Clinical trial NCT02395042
Conditions: Cystitis, Interstitial Ulcer
Sponsor: Allergan
Start date: 2015-04-15; Completion date: 2017-11-20
Enrollment: 59 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a safety and efficacy study of LiRIS® in females with interstitial cystitis with Hunner's lesions.

Detailed description:

Arms: arm 1: Treatment 1 Period (Tx 1): Matching placebo device to the LiRIS inserted into the bladder by cystoscopy on Day 10 and then removed and a second matching placebo device to the LiRIS inserted into the bladder by cystoscopy on Day 14 and removed on Day 28. Treatment 2 Period (Tx 2): optional LiRIS® (continuous release of lidocaine) 400 mg inserted into the bladder by cystoscopy on Day 0 and removed on Day 14. arm 2: Treatment 1 Period: LiRIS® (continuous release of lidocaine) 400 mg inserted into the bladder by cystoscopy on Day 0 then removed and a second LiRIS® 400 mg inserted into the bladder on Day 14 and removed on Day 28. Treatment 2 Period: optional LiRIS® (continuous release of lidocaine) 400 mg inserted into the bladder by cystoscopy on Day 0 and then removed on Day 14. arm 3: Treatment 1 Period: Matching placebo device to the LiRIS inserted into the bladder by cystoscopy on Day 0 and then removed and LiRIS® (continuous release of lidocaine) 400 mg inserted into the bladder by cystoscopy on Day 14 then removed on Day 28. Treatment 2 Period: optional LiRIS® 400 mg inserted into the bladder by cystoscopy on Day 0 then removed on Day 14.
Interventions: intervention 1: LiRIS® intervention 2: LiRIS Placebo
Intervention descriptions: intervention 1: LiRIS® is a drug-device combination product which is placed in the bladder during cystoscopy and remains in the bladder, gradually releasing lidocaine until removed from the bladder via cystoscopy. intervention 2: LiRIS placebo is a drug-device combination product, matching the LiRIS® which is placed in the bladder during cystoscopy, remains in the bladder until removed from the bladder via cystoscopy

Protocol documents:
Prot_000.pdf: 
NCT02395042   
 
Study ID: 201025‐001  
 
 
Title: A Multicenter, Randomized, Double‐blind, Placebo‐controlled Study, Evaluating Safety and Efficacy 
of LiRIS® 400 mg in Females With Interstitial Cystitis With Hunner’s Lesions 
 
 
Protocol Amendment 2 Date: 28‐Apr‐2016 
 


 
 
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Title Page 
ALLERGAN – CONFIDENTIAL 
The following contains confidential, proprietary information 
which is the property of Allergan 
 
STUDY TITLE 
A Multicenter, Randomized, Double-blind, Placebo-controlled Study, Evaluating Safety and 
Efficacy of LiRIS® 400 mg in Females With Interstitial Cystitis With Hunner’s Lesions 
 
Protocol Number:   
201025-001 Amendment 2 
Phase: 
2 
Name of Investigational Product: 
LiRIS® (Lidocaine-releasing intravesical system) 
Sponsor: 
 
Allergan (North America) 
2525 Dupont Drive 
Irvine, California USA 
92612 
+1-714-246-4500 
+1-800-347-4500 
 
Emergency Telephone Number(s): 
Refer to the Study Contacts Page.  
 
 
 
   
 
 
 
  
 
 
 
Refer to the final page of this protocol for electronic 
signature and date of approval. 


 
 
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The following information can be found on FDA Form 1572 and/or study contacts page:  
Name and contact information of Allergan study personnel and Emergency Telephone 
Numbers; name, address, and statement of qualifications of each investigator; name of each 
subinvestigator working under the supervision of the investigator; name and address of the 
research facilities to be used; name and address of each reviewing IRB; US 21 CFR 312.23 
section 6(iii)b. 
 


 
 
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INVESTIGATOR SIGNATURE PAGE 
INVESTIGATOR: 
 
 
 
 
I agree to: 
• Implement and conduct this study diligently and in strict compliance with the protocol, 
good clinical practices and all applicable laws and regulations. 
• Maintain all information supplied by Allergan in confidence and, when this information 
is submitted to an Institutional Review Board (IRB), Independent Ethics Committee 
(IEC) or another group, it will be submitted with a designation that the material is 
confidential. 
• Ensure that all persons assisting with the trial are adequately informed about the protocol, 
the investigational product(s), and their trial-related duties and functions. 
I have read this protocol in its entirety and I agree to all aspects. 
 
 
 
 
 
Investigator Printed Name 
 
Signature 
 
Date 
 
 


 
 
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Table of Contents 
Table of Contents ...................................................................................................................... 4 
List of Tables ............................................................................................................................. 8 
List of Figures ........................................................................................................................... 8 
Protocol Summary .................................................................................................................... 9 
1. 
Background and Clinical Rationale ................................................................................. 19 
1.1 
Study Rationale ...................................................................................................... 20 
1.2 
Investigational Product........................................................................................... 21 
1.3 
Nonclinical Studies ................................................................................................ 22 
1.4 
Clinical Studies ...................................................................................................... 22 
2. 
Study Objective and Clinical Hypothesis ........................................................................ 24 
2.1 
Study Objective ...................................................................................................... 24 
2.2 
Clinical Hypotheses ............................................................................................... 24 
3. 
Study Design .................................................................................................................... 24 
4. 
Study Population and Entry Criteria ................................................................................ 25 
4.1 
Number of Patients ................................................................................................. 25 
4.2 
Study Population Characteristics ........................................................................... 25 
4.3 
Inclusion Criteria .................................................................................................... 25 
4.4 
Exclusion Criteria................................................................................................... 27 
4.5 
Permissible and Prohibited Medications/Treatments ............................................. 29 
4.5.1  Permissible Medications/Treatments ......................................................... 29 
4.5.2  Prohibited Medications/Treatments ........................................................... 30 
4.5.3  Rescue Medications ................................................................................... 31 
4.5.4  Oral Prophylactic Antibiotics ..................................................................... 32 
4.5.5  Study Treatment Anesthesia ....................................................................... 32 
4.5.6  Special Diet or Activities ........................................................................... 32 
5. 
Study Treatments ............................................................................................................. 33 
5.1 
Study Treatments and Formulations ....................................................................... 33 
5.2 
Control Treatment .................................................................................................. 33 
5.3 
Methods for Masking/Blinding .............................................................................. 33 
5.4 
Treatment Allocation Ratio and Stratification........................................................ 33 
5.5 
Method for Assignment to Treatment Groups/Randomization .............................. 34 


 
 
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5.6 
Treatment Regimen and Dosing ............................................................................. 34 
5.6.1  Treatment 1 ................................................................................................ 34 
5.6.2  Treatment 2 ................................................................................................ 34 
5.6.3  Premature IP Removal ............................................................................... 34 
5.7 
Storage of Study Medications/Treatments ............................................................. 35 
5.8 
Treatment Administration ...................................................................................... 35 
5.8.1  Day of Treatment Criteria .......................................................................... 36 
5.8.2  Qualification for Retreatment .................................................................... 36 
6. 
Response Measures and Summary of Data Collection Methods ..................................... 37 
6.1 
Efficacy Measures .................................................................................................. 37 
6.1.1  Primary Efficacy Measure .......................................................................... 37 
6.1.2  Secondary Efficacy Measures .................................................................... 37 
6.3 
Safety Measures ..................................................................................................... 38 
6.4 
Post-use Assessments and Investigational Product Events .................................... 39 
6.5 
Examination Procedures, Tests, Equipment, and Techniques ................................ 39 
6.5.1  Medical History/Demographics ................................................................. 39 
6.5.2  Physical Examination ................................................................................. 39 
6.5.3  Pelvic Examination .................................................................................... 40 
6.5.4  Vital Signs, Weight and Height Measurements .......................................... 40 
6.5.5  Clinical Laboratory Assessments ............................................................... 40 
6.5.6  Pharmacokinetic Analysis Assessments ..................................................... 41 
6.5.7  Bladder Post-void Residual ........................................................................ 42 
6.5.8  Cystoscopic Examination ........................................................................... 42 
6.5.9  Bladder Mapping ........................................................................................ 42 
6.5.10  Insertion and Removal of IP ...................................................................... 42 
6.5.11  Post-use Assessment .................................................................................. 43 
6.5.12  Bladder Pain NRS ...................................................................................... 43 
6.5.13  Bladder Diary ............................................................................................. 44 
6.5.14  Pain Catastrophizing Scale ......................................................................... 44 
6.5.18  Concomitant Medications and Concurrent Procedures .............................. 45 


 
 
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6.5.19  Adverse Events .......................................................................................... 46 
6.5.20  IP Events .................................................................................................... 46 
6.6 
Other Study Supplies .............................................................................................. 47 
6.7 
Summary of Methods of Data Collection .............................................................. 47 
7. 
Statistical Procedures ....................................................................................................... 48 
7.1 
Analysis Populations .............................................................................................. 48 
7.2 
Collection and Derivation of Primary, Secondary, and Other Efficacy Assessments
 ................................................................................................................................ 48 
7.2.1  Primary Efficacy Variables ......................................................................... 49 
7.2.2  Secondary Efficacy Variables ..................................................................... 49 
 
 
7.3 
Hypothesis and Methods of Analysis ..................................................................... 51 
7.3.1  Demographics, Baseline Characteristics and Disposition Analyses .......... 52 
7.3.2  Efficacy Analyses ....................................................................................... 52 
7.3.3  Safety Analyses .......................................................................................... 54 
7.4 
Pharmacokinetic Analysis ...................................................................................... 56 
7.5 
Missing Data .......................................................................................................... 56 
7.6 
Subgroup Analyses ................................................................................................. 56 
7.7 
Sample Size Calculation ........................................................................................ 56 
7.8 
Interim Analyses..................................................................................................... 57 
8. 
Study Visit Schedule and Procedures .............................................................................. 57 
8.1 
Patient Entry Procedures ........................................................................................ 57 
8.1.1  Overview of Entry Procedures ................................................................... 57 
8.1.2  Informed Consent and Patient Privacy ....................................................... 57 
8.2 
Procedures for Final Study Entry ........................................................................... 58 
8.3 
Visits and Associated Procedures ........................................................................... 58 
8.4 
Instructions for the Patients .................................................................................... 58 
8.5 
Unscheduled Visits ................................................................................................. 59 
8.6 
Compliance With Protocol ..................................................................................... 59 
8.7 
Early Discontinuation of Patients .......................................................................... 59 
8.8 
Withdrawal Criteria ................................................................................................ 59 
8.9 
Study Termination .................................................................................................. 60 
9. 
Adverse Events ................................................................................................................ 60 
9.1 
Definitions .............................................................................................................. 60 


 
 
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9.1.1  Adverse Event ............................................................................................ 60 
9.1.2  Definition of Adverse Event of Urinary Tract Infection ............................ 61 
9.1.3  Serious Adverse Event ............................................................................... 61 
9.1.4  Severity ...................................................................................................... 62 
9.1.5  Relationship to Study Investigational Product or Study Procedure ........... 62 
9.2 
Procedures for Reporting Adverse Events ............................................................. 62 
9.3 
Procedures for Reporting a Serious Adverse Event ............................................... 62 
9.4 
Procedures for Unblinding of Study Medication ................................................... 63 
10.  Administrative Items ....................................................................................................... 64 
10.1  Protection of Human Patients ................................................................................ 64 
10.1.1  Compliance With Informed Consent Regulations (US 21 Code of Federal 
Regulations [CFR] Part 50) and Relevant Country Regulations ............... 64 
10.1.2  Compliance With IRB or IEC Regulations ................................................ 64 
10.1.3  Compliance With Good Clinical Practice .................................................. 64 
10.1.4  Compliance With Electronic Records; Electronic Signatures Regulations 
(US 21 CFR Part 11) .................................................................................. 64 
10.2  Changes to the Protocol ......................................................................................... 65 
10.3  Patient Confidentiality ........................................................................................... 65 
10.3.1  Patient Privacy ........................................................................................... 65 
10.4  Documentation ....................................................................................................... 65 
10.4.1  Source Documents ..................................................................................... 65 
10.4.2  Case Report Form Completion................................................................... 66 
10.4.3  Study Summary .......................................................................................... 67 
10.4.4  Retention of Documentation ...................................................................... 67 
10.5  Labeling, Packaging, and Return or Disposal of Study Medications/Treatments .. 67 
10.5.1  Labeling/Packaging .................................................................................... 67 
10.5.2  Clinical Supply Inventory .......................................................................... 68 
10.5.3  Return or Disposal of Study Medications/Treatments and/or Supplies ..... 68 
10.6  Monitoring by the Sponsor .................................................................................... 68 
10.7  Handling of Biological Specimens......................................................................... 68 
10.8  Publications ............................................................................................................ 69 
10.9  Coordinating Investigator ...................................................................................... 69 
11.  References ........................................................................................................................ 69 
12.  Attachments ..................................................................................................................... 73 
12.1  Questionnaires ........................................................................................................ 74 


 
 
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12.1.1  Overview .................................................................................................... 74 
12.2  Handling of Biological Specimens......................................................................... 82 
12.3  Glossary of Abbreviations ...................................................................................... 83 
12.4  Protocol Amendment 1 Summary .......................................................................... 85 
12.5  Protocol Amendment 2 Summary .......................................................................... 86 
 
List of Tables 
Table 1 
Schedule of Visits and Procedures .................................................................. 16 
Table 2 
Summary of IC Medication/Therapy Requirements in the Study................... 18 
 
List of Figures 
Figure 1 
Flow Chart of Study Visits .............................................................................. 15 
 
 


 
 
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Protocol Summary 
 
Study Compound(s):  LiRIS® (Lidocaine-releasing intravesical system) AGN-201025 
Phase:  2 
Study Objective:  To evaluate the safety and efficacy of a 28-day period of continuous release of lidocaine 
inserted into the bladder utilizing 2 consecutive LiRIS 400 mg compared with placebo for the treatment and 
corresponding symptoms of interstitial cystitis (IC) with Hunner’s Lesions (HL) in female patients 
Clinical Hypotheses:  A 28-day period of continuous release of lidocaine inserted into the bladder utilizing 
2 consecutive LiRIS 400 mg will have an acceptable safety profile and is more efficacious than placebo for the 
treatment and corresponding symptoms of IC with HL in female patients 
Study Design 
Structure:  Multicenter, randomized, double-blind, placebo-controlled study  
Duration:   
For patients who participate in the study and receive only one treatment, the duration of study participation will 
be 28 weeks.  For patients who qualify and receive Treatment 2 (active LiRIS only), the minimum duration of 
participation is 16 weeks and the maximum duration of study participation is 36 weeks 
Study Treatment Groups:   
1) LiRIS 400 mg, LiRIS 400 mg (Treatment 1 Period)/LiRIS 400 mg (Treatment 2 Period) 
2) LiRIS Placebo, LiRIS Placebo (Treatment 1 Period)/LiRIS 400 mg (Treatment 2 Period) 
3) LiRIS Placebo, LiRIS 400 mg (Treatment 1 Period)/LiRIS 400 mg (Treatment 2 Period) 
Controls:  LiRIS Placebo 
Dosage/Dose Regimen:  
Treatment 1 Period (Tx 1): 
Treatment 1 includes the following:  2 consecutive LiRIS 400 mg, 2 consecutive LiRIS Placebo, or one LiRIS 
Placebo followed by one LiRIS 400 mg  
Treatment 2 Period (Tx 2): 
One LiRIS 400 mg 
Randomization/Stratification:  Randomization will be centralized and stratified by baseline pain score (≤ 5 or 
> 5) collected during the Screening period.  Each patient within a stratum will be randomized to one of 3 groups 
(2 consecutive LiRIS 400 mg or 2 consecutive LiRIS Placebo or one LiRIS Placebo followed by one 
LiRIS 400 mg) in a 2:1:1 ratio that will define the patient’s assignment in Treatment 1. 
Visit Schedule:   
Treatment 1: 
Patients will be evaluated during the Screening period for eligibility. 
Eligible patients will be: 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 


 
 
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Study Population Characteristics 
Number of Patients:  Approximately 76 patients will be enrolled into the study to ensure 72 evaluable patients 
overall for Treatment 1, including 36 patients in the LiRIS 400 mg/LiRIS 400 mg group, 18 patients in the 
LiRIS Placebo/LiRIS Placebo group, and 18 patients in the LiRIS Placebo/LiRIS 400 mg group. 
Condition/Disease:  Female patients with IC with HL   
Key Inclusion Criteria:   
• females ≥ 18 years of age  
• a diagnosis of IC with HL defined as: 
o 
an unpleasant sensation (pain, pressure, discomfort) perceived to be related to the urinary 
bladder, associated with lower urinary tract symptoms (LUTS) of more than 6 months 
duration in the absence of infection or other identifiable causes (van de Merwe et al, 2008), 
documented history or patient reported 
and 
o 
documented history of an observation of HL via cystoscopic procedure in which a lesion is 
defined as a circumscript, reddened mucosal area that can be small vessels radiating towards a 
central scar, and/or a fibrin deposit of coagulum attached to this area.  Lesions may also be 
linear, fissure-like, and may be bleeding. 
•
 
 
 
 
 
 


 
 
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See Section 4.3 for detailed inclusion criteria 
Key Exclusion Criteria:   
•
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 4.4 for detailed exclusion criteria. 
Response Measures 
Efficacy:  
Primary:  
• average daily bladder pain score patient experienced over the previous 24-hour period as measured by an 
NRS of 0 to 10, recorded on a 7-day pain assessment tool   
 
The primary timepoint is Week 4 following Treatment 1 2nd IP removal. 


 
 
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Secondary: 
• number of HLs assessed by the Principal Investigator (PI) during cystoscopy 
• composite score of HL calculated based on number, size, and severity of the lesions  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
   
 
  
 
 
Safety:   
• adverse events and serious adverse events  
• physical examination 
• vital signs 
• any abnormal cystoscopy findings at insertion and removal 


 
 
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• pregnancy testing for women of childbearing potential 
• urine dipstick reagent test 
• urine analysis (with urine culture and sensitivity, as applicable) 
• urine cytology (at Screening only) 
• post-void residual (PVR) urine volume measurement  
• hematology and non-fasting serum chemistry 
• concomitant medications 
• concurrent procedures 
Post-use Assessments and IP events 
• voiding of the IP  
• damage to the IP during insertion or removal procedures 
• damage to the IP that is not related to insertion or removal procedures 
General Statistical Methods and Types of Analyses:   
Modified intent-to-treat (mITT) analysis population:  The mITT population will include all patients who were 
randomized and received at least 1 IP insertion in Treatment 1.  The efficacy data will be analyzed as 
randomized using the mITT population.  
Safety analysis population:  The safety population will include all patients enrolled in this study and received at 
least one IP.  The safety data will be analyzed as treated using the safety population. 
Pharmacokinetic evaluable population:  The pharmacokinetic population will include all patients enrolled in this 
study and who have at least one plasma or urine pharmacokinetic concentration measurement post-IP insertion 
and for whom the IP is successfully removed. 
Per-protocol (PP) analysis population:  The PP population will include all patients who retain the 2 consecutive 
IPs inserted in Treatment 1 for the 28 days of the treatment period and complete the 4 Week Follow-up Visit 
post removal of the Treatment 1 2nd IP without any significant protocol deviations.  Protocol deviations will be 
determined prior to database lock. 
A primary analysis will be conducted at the time when the last patient has completed the primary timepoint 
(Week 4 following removal of the Treatment 1 2nd IP).  The objective of the primary analysis is to support 
further development of this program in this indication.  The final analysis will be conducted when all patients 
complete or exit the study. 
All continuous variables will be summarized showing the number of observations, mean, median, standard 
deviation, minimum, and maximum values.  Discrete variables will be summarized showing the frequency and 
percentage of the study population.  Visual display of efficacy data (value and/or change from baseline) may be 
presented over time. 
The primary efficacy variable will be analyzed using the analysis of covariance (ANCOVA) model using the 
baseline value as the covariate, and stratification factor (baseline bladder pain NRS:  ≤ 5 or > 5) and treatment 
as factors.  Similar ANCOVA analyses will be used for secondary efficacy analyses. 


 
 
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Sample Size Calculation:  Approximately 76 patients will be enrolled into the study.  Assuming that 5% of the 
randomized patients will not be evaluable for the primary anlysis, this will ensure 72 evaluable patients overall, 
including 36 patients in the LiRIS 400 mg/LiRIS 400 mg group, 18 patients in the LiRIS Placebo/LiRIS 
Placebo group, and 18 patients in the LiRIS Placebo/LiRIS 400 mg group. 
A sample size of 36 patients in the LiRIS 400 mg/LiRIS 400 mg group versus 18 patients in the 
Placebo/Placebo group  will have 76% power to detect a difference of 1.152 in mean daily average bladder Pain 
NRS, assuming that the common standard deviation is 1.67 using a 1-sided 2-group t-test with a 0.05 
significance level.  The calculation was performed using the commercial 
  The standard 
deviation assumption is based on the results of the TAR-100-105 open-label study, where the standard deviation 
is the Week 4 Follow-up raw average daily NRS. 
 


 
 
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Table 2 
Summary of IC Medication/Therapy Requirements in the Study 
 
Required stable 
duration prior to 
Screening 
(If continuing as 
stable therapy in the 
study) 
Period off medication/treatment prior to 
Screening 
 
Permissible Rescuea Therapy  
 
 
 
(Only if previously used the medication prior 
to study entry with no tolerability issues) 
Oral Elmiron® (pentosan polysulfate) 
≥ 6 months 
≥ 4 weeks 
Prohibited 
Narcotic Analgesics 
≥ 8 weeks (at a dose 
no greater than 
120 mg morphine 
equivalent per day) 
≥ 4 weeks 
Permitted 
eg, tramadol, hydrocodone, oxycodone, 
fentanyl 
All other oral medications used for the 
treatment of symptoms of IC such as: 
• 
Non-narcotic analgesics  
• 
Tricyclic antidepressants 
• 
Other antidepressants  
• 
Anticonvulsants and drugs for 
neuropathic pain   
• 
Antihistamines  
• 
Anticholinergics  
• 
Medications for LUTS 
≥ 8 weeks 
≥ 4weeks 
Permitted - Any oral pain relieving 
medications used to treat IC, such as: 
• analgesics (eg, acetaminophen) 
• tricyclic and other antidepressants 
(eg, amitriptyline) 
• anticonvulsants and drugs for neuropathic 
pain (eg, gabapentin) 
 
Prohibited –  
• treatments for LUTS eg, anticholinergics 
• IV lidocaine 
Bladder Instillation Therapy 
N/A 
Last instillation 4 weeks prior to 
Screening  
Prohibited 
Bladder Hydrodistention (or any procedure 
that may result in bladder distention) 
N/A 
Last treatment 6 weeks prior to Screening 
(or until no further beneficial effect is 
noted if greater than 6 weeks)  
Prohibited 
Botulinum toxin therapy (of any serotype) 
for any genitourinary condition 
N/A 
≥ 6 months 
Prohibited 
Physical Therapy 
≥ 8 weeks 
≥ 2 weeks 
N/A 
Fulguration 
N/A 
≥ 4 weeks 
Prohibited 
IC = interstitial cystitis; IV = intravenous; LUTS = lower urinary tract symptoms; N/A = not applicable 
a 
Use of rescue medications should be minimized in the study and avoided if possible.  They may be used on an as needed, short-term basis according to local site practice for 
patients who have an acute exacerbation of pain (“flare”).  All use (dose and time of use) of rescue medication should be recorded in the pain diary. 
 


