Conditions: Interstitial Cystitis Bladder Pain Syndrome
Keywords: Bladder Intravesical Injection Interstitial Cystitis
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 33
Healthy volunteers: no

Brief summary:
This study is designed randomized, double-blind, placebo-controlled trial in Interstitial Cystitis/Bladder Pain Syndrome patients.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: SI-722 intervention 2: Placebo
Intervention descriptions: intervention 1: SI-722 will be intravesically instilled. intervention 2: Placebo will be intravesically instilled.

Protocol document:
Prot_SAP_000.pdf: 
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Clinical Study Protocol 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled, Single 
Ascending Dose Study to Evaluate the Pharmacokinetics, 
Safety, and Tolerability of SI-722 Intravesical Instillation 
in Interstitial Cystitis/Bladder Pain Syndrome Subjects 
Protocol Number: 
722/1121 
Study Phase: 
Phase 1/2 
Investigational Product: 
SI-722 
IND Number: 
138170 
Sponsor: 
Seikagaku Corporation 
6-1, Marunouchi 1-chome 
Chiyoda-ku, Tokyo 100-0005, Japan 
Date of Protocol: 
July 17, 2020 
Version Number: 
4.0 
 
 
 
This document contains confidential information of Seikagaku Corporation. 
Do not copy or distribute without written permission from the Sponsor. 
CONFIDENTIAL 
 
 






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Declaration of the Investigator 
Title: A Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Study 
to Evaluate the Pharmacokinetics, Safety and Tolerability of SI-722 Intravesical 
Instillation in Interstitial Cystitis/Bladder Pain Syndrome Subjects 
 
All documentation for this study that is supplied to me and that has not been previously 
published will be kept in the strictest confidence.  This documentation includes this study 
protocol, Investigator's Brochure, electronic Case Report Form, and other scientific data. 
The study will not be commenced without the prior written approval of a properly constituted 
Institutional Review Board (IRB).  No changes will be made to the study protocol without 
the prior written approval of the Sponsor and the IRB, except where necessary to eliminate an 
immediate hazard to the subjects. 
I have read and understood and agree to abide by all the conditions and instructions contained 
in this protocol. 
 
Responsible Investigator of the study site 
 
 
 
 
 
 
Signature 
 
Date 
 
 
 
 
 
 
Name (block letters) 
 
 
 
 
 
 
 
 
Title (block letters) 
 
 
 
 
 
 
 
 
Institution (block letters) 
 
 
 
 
 
 
 
 
Phone number 
 
 


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SYNOPSIS 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled, 
Single Ascending Dose Study to Evaluate the 
Pharmacokinetics, Safety and Tolerability of SI-722 
Intravesical Instillation in Interstitial Cystitis/Bladder 
Pain Syndrome (IC/BPS) Subjects 
Protocol Number: 
722/1121 
Investigational Product: 
SI-722 
Study Phase: 
Phase 1/2 
Objectives: 
Primary Objectives:  
• To provide the Pharmacokinetics (PK) profiles 
of single intravesical instillations of SI-722 in 
IC/BPS subjects 
• To assess the safety and tolerability of single 
intravesical instillations of SI-722 in IC/BPS 
subjects 
Secondary Objective:  
• To assess the preliminary efficacy of single 
intravesical instillations of SI-722 in IC/BPS 
subjects  
Planned Study Period: 
November 2019 through March 2021 
Overall Study Design 
Study Design: 
This is a Phase 1/2, randomized, double-blind, placebo-
controlled, single ascending dose study in IC/BPS 
subjects. 
Dosage/Dose Regimen: 
Eligible subjects will be assigned to one of four 
treatment cohorts of SI-722 or placebo in a 6:2 ratio:  
• Cohort 1 = 
 of SI-722 or placebo 
 
• Cohort 2 = 
 of SI-722 or placebo 
 
• Cohort 3 = 
 of SI-722 or placebo 
 
• Cohort 4 = 
 of SI-722 or placebo 
 
Duration of Treatment: 
Screening visit (assessment in site): Day -28 to Day -7 
Screening period (assessment by subject daily diary): 
Day -7 to Day -1 


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Investigational drug administration: Day 1 
Follow-up and evaluation phase: Day 1 (post-dose) to 
Day 29 
Planned Number of Subjects: A total 32 subjects (SI-722 group: 24 subjects, placebo 
group: 8 subjects) 
Study Population 
Inclusion Criteria:  
Subjects must meet all of the following criteria to be 
eligible for inclusion in the study: 
1. Provide written informed consent form (ICF) 
which includes agreement for compliance with 
the requirements and restrictions listed in the ICF 
and in this protocol and the willingness and 
ability to comply with all aspects of the study 
requirements 
2. Males or females, ≥18 and ≤80 years of age 
3. Have symptoms of pelvic pain, pressure and/or 
discomfort perceived to be related to the urinary 
bladder, associated with lower urinary tract 
symptoms for greater than 6 months duration 
prior to the start date of Screening and continue 
to experience symptoms during the Screening 
period 
4. A score of 19 or greater on the Bladder 
Pain/Interstitial Cystitis Symptom Score (BPIC-
SS) at Screening visit 
5. Must be capable of voiding without need for 
catheterization 


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6. Ability and willingness to abstain from 
methylxanthine-containing products (eg, coffee, 
tea, cola drinks, chocolate and energy drinks) and 
alcohol from 24 hours prior to each visit and red 
wine, oranges, grapefruit (juice) from 7 days 
prior to Day 1 and 24 hours prior to each visit 
until after collection of the PK sample in each 
treatment period 
Exclusion Criteria:  
The presence of the following criteria excludes a 
subject from study enrollment: 
1. Has a known allergy or contraindication to 
, chondroitin sulfate 
or acetaminophen 
2. Urinary tract infection ≤30 days prior to date of 
first Screening visit and during the Screening 
period, or who have recurrent infections 
documented by positive urine culture (ie, >10,000 
colony-forming units growth, <2 separate isolates 
recovered on culture) of ˃3 per 12 months in the 
last year 
3. History of the following medical conditions or 
diseases: 
• Chemical cystitis, urinary tuberculosis, or 
radiation cystitis 
• Bladder cancer 
• Female subjects: uterine, cervical, vaginal, 
urethral cancer or urethral diverticulum 
• Male subjects: prostate cancer 
4. Female subjects: Have gynecologic conditions that 
could reflect an etiology of their bladder pain at 
Screening visit 
5. Male subjects: Have history of prostate surgery 
(transurethral resection of the prostate, 
transurethral incision of the prostate, transurethral 
needle ablation etc.) ≤6 months prior to date of 
first Screening visit and during the Screening 
period, or currently being treated for chronic 
bacterial prostatitis 


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6. Have urinary incontinence due to urinary urgency 
≤30 days prior to date of first Screening visit and 
during the Screening period 
7. Has taken intramuscular injection and 
intraarticular injection of 
 
 ≤120 days prior to date of 
first Screening visit and during the Screening 
period, and any other route of 
 
≤30 days prior to date of first Screening visit and 
during the Screening period 
8. Treatment with intravesical therapy ≤60 days prior 
to date of first Screening visit and during the 
Screening period 
9. Treatment with any opioid therapy ≤7 days prior 
to date of first Screening visit and during the 
Screening period, and positive urine drug test at 
Screening visit 
10. Has taken any of the following prohibited 
medications ≤1 day prior to date of first Screening 
visit and during the Screening period.  Unless 
noted, these medications are prohibited in oral, 
injectable, and suppository forms, but they can be 
used in inhaled, nasal, or ophthalmic formulations, 
topical administration except for intravesical 
therapy 
• Nonsteroidal anti-inflammatory drugs 
• Any nonopioid analgesics 
• Steroids (except for 
 and topical 
treatment) 
• Any over the counter medications containing 
analgesic ingredients 
11. Has taken any medications used for symptomatic 
relief of IC/BPS ≤1 day prior to date of first 
Screening visit and during the Screening period 
12. Has taken any Cytochrome P450 3A4 (CYP3A4) 
inducers and inhibitors (eg. protease inhibitors, 
macrolides and barbiturates) ≤1 day prior to date 
of first Screening visit and during the Screening 
period 
13. History of procedure(s) that has significantly 
affected bladder function, such as augmentation 
cystoplasty, cystectomy, cytolysis, or bladder 
catheterization 


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14. InterStim placed, or botulinum toxin received ≤6 
months prior to date of first Screening visit and 
during the Screening period or change in 
previously placed InterStim settings ≤3 months 
prior to date of first Screening visit and during the 
Screening period 
15. History of bladder hydrodistension ≤3 months 
prior to date of first Screening visit and during the 
Screening period 
16. Has the following exclusionary laboratory test 
results at Screening visit: 
• Aspartate aminotransferase (AST) >1.5 times 
the upper limit of normal (ULN) 
• Alanine aminotransferase (ALT) >2.5 times 
ULN 
• Creatinine >1.5 times the ULN 
• Positive human immunodeficiency virus (HIV) 
antibodies, hepatitis C (HCV) antibodies, or 
hepatitis B surface antigen (HBsAg) 
• Positive tuberculosis (TB) blood test 
17. Body mass index (BMI) ≥40 kg/m2 
18. Sexually active male or female subjects of 
childbearing potential who are not willing to use 
adequate contraceptive measures to avoid 
pregnancy.  Adequate methods of birth control 
include hormonal contraception (female subjects), 
use of at least 1 acceptable double barrier method, 
vasectomy, intrauterine device, and/or exclusive 
sexual partner for whom 1 of the above acceptable 
methods applies.  Acceptable double barrier 
methods include condoms (male or female) plus a 
spermicidal agent 
19. Has cancer or a past history of any cancer ≤5 years 
prior to date of first Screening visit and during the 
Screening period 
20. History of the following medical conditions or 
diseases: 
• Chronic substance abuse (including alcohol), 
dependency or abuse of opiates, or other 
marijuana or other illicit drugs within the last 5 
years prior to date of first Screening visit and 
during the Screening period 


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• Recurrent, severe allergic or immune-mediated 
reactions, or other autoimmune disorders 
• Any clinically significant psychiatric disorder 
21. Subjects who have been diagnosed with a sexually 
transmitted infection by the examination at the 
Screening visit; subject can be rescreened after 
documented test of cure 
22. Subjects with diagnosed or suspected significant 
medical illness including (but not limited to) 
pulmonary, cardiovascular, cerebrovascular, renal, 
hepatic or hematological disease 
23. Subjects who have difficulty receiving 
administration of investigational product (IP), or 
subjects with a tendency to bleed or with bleeding 
disorders such as (but not limited to) hemophilia, 
aplastic anemia, cirrhosis of the liver, leukemia, 
thrombocytopenia, and vitamin K deficiency.  
Subjects using medication for the purpose of 
anticoagulation, including heparin and warfarin, 
which cannot be reversed preoperatively will also 
be excluded 
24. Is receiving worker’s compensation or is currently 
involved in medical litigation 
25. Have participated in a clinical study of an 
investigational drug, device, or biologics ≤90 days 
prior to date of informed consent 
26. Any condition that, in the opinion of the 
Investigator, might interfere with the evaluation of 
the study objectives 
Criteria for Evaluation 
Pharmacokinetics 
Assessments: 
• Plasma 
and SI-722 concentrations 
• Plasma 
and SI-722 PK parameters (AUC0-t, 
AUC0-last, AUC0-∞, Cmax, Tmax, t1/2, Vz/F, CL/F) 
• Urine 
 and SI-722 concentrations 
• Urine 
 and SI-722 PK parameters (Ae) 
Safety Assessments: 
• Adverse events (AEs) 
• Cystoscopy 
• Vital signs 
• Electrocardiograms (ECGs) 


