Real-world Evidence Observational Study to Evaluate Performance and Safety of Intravesical Sodium Hyaluronate (Cystistat®) in the Treatment of Patients With Interstitial Cystitis (IC) / Bladder Pain Syndrome (BPS)
Conditions: Interstitial Cystitis and Bladder Pain Syndrome
Sponsor: MEDA Pharma GmbH & Co. KG

Version 1.0, 06-Apr-2022
Confidential
CYST-SLZ-7001
CLINICAL INVESTIGATION PLAN (PROTOCOL)
Protocol Title
Real-world evidence observational study to evaluate performance and safety 
of intravesical sodium hyaluronate (Cystistat®) in the treatment of patients 
with interstitial cystitis (IC)/bladder pain syndrome (BPS).
Short Title
Real-world evidence study on Cystistat
Protocol Number
CYST-SLZ-7001
Product
Cystistat
Study Type
Non-interventional study (NIS)
Version
1.0
Protocol Date
06-Apr-2022
Legal/Filing 
Sponsor
MEDA Pharma GmbH & Co. KG (A Viatris Company)
Benzstrasse 1, 61352 Bad Homburg, Germany
Confidentiality:
This protocol is the confidential, intellectual property of MEDA Pharma GmbH & Co. KG (A 
Viatris Company). It should not be disclosed to a third party with the exception of regulatory 
agencies and study audit personnel that being Viatris employees, representatives, agents 
and/or contractors responsible for conducting the clinical study/trial, audits. Reproduction, 
modification, or adaption in part or in total is strictly forbidden without prior written approval 
by MEDA Pharma GmbH & Co. KG (A Viatris Company).

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DOCUMENT HISTORY
Document 
Version, Date
Summary of Changes with Rationale
1.0
06-Apr-2022
NA

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PROTOCOL SYNOPSIS
Protocol Title
Real-world evidence observational study to evaluate performance and safety of 
intravesical sodium hyaluronate (Cystistat®) in the treatment of patients with 
interstitial cystitis (IC)/bladder pain syndrome (BPS)
Short Title
Real-world evidence study on Cystistat
Protocol 
Number
CYST-SLZ-7001
Study Sites
European multicenter study with approximately 15 study sites (approximately up
to 15 patients per site)
Co-ordinating 
Investigator
Study Period 
Planned
Period from start of recruitment till end of study: 
Q2 2022 to Q3 2023
Duration of 
Individual 
Treatment
For assessment of performance and safety the intended duration of observation 
per patient is approximately 6 months
End of Study
Date of the last visit of the last patient included in the study
Background 
and Rationale
Hyaluronan, the biologic form of hyaluronic acid, is found in numerous tissues 
in the human body. It is part of interstitial fluids in connective tissues and is also 
an important contributor to surface barriers. Specifically, the importance of 
hyaluronan as the predominant substance of the Glycosaminoglycan (GAG) 
layer that protects the urothelial surface of the urinary bladder has been well 
investigated and documented (1, 2). 
The impact of a GAG layer defect in Bladder Pain Syndrome (BPS)/Interstitial
Cystitis (IC), a chronic bladder disease characterized by bladder pain and a
variety of voiding symptoms was recognized about two decades ago. The 
protective effect of the GAG layer on the transitional surface of the bladder is 
explained as follows: The hydrophilic glycosaminoglycans bind water molecules 
in preference to other cations and thus form a molecular layer of water at the 
bladder surface which acts as a barrier to urinary solutes, crystals and bacteria. 
Relevant components of the GAG layer include hyaluronic acid, chondroitin 
sulphate, heparin, heparin sulfate, dermatan sulfate and keratan sulfate.
Impairment of this specific layer maybe an initial etiologic event in IC/BPS 
resulting in a leaky epithelium which is permeable to urinary solutes. An
increased uptake of potassium through the leaky surface may induce urgency 

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and pain, damage tissue and promote the pathogenesis of IC/BPS. This 
postulated pathogenetic mechanism may explain the main disease symptoms.
The benefit of GAG substitution therapy in such cases of GAG layer injury has 
been well documented in several clinical studies since then. Various 
investigators have reported clinically significant remission rates for intravesical 
hyaluronan instillation therapy. Several uncontrolled as well as a controlled 
study have shown remission rates between 60 and 85% (3-8). In addition to its 
efficacy, Cystistat is known to have a good safety profile with a low level of
adverse events (9). 
In the past years the term IC has become misleading since inflammatory changes 
have not been detected in all symptomatic patients and was therefore replaced by 
an expert panel with the term BPS. This name is in line with recent 
recommendations by the European Association of Urology and is based on the 
axial structure of the International Association for the Study of Pain 
classification. To facilitate this name change, the European Society for Studies
of Interstitial Cystitis (ESSIC) agreed to include IC in the overall term during a 
transition period (10). Based on that, the aim of this study is assessment of 
Cystistat therapy in IC/BPS patients.
This study will be conducted with the aim of ensuring the continued
acceptability of the benefit-risk ratio and confirming the safety and performance 
of the device throughout its expected lifetime.
Real-world evidence observational studies are considered as an expedient tool to 
reflect the use of a product under real life conditions. However, due to the 
known difficulties with the diagnosis of IC/BPS, only clinical sites using state of 
the art diagnostic measures according to current therapeutic guidelines will be 
selected for this study.
A previous randomized, placebo-controlled trial with Cystistat showed 
limitations of using a placebo group. In this study, the initial response rate in the 
placebo group was higher than in the Cystistat group, with a turnaround of 
results at a later timepoint. Several possible explanations for these unexpected 
findings have been published (8). As the most likely reason for the placebo 
efficacy the possible beneficial effect from the alkalizing placebo solution has
been assumed.
Based on these considerations and on the known difficulties in recruiting high 
number of patients in this indication, an observational real world evidence study 
was chosen as the best feasible way to collect additional data to demonstrate the 
benefit/risk profile of Cystistat and compliance with the safety and performance
requirements of the Medical Device Regulation (MDR) (11, 12).
Primary 
Objective
To collect data on the performance of Cystistat on patients’ overall IC/BPS 
condition at end of treatment or latest at week 12 in routine clinical practice.
Primary 
Endpoint
Responder rate to treatment at end of treatment or latest at week 12 as indicated 
by improvement on a seven-point Patient Global Assessment (PGA) scale where 
the patient is able to evaluate the overall change in her/his IC/BPS condition as 
markedly improved, moderately improved, slightly improved, no change, 
slightly worse, moderately worse or markedly worse. For the primary analysis, a 
responder is defined as a patient who has experienced an improvement on the 
PGA scale (i.e., PGA evaluated as markedly improved, moderately improved, or

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slightly improved. In case of slightly improved, patients will only be considered 
as responders if the question “Did therapy have a positive effect on your life and 
would you undergo this treatment again?” is answered with “Yes”.).
Secondary 
Objectives
x
Evaluation of the change of morning voiding volume over time (until 
month 6)
x
Evaluation of the change of 24-hour urinary frequency and voiding volume
(daytime and nighttime) over time (until month 6)
x
Evaluation of change from baseline in Bladder Pain/Interstitial Cystitis 
Symptom Score (BPIC-SS) (at end of treatment or latest at week 12 and at
month 6)
x
Evaluation of patients’ overall IC/BPS condition at month 6 (using the same
approach as for the primary objective)
x
Evaluation of patients’ overall IC/BPS condition at end of treatment or latest 
at week 12 and at month 6 (using the PGA but with an alternative responder 
definition)
x
Evaluation of the change from baseline in bladder pain and urinary urgency 
on Visual Analogue Scale (VAS) (until month 6)
x
Evaluation of the change from baseline in quality of life (QoL) on Visual 
Analogue Scale (VAS) (until month 6) 
x
Evaluation of concomitant IC/BPS and pain medication use (until month 6)
x
Evaluation of flares (symptom deterioration) (until month 6)
x
Evaluation of premature termination of treatment
x
Assessment of tolerability and safety (until month 6)
Secondary
Endpoints
x
Morning voiding volume over time (from patient diaries, until month 6).
x
Total number of voids and total voiding volume (daytime and nighttime)
over the last 24 hours (from patient diaries, until month 6)
x
Change from baseline to end of treatment or latest to week 12 and to month 
6 in Bladder Pain/Interstitial Cystitis Symptom Score (BPIC-SS).
x
Percent responders at month 6 as indicated by improvement on the 7-point 
Patient Global Assessment (PGA) scale using the same responder definition
as for the primary endpoint.
x
Percent responders at end of treatment or latest at week 12 and at month 6 as 
indicated by improvement on the 7-point Patient Global Assessment (PGA) 
scale using an alternative responder definition (i.e. a responder is defined as 
a patient who experiences moderate or marked improvement).
x
Change from baseline to end of treatment or latest to week 12 and to 
month 6 in bladder pain and urinary urgency on Visual Analogue Scale 
(VAS) scored from 0 to 100.
x
Change from baseline to end of treatment or latest to week 12 and to month 
6 in quality of life (QoL) on Visual Analogue Scale (VAS) scored from 0 to 
100.

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x
Use of concomitant IC/BPS and pain medication count (until month 6).
x
Occurrence of flares (documented as adverse events) and additional BPIC-
SS (at the time of occurrence) (until month 6).
x
Premature termination of treatment.
x
Safety assessments: Adverse events and incidents (until month 6).
Methodology
Multinational, multicenter, prospective, real-world evidence (RWE) 
observational study.
Patients will be enrolled in the study upon signing an Informed Consent.
Cystistat will be instilled into the bladder according to the instructions for use. 
The observation period for this study will end approximately 6 months after start 
of treatment (irrespective of the duration of treatment). If required, treatment 
will be continued thereafter under regular medical care.
Investigational 
Medical Device
This non-interventional study (NIS) refers only to the regular prescription of 
commercially available Cystistat according to instructions for use (IFU).
Cystistat is a clear colorless solution presented in a 50 mL glass vial containing 
40 mg sodium hyaluronate. It is manufactured by Mylan 
and distributed by third companies in some countries.
Inclusion/ 
exclusion 
criteria
To be eligible for inclusion, a patient must comply with all of the following 
criteria:
x
First prescription of Cystistat according to instructions for use.
x
Female patients of any ethnic origin with clinical diagnosis of interstitial 
cystitis (IC)/bladder pain syndrome (BPS). If in accordance with routine 
clinical practice at the site, ESSIC diagnostic criteria will be used.
x
Age: 18 years and older. 
x
At least 6 months duration of bladder pain/discomfort symptom(s), e.g. 
constant bladder pain/discomfort or bladder pain/discomfort when voiding 
or as a burning sensation between voids as the bladder fills with urine.
x
At least one accompanying intermittent or persistent lower urinary tract 
symptom, such as urinary frequency, urgency, or nocturia during the 
previous 6 months.
x
Bladder Pain/ Interstitial Cystitis Symptom Score (BPIC-SS) > 18 prior to 
first treatment.
x
Written informed consent.
The patient is not eligible for participating in this study, if one or more of the 
following criteria are met:
x
Known hypersensitivity reactions to sodium hyaluronate.
x
Pregnancy / planned pregnancy or breastfeeding during the course of this 
NIS.
x
Known history of any GAG substitution therapy within the last 2 years.
x
Known history of fulguration or resection of Hunner’s lesions.
x
Known diagnosis of recurrent urinary tract infection or overactive bladder.
x
Any other conditions or diseases that can cause similar symptoms, using 
information from medical history, physical examination findings, laboratory
studies (e.g., urine bacterial culture), and other previously performed 

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procedures (e.g., urodynamics, cystoscopy, laparoscopy, radiological 
studies).
x
Patients are not able to fulfil study requirements according to physician’s 
opinion.
Planned 
Number of
Patients
Approximately 74 patients (including approximately 10% drop-outs).
Accounting for approximately 10% drop-outs, further 7 patients and a total of 74
patients should be included in this study.
Statistical 
Methods
All analyses will be exploratory in character and all assessed measures will be 
analyzed. Continuous variables will be summarized by number (N), mean, 
standard deviation (SD), minimum, 5% percentile (P5), lower quartile (Q1), 
median, upper quartile (Q3), 95% percentile (P95) and maximum. Categorical 
variables will be presented in frequency distribution tables with number (N) and
percentage. All endpoint assessments with more than two time points will be 
tabulated by timepoint and displayed graphically for absolute values and change 
from baseline values.
If there is a substantial rate of patients with rescue medication (n> 20), 
explorative subgroup analyses will be provided for patients with and without 
rescue medication.
Populations for statistical analyses:
Safety (SAF) population: All enrolled patients who received at least one 
instillation of Cystistat and validity of data is confirmed by the physician.
Full analysis set (FAS) population: All patients of the SAF, who have at least 
one post baseline assessment.