 
 
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1. 
Background and Clinical Rationale  
Interstitial cystitis (IC)/bladder pain syndrome (BPS) is a chronic and debilitating urological 
complex of disorders characterized by symptoms of bladder pain, urinary frequency and 
urgency.  The underlying disease process is poorly understood, however, there are 2 
distinguishable and agreed upon phenotypes:  the classic form of IC with Hunner’s Lesions 
(HL) (type 3C) and non-lesion IC/BPS (Fall et al, 2014; Logadottir et al, 2014). 
IC with HLs was originally described in 1887 as an inflammatory condition of the bladder, as 
the availability of cystoscopies in the early twentieth century allowed visualization of the 
pathognomonic bleeding lesions now referred to as HLs (Nordling et al, 2012).  The 
European Society for the Study of IC (ESSIC) provides the following description of these 
lesions:  “The Hunner’s lesion typically presents in a singular or multiple form as a 
circumscript, reddened mucosal area with small vessels radiating towards a central scar, with 
a fibrin deposit of coagulum attached to this area.  This site ruptures with increasing bladder 
distension, with petechial oozing of blood from the lesion and the mucosal margins in a 
waterfall manner.  A rather typical edema develops post-distension with varying peripheral 
extension” (Nordling et al, 2012; Logadottir et al, 2012; Killinger et al, 2012). 
The disease prevalence of IC/BPS varies widely due to lack of global epidemiological studies 
as various definitions are still being utilized in the diagnosis of IC/BPS.  This is due to the 
fact that the identification of patients was primarily developed to track the course of the 
condition and not by identifying IC/BPS patients via patient-reported symptoms which is the 
current recommendation (Berry et al, 2010).  Based on patient self-reported studies of the 
prevalence of IC/BPS in the United States (US), there are approximately 83,000 men and 
1.2 million women with IC/BPS across the US (Hanno et al, 2014).  In symptoms-based 
studies evaluating the prevalence of IC/BPS in the US, across multiple definitions, symptoms 
of IC/BPS were typically 2 to 3 times more common in women as in men, in which the 
prevalence was estimated to be approximately 3.3 to 7.9 million women, age 18 or older.  
Only 9.7% of these women reported having been given an IC/BPS diagnosis which suggests 
that IC/BPS may be underdiagnosed (Berry et al, 2011; Suskind et al, 2013).  The 
confounding and overlapping conditions that are contributing to the underdiagnoses of 
IC/BPS seem to be chronic pelvic pain syndrome in women and chronic prostatitis in males 
(Berry et al, 2011; Suskind et al, 2013). 
With regards to the prevalence of the phenotype of IC with HL, the ESSIC (van de Merwe et 
al, 2008) and the International Painful Bladder Foundation (IPBF) (Meijlink, 2014) describes 


 
 
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IC with HL in the range of 10% to50% of the BPS patient’s population.  IC with HL patients 
are underdiagnosed due to confounding factors such as: 
• confusion caused by the name Hunner's ulcer while it is not an ulcer:  the term 
Hunner's ulcer suggests that it can always been seen at cystoscopy without 
hydrodistention 
• false impression that HL are rare 
• even when cystoscopy with hydrodistention is performed, HL are likely to be detected 
mainly by experienced urologists.  Biopsy may be necessary to prove that it is a HL 
and/or to exclude a carcinoma in situ 
Current guidelines from the American Urological Association (AUA) and ESSIC state that 
the most effective treatments for IC with HL are fulguration by electrocoagulation, 
lasercoagulation (burning out and sealing the lesion), or resection (surgical removal of the 
lesion) (Hanno et al, 2014; Meijlink, 2014).  These treatments seem to be most effective, 
improving dramatically symptoms caused by lesions.  Unfortunately, the lesions tend to recur 
with this chronic condition and these treatments need to be administered accordingly between 
several months up to 5 years depending on the individual patients.  These treatments are 
considered extremely invasive and painful procedures, they require general anesthesia and 
might introduce surgical complications.  In addition, with repeated treatments, they may 
compromise the functionality of the bladder with accumulating fibrotic tissue from repeated 
fulgurations or repeated resections.  Current oral treatments targeting symptomatic relief 
utilized both in IC/BPS and IC with HL are generally unsatisfactory, showing limited 
efficacy compared with placebo and introduces a systemic side-effects profile (Chancellor 
and Yoshimura, 2004). 
1.1 
Study Rationale 
A major challenge in the treatment of IC with HL is to deliver effective therapeutic agents to 
ameliorate bladder symptoms and to intervene in the course of the disease, while minimizing 
adverse effects in a less invasive and compromising manner. 
Lidocaine is a common local anesthetic used in many pain indications across different 
therapeutic areas.  In IC/BPS lidocaine is used for pain treatment as a single agent or in 
combination with other agents (such as sodium bicarbonate or heparin) via bladder 
instillation aimed as a multi-modal treatments.  It is also used as a rescue treatment for the 
relief of severe pain in a flare (Meijlink, 2014). 


 
 
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In addition to lidocaine’s well established effects on nociception, studies suggest local 
anesthetics, including lidocaine, may also secondarily suppress inflammation and associated 
hyperalgesia (Cassuto et al, 2006).  In chronic inflammatory conditions such as asthma, 
lidocaine and lidocaine derivative (non-anesthetic lidocaine analog JMF2-1) exhibit anti-
inflammatory properties.  Some animal models suggest that lidocaine inhibits respiratory 
smooth muscle contraction as well as T-cell proliferation and survival through enhancement 
of intracellular cAMP levels (Olsen et al, 2012; Olsen et al, 2011; Nakahara et al, 2001).  
Other animal models suggest that lidocaine potentiates the relaxant effect of agents that 
activate adenylyl cyclase in bovine tracheal smooth muscle due to blockade of muscarinic 
M2 receptor-mediated signal transduction.  It is likely that lidocaine exerts a synergistic 
effect on the responses to agents that activate adenylyl cyclase in bronchoconstriction 
associated with the enhanced parasympathetic nerve activity (Yunoki et al, 2003). 
Studies of lidocaine intravesical instillation in the bladder of IC/BPS patients and healthy 
subjects have consistently reported that intravesical administration of lidocaine at exposures 
up to 800 mg, for durations ranging from 15 minutes to 2 hours, is safe and well tolerated 
(Birch and Miller, 1994; Henry et al, 2001; Parsons, 2005; Nickel et al, 2008; Higson et al, 
1979; Yokoyama et al, 1997; Yokoyama et al, 2000).  Preliminary pharmacokinetic data from 
these studies also indicate a relatively small fraction of the dose administered intravesically is 
absorbed systemically.  In one study, for example, peak lidocaine serum levels observed 
following daily intravesical instillations of 5mg/kg (~ 350 mg) of lidocaine for 2 days in IC 
patients averaged 1.3 µg/mL (range:  0.2 to 2.0) (Henry et al, 2001).  This exposure is below 
that commonly achieved following intravenous (IV) lidocaine administration for the 
management of cardiac ventricular arrhythmias and is well below systemic levels associated 
with lidocaine toxicity (> 5.0 µg/mL; Lidoderm® Prescribing Information, 2013). 
1.2 
Investigational Product  
The investigational product (IP), LiRIS®, is a passive nonresorbable Lidocaine-releasing 
intravesical system (LiRIS) whose primary mode of action is the controlled release of 
lidocaine into the bladder over a 14-day period.  
 
 
 
 
 
 
 


 
 
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1.3 
Nonclinical Studies 
A series of Good Laboratory Practice (GLP)-compliant repeat-dose toxicity studies have 
been conducted in female mixed-breed hounds to assess the safety of TARIS Placebo 
platform (empty device constituent) and LiRIS (100 mg, 200 mg, 400 mg, and 650 mg).  
Across all studies the system was shown to be well tolerated with no evidence of local or 
systemic effects, no systemic toxicity and no impact on urodynamics. 
1.4 
Clinical Studies 
A series of phase 1 and phase 2 studies have been conducted in humans including healthy 
female adults, IC/BPS and IC with HL female patients to assess the safety and efficacy of 
TARIS Placebo and LiRIS (200 mg, 400 mg, and 650 mg). 
The TARIS Placebo system was tested in a phase 1, single-blind, randomized, placebo-
controlled (via sham procedure), parallel group study (Study TAR-100-101), to evaluate the 
positional stability and patient tolerance of the system within the bladder over 14 days, 
evaluating design implications of the insertion and removal procedures.  A total of 10 healthy 
female volunteers were enrolled in the study; 7 patients underwent insertion and retrieval of 
the TARIS Placebo system and 3 patients had the sham procedure (cystoscopy only).  The 
results of this study showed that the TARIS Placebo system was generally well tolerated in 
healthy female volunteers as adverse events such as haematuria, dysuria, urethral pain, and 
abdominal pain were similar to those seen with the sham procedure. 
The LiRIS 400 mg was tested in a phase 2a multicenter, randomized, double-blinded, 
placebo-controlled study (Study TAR-100-201) to evaluate safety, tolerability, and efficacy in 
female patients with IC/BPS in North America.  The study compared LiRIS 400 mg to LiRIS 
Placebo over a 14-day treatment period and 4-week follow-up period.  Data collected from 
the 104 enrolled patients showed trends of improvement with LiRIS 400 mg in sub-
populations of IC/BPS patients with high bladder pain at baseline (7 or greater on 0 to 10 cm 
visual analogue scale [VAS]) and in patients 40 years of age or older at time of enrollment.  
Overall, adverse events seen in 10% or more of enrolled patients were bladder pain, dysuria, 
haematuria, and urinary tract infections (UTIs).  The majority of adverse events were mild or 
moderate in intensity.  There was no meaningful difference in the incidence of these events 
between the LiRIS 400 mg and LiRIS Placebo groups. 
A phase 1b pilot safety, tolerability and preliminary efficacy, multicenter, open-label, 
ascending dose study (Study TAR-100-103) of LiRIS was conducted in a mixed female 
patient population with IC/BPS and IC with HL.  The study enrolled 16 patients in 2 cohorts 


 
 
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with 7 patients diagnosed with IC with HL and the remaining the 9 patients with IC/BPS.  
Cohort 1 (200 mg) enrolled 9 patients, and 8 patients completed.  Cohort 2 (650 mg) enrolled 
9 patients and all 9 patients completed.  All enrolled patients had LiRIS inserted and 
indwelling in the bladder for up to a 14-day period and were followed for safety assessments 
for 14 days after removal of LiRIS.  Cohort 2 (650 mg) patients also had additional long-term 
safety and efficacy assessments at 60 and 90 days postinsertion.  The results of this study 
show that LiRIS 200 mg and LiRIS 650 mg are well tolerated with the most common adverse 
events (> 20 % overall) being dysuria, haematuria, and bladder pain.  The majority of adverse 
events observed were mild or moderate in intensity.  One serious adverse event of “suicidal 
ideations” was reported and deemed to be unrelated to LiRIS or the cystoscopy procedure.  
LiRIS 650 mg resulted in higher plasma concentrations and greater amount of lidocaine and 
2,6-xylidine recovered in urine compared with LiRIS 200 mg.  However, these plasma 
concentrations of lidocaine after LiRIS insertion were much lower than those associated with 
toxicity (> 5.0 µg/mL).  2,6-xylidine concentrations were on average < 10% of the observed 
plasma concentrations of lidocaine.  Overall, both LiRIS 200 mg and LiRIS 650 mg appear 
to be safe, tolerable, and efficacious in the treatment of bladder pain and irritative voiding 
symptoms.  A subanalysis of the IC with HL patients, showed improvement in inflammatory 
findings with 6 out of the 7 patients enrolled with pre-existing HLs, revealing a resolution of 
lesions at the time of LiRIS removal.  This interesting finding might be attributed to the anti-
inflammatory properties of lidocaine described earlier. 
Based on the results from the TAR-100-103 study that showed resolution of lesions, a 
phase 1b open-label study of LiRIS 400 mg in female IC patients with HL (Study 
TAR-100-105) was initiated.  In this study, patients were treated with 2 consecutive LiRIS 
400 mg each, to support the evaluation of lesions resolution compared to baseline as a 
response to an accumulative dose of 800 mg of lidocaine released continuously over a period 
of 28 days.  This is based on the assumption that the anti-inflammatory mechanism of action 
would require a higher dose over a longer treatment period to show further improvement in 
lesion resolution compared to results shown in the TAR-100-103 study, with no additional 
risk to the patients.  The study has completed enrollment (N = 10) at 2 centers in the US.  The 
last patient completed the final study visit, and the data are not yet available for final 
analysis.  To date, no serious adverse events have been reported in the trial. 
The LiRIS platform for bladder pain indication was acquired by Allergan from TARIS 
Biomedical Inc. in August 2014. 
The purposes of this study is to develop a better understanding IC with HL and the potential 
of the LiRIS 400 mg as a therapeutic agent in both symptoms relief and intervening in the 


 
 
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natural course of the disease with resolution of lesions.  Therefore, this study is designed to 
evaluate the treatment of 2 consecutive LiRIS 400 mg versus LiRIS Placebo and will explore 
the dosing with 2 consecutive LiRIS 400 mg compared with one in population of IC with 
HL. 
2. 
Study Objective and Clinical Hypothesis  
2.1 
Study Objective 
To evaluate the safety and efficacy of a 28-day period of continuous release of lidocaine 
inserted into the bladder utilizing 2 consecutive LiRIS 400 mg compared with placebo for the 
treatment and corresponding symptoms of IC with HL in female patients. 
2.2 
Clinical Hypotheses 
A 28-day period of continuous release of lidocaine inserted into the bladder utilizing 
2 consecutive LiRIS 400 mg will have an acceptable safety profile and is more efficacious 
than placebo for the treatment and corresponding symptoms of IC with HL in female 
patients. 
3. 
Study Design 
This study is a multicenter, randomized, double-blind, placebo-controlled, study to evaluate 
the safety and efficacy of the LiRIS 400 mg in female patients with IC with HL.  This study 
includes up to 2 treatments.  To receive Treatment 1, patients will be randomized in a 2:1:1 
ratio to 1 of 3 treatment groups receiving over a 28-day treatment period either: 
Group 1:  2 consecutive LiRIS 400 mg (N = 38)  
Group 2:  2 consecutive LiRIS Placebo (N = 19) 
Group 3:  LiRIS Placebo followed by LiRIS 400 mg (N = 19)  
Patients who qualify for Treatment 2, will receive LiRIS 400 mg over a 14-day treatment 
period followed by 4 weeks of observation until exit.  Patients will be stratified based on 
screening baseline pain score (≤ 5 or > 5). 
For patients who participate in the study and receive only Treatment 1, the duration will be 
28 weeks, including a maximum of 4 weeks of screening, 4 weeks of randomized treatment, 
and 20 weeks of follow-up post IP removal.  For patients who qualify and receive 


 
 
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Treatment 2 (active LiRIS only), the minimum duration of participation is 16 weeks (if 
qualification and Treatment 2 IP insertion occurs on Week 4 Follow-up Visit post removal of 
Treatment 1 IP) and the  maximum duration of study participation is 36 weeks (if 
qualification and Treatment 2 IP insertion occurs on Week 20 Follow-up Visit post removal 
of Treatment 1 IP). 
The study IP will be inserted into the bladder using a rigid cystoscope and removed using 
grasping forceps and a rigid or flexible cystoscope. 
Patient-reported pain via the Numeric Rating Scale (NRS), and pain medication use will be 
recorded on a daily basis throughout the duration of the study on an electronic diary.  Patient 
reported voiding frequency and urgency, including pre- and post-voiding pain will be 
recorded on a paper bladder diary.  
 
 
 
  
4. 
Study Population and Entry Criteria 
4.1 
Number of Patients 
Approximately 76 patients will be enrolled at approximately 25 sites in the US and Canada to 
achieve 72 evaluable patients (N = 36, N = 18, and N = 18 in the 3 treatment groups, 
respectively) based on an anticipated dropout rate of 5%.   
4.2 
Study Population Characteristics 
The study population will consist of adult female patients with a history of IC with HL along 
with the associated symptoms as previously reported in guidelines by van de Merwe et al 
(2008). 
4.3 
Inclusion Criteria 
The following are requirements for entry into the study: 
 
 
 


 
 
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5. A diagnosis of IC with HL defined as: 
• an unpleasant sensation (pain, pressure, discomfort) perceived to be related to the urinary 
bladder, associated with lower urinary tract symptoms (LUTS) of more than 6 months 
duration in the absence of infection or other identifiable causes (van de Merwe et al, 
2008), documented history or patient reported 
and  
• documented history of an observation of HL via cystoscopic procedure in which a 
lesion is defined as a circumscript, reddened mucosal area that can be small vessels 
radiating towards a central scar, and/or a fibrin deposit of coagulum attached to 
this area.  Lesions may also be linear, fissure-like, and may be bleeding. 
 
 
 
 
 
  
 
 
 
 


 
 
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4.4 
Exclusion Criteria 
The following are criteria for exclusion from participating in the study: 
1. Patient who is pregnant, nursing, or planning a pregnancy during study participation 
2. Patient of childbearing potential who is unable or unwilling to use a reliable form of 
contraception during the study (as defined in Section 4.5.1.1)  
 
 
 
 
 
 
 
 
 
 
 


 
 
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19. Previous exposure to LiRIS in a TARIS clinical study within 6 months prior to 
Screening. 
 
 
 
 
 
4.5 
Permissible and Prohibited Medications/Treatments 
4.5.1 
Permissible Medications/Treatments 
Therapy considered necessary for the patient’s welfare may be given at the discretion of the 
investigator.  Patient should be instructed to maintain a stable dose of chronic medications 
during the study whenever possible.  Please see Table 2 for a list of permissible medications 
with the required stable duration prior to Screening (if continuing as stable therapy in the 
study), the period off medication/treatment prior to Screening, and permissible short-term 
rescue therapy (medication must have been used previously, prior to study entry with no 
tolerability issues).  See Section 4.5.3 regarding rescue medication. 


 
 
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All medications, adjunct therapies, and concurrent procedures should be recorded on the 
appropriate electronic case report form (eCRF).  If the permissibility of a specific 
medication/treatment is in question, please contact the assigned Medical Safety Physician of 
the study. 
4.5.1.1 
Definition of Females of (Non)Childbearing Potential and/or 
Acceptable Contraceptive Methods 
For purposes of this study, females will be considered of childbearing potential unless they 
are naturally postmenopausal or permanently sterilized (ie, hysterectomy).  Natural 
menopause is defined as the permanent cessation of menstrual periods, determined 
retrospectively after a woman has experienced 12 months of amenorrhea without any other 
obvious pathological or physiological cause.  For women of childbearing potential who may 
participate in the study, the following methods of contraception, if properly used, are 
generally considered reliable:  hormonal contraceptives (ie, oral, patch, injection, implant), 
male condom with intravaginal spermicide, diaphragm or cervical cap with spermicide, 
vaginal contraceptive ring, intrauterine device, surgical sterilization (bilateral tubal ligation, 
bilateral salpingectomy), vasectomized partner, or total sexual abstinence (when this is in line 
with the preferred or usual lifestyle of the patient). 
The investigator and each patient will determine the appropriate method of contraception for 
the patient during the participation in the study. 
If a female becomes pregnant during the study, the investigator will notify Allergan 
immediately after the pregnancy is confirmed and the patient will be exited from the study 
after appropriate safety follow-up.  The investigator will (1) notify the patient’s physician 
that the patient was being treated with an investigational drug LiRIS 400 mg or LiRIS 
Placebo, and (2) follow the progress of the pregnancy.  The investigator must document the 
outcome of the pregnancy and provide a copy of the documentation to the Medical Safety 
Physician assigned to this study. 
4.5.2 
Prohibited Medications/Treatments 
Use of the following medications/treatments is prohibited throughout study participation: 
• botulinum toxin treatment of any serotype for any genitourinary indication 


 
 
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• patients who are not on a stable dose of any oral medications/physical therapy (see 
Table 2) for the treatment of IC should not use them for the duration of the study 
unless they are being used as a rescue medication (Section 4.5.3) 
Note:  Possible effects on study safety and endpoints should be taken into 
consideration when initiating treatment during the trial with any of the oral 
medications listed in Table 2 for an indication outside of IC.   
• any intravesical pharmacotherapies (eg, dimethyl sulfoxide [DMSO], sodium 
hyaluronate [Cystistat®], chondroitin [Uracyst®], pentosan polysulfate sodium 
[Elmiron®], heparin, lidocaine, sodium bicarbonate, capsaicin or resiniferatoxin) 
• use of electrical stimulation or neuromodulation devices (implanted and external) for 
the treatment of LUTS or pain.  If a patient is enrolled into the study with a device 
still implanted, it must be inactive for 4 weeks prior to treatment on 
Randomization/Day 0 and must remain inactive for the duration of the study 
• hydrodistention (or any other procedure that may result in bladder distention) 
• general or spinal anesthesia may not be administered at the same time as the IP 
insertion/removal 
• products other than IP that would result in systemic lidocaine exposure (eg, lidocaine 
patch [Lidoderm], IV lidocaine, intrathecal lidocaine) 
The decision to administer a prohibited medication/treatment is done with the safety of the 
study participant as the primary consideration.  When possible, the assigned Medical Safety 
Physician for this study should be notified before the prohibited medication/treatment is 
administered. 
4.5.3 
Rescue Medications  
Use of confounding medications should be minimized in the study and avoided if possible, 
however rescue medications may be used on an as needed, short-term basis according to 
local site practice for patients who have an acute exacerbation of pain (“flare”) (Table 2).  
The following medications may be used: 
• any oral pain relieving medication (except herbal medications) that the patient has 
previously used for IC within the 3 months prior to Screening and has been tolerated  


 
 
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Use of any nonpain relieving medications (eg, anticholinergics) is prohibited as rescue 
medication. 
All usage of rescue medication should be recorded (time of use and dose) on the pain diary 
by the patient and on the appropriate eCRF by the site staff.  In addition sites should question 
patients at all visits regarding the use of rescue medications between visits and any such 
usage should be recorded in the appropriate eCRF. 
4.5.4 
Oral Prophylactic Antibiotics 
Oral prophylactic antibiotics use before and after cystoscopy procedures are recommended 
and should be used per local site practice.  Patients shall begin oral prophylactic antibiotics 3 
days prior to, on the day of, and following the procedure, for 3 days . 
Any oral antibiotics approved for the treatment of UTIs may be used at the discretion of the 
investigator and must be recorded on the concomitant medications eCRF. 
4.5.5 
Study Treatment Anesthesia 
Study treatment administration and removal may be performed using local anesthesia 
(general or spinal anesthesia is prohibited) and/or sedation.  The type of anesthesia used is at 
the investigator’s discretion, depending on the patient’s expected tolerability and available 
facilities.   
One or more of the following options are permitted as per local site practice: 
• local anesthesia or lubricating gel to the urethra to facilitate cystoscope insertion 
• sedatives (oral or IV) may be administered 
All anesthesia should be recorded on the appropriate eCRF. 
4.5.6 
Special Diet or Activities  
No restriction on meals or diet is required for this study.  Information about patient tobacco 
use will be collected in order to exclude those patients samples from the 2,6-xylidine 
analyses.  Information about patients dietary lifestyle will be collected (vegan, vegetarian, 
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5. 
Study Treatments 
5.1 
Study Treatments and Formulations 
The study treatment is LiRIS 400 mg (AGN-201025). 
LiRIS is a passive nonresorbable lidocaine-releasing intravesical system whose primary 
mode of action is the controlled release of lidocaine into the bladder over a 2-week period.  
The device constituent of LiRIS (both active and placebo) is constructed of medical grade 
silicone (elastomer) and nitinol wire, which provides the bladder-retentive property of the 
system. 
 