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• Clinical laboratory assessments 
Efficacy Assessments:  
• Subject Daily diary 
o Bladder pain (maximum and average bladder 
pain, bladder pain at that time) 
o Symptoms of IC/BPS (pain, burning, 
discomfort, and pressure) 
o Voiding frequency 
 Diurnal (from the time of getting up to the 
time of going to bed) 
 Nocturnal (overnight)  
o Frequency of bladder pain (frequency of 
bladder pain when subjects urinate and 
frequency of voiding caused by bladder pain) 
o Voiding volume 
o Acetaminophen consumption (amount of 
acetaminophen, date and time of taking 
medicine and bladder pain at that time) 
• Patient reported outcome (PRO) at the study site 
o Interstitial Cystitis Symptom Index 
Score/Problem Index (ICSI/PI) score 
o BPIC-SS 
o Global Response Assessment (GRA) 
• Voiding volume (during confinement) 
• Inflammatory markers: Erythrocyte sedimentation 
rate (ESR), C-reactive protein (CRP) 
Statistical Methods: 
Analysis populations: 
• 
The intention-to-treat (ITT) population includes all 
randomized subjects regardless of whether the 
subject received any IP or had any efficacy 
assessment collected. 
• 
The Per-protocol (PP) population includes all ITT 
subjects without major protocol deviation. 
• 
The safety population includes all randomized 
subjects who received IP.  If a subject receives IP 
other than the subject’s randomized treatment 


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assignment, then the subject is assigned to the 
treatment arm reflecting the treatment that the 
subject actually received during the study. 
• 
The PK population includes all subjects who 
received SI-722 and who provided at least 1 
evaluable PK sample. 
 
PK analysis: 
Plasma and urine concentrations of SI-722 and 
 will 
be determined for the safety population.  The other PK 
analyses will be conducted based on the PK population.  
Pharmacokinetic profiles will be assessed by plasma 
SI-722 and 
concentrations, urine SI-722 and 
 
concentrations, and the corresponding PK parameters. 
Additional PK parameters will be estimated and 
analyzed for SI-722 and 
 if needed.  PK data for 
SI-722 and 
will be summarized using descriptive 
statistics based on the PK population. 
 
Safety analyses: 
All safety analyses will be conducted based on the 
safety population. 
AEs will be analyzed in terms of treatment-emergent 
AE (TEAE) defined to be any event that begins or 
worsens in grade after the start of IP throughout of the 
study.  All AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA).  The 
number of events and number (percentage) of subjects 
reporting TEAEs for each preferred term will be 
tabulated by system-organ class, by system-organ class 
and severity, and by system organ class and relationship 
to IP. 
Safety endpoints of laboratory values, vital signs, ECGs 
and cystoscopy will be summarized by treatment group. 
 
Efficacy analyses: 
All efficacy analyses will be conducted based on the 


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ITT population.  Each efficacy assessment will be 
summarized for all subjects by treatment group at each 
assessment visit.  The assessments collected on daily 
diary will be calculated by average at each assessment 
visit.  Efficacy assessments from the daily diary such 
as bladder pain and symptoms of IC/BPS will be 
summarized by study day in addition to the summary at 
each assessment visit. 
 
 






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TABLE OF CONTENTS 
LIST OF STUDY PERSONNEL......................................................................................... 2 
SIGNATURE PAGE ........................................................................................................... 3 
SYNOPSIS ........................................................................................................................... 5 
TABLE OF CONTENTS ................................................................................................... 16 
LIST OF ABBREVIATIONS ............................................................................................ 21 
1 
INTRODUCTION ...................................................................................................... 23 
1.1 
Background ........................................................................................................... 23 
1.2 
Nonclinical and Clinical Studies ........................................................................... 24 
1.3 
Summary of Possible Risk and Benefits to Subjects ............................................ 24 
1.3.1 
Possible Risks .................................................................................................. 24 
1.3.2 
Possible Benefits ............................................................................................. 24 
2 
OBJECTIVES ............................................................................................................. 25 
3 
STUDY DESIGN AND PLAN .................................................................................. 25 
3.1 
Study Design ......................................................................................................... 25 
3.2 
Dosage/Dose Regimen .......................................................................................... 25 
3.3 
Duration of Study .................................................................................................. 25 
3.4 
Planned Number of Subjects ................................................................................. 25 
3.5 
Randomization ...................................................................................................... 25 
4 
STUDY POPULATION ............................................................................................. 26 
4.1 
Inclusion Criteria .................................................................................................. 26 
4.2 
Exclusion Criteria ................................................................................................. 26 
5 
SUBJECT WITHDRAWAL FROM THE STUDY ................................................... 29 
5.1 
Criteria for Subject Withdrawal ............................................................................ 29 
5.2 
Procedures for Subject Withdrawal ...................................................................... 29 
5.3 
Lost to Follow-up .................................................................................................. 29 
6 
STUDY METHOD AND PROCEDURES ................................................................ 31 
6.1 
Informed Consent ................................................................................................. 31 
6.1.1 
Subject Identification ...................................................................................... 31 
6.2 
Subject Entry ......................................................................................................... 31 
6.3 
Screen Failure ....................................................................................................... 31 
6.4 
Re-screening ......................................................................................................... 31 
6.5 
Administration ...................................................................................................... 32 
6.6 
Blinding ................................................................................................................ 32 
6.7 
Unblinding ............................................................................................................ 32 
6.8 
Safety Review Committee .................................................................................... 32 


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6.9 
Concomitant Medications ..................................................................................... 32 
6.9.1 
Prohibited Concomitant Medications .............................................................. 33 
6.9.2 
Restricted Concomitant Medications .............................................................. 33 
6.9.3 
Rescue Medication .......................................................................................... 33 
6.10 Concomitant Therapies ......................................................................................... 34 
6.10.1 Prohibited Concomitant Therapies .................................................................. 34 
6.10.2 Restricted Concomitant Therapies .................................................................. 34 
6.11 Lifestyle Restrictions ............................................................................................ 34 
6.11.1 Meals and Dietary Restrictions ....................................................................... 34 
6.11.2 Caffeine and Alcohol ....................................................................................... 34 
6.11.3 Ingesting Water ............................................................................................... 34 
7 
INVESTIGATIONAL PRODUCT ............................................................................ 35 
7.1 
Identity of Investigational Products ...................................................................... 35 
7.1.1 
Investigational Product .................................................................................... 35 
7.2 
Treatment Administered ....................................................................................... 35 
7.3 
Packaging and Labeling ........................................................................................ 36 
7.4 
Preparation, Handling, Storage, and Accountability ............................................ 36 
8 
STUDY ASSESSMENTS .......................................................................................... 37 
8.1 
Pharmacokinetics Assessments ............................................................................. 37 
8.1.1 
Plasma Pharmacokinetics Assessments ........................................................... 37 
8.1.2 
Urine Pharmacokinetics Assessment ............................................................... 37 
8.2 
Safety Assessments ............................................................................................... 37 
8.2.1 
Adverse Events ................................................................................................ 37 
8.2.2 
Cystoscopy ...................................................................................................... 37 
8.2.3 
Physical Examination ...................................................................................... 38 
8.2.4 
Vital Signs ....................................................................................................... 38 
8.2.5 
Electrocardiograms .......................................................................................... 38 
8.2.6 
Clinical Laboratory Assessments .................................................................... 38 
8.3 
Efficacy Assessments ........................................................................................... 39 
8.3.1 
Daily Diary ...................................................................................................... 39 
8.3.2 
Patient Reported Outcomes at the Study Site .................................................. 40 
8.3.3 
Voiding Volume (During confinement) .......................................................... 40 
8.3.4 
Inflammatory Markers ..................................................................................... 41 
8.4 
Other Assessments ................................................................................................ 41 
8.4.1 
BS-POP ........................................................................................................... 41 
9 
STUDY SCHEDULE AND VARIABLES ................................................................ 42 
9.1 
Visit 1: Screening Period (Day -28 to Day 1 [pre-dose]) ..................................... 42 


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9.2 
Visit 2: Treatment with inpatient (Day 1) ............................................................. 43 
9.3 
Visit 2: Follow-up and Evaluation Period with Inpatient (Day 2) ........................ 44 
9.4 
Visit 3: Follow-up and Evaluation Period (Day 3 [Week 0]) ............................... 44 
9.5 
Visit 4: Follow-up and Evaluation Period (Day 5 ± 1 day) .................................. 45 
9.6 
Visit 5: Follow-up and Evaluation Period (Day 8 ± 3 days) ................................ 45 
9.7 
Visit 6: Follow-up and Evaluation Period (Day 15 ± 3 days [Week 2])............... 45 
9.8 
Visit 7: Follow-up and Evaluation Period (Day 29 ± 5 days [Week 4])............... 46 
9.9 
An Early Withdrawal Visit ................................................................................... 46 
9.10 Unscheduled Visit ................................................................................................. 47 
10 ADVERSE EVENTS ................................................................................................. 48 
10.1 Adverse Events ..................................................................................................... 48 
10.2 Serious Adverse Events ........................................................................................ 48 
10.3 Cystoscopy, Vital Signs, Electrocardiograms and Laboratory Tests .................... 49 
10.4 Process for Collecting Adverse Events and Serious Adverse Events 
Information ........................................................................................................... 49 
10.5 Method of Detecting Adverse Events and Serious Adverse Events ..................... 50 
10.6 Follow-up of Adverse Events and Serious Adverse Events ................................. 50 
10.7 Regulatory Reporting Requirements for Serious Adverse Events ........................ 50 
10.8 Pregnancy .............................................................................................................. 50 
11 STATISTICAL METHODS ...................................................................................... 51 
11.1 Analysis Populations ............................................................................................. 51 
11.1.1 Intention-to-treat Population ........................................................................... 51 
11.1.2 Per Protocol Population ................................................................................... 51 
11.1.3 Safety Population ............................................................................................ 51 
11.1.4 Pharmacokinetic Population ............................................................................ 51 
11.2 Demographics, Baseline Characteristics, Medical History, and Concomitant 
Medications ........................................................................................................... 51 
11.3 Pharmacokinetic Analyses .................................................................................... 51 
11.4 Safety Analyses ..................................................................................................... 52 
11.4.1 Adverse Events ................................................................................................ 52 
11.4.2 Laboratory Tests .............................................................................................. 52 
11.4.3 Vital Signs ....................................................................................................... 52 
11.4.4 Electrocardiograms .......................................................................................... 53 
11.4.5 Cystoscopy ...................................................................................................... 53 
11.5 Efficacy Analyses ................................................................................................. 53 
11.6 General Considerations ......................................................................................... 53 
11.6.1 Visit Window and Unscheduled Assessments ................................................ 53 


