a 
quantitative interaction where the effect size at some sites is greater than at other 

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sites, but all sites have a positive effect size for the active treatment.  Qualitative 
interactions require additional investigation because of the mixed signals on the effect 
of a study treatment by study site. 
 
In order to minimize the impact of a small sample effect, for the purposes of the 
interim analysis, the smaller study sites will be merged to form a pseudo-site.  In this 
way a possible aberration in outcomes that might arise from small samples due to 
over or under representation of patients with characteristics that may either increase 
or decrease study results will have a diminished impact on the sample size 
recalculation.         
 
 
  
  
 
 
 
  
 
 
 
 
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=
1
1
α
α
 
 
 
)
0
Z
 
 
(
Z
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 

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σ
   
 
 
 
 
 
 
 
 
 
 
 
z
ˆσ
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
=
i
W
  
 
 
 
 
: 

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Version
 
 
 
W
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 

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The IDMC will make one of following non-binding recommendations to the sponsor: 
• Continue enrolling patients to the pre-specified target sample size 
• Continue enrolling patients to a sample size that exceeds the pre-specified target 
sample size but ≤ the maximum sample size 
• Stop enrolling patients based on futility 
The instructions from the IDMC for the sample size adjustment will be described in 
detail in the IDMC Charter.  An alpha level adjustment will not be necessary for the 

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procedure described below if the conditional power for the primary endpoint is 
> 39%.    
9.7.5 
Other Statistical and Analytical Issues 
Not applicable. 
9.7.6 
Procedure for Revising the Statistical Analysis Plan 
If the SAP requires revision after finalization, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details 
of the revision will be documented and described in the clinical study report. 

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10.0 
ADMINISTRATIVE PROCEDURES AND INSTRUCTIONS 
10.1 
CHANGES TO THE PROTOCOL 
Any change to the protocol requires a written protocol amendment or administrative 
change that must be approved by the investigator, IRB, and Urigen before 
implementation.  Amendments specifically affecting the safety of subjects, the scope 
of the investigation, or the scientific quality of the study require submission to health 
or regulatory authorities as well as additional approval by the applicable IRBs.  These 
requirements should in no way prevent any immediate action from being taken by the 
investigator, in the interest of preserving the safety of all subjects included in the 
study.  If the investigator determines that an immediate change to or deviation from 
the protocol is necessary for safety reasons to eliminate an immediate hazard to the 
subjects, Urigen and the IRB for the site must be notified immediately.  The sponsor 
must notify the health or regulatory authority as required per local regulations. 
Protocol amendments that affect only administrative aspects of the study may not 
require submission to health or regulatory authority or the IRB, but the health or 
regulatory authority and IRB should be kept informed of such changes as required by 
local regulations.  In these cases, the sponsor may be required to send a letter to the 
IRB detailing such changes. 
10.2 
ADHERENCE TO THE PROTOCOL 
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5). 
10.3 
MONITORING PROCEDURES 
The sponsor’s contract research organization or clinical research associate (CRA) will 
maintain contact with the investigator and designated staff by telephone, letter, or 
email between study visits.  Monitoring visits to each site will be conducted by the 
assigned CRA as described in the monitoring plan.  The investigator, or if regionally 
required, the head of the medical institution will allow the CRA to inspect the 
clinical, laboratory, and pharmacy facilities to assure compliance with GCP and local 
regulatory requirements.  The CRFs and subject’s corresponding original medical 
records (source documents) are to be fully available for review by the sponsor’s 