  
 
 
 
 
 
 
5.2 
Control Treatment  
LiRIS Placebo contains lactose minitablets in place of the lidocaine. 
5.3 
Methods for Masking/Blinding 
All study treatments (active and placebo) and packaging will be identical in order to maintain 
masking of the study.  The study treatment will be identified as an investigational compound.  
The study number and kit number will be identified on the unit label. 
5.4 
Treatment Allocation Ratio and Stratification  
Patients will be randomized centrally and stratified on Randomization/Day 0 by baseline pain 
score (≤ 5 or > 5).  Each patient within a stratification group will be randomized using an 
automated randomization system to 1 of 3 treatment groups (LiRIS 400 mg/LiRIS 400 mg; 
LiRIS Placebo/LiRIS Placebo; LiRIS Placebo/LiRIS 400 mg) in a 2:1:1 ratio. 


 
 
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5.5 
Method for Assignment to Treatment Groups/Randomization 
Following the Screening period, patients who meet the study inclusion/exclusion criteria and 
day of treatment criteria will be assigned a randomization number through the interactive 
voice response system (IVRS)/ interactive web response system (IWRS) which determines 
the treatment group assignment.  Study medication will be labeled with medication kit 
numbers.  The IVRS/IWRS system will provide the site with the specific medication kit 
number(s) for the patient that corresponds to the treatment group to which the patient was 
assigned.  The site will also use IVRS/IWRS to assign a new kit number to each patient who 
meets Treatment 2 criteria. 
5.6 
Treatment Regimen and Dosing 
5.6.1 
Treatment 1  
Eligible patients will be randomized on Randomization/Day 0 to receive Treatment 1, 
LiRIS 400 mg/LiRIS 400 mg; LiRIS Placebo/LiRIS Placebo or LiRIS Placebo/LiRIS 400 mg 
(Section 5.4).  Patients will have the Treatment 1, 1st IP inserted on Randomization/Day 0 
and removed on Day 14.  On the same day, following the 1st IP removal, the 2nd IP 
(LiRIS 400 mg or LiRIS Placebo) will be inserted and subsequently removed on Day 28.  
Patients will be followed for 20 weeks post IP removal for additional safety and efficacy 
assessments.  In the event that a patient does not receive Treatment 2, they will exit the study 
at Treatment 1 Week 20 Follow-up Visit. 
5.6.2 
Treatment 2  
All patients will receive LiRIS 400 mg for their second treatment.  Patients may request, 
qualify, and receive Treatment 2 IP from Week 4 Follow-up until Week 20 of Treatment 1.  In 
the event that the Treatment 2 IP cannot be inserted on the day of qualification, Treatment 2 
may be rescheduled within 14 days of qualification.  The LiRIS will be inserted on 
Treatment 2/Day 0, and will be removed on Day 14.  Patients will be followed for 4 weeks 
post-removal and will be exited from the study. 
5.6.3 
Premature IP Removal  
The IP will be removed immediately and appropriate medical therapy should be instituted 
immediately, if any of the following occur: 
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• if patient becomes pregnant 
• haematuria that is considered by the investigator to be clinically significant 
• urinary retention that is considered by the investigator to be clinically significant 
• allergic reaction (shortness of breath, generalized edema, etc) to either LiRIS device 
constituent materials (silicone, nitinol), drug (lidocaine or lactose) and/or excipients 
(povidone, polyethylene glycol)  
• signs of lidocaine toxicity (Xylocaine® Injection Package Insert, 2010) where 
toxicities associated with lidocaine include but are not limited to light-headedness, 
nervousness, perioral tingling, tingling or numbness of the tongue, confusion, 
dizziness, drowsiness, tinnitus, blurred or double vision, vomiting, sensations of heat, 
cold or numbness, twitching, tremors, convulsions, unconsciousness, respiratory 
depression, respiratory arrest and cardiovascular reactions which are usually 
depressant in nature and are characterized by bradycardia, hypotension, and 
cardiovascular collapse, which may lead to cardiac arrest 
• a condition or situation that, in the investigator’s opinion, may put the patient at 
significant risk 
5.7 
Storage of Study Medications/Treatments 
The study medication must be stored in a secure area and administered only to patients 
entered into the clinical study, at no cost to the patient, in accordance with the conditions 
specified in this protocol. 
IP must be stored at room temperature 
 and protected from light, 
representing a usual and customary working environment.  The IP must not be frozen.  Sites 
must report any temperature excursions as described in the Study Manual or contact Allergan 
or its designee for further instructions. 
5.8 
Treatment Administration  
The insertion, removal, and inspection of the IP are to be completed by the investigator(s) 
involved with the study.  Detailed instructions for the insertion and removal of the IP are in 
the Study Manual . 


 
 
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5.8.1 
Day of Treatment Criteria 
The following day of treatment criteria must be fulfilled prior to the administration of study 
treatment. 
• confirm that patient did not have a symptomatic UTI during the baseline pain 
eligibility criteria assessment period 
• negative urine dipstick reagent strip test (for leukocyte esterase and/or nitrites) and, in 
the investigator’s opinion, patient is asymptomatic for a UTI on the day of study 
treatment 
• negative urine pregnancy result (for patients that are of child bearing potential) 
• investigator continues to deem treatment is appropriate and no condition or situation 
exists which, in the investigator’s opinion, puts the patient at significant risk from 
receiving treatment 
5.8.2 
Qualification for Retreatment  
Patients can request retreatment (Treatment 2) at any time from the Week 4 Follow-up clinic 
visit up through the Week 20 Follow-up clinic visit.  A patient will be eligible to receive 
Treatment 2 (LiRIS 400 mg) only if all of the following criteria are met: 
• completed Treatment 1 schedule of visits and procedures from the Week 4 Follow-up 
visit through qualification, in the opinion of the investigator 
• negative urine dipstick reagent strip test (for leukocyte esterase and/or nitrites) and, in 
the investigator’s opinion, patient is asymptomatic for a UTI on the day of study 
treatment 
• negative urine pregnancy result (for patients that are child bearing potential) and are 
willing to continue using acceptable method of contraception 
• Investigator continues to deem treatment is appropriate and no condition or situation 
exists which, in the investigator’s opinion, puts the patient at significant risk from 
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6. 
Response Measures and Summary of Data Collection Methods 
6.1 
Efficacy Measures 
6.1.1 
Primary Efficacy Measure 
• average daily bladder pain score patient experienced over the previous 24-hour period 
as measured by an NRS of 0 to 10, recorded on a 7-day pain assessment tool.   
The primary timepoint is Week 4 following Treatment 1 2nd IP removal. 
6.1.2 
Secondary Efficacy Measures 
• number of HLs assessed by the PI during cystoscopy 
• composite score of HL calculated based on number, size, and severity of the lesions 
6.1.3 
Other Efficacy Measures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1.4 
Health Outcomes Measures 
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6.2 
Pharmacokinetics Measures  
 
 
 
 
 
 
 
6.3 
Safety Measures 
• adverse events and serious adverse events  
• physical examination 
• vital signs 
• any abnormal cystoscopy findings at insertion and removal 
• pregnancy testing for women of childbearing potential 
• urine dipstick reagent test 
• urine analysis (with urine culture and sensitivity, as applicable) 
• urine cytology (at Screening only) 
• post-void residual (PVR) urine volume measurement 
• hematology and non-fasting serum chemistry 
• concomitant medications 
• concurrent procedures 


 
 
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6.4 
Post-use Assessments and Investigational Product Events 
• voiding of the IP  
• damage to the IP during insertion or removal procedures 
• damage to the IP that is not related to insertion or removal procedures 
6.5 
Examination Procedures, Tests, Equipment, and Techniques  
Screening procedures can commence once the informed consent and data 
authorization/protection form have been obtained.  Screening will be considered to have 
started (eg, Day -28) at the time of the first Screening activity or procedure.  On completion 
of Screening, when all the required inclusion/exclusion have been met, the patient will be 
randomized and be considered enrolled into the study. 
Evaluations should be performed by the same evaluator throughout the study whenever 
possible.  If it is not possible to use the same evaluator to follow the patient, then it is 
preferable to have the evaluations overlap (examine the patient together and discuss findings 
for at least one visit). 
6.5.1 
Medical History/Demographics 
A complete medical history will be obtained and is to include diagnosis or symptom, date of 
onset, current status, associated surgical procedures, detailed genitourinary history, prior 
medications/treatments, and reasons for discontinuation.  In addition key demographics (ie, 
information about patients dietary lifestyle [vegan, vegetarian, non-vegetarian], smoker 
versus non-smoker) will be documented for each patient. 
6.5.2 
Physical Examination 
The physician or appropriately qualified designee will perform a complete physical 
examination (PE) and examine the patient for any physical abnormalities of the following 
body systems:  head, ears, eyes, nose, and throat (HEENT) and neck, cardiovascular, 
respiratory, abdomen, musculoskeletal, and skin systems will be performed at the appropriate 
scheduled visits (see Table 1). 
An abbreviated PE includes cardiovascular, respiratory, and abdomen examination.  Please 
refer to Table 1 for the scheduled visit in which the abbreviated PE should be performed 
compared with a complete PE. 


 
 
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6.5.3 
Pelvic Examination 
A pelvic examination by a physician investigator should be performed to ensure that the 
urethra and bladder are palpated last.  The initial examination should comprise visual 
inspection of the external genitalia for signs of infection, tumors, or urethral caruncle, a 
superficial tactile examination of the external genitalia to elicit superficial non-bladder 
related tenderness and a careful, gentle palpation of the vulval fourchette and levator ani 
muscles to assess pelvic floor pain etiology and to rule out high muscle-tone pelvic floor 
dysfunction as the primary source of the patient’s pain.  Finally the posterior urethra, bladder 
neck, and bladder should be palpated to elicit bladder-related pain.  This examination must be 
included as a part of the Screening period PE. 
6.5.4 
Vital Signs, Weight and Height Measurements 
Vital signs will be measured prior to any invasive procedures as outlined below: 
• pulse rate (beats per minute):  patients should be resting in a seated position 
• blood pressure (mm Hg):  patients should be resting in a seated position.  
Systolic/diastolic blood pressure is then measured with a sphygmomanometer. 
• temperature (oF or oC):  patients should be seated and the body temperature taken 
according to local site practice 
• body weight (Screening and exit) and height (Screening visit only) will be measured 
according to local site practice 
6.5.5 
Clinical Laboratory Assessments 
All clinical laboratory samples will be analyzed at a central facility.  For schedule of blood 
and urine samples collection, please refer to Table 1. 
Analytes will be tested as specified below: 
Hematology:  red blood cells (RBC); RBC Indices:  mean corpuscular volume (MCV), mean 
corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), 
RBC morphology; white blood cells (WBC); WBC differential (% and absolute):  
neutrophils, lymphocytes, monocytes, eosinophils, basophils, hematocrit; hemoglobin; and 
platelets 


 
 
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Blood Chemistry:  albumin, alkaline phosphatase, alanine aminotransferase (ALT [SGPT]), 
aspartate aminotransferase (AST [SGOT]), total and direct bilirubin, blood urea nitrogen 
(BUN), calcium, chloride, creatinine, gamma glutamyltransferase (GGT), globulin, non-
fasting glucose, potassium, total protein, and sodium  
Urine Analysis and Urine Culture and Sensitivity:  Urinalysis will be performed at all clinic 
study visits; a urine culture and sensitivity test will also be performed when urinalysis results 
are suggestive of a potential UTI (positive leukocyte esterase, nitrites, blood and/or 
microscopic sediments such as WBCs, RBCs, and/or bacteria). 
Urine analytes to be tested are listed below: 
Urinalysis:  Color, appearance, specific gravity; pH, protein, glucose, ketones, occult blood, 
leukocyte esterase, nitrite, bilirubin, urobilinogen, crystals; microscopic examination if 
positive for protein, leukocyte, occult blood, nitrite, or crystals 
Urine Culture and Sensitivity:  Culture, quantitation, isolation, identification, and 
susceptibility 
Urine cytology is performed at the Screening visit only.  Abnormal urine cytology suspicious 
for a urothelial malignancy should be investigated by the investigator according to local site 
practice, and only if such malignancy is ruled out should the patient be enrolled.  Results of 
the investigation will be recorded in the source documents. 
Serum and Urine Pregnancy Test:  Beta-human chorionic gonadotropin (β-HCG) performed. 
Pregnancy testing will be conducted for women of childbearing potential using serum β-HCG 
test with the exception of any day of IP insertion where urine will be used. 
Urine Dipstick Reagent Strip Tests (Urine Dipstick): The urine dipstick is used to identify a 
potential UTI and to provide immediate information to the investigator. 
6.5.6 
Pharmacokinetic Analysis Assessments 
All enrolled patients will have blood and urine collected for pharmacokinetic analysis of 
lidocaine and 2,6-xylidine (non-smokers only) during both Treatment 1 and Treatment 2 (if 
applicable). 
Plasma samples will be collected and stored at -20°C or colder until shipped to the central 
laboratory facility.  Detailed instructions for the collection, processing, storage and shipment 
of samples are provided in the Central Laboratory Manual. 


 
 
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6.5.7 
Bladder Post-void Residual  
Bladder PVR is to be assessed per the site’s standard of care method (eg, bladder scan) but 
should be performed preferably immediately after voiding.  The same method should be 
consistently used throughout the study.  Please see Table 1 for the visits at which PVR should 
be assessed.   
6.5.8 
Cystoscopic Examination 
All patients will undergo a cystoscopic examination on the days of Insertion of the IP to rule 
out the presence of any bladder or urethra anatomical feature that, in the opinion of the 
investigator, might prevent the safe placement, indwelling use, or removal of IP, such as 
bladder fistulae or stone.  In addition, prior to the intial IP insertion on Day 0, the presence of 
HLs will be confirmed.  If during the cystoscopic exam, the investigator discovers an 
abnormality that would prevent the safe placement, indwelling use, or removal of the IP, the 
patient will not receive treatment and will be withdrawn from the study.  
A brief cystoscopic examination for safety purposes will also be conducted on all patients at 
the Treatment 1 and Treatment 2 Day of Removal Visits (see Table 1). 
During each cystoscopy, the investigator will count the number of lesions visible while 
performing the bladder scan for bladder mapping. 
Investigators may recommend that the patient take pain medication up to 6 hours prior to the 
cystoscopic procedure and continuing for 24 hours after the procedure to minimize patient 
anxiety and discomfort. 
6.5.9 
Bladder Mapping 
During the cystoscopic exams, a standardized video capture protocol for bladder mapping 
will be followed in order to assess any changes in the number, size, and severity of lesions 
during the study as a result of treatment.  
6.5.10 
Insertion and Removal of IP 
For instructions on insertion and removal of IP, please see the Study Manual. 


 
 
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6.5.11 
Post-use Assessment 
Immediately after removal of the IP, the investigator will take 2 photographs of the IP 
(wireform side up and wireform side down), and will perform a visual inspection of the IP to 
confirm that it was removed from the patient in its entirety and none of the IP components 
(nitinol wire, silicone) are missing.  The investigator will document any observations of 
visible damage or changed appearance of IP (eg, wireform protrusion, torn silicone, change 
in color, etc) in the eCRF, and notify Allergan or designee within 48 hours so that a product 
investigation can be initiated if appropriate.  If the IP is not removed from the patient in its 
entirety, the investigator should conduct appropriate testing to confirm that no IP components 
are left indwelling in the patient, such as a pelvic examination, abdominal x-ray, abdominal 
ultrasound, and/or cystoscopic exam. 
Each IP removed from the bladder of a study patient will be retained and sent to Allergan for 
a post-use assessment.  Detailed instructions for the storage and shipment of the IP 
post-removal are provided in the Study Manual. 
6.5.12 
Bladder Pain NRS 
A pain assessment tool will be utilized in the study to capture the daily average pain and the 
daily worst pain scores on an electronic hand held device.  Patients will be asked to rate their 
daily pain on a pain NRS consisting of an 11-point integer scale ranging from 0 for “no pain” 
to 10 for “worst pain imaginable”.  The pain assessment tool will be provided to patients at 
the Screening visit and patients will be instructed on how to correctly complete the bladder 
pain assessment by the site staff.  If the patient has a confirmed or suspected UTI, pain data 
should not be collected until the signs and symptoms of the UTI have resolved. 
The pain assessment will continue every day up to and including the day prior to the Exit 
Visit.  Patients should complete the pain assessment questions at approximately the same 
time each day on the pain assessment tool (preferably at the end of each day, prior to 12:00 
midnight, with instruction that it reflects the last 24-hour period).   
Baseline and Follow-up Visit Pain Assessment 
The baseline pain assessment will be calculated based on at least 5 consecutive days of data 
collected in the 7 days immediately prior to the Randomization/Day 0 visit to determine 
eligibility and obtain baseline values. Pain assessment data collection should be completed 
for at least 14 days immediately prior to Randomization/Day 0 in order to acclimate the 
patient to the process of assessing their pain on a daily basis.The primary timepoint for the 


 
 
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daily average pain score is at 4 weeks following Treatment 1, 2nd IP removal.  The patient’s 
Pain NRS for this timepoint will be the average of the 7-day “average pain in your bladder 
over the last 24 hours”. 
If the patient’s study visit is rescheduled, the site must ensure that adequate time has been 
provided for the patient to record at least 5 consecutive pain assessment days during the 
7 days immediately prior to the rescheduled visit. 
6.5.13 
Bladder Diary 
A paper bladder diary will be utilized in the study to capture micturition parameters.  Prior to 
receiving the diary, patients will be instructed and trained on the use of the diary, the data to 
be collected and instructed on how to correctly complete the bladder diary by the site staff. 
Patients should enter data into the bladder diary following each void (day and night) for 
3 consecutive days immediately prior to the designated clinic visit (see Table 1). 
The 3-day bladder diary will capture the number of day-time voids and the number of night-
time voids (where night time is defined as the time the patient goes to bed until the time the 
patient gets out of bed the next morning) over a period of 3 days.  Patient will also indicate 
all urinary urgency episodes defined as time they experienced a sudden and urgent need to 
urinate whether it was associated with a recorded void or not.  The bladder diary will also 
capture patient-reported pre-void and post-void bladder pain. 
6.5.14 
Pain Catastrophizing Scale  
The PCS is a 13-item self-administered scale which assesses the psychological impact of 
pain that will be evaluated at the Screening visit for study eligibility.  Items are rated on a 
scale from 0 to 4 and the PCS has 3 different categories:  Rumination, Magnification, and 
Helplessness.  It is hypothesized that pain catastrophizing is related to various levels of pain, 
physical disability, and psychological disability in clinical and nonclinical populations. 
 
 
 
 
 
 
 


 
 
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6.5.18 
Concomitant Medications and Concurrent Procedures 
Patients will be instructed to capture all pain medication (stable dose and rescue medications) 
taken for IC pain during the study on the electronic diary which will capture what medication 
was taken and when (date and time).  Site staff will review the pain medication electronic 


 
 
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diary and capture missing or incomplete pain medication information as required.  Site staff 
will also query patients regarding use of any other medications while participating in the 
study. 
Concomitant medication information, including name of medication, dose, route, date will be 
collected at each study clinic and phone visit starting at the time of Screening and ending at 
the patient Exit Visit (either at completion of follow-up to Treatment 1 or Treatment 2, as 
applicable).   
All concomitant medications and concurrent procedures must be recorded in the eCRF with 
all specific details associated with each use of the medication/procedure. 
6.5.19 
Adverse Events  
Details regarding the definitions, documentation, and reporting of  adverse events/serious 
adverse events are in Section 9. 
6.5.20 
IP Events 
An IP event includes any observation of the IP not performing as intended.  Examples of IP 
Events are: 
• voiding of the IP  
• damage to the IP during insertion or removal procedures 
• damage to the IP that is not related to insertion or removal procedures 
An IP Event could occur any time between when the IP is removed from the packaging 
through the insertion/removal procedures and the return of the IP.  
Each IP Event will be assessed by the investigator to determine if it is associated with an 
adverse event, and any adverse events identified will be managed according to details in 
Section 9. 
All IP Events, in the opinion of the investigator, should be reported to Allergan or designated 
representative. 


 
 
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6.6 
Other Study Supplies 
The following will be provided by Allergan: 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.7 
Summary of Methods of Data Collection 
Pain assessment and pain medication use will be recorded by the patient on an electronic 
diary.  Voiding frequency and urgency, and pre- and post-void pain scores will be reported by 
patients in a paper bladder diary.  
 
  All clinical study data will be entered into an electronic data 


 
 
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capture (EDC) system via eCRFs.  Source documents will be used and stored at the sites, and 
may include a patient’s medical records, hospital charts, clinical charts, patient chart, copy of 
the EDC file, as well as the results of diagnostic tests (if performed). 
7. 
Statistical Procedures 
All statistical analyses will be detailed in the study statistical analysis plan (SAP), which will 
be finalized prior to database lock.  This document will provide a more technical and detailed 
description of the proposed data analysis methods and procedures.  Two analyses are planned 
for this study, including the primary analysis and the final analysis.  The primary analysis 
will be conducted at the time when the last patient completes the primary timepoint that is 
Week 4 following Treatment 1 2nd IP removal.  The final analysis will be conducted when all 
patients complete or exit the study. 
7.1 
Analysis Populations 
The modified intent-to-treat (mITT) analysis population:  The mITT population will include 
all patients who were randomized and received at least 1 IP insertion in Treatment 1.  The 
efficacy data will be analyzed as randomized using the mITT population. 
Safety analysis population:  The safety population will include all patients enrolled in this 
study and received at least one IP.  The safety data will be analyzed as treated using the safety 
population. 
Pharmacokinetic evaluable  population:  The pharmacokinetic population will include all 
patients enrolled in this study and who have at least one plasma or urine pharmacokinetic 
concentration measurement post-IP insertion and for whom the IP is successfully removed. 
Per-protocol (PP) analysis population:  The PP population will include all patients who retain 
the 2 IP inserted in Treatment 1 for the 28 days of the treatment period and complete the 
4 Week Follow-up Visit post removal of the 2nd IP of Treatment 1 without any significant 
protocol deviations.  Protocol deviations will be determined prior to database lock. 
7.2 
Collection and Derivation of Primary, Secondary, and Other 
Efficacy Assessments 
Average daily bladder pain NRS:  The pain NRS will be used to assess bladder pain over the 
previous 24-hour period.  The pain NRS consists of an 11-point integer scale ranging from 0 
for “no pain” to 10 for “worst pain imaginable.”  Patients are instructed to complete the pain 


 
 
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NRS in an electronic handheld diary by choosing the number that answers the following 
question regarding their bladder pain: 
Please describe the average pain in your bladder over the last 24 hours. 
The patient’s baseline pain NRS will be the average of the 7-day “average pain in your 
bladder over the last 24 hours” NRS scores from the 7 reported days prior to 
randomization/1st IP insertion.   
Study baseline for a patient is defined as the last measurement available prior to the first 
treatment. 
Missing Data 
Every effort will be made to obtain required data at each scheduled evaluation from all 
patients who have been enrolled.  Missing data will only be imputed for the analysis of the 
primary efficacy variable. 
7.2.1 
Primary Efficacy Variables  
The primary efficacy variable is the change in average daily bladder pain NRS at Week 4 
Follow-up Visit post removal of 2nd IP of Treatment 1 as compared to study baseline. 
The average daily pain NRS of the preceding 7 days (at least 5 consecutive days) will be 
calculated and used to calculate baseline and change from baseline at each scheduled visit.  If 
no data are available for at least a period of 5 consecutive days, that average will be 
considered missing for that patient.   The primary timepoint is 4-week follow up after 
removal of the 2nd IP of Treatment 1.  If there is no valid Week 4 Follow-up NRS assessment 
and there is a valid Week 2 or 3 Follow-up NRS assessment, the Week 4 Follow-up value 
will be imputed using the latest of the 2 values that is available (ie, Week 2 or 3 Follow-up).     
7.2.2 
Secondary Efficacy Variables 
There are 2 secondary efficacy variables: 
• change from baseline in number of HLs assessed by the PI during cystoscopy 
During each cystoscopy, the investigator will count the number of lesions visible 
while preforming the bladder scan for bladder mapping.  