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11.6.2 Significance Level and Confidence Coefficient .............................................. 53 
11.6.3 Missing Data .................................................................................................... 53 
12 ETHICAL CONSIDERATION .................................................................................. 54 
12.1 Good Clinical Practice Compliance ...................................................................... 54 
12.2 Institutional Review Board Approval ................................................................... 54 
12.3 Informed Consent ................................................................................................. 54 
12.4 Data Protection ..................................................................................................... 55 
12.5 Financial Disclosure ............................................................................................. 55 
13 PROCEDURE FOR COMPLETION AND CORRECTION OF THE CASE 
REPORT FORM ........................................................................................................ 56 
14 DIRECT ACCESS TO SOURCE DATA .................................................................. 57 
15 DATA QUALITY ASSURANCE ............................................................................. 58 
16 ARCHIVING OF SOURCE DATA AND OTHER RECORDS ............................... 59 
17 PUBLICATION POLICY .......................................................................................... 60 
18 COVID-19 PANDEMIC AND SUGGESTED MEASURES .................................... 61 
18.1 Screening Questions to Identify Potential COVID-19 Exposure ......................... 61 
18.2 Screening Window ................................................................................................ 61 
18.3 Follow-Up Visit by Phone .................................................................................... 61 
18.4 Remote Monitoring ............................................................................................... 62 
18.5 Data Management ................................................................................................. 62 
19 REFERENCES ........................................................................................................... 63 
 
LIST OF TABLES 
Table 1 Time and Events Schedule .................................................................................14 
Table 2 Composition of SI-722 Drug Product ................................................................35 
Table 3 Composition of SI-722 Diluent..........................................................................35 
Table 4 Protocol-required Safety Laboratory Assessments ............................................64 
 
LIST OF APPENDICES 
Appendix 1 
Clinical Laboratory Tests .......................................................................64 
Appendix 2 
Pain Score 0-10 Numerical Rating Scale ...............................................66 
Appendix 3 
Symptoms of Interstitial Cystitis/Bladder Pain Syndrome .....................67 
Appendix 4 
Voiding Frequency .................................................................................68 
Appendix 5 
Frequency of Bladder Pain .....................................................................69 
Appendix 6 
Voiding Volume .....................................................................................70 
Appendix 7 
Acetaminophen Consumption ................................................................71 


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Appendix 8 
Interstitial Cystitis Symptom/Problem Index .........................................72 
Appendix 9 
Bladder Pain Interstitial Cystitis Symptom Score ..................................73 
Appendix 10 Global Response Assessment .................................................................74 
Appendix 11 Brief Scale for Psychiatric Problem in Orthopaedic Patients .................75 
Appendix 11.1 Questionnaire for medical personnel ................................................75 
Appendix 11.2 Questionnaire for patients ................................................................75 
Appendix 12 Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting .......................................................................76 
 
 
 


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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
adverse event 
AUA 
American Urological Association 
BLQ 
below the limit of quantification 
BMI 
body mass index 
BPIC-SS 
Bladder Pain/Interstitial Cystitis Symptom Score 
BPS 
Bladder Pain Syndrome 
BS-POP 
Brief Scale for Psychiatric Problem in Orthopaedic Patients 
CFR 
Code of Federal Regulations 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract reasearch organization 
CRP 
c-reactive protein 
CS 
chondroitin sulfate 
CYP 
cytochrome P450 
DMSO 
dimethyl sulfoxide 
ECG 
electrocardiogram 
ESR 
erythrocyte sedimentation rate 
FDA 
the Food and Drug Administration 
GCP 
Good Clinical Practice 
GRA 
Global Response Assessment 
HBsAg 
Hepatitis B surface antigen 
hCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HIV 
human immunodeficiency virus 
IB 
investigator’s brochure 
IC 
interstitial cystitis 
ICSI/PI 
Interstitial Cystitis Symptom Index/Problem Index 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IP 
investigational product 
IRB 
Institutional Review Board 
ITT 
intention-to-treat 


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Abbreviation 
Definition 
LC-MS/MS 
liquid chromatography/tandem mass spectrometry 
MedDRA 
Medical Dictionary for Regulatory Activities 
NAAT 
nucleic acid amplification testing 
NRS 
numerical rating scale 
PK 
pharmacokinetics 
PP 
per-protocol 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SRC 
Safety Review Committee 
 
 
TB 
tuberculosis 
TEAE 
treatment-emergent adverse event 
 
 
ULN 
upper limit of normal 
VAS 
visual analog scale 
WOCBP 
woman of childbearing potential 
 




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Based on the Phase 1 study results, SKK plans to conduct Phase 1/2, randomized, double-
blind, placebo-controlled, single ascending dose study (722/1121) to evaluate the 
pharmacokinetics (PK), safety, tolerability and exploratory efficacy of SI-722 when 
administered by intravesical instillation to patients with IC/BPS. 
1.2 
Nonclinical and Clinical Studies 
A summary of nonclinical studies and prior clinical studies of SI-722 can be found in the 
current edition of the investigator’s brochure (IB). 
1.3 
Summary of Possible Risk and Benefits to Subjects 
1.3.1 
Possible Risks 
Safety data obtained from nonclinical and clinical studies indicated that there were no major 
safety concerns and SI-722 has an acceptable safety profile.  
Based on the results of Phase1 study, dysuria, hematuria, and urethral irritation were 
identified as potential risks.  No severe or serious events related to the urinary system were 
reported, but as a precaution, any changes of urinary function will be carefully monitored in 
the phase 1/2 clinical study. 
1.3.2 
Possible Benefits 
This is the first clinical study to evaluate efficacy in subjects with IC/BPS. Based on the 
results of the cystitis model in rats, SI-722 at doses 
 is expected to improve urinary 
frequency and ameliorate symptoms of bladder pain in IC/BPS subjects.  When 
 
 the SI-722 is instilled into the bladder, 
urinary frequency and bladder pain may be improved. 
 
 


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2 
OBJECTIVES 
Primary Objectives:  
• To provide the PK profiles of single intravesical instillations of SI-722 in IC/BPS 
subjects 
• To assess the safety and tolerability of single intravesical instillations of SI-722 in 
IC/BPS subjects 
Secondary Objective:  
• To assess the preliminary efficacy of single intravesical instillations of SI-722 in 
IC/BPS subjects  
 
3 
STUDY DESIGN AND PLAN 
3.1 
Study Design 
This is a Phase 1/2, randomized, double-blind, placebo-controlled, single ascending dose 
study in IC/BPS subjects. 
3.2 
Dosage/Dose Regimen 
Eligible subjects will be assigned to one of four treatment cohorts of SI-722 or placebo in a 
6:2 ratio:  
• Cohort 1 = 
 of SI-722 or placebo (
) 
• Cohort 2 = 
 of SI-722 or placebo (
) 
• Cohort 3 = 
 of SI-722 or placebo (
) 
• Cohort 4 = 
 of SI-722 or placebo (
) 
3.3 
Duration of Study 
Screening visit (assessment in site): Day -28 to Day -7 
Screening period (assessment by subject daily diary): Day -7 to Day -1 
Investigational drug administration: Day 1 
Follow-up and evaluation phase: Day 1 (Post-dose) to Day 29 
3.4 
Planned Number of Subjects 
A total 32 subjects (SI-722 group: 24 subjects, placebo group: 8 subjects) 
 
3.5 
Randomization 
Randomization will be utilized to minimize bias in study evaluations.  On Day 1, subjects 
will be randomized to SI-722 or placebo in a 6:2 ratio within four treatment cohorts.  
Cohorts will be filled sequentially as subjects are determined to be eligible during Screening.  
An unblinded Safety Review Committee (SRC) will evaluate the safety and tolerability of 
SI-722 1 week after administration for each cohort before advancing to the next higher dose. 


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4 
STUDY POPULATION 
4.1 
Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for inclusion in the study: 
1. Provide written informed consent form (ICF) which includes agreement for compliance 
with the requirements and restrictions listed in the ICF and in this protocol and the 
willingness and ability to comply with all aspects of the study requirements 
2. Males or females, ≥18 and ≤80 years of age 
3. Have symptoms of pelvic pain, pressure and/or discomfort perceived to be related to the 
urinary bladder, associated with lower urinary tract symptoms for greater than 6 months 
duration prior to the start date of Screening and continue to experience symptoms 
during the Screening period 
4. A score of 19 or greater on the Bladder Pain/Interstitial Cystitis Symptom Score (BPIC-
SS) at Screening visit 
5. Must be capable of voiding without need for catheterization 
6. Ability and willingness to abstain from methylxanthine-containing products (eg, coffee, 
tea, cola drinks, chocolate and energy drinks) and alcohol from 24 hours prior to each 
visit and red wine, oranges and grapefruit (juice) from 7 days prior to Day 1 and 24 
hours prior to each visit until after collection of the PK sample in each treatment period 
4.2 
Exclusion Criteria 
The presence of the following criteria excludes a subject from study enrollment: 
1. Has a known allergy or contraindication to 
 CS or acetaminophen 
2. Urinary tract infection ≤30 days prior to date of first Screening visit and during the 
Screening period, or who have recurrent infections documented by positive urine 
culture (ie, >10,000 colony-forming units growth, <2 separate isolates recovered on 
culture) of ˃3 per 12 months in the last year 
3. History of the following medical conditions or diseases: 
• Chemical cystitis, urinary tuberculosis, or radiation cystitis 
• Bladder cancer 
• Female subjects: uterine, cervical, vaginal, urethral cancer or urethral diverticulum 
• Male subjects: prostate cancer 
4. Female subjects: Have gynecologic conditions that could reflect an etiology of their 
bladder pain at Screening visit 
5. Male subjects: Have history of prostate surgery (transurethral resection of the prostate, 
transurethral incision of the prostate, transurethral needle ablation etc.) ≤6 months prior 
to date of first Screening visit and during the Screening period, or currently being 
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6. Have urinary incontinence due to urinary urgency ≤30 days prior to date of first 
Screening visit and during the Screening period 
7. Has taken intramuscular injection and intraarticular injection of 
 