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representatives at regular intervals.  These reviews verify adherence to study protocol 
and data accuracy in accordance with local regulations.  All records at the site are 
subject to inspection by the local auditing agency and IRB or IEC review. 
In accordance with ICH E6, Section 1.52, source documents include, but are not 
limited to the following: 
• 
Clinic, office, or hospital charts 
• 
Copies or transcribed health care provider notes which have been certified for 
accuracy after production 
• 
Recorded data from automated instruments such as IxRS, x-rays, and other 
imaging reports (e.g., sonograms, computed tomography scans, magnetic 
resonance images, radioactive images, ECGs, rhythm strips, polysomnographs, 
pulmonary function tests), regardless of how these images are stored, including 
microfiche and photographic negatives 
• 
Pain, quality-of-life, or medical history questionnaires completed by subjects 
• 
Records of telephone contacts 
• 
Diaries or evaluation checklists 
• 
Drug distribution and accountability logs maintained in pharmacies or by research 
personnel 
• 
Laboratory results and other laboratory test outputs (e.g., urine pregnancy test 
result documentation and urine dip-sticks) 
• 
Correspondence regarding a study subject’s treatment between physicians or 
memoranda sent to the IRBs 
• 
CRF components (e.g., questionnaires) that are completed directly by subjects and 
serve as their own source 

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10.4 
RECORDING OF DATA 
A CRF is required and must be completed for each subject by qualified and 
authorized personnel.  All data on the CRF must reflect the corresponding source 
document, except when a section of the CRF itself is used as the source document.  
Any correction to entries made on the CRF must be documented in a valid audit trail 
where the correction is dated, the individual making the correction is identified, the 
reason for the change is stated, and the original data are not obscured.  Only data 
required by the protocol for the purposes of the study should be collected. 
The investigator must sign each CRF. 
10.5 
IDENTIFICATION OF SOURCE DATA 
All data to be recorded on the CRF must reflect the corresponding source documents. 
10.6 
RETENTION OF RECORDS 
The circumstances of completion or termination of the study notwithstanding, the 
investigator is responsible for retaining all study documents, including but not limited 
to the protocol, copies of CRFs, the Investigator's Brochure, and regulatory agency 
registration documents (e.g., Form FDA 1572, ICFs, and IRB correspondence).  The 
site should plan to retain study documents for the length of time agreed upon in the 
study contract. 
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact Urigen, allowing Urigen the 
option of permanently retaining the study records. 
10.7 
AUDITING PROCEDURES AND INSPECTION 
In addition to the routine monitoring procedures, the Urigen Clinical Quality 
Assurance department conducts audits of clinical research activities in accordance 
with Urigen’s procedures to evaluate compliance with the principles of ICH GCP and 
all applicable local regulations.  If a government regulatory authority requests an 
inspection during the study or after its completion, the investigator must inform 
Urigen immediately. 

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10.8 
REPORTING AND PUBLICATION OF RESULTS 
A clinical study report will be finalized within 1 year of the end of data collection. 
All manuscripts, abstracts, or other modes of presentation arising from the results of 
the study must be reviewed and approved in writing by Urigen in advance of 
submission pursuant to the terms and conditions set forth in the executed Clinical 
Study Agreement between Urigen and the institution or investigator.  The review is 
aimed at protecting Urigen's proprietary information existing either at the date of the 
commencement of the study or generated during the study. 
The detailed obligations regarding the publication of any data, material results, or 
other information, generated or created in relation to the study, will be set out in the 
agreement between the investigator and Urigen, as appropriate. 
10.9 
DISCLOSURE AND CONFIDENTIALITY 
The contents of this protocol and any amendments and results obtained during the 
study should be kept confidential by the investigator, the investigator’s staff, and the 
IRB and will not be disclosed in whole or in part to others, or used for any purpose 
other than reviewing or performing the study, without the written consent of Urigen.  
No data collected as part of this study will be used in any written work, including 
publications, without the written consent of Urigen.  These obligations of 
confidentiality and nonuse will in no way diminish such obligations as set forth in 
either the Confidentiality Agreement or Clinical Study Agreement executed between 
Urigen and the institution or investigator. 
All persons assisting in the performance of this study must be bound by the 
obligations of confidentiality and nonuse set forth in either the Confidentiality 
Agreement or Clinical Study Agreement executed between the institution or 
investigator and Urigen. 
10.10 
DISCONTINUATION OF STUDY 
Urigen reserves the right to discontinue the study for medical reasons or any other 
reason at any time.  If a study is prematurely terminated or suspended, Urigen will 
promptly inform the investigators or institutions and the investigator will inform the 