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Interim analysis:

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Table 0-1
Study Schedule
Baseline1)
During 
Treatment
End of
Treatment2)
Follow-up3)
STUDY DAY
Before first 
treatment
Week 1-11 
(as per 
standard of 
care)
Latest 
Week 12
(Month 3)
Approximately
Month 6
Written informed consent
X
Demography and medical history4)
X
In-/exclusion criteria
X
Patient Global Assessment of overall
IC/BPS condition improvement5)
X
X
Assessment of BPIC-SS6)
X
X
X
Assessment of VAS7)
X
X
X
Instillation of Cystistat8)
X
X
(X)
Dispense of diary card9)
X
X
Review of diary card
X
X
X
Collection of diary card
X
X
Assessment of concomitant medications10)
X
X
X
Assessment of adverse events, incidents11)
X
X
X
X
1
Baseline assessments may be performed on the first treatment visit prior to instillation of Cystistat according to routine
clinical practice.
2
This assessment will be performed on the last treatment day or latest at week 12; if required, treatment will be 
continued after week 12 under regular medical care.
3
Follow-up will be performed as an on-site visit if in accordance with routine clinical practice; if not possible as an on-
site visit, the information will be collected remotely (e.g., via phone and postal mail) from the patient.
4
Demography and medical history:
x
Patients’ demographic and anamnestic background data
x
Diagnostic criteria of IC/BPS diagnosis
x
Previous and current treatments
5
Patient Global Assessment of overall IC/BPS condition improvement: To be completed at end of treatment or latest at 
week 12 and at month 6.
6
Bladder Pain/ Interstitial Cystitis Symptom Score (BPIC-SS): To be completed prior to the first treatment, at end of 
treatment or latest at week 12, and at month 6.
7
Visual Analogue Scale (VAS) for bladder pain, urinary urgency, and quality of life (QoL): To be completed prior to 
first treatment, at end of treatment or latest at week 12, and at month 6.
8
Instillation of Cystistat: Cystistat will be instilled into the bladder according to the instructions for use; the regimen and 
duration of treatment will depend on the investigators’ discretion; each instillation of Cystistat until month 6 will be 
recorded in the eCRF; the observation period for this study will end approximately at month 6 (irrespective of the
duration of treatment); if required, treatment will be continued after month 6 under regular medical care.
9
Diary card: The following assessments are to be filled out by the patient:
x
Morning voiding volume once a week, preferably on the treatment day (until end of treatment or latest week 12)
and once at month 6
x
Urinary voids and the respective volumes over a period of 24 hours once a week, preferably starting the day before
the treatment day (until end of treatment or latest week 12) and once at month 6
x
Use of concomitant IC/BPS medication, pain medication, and other relevant concomitant medication (until 
month 6)
x
Adverse events (until month 6)
10
The use of concomitant IC/BPS medication, pain medication, and other relevant concomitant medication will be 
recorded; it is not required to collect all concomitant medication
11
Adverse events and incidents will be recorded after first instillation of Cystistat; prior to first instillation of Cystistat
only adverse events will be recorded.

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SIGNATURE PAGE
Protocol Title
Real-world evidence observational study to evaluate 
performance and safety of intravesical sodium hyaluronate
(Cystistat®) in the treatment of patients with interstitial cystitis 
(IC)/bladder pain syndrome (BPS)
Protocol Number
CYST-SLZ-7001
Version
1.0
Protocol Date
06-Apr-2022
Clinical Sciences Lead (Author):
Urology, Allergy
Global Clinical Sciences
Safety Lead (Reviewer):
Global Parapharmaceutical 
Science
Quality Assurance Lead (Reviewer):
Global Quality
Statistical Lead (Reviewer):
Global Clinical Operations
Clinical Operations Program Lead (Reviewer):
Sponsor Global Clinical Sciences Representatives (Approver):
Allergy, Dermatology, CV and 
Pain

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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................2 
PROTOCOL SYNOPSIS........................................................................................................3 
SIGNATURE PAGE..............................................................................................................10 
TABLE OF CONTENTS ......................................................................................................11 
LIST OF COMMONLY USED ABBREVIATIONS .........................................................15 
1.0 
INTRODUCTION.......................................................................................................17 
1.1 
Indication...................................................................................................................17 
1.2 
Background and Rationale.........................................................................................17 
1.3 
Investigational Medical Device .................................................................................18 
1.4 
Ethics and Benefit-Risk Considerations ....................................................................18 
2 
OBJECTIVES AND ENDPOINTS ...........................................................................18 
2.1 
Objectives ..................................................................................................................18 
2.1.1 
Primary Objective......................................................................................................18 
2.1.2 
Secondary Objectives.................................................................................................18 
2.1.3 
Other Objectives ........................................................................................................19 
2.2 
Endpoints...................................................................................................................19 
2.2.1 
Primary Endpoint ......................................................................................................19 
2.2.2 
Secondary Endpoints .................................................................................................19 
2.2.3 
Other Endpoints (Efficacy)........................................................................................20 
3 
STUDY DESIGN.........................................................................................................20 
3.1 
Overall Design...........................................................................................................20 
3.2 
Rationale for Study Design........................................................................................20 
3.3 
End of Study Definition.............................................................................................21 
4 
STUDY POPULATION .............................................................................................21 
4.1 
Study Population........................................................................................................21 
4.2 
Inclusion and Exclusion Criteria ...............................................................................21 
4.2.1 
Inclusion Criteria.......................................................................................................21 
4.2.2 
Exclusion Criteria......................................................................................................21 
4.2.3 
Criteria for Study Treatment Termination, Withdrawal from the Study and Study 
Termination................................................................................................................22 
4.3 
Replacement Policy ...................................................................................................22 
4.4 
Lifestyle Guidelines...................................................................................................22 
4.5 
Contraception.............................................................................................................23 

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4.6 
Pregnancy Testing .....................................................................................................23 
5 
STUDY TREATMENT ..............................................................................................23 
5.1 
Investigational Medical Device .................................................................................23 
5.2 
Administration of Investigational Medical Device....................................................23 
5.3 
Supply of Investigational Medical Device ................................................................23 
5.4 
Storage, Disposition of Unused Investigational Medical Device and Accountability
...................................................................................................................................23 
5.5 
Randomization...........................................................................................................23 
5.6 
Breaking the Blind.....................................................................................................24 
5.7 
Rescue Medication.....................................................................................................24 
5.8 
Concomitant Medications..........................................................................................24 
5.9 
Treatment Compliance...............................................................................................24 
5.10 
Therapy at End of Study for Compassionate Use......................................................24 
6 
STUDY CONDUCT....................................................................................................24 
6.1 
Baseline (before first treatment)................................................................................25 
6.2 
During Treatment (Week 1-11, as per standard of care) ...........................................25 
6.3 
End of Treatment (or latest at Week 12, Month 3)....................................................26 
6.4 
Follow up (approximately at Month 6)......................................................................27 
6.5 
Withdrawal and Early Termination ...........................................................................28 
7 
TREATMENT PROCEDURES AND ASSESSMENT CRITERIA......................29 
7.1 
Performance Assessments .........................................................................................29 
7.1.1 
Patient Global Assessment (PGA).............................................................................29 
7.1.2 
Bladder Pain/Interstitial Cystitis Symptom Score (BPIC-SS) ...................................30 
7.1.3 
Visual Analogue Scale (VAS).....................................................................................30 
7.1.3.1 Bladder Pain..............................................................................................................30 
7.1.3.2 Urinary Urgency........................................................................................................30 
7.1.3.3 Quality of Life (QoL) .................................................................................................30 
7.1.4 
Morning Voiding Volume ..........................................................................................30 
7.1.5 
24-hour Urinary Frequency and Voiding Volume.....................................................31 
7.1.6 
Use of Concomitant IC/BPS and Pain Medication....................................................31 
7.1.7 
Occurrence of Flares.................................................................................................31 
7.1.8 
Premature Termination of Treatment........................................................................31 
7.2 
Safety Assessment .....................................................................................................31 
7.2.1 
Adverse Events and Incidents ....................................................................................31 

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8 
STATISTICAL CONSIDERATIONS ......................................................................32 
8.1 
Sample Size Determination-......................................................................................32 
8.2 
Populations for Analyses ...........................................................................................32 
8.3 
Statistical Analyses....................................................................................................33 
8.3.1 
Definition of the Primary Efficacy Endpoint.............................................................33 
8.3.2 
Primary Analysis of Primary Endpoint .....................................................................33 
8.3.3 
Sensitivity Analysis of Primary Endpoint ..................................................................33 
8.3.4 
Missing Data..............................................................................................................33 
8.3.5 
Sub-Group Analyses ..................................................................................................34 
8.3.6 
Definition and Analysis of the Secondary Endpoint(s)..............................................34 
8.3.7 
Safety Analyses ..........................................................................................................34 
8.3.7.1 Adverse Events and Incidents ....................................................................................34 
8.3.8 
Planned Interim Analyses..........................................................................................35 
9 
ADMINISTRATIVE PROCEDURES......................................................................35 
9.1 
Source Documentation...............................................................................................35 
9.2 
Access to Data/Source Documentation .....................................................................35 
9.3 
Final Clinical Study Report and Case Report Forms (CRFs)....................................35 
9.4 
Adherence to Protocol ...............................................................................................36 
9.5 
Monitoring and Site Training ....................................................................................36 
9.6 
Data Handling and Record Retention........................................................................36 
9.6.1 
Data Management .....................................................................................................37 
9.6.2 
Archiving....................................................................................................................37 
9.7 
Data Protection and Confidentiality ..........................................................................38 
9.8 
Ethics and Regulatory Authorities.............................................................................38 
9.9 
Informed Consent ......................................................................................................39 
9.10 
Study Registration .....................................................................................................39 
9.11 
Disclosure and Publication of Clinical Study Data ...................................................39 
9.12 
Financing and Insurance............................................................................................39 
9.13 
Quality Assurance......................................................................................................40 
9.14 
Audits and Inspections...............................................................................................40 
9.15 
End of Trial................................................................................................................40 
10 
ADVERSE EVENTS AND INCIDENTS REPORTING ........................................41 
10.1 
Definitions .................................................................................................................41 

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10.2 
Collection and Recording of Adverse Events and Incidents .....................................43 
10.3 
Classification of Adverse Events and Incidents ........................................................44 
10.3.1 
Severity ......................................................................................................................44 
10.3.2 
Causality....................................................................................................................45 
10.3.3 
Expectedness..............................................................................................................47 
10.3.4 
Outcome.....................................................................................................................47 
10.3.5 
Action Taken with the Investigational Medical Device .............................................47 
10.4 
Reporting of Adverse Events and Incidents ..............................................................48 
10.4.1 
Investigator Reporting: Notifying the Study Sponsor................................................48 
10.4.2 
Follow-up...................................................................................................................49 
10.4.3 
Investigator Reporting: Notification of Ethics Committee........................................49 
10.4.4 
Investigator Reporting of Pregnancy - notifying the study sponsor..........................49 
11 
REFERENCE LIST....................................................................................................50 
LIST OF TABLES
Table 0-1 
Study Schedule.....................................................................................................9 
LIST OF FIGURES
Not applicable.