 ≤120 days prior to date of first Screening visit and during the 
Screening period, and any other route of 
 ≤30 days prior to date of first 
Screening visit and during the Screening period 
8. Treatment with intravesical therapy ≤60 days prior to date of first Screening visit and 
during the Screening period  
9. Treatment with any opioid therapy ≤7 days prior to date of first Screening visit and 
during the Screening period, and positive urine drug test at Screening visit 
10. Has taken any of the following prohibited medications ≤1 day prior to date of first 
Screening visit and during the Screening period.  Unless noted, these medications are 
prohibited in oral, injectable, and suppository forms, but they can be used in inhaled, 
nasal, or ophthalmic formulations, topical administration except for intravesical therapy 
• Nonsteroidal anti-inflammatory drugs 
• Any nonopioid analgesics 
• Steroids (except for 
, and topical treatment) 
• Any over the counter medications containing analgesic ingredients 
11. Has taken any medications used for symptomatic relief of IC/BPS ≤1 day prior to date 
of first Screening visit and during the Screening period 
12. Has taken any Cytochrome P450 3A4 (CYP3A4) inducers and inhibitors (eg. protease 
inhibitors, macrolides and barbiturates) ≤1 day prior to date of first Screening visit and 
during the Screening period  
13. History of procedure(s) that has significantly affected bladder function, such as 
augmentation cystoplasty, cystectomy, cytolysis, or bladder catheterization 
14. InterStim placed, or botulinum toxin received ≤6 months prior to date of first Screening 
visit and during the Screening period or change in previously placed InterStim settings 
≤3 months prior to date of first Screening visit and during the Screening period  
15. History of bladder hydrodistension ≤3 months prior to date of first Screening visit and 
during the Screening period  
16. Has the following exclusionary laboratory test results at Screening visit: 
• Aspartate aminotransferase (AST) >1.5 times the upper limit of normal (ULN) 
• Alanine aminotransferase (ALT) >2.5 times ULN 
• Creatinine >1.5 times the ULN 
• Positive human immunodeficiency virus (HIV) antibodies, hepatitis C antibodies 
(HCV), or hepatitis B surface antigen (HBsAg) 
• Positive tuberculosis (TB) blood test 
17. Body mass index (BMI) ≥40 kg/m2 


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18. Sexually active male or female subjects of childbearing potential who are not willing to 
use adequate contraceptive measures to avoid pregnancy.  Adequate methods of birth 
control include hormonal contraception (female subjects), use of at least 1 acceptable 
double barrier method, vasectomy, intrauterine device, and/or exclusive sexual partner 
for whom 1 of the above acceptable methods applies.  Acceptable double barrier 
methods include condoms (male or female) plus a spermicidal agent 
19. Has cancer or a past history of any cancer ≤5 years prior to date of first Screening visit 
and during the Screening period 
20. History of the following medical conditions or diseases: 
• Chronic substance abuse (including alcohol), dependency or abuse of opiates, or 
other marijuana or other illicit drugs within the last 5 years prior to date of first 
Screening visit and during the Screening period 
• Recurrent, severe allergic or immune-mediated reactions, or other autoimmune 
disorders 
• Any clinically significant psychiatric disorder 
21. Subjects who have been diagnosed with a sexually transmitted infection by the 
examination at the Screening visit; subject can be rescreened after documented test of 
cure 
22. Subjects with diagnosed or suspected significant medical illness including (but not 
limited to) pulmonary, cardiovascular, cerebrovascular, renal, hepatic or hematological 
disease 
23. Subjects who have difficulty receiving administration of IP, or subjects with a tendency 
to bleed or with bleeding disorders such as (but not limited to) hemophilia, aplastic 
anemia, cirrhosis of the liver, leukemia, thrombocytopenia, and vitamin K deficiency.  
Subjects using medication for the purpose of anticoagulation, including heparin and 
warfarin, which cannot be reversed preoperatively will also be excluded 
24. Is receiving worker’s compensation or is currently involved in medical litigation 
25. Have participated in a clinical study of an investigational drug, device, or biologics 
≤90 days prior to date of informed consent 
26. Any condition that, in the opinion of the Investigator, might interfere with the 
evaluation of the study objectives 


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5 
SUBJECT WITHDRAWAL FROM THE STUDY 
5.1 
Criteria for Subject Withdrawal 
A subject may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator or sponsor for safety, behavioral, 
compliance, or administrative reasons.  Reasons for withdrawal may include, but are not 
limited to: 
• Occurrence of a treatment-emergent AE (TEAE) that represents an unacceptable risk to 
the subject in the judgment of the Investigator 
• The subject dies 
• If the Investigator determines it would be impossible to continue the study because: 
• the subject won’t comply with protocol requirements 
• the subject is lost to follow-up 
• there are technical issues at the site 
• If a subject becomes pregnant 
• The Investigator determines it is necessary to discontinue the study 
• The subject withdraws his or her consent 
• The Sponsor discontinues the study at a specific site 
• The Sponsor prematurely terminates the study 
• If a protocol deviation leads the investigator to judge it difficult for the subject to 
continue the study 
• Any other reason documented by the investigator 
5.2 
Procedures for Subject Withdrawal 
Subjects may withdraw from the entire study, including follow-up, at any time without 
penalty and for any reason without prejudice to his or her future medical care. In all cases, the 
reason(s) for withdrawal, including the primary reason, must be recorded on the electronic 
case report form (eCRF).  If a subject is prematurely withdrawn from the study for any 
reason, the Investigator must make every effort to perform the evaluations described for the 
appropriate early withdrawal visit.  If a subject withdraws consent and still agrees to 
undergo a final examination, this will be documented in the eCRF.  A subject may also be 
withdrawn from the study by the Investigator, Sponsor, regulatory authority(ies), or an 
Institutional Review Board (IRB).  Subjects will also be withdrawn if the entire study is 
terminated prematurely.  Withdrawn subjects will not be replaced. 
5.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required 
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• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 
• Before a subject is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, if 
necessary, a certified letter to the subject’s last known mailing address or local 
equivalent methods).  These contact attempts should be documented in the subject’s 
medical record. 
• Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
 


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6 
STUDY METHOD AND PROCEDURES 
6.1 
Informed Consent 
Before each subject is enrolled to the study, informed consent, using a form approved by the 
IRB responsible for that site, will be obtained from the subject according to the regulatory 
and legal requirements of the participating country/state.  This consent form must be signed, 
dated, and retained by the Investigator as part of the study records.  The Investigator will not 
undertake any investigation specifically required only for the clinical study until valid 
consent has been obtained.  When consent is obtained must also be documented in the 
subject source record and eCRF. 
If a protocol amendment is required, the ICF may need to be revised to reflect the changes to 
the protocol.  If the ICF is revised, it must be reviewed and approved by the appropriate IRB 
and signed by all subjects subsequently enrolled in the study as well as those currently 
enrolled in the study, except for when the change is administrative or resigning is not 
required per the IRB.  If the IB is updated during the study or new risks/information 
becomes available, ICF will need to be updated and new form signed by subjects still in study 
or entering study. 
6.1.1 
Subject Identification 
At the screening visit, a unique subject number will be assigned consecutively for each 
subject after he or she signs the ICF.  Subjects who drop out of the study before 
randomization will retain their unique subject number (ie, the subject number will not be 
reassigned).  If a subject is rescreened after being designated as a screen failure, the subject 
will receive a new unique subject number upon rescreening. 
6.2 
Subject Entry 
At the time of each subject’s entry into the study, the investigator will perform all the 
examinations described in Table 1 and confirm that the subject is eligible for the study.  
Each subject who is judged as eligible for the study by the Investigator will be enrolled into 
the study. 
6.3 
Screen Failure 
Screen failures are defined as subjects who consent to participate in the clinical study but are 
not subsequently randomized in the study.  A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure subjects to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to 
queries from regulatory authorities.  Minimal information includes demographics and reason 
for screen failure. 
6.4 
Re-screening 
Re-screening of subjects may be allowed if the reason for screen failure is any of the 
following Inclusion and Exclusion Criteria:  
Inclusion Criteria 3 
Exclusion Criteria 2, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 17, 21 and 25 
Additionally, re-screening of subjects who were screened but were not dosed because of 
cohort closing may be allowed. 




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The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.9.1 
Prohibited Concomitant Medications 
The following medications are prohibited for the periods specified prior to the start date of 
Screening and through study completion. 
• 120 days prior to the start date of Screening: Any 
 are prohibited by 
intramuscular injection and intraarticular injection 
• 60 days prior to the start date of Screening: Any bladder instillation medication (ex. 
DMSO, cocktail, etc.) 
• 30 days prior to the start date of Screening: Any route of 
 are prohibited 
(except for intramuscular injection and intraarticular injection) 
• 7 days prior to the start date of Screening: Any opioids are prohibited by any route of 
administration 
• 1 day prior to the start date of Screening: Nonsteroidal anti-inflammatory drugs, any 
nonopioid analgesics and steroids (except for 
, and topical treatment)* 
• 1 day prior to the start date of Screening: Any over the counter medication containing 
the analgesic ingredient* 
• 1 day prior to the start date of Screening: Any other medications used for symptomatic 
relief of IC/BPS 
• 1 day prior to the start date of Screening: Any CYP3A4 inducers and inhibitors (eg. 
protease inhibitors, macrolides, and barbiturates) 
* Unless noted, these medications are prohibited in oral, injectable, and suppository 
forms, but they can be used in inhaled, nasal, ophthalmic formulations, or topical 
administration except for intravesical therapy. 
6.9.2 
Restricted Concomitant Medications 
The following medications are allowed to be used during the study if the subjects have been 
on a stable dosage for 3 months prior to the start date of Screening. 
• Elmiron® (pentosan polysulfate sodium) 
• Tricyclic antidepressants (eg, amitriptyline, nortriptyline) 
6.9.3 
Rescue Medication 
Acetaminophen will be provided to subjects as a rescue medication for relief of the bladder 
pain.  Subjects will be required to use only the provided acetaminophen to treat 
breakthrough pain in the bladder.  Acetaminophen will be used only if subjects feel the need 
to use rescue medication and will not be used excursively.  The usage of subject’s 
acetaminophen is 1 or 2 caplets at 1 time and the limitation is up to 3,000 mg/day.  An 
interval between doses of at least 4 hours is recommended. 
Subjects will be recommended not to use other medications that contain acetaminophen, such 
as cold medicine which may cause the subject to consume more than 3,000 mg of 
acetaminophen in 1 day. 