 
 
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• change from baseline in composite score of HL calculated based on number, size, and 
possibly severity of the lesions 
A standardized video capture protocol for bladder mapping will be followed in order 
to assess any changes in the number, the size and the severity, of lesions during the 
study as a result of treatment. 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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7.3 
Hypothesis and Methods of Analysis 
For the primary efficacy analysis, the null hypothesis is that the mean change from baseline 
in average daily bladder pain NRS at Week 4 Follow-up post IP removal visit is the same 


 
 
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between the LiRIS 400 mg/LiRIS 400 mg group and the LiRIS Placebo/LiRIS Placebo group 
(2 consecutive placebo’s). 
The alternative hypothesis is that the mean change from baseline in average daily bladder 
pain NRS at Week 4 Follow-up post IP removal is different between the 
LiRIS 400 mg/LiRIS 400 mg group and the LiRIS Placebo/LiRIS Placebo group. 
Methods of Analysis 
All continuous variables will be summarized showing the number, mean, median, standard 
deviation, minimum, and maximum values.  Discrete variables will be summarized showing 
the frequency and percentage of the study population.  As this is a phase 2 trial, there will be 
no p-value adjustment for multiplicity.  Plots of efficacy variables (value and/or change from 
baseline) will be presented over time. 
7.3.1 
Demographics, Baseline Characteristics and Disposition 
Analyses 
Demographic and baseline characteristic data, including age, race, ethnicity, and abnormal 
PE results will be summarized and presented by treatment group for Treatment 1 and 
Treatment 2 separately. 
Patient disposition for both Treatment 1 and Treatment 2 will be displayed by treatment 
group.  For those discontinuing the study prematurely, the reason for study termination will 
be recorded and time on study will be calculated. 
7.3.2 
Efficacy Analyses 
All efficacy analyses will be performed on the mITT population.  Analyses of the primary 
efficacy variable will also be performed on the PP population.   
Plots of values and change from baseline or percentage in each variable category, as 
appropriate, will be presented by treatment over time. 
All analyses are based on 2-sided tests with significance level of 0.10 unless otherwise 
specified. 


 
 
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7.3.2.1 
Primary Efficacy Analyses 
The primary endpoint was the change in bladder pain at Week 4 Follow-up Visit post last IP 
removal of Treatment 1 as compared to study baseline. 
The average daily pain NRS of the preceding 7 days (at least 5 consecutive days) will be 
calculated and used to calculate change from baseline at each scheduled visit.  Calculation of 
averages will employ available data without imputation.  If no data are available for a given 
7-day period (at least 5 consecutive days) that average will be considered missing for that 
patient. 
The change from baseline in average daily bladder pain score at Week 4 Follow-up Visit post 
IP removal of Treatment 1 will be analyzed using the analysis of covariance (ANCOVA) 
model, using the baseline value as the covariate, and stratification factor (baseline bladder 
pain NRS:  ≤ 5 or > 5) and treatment as factors.  If there is no valid Week 4 Follow-up NRS 
assessment and there is a valid Week 2 or 3 Follow-up NRS assessment, the Week  4 Follow-
up value will be imputed using the latest of the 2 values that is available (ie, Week 2 or 3 
Follow-up).    
The same ANCOVA analysis will also be performed at all other postbaseline timepoints. 
7.3.2.2 
Secondary Efficacy Analyses  
The analysis of the continuous secondary efficacy variables at Week 4 Follow-up Visit post 
IP removal of Treatment 1 may be analyzed similarly as for the primary efficacy variable of 
average daily bladder pain NRS, as described in Section 7.3.2.1 Primary Efficacy Analyses.  
However, no imputation method will be applied. 
 
 
 
 
 
 
 


 
 
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7.3.3 
Safety Analyses 
Safety data will be analyzed using safety population. 
Safety assessments will be reported by treatment group and will include: 
• adverse events  
• clinical laboratory results  
• urinalysis  
• urine culture and sensitivity  
• vital signs  
• PVR volumes 


 
 
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Adverse events will be mapped to a Medical Dictionary for Regulatory Activities (MedDRA) 
preferred term and system organ classification (SOC) using MedDRA. 
The following analyses will be performed: 
1. Summaries by treatment group and overall for Treatment 1 
2. Overall summaries for all patients who received Treatment 2 
3. Summaries for patients who participated in both Treatment 1 and Treatment 2 by 
treatment group and overall 
Safety Analyses 
1. Occurrence of adverse events using MedDRA preferred term, primary SOC, and 
severity.  If a patient experiences multiple events that map to a single preferred term, 
the greatest severity and strongest investigator assessment of relation to the IP will be 
assigned to the primary SOC and preferred term for the appropriate summaries. 
2. All adverse events for individual patients showing both verbatim, preferred term, and 
primary SOC 
3. Serious adverse events and adverse events related to the IP, the device constituent 
alone (silicone device/nitinol wire/elastomer components), and the drug (lidocaine) 
constituent alone; overall summary by preferred term, primary SOC, and severity 
4. Serious adverse events  and adverse events related to the procedure (cystoscopy, IP 
insertion procedure or the IP removal procedure); overall summary and summary by 
preferred term, primary SOC, and severity 
5. Descriptive summaries of clinical laboratory results (see Section 6.5.5 for detailed 
listings of the specific laboratory analytes)  
6. Clinical laboratory abnormality shifts from baseline 
7. Descriptive summaries of vital signs including systolic and diastolic blood pressure, 
heart rate, respiratory rate, and body temperature 
8. Descriptive summaries of PVR volume measurements 


 
 
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9. Prior and concomitant medication (coded using World Health Organization [WHO]-
Drug Dictionary) 
7.4 
Pharmacokinetic Analysis 
Blood and urine concentration data generated for lidocaine and 2,6-xylidine will be used for 
pharmacokinetic assessment in plasma and urine.  A contributing report will be provided for 
inclusion in the final report. 
7.5 
Missing Data 
Every effort will be made to obtain required data at each scheduled evaluation from all 
patients who have been enrolled.  Missing data will only be imputed for the analysis of the 
primary efficacy variable.  Any deviations to the SAP made after database lock will be 
documented in the final Clinical Study Report. 
7.6 
Subgroup Analyses 
There is no pre-planned subgroup analysis.  Any subgroup analysis will be done in an ad hoc 
manner after data base lock. 
7.7 
Sample Size Calculation 
Based on the assumption that 5% of the randomized patients will not be evaluable for the 
primary analysis, approximately 76 patients will be enrolled into the study to ensure 
72 evaluable patients overall.  At a randomization ratio of 2:1:1, 72 evaluable patients will 
ensure that there will be about 36 patients in the LiRIS 400 mg/LiRIS 400 mg group, 
18 patients in the LiRIS Placebo/LiRIS 400 mg group, and 18 patients in the LiRIS 
Placebo/LiRIS Placebo group. 
A sample size of  36 patients in the LiRIS 400 mg/LiRIS 400 mg group versus 18 patients in 
the LiRIS Placebo/LiRIS Placebo group will have 76% power to detect a difference of 1.152 
in mean daily average bladder Pain NRS, assuming that the common standard deviation is 
1.67 using a 1-sided 2-group t-test with a 0.05 significance level.  
 
The standard deviation assumption is 
based on the results of the TAR-100-105 open-label study, where the standard deviation is the 
Week 4 Follow-up raw average daily NRS. 


 
 
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7.8 
Interim Analyses 
After approximately 50% of patients enrolled complete the Treatment 1 Week 4 Follow-up 
visit, an estimate of the standard deviation for the primary variable may be derived based on 
the blinded data review.  If such an assessment results in a drastically different standard 
deviation than what is assumed for the derivation of the sample size in the protocol, the study 
sample size may be decreased or increased, depending on the result of the sample size 
derivation. 
Futhermore, an interim analsyis may be performed after at least 25 patients have been 
enrolled.  If such an interim analysis is to be performed, details of the interim analysis and 
procedures to maintain blinding of treatment groups and confidentiality of results will be 
presented in the SAP. 
8. 
Study Visit Schedule and Procedures 
Please see Table 1 for the schedule of visits and procedures, Figure 1 for the visit flow chart, 
and Section 6.5 for detailed information on study procedures, tests, equipment, and 
techniques. 
8.1 
Patient Entry Procedures  
8.1.1 
Overview of Entry Procedures 
Prospective patients as defined by the criteria in Sections 4.3 and 4.4 (inclusion/exclusion 
criteria) will be considered for entry into this study. 
8.1.2 
Informed Consent and Patient Privacy 
The study will be discussed with the patient and a patient wishing to participate must give 
informed consent prior to any study-related procedures or change in treatment.  The patient 
must also give authorization (US only) and other written documentation in accordance with 
the relevant country and local privacy requirements (where applicable) prior to any study-
related procedures or change in treatment. 
Each patient that provides informed consent and/or assent will be assigned a patient number 
by IVRS/IWRS that will be used on patient documentation throughout the study. 


 
 
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8.2 
Procedures for Final Study Entry 
Final study eligibility will be determined at the Randomization/Day 0 visit to confirm that 
patient baseline pain assessment and bladder diary record support protocol requirement for 
IC with HL.  In addition, the investigator should confirm that the “day of treatment criteria” 
have been fulfilled (Section 5.8.1).  Patients should continue to meet other inclusion and 
exclusion criteria as specified in Sections 4.3 and 4.4 of the protocol. 
A patient is considered to have entered the study when they are randomized to treatment. 
See Section 5.5 for the method for assignment to treatment groups/randomization. 
8.3 
Visits and Associated Procedures  
For a summary of the procedures to be performed, see Table 1 (Schedule of Visits and 
Procedures).  A description of individual procedures is provided in Section 6.5.  The total 
number of clinic visits and study duration for each patient will depend on whether patients 
request and qualify for retreatment.  Evaluations should be performed by the same evaluator 
throughout the study whenever possible.  During the study, every effort should be made to 
perform the study procedures as indicated in Table 1. 
8.4 
Instructions for the Patients 
Patients will be instructed on the following: 
• pain assessment tool and bladder diary completion (Sections 6.5.12 and 6.5.13) 
• complete and bring diaries (electronic and paper) to the study site at each scheduled 
clinic study visit 
• contact the study site (or have a family member or friend contact the study site) to 
report any hospitalizations 
• maintain the dose of any concurrent medication.  If there are changes to medications, 
dosage, or frequency, the changes should be reported to the investigator at the next 
study visit. 
• report all usage of rescue medications to the investigator at the next study visit (see 
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• call the study site if they are experiencing any difficulties following study procedures 
• call the study site as soon as possible in order to reschedule, if the patient cannot 
make their next scheduled study visit 
8.5 
Unscheduled Visits 
Unscheduled visits can be performed if safety concerns arise and at the discretion of the 
investigator.  Additional examinations may be performed as necessary to ensure the safety 
and wellbeing of patients during the study.  eCRFs will be completed for each unscheduled 
visit. 
8.6 
Compliance With Protocol 
Participating patients should be able to adhere to the diary completion and testing parameters 
as described in this protocol. 
Data will be recorded on the appropriate eCRF supported by appropriate source 
documentation.  At each visit, patients should be asked if any concomitant medications had 
been used, if they had undergone any concurrent procedures (nonstudy procedures), and their 
compliance with the protocol since the previous visit. 
8.7 
Early Discontinuation of Patients 
Patients may voluntarily withdraw from the study at any time.  If the withdrawal occurs 
during the treatment period in which the IP is in the patient’s bladder, the patient should 
contact the study site to schedule a visit for IP removal.  If a patient exits the study prior to 
completion, all Exit Visit assessments should be performed at the time of exit. 
Notification of early patient discontinuation from the study and the reason for discontinuation 
will be made to Allergan and will be clearly documented on the appropriate eCRF.   
8.8 
Withdrawal Criteria 
Patients have the right to withdraw from the study at any time and for any reason without 
prejudice to his or her future medical care by the physician or the institution.  The 
investigator and Allergan also have the right to withdraw a patient from the study at any time 
for any reason. 
Patients should be discontinued from the study if any of the following criteria are met: 


 
 
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• patient develops (or has an exacerbation of) any medical condition that, in the opinion 
of the investigator, would put the patient at an unacceptable medical risk or 
compromises the patient’s ability to participate in the study 
• patient becomes pregnant (see Section 4.5.1.1 for Definition of Females of 
Childbearing Potential and Acceptable Contraceptive Methods) 
• patient is unwilling or unable to continue to comply with study procedures   
Where possible, the decision to withdraw a patient from study treatment or the study should 
be discussed with Allergan. 
8.9 
Study Termination 
The study may be stopped at his/her study site at any time by the site investigator.  Allergan 
may stop the study (and/or the study site) for any reason with appropriate notification. 
9. 
Adverse Events  
Adverse events occurring during the study will be recorded on an adverse event eCRF.  If 
adverse events occur, the first concern will be the safety of the study participants. 
9.1 
Definitions 
9.1.1 
Adverse Event 
An adverse event is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.  In addition, during the Screening period, adverse events 
will be assessed regardless of the administration of a pharmaceutical product. 
Note:  Adverse events must be collected once informed consent has been obtained, regardless 
of whether or not the patient has been administered study IP. 
Progression of treatment indication including new or worsening of anticipated clinical signs 
or symptoms, which are collected as clinical efficacy variables and assessed as unequivocally 
associated with the disease progression and/or lack of efficacy, should NOT be reported as 


 
 
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adverse events unless the disease progression is greater than anticipated in the natural course 
of the disease. 
Adverse events will be assessed, documented, and recorded in the eCRF throughout the study 
(ie, after informed consent has been obtained).  At each visit, the investigator will begin by 
querying for adverse events by asking each patient a general, non-directed question such as 
“How have you been feeling since the last visit?”  Directed questioning and examination will 
then be done as appropriate.  All reported adverse events will be documented on the 
appropriate eCRF. 
9.1.2 
Definition of Adverse Event of Urinary Tract Infection 
An adverse event of UTI is defined as a UTI based on the investigator’s decision to initiate 
antibiotic treatment (due to results from urine analysis + urine culture or patient’s symptoms 
with appropriate findings in the urine analysis and culture in the investigator’s opinion). 
Note:  If urinalysis/culture results are reported which, in the opinion of the investigator, are 
considered clinically relevant but do not fulfill the above definition of a UTI as no antibiotic 
treatment is initiated by the investigator, the findings should be recorded as adverse events 
(eg, bacteriuria, leukocyturia).  
9.1.3 
Serious Adverse Event 
A serious adverse event is any adverse event occurring at any dose that results in any of the 
following outcomes:  death, a life-threatening adverse event, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a 
congenital anomaly/birth defect.  Important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, they may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  (See Section 9.3 for procedures for reporting a serious adverse event.) 
Allergan considers all cancer adverse events as serious adverse events.  In addition, Allergan 
considers any abortion (spontaneous or nonspontaneous) as a serious adverse event. 
Pre-planned surgeries or procedures for pre-existing, known medical conditions for which a 
patient requires hospitalization is not reportable as a serious adverse event. 
Any pre-planned surgery or procedure should be clearly documented in the site source 
documents by the medically qualified investigator at the time of the patient’s entry into the 


 
 
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study.  If it has not been documented at the time of the patient’s entry into the study, then it 
should be documented as a serious adverse event and reported to Allergan. 
9.1.4 
Severity 
A clinical determination will be made of the intensity of an adverse event.  The severity 
assessment for a clinical adverse event must be completed using the following definitions as 
guidelines: 
Mild 
Awareness of sign or symptom, but easily tolerated. 
Moderate 
Discomfort enough to cause interference with usual activity. 
Severe 
Incapacitating with inability to work or do usual activity. 
Not applicable 
In some cases, an adverse event may be an “all or nothing” finding 
which cannot be graded. 
 
9.1.5 
Relationship to Study Investigational Product or Study 
Procedure 
A determination will be made of the relationship (if any) between an adverse event and the 
study IP or study procedure, as applicable.  A causal relationship is present if a determination 
is made that there is a reasonable possibility that the adverse event may have been caused by 
the IP or study procedure.   
9.2 
Procedures for Reporting Adverse Events 
Any adverse event must be recorded on the appropriate eCRF. 
All adverse events that are IP-related and unexpected (not listed as treatment-related in the 
current Investigator's Brochure) must be reported to the governing Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) as required by the IRB/IEC, local 
regulations, and the governing health authorities.  Any adverse event that is marked 
”ongoing” at the Exit Visit must be followed-up as appropriate. 
9.3 
Procedures for Reporting a Serious Adverse Event 
Any serious adverse event occurring during the study period (beginning with informed 
consent) and for at least 28 days after the last dose of study IP must be immediately reported 
but no later than 24 hours after learning of a serious adverse event.  Serious adverse events 


 
 
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must be reported to Allergan (or agent of Allergan) as listed on the Allergan Study Contacts 
Sheet and recorded on the serious adverse event Form.  All patients with a serious adverse 
event must be followed up and the outcomes reported.  The investigator must supply Allergan 
and the IRB/IEC with any additional requested information (eg, autopsy reports and 
discharge summaries). 
In the event of a serious adverse event, the investigator must: 
1. Notify Allergan immediately by fax or email using the serious adverse event form 
(contact details can be found on page 1 of the serious adverse event form); phone 
numbers and relevant Allergan personnel contacts are also on the front page of 
protocol. 
2. Obtain and maintain in his/her files all pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and follow-up of the 
patient. 
3. Provide Allergan with a complete, written description of the adverse event(s) on the 
serious adverse event form describing the event chronologically, including any 
treatment given (eg, medications administered, procedures performed) for the adverse 
event(s).  Summarize relevant clinical information about the event:  signs, symptoms, 
diagnosis, clinical course and relevant clinical laboratory tests, etc.  Include any 
additional or alternative explanation(s) for the causality which includes a statement as 
to whether the event was or was not related to the use of the investigational IP. 
4. Promptly inform the governing IRB/IEC of the serious adverse event as required by 
the IRB/IEC, local regulations, and the governing health authorities. 
9.4 
Procedures for Unblinding of Study Medication 
When necessary for the safety and proper treatment of the patient, the investigator can 
unblind the patient’s treatment assignment to determine which treatment has been assigned 
and institute appropriate follow-up care.  When possible, the sponsor (Allergan Medical 
Safety Physician) should be notified prior to unblinding study medication.  The investigator 
should inform the sponsor (Allergan Medical Safety Physician) of the unblinding if there is 
no notification prior to the unmasking.   
The treatment assignment for the patient can be determined by designated site personnel 
calling into the IVRS or IWRS system via password protected access.  The reason for 
breaking the code must be recorded in the patient’s source documents. 


 
 
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10. 
Administrative Items 
This protocol is to be conducted in accordance with the applicable Good Clinical Practice 
(GCP) regulations and guidelines, eg, the International Conference on Harmonisation (ICH) 
Guideline on GCP. 
10.1 
Protection of Human Patients 
10.1.1 
Compliance With Informed Consent Regulations (US 21 Code 
of Federal Regulations [CFR] Part 50) and Relevant Country 
Regulations 
Written informed consent is to be obtained from each patient prior to any study-related 
activities or procedures in the study, and/or from the patient's legally authorized 
representative.  If the patient is under the legal age of consent, the consent form must be 
signed by the legally authorized representative in accordance with the relevant country and 
local regulatory requirements. 
10.1.2 
Compliance With IRB or IEC Regulations 
This study is to be conducted in accordance with IRB regulations (US 21 CFR Part 56.103) 
or applicable IEC regulations.  The investigator must obtain approval from a properly 
constituted IRB/IEC prior to initiating the study and re-approval or review at least annually.  
Allergan is to be notified immediately if the responsible IRB/IEC has been disqualified or if 
proceedings leading to disqualification have begun.  Copies of all IRB/IEC correspondence 
with the investigator should be provided to Allergan. 
10.1.3 
Compliance With Good Clinical Practice 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines.  
10.1.4 
Compliance With Electronic Records; Electronic Signatures 
Regulations (US 21 CFR Part 11) 
This study is to be conducted in compliance with the regulations on electronic records and 
electronic signature. 