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LIST OF COMMONLY USED ABBREVIATIONS
Abbreviation
Description
AE
Adverse Event
ANCOVA
Analysis of Covariance
BPS
Bladder Pain Syndrome
BPIC-SS
Bladder Pain/Interstitial Cystitis Symptom Score
CE
European Conformity (Conformité Européene)
CI 
Confidence Interval
CIP
Clinical Investigation Plan (synonymous with Protocol)
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Clinical Research Organization
DMP
Data Management Plan
DVP
Data Validation Plan
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EEA
European Economic Area
ESSIC
European Society for the Study of Interstitial Cystitis
FAS
Full Analysis Set
GAG
Glycosaminoglycan
GDPR
General Data Protection Regulation
IC
Interstitial Cystistis
ICF
Informed Consent Form
IEC
Independent Ethics Committee
IFU
Instructions for Use
IMDRF
International Medical Device Regulators Forum
IRB
Institutional Review Board
ISF
Investigator’s Site File
ISO
International Organization for Standardization
LEC
Local Ethics Committee
MDCG
Medical Device Coordination Group
MDR
Medical Device Regulation
MedDRA
Medical Dictionary for Regulatory Activities
N
Number
NIS
Non-interventional Study
NSAID
Non-steroidal Anti-inflammatory Drug
PDF
Portable Document Format
PGA
Patient Global Assessment
P5
5% Percentile
P95
95% Percentile
PI
Principal Investigator
Q1
Lower Quartile
Q3
Upper Quartile
QA
Quality Assurance

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QoL
Quality of Life
RWE
Real World Evidence
SAF
Safety (Population)
SAP
Statistical Analysis Plan
SD
Standard Deviation
SOP
Standard Operating Procedure
TMF
Trial Master File
USA
United States of America
VAS
Visual Analogue Scale
WHO
World Health Organization

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1.0
INTRODUCTION
1.1
Indication
Interstitial Cystitis (IC)/Bladder Pain Syndrome (BPS) is a chronic bladder disease
characterized by bladder pain and a variety of voiding symptoms.
The impact of a glycosaminoglycan (GAG) layer defect in this indication was recognized 
about two decades ago. The protective effect of the GAG layer on the transitional surface of 
the bladder is explained as follows: The hydrophilic glycosaminoglycans bind water 
molecules in preference to other cations and thus form a molecular layer of water at the 
bladder surface which acts as a barrier to urinary solutes, crystals and bacteria. Relevant 
components of the GAG layer include hyaluronic acid, chondroitin sulphate, heparin, heparin 
sulfate, dermatan sulfate and keratan sulfate.
Impairment of this specific layer maybe an initial etiologic event in IC/BPS resulting in a 
leaky epithelium which is permeable to urinary solutes. An increased uptake of potassium 
through the leaky surface may induce urgency and pain, damage tissue and promote the 
pathogenesis of IC/BPS. This postulated pathogenetic mechanism may explain the main 
disease symptoms.
In the past years the term IC has become misleading since inflammatory changes have not 
been detected in all symptomatic patients and was therefore replaced by an expert panel with 
the term BPS. This name is in line with recent recommendations by the European Association 
of Urology and is based on the axial structure of the International Association for the Study 
of Pain classification. To facilitate this name change, the European Society for Studies of 
Interstitial Cystitis (ESSIC) agreed to include IC in the overall term during a transition period 
(10). Based on that, the aim of this study is assessment of Cystistat therapy in IC/BPS
patients.
1.2
Background and Rationale
Cystistat is supplied as a 50 mL solution containing 40 mg of sodium hyaluronate. It is 
indicated for the temporary replacement of the GAG layer in the bladder. 
Hyaluronan, the biologic form of hyaluronic acid, is found in numerous tissues in the human 
body. It is part of interstitial fluids in connective tissues and is also an important contributor 
to surface barriers. Specifically, the importance of hyaluronan as the predominant substance 
of the GAG layer that protects the urothelial surface of the urinary bladder has been well 
investigated and documented (1, 2).
The benefit of GAG substitution therapy in such cases of GAG layer injury has been well 
documented in several clinical studies since then. Various investigators have reported 
clinically significant remission rates for intravesical hyaluronan instillation therapy. Several 
uncontrolled as well as a controlled study have shown remission rates between 60 and 85% 
(3-8). In addition to its efficacy, Cystistat is known to have a good safety profile with a low 
level of adverse events (9).

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Cystistat was first CE marked in 1998 and has been on the European market for >20 years 
and is available in more than 20 international markets outside Europe. This study will be 
conducted with the aim of ensuring the continued acceptability of the benefit-risk ratio and 
confirming the safety and performance of the device throughout its expected lifetime.
1.3
Investigational Medical Device
This non-interventional study (NIS) refers only to the regular prescription of commercially
available Cystistat according to the instructions for use (IFU) (13).
1.4
Ethics and Benefit-Risk Considerations
This represents a NIS, meaning that the investigator will document ongoing medical care, 
without conducting any intervention beyond normal medical practice.
The decision to prescribe Cystistat must be previous and independent from the decision to 
include the patient in the NIS. Before the study is started, the sponsor will comply with all 
national regulations, regarding notifications, approvals, or any other required administrative 
obligation.
Cystistat can be considered a well-established medical device; it was first CE marked in 1998 
and has been on the European market for >20 years and is available in more than 20 
international markets outside Europe. Cystistat has a good safety profile and low level of 
adverse events (incidents/serious incidents).
Complete information for Cystistat may be found in the Single Reference Safety Document, 
which for this study is the instructions for use (13).
2
OBJECTIVES AND ENDPOINTS
2.1
Objectives
2.1.1
Primary Objective
To collect data on the performance of Cystistat on patients’ overall IC/BPS condition at end 
of treatment or latest at week 12 in routine clinical practice.
2.1.2
Secondary Objectives
x
Evaluation of the change of morning voiding volume over time (until month 6)
x
Evaluation of the change of 24-hour urinary frequency and voiding volume (daytime and
nighttime) over time (until month 6)
x
Evaluation of change from baseline in Bladder Pain/Interstitial Cystitis Symptom Score 
(BPIC-SS) (at end of treatment or latest at week 12 and at month 6)
x
Evaluation of patients’ overall IC/BPS condition at month 6 (using the same approach as 
for the primary objective) 

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x
Evaluation of patients’ overall IC/BPS condition at end of treatment or latest at week 12
and at month 6 (using the PGA but with an alternative responder definition)
x
Evaluation of the change from baseline in bladder pain and urinary urgency on Visual 
Analogue Scale (VAS) (until month 6)
x
Evaluation of the change from baseline in quality of life (QoL) on Visual Analogue Scale 
(VAS) (until month 6) 
x
Evaluation of concomitant IC/BPS and pain medication use (until month 6)
x
Evaluation of flares (symptom deterioration) (until month 6)
x
Evaluation of premature termination of treatment
x
Assessment of tolerability and safety (until month 6)
2.1.3
Other Objectives
Not applicable.
2.2
Endpoints
2.2.1
Primary Endpoint
Responder rate to treatment at end of treatment or latest at week 12 as indicated by
improvement on a seven-point Patient Global Assessment (PGA) scale where the patient is 
able to evaluate the overall change in her/his IC/BPS condition as markedly improved, 
moderately improved, slightly improved, no change, slightly worse, moderately worse or 
markedly worse. For the primary analysis, a responder is defined as a patient who has
experienced an improvement on the PGA scale (i.e., PGA evaluated as markedly improved,
moderately improved, or slightly improved. In case of slightly improved, patients will only be 
considered as responder if the question “Did therapy have a positive effect on your life and 
would you undergo this treatment again?” is answered with “Yes”.).
2.2.2
Secondary Endpoints
The secondary endpoints of the study are:
x
Morning voiding volume over time (from patient diaries, until month 6).
x
Total number of voids and total voiding volume (daytime and nighttime) over the last 24
hours (from patient diaries, until month 6)
x
Change from baseline to end of treatment or latest to week 12 and to month 6 in Bladder 
Pain/Interstitial Cystitis Symptom Score (BPIC-SS).
x
Percent responders at month 6 as indicated by improvement on the 7-point Patient Global 
Assessment (PGA) scale using the same responder definition as for the primary endpoint.
x
Percent responders at end of treatment or latest at week 12 and at month 6 as indicated by
improvement on the 7-point Patient Global Assessment (PGA) scale using an alternative 
responder definition (i.e. a responder is defined as a patient who experiences moderate or 
marked improvement).

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x
Change from baseline to end of treatment or latest to week 12 and to month 6 in bladder 
pain and urinary urgency on Visual Analogue Scale (VAS) scored from 0 to 100.
x
Change from baseline to end of treatment or latest to week 12 and to month 6 in quality of 
life (QoL) on Visual Analogue Scale (VAS) scored from 0 to 100.
x
Use of concomitant IC/BPS and pain medication count (until month 6).
x
Occurrence of flares (documented as adverse events) and additional BPIC-SS (at the time 
of occurrence) (until month 6).
x
Premature termination of treatment.
x
Safety assessments: Adverse events and incidents (until month 6).
2.2.3
Other Endpoints (Efficacy)
Not applicable.
3
STUDY DESIGN
3.1
Overall Design
The present study is a prospective, multicenter, non-interventional study to be conducted in 
several European countries. It is planned to include approximately 15 study sites. The 
recruitment will be competitive, with a maximum of approximately 15 patients per site.
Due to the known difficulties with the diagnosis of IC/BPS, only clinical sites using state of
the art diagnostic measures according to current therapeutic guidelines will be selected for 
this study.
3.2
Rationale for Study Design
Real world evidence observational studies are considered as an expedient tool to reflect the 
use of a product under real life conditions. However, due to the known difficulties with the 
diagnosis of IC/BPS, only clinical sites using state of the art diagnostic measures according to 
current therapeutic guidelines will be selected for this study. 
A previous randomized, placebo-controlled trial with Cystistat showed limitations of using a 
placebo group. In this study, the initial response rate in the placebo group was higher than in 
the Cystistat group, with a turnaround of results at a later timepoint. Several possible 
explanations for these unexpected findings have been published (8). As the most likely reason
for the placebo efficacy the possible beneficial effect from the alkalizing placebo solution has 
been assumed.
Based on these considerations and on the known difficulties in recruiting high number of 
patients in this indication, an observational real world evidence study was chosen as the best 
feasible way to collect additional data to demonstrate the benefit/risk profile of Cystistat and
compliance with the safety and performance requirements of the Medical Device Regulation
(MDR) (11, 12).