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regulatory authorities of the termination or suspension and the reason(s) for the 
termination or suspension.  The IRB will also be informed promptly and provided the 
reason(s) for the termination or suspension by the investigator or institution, as 
specified by the applicable regulatory requirement(s). 
The investigator reserves the right to discontinue the study if his or her judgment so 
dictates.  If the investigator terminates or suspends a study without prior agreement of 
Urigen, the investigator should inform the institution where applicable, and the 
investigator or institution should promptly inform Urigen and the IRB and provide 
Urigen and the IRB with a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above. 

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11.0 
REFERENCE LIST 
1. 
Nickel JC, Barkin J, Forrest J, Mosbaugh PG, Hernandez-Graulau J, Kaufman D, 
Lloyd K, Evans RJ, Parsons CL, Atkinson LE; Elmiron Study Group. 
Randomized, double-blind, dose-ranging study of pentosan polysulfate sodium 
for interstitial cystitis. Urology. 2005 Apr;65(4):654-8. 
2. 
Mayer R, Propert KJ, Peters KM, Payne CK, Zhang Y, Burks D, Culkin DJ, 
Diokno A, Hanno P, Landis JR, Madigan R, Messing EM, Nickel JC, Sant GR, 
Warren J, Wein AJ, Kusek JW, Nyberg LM, Foster HE, Interstitial Cystitis 
Clinical Trials Group. A randomized controlled trial of intravesical bacillus 
calmette-guerin for treatment refractory interstitial cystitis. J Urol. 2005 
Apr;173(4):1186-91. 
3. 
Parsons CL and Tatsis V. Prevalence of interstitial cystitis in young women. 
Urology, 2004. 64(5):  866-70. 
4. 
Jones CA and Nyberg L. Epidemiology of interstitial cystitis. Urology, 1997. 
49(5A Suppl):   2-9. 
5. 
Berry SH, Elliott MN, Suttorp M, Bogart LM, Stoto MA, Eggers P, Nyberg L, 
Clemens JQ. Prevalence of symptoms of bladder pain syndrome/interstitial 
cystitis among adult females in the United States. J Urol. 2011;186(2):540-544. 
6. 
Rosenberg MT, Page S, Hazzard MA.  Prevalence of interstitial cystitis 
symptoms in women: a population based study in the primary care office. J Urol. 
2005 Dec;174(6):2231-2234 
7. 
Parsons CL, Zupkas P, Parsons JK. Intravesical potassium sensitivity in patients 
with interstitial cystitis and urethral syndrome.Urology. 2001 Mar;57(3):428-32; 
discussion 432-3. 
8. 
Driscoll A, Teichman JM. How do patients with interstitial cystitis present? J 
Urol. 2001 Dec;166(6):2118-20RE. 