 
 
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10.2 
Changes to the Protocol 
The investigator must not implement any deviation from or changes of the protocol without 
approval by Allergan and prior review and documented approval/favorable opinion from the 
IRB/IEC of a protocol amendment, except where necessary to eliminate immediate hazards 
to study patients, or when the changes involve only logistical or administrative aspects of the 
study (eg, change in monitors, change of telephone numbers). 
10.3 
Patient Confidentiality 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study drug may ultimately be marketed, but the 
patient’s name will not be disclosed in these documents.  The patient's name may be 
disclosed to the sponsor of the study, Allergan, or the governing health authorities or the 
Food and Drug Administration (FDA) if they inspect the study records.  Appropriate 
precautions will be taken to maintain confidentiality of medical records and personal 
information. 
10.3.1 
Patient Privacy 
Written authorization (US sites only) and other documentation in accordance with the 
relevant country and local privacy requirements (where applicable) is to be obtained from 
each patient prior to enrollment into the study, and/or from the patient's legally authorized 
representative in accordance with the applicable privacy requirements (eg, the Health 
Insurance Portability and Accountability Act Standards for Privacy of Individually 
Identifiable Health Information (“HIPAA”). 
In accordance with HIPAA requirements, additional purposes of this study may include 
publishing of anonymous patient data from the study.  
10.4 
Documentation 
10.4.1 
Source Documents 
Source documents may include a patient's medical records, hospital charts, clinic charts, the 
investigator's patient study files, electronic diaries, as well as the results of diagnostic tests 
such as x-rays, and laboratory tests.  The investigator's copy of the eCRFs serves as part of 
the investigator's record of a patient's study-related data. 
The following information should be entered into the patient's medical record: 


 
 
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• patient’s name 
• patient’s contact information 
• a statement that informed consent was obtained (including the date).  A statement that 
written authorization (US sites only), or other country and local patient privacy 
required documentation for this study has been obtained (including the date). 
• the date that the patient was randomized into the study, patient number, and patient 
medication kit number, and date and details of study IP administration  
• the study title and/or the protocol number of the study and the name of Allergan 
• dates of all patient visits and date of any request for retreatment 
• all concurrent medications (List all prescription and non-prescription medications 
being taken at the time of enrollment.  At each subsequent visit, changes to the list of 
medications should be recorded.) 
• all usage of rescue medications 
• occurrence and status of any adverse events (including any procedure-related adverse 
events) 
• date the patient exited the study, and a notation as to whether the patient completed 
the study or reason for discontinuation 
• results of laboratory tests performed by the central laboratory 
• concurrent procedures performed during the study 
• vital signs and PE findings 
• questionnaire/diary data entered directly onto the appropriate form will be considered 
source data 
10.4.2 
Case Report Form Completion 
The investigator is responsible for ensuring that data are properly recorded on each patient's 
eCRF and related documents.  An investigator who has signed the protocol signature page 
should personally sign for the eCRF (as indicated in the eCRF) to ensure that the 


 
 
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observations and findings are recorded on the eCRF correctly and completely.  The eCRFs 
are to be submitted to Allergan in a timely manner at the completion of the study, or as 
otherwise specified by Allergan and will be maintained in a central data repository. 
10.4.3 
Study Summary 
An investigator's summary will be provided to Allergan within a short time after the 
completion of the study, or as designated by Allergan.  A summary is also to be provided to 
the responsible IRB/IEC. 
10.4.4 
Retention of Documentation 
All study-related correspondence, patient records, consent forms, patient privacy 
documentation, records of the distribution and use of all investigational products, and copies 
of eCRFs should be maintained on file. 
For countries falling within the scope of the ICH guidelines, Allergan-specific essential 
documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirement(s) or if needed by Allergan. 
In addition, for countries not falling within the scope of the ICH guidelines, local regulatory 
requirements should be followed regarding the retention of clinical study documentation. 
Allergan requires that it be notified in writing if the investigator wishes to relinquish 
ownership of the data so that mutually agreed-upon arrangements can be made for transfer of 
ownership to a suitably qualified, responsible person. 
10.5 
Labeling, Packaging, and Return or Disposal of Study 
Medications/Treatments 
10.5.1 
Labeling/Packaging 
Each LiRIS (both active and placebo) is provided sterile and in an individually labeled Tyvek 
sealed pouch.  The pouch is placed into a secondary, standard paper based carton stock, 
which is labeled with a standard adhesive backed paper label containing appropriate clinical 


 
 
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study information and sealed with tamper proof seals.  Active and placebo treatments will be 
provided in identical appearing pouches. 
10.5.2 
Clinical Supply Inventory 
The investigator must keep an accurate accounting of the number of investigational units 
received from Allergan, dispensed to the patients, the number of units returned to the 
investigator by the patient, and the number of units returned to Allergan during and at the 
completion of the study.  A detailed inventory must be completed for the study medication.  
The study medication must be dispensed only by an appropriately qualified person to patients 
in the study.  The medication is to be used in accordance with the protocol by patients who 
are under the direct supervision of an investigator.  A unit is defined as one LiRIS. 
10.5.3 
Return or Disposal of Study Medications/Treatments and/or 
Supplies 
All clinical study medications/treatments and/or supplies will be returned to Allergan or 
Allergan designee for destruction. 
Each LiRIS removed from the bladder of a study patient will be retained and sent to Allergan 
for a post-use assessment.  Detailed instructions for the storage and shipment of LiRIS post-
removal are provided in the Study Manual. 
10.6 
Monitoring by the Sponsor 
A representative of Allergan will monitor the study on a periodic basis.  The determination of 
the extent and nature of monitoring will be based on considerations such as the objective, 
purpose, design, complexity, blinding, size, and endpoints of the study. 
Authorized representatives of Allergan or regulatory authority representatives will conduct 
on-site visits to review, audit and copy study-related documents.  These representatives will 
meet with the investigator(s) and appropriate staff at mutually convenient times to discuss 
study-related data and questions. 
10.7 
Handling of Biological Specimens  
Blood and urine samples will be analyzed for lidocaine and 2,6-xylidine concentrations 
(pharmacokinetics) at a bioanalytical laboratory that meets GLP requirements. 


 
 
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Samples of blood and urine specified in Section 6.5 will be analyzed at a central laboratory 
with certification from a recognized accreditation agency (eg, College of American 
Pathology [CAP] or Clinical Laboratory Improvement Amendments [CLIA] certification).    
The Central Laboratory Manual provides details regarding laboratory collection and 
shipment procedures for blood and urine samples in this study. 
Allergan shall have full ownership rights to any biological samples derived from the study. 
10.8 
Publications 
Allergan as the sponsor, has proprietary interest in this study.  Authorship and manuscript 
composition will reflect joint cooperation between multiple investigators and sites and 
Allergan personnel.  Authorship will be established prior to the writing of the manuscript.  As 
this study involves multiple centers, no individual publications will be allowed prior to 
completion of the final report of the multicenter study except as agreed with Allergan. 
10.9 
Coordinating Investigator 
A signatory Coordinating Investigator will be designated prior to the writing of the Clinical 
Study Report. 
11. 
References 
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and testing of an epidemiological case definition of interstitial cystitis/painful bladder 
syndrome. J Urol. 2010 May;183(5):1848-1852. 
Berry SH, Elliott MN, Suttorp M, Bogart LM, Stoto MA, et al. Prevalence of symptoms of 
bladder pain syndrome/interstitial cystitis among adult females in the United States. J Urol 
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Birch BR, Miller RA. Absorption characteristics of lignocaine following intravesical 
instillation. Scand J Urol Nephrol. 1994;28(4):359-364. 
Brazier JE. The Short-Form 36 (SF-36) Health Survey and its use in pharmacoeconomic 
evaluation. Pharmacoeconomics. 1995 May;7(5):403-415. Review. 
Brooks R. EuroQol: the current state of play. Health Policy. 1996;37:53–72. 


 
 
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Cassuto J, Sinclair R, Bonderovic M. Anti-inflammatory properties of local anesthetics and 
their present and potential clinical implications. Acta Anaesthesiol Scand. 2006;50(3):265-
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Chancellor MB and Yoshimura N. Treatment of interstitial cystitis. Urology. 2004;Mar;63(3 
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Fall M, Logadottir Y, Peeker R. Interstitial cystitis is bladder pain syndrome with Hunner's 
lesion. Int J Urol. 2014;21(Suppl 1):79-82. 
Hanno P, Burks DA, Clemens JQ, Dmochowski RR, Erickson D, FitzGerald MP, et al.  
Diagnosis and treatment of interstitial cystitis/bladder pain syndrome.  American Urological 
Association (AUA) Guideline. 2014:1-45. 
Henry R, Patterson L, Avery N, Tanzola R, Tod D, Hunter D, et al. Absorption of alkalized 
intravesical lidocaine in normal and inflamed bladders: a simple method for improving 
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Higson RH, Smith JC, Hills W. Intravesical lignocaine and detrusor instability. Br J Urol. 
1979;51(6):500-503. 
Killinger KA, Boura JA, Peters KM.  Pain in interstitial cystitis/bladder pain syndrome: do 
characteristics differ in ulcerative and non-ulcerative subtypes?  Int Urogynecol J. 
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Logadottir Y, Delbro D, Lindholm C, Fall M, Peeker R. Inflammation characteristics in 
bladder pain syndrome ESSIC type 3C/classic interstitial cystitis. Int J Urol. 
2014;21(Suppl 1):75-78. 
Logadottir Y, Fall M, Kabjorn-Gustafsson C, Peeker R.  Clinical characteristics differ 
considerably between phenotypes of bladder pain syndrome/interstitial cystitis. Scand J Urol 
Nephrol. 2012: early online, 1-6. 
Lidoderm. Lidocaine Patch 5%. Prescribing Information. Malvern, PA: Endo 
Pharmaceuticals Inc.; 2013. 
Meijlink JM.  Interstitial cystitis and the painful bladder: a brief history of nomenclature, 
definitions and criteria. Int J Urol. 2014;21(Suppl 1):4-12. 


 
 
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Nakahara T, Moriuchi H, Tanaka Y, Yunoki M, Kubota Y, Sakamato K, et al. Role of K+ 
Channels in N-acetylprocainamide-induced relaxation of bovine tracheal smooth muscle. Eur 
J Pharmacol. 2001;415:73-78. 
Nickel JC, Moldwin R, Lee S, Davis EL, Henry RA, Wyllie MG. Intravesical alkalinized 
lidocaine (PSD597) offers sustained relief from symptoms of interstitial cystitis and painful 
bladder syndrome. BJU Int. 2008;103(7):910-918. 
Nordling J, Fall M, Hanno P.  Global concepts of bladder pain syndrome (interstitial cystitis).  
World J Urol. 2012;30:457-464. 
Olsen PC, Ferreira TPT, Serra MF, Farias-Filho FA, Fonseca BP, Viola JPB, et al. Lidocaine-
derivative JMF2-1 prevents ovalbumin-induced airway inflammation by regulating the 
function and survival of T cells. Clinical and Experimental Allergy. 2011;41:250-259. 
Olsen PC, Coelho LP, da Costa JCS, Cordeiro RSB, Silva PMR, Martins MA. Two for one: 
Cyclic AMP mediates the anti-inflammatory and anti-spasmodic properties of the non-
anesthetic lidocaine analog JMF2-1. Eur J Pharmacol. 2012;680:102-107. 
O’Leary MP, Sant GR, Fowler FJ, Whitmore KE, Spolarich-Kroll J. The Interstitial Cystitis 
Symptom Index and Problem Index. Urology. 1997;49(Suppl 5A):58-63. 
Parsons CL. Successful downregulation of bladder sensory nerves with combination of 
heparin and alkalinized lidocaine in subjects with interstitial cystitis. Urology. 2005;65(1):45-
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Suskind AM, Berry SH, Ewing BA, Elliott MN, Suttorp MK, Clemens JQ. The Prevalence 
and overlap of Interstitial Cystitis/Bladder Pain Syndrome and Chronic Prostatitis/Chronic 
Pelvic Pain Syndrome in men: Results of the RAND Interstitial Cystitis Epidemiology Male 
Study. J Urol. 2013;189:141-145. 
van de Merwe JP, Nordling J, Bouchelouche P, Bouchelouche K, Cervigni M, Daha LK, et al. 
Diagnostic criteria, classification, and nomenclature for painful bladder syndrome/interstitial 
cystitis: an ESSIC proposal. Eur Urol. 2008;53(1):60-67. 
Wild D, Grove A, Martin M, Eremenco S, McElroy S, Verjee-Lorenz A, et al. ISPOR Task 
Force for Translation and Cultural Adaptation. Principles of good practice for the translation 
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ISPOR Task Force for Translation and Cultural Adaptation. Value Health. 2005;8(2):94-104. 


 
 
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Xylocaine (lidocaine HCl Injection, USP), Xylocaine (lidocaine HCl and epinephrine 
Injection, USP), for infiltration and nerve block. Package Insert. Schaumberg, IL: APP 
Pharmaceuticals, LLC. 2010. 
Yokoyama O, Ishiura Y, Nakamura Y, Kunimi K, Mita E, Namiki M. Urodynamic effects of 
intravesical instillation of lidocaine in patients with overactive detrusor. J Urol. 
1997;157(5):1826-1830. 
Yokoyama O, Komatsu K, Kodama K, Yotsuyanagi S, Niikura S, Namiki M. Diagnostic 
value of intravesical lidocaine for overactive bladder. J Urol. 2000;164(2):340-343. 
Yunoki M, Nakahara T, Mitani A, Maruko T, Kubota Y, Sakamoto K, et al. Lidocaine 
attenuates muscarinic receptor-mediated inhibition of adenylyl cyclase in airway smooth 
muscle. Eur J Pharmacol. 2003;470:65-71. 
 


 
 
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12. 
Attachments 


 
 
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12.1 
Questionnaires 
12.1.1 
Overview 
Patient questionnaires will be: 
• administered to all patients in the study prior to having any study procedure 
performed 
• completed only by the patient, using a blue or black ballpoint pen on a firm writing 
surface 
• administered in a quiet place with ample time for the patient to complete the 
questionnaire 
• filled out completely by patients (every question must be answered) 
• completed only at protocol-specified study visits (no attempt should be made at any 
subsequent visit to administer missed questionnaires) 
• a source document; please do not make or use any photocopies of the forms 
• checked for completeness, and not content, in the patient’s presence - study site 
personnel should not change responses on the questionnaires 
• administered only in countries where the scale has been appropriately culturally 
adapted in local languages as per the International Society for Pharmacoeconomics 
and Outcomes Research (ISPOR) Principles of Good Practice for the Translation and 
Cultural Adaptation Process for Patient Reported Outcomes Measures 
(Wild et al, 2005).  The versions of the questionnaires provided in the protocol are 
samples and will be replaced with the appropriate versions for the country where the 
questionnaire will be administered. 


 
 
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12.2 
Handling of Biological Specimens  
Details relating to the handling of biological samples are provided in the Central Laboratory 
Manual. 


 
 
Approval Date: 
 
28-Apr-2016
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12.3 
Glossary of Abbreviations 
Term/Abbreviation 
Definition 
ALT 
alanine aminotransferase (SGPT) 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase (SGOT) 
AUA 
American Urological Association 
β-HCG 
beta-human chorionic gonadotropin 
BPS 
bladder pain syndrome 
CFR 
Code of Federal Regulations 
eCRF 
electronic case report form 
EDC 
electronic data capture 
 
 
ESSIC 
European Society for the Study of IC 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyltransferase 
GLP 
Good Laboratory Practice 
HEENT 
head, ears, eyes, nose, and throat 
HIPAA 
Health Insurance Portability and Accountability Act 
HL 
Hunner’s Lesion 
HRQoL 
health-related quality of life 
IC 
interstitial cystitis 
ICH 
International Conference on Harmonisation  
 
 
 
 
IEC 
Independent Ethics Committee 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IL-1β 
interleukin-1 beta 
IV 
intravenous 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
LiRIS 
lidocaine-releasing intravesical system 
MCH 
mean corpuscular hemoglobin 


 
 
Approval Date: 
 
28-Apr-2016
Allergan Confidential 
Protocol 201025-001 Amendment 2 
 
 
84 
GDD-TA-T-004 v2013.9 
 
Term/Abbreviation 
Definition 
MCHC 
mean corpuscular hemoglobin concentration 
MCP-1/CCL2 
monocyte chemotactic protein 1  
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
NRS 
Numerical Rating Scale 
PCS 
Pain Catastrophizing Scale 
PK 
pharmacokinetic 
PI 
Principal Investigator 
PP 
per protocol 
PVR 
post-void residual 
RBC 
red blood cells 
SAP 
Statistical Analysis Plan 
 
 
  
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SOC 
system organ class 
Tx 1 
Treatment 1 Period 
Tx 2 
Treatment 2 Period  
US(A) 
United States (of America) 
USP 
United States Pharmacopeial Convention 
UTI 
urinary tract infection 
WBC 
white blood cells 


 
 
Approval Date: 
 
28-Apr-2016
Allergan Confidential 
Protocol 201025-001 Amendment 2 
 
 
85 
GDD-TA-T-004 v2013.9 
 
12.4 
Protocol Amendment 1 Summary  
Title:  A Multicenter, Randomized, Double-blind, Placebo-controlled Study, Evaluating 
 
Safety and Efficacy of LiRIS® 400 mg in Females With Interstitial Cystitis With 
 
Hunner’s Lesions 
Protocol 201025-001 Amendment 1 
Date of Amendment:  February 2015 
Amendment Summary 
This summary includes changes made to Protocol 201025-001 (20 January 2015).  This 
protocol was amended to delete the instructions for insertion and removal of Investigational 
Product (IP) from the protocol.  The directions for IP use will be included in the 
Study Manual.  
Following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes.  Minor editorial and document formatting 
revisions have not been summarized. 
Section 
Revision 
Rationale 
Section 5.8/Treatment 
Administration and 
Section 6.6.11/Insertion 
and Removal of IP 
Revised the reference for instructions on 
insertion and removal of IP to 
Study Manual instead of protocol 
Attachment 12.1 
The instructions for IP use are 
being included in the Study 
Manual instead of as an 
attachment to the protocol 
Section 7.3.3/Safety 
Analyses 
# 5:  Deleted the detailed list of specific 
laboratory analytes for which descriptive 
summaries will be provided 
The list of laboratory analytes 
are included in 
Section 6.6.5/Clinical 
Laboratory Assessments.  A 
reference has been provided 
to Section 6.6.5.  
Section 7.3.3/Safety 
Analyses, 
Section 10.4.1/Source 
Documents 
Deleted electrocardiogram (ECG) 
ECG will not be assessed 
during this study  
Section 12.1/ 
Investigational Product 
Directions for Use 
Deleted Attachment 12.1 Investigational 
Product Directions for Use including 
Attachment 12.1.1 Directions for 
Insertion of LiRIS® 400 mg and LiRIS® 
Placebo and Attachment 12.1.2 Directions 
for Removal of LiRIS® 400 mg and 
LiRIS® Placebo 
The instructions for IP use are 
being included in the Study 
Manual instead of as an 
attachment to the protocol.  
Succeeding attachment 
numbers were adjusted 
accordingly. 
 


 
 
Approval Date: 
 
28-Apr-2016
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Protocol 201025-001 Amendment 2 
 
 
86 
GDD-TA-T-004 v2013.9 
 
12.5 
Protocol Amendment 2 Summary 
Title:  A Multicenter, Randomized, Double-blind, Placebo-controlled Study, Evaluating 
 
Safety and Efficacy of LiRIS® 400 mg in Females With Interstitial Cystitis With 
 
Hunner’s Lesions 
Protocol 201025-001 Amendment 2 
Date of Amendment:  April 2016 
Amendment Summary 
This summary includes changes made to Protocol 201025-001 Amendment 1 
(February 2015).  This protocol was amended to expand entry criteria to increase the rate of 
enrollment. 
Following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes.  Minor editorial and document formatting 
revisions have not been summarized. 
Section 
Revision 
Rationale 
Summary, Table 1, Sections 
6.3, 6.6.7, 7.5, 10.7 
 
 
 
Summary, Sections 3, 4.1, 7.7 
Sample size of estimated 
evaluable population was 
increased 
Revision based on results of 
Study TAR-100-105 
Summary, Sections 4.2, 4.3 
AUA guidelines were replaced 
with ESSIC (van de Merwe et 
al, 2008) in diagnostic criteria 
Clarification of diagnostic 
criteria: ESSIC requires 6 
months of symptoms before 
confirmed diagnosis, consistent 
with protocol (AUA requires 6 
weeks) 
Table 2, Section 4.4 
Period off medication/treatment 
before screening was reduced 
for Elmiron and Botulinum 
toxin for genitourinary 
treatment 
There is no indication of any 
increased risk resulting from 
this change based on previous 
LiRIS studies 
Section 4.1 
Increased number of study sites 
Increase enrollment 
Section 4.4 
Cardiac & pelvic pain exclusion 
criteria were generalized to 
specify investigator judgment 
There is no indication of any 
increased risk resulting from 
this change based on previous 
LiRIS studies 


 
 
Approval Date: 
 
28-Apr-2016
Allergan Confidential 
Protocol 201025-001 Amendment 2 
 
 
87 
GDD-TA-T-004 v2013.9 
 
Section 
Revision 
Rationale 
Section 4.4 
 
There is no indication of any 
increased risk resulting from 
this change based on previous 
LiRIS studies 
Section 4.4 
 
 
 
There is no indication of any 
increased risk resulting from 
this change 
Section 4.4 
 
 
 
There is no indication of any 
increased risk resulting from 
this change based on previous 
LiRIS studies 
Section 4.5.2 
Removed prohibition on 
medications for treating LUTS 
Based on results from previous 
LiRIS studies, LUTS 
medications did not affect 
outcomes 
Section 5.8.2 
Removed requirement that 
request for retreatment occur at 
a study visit 
In practice, patients often want 
to request retreatment by phone 
in between visits 
Section 6.5.12 
Collection of baseline pain 
assessment specified to be 
calculated based on at least 5 
consecutive days 
To allow 5 consecutive days out 
of 7 instead of 7 consecutive 
days to allow patients more 
flexibility 
Section 7.1 
Clarified the mITT definition 
Clarification 
Section 7.2 and throughout  
Removed the Day 1 reference 
and replaced it with Day 0  
Clarification for investigators to 
make consistent with the 
procedures intended and that 
the sites have been trained on 
Sections 7.2  and 7.3.2.1 
Included imputation for primary 
analysis 
Patients that have values close 
to the primary timepoint can 
now be included in the primary 
analysis 
Section 7.2.1 
Clarified the baseline NRS 
calculation and imputation 
method to be applied 
Clarification 
Section 7.2.2 
Clarified that severity of lesions 
may not be analyzed 
This may be highly variable and 
difficult to quantify 
Section 7.2.3 
Removed the analysis of 
threshold of reduction in the 
number of lesions 
There is no consensus in the 
field as to what defines a 
meaningful threshold 
Section 7.3  
Clarified the treatment arms 
Clarification 
Section 7.3.2 
Removed sensitivity analysis 
based on last observation 
carried forward method  
For pain medication this is not 
standard 


 
 
Approval Date: 
 
28-Apr-2016
Allergan Confidential 
Protocol 201025-001 Amendment 2 
 
 
88 
GDD-TA-T-004 v2013.9 
 
Section 
Revision 
Rationale 
Section 7.3.2 
Changed the significance level 
from 0.05 to 0.1 
To reflect exploratory nature of 
the study 
Section 7.3.2.2 
Clarified that no imputation 
method will be used for 
secondary efficacy variables 
analysis 
Clarification 
Sections 7.3.2.3 and 7.3.2.4 
Clarified the treatment arms to 
be compared 
Clarification 
Section 7.3.3 
Removed the adverse event 
analysis based on onset time 
and the analysis of clinically 
significant laboratory 
abnormalities 
These safety variables were not 
considered to be relevant to this 
study 
Section 7.5 
Clarified that imputation 
method will only be applied to 
the primary analysis 
Clarification 
Section 7.6  
Removed the pre-planned 
subgroup analysis for efficacy 
Such analysis was deemed non-
essential and can be done in ad 
hoc manner post database lock 
Section 7.7 
Corrected the sample size 
derivation 
Clarification 
Section 7.8 
Added that blinded sample size 
estimation may be conducted. 
Clarified when a potential 
interim analysis may occur. 
Clarification 
 


 
 
Approval Date: 
 
28-Apr-2016
ALLERGAN 
 
 
 
 
 
 
 
 
 
Date (DD/MMM/YYYY)/Time (PT) 
Signed by: 
Justification 
  
 
 
            
 
           
 
            
 
           
 
            
 
           
 
     
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
 
Protocol 201025-001 Amendment 2

SAP_001.pdf: 
NCT02395042   
 
Study ID: 201025‐001  
 
 
Title: A Multicenter, Randomized, Double‐blind, Placebo‐controlled Study, Evaluating Safety and Efficacy 
of LiRIS® 400 mg in Females With Interstitial Cystitis With Hunner’s Lesions 
 
 
Statistical Analysis Plan Date: 27‐Mar‐2018 
 


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27MAR2018 CSR 201025-001
1


2
2.
3.
4.
5.
6.
7.
8.
9.
10
11
12
 
.0
 
TABLE
.0
 
LIST O
.0
 
INTRO
.0
 
OBJEC
.0
 
PATIE
.0
 
6.1
 
6.2
 
6.3
 
6.4
 
6.5
 
6.6
 
PATIE
.0
 
DEMO
.0
 
8.1
 
8.2
 
8.3
 
Prior o
.0
 
9.1
 
9.2
 
EXTEN
0.0
 
10.1
 
10.2
 
EFFICA
1.0
 
11.1
 
11.2
2.0
 
12.1
 
12.2
 
12.3
TABL
E OF CONTEN
OF ABBREVIA
ODUCTION ...
CTIVES ..........
ENT POPULAT
Intent-to-Tre
MODIFIED
Safety Popu
Per-Protocol
Pharmacokin
Data Collect
ENT DISPOSIT
OGRAPHICS A
Demographi
Disease Cha
Past Medica
r Concomitant
Bladder Pain
Medication o
NT OF EXPOS
Extent of Ex
Measuremen
ACY ANALY
Primary Effi
 