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3.3
End of Study Definition
The end of study is defined as the date of the last visit (or remote contact) of the last patient 
included in the study.
Cystistat will be instilled into the bladder according to the instructions for use (13). The
observation period for a patient in this study will end approximately 6 months after start of 
treatment (irrespective of the duration of treatment). If required, treatment will be continued 
thereafter under regular medical care.
4
STUDY POPULATION
4.1
Study Population
Approximately 74 female patients with IC/BPS should be included in the study.
4.2
Inclusion and Exclusion Criteria
4.2.1
Inclusion Criteria
To be eligible for inclusion, a patient must comply with all of the following criteria:
x
First prescription of Cystistat according to instructions for use.
x
Female patients of any ethnic origin with clinical diagnosis of interstitial cystitis 
(IC)/bladder pain syndrome (BPS). If in accordance with routine clinical practice at 
the site, ESSIC diagnostic criteria will be used.
x
Age: 18 years and older. 
x
At least 6 months duration of bladder pain/discomfort symptom(s), e.g. constant 
bladder pain/discomfort or bladder pain/discomfort when voiding or as a burning 
sensation between voids as the bladder fills with urine.
x
At least one accompanying intermittent or persistent lower urinary tract symptom, 
such as urinary frequency, urgency, or nocturia during the previous 6 months.
x
Bladder Pain/ Interstitial Cystitis Symptom Score (BPIC-SS) > 18 prior to first 
treatment
x
Written informed consent.
4.2.2
Exclusion Criteria
The patient is not eligible for participating in this study, if one or more of the following 
criteria are met:
x
Known hypersensitivity reactions to sodium hyaluronate.
x
Pregnancy / planned pregnancy or breastfeeding during the course of this NIS.
x
Known history of any GAG substitution therapy within the last 2 years.

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x
Known history of fulguration or resection of Hunner’s lesions.
x
Known diagnosis of recurrent urinary tract infection or overactive bladder.
x
Any other conditions or diseases that can cause similar symptoms, using information 
from medical history, physical examination findings, laboratory studies (e.g., urine 
bacterial culture), and other previously performed procedures (e.g., urodynamics,
cystoscopy, laparoscopy, radiological studies).
x
Patients are not able to fulfil study requirements according to physician’s opinion.
4.2.3
Criteria for Study Treatment Termination, Withdrawal from the Study and 
Study Termination
Patients may terminate the treatment with the investigational medical device or withdraw 
from the study at any time and for any reason without prejudice to their future medical care 
by the investigator or the study center. When available, a reason for not completing the study 
will be recorded in the electronic case report form (eCRF).
After enrolling in the study, patients will come to the study site on a weekly basis up to week
12 for the instillation of Cystistat according to the instructions for use (13). If required, 
treatment will be continued thereafter under regular medical care. A follow-up visit is 
scheduled for approximately month 6 as an on-site visit if in accordance with routine clinical 
practice. If not possible as an on-site visit, the information will be collected remotely (e.g., 
via phone and postal mail) from the patient.
Possible reasons for not completing the study may include, but are not limited to, the
following:
x
The patient withdraws consent.
x
Diagnosis of pregnancy or stated intention to become pregnant. 
x
At the investigator’s discretion, if it is in the patient’s best interest due to occurrence 
of an AE or other finding (e.g. pregnancy, other exclusion criteria) considered to 
present a safety concern to continued treatment with the medical device, and warrants 
treatment withdrawal. 
x
Lost to follow-up.
The principal investigator and/or sponsor reserves the right to terminate the study for any 
reason.
4.3
Replacement Policy
Patients who are withdrawn from the study will not be replaced.
4.4
Lifestyle Guidelines
There are no special requirements as this is a non-interventional study.

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4.5
Contraception
There are no special requirements as this is a non-interventional study.
4.6
Pregnancy Testing
Pregnancy testing will be at the discretion of the investigator and as per site’s routine 
practice. 
5
STUDY TREATMENT
5.1
Investigational Medical Device
This NIS refers only to the regular prescription of commercially available Cystistat according
to the instructions for use (13).
Cystistat is a clear colourless solution presented in a 50 mL glass vial containing 40 mg 
sodium hyaluronate. It is manufactured by Mylan 
and distributed by third companies in some countries.
5.2
Administration of Investigational Medical Device
Cystistat will be instilled into the bladder according to the instructions for use (13).
Instillation is intended to be performed by a qualified healthcare professional with the use of
a sterile catheter and sterile syringe using appropriate hygienic technique, to minimize risk of 
infection.
At instillation, the clinician will check that the content of the instructions for use (13),
warnings and precautions especially, are followed before and during each treatment.
If in accordance with routine clinical practice at the site, a single-shot oral antibiotic will be 
given on instillation day.
In the event of any incident, the CRA, or sponsor study contact should be contacted 
immediately, and the event must be reported as described in Section 10.4.1.
5.3
Supply of Investigational Medical Device
Commercially available Cystistat will be prescribed as per routine clinical practice (i.e., the 
investigational medical device will not be supplied by the sponsor).
5.4
Storage, Disposition of Unused Investigational Medical Device and 
Accountability
Not required in this non-interventional study.
5.5
Randomization
Not applicable.

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5.6
Breaking the Blind
Not applicable.
5.7
Rescue Medication
Not applicable.
5.8
Concomitant Medications
It is not required to collect all concomitant medication taken during this non-interventional 
study. The use of IC/BPS medication, pain medication, and other relevant concomitant 
medication (e.g. if in context with an adverse event or incident) will be captured by the 
patient in the diary card and the investigator will provide documentation in the eCRF, 
including at least indication, daily dose, and start and stop dates of administration.
5.9
Treatment Compliance
Not applicable.
5.10
Therapy at End of Study for Compassionate Use
Not applicable.
6
STUDY CONDUCT
When the clinical decision has been made to prescribe Cystistat for the first time to a patient 
according to the instructions for use (13), the investigator will consider enrolling the patient 
into this NIS. The decision to prescribe Cystistat must be previous and independent from the
decision to include the patient in the NIS.
Patients eligible for study recruitment will have the nature, purpose, and risks of the study
explained to them by the investigator. They will be provided with a written copy of the 
informed consent form (ICF) for the study and given sufficient time to consider the study’s 
implications before deciding to participate. Patients agreeing to participate in the study will 
sign the ICF and be given a duplicate copy before recording any personal data.
In cases where the patient does not return to the next routine treatment, the site should make 
every effort to contact the patient so that they can appropriately be withdrawn from the study.
All contact attempts should be documented in the patient's medical record. Should the patient
continue to be unreachable, then she will be considered to have withdrawn from the study as
"Lost to Follow-up." For all other patients withdrawing from the study, an alternative reason 
for discontinuation should be recorded in the eCRF. Patients may voluntarily withdraw from 
the trial for any reason and at any time.
In this NIS, the intended duration of observation per patient is approximately 6 months after 
start of treatment (irrespective of the duration of treatment). For details and timings of 
assessments, refer to Section 7.0 and Table 0-1.

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6.1
Baseline (before first treatment)
Patients for whom Cystistat is prescribed by the treating investigator will be enrolled in the 
study after signing a written informed consent form. No personal data will be recorded for the 
study before the consent procedure. Once eligible patients provide written informed consent, 
baseline assessments will be completed (this may be performed on the first treatment visit 
prior to instillation of Cystistat according to routine clinical practice):
x
The investigator will review and document the patient’s demography and medical
history. This includes patients’ demographic and anamnestic background data, 
diagnostic criteria of IC/BPS diagnosis, and previous and current treatments.
x
Patients will be asked to complete the Bladder Pain/ Interstitial Cystitis Symptom 
Score (BPIC-SS). If WKH VFRUH LV 18, the patient will not be suitable for entering this 
NIS.
x
The investigator will evaluate if the patient meets the inclusion/exclusion criteria.
x
Patients will be asked to complete the Visual Analogue Scale (VAS) for bladder pain,
urinary urgency, and quality of life (QoL).
x
The investigator will assess and record any adverse events that occurred during this 
visit after signing the informed consent form.
x
The investigator will provide the patient with the diary card and instruct her on how to 
record study related data at home. The following assessments are to be filled out by 
the patient: 
1. Morning voiding volume (once a week, preferably on the treatment day)
2. Urinary voids and the respective volumes over a period of 24 hours (once a 
week, preferably starting the day before the treatment day)
3. Use of concomitant IC/BPS medication, pain medication, and other relevant 
concomitant medication
4. Adverse events 
x
A date for the next visit for the first treatment with Cystistat will be arranged and the 
investigator will remind the patient not to forget to take the diary card with her that 
day (not required if the first treatment with Cystistat is performed during the same 
visit according to routine clinical practice).
x
The investigator will enter all required data from this visit in the eCRF within 5
business days.
6.2
During Treatment (Week 1-11, as per standard of care)
The patient will visit the site on a weekly basis for the instillation of Cystistat according to 
the instructions for use (13). The first treatment with Cystistat may be performed during the 
same visit as for the baseline assessments according to routine clinical practice (in this case 
not all of the below mentioned procedures need to be performed at the first treatment visit).
At each visit, procedures will be completed in the following order:

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x
The investigator will review the paper diary card, copy new entries, and transcribe the 
information recorded by the patient into the eCRF (not required at first treatment visit 
if performed on same visit as for the baseline assessment).
x
The investigator will assess and record any adverse events that occurred since the last 
visit (not required at first treatment visit if performed on same visit as for the baseline 
assessment).
x
The investigator will record any concomitant use of IC/BPS medication, pain 
medication, and other relevant concomitant medication that were taken since the last
visit; it is not required to collect all concomitant medication (not required at first
treatment visit if performed on same visit as for the baseline assessment).
x
Cystistat will be instilled into the bladder according to the instructions for use and as 
per standard of care.
x
The investigator will assess and record any adverse events and incidents, including 
any related adverse events (side effects), use errors, and malfunction (see “incident” 
definition, Section 10.1), that occurred during or between the visits. All adverse 
events and incidents must be transmitted to the sponsor via the eCRF (see Section 
10.4.1 for reporting requirements).
Special focus will be posed on the side effects listed in the instructions for use of the 
investigational medical device: allergic reaction (local rash and/or itching), 
bladder/urethral pain and discomfort, or urinary tract infection.
x
The investigator will re-dispense the diary card to the patient and instruct her on how 
to record study related data at home. The following assessments are to be filled out by 
the patient:
1. Morning voiding volume (once a week, preferably on the treatment day)
2. Urinary voids and the respective volumes over a period of 24 hours (once a 
week, preferably starting the day before the treatment day)
3. Use of concomitant IC/BPS medication, pain medication, and other relevant 
concomitant medication
4. Adverse events 
(not required at first treatment visit if performed on same visit as for the baseline 
assessment)
x
A date for the next visit for the next treatment with Cystistat will be arranged and the
investigator will remind the patient not to forget to take the diary card with her that 
day.
x
The investigator will enter all required data from this visit in the eCRF within 5
business days. Specific reporting requirements for AEs and incidents are described in 
Section 10.4.1.
6.3
End of Treatment (or latest at Week 12, Month 3)
This assessment will be performed at end of treatment or latest at week 12. Procedures will
be completed in the following order:

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x
The investigator will collect the paper diary card and transcribe the information 
recorded by the patient into the eCRF. The paper diary card will be stored with the 
patient’s medical record.
x
The investigator will assess and record any adverse events that occurred since the last
visit. 
x
The investigator will record any concomitant use of IC/BPS medication, pain 
medication, and other relevant concomitant medication that were taken since the last 
visit; it is not required to collect all concomitant medication.
x
Patients will be asked to complete the Bladder Pain/Interstitial Cystitis Symptom 
Score (BPIC-SS). 
x
Patients will be asked to complete the Patient Global Assessment (PGA).
x
Patients will be asked to complete the Visual Analogue Scale (VAS) for bladder pain,
urinary urgency, and quality of life (QoL).
x
Cystistat will be instilled into the bladder according to the instructions for use.
x
The investigator will provide the patient with the diary card and instruct her on how to 
record study related data at home. The following assessments are to be filled out by 
the patient: 
1. Morning voiding volume (once at month 6)
2. Urinary voids and the respective volumes over a period of 24 hours (once at
month 6)
3. Use of concomitant IC/BPS medication, pain medication, and other relevant
concomitant medication
4. Adverse events 
x
The investigator will assess and record any adverse events and incidents, including 
any related adverse events, use error, and malfunction (see “incident” definition,
Section 10.1), that occurred until or during this visit. All adverse events and incidents
must be transmitted to the sponsor via the eCRF (see Section 10.4.1 for reporting 
requirements).
Special focus will be posed on the side effects listed in the instructions for use of the 
investigational device: allergic reaction (local rash and/or itching), bladder/urethral 
pain and discomfort, or urinary tract infection.
x
The investigator will enter all required data from this visit in the eCRF within 5
business days. Specific reporting requirements for AEs and incidents are described in 
Section 10.4.1.
x
If required, treatment with Cystistat will be continued thereafter under regular medical 
care. For all patients, a follow-up visit will be scheduled for approximately month 6.
6.4
Follow up (approximately at Month 6)
Follow-up will be performed as an on-site visit if in accordance with routine clinical practice; 
if not possible as an on-site visit, the information will be collected remotely (e.g., via phone 
and postal mail) from the patient.

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Procedures will be completed in the following order:
x
The investigator will collect the paper diary card and transcribe the information 
recorded by the patient into the eCRF. The paper diary card will be stored with the 
patient’s medical record.
x
The investigator will assess and record any adverse events that occurred since the last 
visit. 
x
The investigator will record any concomitant use of IC/BPS medication, pain 
medication, and other relevant concomitant medication that were taken since the last 
visit; it is not required to collect all concomitant medication.
x
Patients will be asked to complete the Bladder Pain/Interstitial Cystitis Symptom 
Score (BPIC-SS). 
x
Patients will be asked to complete the Patient Global Assessment (PGA).
x
Patients will be asked to complete the Visual Analogue Scale (VAS) for pain.
x
The investigator will assess and record any adverse events and incidents, including 
any related adverse events, use error, and malfunction (see “incident” definition, 
Section 10.1), that occurred until or during this visit. All adverse events and incidents
must be transmitted to the sponsor via the eCRF (see Section 10.4.1 for reporting
requirements).
Special focus will be posed on the side effects listed in the instructions for use of the 
investigational device: allergic reaction (local rash and/, or itching), bladder/urethral 
pain and discomfort, or urinary tract infection.
x
The investigator will enter all required data from this visit in the eCRF within 5
business days. Specific reporting requirements for AEs and incidents are described in 
Section 10.4.1.
6.5
Withdrawal and Early Termination
Patients may request termination of the treatment with the investigational medical device or 
withdrawal from the study at any time or be required to withdraw or terminate treatment with 
the investigational medical device by the investigator or sponsor for reasons as per 
Section 4.2.3. If the patient terminates early, withdraws or is withdrawn, the reason for early 
termination/withdrawal should be established and recorded. 
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient. In any circumstance, every effort should be made to document the outcome of patient
contact attempt, if possible. The investigator will contact sponsor or designee in the event that 
a patient fails to complete the study.
Every effort should be made to complete the following procedures and obtain the data from 
the patients:
x
The investigator will collect the paper diary card and transcribe the information 
recorded by the patient into the eCRF. The paper diary card will be stored with the 
patient’s medical record.

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x
The investigator will assess and record any adverse events that occurred since the last 
visit. 
x
Patients will be asked to complete the Bladder Pain/Interstitial Cystitis Symptom 
Score (BPIC-SS). 
x
Patients will be asked to complete the Patient Global Assessment (PGA).
x
Patients will be asked to complete the Visual Analogue Scale (VAS) for bladder pain,
urinary urgency, and quality of life (QoL)
x
The investigator will enter all required data for withdrawal/early termination in the
eCRF within 5 business days. If withdrawal is due to an AE or incident, please 
consider specific reporting requirements described in Section 10.4.1.
If the patient withdraws from the study and also withdraws consent for disclosure of future 
information, no additional data should be collected. The sponsor may retain and continue to 
use any data collected before such withdrawal of consent.
7
TREATMENT PROCEDURES AND ASSESSMENT CRITERIA
Cystistat will be instilled into the bladder according to the instructions for use (13) and in line 
with the routine clinical practice.
7.1
Performance Assessments
For timing of methods and assessments see also the study schedule in Table 0-1.
7.1.1
Patient Global Assessment (PGA)
The PGA is a patient reported outcome (PRO) which has been used widely in recent IC/BPS
studies. PROs are encouraged by the FDA guidance for IC/BPS studies (14).
The patient will evaluate the overall change in her IC/BPS condition on the following seven-
point scale: 
x
markedly improved
x
moderately improved 
x
slightly improved
x
no change
x
slightly worse
x
moderately worse
x
markedly worse
In case of “slightly improved”, the following additional question will be given to the patients:
“Did therapy have a positive effect on your life and would you undergo this treatment again?
(Yes/No)”.

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The PGA will be provided in local language. It will be completed by the patient at the end of 
treatment or latest at week 12 and at month 6. Data will be transferred into the eCRF by the 
site staff.
7.1.2
Bladder Pain/Interstitial Cystitis Symptom Score (BPIC-SS)
The BPIC-SS is a validated questionnaire for the measurement of IC/BPS symptoms. It 
contains 8 questions and the total score ranges from 0 to 38 (15).
The BPIC-SS will be provided in local language. It will be completed by the patient at 
baseline, at end of treatment or latest at week 12, and at month 6. Additional BPIC-SS will be 
completed in case of flares (see Section 7.1.7). Data will be transferred into the eCRF by the
site staff.
7.1.3
Visual Analogue Scale (VAS)
The VAS will be provided to assess disease-related symptom severity and general quality of 
life (QoL). It has been widely used in clinical studies with the indication IC/BPS (e.g. 8, 16,
17,).
The related question for the VAS will be provided in local language. It will be completed by 
the patient at baseline, at the end of treatment or latest at week 12, and at month 6. Data will
be transferred into the eCRF by the site staff.
7.1.3.1 Bladder Pain
Patients will be asked to assess their bladder pain on the VAS using the question “How was
your bladder pain over the last 3 days?”. The VAS will be an unmarked line ranging from 0 
to 100 mm, where 0 = “no pain” and 100 = "worst possible pain".
7.1.3.2 Urinary Urgency
Patients will be asked to assess their urinary urgency on the VAS using the question “How 
intense was urinary urgency over the last 3 days?”. The VAS will be an unmarked line 
ranging from 0 to 100 mm, where 0 = “no urgency” and 100 = “worst possible urgency”.
7.1.3.3 Quality of Life (QoL)
Patients will be asked to assess QoL on the VAS using the question “How good or bad would 
you rate your overall health condition throughout the last 3 days?”. The VAS will be an 
unmarked line ranging from 0 to 100 mm, where 0 = “the worst health you can imagine” and
100 = “the best health you can imagine”.
7.1.4
Morning Voiding Volume
The morning voiding volume will be measured by the patients at home once a week
(preferably in the morning of the treatment day) until end of treatment or latest week 12. One 
additional measurement will be performed at month 6. The patients will be provided with a 

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measuring cup and the measured voiding volume will be captured in the diary card. The 
entries from the diary cards will be transferred into the eCRF by the site staff.
7.1.5
24-hour Urinary Frequency and Voiding Volume
The patients will document each urinary void and the respective volume over a period of 24
hours in the diary at home once a week (preferably starting the day before the treatment day)
until end of treatment or latest week 12. One additional documentation will be performed at 
month 6. The total number of voids and the total voiding volume over the 24-hour period 
(daytime and nighttime) will be transferred into the eCRF by the site staff.
7.1.6
Use of Concomitant IC/BPS and Pain Medication
The use of concomitant IC/BPS and pain medication during the treatment will be captured by 
the patient in the diary card and the investigator will provide documentation in the eCRF, 
including at least indication, daily dose, and start and stop dates of administration.
Relevant IC/BPS medication includes amitriptyline, pentosan polysulfate, antihistamines,
anticholinergics, pain medication (e.g. Tramadol (retard formulation) or NSAID followed by
Tramadol), H2 blockers/antacids.
In addition, the use of all other pain medication (irrespective of indication) will be 
documented.
7.1.7
Occurrence of Flares
Flares are defined as symptom deteriorations and will be considered as adverse events. 
Adverse events will be recorded by the patient in the diary and also assessed and recorded by 
the investigator at the weekly controls/instillations and at the follow-up visit. In case of a 
flare, and additional BPIC-SS (see Section 7.1.2) will be completed by the patient at the time
of occurrence.
7.1.8
Premature Termination of Treatment
Treatment with Cystistat may be terminated prematurely by the patient or investigator (see
Section 4.2.3). In such a case, the investigator will provide documentation in the eCRF,
including at least the date of last treatment and the reason for premature termination.
7.2
Safety Assessment
7.2.1
Adverse Events and Incidents
Relevant medical conditions from baseline (i.e. before signature of the ICF) will be recorded 
as medical history. Clinically significant worsening from these conditions will be recorded as 
adverse events (causality to be assessed).
Before first instillation of Cystistat, AEs should be assessed as not related to investigational 
device.