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6.10 Concomitant Therapies 
Investigators will record the information for therapies used concomitantly from time of 
informed consent until Day 29 or study discontinuation whichever occurs first. 
6.10.1 Prohibited Concomitant Therapies 
History of augmentation cystoplasty, cystectomy, cytolysis, bladder catheterization and other 
procedures significantly affecting bladder function are prohibited. 
Placing InterStim and receiving botulinum toxin are prohibited for 6 months prior to the start 
date of Screening and during Screening period. Change in InterStim and bladder 
hydrodistention are prohibited for 3 months prior to the start date of Screening and during the 
Screening period. 
6.10.2 Restricted Concomitant Therapies 
Subjects can remain on stable frequency of therapies performed for treatments of IC/BPS 
(stable defined as continuous treatment for 30 days prior to the start date of Screening). 
6.11 Lifestyle Restrictions 
6.11.1 Meals and Dietary Restrictions 
Refrain from consumption of red wine, oranges, grapefruit or grapefruit juice (pomelos, 
exotic citrus fruits, grapefruit hybrids, or fruit juices) from 7 days prior to Day 1 until after 
the collection of the 48 hour PK sample.  Subjects are asked to refrain from such products 
for 24 hours prior to their next scheduled visit. 
6.11.2 Caffeine and Alcohol 
Ingesting methylxanthine-containing products (eg, coffee, tea, cola drinks, chocolate and 
energy drinks) and alcohol will be prohibited for 24 hours before study treatment 
administration until after the collection of the 48 hour PK sample.  Subjects are asked to 
refrain from such products for 24 hours prior to their next scheduled visit. 
6.11.3 Ingesting Water 
Ingesting any water over 250 mL will be prohibited from morning on Day 1 until study 
treatment administration. 
 




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5. The actual amount instilled will be documented, and the time of instillation will be 
recorded on the source documents and eCRF 
6. The catheter will be removed 
7. The solution will remain in the bladder for 30 minutes.  Subject should make an effort 
not to void within 30 minutes after study treatment administration.  During the 
30 minutes immediately following bladder instillation subjects should be instructed to 
switch positions from supine, to alternating lateral sides every five minutes for 
30 minutes (eg, supine, right lateral, left lateral, supine, etc.). 
7.3 
Packaging and Labeling 
SI-722 and SI-722 diluent will be packaged separately in single-dose vials and will be labeled 
appropriately as IP for this study according to regulatory requirements.  SI-722 will be 
supplied in a carton containing 1 bottle of SI-722 and 1 bottle of solution. 
7.4 
Preparation, Handling, Storage, and Accountability 
Information on the preparation, handling, storage, and accountability of SI-722 can be found 
in the pharmacy manual. 
 


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8 
STUDY ASSESSMENTS 
8.1 
Pharmacokinetics Assessments 
8.1.1 
Plasma Pharmacokinetics Assessments 
Blood samples of approximately 10 mL each will be collected for measurement of SI-722 and 
 concentrations.  SI-722 and 
 concentrations in plasma will be measured using a 
validated high-performance liquid chromatography/tandem mass spectrometry (LC-MS/MS) 
method.  Plasma PK parameters (AUC0-t, AUC0-last, AUC0-∞, Cmax, Tmax, t1/2, Vz/F, CL/F) for 
SI-722 and 
 will be estimated.  PK blood sampling will occur pre-dose and 0.25, 0.5, 1, 
2, 4, 6, 8, 12, 24, 48, 96, 168, 336 and 672 hours post-dose.  Additional samples may be 
collected at additional time points during the study if warranted by the Investigator.  
Instructions for the collection and handling of biological samples will be provided by the 
Sponsor.  The actual date and time (24-hour clock time) of each blood sample collected will 
be recorded in the CRF. 
8.1.2 
Urine Pharmacokinetics Assessment 
Urine samples of approximately 8 mL will be collected for measurement of SI-722 and 
 
concentrations.  SI-722 and 
 concentrations in urine will be measured using a validated 
LC-MS/MS method.  Urine PK parameters (Ae) for SI-722 and 
 will be estimated.  PK 
urine sample will be collected pre-dose (at least once) and 0 to 24 hours post-dose.  Urine 
sample will be also collected on Day 2, Day 3, Day 5, Day 8, Day 15 and Day 29, and these 
samples will be used for measurement of SI-722 and 
 concentrations if needed.  After 
each urine sample collection, voiding volume will be measured.  Instructions for the 
collection and handling of biological samples will be provided by the Sponsor.  The actual 
date and time (24-hour clock time) of each urine sample collected will be recorded in the 
CRF. 
All collected urine samples are used for further analysis of metabolites which might be 
conducted separately from this study.  A portion of plasma samples as well as urine samples 
from this study will be saved for the metabolite analysis study. 
 
8.2 
Safety Assessments 
8.2.1 
Adverse Events 
• Assessment Points: AE will be reported from Informed Consent to Day 29 or an early 
withdrawal visit. 
• Method: See Section 10.4 for collecting AE information 
8.2.2 
Cystoscopy 
• Assessment Points: Cystoscopy will be performed on Day 1 (pre-dose) to identify 
presence or absence of Hunner’s leasion as well as Day 8, and Day 29 or an early 
withdrawal visit to evaluate abnormal change from Day 1. 
• Method: Subjects must fully void their bladders after the cystoscopy procedure in 
preparation for the IP instillation.  About five photographs inside the bladder will be 
printed and filed with each subject’s source document. 


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8.2.3 
Physical Examination 
• Assessment Points: Screening, Day 1 (pre-dose), Day 2, Day 3, Day 5, Day 8, Day 15 
and Day 29 or an early withdrawal visit. 
• Method: Physical examination will be performed to identify presence or absence of any 
abnormality.  At Screening, gynecological examination will be performed to exclude 
subjects with gynecologic conditions that could reflect an etiology of their bladder pain 
(see Section 4.2).  It is not necessary to exclude subjects with any abnormal 
gynecologic conditions if these conditions do not reflect an etiology of their bladder 
pain. 
8.2.4 
Vital Signs 
• Assessment Points: Screening, Day 1 (pre-dose, and 1 hour post dosing), Day 2, Day 3, 
Day 5, Day 8, Day 15 and Day 29 or an early withdrawal visit. 
• Method: Vital signs (to be taken before blood collection) will be measured and will 
include body temperature, systolic and diastolic blood pressure, heart rate, and 
respiratory rate.  A completely automated device will be used.  Manual techniques 
will be used only if an automated device is not available. 
8.2.5 
Electrocardiograms 
• Assessment Points: Day 1 (pre-dose; and 1 hour post dosing), Day 2. 
• Method: Using an electrocardiogram (ECG) machine that automatically measures PR, 
QRS, QT, and QTc intervals. 
8.2.6 
Clinical Laboratory Assessments 
• Assessment Points: Blood and urine samples for clinical laboratory tests (blood: 
hematology, coagulation and clinical chemistry, urine: urinalysis) will be collected at 
Screening, pre-dose on Day 1, Day 2, Day 3, Day 5, Day 8, Day 15 and Day 29 or early 
withdrawal. 
Serology (HIV antibodies, HBsAg, and HCV antibody), TB blood test, Nucleic acid 
amplification testing (NAAT) for Neisseria. gonorrhoeae and Chlamydia. trachomatis 
and Urine drug screen will be done at Screening only.  
Pregnancy tests will be done at Screening (serum), pre-dose on Day 1 (urine), and on 
Day 29 or early withdrawal (urine).  Urine culture will be done at Screening, and on 
Day 29 or early withdrawal. 
• Method: The Investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE section in 
the eCRF.  The laboratory reports must be filed with the source documents.  All 
laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or 
baseline, or are no longer considered clinically significant by the Investigator, or are 
otherwise explained and any appropriate action taken. 
 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and the Sponsor 
notified. 


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 
All protocol-required laboratory assessments, as defined in Appendix 1, must be 
conducted in accordance with the laboratory manual and the Schedule of 
Activities (see Table 1). 
 
If laboratory values from non-protocol specified laboratory assessments performed 
at the institution’s local laboratory require a change in subject management or are 
considered clinically significant by the Investigator (eg, serious AE [SAE], AE, or 
dose modification), then the results must be recorded in the eCRF. 
Immediate safety concerns should be discussed with the medical monitor upon occurrence or 
awareness to determine if the subject should discontinue study treatment (See Appendix 1). 
 
8.3 
Efficacy Assessments 
8.3.1 
Daily Diary 
8.3.1.1 
Bladder Pain 
• Assessment Points: Daily from Day -7 until Day 29.  Bladder pain assessment must be 
taken at least 5 days in a week prior to Day 1. 
• Item: Daily bladder pain score using a standardized 11-points numerical rating scale 
(NRS) pain scale in subject daily diary (See Appendix 2). 
• Method: Subjects will record daily maximum and average bladder pain over the last 
24 hours and bladder pain at that time, basically before going to bed. 
8.3.1.2 
Symptoms of IC/BPS (Pain, Burning, Discomfort, and Pressure) 
• Assessment Points: Daily from Day -7 until Day 29.  This assessment must be taken at 
least 5 days in a week prior to Day 1. 
• Item: See Appendix 3 
• Method: Subjects will record maximum daily symptoms of pain, burning, discomfort, 
and pressure over the last 24 hours, basically before going to bed. 
8.3.1.3 
Voiding Frequency 
• Assessment Points: Daily from Day -7 until Day 29.  This assessment must be taken at 
least 5 days in a week prior to Day 1. 
• Item: See Appendix 4 
• Method: Subjects will record the number of times of the diurnal (from the time of 
getting up to the time of going to bed) and nocturnal (overnight) urination.  
8.3.1.4 
Frequency of Bladder Pain 
• Assessment Points: Daily from Day -7 until Day 29.  This assessment must be taken at 
least 5 days in a week prior to Day 1. 
• Item: See Appendix 5 
• Method: Subjects will record daily frequency of bladder pain when they urinate and 
frequency of voiding caused by bladder pain, basically before going to bed. 


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8.3.1.5 
Voiding Volume 
• Assessment Points: One day within 7 days before Day 1, within 3 days before or after 
Day 8 and Day 15, and within 5 days before Day 29. 
• Item: See Appendix 6 
• Method: Subjects will measure voiding volume at least 5 times in a day preferably 
including the first and last urine. 
8.3.1.6 
Acetaminophen Consumption and Pain 
• Assessment Points: Daily from Day -7 until Day 29. 
• Item: See Appendix 7 
• Method: Subjects will record daily amount of acetaminophen (rescue medication), date 
and time of taking medicine over the last 24 hours (from the time of going to bed to the 
time of next going to bed), and bladder pain at that time when subject takes 
acetaminophen. 
8.3.2 
Patient Reported Outcomes at the Study Site 
8.3.2.1 
Interstitial Cystitis Symptom Index Score/Problem Index 
• Assessment Points: Day 1 (pre-dose) and Day 29 or an early withdrawal visit. 
• Item: See Appendix 8 
• Method: The Interstitial Cystitis Symptom Index/Problem Index (ICSI/PI) questionnaire 
will be administered to the subjects at each listed visit. 
8.3.2.2 
Bladder Pain/Interstitial Cystitis Symptom Score 
• Assessment Points: Screening, Day 1 (pre-dose), Day 8, Day 15 and Day 29 or an early 
withdrawal visit. 
• Item: See Appendix 9 
• Method: The BPIC-SS questionnaire will be administered to the subjects at each listed 
visit. 
8.3.2.3 
Global Response Assessment 
• Assessment Points: Day 8, Day 15 and Day 29 or an early withdrawal visit. 
• Item: See Appendix 10 
• Method: The Global Response Assessment (GRA) questionnaire will be administered to 
subjects at each listed visit. 
8.3.3 
Voiding Volume (During confinement) 
• Assessment Points: Day 1 to Day 2 (during confinement). 
• Item: Not applicable 
• Method: Subjects collect urine void sample with container and voiding volume will be 
measured by site staff. 