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9. 
Sant GR,, Propert KJ, Hanno PM, Burks D, Culkin D, Diokno AC, Hardy C, 
Landis JR, Mayer R, Madigan R, Messing EM, Peters K, Theoharides TC, 
Warren J, Wein AJ, Steers W, Kusek JW, Nyberg LM.  A pilot clinical trial of 
oral pentosan polysulfate and oral hydroxyzine in patients with interstitial 
cystitis.Interstitial Cystitis Clinical Trials Group.J Urol. 2003 Sep;170(3):810-5. 
10. DietschyJM, Sallee VL, and Wilson F. Unstirred water layers and absorption 
across the intestinal mucosa. Gastroenterology, 1971. 61(6):  932-4. 
11. Perez-Marrero R, Emerson LE, Maharajh DO, Juma S. Prolongation of response 
to DMSO by heparin maintenance. Urology. 1993 Jan;41(1 Suppl):64-6. 
12. Parsons CL. Evidence-based strategies for recognizing and managing IC. 
Contemporary Urology. 2003 Feb. 22-35.  
13. Parsons CL. Successful downregulation of bladder sensory nerves with 
combination of heparin and alkalinized lidocaine in patients with interstitial 
cystitis. Urology. 2005 Jan;65(1):45-8.  
14. Chancellor MB, Yoshimura N. Treatment of interstitial cystitis. Urology. 2004 
Mar;63(3 Suppl 1):85-92.  
15. Nickel JC, Moldwin R, Lee S, Davis EL, Henry RA, and Wyllie MG. 
Intravesical alkalinized lidocaine (PSD597) offers sustained relief from 
symptoms of interstitial cystitis and painful bladder syndrome. BJU Int, 2009. 
103(7): p. 910-8. 
16. Ratner, V.  Current controversies that adversely affect interstitial cystitis 
patients. Urology 2001 Jun;57(6 Suppl 1):89-94. 
17. Henry R, Patterson L, Avery N, Tanzola R, Tod D, Hunter D, Nickel JC, and 
Morales A. Absorption of alkalized intravesical lidocaine in normal and inflamed 
bladders: a simple method for improving bladder anesthesia. J Urol, 2001. 165(6 
Pt 1): p. 1900-3. 
18. CL Parsons, Housley T, Schmidt JD, and Lebow D. Treatment of interstitial 
cystitis with intravesical heparin. Br J Urol, 1994. 73(5): p. 504-7. 

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19. CL Parsons, Benson G, Childs SJ, Hanno P, Sant GR, and Webster G. A 
quantitatively controlled method to study prospectively interstitial cystitis and 
demonstrate the efficacy of pentosanpolysulfate. J Urol, 1993. 150(3): p. 845-8. 
20. Parsons CL, Zupkas P, Proctor J, Koziol J, Franklin A, Giesing D, Davis E, 
Lakin CM, Kahn BS, and Garner WJ. Alkalinized lidocaine and heparin provide 
immediate relief of pain and urgency in patients with interstitial cystitis. J Sex 
Med 2012;9:207–212. 
21. Parsons CL. The role of a leaky epithelium and potassium in the generation of 
bladder symptoms in interstitial cystitis/overactive bladder, urethral syndrome, 
prostatitis 
and 
gynaecological 
chronic 
pelvic 
pain. 
BJU 
Int. 
2011 
Feb;107(3):370-5. 
22. Mehta CR, and Pocock SJ. Adaptive increase in sample size when interim results 
are promising: a practical guide with examples. Stat Med. 2011 Dec 10; 30(28): 
3267-84. 
23. Chen YH, DeMets DL, and Lan KK. Increasing the sample size when the 
unblinded interim result is promising. Stat Med. 2004 Apr 15;23(7):1023-28. 
24. Fleiss JL. The statistical basis of meta-analysis. Stat Methods Med Res. 1993; 
2(2):121-45. 

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12.0 
APPENDICES 
Appendix 1 
Pelvic Pain and Urgency/Frequency Questionnaire 
Appendix 2 
Guideline Script for Pelvic Pain and Urgency/Frequency 
Questionnaire 
Appendix 3 
11-Point Pain and Urgency Scales 
Appendix 4 
Guideline Script for 11-Point Pain and Urgency Scales 
Appendix 5 
Patient Overall Rating of Improvement of Symptoms Questionnaire 
Appendix 6 
Guideline Script for Patient Overall Rating of Improvement of 
Symptoms Questionnaire 
Appendix 7 
Protocol Signature Pages 
 

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Appendix 1: Pelvic Pain and Urgency/Frequency Questionnaire  
PELVIC PAIN and URGENCY/FREQUENCY SCALE 
Please circle the answer that best describes how you feel for each question. 
 