Oth
11.1.1
Secondary E
Adverse Eve
Clinical Lab
Vital Signs .
LE OF CON
NTS ................
ATIONS .........
.......................
.......................
TIONS ............
eat Population .
 Intent-to-Trea
lation ..............
l Population ....
netic Evaluable
ted but not Ana
TION ..............
AND OTHER B
ic ....................
aracteristics .....
al History .........
t Medication ....
n Medication ..
other than Blad
SURE AND TR
xposure (Durat
nt of Treatmen
YSES ...............
icacy Paramete
her Analysis of
Efficacy Param
ents .................
boratory Param
.......................
NTENTS 
.......................
.......................
.......................
.......................
.......................
.......................
at Population ..
.......................
.......................
e Population ..
alyzed ............
.......................
BASELINE CH
.......................
.......................
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dder Pain Med
REATMENT C
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t Compliance a
.......................
er(s) ................
f Primary Effic
meter(s) ............
.......................
meters ..............
.......................
.......................
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HARACTERI
.......................
.......................
.......................
.......................
.......................
dication ...........
COMPLIANC
.......................
and Tolerabilit
.......................
.......................
cacy Variable ..
.......................
.......................
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.......................
TI
 1
 
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STICS ............
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TLE PAGE
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27MAR2018 CSR 201025-001
2


14
15
16
17
18
19
 
 
12.4
 
12.5
 
INTER
4.0
 
DETER
5.0
 
STATI
6.0
 
DATA
7.0
 
17.1
 
17.2
 
17.3
 
17.4
 
17.5
 
17.6
 
17.7
 
17.8
 
17.9
 
CHAN
8.0
 
REFER
9.0
Electrocardi
Other Safety
 
Bla
12.5.1
 
Phy
12.5.2
 
Cys
12.5.3
 
Inv
12.5.4
 
Pre
12.5.5
 
Uri
12.5.6
 
Uri
12.5.7
 
Sui
12.5.8
 
Pot
12.5.9
RIM ANALYS
RMINATION 
ISTICAL SOFT
A HANDLING 
Visit Time W
Derived Var
 
Pain
17.2.1
 
Voi
17.2.2
Repeated or 
Missing Dat
Missing Sev
Missing Cau
Missing Dat
Missing Dat
 
Inc
17.8.1
 
Inc
17.8.2
Character V
NGES TO ANA
RENCES ........
ogram .............
y Parameters ...
adder Post-Void
ysical Examina
stoscopic Exam
vestigational Pr
egnancy Test ...
ine Cytology ...
ine Culture ......
icidality Assess
tential Hy’s La
IS ...................
OF SAMPLE 
TWARE .........
CONVENTIO
Windows .........
riables .............
n Data Derivat
id Data Deriva
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.......................
SIZE .............
.......................
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.......................
tions ...............
ations ..............
Assessments o
Dose of Study T
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Date ...............
Date ...............
cal Laboratory 
CIFIED IN PRO
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of Safety Param
Treatment .......
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Parameters .....
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27MAR2018 CSR 201025-001
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27MAR2018 CSR 201025-001
4


PID 
patient identification 
PK 
pharmacokinetics 
PP 
Per Protocol 
PVR 
post-void residual 
QoL 
Quality of life 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
Standard deviation 
TEAE 
treatment-emergent adverse event 
WBC 
white blood cell 
 
27MAR2018 CSR 201025-001
5


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This statistica
he statistical 
inal protocol
mendment (A
ata listings a
tudy 201025
ontrolled, stu
atients with 
o 2 treatment
f 3 treatmen
Group 1:  2 c
Group 2:  2 c
Group 3:  LiR
atients who 
eriod follow
creening bas
The primary a
rimary timep
nvestigationa
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ncluded in th
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INTRO
al analysis pl
analyses of 
l of Study 20
Amendment
are contained
5-001 is a ph
udy to evalu
interstitial c
ts.  To receiv
nt groups rec
onsecutive L
onsecutive L
RIS Placebo 
qualify for T
wed by 4 wee
seline pain sc
analysis will
point that is 
al product (I
plete or exit 
he analysis. T
final  analysi
ted in Table 
ends with th
ment 1 period
ODUCTION
lan (SAP) pr
the efficacy
01025-001 (v
t 2 dated [28
d in a separa
hase 2  multi
uate the safet
cystitis (IC) w
ve Treatmen
eiving over 
LiRIS 400 m
LiRIS Placeb
followed by
Treatment 2,
eks of observ
core (≤ 5 or 
l be conduct
Week 4 foll
IP) removal. 
the study. Fo
The analyses
is timepoints
4–1.  The d
he last assess
d. 
N 
rovides a mo
y and safety d
version date
8 April 2016]
ate document
icenter, rand
ty and effica
with Hunner
nt 1, patients
a 28-day tre
mg (N = 38) 
bo (N = 19)
y LiRIS 400 
, will receive
vation until e
> 5). 
ted at the tim
lowing remo
 The final a
or each anal
s outputs to b
s.  The sched
double-blind 
sment prior t
ore technical
data as outlin
d 20 January
]). Specifica
t.  
domized, dou
acy of the LiR
r’s lesions (H
s will be rand
atment perio
mg (N = 19
e LiRIS 400
exit.  Patient
me when the 
oval of the Tr
analysis will 
lysis timepoi
be included 
dule of evalu
treatment pe
to Treatmen
l and detaile
ned and/or s
y 2015) and 
ations of tabl
uble-blind, p
RIS 400 mg
HL).  This st
domized in a
od either: 
)  
0 mg over a 1
ts will be str
last patient c
reatment 1 s
be conducte
int all data a
will be the s
uations for S
eriod starts w
nt 2 IP inserti
ed elaboratio
specified in t
the most rec
les, figures, 
placebo-
g in female 
tudy include
a 2:1:1 ratio 
14-day treatm
ratified based
completes th
second 
ed when all 
available will
same for the
Study 20102
with the first
ion or Exit v
on of 
the 
cent 
and 
s up 
to 1 
ment 
d on 
he 
l be 
e 
5-
t IP 
visit 
27MAR2018 CSR 201025-001
6


Table 4–1. 
Schedule of Evaluation for  Study 201025-001 
27MAR2018 CSR 201025-001
7


Table 4–1. 
Schedule of Evaluation for  Study 201025-001 
27MAR2018 CSR 201025-001
8


Table 4–1. 
Schedule of Evaluation for  Study 201025-001 
27MAR2018 CSR 201025-001
9


5
T
co
4
H
re
h
tr
T
p
gr
 
G
G
G
P
14
T
(N
th
in
2
T
w
p
w
p
D
 
.0
The study obj
ontinuous re
00 mg comp
HL in female
elease of lido
ave an accep
reatment and
The study wil
eriod (Treatm
roups receiv
Group 1:  2 c
Group 2:  2 c
Group 3:  LiR
atients, who
4-day treatm
The central ra
NRS) (≤ 5 or
he study and
ncluding a m
0 weeks of f
Treatment 2 (
weeks (if qua
ost removal 
weeks (if qua
ost removal 
Details of the
OBJE
jective is to 
elease of lido
pared with pl
 patients.  Th
ocaine insert
ptable safety
d correspond
ll consist of 
ment 1) pati
ving over a 2
onsecutive L
onsecutive L
RIS Placebo 
o qualify for 
ment period f
andomization
r > 5) collec
d receive only
maximum of 
follow-up po
(open label L
alification an
of Treatmen
alification an
of Treatmen
e study desig
CTIVES 
evaluate the
ocaine insert
lacebo for th
he clinical h
ted into the b
y profile and 
ding symptom
up to two tre
ents will be 
28-day treatm
LiRIS 400 m
LiRIS Placeb
followed by
Treatment 2
followed by 
n will be str
cted during th
y Treatment
4 weeks of s
ost IP remov
LiRIS 400 m
nd Treatment
nt 1 IP) and t
nd Treatment
nt 1 IP). 
gn and object
e safety and e
ted into the b
he treatment 
hypotheses is
bladder utiliz
will be mor
ms of IC wit
eatment peri
randomized
ment period e
mg (N = 38) 
bo (N = 19)
y LiRIS 400 
2, will receiv
4 weeks of o
atified by ba
he Screening
t 1, the maxim
screening, 4 
val.  For patie
mg), the mini
t 2 IP inserti
the maximum
t 2 IP inserti
tives are giv
efficacy of a
bladder utiliz
and corresp
s that a 28-d
zing two con
re efficaciou
th HL in fem
iods.  At the
d in a 2:1:1 ra
either: 
mg (N = 19
ve open label
observation 
aseline pain 
g period.   Fo
mum duratio
weeks of ra
ents who qu
imum durati
ion occurs on
m duration o
ion occurs on
ven in the stu
a 28-day peri
zing 2 conse
ponding sym
day period of
nsecutive Li
us than placeb
male patients
e start of the 
atio to 1 of 3
)  
l LiRIS 400 
until exit.  
Numeric Ra
or patients w
on will be 28
andomized tr
ualify and rec
on of partici
n Week 4 Fo
of study part
n Week 20 F
udy protocol
iod of 
ecutive LiRI
mptoms of IC
f continuous 
iRIS 400 mg
bo for the 
. 
first treatme
3 treatment 
mg over a 
ating Scale 
who participa
8 weeks, 
reatment, and
ceive 
ipation is 16
ollow-up Vis
ticipation is 
Follow-up V
.   
S 
C with 
g will 
ent 
ate in 
d 
6 
sit 
36 
Visit 
27MAR2018 CSR 201025-001
10


6
6
N
6
T
ra
ef
6
T
on
6
T
T
in
T
d
6
T
h
in
14
6
T
 
.0
 
.1
Not applicabl
 
.2
The Modified
andomized a
fficacy data 
 
.3
The safety po
ne IP.  The s
 
.4
The Per-Proto
Treatment 1 f
nsertion) and
Treatment 1 w
etermined pr
 
.5
The pharmaco
ave at least o
nsertion and 
4 visit. 
 
.6
The Investiga
PATIE
INTEN
le. 
MODI
d Intent-to-T
and received 
will be analy
SAFE
opulation wil
safety data w
PER-P
ocol (PP) po
for the 28 da
d complete th
without any 
rior to datab
PHAR
okinetic pop
one plasma o
for whom th
DATA
ator’s signatu
ENT POPU
NT-TO-TR
IFIED INTE
Treat (mITT)
 at least one
yzed as rand
TY POPUL
ll include all
will be analy
PROTOCO
opulation wil
ays of the tre
he 4 Week F
significant p
base lock. 
RMACOKIN
pulation will 
or urine phar
he IP is succ
A COLLEC
ure will not b
ULATIONS
EAT POPU
ENT-TO-TR
) Population 
e IP insertion
domized usin
LATION 
l patients enr
yzed as treate
OL POPULA
ll include all
eatment perio
Follow-up V
protocol dev
NETIC EVA
include all p
rmacokinetic
cessfully rem
TED BUT N
be analyzed
ULATION
REAT POP
will include
n in the Trea
ng the mITT
rolled in this
ed using the 
ATION  
l patients wh
od (complete
Visit post rem
viations.  Pro
ALUABLE 
patients enro
c concentrat
moved at the 
NOT ANAL
.   
PULATION
e all patients
atment 1 per
T population.
s study and r
safety popu
ho retain the 
e the two cy
moval of the 
otocol deviat
POPULAT
olled in this 
tion measure
scheduled T
LYZED 
N 
 that are 
iod.  The 
. 
received at l
lation. 
2 IP inserted
ycles of IP 
2nd IP of 
tions will be 
TION 
study and w
ement post-I
Treatment 1 D
east 
d in 
who 
IP 
Day 
27MAR2018 CSR 201025-001
11


7
T
b
b
S
re
p
th
gr
th
su
P
p
re
 
.0
The number a
e summarize
e summarize
creen-failure
easons for fa
ercentage of
he same peri
roups for the
he study  as r
ummarized (
opulation. F
atients that r
easons for pr
PATIE
and percenta
ed by treatm
ed overall by
e patients (i.
ailure to rand
f patients wh
iod will be p
e mITT and 
recorded on 
(number and
Furthermore,
receive Trea
remature stu
ENT DISPO
age of patien
ment group an
y study cente
e., patients s
domize will b
ho complete 
resented for 
PP Populati
the terminat
d percentage)
 this summa
atment 2. Ass
udy discontin
OSITION 
nts in 2 of the
nd study cen
er. 
screened but
be presented
the study an
each treatm
on. The reas
tion pages o
) by treatme
ary table will
sociated pati
nuation will b
e study popu
nter; the num
t not random
d in a patient
nd who prem
ment group an
sons for prem
f the electro
ent group for
l be generate
ient listing c
be generated
ulations (mIT
mber of patien
mized) and th
t listing. The
maturely disc
nd pooled ac
mature disco
nic case rep
r the mITT a
ed for cohort
containing in
d. 
TT and PP) w
nts screened
he associated
e number an
continue duri
cross treatme
ontinuation f
ort form wil
and PP 
t of mITT 
nformation o
will 
d will 
d 
nd 
ing 
ent 
from 
ll be 
on 
27MAR2018 CSR 201025-001
12


8
8
D
li
w
m
C
m
an
8
T
d
th
• 
• 
• 
• 
• 
• 
• 
• 
8
A
D
o
an
st
 
.0
 
.1
Demographic
ifestyle),base
weight [kg]/(h
mITT and PP
Continuous v
minimum, an
nd percentag
 
.2
The following
emographic 
he cohort of 
informatio
daily aver
daily aver
Pain Cata
daily aver
daily  ave
daily aver
result of p
 
.3
Abnormalitie
Dictionary fo
f patients wi
nd preferred
tatistical com
DEMO
CHAR
DEMO
c parameters
eline charact
height [m])2
P populations
variables will
nd maximum
ge of patient
DISEA
g baseline di
information
mITT patien
on on stratif
rage 24-hour
rage worst p
astrophizing 
rage number
erage numbe
rage pre- and
pelvic exami
PAST 
s in patients
or Regulatory
ith abnormal
d term will be
mparisons w
OGRAPHIC
RACTERIS
OGRAPHIC
 (age; age gr
teristics (wei
2), will be sum
s and for the
l be summar
m values. Cat
ts. 
ASE CHAR
isease inform
n, by treatme
nts that recei
fication facto
r pain Nume
ain NRS, 
Scale (PCS)
r of micturiti
r of urgency
d post-void b
ination at ba
MEDICAL
’ medical an
y Activities,
lities in med
e summarize
ill be perform
CS AND OT
STICS 
C 
roup; race; e
ight; height;
mmarized d
e cohort of m
rized by num
egorical vari
RACTERIST
mation will b
ent group for
ived Treatm
ors  baseline 
eric Rating S
) total score,
ion episodes
y episodes, 
bladder pain
aseline. 
L HISTORY
nd surgical h
version 18.1
dical and surg
ed by treatm
med. 
THER BAS
ethnicity; sex
; and body m
descriptively 
mITT patient
mber of patie
riables will b
TICS 
be summariz
r the mITT a
ent 2: 
average pai
Scale (NRS),
 
s, 
n NRS, and 
Y 
histories will
1 or newer. T
gical historie
ment group fo
ELINE 
x, smoking s
mass index, c
by treatmen
ts that receiv
ents and mea
be summariz
zed as descri
and PP popu
in score  ≤ 5 
,  
l be coded us
The number 
es in each sy
or the mITT 
status and di
calculated as
nt group for t
ved Treatmen
an, SD, medi
zed by numb
ibed for the 
lations and f
vs. > 5 ), 
sing the Med
and percent
ystem organ 
Population. 
etary 
s 
the 
nt 2. 
ian, 
er 
for 
dical 
tage 
class 
No 
27MAR2018 CSR 201025-001
13


9
P
in
o
u
9
D
d
b
th
p
a 
th
th
in
P
T
b
9
M
m
fr
(d
C
T
m
m
 
.0
Prior medica
nsertion. Con
f first IP inse
sed to classi
 
.1
Daily bladder
iary for the s
ladder pain m
hese prior an
ercentage of
specific me
herapeutic cl
herapeutic cl
ngredient wi
rior and con
The number o
e summarize
 
.2
Medication o
medication eC
requency and
drug) name (
Class and Pre
The clinical t
medication eC
medication ta
PRIOR
tion is defin
ncomitant m
ertion. The W
ify prior and 
BLAD
r pain and re
screening pe
medication w
nd concomita
f patients in 
dication mul
lass, that pat
lass. Formul
ll be pooled 
ncomitant res
of days a giv
ed by treatm
MEDI
MEDI
ther than bla
CRF. For bo
d percentage
(WHODDE)
eferred Term
eam will als
CRF prior to
able will be s
R OR CON
ed as any m
medication is 
WHO drug d
concomitan
DDER PAIN
escue bladde
eriod and tre
will be coded
ant medicati
each treatme
ltiple times o
tient would b
ations (inclu
under the co
scue bladder
ven patient to
ment group an
ICATION O
ICATION 
adder pain m
oth prior and 
e of medicati
) with the sa
m of the MedD
o identify pa
o data base lo
similarly gen
NCOMITAN
edication tak
defined as a
dictionary, v
nt medication
N MEDICAT
r pain medic
atment perio
d by drug na
ons will be s
ent group for
or took mult
be counted o
uding salts, e
oded drug na
r pain medic
ook concom
nd overall fo
OTHER TH
medication w
concomitan
ions will be 
ame active in
DRA diction
ain medicati
ock. For thes
nerated. 
NT MEDICA
ken before th
any medicati
version 2015
ns by therap
TION 
cation is reco
od. Both prio
ame and ther
summarized
r the mITT P
tiple medicat
only once for
esters, etc.) c
ame of the b
ation will be
mitant rescue 
or the mITT 
HAN BLADD
will be collec
nt medication
summarized
ngredients by
nary. 
ion recorded
se medicatio
ATION 
he date of th
ion taken on
 quarter 4 or
eutic class a
orded in the 
or and conco
rapeutic clas
d by the num
Population. I
tions within 
r the coded d
containing th
base compou
e similarly su
bladder pain
population. 
DER PAIN 
cted in the co
n collected i
d for the base
y the Primar
d in the conco
ons a prior an
he first IP 
n or after the 
r newer, will
and drug nam
bladder pain
omitant daily
ss. The use o
mber and 
If a patient t
a specific 
drug name o
he same activ
und.  
ummarized.
n medication
oncomitant 
n the eCRF, 
e preferred 
ry System Or
omitant 
nd concomit
date 
l be 
me. 
n 
y 
of 
took 
or 
ve 
n will 
the 
rgan 
tant 
27MAR2018 CSR 201025-001
14


1
In
in
re
h
tr
w
co
1
T
gr
T
fo
 
 
 
 
fo
 
 
 
If
1
In
is
re
fo
 
0.0
n this study p
n Treatment 
e-treatment. 
ad been rem
reatment per
was complete
ompleted the
 
0.1
Treatment du
roups as wel
Treatment 1 p
ollowing for
Cumulative
Cumula
Treatment 1
exit date
or patients th
Date of 
Treatment 2
exit date
f the date of 
 
0.2
n this study, 
s assessed by
emoval eCR
or each treatm
EXTE
patients rece
2. Treatmen
A request fo
moved. Hence
riod (Treatm
ed as per the 
e 14 days cy
EXTE
uration for ea
ll as the cum
period, the tr
rmula will be
e treatment d
ative duration
1 duration: 
e – Date of T
hat exit with
f Treatment 2
2 duration: 
e – Date of T
exit date is m
MEAS
TOLE
compliance 
y the investig
RFs. The info
ment period
ENT OF EX
eive two inse
nt 2 is provid
or re-treatme
e, what are r
ent 1 and 2)
instruction p
ycle for each 
ENT OF EX
ach Treatmen
mulative stud
reatment dur
e used to der
duration: 
n = exit date
Treatment 1 
out receiving
2 IP insertion
Treatment 2
missing, the 
SUREMEN
ERABILITY
to the insert
gator. This in
ormation in t
d. Furthermor
XPOSURE A
ertions of IP
ded if the pat
ent can only 
relevant in th
,  whether or
provided in 
inserted IP.
XPOSURE (D
nt period (1 
dy duration o
ration could 
rive treatmen
e – Date of T
first IP inse
g Treatment
n -  Date of T
IP insertion
date of the l
T OF TREA
Y 
tion and rem
nformation i
hese eCRFs
re,  associate
AND TREA
in Treatmen
tient makes 
be made  4-
his study wo
r not the inse
the protocol
 
DURATION
or 2) will be
over the entir
be thought o
nt duration:
Treatment 1 f
rtion + 1,  
t 2 or, 
Treatment 1
n + 1, 
last visit wil
ATMENT C
moval proced
is collected i
 will be sum
ed listing wi
ATMENT CO
nt 1 and one 
a request an
-weeks after 
ould be the du
ertion and re
l and whethe
N OF EFFE
e displayed b
re study peri
of as duratio
first IP inser
 first IP inse
ll be used. 
COMPLIAN
dures outline
in the IP ins
mmarized by 
ill be produc
OMPLIAN
insertion of
nd qualifies f
the second I
uration of ea
emoval of th
er or not a pa
ECT) 
by treatment
iod. For 
on of effect. 
rtion + 1 
ertion  
NCE AND 
ed in the prot
ertion and 
treatment gr
ced. 
CE 
f IP 
for 
IP 
ach 
he IP 
atient 
t 
The 
tocol 
roup 
27MAR2018 CSR 201025-001
15


For patients that spontaneously abort the IP or ask the IP to be removed prior to the  Day 
14  post-IP insertion, a summary table of such events will be presented by treatment 
group and overall. 
27MAR2018 CSR 201025-001
16


1
T
ta
ef
IP
o
in
1
T
(S
T
re
b
p
in
an
T
in
th
co
p
N
d
av
co
d
as
to
F
th
th
th
U
 F
F
th
la
 
1.0
The efficacy 
ables being r
fficacy is de
P insertion. A
f significanc
ntervals, unle
 
1.1
The primary e
See Section 
The primary e
emoval of  th
ladder pain N
eriod and th
nsertion in th
nalysis.  
The baseline 
nformation f
he Week 4 F
ollected from
atients that r
NRS will be d
ay assessme
vailable is fo
onsidered m
erived if the
ssessment w
o Day 42  for
or the prima
he Week 4 F
hat just recei
he IP remova
Up assessmen
For the prima
ollow-Up N
he average d
atest of the tw
EFFIC
analyses wil
repeated usin
fined as the 
All statistica
ce for main e
ess stated oth
PRIM
efficacy mea
17.2.1 for de
efficacy vari
he  last IP in
NRS score. P
en a Week 4
he study and
7-day mean 
from Day -7 
Follow-Up m
m Day 50 to 
receive just o
derived if th
ent window  
or less than 5
missing for th
re are at leas
window (Day
r patients tha
ary analysis, 
Follow-up is 
ived one IP b
al date. Henc
nt are from l
ary analysis,
NRS assessm
daily bladder
wo values th
CACY ANA
ll be primari
ng the PP po
last non-mis
al tests will b
effects. All c
herwise.  
MARY EFFI
asure is the 7
efinition of a
iable is the c
n Treatment 
Patients are 
4 Follow-Up
d has Week 4
daily averag
to Day -1. In
mean 7-day av
Day 56 from
one insertion
ere are at lea
(i.e., for bas
5 consecutiv
hat patient. S
st any 5 cons
y 50 to Day 5
at received j
for patients 
counted from
before exitin
ce, for Treat
last IP remov
, for patients
ent and there
r pain NRS, t
hat is availab
ALYSES 
ly based on 
opulation. Un
ssing efficac
be 1-sided hy
confidence in
CACY PAR
7-day mean 
average daily
change from 
1 period,  us
scheduled to
p visit. Howe
4 Follow-Up
ge NRS scor
n contrast, fo
verage daily
m date of 1nd
n during Tre
ast any 5 con
seline it wou
ve days, as de
imilarly, the
secutive vali
56 for patien
ust one IP in
that get two
m the 2nd IP 
ng the study,
tment 1 perio
val, whether 
s that have IP
e is a valid W
the Week  4 
ble (i.e., Wee
the mITT Po
nless stated o
cy assessmen
ypothesis tes
ntervals will
RAMETER
of the avera
y bladder pa
baseline to 
sing the 7-da
o have two I
ever, if a pati
p assessment
re will be de
for patients th
y pain score w
d IP insertion
eatment 1 per
nsecutive va
uld be day -7
escribed abo
e Week 4 Fo
id assessmen
nts that receiv
n Treatment 
o IP inserted 
removal tim
, the Week 4
od, Week 1 F
r or not a pat
P inserted, if
Week 2 or 3 
Follow-Up 
ek 2 or 3 Fol
opulation wi
otherwise, b
nt prior to fir
sts performe
l be 2-sided 9
R(S) 
ge daily blad
ain score). 
Week 4 Foll
ay mean of th
IP insertion i
ients receive
t, it will be c
erived using 
hat receive t
will be deriv
n or Day 36 
riod. The me
alid assessme
7 to day -1). I
ove, then the
ollow-Up NR
nts within th
ved two inse
1).   
during Trea
me. In contra
4 Follow-Up 
Follow-Up- 
tient received
f there is no 
Follow-Up,
value will b
llow-Up). 
ith selected 
baseline for 
rst Treatmen
ed at the 5% 
90% confide
dder pain NR
low-Up post
he average d
in Treatment
es only one I
onsidered in
the diary 
two IP insert
ved from dat
to Day 42  f
ean baseline
ents within t
If the data th
e value will b
RS will be 
he 7-day 
ertion or Day
atment 1 peri
ast, for patien
is counted f
Week 4 Fol
d one or two
valid Week 
 weekly mea
be imputed b
nt 1 
level 
ence 
RS 
t 
daily 
t 1 
IP 
n the 
tion, 
ta 
for 
e 
the 7-
hat is 
be 
y 36 
iod, 
nts 
from 
llow-
o IPs. 
4 
an of  
y the 
27MAR2018 CSR 201025-001
17