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8.3.4 
Inflammatory Markers 
• Assessment Points: Screening, Day 1 (pre-dose), Day 2, Day 3, Day 5, Day 8, Day 15 
and Day 29 or an early withdrawal visit 
• Method: Erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP) blood 
markers testing will be performed by collecting the blood samples 
 
8.4 
Other Assessments 
8.4.1 
BS-POP 
• Assessment Points: Screening 
• Item: BS-POP (See Appendix 11) 
• Method: The subjects will answer the BS-POP questionnaire (Appendix 11.1) at 
Screening visit. Investigator will answer the BS-POP questionnaire (Appendix 11.2) at 
Screening visit. 
 


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9 
STUDY SCHEDULE AND VARIABLES 
Adherence to the study design requirements is essential and required for study conduct.  
Study procedures and schedule are listed below and summarized in the Time and Events 
Schedule (See Table 1). 
Study procedures: 
Each subject will be asked to complete 7 study visits: 
• Screening visit (Visit 1) 
• Randomization and IP administration at Day 1 and confinement for assessment of PK 
and safety until Day 2 (Visit 2) 
• Follow-up visits at Day 3, Day 5, Day 8, Day 15 and Day 29  
Subjects who discontinued the study in mid-course will be asked to complete an early 
withdrawal visit. 
Study procedures to be performed at each respective visit is provided in detail below. 
 
9.1 
Visit 1: Screening Period (Day -28 to Day 1 [pre-dose]) 
The following procedures will be performed at Screening visit (Visit 1) or during the 
Screening period (Day -28 to Day 1 [pre-dose]). 
Before performing any screening procedures: 
• Obtain written informed consent 
After informed consent is obtained: 
• Perform eligibility check in accordance with study protocol inclusion/exclusion criteria 
• Perform physical examination 
• Perform gynecological examination 
• Collect demographics and baseline characteristics (eg, physical examination, height, 
body weight) 
• Collect medical history 
• Collect IC/BPS history and treatment history 
• Perform urine drug screen test 
• Collect blood sample for laboratory tests (hematology, coagulation, chemistry, 
Serology, TB blood test) 
• Collect urine samples for urinalysis and urine culture 
• Collect sample for NAAT 
• Collect sample for serum β human chorionic gonadotropin (β-hCG) pregnancy test 
• Record vital signs 


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• Distribute acetaminophen as rescue medication 
• Record Patient Reported Outcome (PRO) assessments (BPIC-SS and BS-POP) 
• Record AEs 
• Collect concomitant medication and therapy information: 
1. Confirm use and amount of concomitant medication(s)/therapy(ies) 
2. Assess use of restricted medication(s)/therapy(ies) 
3. Assess washout of prohibited medication(s)/therapy(ies) 
• Provide instructions for refraining from any water over 250 mL from morning on Day 1 
until study treatment administration. 
At least 7 days prior to randomization date, sites should: 
• Distribute subject daily diary 
• Provide instructions for recording subject daily diary which must be taken at least 
5 days in a week prior to the start date of IP administration 
• Provide subject education and materials on accurate pain reporting 
• Provide instructions and containers with scale for recording voiding volume by subject 
daily diary which must be measured at least 5 times in a day within 7 days before Day 1 
9.2 
Visit 2: Treatment with inpatient (Day 1)  
Pre-dose: 
• Perform eligibility check in accordance with study protocol inclusion/exclusion criteria 
• Perform physical examination 
• Collect concomitant medication and therapy information 
• Review of subject daily diary 
• Record PRO assessments (BPIC-SS and ICSI/PI) 
• Record vital signs 
• 12-lead ECG 
• Record AEs 
• Collect blood sample for laboratory tests (hematology, chemistry and coagulation) and 
PK 
• Collect urine sample for urinalysis and PK 
• Perform urine pregnancy test 
• Record urine volume 
• Distribute subject daily diary 
• Distribute acetaminophen, if necessary 
• Perform cystoscopy 


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• Randomization 
IP administration (0 hour) 
• IP administration 
Post-dose: 
• Record the time of first voiding 
• Record urine volume 
• Collect blood sample for PK at 0.25, 0.5, 1, 2, 4, 6, 8, 12 hours after administration 
• Collect urine sample for PK over interval of 0 to 24 hours after administration 
• Record vital signs at 1 hour after administration 
• 12-lead ECG at 1 hour after administration 
• Record AEs 
9.3 
Visit 2: Follow-up and Evaluation Period with Inpatient (Day 2) 
• Perform physical examination 
• Record vital signs 
• 12-lead ECG 
• Collect blood sample for laboratory tests (hematology, chemistry and coagulation) and 
PK 
• Collect urine sample for urinalysis and PK 
• Distribute subject daily diary 
• Distribute acetaminophen, if necessary 
• Record urine volume 
• Collect concomitant medication and therapy information 
• Review subject daily diary 
• Record AEs 
9.4 
Visit 3: Follow-up and Evaluation Period (Day 3 [Week 0]) 
• Perform physical examination 
• Record vital signs 
• Collect blood sample for laboratory tests (hematology, chemistry and coagulation) and 
PK 
• Collect urine sample for urinalysis and PK 
• Distribute subject daily diary 
• Distribute acetaminophen, if necessary 
• Collect concomitant medication and therapy information 
• Review subject daily diary 


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• Record AEs 
9.5 
Visit 4: Follow-up and Evaluation Period (Day 5 ± 1 day) 
• Perform physical examination 
• Record vital signs 
• Collect blood sample for laboratory tests (hematology, chemistry and coagulation) and 
PK 
• Collect urine sample for urinalysis and PK 
• Distribute subject daily diary 
• Distribute acetaminophen, if necessary 
• Provide instructions and containers with scale for recording voiding volume by subject 
daily diary which must be measured at least 5 times in a day within 3 days before or 
after Day 8 
• Collect concomitant medication and therapy information 
• Review subject daily diary 
• Record AEs 
9.6 
Visit 5: Follow-up and Evaluation Period (Day 8 ± 3 days) 
• Perform physical examination 
• Record vital signs 
• Collect blood sample for laboratory tests (hematology, chemistry and coagulation) and 
PK 
• Collect urine sample for urinalysis and PK 
• Perform cystoscopy 
• Distribute subject daily diary 
• Distribute acetaminophen, if necessary 
• Provide instructions and containers with scale for recording voiding volume by subject 
daily diary which must be measured at least 5 times in a day within 3 days before or 
after Day 15 
• Record PRO assessments (BPIC-SS and GRA) 
• Collect concomitant medication and therapy information 
• Review subject daily diary 
• Record AEs 
9.7 
Visit 6: Follow-up and Evaluation Period (Day 15 ± 3 days [Week 2]) 
• Perform physical examination 
• Record vital signs 


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• Collect blood sample for laboratory tests (hematology, chemistry and coagulation) and 
PK 
• Collect urine sample for urinalysis and PK 
• Distribute subject daily diary 
• Distribute acetaminophen, if necessary 
• Provide instructions and containers with scale for recording voiding volume by subject 
daily diary which must be measured at least 5 times in a day within 5 days before 
Day 29 
• Record PRO assessment (BPIC-SS and GRA) 
• Collect concomitant medication and therapy information 
• Review of subject daily diary 
• Record AEs 
9.8 
Visit 7: Follow-up and Evaluation Period (Day 29 ± 5 days [Week 4]) 
• Perform physical examination 
• Record vital signs 
• Collect blood sample for laboratory tests (hematology, chemistry and coagulation) and 
PK 
• Collect urine sample for urinalysis, urine culture, and PK 
• Perform urine pregnancy test 
• Perform cystoscopy 
• Record PRO assessments (BPIC-SS, ICSI/PI, and GRA) 
• Collect concomitant medication and therapy information 
• Review of subject daily diary 
• Record AEs 
9.9 
An Early Withdrawal Visit 
Subjects who discontinue early from the study will be asked to complete an early withdrawal 
visit.  The following activities will be performed at the early withdrawal visit: 
• Perform physical examination 
• Record vital signs 
• Collect blood sample for laboratory tests (hematology, chemistry and coagulation) and 
PK 
• Collect urine sample for urinalysis, urine culture, and PK 
• Perform urine pregnancy test 
• Perform cystoscopy 
• Record PRO assessments (BPIC-SS, ICSI/PI, and GRA) 


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• Collect concomitant medication and therapy information 
• Review of subject daily diary 
• Record AEs 
9.10 Unscheduled Visit 
In the event the Investigator needs to conduct follow-up assessments to evaluate an AE, the 
following safety assessments may be performed on an unscheduled visit: 
• Physical examination 
• Record vital signs 
• Collect blood sample for laboratory tests (hematology and chemistry) and PK if 
considered appropriate 
• Perform cystoscopy, if necessary 
 