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After first treatment, the patients will be routinely queried regarding the presence or absence 
of adverse events using open ended questions.
At each visit, clinic will also assess if any incident occurs during the instillation. The clinic 
will document any incident, including any related adverse events, use errors, malfunctions
(see “incident” definition, Section 10.1) in the patient’s eCRF.
All AEs, incidents and serious incidents should be reported to the Sponsor as described in 
section Section 10.4.1 “Reporting of Adverse Events and Incidents”
The investigator should forward any event to the sponsor, including an investigator’s
causality assessment in the notification (eCRF form). The sponsor will check and assess the 
events as well.
Special focus will be posed on the expected side effects as mentioned in the instructions for 
use: allergic reaction (local rash and/or itching), bladder/urethral pain and discomfort, or
urinary tract infection.
8
STATISTICAL CONSIDERATIONS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan (SAP), which will be dated and maintained 
by the sponsor. This document may modify the plans outlined in the protocol; however, any
major modifications of the primary endpoint definition and/or its analysis will also be 
reflected in a protocol amendment.
8.1
Sample Size Determination-
Approximately 74 patients (including approximately 10% drop-outs).
Accounting for approximately 10% drop-outs, further 7 patients and a total of 74 patients 
should be included in this study.
8.2
Populations for Analyses
Safety (SAF) population: All enrolled patients who received at least one instillation of 
Cystistat and validity of data is confirmed by the physician.
Full analysis set (FAS) population: All patients of the SAF, who have at least one post 
baseline assessment.

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8.3
Statistical Analyses
All analyses will be exploratory in character. Continuous variables will be summarized by
number (N), mean, standard deviation (SD), minimum, 5% percentile (P5), lower quartile 
(Q1), median, upper quartile (Q3), 95% percentile (P95) and maximum. Categorical variables 
will be presented in frequency distribution tables with number (N) and percentage.
Detailed methodology for summary and statistical analyses of the data collected in this study
will be documented in an SAP.
8.3.1
Definition of the Primary Efficacy Endpoint
Responder rate at end of treatment or latest at week 12 as indicated by improvement on a
seven-point Patient Global Assessment (PGA) scale where the patient is able to evaluate the 
overall change in her/his IC/BPS condition as markedly improved, moderately improved,
slightly improved, no change, slightly worse, moderately worse or markedly worse. For the 
primary analysis, a responder is defined as a patient who had an improvement on the PGA 
scale (i.e. PGA evaluated as markedly improved, moderately improved, or slightly improved.
In case of slightly improved, patients will only be considered as responder if the question 
“Did therapy have a positive effect on your life and would you undergo this treatment
again?” is answered with “Yes”.).
8.3.2
Primary Analysis of Primary Endpoint
If there is a substantial rate of patients with rescue medication (n>20), explorative subgroup 
analyses will be provided for patients with and without rescue medication.
8.3.3
Sensitivity Analysis of Primary Endpoint
8.3.4
Missing Data
Missing data will not be imputed. More details will be specified in the SAP.

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8.3.5
Sub-Group Analyses
According to the instructions for use, the subgroup of patients who have at least 4 weeks of 
treatment will be analyzed if relevantly different from the FAS. According to the low sample 
size, no other subgroup analyses are planned for the study. However, descriptive analyses of
subgroups might be relevant and will be described in the SAP.
8.3.6
Definition and Analysis of the Secondary Endpoint(s)
The following secondary endpoints will be analyzed and reported similar to the analysis 
method and reporting of the primary endpoint as described above (all endpoint assessments 
will be tabulated by timepoint and in case of more than 2 timepoints additionally be displayed 
graphically):
x
Time course of morning voiding volume, 24-hour urinary frequency and voiding 
volume (daytime and nighttime) (from patient diaries)
x
Change from baseline to end of treatment or latest week 12 and month 6 in Bladder 
Pain/Interstitial Cystitis Symptom Score (BPIC-SS) will be analyzed by Analysis of 
Covariance (ANCOVA) using baseline and eventually categories of concomitant 
IC/BPS and pain medication as covariate.
x
Responder rate and CI at month 6 as indicated by improvement on a seven-point 
Patient Global Assessment (PGA) scale (same responder definition as for the primary 
endpoint) will be analyzed with the same approach as the primary analysis.
x
Responder rate and CI at the end of treatment or latest at week 12 and at month 6 as 
indicated by improvement on a seven-point Patient Global Assessment (PGA) scale 
(responder defined as a patient who had moderate or marked improvement on the 
PGA scale) will be analyzed with the same approach as the primary analysis.
x
Change from baseline to end of treatment or latest week 12 and month 6 in Visual 
Analog Scale (bladder pain, urinary urgency, and quality of life) will be analyzed by 
Analysis of Covariance (ANCOVA) using baseline and eventually categories of 
concomitant IC/BPS and pain medication as covariate.
x
Number and percentage of premature termination of treatment will be given.
x
Use of concomitant IC/BPS and pain medication count will be analyzed by frequency 
tables.
8.3.7
Safety Analyses
Analysis of all safety data will be performed on the SAF Population. 
8.3.7.1 Adverse Events and Incidents
Adverse events and incidents will be coded using current version of Medical Dictionary for 
Regulatory Authorities (MedDRA). In addition, all incidents (as defined in Section 10.1) will 
be coded according to IMDRF Problem code A.

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The occurrence of AEs will be summarized in terms of affected patients, as well as in terms 
of total number of AEs. In addition, analysis of AEs by severity and by relatedness will also 
be provided. 
The occurrence of incidents will be summarized in terms of affected patients, as well as in
terms of total number of incidents. In addition, analysis of incidents by severity will also be 
provided.
Additional analysis of side effects mentioned in the IFU will be performed (number and 
percentage per incident as well as total number/percentage).
Concomitant IC/BPS and pain medications will be coded by the WHO Drug Dictionary 
Enhanced and will be summarized. Medical history will be listed by patient and coded using 
the current version of MedDRA and will be summarized. 
8.3.8
Planned Interim Analyses
9
ADMINISTRATIVE PROCEDURES
9.1
Source Documentation
All clinical data will be recorded by the clinical staff on the patient’s medical record and/or 
recorded electronically using validated software. If computerized systems are used to create,
modify, maintain, archive, retrieve or transmit source data, they must comply with the 
applicable regulatory regulations and/or guidance.
Source data should be attributable, legible, contemporaneous, original, accurate, and
complete. Changes to source data should be traceable, should not obscure the original entry, 
and should be explained if necessary.
The nature and location of all source documents will be documented separately. Source data 
may be directly captured from devices, transferred from 3rd parties (e.g. laboratory data) or 
entered manually into eCRF/database.
9.2
Access to Data/Source Documentation
The investigator or designated representative will permit full access to data and source 
documentation for the purpose of clinical monitoring, audits, IRB/IEC review and regulatory 
inspections.
9.3
Final Clinical Study Report and Case Report Forms (CRFs)
A written study report will be issued within one year after completion of the NIS in all
participating countries based on statistical tables. Summaries of related-adverse events as 

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well as incidents by severity and listed side effects reported in the IFU will be presented as 
applicable. In the final report, not-related AE will be reported in a summary table, if 
applicable. An extract (synopsis) of this report will be provided to the participating
investigators on request. 
Case Report Forms (CRFs) containing data transcribed from subject source documents (as
appropriate) and copies of other source documents will be supplied by the clinical site. The
principal investigator must sign each patient’s CRF after completion of data entry, signifying
that the data entered in the CRF is complete and accurate. Electronic CRFs will be provided
for this study.
9.4
Adherence to Protocol
The study will be conducted as described in the approved protocol (and amendments, if 
applicable), and applicable SOPs. In addition, the study will be conducted in compliance with 
ISO 14155:2020 (19) and any regional or national regulations, as appropriate.
9.5
Monitoring and Site Training
Site initiation visits will be performed before patient enrolment and data documentation is
started. Site staff will be trained on study protocol, study background, how to use/access the 
eCRF, obtaining of Informed Consent, safety reporting and further study requirements and 
procedures (e.g. Patient Diary).
Central data monitoring will be performed by the CRO on a regular basis and details will be 
specified in a monitoring plan. Monitoring includes at least enrolment status, completion 
status, safety data and predefined key data (e.g. Informed Consent, In-/Exclusion Criteria). In 
case any general issues/misunderstandings are identified, this will be brought to the attention 
of the Sponsor/the site.
One on-site monitoring visit per study site is planned. Source data verification will include 
100% of Informed Consents, 100% of safety data, and predefined key data that will be 
described in the monitoring plan. An adaptive approach of monitoring will be conducted 
during the study period based on the risk or critical data/process evaluation at the site.
9.6
Data Handling and Record Retention
All clinical information shall be recorded, handled, and stored in such a way that it can be
accurately reported, interpreted and verified, while the confidentiality of records of the trial 
patients remains protected.
An eCRF is required to be completed for each enrolled patient. The eCRF is property of the 
sponsor and the investigator must review and electronically sign all CRFs prior to database
lock.
All data collected in the study will be captured and maintained in a secure and validated 
electronic data capture (EDC) system and provided to clinical data management. 

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The paper diary cards serve as basis of information for the investigator to transfer relevant 
information to the eCRF. Completed diary cards will be stored with the patients’ source 
documents.
9.6.1
Data Management 
All data will be recorded in a standardized, validated EDC system complying with 
international quality standards. 
Data will be overseen centrally, all data acquired at the participating sites will be entered into 
the eCRF by the site team. The data will be checked for integrity, consistency and plausibility 
using preassigned checks, details are described in the Data Validation Plan (DVP). In the case 
of open queries, the affected site will be immediately informed. Each investigator agrees in 
providing support on request for clarifying possible queries on contradictions. Any change on 
data, e.g. due to adjustment of pending queries, will be documented through an audit trail of 
the database. Prior to database lock, a reconciliation of all adverse events, and incidents with 
the sponsor’s database will be performed.
Details are described in the Data Management Plan (DMP).
9.6.2
Archiving
The sponsor and the investigator will each maintain a Trial Master File (TMF) for the
“essential documents”. Sponsor or its designated CRO will provide an Investigator’s Site File 
(ISF) as a part of the TMF to each PI containing a cover page with a description of the 
required contents for each binder section and any project specific standardized forms.
All data including the analysis programs and their description will be archived at the
biostatistical department of the sponsor.
Archiving of items pertinent to this study at each site is the responsibility of the participating 
investigator and should follow national regulations. These items include:
x
Signed copy of protocol (principal investigator protocol signature page)
x
Signed copy of patients’ consent forms (if applicable according to local regulations)
x
Patient diary cards
x
Patient identification list 
x
Site personnel delegation list
x
Signed clinical study agreement between sponsor and/or CRO and the participating 
investigator 
x
Any other document required by specific national regulations (e.g. ethics committee 
approval)
When a copy is used to replace an original document (e.g., source documents), the copy 
should fulfil the requirements for certified copies as specified by ISO 14155:2020.