F
N
W
ut
co
A
N
2 
L
T
u
fr
o
u
b
d
[L
th
co
in
is
fi
9
L
 
1
T
th
o
A
al
T
an
m
or the prima
Null hypothe
Week 4 Follo
tilizes 2 con
onsecutive L
Alternative hy
NRS at Week
consecutive
LiRIS Placeb
The change fr
sing descrip
rom baseline
f Treatment 
sing the base
ladder pain N
erive the adj
LS] mean di
hat utilizes 2
onsecutive L
n the treatme
s rejected in 
itted model w
0% CI betw
LiRIS 400 mg
 
1.1.1
The ANCOV
he PP popula
f  the averag
Average daily
lso be summ
Table 17.2.1–
nalysis outli
missing value
ary efficacy a
sis: The mea
ow-Up post I
nsecutive LiR
LiRIS Placeb
ypothesis: T
k 4 Follow-U
e LiRIS 400 
bo. 
from baseline
tive statistic
e in average 
1 will be an
eline values 
NRS: ≤ 5 or
justed mean 
fference) an
2 consecutive
LiRIS Placeb
ent group tha
favor of the 
will also be u
een treatmen
g versus the 
Other 
VA Analyses 
ation and wit
ge daily blad
y 24-hour pa
marized for e
–1). For each
ned for the p
es.  
analysis, the
an change fro
IP removal i
RIS 400 mg  
bo. 
The mean cha
Up post IP re
mg  compar
e in average
cs by treatme
daily bladde
nalyzed using
as the covar
r > 5) and tre
treatment di
nd associated
e LiRIS 400 
bo. If the 1-s
at utilizes 2 c
treatment gr
used to estim
nt group that
treatment gr
Analysis of
of the prima
th no imputa
dder pain NR
ain NRS and
ach week po
h weekly (m
primary time
e null and the
om baseline
s the same o
compared to
ange from ba
emoval is gre
red to the tre
daily bladde
ent group. Be
er pain NRS 
g the analysi
riate, and str
eatment as fa
ifferences fo
d 90% CI, fo
mg  versus
sided p-value
consecutive 
roup that uti
mate the adju
t utilizes con
roup that uti
f Primary E
ary efficacy 
ations for mi
RS.  
d the corresp
ost randomiz
ean) change
epoint will b
e alternate h
 in average d
or worse for
o the treatm
aseline in av
eater for the
eatment grou
er pain NRS
etween grou
at Week 4 F
is of covaria
ratification fa
actors. The f
or the primar
r the compar
the treatmen
e is < 5% an
LiRIS 400 m
ilizes 2 cons
usted treatme
nsecutive tre
ilizes 2 cons
Efficacy Var
variable wil
issing Week
onding chan
zation for the
e from baseli
be applied wi
hypothesis ar
daily bladde
the treatmen
ment group th
verage daily 
treatment gr
up that utiliz
S score will b
up compariso
Follow-Up p
ance (ANCO
factor (baseli
fitted model 
ry variable (l
rison of the 
nt group that
nd there is gr
mg then the 
ecutive LiRI
ent differenc
eatment of L
ecutive LiRI
riable 
ll also be per
k 4 Follow-U
nge from bas
e Treatment 
ine values, th
ithout any im
re as follows
er pain NRS 
nt group that
hat utilizes 2 
bladder pain
roup that uti
es 2 consecu
be summariz
on of the cha
post IP remov
OVA) model,
ine average d
will be used
least-square
treatment gr
t utilizes 2 
reater reduct
null hypothe
IS 400 mg. T
ce and assoc
iRIS placebo
IS Placebo.
rformed usin
Up weekly m
seline values
1 Period (se
he ANCOVA
mputation fo
s: 
at 
t 
n 
ilizes 
utive 
zed 
ange 
val 
, 
daily 
d to 
s 
roup 
tion 
esis 
The 
ciated 
o and  
ng 
mean 
s will 
ee 
A 
or 
27MAR2018 CSR 201025-001
18


A
(M
T
p
gr
an
th
P
fr
1
A
as
a 
b
to
w
an
b
p
D
pr
fr
tr
 
A sensitivity 
Mallinckrodt
Treatment 1 W
ost-baseline 
roup, assessm
nd baseline v
he correlatio
lots of week
rom baseline
 
1.2
A standardize
ssess any ch
result of tre
aseline visit
o categories 
worsened dise
nalyzed by t
aseline visit
ain NRS wil
During each c
reforming th
rom baseline
reatment gro
analysis usin
t et al, 2001a
Week 4 Foll
week (see T
ment week, 
value as cov
n over time 
kly mean of  
e values will
SECO
ed video cap
hanges in the
atment. The
s. These wil
such as  com
ease. The nu
treatment gro
, the number
ll be summar
cystoscopy, 
he bladder sc
e in the numb
oup. 
ng a mixed-e
a and 2001b
ow-Up, will
Table 17.2.1–
and treatmen
variate. An u
in change fr
the average 
 be presente
ONDARY EF
pture protoco
 number, the
 video image
l be used to 
mplete respon
umber and pe
oup. Further
r of patients 
rized by trea
the investiga
can for bladd
ber of lesion
effects mode
b) based on a
l be performe
–1). The MM
nt group–by
unstructured 
rom baseline
daily bladde
d by treatme
FFICACY P
ol for bladde
e size and th
e will be cap
categorize th
nders, partia
ercentage of
rmore, for ea
with 1, 2 an
atment group
ator will cou
der mapping
ns will be sum
el for repeate
all post-basel
ed to compa
MRM analys
y-assessment
covariance m
e values for t
er pain value
ent group ov
PARAMET
r mapping w
he severity, o
ptured at bas
he change fr
al responders
f patients in 
ach category
nd ≥ 3 point r
p. 
unt the numb
g. The numbe
mmarized fo
ed measures
line weekly 
are treatment
sis will inclu
t week intera
matrix will b
the primary e
es and the as
ver time. 
TER(S) 
will be follow
of lesions du
seline and at
rom baseline
s, stable dise
each categor
y of responde
reduction in
ber of lesion
er of lesions
or each relev
s (MMRM) 
mean data u
t effect at ea
ude treatmen
action as fac
be used to m
efficacy vari
ssociated cha
wed in order
uring the stud
t scheduled p
e bladder ima
ease and 
ry will be 
ers, at each p
n daily averag
s visible wh
s and the cha
vant visit by 
up to 
ach 
nt 
ctors 
model 
iable.  
ange 
r to 
dy as 
post-
ages 
post-
ge 
hile 
ange 
27MAR2018 CSR 201025-001
19


 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
27MAR2018 CSR 201025-001
20


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
27MAR2018 CSR 201025-001
21


 
  
 
 
 
 
27MAR2018 CSR 201025-001
22


1
T
w
ph
th
u
su
v
A
su
v
T
1
A
D
A
af
st
se
fi
gr
p
A
th
in
st
T
 
 
2.0
The safety an
will include a
hysical and  
he last non-m
sed as the ba
ummarized b
alues. Categ
All safety ana
ubjects will b
isit (i.e., “as
The following
• Summ
• Summ
Treatm
analysi
 
2.1
Adverse even
Dictionary fo
An AE will b
fter the first 
tudy treatme
erious after t
irst dose of s
reatest sever
eriod.  
Analysis of th
he Safety pop
ncidence of T
tudy period (
TEAEs at eac
SAFE
nalysis will b
adverse even
pelvic asses
missing safet
aseline for al
by number o
gorical variab
alyses will b
be analyzed 
 treated” rath
g safety anal
maries by trea
maries for pat
ment 2 period
is, the treatm
ADVE
nts will be co
or Regulatory
be considered
dose of stud
ent and incre
the first dose
study treatme
rity will be u
he incidence
pulation. Fo
TEAEs will 
(Treatment 1
ch treatment 
TY ANALY
be performed
nts (AEs) and
ssments. For
ty assessmen
ll analyses o
of patients an
bles will be s
be performed
according to
her than “as 
lyses will be
atment group
tients who pa
d  by treatme
ment groups 
ERSE EVEN
oded by syst
y Activities,
d a treatment
dy treatment 
eased in seve
e of study tre
ent and code
used for com
e of TEAEs w
r the cohort 
be summari
1 and 2 perio
period. 
YSES 
d using the S
d clinical lab
r each clinica
nt before the
of that safety
nd mean, SD
summarized
d using the sa
o actual trea
randomized
e performed 
p and overall
articipated in
ent group an
will be the s
NTS 
em organ cla
version 18.1
t-emergent a
or was pres
erity after the
eatment. If m
ed to the sam
mparison with
will be perfo
of  safety pa
zed over the
od). The foll
Safety Popul
boratory and
al laboratory
e first Treatm
y parameter. 
D, median, m
d by number 
afety popula
atment receiv
d”).   
unless other
l for the Trea
n both the Tr
nd overall pa
safety treatm
ass and pref
1 or newer. 
adverse even
ent before th
e first dose o
more than 1 A
me preferred 
h the AEs oc
ormed for the
atients that r
e Treatment 
lowing rules
lation. The sa
d vital signs p
y and vital si
ment 1 IP ins
Continuous 
minimum, and
and percent
ation.  For su
ved at the stu
rwise mentio
atment 1 per
reatment 1 p
atient popula
ment groups. 
ferred term u
nt (TEAE) if
he date of th
of study trea
AE was repo
term, the AE
ccurring dur
e Treatment 
received Tre
2 Period and
s will be used
afety parame
parameters, 
ign paramete
sertion will b
variables w
d maximum 
tage of patien
uch analyses
udy treatmen
oned: 
riod  
period and 
ation. In this 
using the Me
f it was prese
he first dose o
atment or bec
orted before 
E with the 
ing the study
1 Period us
atment 2 IP,
d over the en
d to count 
eters 
ers, 
be 
will be 
 
nts. 
s, 
nt 
edical 
ent 
of 
came 
the 
y 
ing 
, the  
ntire 
27MAR2018 CSR 201025-001
23


• For the analyses of TEAEs by treatment period, an event will be counted once in 
the particular period if the onset of this event begins during that corresponding 
period. 
• If an event occurs during the Treatment 1 period and continues to the Treatment 2 
period without increasing in severity, this event will be counted as an event during 
the Treatment 1 period but will not be counted again as an event in the Treatment 
2 period. 
• If an event occurs during the Treatment 1 period or earlier and continues to the 
Treatment 2 period and the severity increases to a grade that is greater than the 
maximum severity of the Treatment 1 period or the pre-treatment period or 
becomes serious in Treatment 2 period then the event will be counted as an event 
in the Treatment 2 period. 
For each treatment phase and for the overall treatment period the number and percentage 
of patients reporting TEAEs in each treatment group will be tabulated by descending 
percentage in any group, by system organ class and preferred term, and further 
categorized by severity and causal relationship to the study treatment. If more than 1 AE 
is coded to the same preferred term for the same patient, the patient will be counted only 
once for that preferred term using the greatest severity and strictest causality for the 
summarization by severity and causal relationship. All AE summary tables will be by 
treatment group and the overall safety population. 
The total number of TEAEs by severity and causal relationship to the study treatment will 
be summarized by treatment group. 
The number and percentage of patients who have Treatment emergent SAEs will be 
summarized by preferred term and treatment group. In addition, the incidence of 
treatment emergent SAEs that led to death will be summarized separately by preferred 
term for each treatment group. 
The number and percentage of patients in the Safety Population who have AEs leading to 
premature discontinuation of the study treatment will be summarized by preferred term 
and treatment. 
Pretreatment AEs are the AEs that occur after signing of the informed consent (IC) and 
prior to first dose of study medication. Such AEs will be presented in a patent listing.  
27MAR2018 CSR 201025-001
24


T
li
o
n
F
T
ev
fo
u
 
M
w
M
D
 
So
N
Fe
Fe
C
C
C
Se
V
D
H
Pa
 
H
H
B
R
R
T
Tr
M
L
V
1
D
b
fo
The table belo
idocaine trea
f special inte
eed to occur
or Treatmen
Treatment 2 i
vents by trea
or consistenc
sed for the a
MedDRA v1
with of lidoc
MedDRA Prefer
Dizziness 
omnolence 
Nervousness 
eeling cold 
eeling hot 
onfusional stat
ardiac arrest 
irculatory colla
eizure 
Vision blurred 
Diplopia  
Hypoaesthesia 
araesthesia ora
Hypoaesthesia o
Hypotension 
radycardia 
Respiratory arre
Respiratory dep
innitus 
remor 
Muscle twitchin
oss of consciou
Vomiting 
 
2.2
Descriptive st
aseline value
ollowing lab
ow presents 
atment.  Sinc
erest for lido
r on or after t
nt 1 period it
it will be the
atment group
cy with the M
analysis.  
8.1 PT for A
aine toxicity
rred term 
te 
apse 
al 
oral  
est 
ression 
ng 
usness 
CLINI
tatistics for c
es at each as
boratory para
the preferre
ce lidocaine h
ocaine treatm
the day of IP
t will be up t
e day after th
p and overal
MedDRA ve
AEs associat
y 
ICAL LABO
clinical labo
ssessment tim
ameters: 
d terms  iden
has a short h
ment and to b
P insertion a
to the day aft
he IP remova
l. This table 
ersion (versio
ted 
ORATORY
oratory value
me point wil
ntified to be
half-life, for 
be further su
and up to the
fter the 2nd IP
al. The summ
 will be upd
on presented
Y PARAME
es (in SI unit
ll be presente
e of special in
these AEs to
ummarized in
e day after th
P removal w
mary table w
dated prior to
d below is 18
ETERS 
ts) and chang
ed by treatm
nterest for 
o be conside
n a table  the
he IP remova
while for 
will present s
o database lo
8.1) that will
ges from the
ment group fo
ered 
ey 
al. 
uch 
ock 
l be 
e 
or the 
27MAR2018 CSR 201025-001
25


H
C
U
S
pr
ar
 
1
D
ra
th
1
N
1
1
P
m
w
Hematology: 
Chemistry: 
Urinalysis: 
hift tables fr
resented by 
re provided b
 
2.3
Descriptive st
ate, pulse rat
he end of eac
 
2.4
Not Applicab
 
2.5
 
2.5.1
ost-void resi
measurement
where PVR a
red blo
corpus
concen
differe
eosino
albumi
aminot
calcium
nonfas
color, 
ketone
urobili
leukoc
rom baseline
treatment gr
by lab vendo
VITAL
tatistics for v
te, body tem
ch treatment
ELEC
ble. 
OTHE
Bladd
idual (PVR)
ts will be wil
assessment is
ood cells (RB
scular hemog
ntration, RBC
ential (% and
ophils, basop
in, alkaline p
transferase, t
m, chloride, 
sting glucose
appearance o
es, occult blo
inogen, cryst
cyte, occult b
e to end of st
roup for the 
or. 
L SIGNS 
vital signs (s
mperature ) an
t phase and s
CTROCARD
ER SAFETY
er Post-Voi
 volume me
ll be summa
s done)  usin
BC); RBC in
globin, and m
C morpholog
d absolute): n
phils, hemato
phosphatase
total and dir
creatinine, g
e, potassium
of urine, spe
ood, leukocy
tals; microsc
blood, nitrite
tudy for clin
following ca
systolic and 
nd changes f
study will be
DIOGRAM
Y PARAME
id Residual
asurement a
arized by trea
ng descriptiv
ndices:  mea
mean corpus
gy; white bl
neutrophils, 
ocrit, hemog
, alanine am
rect bilirubin
gamma gluta
, total protei
ecific gravity
yte esterase, n
copic examin
e, or crystals
nical laborato
ategories: low
diastolic blo
from baselin
e presented b
M 
ETERS 
and change fr
atment phase
ve statistics.
an corpuscula
scular hemog
lood cells (W
lymphocyte
lobin, and p
minotransfera
n, blood urea
amyltransfer
in, and sodiu
y, pH, protei
nitrite, biliru
nation if pos
s 
ory paramete
w, normal, a
ood pressure
ne values at e
by treatment
from baseline
e for each vi
ar volume, m
globin 
WBC); WBC
es, monocyte
latelets 
ase, aspartate
a nitrogen, 
rase, globulin
um 
in, glucose, 
ubin, 
sitive for pro
ers will be 
and high, wh
es, respirator
each visit an
t group. 
e volume 
isit (for visit
mean 
C 
es, 
e 
n, 
otein, 
hich 
ry 
nd at 
ts 
27MAR2018 CSR 201025-001
26


1
C
tr
ph
p
1
A
o
in
1
T
th
re
1
P
1
U
pr
1
A
1
N
1
N
 
2.5.2
Complete Phy
reatment pha
hase. The co
atient listing
 
2.5.3
All patients w
f the IP, Tre
nto Treatmen
 
2.5.4
The investiga
he bladder. T
emoval will 
 
2.5.5
regnancy tes
 
2.5.6
Urine Cytolog
resented in p
 
2.5.7
A listing of pa
 
2.5.8
Not applicabl
 
2.5.9
Not applicabl
Physic
ysical exami
ase. Abnorm
omplete and 
g  
Cystos
will undergo 
atment 1 We
nt 2 period.  
Invest
ational produ
The findings 
be presented
Pregn
st results for
Urine 
gy test will b
patient listin
Urine 
atient’s urine
Suicid
le. 
Potent
le. 
cal Examina
inations are p
mal findings a
abbreviated
scopic Exam
a cystoscop
eek 4 Follow
Abnormal f
tigational Pr
uct will be as
on the cond
d in a listing
ancy Test 
r patients wil
Cytology 
be performed
ng. 
Culture  
e culture res
dality Assess
tial Hy’s La
ation 
performed a
at these visit
d physical ex
m 
ic examinati
w-up and at s
findings will
roduct 
ssessed prior
dition of the 
. 
ll be provide
d at screenin
sults will be p
sment  
aw   
at the baselin
ts will be sum
xaminations r
ion on the da
study exit if 
l be summari
r to insertion
IP prior to in
ed in a data l
ng. The resu
presented by
ne and at the
mmarized by
results will b
ays of insert
f the patient d
ized by treat
n and after th
nsertion and
listing. 
ults of this tes
y treatment g
 end of each
y treatment 
be presented
tion and rem
does not con
tment phase.
he removal f
d after the 
sts will be 
group and vi
h 
d in a 
moval 
ntinue 
. 
from 
isit. 
27MAR2018 CSR 201025-001
27


27MAR2018 CSR 201025-001
28


27MAR2018 CSR 201025-001
29


14
A
an
ra
en
co
gr
in
 
4.0
Assuming tha
nalysis, to en
andomized in
nsures that th
onsecutive L
roup that get
n the treatme
INTER
at 5% of the 
nsure that th
nto the study
here will be 
LiRIS 400 m
ts Placebo an
ent group tha
RIM ANAL
randomized
here are 72 ev
y.  At a rand
about 36 pa
mg (LiRIS 40
nd then LiR
at gets two c
LYSIS 
d patients wil
valuable pat
domization ra
atients in the 
00 mg/LiRIS
IS 400 mg (P
consecutive P
ll not be eva
tients approx
atio of 2:1:1
 treatment g
S 400 mg), 1
Placebo/LiR
Placebo (Pla
aluable for th
ximately 76 p
, 72 evaluab
group that ge
8 patients in
RIS 400 mg)
acebo/Placeb
he primary 
patients will
ble patients 
ets two 
n the treatme
, and 18 pati
bo). 
l be 
ent 
ients 
27MAR2018 CSR 201025-001
30


1
A
p
m
1
w
as
F
 
5.0
A sample size
atients in the
mean daily av
.67 using a 1
was performe
ssumption is
ollow-Up ra
DETE
e of  36 patie
e Placebo/Pl
verage bladd
1-sided two 
ed using the 
s based on th
aw average d
ERMINATIO
ents in the  L
lacebo group
der Pain NRS
sample t-tes
commercial 
he TAR-100
daily NRS. 
ON OF SAM
LiRIS 400 m
p  has 76% p
S, assuming 
t with a type
software 
-105 open la
MPLE SIZE
mg/LiRIS 400
power to dete
that the com
e 1 error rate
 T
abel study, w
E 
0 mg group 
ect a differen
mmon standa
e of 0.05.  Th
The standard
where the SD
versus 18 
nce of 1.152
ard deviation
he calculatio
d deviation 
D is the Wee
2 in 
n is 
on 
k 4 
27MAR2018 CSR 201025-001
31


 
 
 
27MAR2018 CSR 201025-001
32


1
1
T
(e
ra
F
T
D
d
T
w
li
A
S
st
T
   
T
   
T
 
 
7.0
 
7.1
Table 17.1–1 
excluding ef
ange of study
ollowing SD
Treatment 1 D
Day 1. Howe
ocument and
Treatment 2 D
will follow th
isting will al
ADaM standa
creening & b
tudy day = v
Treatment 1 p
study day =
Treatment 2 P
 study day =
Throughout th
DATA
VISIT
presents, fo
fficacy based
y days (wind
DTM and AD
Day 1. Simil
ver, in the a
d in the eCR
Day 0, respe
hese protocol
so display st
ards study da
baseline per
visit date - 1s
period : 
= visit date - 
Period : 
= visit date -
his documen
A HANDLIN
T TIME WIN
or both treatm
d on daily pa
dow) during 
DaM standar
larly, the dat
ssessment ta
RF pages this
ectively. For 
l and eCRF v
tudy day usi
ay is calcula
riod (prior to
st IP insertio
1st IP insert
- 2st IP inser
nt ,unless oth
NG CONVE
NDOWS 
ments period
ain diary) and
which an ac
rd,  the date 
te of 2nd IP 
ables of the p
s is considere
by visit ana
visit definiti
ng the SDTM
ated as follow
o IP insertion
on date 
tion date +1
rtion date +1
herwise state
ENTIONS 
ds,  the deriv
d safety ana
ctual visit m
of first IP in
insertion wi
protocol and
ed to be Trea
alysis tables a
ions (3rd col
M definition
ws (see 2nd 
n) 
 
ed, this defin
ved visits for
alyses and th
ay occur. 
nsertion will 
ill be conside
d in Section 4
atment 1 Da
and listings 
lumn in table
n. Hence, usi
column in T
nition of stud
r efficacy 
e correspond
be consider
ered Treatm
4 of this 
ay 0 and 
the visit labe
e 17.1-1). So
ing SDTM a
Table 17.1-1)
dy day is use
ding 
red as 
ent 2 
el 
ome  
and 
): 
ed. 
27MAR2018 CSR 201025-001
33