 
0 
1 
2 
3 
4 
Symptom 
Score 
Bother 
Score 
1 How many times do you go to the 
bathroom during the day? 
3-6 
7-10 
11-14 
15-19 20+ 
 
 
2 a. How many times do you go to 
the bathroom at night? 
0 
1 
2 
3 
4+ 
 
 
 
b. If you get up at night to go to 
the bathroom, does it bother you? 
Never 
Bothers Occasionally Usually 
Always  
 
 
3 a. Do you now or have you ever 
had pain or symptoms during or 
after sexual intercourse? 
Never 
Occasionally Usually 
Always  
 
 
 
b. Has pain or urgency ever made 
you avoid sexual intercourse? 
Never 
Occasionally Usually 
Always  
 
 
4 Do you have pain associated with 
your bladder or in your pelvis 
(vagina, labia, lower abdomen, 
urethra, 
perineum, 
testes, 
or 
scrotum)? 
Never 
Occasionally Usually 
Always  
 
 
5 a. If you have pain, is it usually 
 
Mild 
Moderate Severe  
 
 
 
b. Does your pain bother you? 
Never 
Occasionally Usually 
Always  
 
 
6 Do you still have urgency after 
going to the bathroom? 
Never 
Occasionally Usually 
Always  
 
 
7 a. If you have urgency, is it 
usually 
 
Mild 
Moderate Severe  
 
 
 
b. Does your urgency bother you? Never 
Occasionally Usually 
Always  
 
 
8 Are you sexually active?  
  Yes____        No____    
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
SYMPTOM SCORE  = 
(Add scores from top of column: 1, 2a, 3a, 4, 5a, 6, 7a)  
 
 
BOTHER SCORE  = 
(Add scores from top of column: 2b, 3b, 5b, 7b)  
 
TOTAL SCORE (Symptom Score + Bother Score)  =  
 

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Appendix 2: Guideline Script for Pelvic Pain and Urgency/Frequency Questionnaire 
Guideline script:  
 
   
   
 
 
 
   
  
  
 
 
 
…………………… 
 
Once the subject has answered all questions the coordinator will enter the scores (0, 1, 2, 3, 
or 4 as indicated at the top of the page) to the right, and then calculate the total 
SYMPTOM SCORE, total BOTHER SCORE, and TOTAL SCORE (Symptom score + 
Bother Score).  

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Appendix 3: 11-Point Bladder Pain and Urgency Scales 
1. Please circle the number that best describes the PAIN ASSOCIATED WITH YOUR BLADDER you are 
EXPERIENCING NOW. 
 
 
 
BLADDER PAIN  
 
 
 
 
                                 none 
 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
2. Please circle the number that best describes the URGENCY or NEED TO URINATE that you are 
EXPERIENCING NOW. 
 
 
 
URINARY URGENCY 
 
 
 
                                 none 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
worst
ever 
worst 
ever 

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Appendix 4: Guideline Script for 11-Point Bladder Pain and Urgency Scales  
 
   
 
    
 
   
  
 
   
  
 

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Appendix 5: PORIS Questionnaire 
PATIENT OVERALL RATING OF IMPROVEMENT OF SYMPTOMS 
Please check the category that BEST describes your condition NOW in COMPARISON to 
your condition BEFORE you started study medication. 
1. 
Please check the category that best describes the OVERALL CHANGE in PAIN 
associated with your pelvic/bladder pain now compared to before receiving study 
medication. (Check one box) 
[  ] 
Worse 
[  ] 
No better (0% improvement) 
[  ] 
Slightly improved (25% improvement) 
[  ] 
Moderately improved (50% improvement) 
[  ] 
Greatly improved (75% improvement) 
[  ] 
Symptoms gone (100% improvement) 
2. 
Please check the category below that best describes the OVERALL CHANGE in 
URGENCY to urinate associated with your bladder now compared to before receiving the 
study medication. (Check one box) 
[  ] 
Worse 
[  ] 
No better (0% improvement) 
[  ] 
Slightly improved (25% improvement) 
[  ] 
Moderately improved (50% improvement) 
[  ] 
Greatly improved (75% improvement) 
[  ] 
Symptoms gone (100% improvement) 
3. 
Considering your response to items 1 and 2, please check the category below that best 
describes the OVERALL CHANGE in your problem COMPARED TO BEFORE YOU 
RECEIVED the study medication. (Check one box) 
[  ] 
Worse 
[  ] 
No better (0% improvement) 
[  ] 
Slightly improved (25% improvement) 
[  ] 
Moderately improved (50% improvement) 
[  ] 
Greatly improved (75% improvement) 
[  ] 
Symptoms gone (100% improvement) 