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All relevant site documents of this study including eCRFs and other patient records will be 
stored after the end or termination of the study according to the local requirements. Archiving 
of documents pertinent to this study at each site is the responsibility of the investigator and 
should follow national regulations.
All study data remain the sole property of the sponsor. The investigator must obtain in 
writing the sponsor’s agreement to dispose of any records, even if the retention period has 
been reached.
9.7
Data Protection and Confidentiality
Information furnished to clinical investigators and IRBs/Ethics Committees will be 
maintained in confidence by the clinical investigator and IRB/Ethics Committee. By signing
this protocol, the investigator affirms to the sponsor that he/she will maintain, in confidence, 
information furnished to the IRB/Ethics Committee relevant to this study under appropriate 
understanding of confidentiality with such IRB/Ethics Committee.
By signing the protocol, the investigator agrees that within local regulatory restrictions and 
institutional and ethical considerations, the sponsor may consult and/or copy source 
documents (e.g. laboratory reports, workbooks, medical records) in order to verify CRF data.
Data, including personal data, from source documents may be transferred to sponsor entities 
or service providers which may be located outside the European Economic Area (EEA)
including, but not limited to, the USA. In such cases, sponsor ensures that such transfers are 
carried out in compliance with all applicable data protection laws and regulations and signed 
ICF.
Personal study related data will be kept confidential. Study documents submitted to the 
sponsor, e.g. eCRFs, etc., are only identifiable by pseudonym, i.e. the patient no. The 
investigator will keep the original of the patient identification list (including complete name 
and date of birth of each patient). To allow compliance with applicable regulations, each 
patient will be asked for consent regarding the access to her personal study related data for 
monitoring, audits, and inspections as well as regarding transmission and storage of his/her 
pseudonymous data; a respective statement will be part of the informed consent. The patient
has the right to access and rectification of his/her personal data according to the General Data 
Protection Regulation (GDPR) (18).
9.8
Ethics and Regulatory Authorities
This represents a NIS, meaning that the investigator will document ongoing medical care, 
without conducting any intervention beyond normal medical practice.
The decision to prescribe Cystistat must be previous and independent from the decision to 
include the patient in the NIS. Before the study is started, the sponsor will comply with all 
national regulations, regarding notifications, approvals, or any other required administrative 
obligation.
In this respect, the participating investigator declares consent with the transmission of his/her 
name and address. National regulations will govern any aspect related to patient’s 

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information and consent. This clinical study protocol together with a sample CRF, if 
applicable, will be submitted to a competent ethics committee for review and opinion. A copy
of their final vote will be included in the investigator’s study file.
This clinical study will not begin until the required approval/favorable opinion from the 
ethics committee has been obtained. Any additional requirements imposed by the ethics 
committee will be followed, if appropriate. 
The study will be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki.
9.9
Informed Consent
A properly executed, written informed consent in compliance with current guidelines shall be 
obtained from each volunteer prior to entering the study. A copy of the informed consent 
document to be used will be submitted by the investigator to an independent institutional 
review board (e.g. IRB or ethics committee) and the sponsor and/or its agent for review and 
approval prior to the start of the study. The investigator shall provide a copy of the signed and 
dated informed consent to the patient, and a signed and dated copy shall be maintained in the 
patient’s medical record.
9.10
Study Registration
This clinical study will be registered in a publicly accessible database before start of 
recruitment.
9.11
Disclosure and Publication of Clinical Study Data
The disclosure and publication of clinical study data will be detailed in the clinical trial 
agreement with the investigators.
9.12
Financing and Insurance
MEDA Pharma GmbH & Co. KG (A Viatris company), Benzstrasse 1, D-61352, Bad 
Homburg, Germany ("Sponsor") will act as legal sponsor 
Financial aspects will be subject to the formal agreement with each participating site. 
Refunds are based on the national fair market value.

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9.13
Quality Assurance
This clinical study will be conducted in accordance with Standard Operating Procedures 
(SOP) of the sponsor and the CRO, as well as in accordance with the applicable national and 
local laws.
The study sites will receive data collection tools (eCRFs) from Sponsor/CRO. Complete data 
should be entered into the eCRF within 5 business days after each patient visit and updated as 
necessary if new information is available. Paper-based questionnaires and diary cards 
completed by the patients in local language will be collected by sites and data entered into the 
eCRF accordingly.
The Investigator is responsible for the accurate and complete documentation of study-related 
data in each patient’s eCRF after the patient’s Informed Consent has been received. Data 
should be entered in the eCRF in a timely manner (see special requirements for AEs and 
incidents, Section 10.4.1).
The investigator must sign off electronically the complete eCRF for each patient, confirming 
the validity of the data. Sponsor/CRO representatives will instruct investigators on how to 
use/access the eCRF. They will be responsible for the delivery and collection of study 
documents. CRO representatives are responsible for Study Monitoring. A Monitoring Plan
will be prepared and describing details of remote data monitoring and risk-based approach of
source data verification. Auditing in the sense of Good Clinical Practice is not intended. The 
study will be conducted in compliance with DIN EN ISO 14155:2021-05 (19) and any 
regional or national regulations, as appropriate.
Data checks regarding incidents and listed adverse events in the IFU reporting may trigger 
queries. Each participating investigator agrees to provide support on request for clarifying 
possible queries or contradictions.
In case of an incident during the instillation of Cystistat, the site will provide documentation 
in the patient’s CRF and proceed as described in Section 10.4.1.
9.14
Audits and Inspections
Inspections by regulatory authority representatives and IECs are possible at any time, even 
after the end of the study. The investigator must notify the sponsor immediately of any such 
inspection. 
Audits are not planned, but for cause audits may be performed by the sponsor’s QA or 
delegates in order to scrutinize the performance and quality at the study site. In this case, the 
sponsor QA will agree with the contract auditor regarding the timing and extent of the 
audit(s). In case of audits at the study site, a representative from the CRO will usually 
accompany the auditor(s).
9.15
End of Trial
The end of trial is considered to be the date of last patient last visit (or remote contact) or the 
date of early termination of the study whichever is the later.

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10
ADVERSE EVENTS AND INCIDENTS REPORTING
The adverse event collection period begins at signing of informed consent and incident 
collection period begins with the first administration of the investigational medical device.
The collection time for adverse events and incidents continues until the end of the last study
visit (or (e-)mail contact) of the patient. Adverse events and incidents occurring during this 
period need to be reported to the sponsor according to Section 10.4.1 ‘Reporting of Adverse 
Events and Incidents’. The investigator is also responsible for notifying the sponsor if he/she 
becomes aware of any adverse event or incident after the study period has ended and it is 
considered related to the investigational medical device. Once an AE or incident is detected,
it should be followed until its resolution or until it is judged by the principal investigator to be 
stable or permanent.
10.1
Definitions
Adverse Event
For the scope of this document, an adverse event (AE), is an untoward medical occurrence, 
unintended disease or injury, or any untoward clinical signs (including an abnormal 
laboratory finding) in subjects, users or other persons whether or not related to the
investigational medical device and whether anticipated or unanticipated.
Note to entry:
This definition includes events related to the procedures involved.
Note to entry:
For users or other persons, this definition is restricted to events related to 
the use of the investigational medical device.
All AEs judged by either the reporting investigator or the sponsor as having a reasonable 
causal relationship to an investigational medical device will be designated as related AEs,
thus incidents.
Reasonable causal relationship means that the causal relationship to the investigational 
medical device is reported as “possible”, “probable” or “causal relationship” or similar. If the 
relationship to the investigational medical device is not given, then the AE must be treated as 
if the relationship were “possible”.
Before the first instillation of Cystistat, AEs are considered not related.
Side Effect
For the scope of this document, side effects are adverse events with a reasonable causal 
relationship to the investigational medical device.
Incident
Any malfunction or deterioration in the characteristics or performance of a device made 
available on the market, including use-error due to ergonomic features, as well as any 
inadequacy in the information supplied by the sponsor and any undesirable side-effect (i.e. 
related adverse event)

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For the scope of this document, a device malfunction is a failure of an investigational 
medical device to perform in accordance with its intended purpose when used in accordance
with the instructions for use.
For the scope of this document, a use error is a user action or lack of user action while using
the medical device that leads to a different result than that intended by the manufacturer or 
expected by the user.
It should be noted:
x
Use error includes the inability of the user to complete a task.
x
Use errors can result from a mismatch between the characteristics of the user, user 
interface, task or use environment.
x
Users might be aware or unaware that a use error has occurred.
x
An unexpected physiological response of the patient is not by itself considered a use
error.
x
A malfunction of a medical device that causes an unexpected result is not considered a 
use error.
Serious Incident
Any incident that directly or indirectly led, might have led or might lead to any of the 
following: 
a) Death, of a patient, user or other person,
b) Temporary or permanent serious deterioration in the health of the subject, users, or 
other persons as defined by one or more of the following:
1) A life-threatening illness or injury, or
2) A permanent impairment of a body structure or a body function including 
chronic diseases, or
3) In-patient or prolonged hospitalization, or
4) Medical or surgical intervention to prevent life-threatening illness or injury, or 
permanent impairment to a body structure or a body function,
5) Foetal distress, foetal death, a congenital abnormality, or birth defect including 
physical or mental impairment,
c) Serious public health threat (event which could result in imminent risk of death,
serious deterioration in a person's state of health, or serious illness, that may require 
prompt remedial action, and that may cause significant morbidity or mortality in 
humans, or that is unusual or unexpected for the given place and time). 
Note to entry:
Planned hospitalization for a pre-existing condition, or a procedure required 
by the Clinical Investigation Plan (CIP), without serious deterioration in 
health, is not considered a serious incident.
Not Related Serious Adverse Event (SAE)

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For the scope of this document, any adverse event (not related to the investigational medical 
device) that led to any of the following:
a) Death,
b) Serious deterioration in the health of the subject, that resulted in any of the following:
i. life-threatening illness or injury,
ii. permanent impairment of a body structure or a body function,
iii. hospitalisation or prolongation of patient hospitalisation,
iv. medical or surgical intervention to prevent life-threatening illness or injury 
or permanent impairment to a body structure or a body function,
v. chronic disease,
c) Foetal distress, foetal death or a congenital physical or mental impairment or birth 
defect.
Preexisting Condition
Any medical condition that is present before signature of the ICF will be considered as 
baseline medical history and not reported as an AE. A baseline or preexisting condition 
should be recorded as an adverse event only if the frequency, intensity, or the character of the 
condition worsens during the study period.
General Physical Examination Findings
Any new clinically significant findings/abnormalities that meet the definition of an adverse 
event must also be recorded and documented as an adverse event. 
10.2
Collection and Recording of Adverse Events and Incidents 
During the visits, the investigator will record all adverse events and incidents. At each contact 
with the patient, the investigator must seek information on adverse events from diary cards,
by specific questioning and, as appropriate, by examination. Information on adverse events 
and incidents should be recorded immediately in the source document and in the respective 
eCRF forms.
Special focus will be posed in the side effects listed in the instructions for use of the 
investigational device: allergic reaction (local rash and/or itching), bladder/urethral pain and
discomfort, or urinary tract infection.
In the event of an AE and/or incident, as a minimum the following information should be 
documented in the respective eCRF:
x
Study number (pre-filled)
x
Investigator/Reporter name and contact details
x
Patient number (pre-filled)
x
Date of occurrence of incident/AE

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x
Description of incident (facts)/AE
x
AE/incident name or term (in standard medical terminology) and final diagnosis, time 
and date of onset, clinician’s assessment of severity, seriousness,
x
Relationship of AE to study product (assessed only by those with the training and 
authority to make a diagnosis) 
x
Action taken with the study product, treatment for the event and time (if available) 
and date of resolution/stabilization of the event.
Additional information and potentially the return of the product may be requested by the 
Sponsor in order to investigate the AE/incident.
Once these minimum data are entered in the respective eCRF form, the investigator/reporter
will submit the information electronically by clicking “Submit & Next” button on the bottom 
of the eCRF form. An email notification along with a PDF report will be generated informing 
the sponsor and CRO that an AE/incident is reported in the study. If there is any change in 
original data entry, again an Email notification will get generated with updated PDF report
(marked updates/changes).
All clearly related signs, symptoms, and abnormal results of diagnostic procedures should be 
grouped under one diagnosis on the eCRF where possible and appropriate.
The clinical course of each (related) adverse event should be followed until resolution or 
stabilization. Adverse events related to the investigational medical device that are still 
ongoing at the end of the study period must be followed up to determine the outcome. Any 
adverse event that occurs after the study period and is related to the investigational medical 
device or study participation should be recorded and communicated to the sponsor as per
already described timelines in Section 10.4.1.
10.3
Classification of Adverse Events and Incidents
10.3.1 Severity
The investigator will assign a severity rating to each AE and incident. For purposes of 
consistency, the following scale is to be used:
Grade 1 - MILD
Does not interfere with subject's usual function.
Grade 2 - MODERATE
Interferes to some extent with subject's usual function.
Grade 3 - SEVERE
Interferes significantly with subject's usual function.
Severity is a classification of intensity, whereas a serious event meets any of the defined
criteria (e.g. hospitalization; see definitions in Section 10.1).