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10 ADVERSE EVENTS 
10.1 Adverse Events 
An AE is any untoward medical occurrence that occurs in a subject administered with IP, and 
that does not necessarily have to have a causal relationship with the treatment.  An AE can 
therefore be any unfavorable and unintended sign (including abnormal laboratory findings 
and the cystoscopy), symptom, or disease temporally associated with the use of IP, whether 
or not considered related to the product. 
All AEs occurring after obtaining written informed consent will be documented in the subject 
source record and eCRF.  Concomitant illnesses that existed before entry into the study will 
not be considered AEs unless they worsen after IP administration.  All AEs, regardless of 
the source of identification (eg, laboratory assessments, cystoscopy findings, subject reports) 
must be documented. 
Pre-existing conditions will be recorded in the subject source record and eCRF on the 
medical history or appropriate page. 
TEAE will be defined as an AE that begins or that worsens in severity after IP has been 
administered. 
All AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
AE will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject’s legally authorized representative). 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE and remain responsible for following up AEs 
that are serious, considered related to the study treatment or study procedures, or that caused 
the subject to discontinue the study treatment (see Section 5.1 and 5.2). 
10.2 Serious Adverse Events 
An SAE is defined as any untoward medical occurrence at any dose that: 
• Results in death 
• Is life-threatening, meaning that the subject is at risk of death at the time of the event; it 
does not mean that the event hypothetically might have caused death if it were more 
severe 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Results in a congenital anomaly/birth defect 
• Is an important medical event(s) that may not be immediately life-threatening or result 
in death or hospitalization but that may jeopardize the subject or require intervention to 
prevent one of the above outcomes.  Examples of such events are invasive or 
malignant cancers, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization or 
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Medical and scientific judgment should be exercised in deciding whether a case is serious and 
whether expedited reporting is appropriate. 
AEs reported from clinical studies and associated with hospitalization or prolonged 
hospitalization are considered serious.  Any hospitalization except observational admissions 
of less than 24 hours for logistical reasons meets these criteria.  This category also includes 
transfer within the hospital to an acute/intensive care unit (eg, from a standard-of-care unit to 
an acute/intensive care unit). 
Hospitalization does not include the following: 
• Rehabilitation facilities, hospice facilities, or respite care (eg, caregiver relief) 
• Nursing homes or skilled nursing facilities 
• Emergency room visits 
• Same-day surgeries (such as outpatient/same day/ambulatory procedures) 
• <24-hour admissions for observation or evaluation for logistical reasons 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include the following: 
• Admission for treatment of a pre-existing condition that did not worsen 
• Hospitalizations for cosmetic elective surgery, social, and/or convenience admissions 
• Pre-planned treatments or surgical procedures, which should be noted in the baseline 
documentation for the individual subject 
10.3 Cystoscopy, Vital Signs, Electrocardiograms and Laboratory Tests 
If an abnormal findings of cystoscopy, vital signs, ECGs or laboratory tests are observed, the 
Investigator should judge whether it is an AE or not by referring to the following criteria: 
• When any medical intervention such as pharmacotherapy or surgical care is performed 
in order to improve the abnormality 
• Other than case above, when investigator judges that the abnormality is medically 
important and should be considered an AE 
10.4 Process for Collecting Adverse Events and Serious Adverse Events Information 
All AEs and SAEs will be collected from the signing of the ICF continuously until Day 29 as 
specified in the Schedule of Activities (See Table 1). 
Medical occurrences that begin before the start of study treatment but after obtaining 
informed consent will be recorded on the medical history/current medical conditions section 
in the eCRF not the AE section. 
All SAEs during study treatment period will be recorded and reported to the Sponsor or 
designee within 24 hours, as indicated in Appendix 12. 
The Investigator will submit any updated SAE data to the Sponsor or designee within 
24 hours of it being available. 
Investigator will conduct physical examination to collect on Screening, Day 1 (pre-dose), 
Day 2, Day 3, Day 5, Day 8, Day 15 and Day 29 or an early withdrawal visit.  Investigators 
should pay special attention to clinical signs related to previous serious illnesses. 


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Investigators are not obligated to actively seek AE or SAE reports from former study 
subjects.  However, if the Investigator learns of any SAE, including a death, at any time 
after a subject has been discharged from the study, and he/she considers the event to be 
reasonably related to the study treatment or study participation, the Investigator must 
promptly notify the Sponsor. 
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix 12. 
10.5 Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about AE 
occurrences. 
10.6 Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the Investigator is required to proactively follow each subject 
at subsequent visits/contacts.  All SAEs will be followed until resolution, stabilization, the 
event is otherwise explained, or the subject is lost to follow-up (as defined in Section 5.3). 
Further information on follow-up procedures is given in Appendix 12. 
10.7 Regulatory Reporting Requirements for Serious Adverse Events 
Prompt notification (within 24 hours) by the Investigator to the Sponsor of a SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of subjects and the 
safety of a study treatment under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation.  The 
Sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB, and Investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and Sponsor policy and forwarded to 
Investigators as necessary. 
An Investigator who receives an Investigator safety report describing a SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then 
file it along with the Investigator’s Brochure and will notify the IRB, if appropriate according 
to local requirements. 
10.8 Pregnancy 
Details of all pregnancies in female subjects and, if indicated, female partners of male 
subjects which occur during the study, will be collected. 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 


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11 STATISTICAL METHODS 
While key analyses are described in this section, additional analyses, including supportive 
analysis, sensitivity analysis, and subgroup analysis, and details such as data handling will be 
specified in the statistical analysis plan (SAP). 
The impact of COVID-19 will be evaluated i.e. based on the missing data, and if deemed 
necessary appropriate sensitivity analyses will be performed and documented. 
 
11.1 Analysis Populations 
11.1.1 Intention-to-treat Population 
The intention-to-treat (ITT) population includes all randomized subjects regardless of 
whether the subject received any IP or had any efficacy assessment collected. 
11.1.2 Per Protocol Population 
The Per-protocol (PP) population includes all ITT subjects without major protocol deviation. 
11.1.3 Safety Population 
The safety population includes all randomized subjects who received IP.  If a subject 
receives IP other than the subject’s randomized treatment assignment, then the subject is 
assigned to the treatment arm reflecting the treatment that the subject actually received during 
the study.  
11.1.4 Pharmacokinetic Population 
The PK population includes all subjects who received SI-722 and who provided at least 1 
evaluable PK sample. 
11.2 
Demographics, Baseline Characteristics, Medical History, and Concomitant 
Medications 
Subjects’ age, height, weight, and other continuous baseline characteristics will be 
summarized using descriptive statistics, while sex, race, and other categorical variables will 
be provided using frequency tabulations.  Medical history and concomitant medications will 
be summarized using frequency tabulations by system organ class and preferred term of the 
MedDRA and Anatomical Therapeutic Chemical class and standardized drug name of WHO 
Drug Global, respectively. 
11.3 Pharmacokinetic Analyses 
Plasma and urine concentrations of SI-722 and 
 will be determined for the safety 
population.  The other PK analyses will be determined based on the PK population. 
Pharmacokinetic profiles will be assessed by plasma SI-722 and 
 concentrations, urine 
SI-722 and 
 concentrations, and the corresponding PK parameters. 
The following PK parameters for SI-722 and 
 will be estimated, where possible, using 
Phoenix WinNonlin v8.0 software (or higher) and actual blood sample collection times: 
Plasma PK parameter 
Cmax 
maximum concentration after dosing 


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tmax 
time to reach the maximum plasma concentration 
AUC0-t 
area under the plasma concentration-time curve from time 0 to t hours after 
dosing, in which time t is the last time at which the concentration can be 
observed in all cohorts. 
AUC0-last 
area under the concentration-time curve from time 0 to time the last 
quantifiable concentration 
AUC0-∞ 
area under the plasma concentration-time curve from time 0 to infinite time, 
calculated as the sum of AUClast and Clast/λz, in which Clast is the last observed 
quantifiable concentrations 
t1/2 
terminal half-life 
Vz/F 
apparent volume of distribution 
CL/F 
apparent total plasma clearance 
Urine PK parameter 
Ae 
cumulative amount of excreted in urine 
Details will be outlined in the SAP.  Additional PK parameters will be estimated and 
analyzed if needed. 
11.4  Safety Analyses 
All safety analyses will be conducted based on the safety population. 
11.4.1 Adverse Events 
AEs will be analyzed in terms of TEAEs, defined to be any event that begins or worsens in 
grade after the start of IP throughout of the study.  All AEs will be coded using MedDRA. 
The number of events and number (percentage) of subjects reporting TEAEs for each 
preferred term will be tabulated by system-organ class, by system-organ class and severity, 
and by system-organ class and relationship to IP.  If more than 1 event occurred with the 
same preferred term for the same patient, the subject will be counted only once for that 
referred term using the most severe or related occurrence for the summary by severity, or 
relationship to IP, respectively. 
11.4.2 Laboratory Tests 
Laboratory values will be summarized by treatment group, including changes from baseline 
at each time point.  The number (percentage) of subject with abnormal will be summarized 
and the shift tables will be tabulated by treatment group and time points. 
11.4.3 Vital Signs 
Vital sign measurements will be summarized by treatment group, including changes from 
baseline at each time point. 


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11.4.4 Electrocardiograms 
ECGs will be summarized by treatment group, including changes from baseline at each time 
point. 
11.4.5 Cystoscopy 
The number (percentage) of subjects with abnormal cystoscopy will be summarized by 
treatment group. 
11.5 Efficacy Analyses 
All efficacy analysis will be conducted based on the ITT population. 
Each efficacy assessment will be summarized for all subjects by treatment group at each 
assessment visit.  The assessments collected on daily diary will be calculated by average at 
each assessment visit.  Efficacy assessments from the daily diary such as bladder pain and 
symptoms of IC/BPS will be summarized by study day in addition to the summary at each 
assessment visit.  
11.6 General Considerations 
Placebo group will be combined regardless of planned volume.  All study-collected data will 
be summarized by treatment group using descriptive statistics, graphs, and/or data listings. 
Unless otherwise specified, descriptive statistics for continuous variables will include number 
of subjects (n), mean, standard deviation (SD), median, and minimum (min) and maximum 
(max) values, and analysis of categorical variables will include number of patients (n) and 
percentage. 
11.6.1 Visit Window and Unscheduled Assessments 
The data collected during follow-up time point will be displayed and analyzed according to 
the actual visit date in the eCRF.  Assessments taken outside of protocol-allowable windows 
will be displayed according to the eCRF assessment recorded by the Investigator. 
Unscheduled assessments (laboratory data or vital signs associated with non-protocol clinical 
visits or obtained in investigating or managing AEs) will be included in listings but not 
summaries of the data. 
11.6.2 Significance Level and Confidence Coefficient 
A two-sided 5% significance level will be used, and a two-sided 95% confidence coefficient 
will be used for interval estimation. 
11.6.3 Missing Data 
Missing data will not be imputed and will be excluded from the analysis. 
 
 


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12 ETHICAL CONSIDERATION 
12.1 Good Clinical Practice Compliance 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
• Applicable International Council for Harmonization (ICH) Good Clinical Practice 
(GCP) Guidelines 
• Applicable laws and regulations 
12.2 Institutional Review Board Approval 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB by the Investigator and 
reviewed and approved by the IRB before the study is initiated. 
Any amendments to the protocol will require IRB approval before implementation of changes 
made to the study design, except for changes necessary to eliminate an immediate hazard to 
subjects. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB 
• Notifying the IRB of SAEs or other significant safety findings as required by IRB 
procedures 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of Title 21 of the Code of Federal Regulations (CFR), ICH guidelines, the 
IRB, European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations 
12.3 Informed Consent 
The Investigator or his/her representative will explain the nature of the study to the subjects 
and answer all questions regarding the study. 
Subjects must be informed that their participation is voluntary.  Subjects will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
requirements, where applicable, and the IRB or study center. 
The medical record must include a statement that written informed consent was obtained and 
the date the written consent was obtained.  The authorized person obtaining the informed 
consent must also sign the ICF. 
Subjects must be reconsented to the most current version of the ICF(s) during their 
participation in the study. 
A copy of the ICF(s) must be provided to the subjects. 