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Clinical Protocol  
Protocol:  URG101-105 (ENGAGE-24) 
 
 
Version 5.0, 18 April 2017 
Page 88 
Appendix 6: Guideline Script for PORIS Questionnaire  
 
  
 
 
 
 
  
  
 
 
 

CONFIDENTIAL  
Urigen N.A., Inc. 
 
 
Clinical Protocol  
Protocol:  URG101-105 (ENGAGE-24) 
 
 
Version 5.0, 18 April 2017 
Page 89 
Appendix 7: Protocol Signature Pages 
Protocol Signature Page 
 
 
Study Protocol Title: 
A Phase 2a, Randomized, Double-Blind, Placebo-Controlled 
Multi-Center Single Dose Study to Evaluate the Safety and 
Effectiveness of URG101 Compared with the Individual 
Components Lidocaine and Heparin in Subjects with 
Interstitial 
Cystitis/Bladder 
Pain 
Syndrome 
(Protocol 
URG101-105, the ENGAGE-24 Study) 
 
 
Investigational Product: 
URG101 (Alkalinized lidocaine-heparin) 
 
SIGNATURES 
 
 
 
:  Project Manager 
 
 
 
 
 
  
 
 
Date 
 
:  Medical Monitor 
 
 
 
 
 
 
 
 
Date 
 
:  Statistician 
 
 
 
 
 
 
 
 
 
Urigen N.A., Inc. 
 
 
 
Date 
 
 
 
 
Date 
 

CONFIDENTIAL  
Urigen N.A., Inc. 
 
 
Clinical Protocol  
Protocol:  URG101-105 (ENGAGE-24) 
 
 
Version 5.0, 18 April 2017 
Page 90 
 
PI Signature Page 
 
 
Study Protocol Title: 
A Phase 2a, Randomized, Double-Blind, Placebo-Controlled 
Multi-Center Single Dose Study to Evaluate the Safety and 
Effectiveness of URG101 Compared with the Individual 
Components Lidocaine and Heparin in Subjects with 
Interstitial Cystitis/Bladder Pain Syndrome  (Protocol 
URG101-105, the ENGAGE-24 Study) 
 
 
Investigational Product: 
URG101 (Alkalinized lidocaine-heparin) 
 
I have read this protocol and agree to conduct this trial in accordance with all stipulations of the 
protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use and all applicable local Good 
Clinical Practice guidelines, including the Declaration of Helsinki. 
I have read the attached protocol and agree that it contains all the necessary details for 
performing the study. 
I will provide copies of the protocol and of the additional information on the test article, which 
was furnished to me by the sponsor, to all members of the study team.  I will discuss the material 
with them to ensure they are fully informed regarding the test article and the conduct of the 
study. 
Once the protocol has been approved by the institutional review board (IRB) or ethics 
committee, I will not modify this protocol without obtaining the prior approval of the sponsor 
and of the IRB or ethics committee.  If I would like the protocol or informed consent form 
modified, I will first submit the proposed modifications to the sponsor for review and, if approved, 
to the IRB or ethics committee before any modifications are implemented.   
<Name of institution> 
Medical Institution 
 
<Name, degree(s)> 
  
  
Investigator 
 Signature 
 Date