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10.3.2 Causality
For all adverse events, sufficient information should be obtained by the investigator to
determine the causality of the adverse event. The investigator is required to assess causality 
of each AE.
An investigator’s causality assessment is the determination of whether there exists a 
reasonable possibility that the investigational medical device caused or contributed to an AE. 
The investigator must make an assessment of the relationship of each AE to the 
investigational medical device and record this relationship in the eCRF.
During the causality assessment, clinical judgement must be used and the relevant documents 
must be consulted, such as the medical device leaflet (instructions for use).
Factors that need to be considered when making a causality assessment include: Temporal 
relationship, clinical and pathological characteristics of the event(s), exclusion of
confounding factors (medical and medication history), de-challenge/re-challenge.
A suspected relationship (causal relationship, probable, possible) between the events and the 
investigational medical device means, in general, that there are facts (evidence) or arguments 
to suggest a causal relationship. Receipt of additional or clarifying information may warrant 
reassessment of causality. The investigator is responsible for assessing relationship of AEs to 
the investigational medical device in accordance with the following definitions (20):
Category
Causality
Description
CAUSAL 
RELATIONSHIP
Causal 
relationship is 
certain
The event is associated with the investigational device or 
comparator or with procedures beyond reasonable doubt 
when:
-
the event is a known side effect of the product 
category to which the device belongs or of similar
devices and procedures;
-
the event has a temporal relationship with the 
use/application or the procedures;
-
the event affects a site or organ that 
i. the investigational device or procedures are
applied to;
ii. the device or investigational procedures have an 
effect on;
-
the event follows a known response model of the 
medical device (if the response model is previously 
known);
-
the interruption to application of the medical device 
(or reduction in the level of activation/exposure) and 
the reintroduction of its use (or increase in the level of 
activation/exposure), affect the event (when clinically 
feasible);
-
other possible causes (e.g. an underlying or 

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concomitant illness/clinical condition and/or an effect 
of another device, drug or treatment) have been 
adequately ruled out;
-
damage to the subject due to use error;
-
the event depends on a false result provided by the 
investigational device used for the diagnosis, where 
applicable.
PROBABLE
High degree 
of certainty 
for causal 
relationship
The relationship with the use of the investigational device 
or comparator or the relationship with the procedures 
appears relevant and/or the event cannot be reasonably 
explained by another cause.
POSSIBLE
Causal 
relationship is 
uncertain
The relationship with the use of the investigational device 
or comparator or the relationship with the procedures is 
weak but cannot be completely ruled out. Alternative 
causes are also possible (e.g. an underlying or concomitant 
illness/clinical condition and/or an effect of another 
device, drug or treatment). Cases where the correlation 
cannot be assessed or no information was obtained should
be classified as possible.
UNRELATED/NOT 
RELATED
No possible 
relationship
The relationship with the device or the procedures may be 
ruled out when:
-
the event has no temporal relationship with the use of 
the investigational device, or the procedures related to 
application of the investigational device;
- the adverse event does not follow a known response 
pattern to the medical device (if the response pattern is 
previously known) and is biologically implausible;
-
the discontinuation of medical device application or the
reduction of the level of activation/exposure - when 
clinically feasible - and reintroduction of its use (or 
increase of the level of activation/exposure), do not 
impact on the serious adverse event;
-
the event involves a body-site or an organ that cannot 
be affected by the device or procedure;
-
the adverse event can be attributed to another cause 
(e.g. an underlying or concurrent illness/ clinical 
condition, an effect of another device, drug, treatment 
or other risk factors);
-
the event does not depend on a false result given by the
investigational device used for diagnosis, when 
applicable;
In order to establish the non-relatedness, not all the criteria 
listed above might be met at the same time, depending on 
the type of device/procedures and the serious adverse
event.

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For the purpose of establishing the relationship, all criteria listed above could not be met at 
the same time, depending on the type of device/procedures and the event.
The sponsor and the investigators shall distinguish between the adverse events related to the 
investigational device and those related to the procedures (any specific procedure of the
clinical investigation). An adverse event may be related to both the procedures and the 
investigational device. Procedure complications are considered unrelated if those procedures
would have been applied to patients even without the use/application of the investigational 
device.
10.3.3 Expectedness
AEs are expected as mentioned in the instructions for use (allergic reaction (local rash and/, 
or itching), bladder/urethral pain and discomfort, or urinary tract infection) (13).
10.3.4 Outcome
For all adverse events, the investigator must pursue and obtain information adequate both to 
determine the outcome of the adverse event and to assess whether it meets the criteria for
classification as a serious adverse event requiring immediate notification to sponsor or its 
designated representative.
The outcome at the time of last observation will be classified as:
RECOVERED/RESOLVED where the subject recuperated and is free of any pathological
conditions resulting from the prior disease or injury.
RECOVERED WITH SEQUELAE where the subject recuperated but retained pathological 
conditions resulting from the prior disease or injury. 
NOT RECOVERED/NOT RESOLVED (i.e. ongoing) where the subject has not recuperated
from the condition or injury and the event is still considered ongoing
RECOVERING where the subject has begun to recuperate from the condition or injury but
the event is considered ongoing at a reduced intensity
FATAL the condition or injury results in the subject’s death. The investigator should identify 
the principal cause of death and assign Fatal outcome to that event. Other concurrent ongoing
AE/SAEs present at the time of death would remain Not recovered/Not resolved.
UNKNOWN can be selected if none of the other situations apply or are known. Follow-up
should be conducted to obtain one of the preceding outcomes.
10.3.5 Action Taken with the Investigational Medical Device
For all adverse events and incidents, the following information should be provided by the 
investigator.

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Action
Description
Treatment interrupted
The treatment was temporarily discontinued
Treatment withdrawn
The treatment was permanently discontinued
Unknown
Not known, not observed, not recorded, or refused
No action taken
The event did not result in any modification of treatment or 
frequency of treatment
Not applicable
The event occurred prior to first treatment or following last 
scheduled treatment
10.4
Reporting of Adverse Events and Incidents
10.4.1 Investigator Reporting: Notifying the Study Sponsor
Incidents must be notified by investigator within 5 business days after becoming aware of it.
Serious incidents must be notified by investigator within 3 calendar days after becoming
aware of it.
For serious incidents, the investigator should provide further information on the serious 
incident as soon as possible, preferably within 48 hours of awareness. 
Supporting documents can be provided by the Investigator/Reporter if applicable via email to
the Sponsor:
Patient identifying information must not be visible on any documentation provided by the 
investigator via email. Any information that could be used to identify the patient (e.g. name,
address, medical record number) must be de-identified before submission to the sponsor or its 
designee. The patient’s study specific ID number should be recorded on every page of 
documentation forwarded to the sponsor.
The PI should provide the final diagnosis of serious incidents whenever possible. Not related
AEs including an investigator’s causality assessment should be forwarded to the sponsor by 
the investigator within 10 business days.
Once the investigator or designee has entered the minimum data (Section 9.2) in the
respective eCRF form, the Investigator/Reporter will submit the information electronically by 
clicking the “Submit & Next” button on the bottom of the eCRF form. An email notification
along with a PDF report will be generated informing the Sponsor and CRO that an
AE/incident is reported in the study. If there is any change in original data entry, again an 
Email notification will get generated with updated PDF report (marked updates/changes).
Sponsor will comply with country specific regulatory requirements relating to safety 
reporting to the regulatory authority, Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) and investigators.

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10.4.2 Follow-up
New information and any important missing information from prior reports on a serious
incident or serious AE, must be provided promptly to the study sponsor by updating and 
submitting the respective eCRF form. In addition, the investigator may be requested by 
sponsor/designee to obtain specific additional follow-up information in an expedited fashion.
The investigator should respond to targeted follow-up requests as soon as possible and 
preferably within 48 hours from receipt of the request.
New information for non-serious incidents/AEs should be entered in the respective eCRF 
form in the same timely manner as for all other CRF entries.
10.4.3 Investigator Reporting: Notification of Ethics Committee
Investigators are responsible for safety reporting to their local Ethics Committee (LEC) and
complying with their local EC’s reporting requirements. Copies of each report and
documentation of LEC notification and receipt will be kept in the investigator’s study file.
10.4.4 Investigator Reporting of Pregnancy - notifying the study sponsor
All patients who participate in the study should be counseled on the need to practice adequate 
birth control and on the importance of avoiding pregnancy during study participation as 
detailed in the inclusion and exclusion criteria. 
Patients who have been enrolled in the study should be instructed to contact the investigator
or study staff immediately if pregnancy occurs or is suspected. 

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11 REFERENCE LIST
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9. Cystistat Design Dossier Revision 18
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2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 
178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 
90/385/EEC and 93/42/EEC
12. MDCG 2020-6 Regulation (EU) 2017/745: Clinical evidence needed for medical
devices previously CE marked under Directives 93/42/EEC or 90/385/EEC A guide 
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Establishing Effectiveness of Drugs for Treatment. Draft Guidance. U.S. Department 
of Health and Human Services, Food and Drug Administration, Center for Drug 
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Crook T, Abraham L. The bladder pain/interstitial cystitis symptom score: 
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16. Cervigni M, Natale F, Nasta L, Mako A. Intravesical hyaluronic acid and chondroitin 
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Frangione V, Ciani O, Tarricone R, Pappagallo GL. A randomized, open-label, 
multicenter study of the efficacy and safety of intravesical hyaluronic acid and 
chondroitin sulfate versus dimethyl sulfoxide in women with bladder pain 
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2016 Sep 21.
18. Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 
2016 on the protection of natural persons with regard to the processing of personal
data and on the free movement of such data, and repealing Directive 95/46/EC 
(General Data Protection Regulation) Official Journal of the European Union, Vol. 
L119 (4 May 2016), pp. 1-88
19. Clinical investigation of medical devices for human subjects – Good clinical practice
(ISO 14155:2020). English version EN ISO 14155:2020, English translation of DIN 
EN ISO 14155:2021-05
20. MDCG 2020-10/1 Safety reporting in clinical investigations of medical devices under 
the Regulation EU 2017/745 (as needed, for causality assessment definitions)