27MAR2018 CSR 201025-001
34


If not stated otherwise, all by visit analysis will be using the visit windows specified 
above.  The target day for each treatment period is  referenced to days after first IP 
insertion within each treatment period. Treatment 1 Day 1 refers to the first IP insertion 
date while Treatment 2 Day 1 refers to the IP insertion date in Treatment 2 period. In 
contrast,  if the assessment date is before date of Treatment 1 IP insertion, the study day 
is calculated as follows: 
  assessment date – date of Treatment 1 IP insertion. 
 The visit window for each treatment period is defined as follows: 
[(target day of current visit + target day of previous visit)/2+1] to [(target day of current 
visit + target day of next visit)/2] 
If a patient has 2 or more visits within the same visit window, the last visit with a non-
missing value will be used for  the analysis. 
For laboratory and vital signs analysis, baseline refers to study baseline, i.e. the baseline 
information collected at the start of Study 201025-001.  
27MAR2018 CSR 201025-001
35


1
T
d
• 
• 
• 
• 
• 
• 
• 
• 
 
7.2
The data deriv
escribed in t
In this stu
• Tr
an
IP
bo
ph
in
• Tr
ex
Study day
• St
The basel
being inse
Unless oth
analyses w
For analy
randomiz
Data will 
Descriptiv
standard d
confidenc
Summary
(n), and p
DERIV
vations and 
this analysis 
udy there are
reatment per
nd blinded ph
P insertion to
oth the rando
hase of the st
sertion up to
reatment per
xit. 
ys for each tr
tudy day of T
line value of
erted with fir
herwise state
will be based
ses that are b
ation stratifi
be pooled a
ve statistics 
deviation (SD
ce intervals. 
y statistics fo
percentage (%
VED VARI
definitions l
plan, unless
e two treatme
riod 1: for pa
hase of the tr
o study exit. 
omized phas
tudy (Treatm
o Treatment 
riod 2: cover
reatment per
Treatment X
f an assessme
rst Treatmen
ed no imputa
d on the obse
by stratificat
ication levels
cross the inv
for continuo
D), median, 
or categorica
%). 
IABLES 
listed in this 
s otherwise s
ent periods:
atients that ju
rial, it cover
In contrast, 
e of the stud
ment 2) it cov
2 IP insertio
rs the period 
riod X (X=1 
X = visit date
ent will be th
nt 1 IP on Da
ation will be
erved data. 
tion factor, a
s will be use
vestigational
ous/ordinal d
minimum (M
al variables in
section are t
stated. 
ust receive  t
rs the period 
for patients 
dy (Treatmen
vers the peri
on, 
from Treatm
 or 2) will b
e – (day 1 of 
he last value
ay 1. 
e performed 
actual stratif
ed. 
l sites. 
data include t
Min), and m
nclude samp
to be applied
treatment in
d from the fir
that receive 
nt 1) and the
iod from firs
ment 2 IP in
e calculated 
f Treatment X
e recorded pr
for missing 
fication level
the sample s
maximum (M
ple size (N), 
d to all analy
n the random
rst Treatmen
IP insertion
e open label 
st Treatment
sertion to stu
as:  
X) + 1. 
rior to the pa
data.  All 
ls rather than
size (N), mea
Max) and 95%
frequency c
yses 
mized 
nt 1 
ns in 
t 1 IP 
udy 
atient 
n 
an, 
% 
count 
27MAR2018 CSR 201025-001
36


1
A
th
ra
fo
d
T
p
T
o
re
p
th
av
A
p
p
th
 T
fr
w
d
b
ea
su
in
in
in
al
su
co
IP
w
as
5 
re
th
T
 
7.2.1
A pain assess
he daily wor
ate their dail
or “no pain” 
ay up to and
The patient’s 
ain in your b
Treatment 1 D
f the 7 day “
eported days
ain will only
he 7 days pri
vailable, the
Average daily
ost- random
eriod and th
he study the 
Table 17.2.1–
rom first IP i
weekly summ
ays from thi
aseline week
ach weekly s
ummary wee
nsertion or re
nsertion, the 
ncluded in th
ll available v
ummarized (
ontrast, for t
P removal w
week will be 
ssessments t
day criteria
educe the im
he disease un
Table 17.2.1–
Pain D
sment tool w
st pain score
ly pain on a p
to 10 for “w
d including th
baseline ave
bladder over
Day 1. Simil
“worst pain i
s prior to Tre
y be calculat
ior to Day 1 
 baseline sco
y pain NRS 
ization. Pati
en Follow-U
follow up vi
–1, presents 
insertion wit
mary. For pat
is IP insertio
ks that do no
summary if t
ek presented
emoval a dif
day of inser
he weekly av
values, provi
(the days tha
the week wh
will be remov
based on all
to be summa
). The ration
mpact of pain
nder conside
–1 presents t
Data Deriva
will be utilize
es on an elec
pain NRS co
worst pain im
he day prior 
erage daily p
r the last 24 h
larly, a  patie
in your bladd
eatment 1 Da
ted if the info
(i.e., Day -7
ore will be s
and daily wo
ents are sche
Up visit. How
isits follow a
for patients 
thin each tre
tients that on
on the days to
ot cover IP in
they have at
d in Table 17
fferent rule i
rtion and the
verage summ
ided there ar
at are to be re
here IP remov
ved from the 
l available va
arized (the da
nal for exclud
n or pain med
eration. 
the weekly p
ations 
ed in the stud
ctronic hand 
onsisting of a
maginable”.  
to the Exit v
pain NRS wi
hours” score
ent’s baselin
der over the 
ay 1. Baselin
formation is c
7 to Day -1). 
et to missing
orst pain NR
eduled to ha
wever, if a pa
after the IP r
that receive
eatment perio
nly receive o
o be include
nsertion or r
t least 5 cons
7.2.1–1 .  For
s applied. Fo
e two days af
mary. The su
re at least thr
emoved will
val occurs, t
weekly ave
alues provid
ays that are t
ding these IP
dication that
pain assessm
dy to capture
held device
an 11 point i
The pain as
visit. 
ill be the me
es from the 7
ne daily wors
last 24 hour
ne average d
collected for
 If less than 
g.  
RS will be su
ave two IP in
atient receiv
removal.  
e more than o
od the days t
one IP, Table
d in each we
removal, a pa
secutive day
r the week in
or assessmen
fter the day o
ummary for s
ree days of d
l be consider
the IP remov
rage summa
ded there are 
to be remov
P insertion a
t is related to
ment window
e the average
.  Patients w
integer scale
sessment wi
ean of the 7 d
7 reported da
st pain NRS 
rs”  scores fr
daily pain an
r any 5 cons
5 consecutiv
ummarized f
nsertion in T
ves only one 
one IP insert
to be include
e 17.2.1-1 al
eekly summa
atient will be
ys of informa
ntervals that
nt weeks wh
of insertion w
such a week 
daily assessm
red in the 5 d
val date and 
ary. The sum
 at least thre
ed will be co
and removal 
o the procedu
s. 
e daily pain 
will be asked 
e ranging fro
ill continue e
day “average
ays prior to 
will be the m
rom the 7 
nd average w
ecutive  day
ve days are 
for each wee
reatment 1 
IP insertion
tion, in days
ed in each 
lso presents 
ary. For the 
e included in
ation within 
t cover IP 
here there is 
will not be 
will be base
ments to be 
day criteria)
the day after
mmary for su
ee daily 
onsidered in
dates is to 
ure rather th
and 
to 
om 0 
every 
e 
mean 
worst 
ys in 
ek 
n in 
s 
in 
post-
n 
the 
IP 
ed on 
). In 
r the 
uch a 
n the 
han 
27MAR2018 CSR 201025-001
37


1
• 
 
7.2.2
For baseli
based on t
interval co
the time o
Void D
ine and postt
the diary dat
onsists of 3 
of the first ur
Data Deriva
treatment vi
ta collected 
consecutive 
rinary episod
ations 
sits, analyse
during a 3-d
24-hour per
de on the firs
es on void di
day interval f
riods, with th
st of the 3 da
iary efficacy
for each visi
he first perio
ays. 
y variables w
it.  Each 3-da
od starting fr
will be 
ay 
rom 
27MAR2018 CSR 201025-001
38


• 
• 
1
If
fr
b
A valid di
urinary ep
episodes (
For baseli
following
• Ap
th
• De
(in
da
to 
da
th
th
• Us
Ap
fro
is 
24
Ap
• At
vi
 
7.3
f a patient ha
rom the final
e used as ba
7:30am 
 
2:30pm 
 
5:00pm 
Apr 3 
iary day is d
pisodes.  Dat
(i.e., an inva
ine and postt
g algorithm: 
pply visit wi
e date of stu
etermine the
n the exampl
ays.  Note:  t
or on the la
ata will not b
e urinary ep
e IP insertio
sing the exam
pril 3 and en
om 7:30am o
considered a
4 hours.  The
pr 5 and end
t least one va
sit.  Otherwi
REPE
PARA
as repeated a
l non-missin
seline.  
6:15am 
 
 
9:00pm 
Apr 4 
defined as an
ta collected 
alid diary day
treatment vi
indows defin
udy first treat
e time of the 
le below, 7:3
the last 24-ho
st day specif
be used for th
isodes that o
n time will b
mple below,
nds at 7:29 am
on Apr 4 and
as an invalid
e third or the
ds at 7:29 am
alid 24-hour
ise, the 3-da
EATED OR 
AMETERS
assessments 
ng assessmen
 
 
5:30pm 
Apr 5 
ny of the thre
from a 24-ho
y) will be se
sits, the 3-da
ned in Sectio
tment in eac
first urinary
30 am on Ap
our period sh
fied in the w
he correspon
occurred on t
be counted a
, the first 24-
m on Apr 4.
d ends at 7:2
d diary day s
e last 24-hou
m on Apr 6. 
r diary day w
y diary data 
UNSCHED
before the st
nt made prio
11:23am 
 
4:23pm
 
 
Apr 6 
ee 24-hour p
our period w
et to missing
ay diary will
on 17.1, whi
ch treatment 
y episode tha
pril 3).  Coun
hould end w
window defin
nding windo
the day of fi
as baseline d
-hour time p
.  The second
29 am on Ap
since it has ju
ur time perio
within the wi
will be miss
 
DULED ASS
tart of the fir
or to the start
periods with 
with less than
. 
l be determin
ich are based
period. 
at is within th
nt forwards 
within the win
nition; otherw
ow.  For base
irst IP inserti
diary data. 
period starts 
d 24-hour tim
pr 5.  Note th
ust one episo
d starts from
indow is req
sing for the v
SESSMENT
rst treatment
t of the study
2 or more 
n 2 urinary 
ned based on
d on days fro
he visit wind
for 3 consec
ndow, i.e., p
wise, the 24-
eline diary d
ion but befo
from 7:30am
me period st
hat this 24-ho
ode during th
m 7:30 am on
quired for the
visit. 
TS OF SAFE
t, the results
y treatment w
n the 
om 
dow 
cutive 
prior 
-hour 
ata, 
re 
m on 
tarts 
our 
he 
n 
e 
ETY 
s 
will 
27MAR2018 CSR 201025-001
39


1
N
1
If
tr
st
b
su
1
If
af
im
su
1
T
in
M
• 
• 
• 
M
• 
 
7.4
Not applicabl
 
7.5
f severity is m
reatment, an 
tarted on or a
e assigned. T
ummary; the
 
7.6
f the causal r
fter the date 
mputed value
ummary; the
 
7.7
The following
ncomplete (i
Missing mon
If the year
treatment
the missin
If the year
treatment
If the year
treatment
Missing mon
If only the
and the da
MISSI
TREA
le. 
MISSI
missing for a
intensity of 
after the date
The imputed
e values will
MISSI
TREA
relationship 
of the first d
es for causal
e values will
MISSI
g imputation
.e., partly m
nth and day 
r of the inco
, the month 
ng fields 
r of the inco
, December 
r of the inco
, January 1 w
nth only 
e month is m
ay will be re
ING DATE
ATMENT 
ING SEVER
an AE that s
f mild will be
e of the first
d values for s
 be shown a
ING CAUSA
ATMENT FO
to the study 
dose of study
l relationship
 be shown a
ING DATE
n rules only a
missing). 
omplete start 
and day of th
omplete start 
31 will be a
omplete start 
will be assig
missing, the d
eplaced accor
 OF THE L
RITY ASSE
started befor
e assigned. I
t dose of stud
severity asse
s missing in
AL RELAT
OR ADVER
treatment is
y treatment, 
p to study tre
s missing in
 INFORMA
apply to case
date is the s
he first dose
date is befo
ssigned to th
date is after
gned to the m
day will be t
rding to the 
LAST DOSE
ESSMENT F
re the date of
If severity is 
dy treatment
essment will
n the data list
TIONSHIP 
RSE EVEN
s missing for
a causality o
eatment will
n the data list
ATION FOR
es in which t
same as the y
e of study tre
ore the year o
he missing fi
r the year of 
missing field
treated as mi
above proce
E OF STUD
FOR ADVE
f the first do
missing for 
t, an intensit
l be used for 
tings. 
TO STUDY
NTS 
r an AE that 
of yes will b
l be used for
tings. 
R ADVERS
the start date
year of the f
eatment will 
of the first d
fields 
f the first dos
ds 
issing and bo
edure 
DY 
ERSE EVEN
se of study 
an AE that 
ty of severe w
the incidenc
Y 
started on o
be assigned. 
r the inciden
SE EVENTS
e for AEs is 
first dose of s
be assigned
ose of study
se of study 
oth the mont
NTS 
will 
ce 
or 
The 
nce 
S 
study 
d to 
y 
th 
27MAR2018 CSR 201025-001
40


M
• 
• 
• 
If
st
If
al
• 
• 
1
F
p
st
1
T
in
im
u
Missing day 
If the mon
of the firs
assigned t
If either th
dose of st
start date 
day of the
If either th
dose of st
start date 
day of the
f the stop dat
tart date will
f the start da
lgorithm wil
If the stop
dose of st
If the stop
be assigne
 
7.8
or prior or c
artly missing
top date are 
 
7.8.1
The following
ncomplete pr
mputed) and
sing the stop
only 
nth and year
st dose of stu
to the missin
he year of th
tudy treatme
is before the
e month will
he year of th
tudy treatme
is after the m
e month will
te is comple
l be imputed
te is comple
ll be used to 
p date is afte
tudy treatme
p date is befo
ed to the mis
MISSI
CONC
concomitant 
g) start dates
both incomp
Incom
g rules will b
rior or conco
d the imputed
p date. 
r of the incom
udy treatmen
ng day 
he incomplet
nt or if both 
e month of th
l be assigned
he incomplet
nt or if both 
month of the
l be assigned
te and the im
d by the stop 
etely missing
impute the s
er the date of
nt will be as
ore the date 
ssing start da
ING DATE
COMITANT
medications
s and/or stop
plete for a pa
mplete Start 
be applied to
omitant med
d start date is
mplete start 
nt, the day of
te start date i
years are th
he date of th
d to the missi
te start date i
years are th
e date of the 
d to the missi
mputed start 
date. 
g and the stop
start date: 
f the first dos
ssigned to th
of the first d
ate 
 INFORMA
T MEDICA
s, including r
p dates will b
atient, the sta
Date 
o impute the
dication start 
s after the st
date are the 
f the first do
is before the
he same but t
he first dose 
ing day 
is after the y
he same but t
first dose of
ing day 
date as abov
p date is com
se of study t
he missing st
dose of study
ATION FOR
ATIONS 
rescue medic
be imputed. 
art date will 
 missing num
 date. If the 
top date, the 
same as the 
se of study t
e year of the 
the month of
of study trea
year of the da
the month of
f study treatm
ve is after th
mplete, the f
treatment, th
tart date 
y treatment, 
R PRIOR O
cations, inco
When the st
be imputed 
meric fields 
stop date is 
start date w
month and y
treatment wi
date of the f
f the incomp
atment, the l
ate of the fir
f the incomp
ment, the fir
he stop date, 
following 
he date of the
the stop date
OR 
omplete (i.e.
tart date and 
first. 
for an 
complete (o
ill be impute
year 
ill be 
first 
plete 
last 
rst 
plete 
st 
the 
e first 
e will 
, 
the 
r 
ed 
27MAR2018 CSR 201025-001
41


M
• 
• 
• 
M
• 
M
• 
• 
• 
1
T
in
th
th
M
• 
Missing mon
If the year
treatment
the missin
If the year
treatment
If the year
treatment
Missing mon
If only the
and the da
Missing day 
If the mon
of the firs
assigned t
If either th
dose of st
start date 
day of the
If either th
dose of st
start date 
day of the
 
7.8.2
The following
ncomplete pr
he start date 
he start date.
Missing mon
If the year
treatment
fields 
nth and day 
r of the inco
, the month 
ng fields 
r of the inco
, December 
r of the inco
, January 1 w
nth only 
e month is m
ay will be re
only 
nth and year
st dose of stu
to the missin
he year of th
tudy treatme
is before the
e month will
he year of th
tudy treatme
is after the m
e month will
Incom
g rules will b
rior or conco
(imputed or 
 
nth and day 
r of the inco
, the month 
omplete start 
and day of th
omplete start 
31 will be a
omplete start 
will be assig
missing, the d
eplaced accor
r of the incom
udy treatmen
ng day 
he incomplet
nt or if both 
e month of th
l be assigned
he incomplet
nt or if both 
month of the
l be assigned
mplete Stop D
be applied to
omitant med
non-impute
omplete stop 
and day of th
date is the s
he first dose
date is befo
ssigned to th
date is after
gned to the m
day will be t
rding to the 
mplete start 
nt, the day of
te start date i
years are th
he date of th
d to the missi
te start date i
years are th
e date of the 
d to the missi
Date 
o impute the
dication stop 
ed start date)
date is the s
he study exi
same as the y
e of study tre
ore the year o
he missing fi
r the year of 
missing field
treated as mi
above proce
date are the 
f the first do
is before the
he same but t
he first dose 
ing day. 
is after the y
he same but t
first dose of
ing day 
 missing num
date. If the 
), the impute
same as the y
it date will b
year of the f
eatment will 
of the first d
fields 
f the first dos
ds 
issing and bo
edure 
same as the 
se of study t
e year of the 
the month of
of study trea
year of the da
the month of
f study treatm
meric fields 
imputed stop
ed stop date w
year of the la
be assigned t
first dose of s
be assigned
ose of study
se of study 
oth the mont
month and y
treatment wi
date of the f
f the incomp
atment, the l
ate of the fir
f the incomp
ment, the fir
for an 
p date is bef
will be equa
ast dose of s
o the missin
study 
d to 
y 
th 
year 
ill be 
first 
plete 
last 
rst 
plete 
st 
fore 
al to 
study 
ng 
27MAR2018 CSR 201025-001
42


• 
• 
M
• 
M
• 
• 
• 
1
If
su
nu
an
d
T
fo
If the year
treatment
If the year
treatment
Missing mon
If only the
and the da
Missing day 
If the mon
of the last
missing d
If either th
dose of st
stop date 
day of the
If either th
dose of st
stop date 
of the mo
 
7.9
f the reported
ummary tabl
umeric type
nalyses. The
ata listings. 
Table 17.9–1 
or the analys
r of the inco
, December 
r of the inco
, January 1 w
nth only 
e month is m
ay will be re
only 
nth and year
t dose of stud
day 
he year of th
tudy treatme
is before the
e month will
he year of th
tudy treatme
is after the m
nth will be a
CHAR
PARA
d value of a 
le because, f
, a coded val
e actual valu
shows exam
sis. 
omplete stop 
31 will be a
omplete stop 
will be assig
missing, the d
eplaced accor
r of the incom
dy treatment
he incomplet
nt or if both 
e month of th
l be assigned
he incomplet
nt or if both 
month of the
assigned to t
RACTER V
AMETERS
clinical labo
for example,
lue must be 
es, however
mples of how
date is befo
ssigned to th
date is after
gned to the m
day will be t
rding to the 
mplete stop d
t, the day of 
te stop date i
years are th
he date of th
d to the missi
te stop date i
years are th
e date of the 
the missing d
VALUES OF
oratory param
 a character 
appropriatel
, as reported
w some possi
ore the year o
he missing fi
r the year of 
missing field
treated as mi
above proce
date are the 
f the study ex
is before the
he same but t
he last dose o
ing day 
is after the y
he same but t
last dose of 
day 
F CLINICA
meter canno
string is rep
ly determine
d in the datab
ible laborato
of the last do
fields 
the last dose
ds 
issing and bo
edure 
same as the 
xit will be as
e year of the 
the month of
of study treat
year of the da
the month of
study treatm
AL LABORA
t be used in 
ported for a p
ed for use in 
base will be 
ory results sh
ose of study 
e of study 
oth the mont
month and y
ssigned to th
date of the l
f the incomp
tment, the la
ate of the las
f the incomp
ment, the firs
ATORY 
a statistical 
parameter of
the statistica
presented in
hould be cod
th 
year 
he 
last 
plete 
ast 
st 
plete 
st day 
f the 
al 
n the 
ded 
27MAR2018 CSR 201025-001
43


Table 17.9–1. 
Examples of Coding Special Character Values for Clinical Laboratory 
Parameters 
Laboratory Test, 
SI Unit 
Possible Laboratory Results 
Coded Value for Analysis 
CHEMISTRY 
ALT, U/L 
< 5 
5 
AST, U/L 
< 5 
5 
Bilirubin, total, µmol/L 
< 2 
2 
URINALYSIS 
Glucose, mmol/L 
= OR > 55, ≥ 55, > 0 
Positive 
≤ 0, negative 
Negative 
pH 
> 8.0, ≥ 8.0 
8.0 
≥ 8.5 
8.5 
Protein 
= OR > 3.0, ≥ 3.0, > 0 
Positive 
≤ 0 
Negative 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; SI = Le Système International d’Unités 
(International System of Units). 
27MAR2018 CSR 201025-001
44


1
 
8.0
• The A
assess
• The p
remov
CHAN
AE analysis b
sed to be not
rimary effic
ved. This has
NGES TO A
by time of in
t relevant to 
acy analysis
s been replac
ANALYSES
nsertion or re
this study 
s with LOCF
ced with rep
S SPECIFIE
emoval has b
F method of 
peated measu
ED IN PROT
been remove
imputation h
ures mixed m
TOCOL 
ed. It was 
has been 
model analysis. 
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DOCUMENT HISTORY PAGE 
Effect Date 
Revision 
Number 
Primary Author 
Description of Change 
01 July 2015 
0.1 
 
Initial Release 
06 June 2016 
0.2 
 
Changes to conform with Protocol 
Amendment 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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