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12.4 Data Protection 
Participants will be assigned a unique identifier by the Sponsor.  Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law.  The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB members, and by inspectors from regulatory authorities. 
12.5 Financial Disclosure 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate 
financial information as requested to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
 
 
 


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13 PROCEDURE FOR COMPLETION AND CORRECTION OF THE 
CASE REPORT FORM 
The procedures for completion of the eCRFs and reconciliation of data queries will be 
provided in the CRF Completion Guidelines . 
 
 


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14 DIRECT ACCESS TO SOURCE DATA 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.  Source documents are filed at the Investigator’s site. 
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained.  The 
Investigator may need to request previous medical records or transfer records, depending on 
the study.  Also, current medical records must be available. 
 
 


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15 DATA QUALITY ASSURANCE 
All participant data relating to the study will be recorded on printed or eCRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data).  The Investigator 
is responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
The Investigator must permit study-related monitoring, audits, IRB review, and regulatory 
agency inspections and provide direct access to source data documents. 
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH-GCP, and all applicable regulatory requirements. 
 
 


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16 ARCHIVING OF SOURCE DATA AND OTHER RECORDS 
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for at least 2 years after the last marketing application 
approval or, if not approved, 2 years following the discontinuation of the test article for 
investigation.  If this requirement differs from any local regulations, the local regulations 
will take precedence unless the local retention policy is less than 2 years.  No records may 
be destroyed during the retention period without the written approval of the Sponsor.  No 
records may be transferred to another location or party without written notification to the 
Sponsor. 
 
 


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17 PUBLICATION POLICY 
The results of this study may be published or presented at scientific meetings by the Sponsor.  
The results of and data from this study belong to the Sponsor.  No individual subject will be 
identified in any publication. 
The Sponsor will comply with the requirements for publication of study results. 
 
 


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18 COVID-19 PANDEMIC AND SUGGESTED MEASURES 
This section is provided in response to the “FDA Guidance on Conduct of Clinical Trials of 
Medical Products during COVID-19 Pandemic” issued by the FDA on March 2020.  Taking 
the COVID-19 impact into account, this section provides guidance to Investigators and their 
site staff to mitigate risks and suggested measures to modify operations.  Each Investigator 
may choose to implement different measures according to their sites’ operations; which may 
include, but are not limited to the following items. 
 
18.1 Screening Questions to Identify Potential COVID-19 Exposure 
When scheduling an on-site visit for subjects, consider asking the subjects a few, short 
questions regarding potential exposure to COVID-19 before their on-site visit (in-person 
interactions).  For example: 
1. Have you had any of the following symptoms in the past 14 days without confirmation 
of etiology such as a positive flu test, existing chronic medical condition, etc. 
• Fever greater than 100.4 dgrees Fahrenheit 
• Cough 
• Difficulty breathing 
• Sore throat 
2. In the last 14 days, have you lived with, visited, cared for, or been in a room for a 
prolonged period of time with someone who is under investigation or has been 
confirmed for COVID-19? 
 
18.2 Screening Window 
If a subject has completed all Screening Visit procedures and is eligible to proceed to Study 
Day 1 but cannot do so within the allotted timeframe of 28 days, it will be considered to 
extend the visit window on a case by case basis.  The BPIC/SS questionnaire must be 
repeated to ensure it is valid and within 28 days of dosing, but further consultation is 
necessary with Contract Research Organization (CRO) and may necessitate approval by the 
study’s Medical Monitor and Sponsor. 
 
18.3 Follow-Up Visit by Phone 
Should a subject not be able to complete a study visit in-person, the following procedures will 
be completed via phone, as necessary by the schedule of events according to the protocol: 
1. Medical history 
2. IC/BPS history and treatment history 
3. Concomitant medication and therapy information 
4. Adverse events 
5. PRO questionnaires (BPIC-SS, ICSI/PI and GRA) 


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Site staff will capture the above in the source documents and promptly notify CRO and 
Clinical Research Associate (CRA) of the partial phone visit as soon as possible.  All 
missing data, and the phone visit itself, will be considered protocol deviations.  Site staff 
will need to complete additional forms for IRB submission and state "COVID-19" in the 
comment column of the deviation log. 
 
18.4 Remote Monitoring 
Due to travel restrictions, shelter in place or stay at home mandates, sites’ change in 
operations, and a number of other reasons to try to contain the spread of the virus and 
minimize exposure, it is reasonable to conduct monitoring visits remotely, instead of in-
person, whenever feasible.  Site staff/Investigator will work with CRO and the assigned 
CRA to define and understand the logistics of the remote visit such as source data 
verification. 
 
18.5 Data Management 
In order to confirm the effect of COVID-19 on this study, the following information will be 
captured in eCRF. 
• Missed visit due to COVID-19 
• Missed assessment due to COVID-19 
• Screen failed subject due to COVID-19 
• Early discontinuation due to COVID-19 
• AE related to COVID-19 
 
 
 






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Routine 
urinalysis 
• Specific gravity 
• pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase by dipstick 
• Microscopic examination (if blood or protein is abnormal) 
Urine culture 
• Urine culture will be performed at Screening and on Day 29 or early 
withdrawal 
Other screening 
tests 
• Urine drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines) 
• Serum β-human chorionic gonadotropin (hCG) pregnancy test (as 
needed for women of childbearing potential [WOCBP]) at Screening 
• Urine pregnancy tests (pre-dose on Day 1, and Day 29 or early 
withdrawal) 
• Serology (HIV antibody, HBsAg, and HCV antibody) 
• TB blood tests 
• NAAT for Neisseria. gonorrhoeae and Chlamydia. trachomatis 
 
Investigators must document their review of each laboratory safety report. 
 
 


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Appendix 2 
Pain Score 0-10 Numerical Rating Scale  
The NRS is a unidimensional measure of pain intensity in adults, including those with 
chronic pain due to rheumatic diseases. 
The NRS is a segmented numeric version of the visual analog scale (VAS) in which a 
respondent selects a whole number (0–10 integers) that best reflects the intensity of his/her 
pain.  Respondents are most commonly asked to report pain intensity “in the last 24 hours” 
or an average pain intensity.  The common format is a horizontal bar or line. Similar to the 
VAS, the NRS is anchored by terms describing pain severity extremes. 
The 11-point NRS ranges from ‘0’ representing 1 pain extreme (eg, “no pain”) to ‘10’ 
representing the other pain extreme (eg, “pain as bad as you can imagine” or “worst pain 
imaginable”). 
Subjects will select the level that best describes their maximum and average bladder pain 
over the last 24 hours, and their bladder pain at the moment, respectively. 
 
PAIN SCORE 0-10 NUMERICAL RATING 
□0 
□1 
□2 
□3 
□4 
□5 
□6 
□7 
□8 
□9 
□10 
No 
pain 
 
 
 
 
Moderate 
pain 
 
 
 
 
Worst 
possible 
pain 
 
 
 


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Appendix 3 
Symptoms of Interstitial Cystitis/Bladder Pain Syndrome 
Subjects will select the level that best describes the severity of other symptom from their 
bladder over the last 24 hours. 
 
 
Not at all 
Mild 
Moderate 
Severe 
Pain 
□ 
□ 
□ 
□ 
Burning 
□ 
□ 
□ 
□ 
Discomfort 
□ 
□ 
□ 
□ 
Pressure 
□ 
□ 
□ 
□ 
 
 
 


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Appendix 4 
Voiding Frequency 
Subject will record their responses to the following items every day. 
 
Daytime urine: 
 
Night time urine (urination wake you up from sleeping): 
 
 
 
 


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Appendix 5 
Frequency of Bladder Pain 
Subject will select the level that the best describes frequency of bladder pain when they 
urinate and voiding frequency caused by bladder pain. 
 
Never 
Rarely 
Sometimes 
Always 
□ 
□ 
□ 
□ 
 
 
 


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Appendix 6 
Voiding Volume 
Subject will record 5 times of voiding volume with the time in a day.  First voiding in the 
morning and before you go to bed are preferable. 
 
 
Time 
(24-hour notation) 
Volume 
 
Record by container with scale 
Select BLQ if less than the minimum scale 
1 
Time 
(24-hour notation) 
Volume 
 
: 
 
                         mL/ BLQ 
2 
Time 
(24-hour notation) 
Volume 
 
: 
 
                         mL/ BLQ 
3 
Time 
(24-hour notation) 
Volume 
 
: 
 
                         mL/ BLQ 
4 
Time 
(24-hour notation) 
Volume 
 
: 
 
                         mL/ BLQ 
5 
Time 
(24-hour notation) 
Volume 
 
: 
 
                         mL/ BLQ 
 
 
 


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Appendix 7 
Acetaminophen Consumption 
Please record the time, the number of tablets and bladder pain when you take rescue 
medicine. 
 
 
Time 
(24-hour notation) 
Please fill in from 
getting up to getting up 
the next day 
Number of 
tablets 
Please fill in the 
number of tablets 
taken 
Pain score 
Each time you took acetaminophen, select the level of your 
bladder pain from 1 – 10* 
1 
Time 
(24-hour notation) 
 
: 
 
Number of 
tablets 
 
Pain score 
□0  □1  □2  □3  □4  □5  □6  □7  □8  □9  □10 
2 
Time 
(24-hour notation) 
 
: 
 
Number of 
tablets 
 
Pain score 
□0  □1  □2  □3  □4  □5  □6  □7  □8  □9  □10 
3 
Time 
(24-hour notation) 
 
: 
 
Number of 
tablets 
 
Pain score 
□0  □1  □2  □3  □4  □5  □6  □7  □8  □9  □10 
4 
Time 
(24-hour notation) 
 
: 
 
Number of 
tablets 
 
Pain score 
□0  □1  □2  □3  □4  □5  □6  □7  □8  □9  □10 
5 
Time 
(24-hour notation) 
 
: 
 
Number of 
tablets 
 
Pain score 
□0  □1  □2  □3  □4  □5  □6  □7  □8  □9  □10 
6 
Time 
(24-hour notation) 
 
: 
 
Number of 
tablets 
 
Pain score 
□0  □1  □2  □3  □4  □5  □6  □7  □8  □9  □10 
* 0: No pain, 5: Moderate pain, 10: Worst possible pain 
 
 




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Appendix 9 
Bladder Pain Interstitial Cystitis Symptom Score 
 
 
 


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Appendix 10 Global Response Assessment 
 
Global Response Assessment 
As compared to when you started the study, how would you rate your overall symptoms now? 
□ 
Markedly worse 
□ 
Moderately worse 
□ 
Slightly worse 
□ 
No change 
□ 
Slightly improved 
□ 
Moderately improved 
□ 
Markedly improved 
 
 
 


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Appendix 11 Brief Scale for Psychiatric Problem in Orthopaedic Patients 
Appendix 11.1 Questionnaire for medical personnel 
 
Appendix 11.2 Questionnaire for patients