Clinical trial NCT03397771
Conditions: Urinary Incontinence
Keywords: urinary incontinence, SSRI
Sponsor: Ixaltis SA
Start date: 2018-04-03; Completion date: 2019-05-30
Enrollment: 84 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will explore the safety, tolerability and efficacy of litoxetine in men and women who suffer from urinary incontinence

Detailed description:
This is a double blind randomized placebo controlled study which will explore the safety, tolerability and efficacy of oral litoxetine, a highly selective SSRI, provided by dose titration to subjects suffering from urinary incontinence

Arms: arm 1: oral experimental study medication litoxetine arm 2: oral comparator
Interventions: intervention 1: Litoxetine intervention 2: placebo
Intervention descriptions: intervention 1: oral study medication provided in a dose titration manner intervention 2: placebo medication provided in a dose titration manner

Protocol documents:
Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
A Double-Blind, Randomised, Placebo-Controlled, Phase I/IIa, Dose Titration Trial to 
Evaluate the Safety, Tolerability and Efficacy of Oral Litoxetine up to 30 mg versus 
Placebo BID in subjects with Urinary Incontinence 
 
Protocol Number: 
IXA-CSP-002 
Investigational Medicinal Product: 
Litoxetine 10 mg, 20 mg  
Indication: 
Urinary Incontinence 
Phase: 
I/IIa 
Sponsor: 
IXALTIS 
Archamps Technopole 
Acti’Tech 6 
60 avenue Marie Curie 
74160 Archamps, France 
Principal Scientific Advisor 
Pr. Roger Dmochowski MD, MMHC 
Department of Urology 
Vanderbilt University 
Nashville, TN 
USA 
IND: 
PIND 132328 
Protocol Version and Date: 
Version 1 Final Sep 14, 2017 
Version 2 Amendment 1, June 28, 2018 
Version 3 Amendment 2, October 10, 2018 


The study will be conducted according to the protocol and in compliance with Good Clinical 
Practice (GCP), with the Declaration of Helsinki, and with other applicable regulatory 
requirements. 
This document contains confidential information of IXALTIS 
Do not copy or distribute without written permission from the Sponsor. 
CONFIDENTIAL 


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SIGNATURE PAGE 
 
Declaration of Sponsor or Responsible Medical Officer 
 
Title: A Double-Blind, Randomised, Placebo-Controlled, Phase I/IIa, Dose Titration Trial to 
Evaluate the Safety, Tolerability and Efficacy of Oral Litoxetine up to 30 mg versus Placebo 
BID in subjects with Urinary Incontinence 
 
This study protocol was subjected to critical review. The information it contains is consistent 
with current knowledge of the risks and benefits of the investigational product, as well as with 
the moral, ethical and scientific principles governing clinical research as set out in the 
Declaration of Helsinki, and the guidelines on Good Clinical Practice. 
 
 
 
_____________________________________ 
_____________________ 
Elisabeth Svanberg MD, PhD 
Date 
Chief Development Officer 
IXALTIS SA 
 
 
_____________________________________ 
_____________________ 
Jasna Knezevic MD 
Date 
Independent Medical Safety Expert 
 


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Declaration of the Principal Scientific Advisor 
 
Title: A Double-Blind, Randomised, Placebo-Controlled, Phase I/IIa, Dose Titration Trial to 
Evaluate the Safety, Tolerability and Efficacy of Oral Litoxetine up to 30 mg versus Placebo 
BID in subjects with Urinary Incontinence 
 
 
This study protocol was subjected to critical review and has been approved by the Sponsor. The 
information it contains is consistent with the current risk/benefit evaluation of the investigational 
product as well as with the moral, ethical and scientific principles governing clinical research as 
set out in the Declaration of Helsinki, and the guidelines on Good Clinical Practice. 
 
 
Principal Scientific Advisor  
 
 
 
 
 
 
 
 
_____________________________________ 
_____________________ 
Pr. R Dmochowski MD, MMHC                                Date 
Dept of Urology 
Vanderbilt University 
Nashville, TN 
 
 


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Declaration of the Investigator 
 
Title: A Double-Blind, Randomised, Placebo-Controlled, Phase I/IIa, Dose Titration Trial to 
Evaluate the Safety, Tolerability and Efficacy of Oral Litoxetine up to 30 mg versus Placebo 
BID in subjects with Urinary Incontinence 
 
All documentation for this study that is supplied to me and that has not been previously 
published will be kept in the strictest confidence. This documentation includes this study 
protocol, Investigator's Brochure, Case Report Forms, and other scientific data. 
The study will not be commenced without the prior written approval of a properly constituted 
Institutional Review Board (IRB) or Ethics Committee (EC). No changes will be made to the 
study protocol without the prior written approval of the Sponsor and the IRB or IEC, except 
where necessary to eliminate an immediate hazard to the subjects. 
I have read and understood and agree to abide by all the conditions and instructions contained in 
this protocol. 
 
Responsible Investigator of the local study centre 
 
 
 
_____________________________________ 
_____________________ 
Name 
Date 
Title 
Institution 
 


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PROTOCOL SYNOPSIS 
Title: 
Title: A Double-Blind, Randomised, Placebo-Controlled, Phase 
I/IIa, Dose Titration Trial to Evaluate the Safety, Tolerability and 
Efficacy of Oral Litoxetine up to 30 mg versus Placebo BID in 
subjects with Urinary Incontinence 
Protocol Number: 
IXA-CSP-002 
Phase: 
I/IIa 
Sponsor: 
IXALTIS 
Principal Advisor: 
Pr. R Dmochowski 
Objectives: 
The primary objective of this study is to evaluate the safety and tolerability of 
litoxetine up to 30 mg versus placebo administered orally twice daily (BID) for 8 
weeks in subjects with a diagnosis of urinary incontinence (UI). 
The secondary objectives of this study are to evaluate the efficacy of litoxetine 
up to 30 mg BID compared to placebo in subjects with a diagnosis of UI. 
Design: 
All subjects will enter the Screening Placebo Run In Period during which 
eligibility will be assessed, and subjects will receive a single-blind (subject blind) 
placebo treatment, where subjects must have at least 7 days of daily diary 
symptom collection (which will include a weekend). Subjects who continue to 
meet eligibility criteria at the end of the Run-in Period, including collection of 
diary data, (at least 7 incontinence episodes per week in the diary entries) will 
enter the Treatment Period. Subjects will be randomly assigned (2:1) to receive 
study drug (litoxetine for dose titration 10 mg, 20 mg, 30 mg) or placebo BID. 
Litoxetine treatment will be provided with dose titration, starting with 10 mg BID 
for 1 week, escalated to 20 mg BID for 1 week, and subsequently escalated to 30 
mg BID for 6 weeks for a total litoxetine treatment duration of 8 weeks. Placebo 
treatment will be matched. 
If the subject does not tolerate the last dose level escalation (ie can not tolerate 30 
mg BID), the dose can be reduced to the previous dose level (20 mg BID). If the 
patient does not tolerate the lowered dose level (20 mg BID) s/he will be 
discontinued from the study.  
After 8 weeks of treatment, doses will be reduced by 50% over 1 week to taper off 
treatment. A safety follow up visit will occur 4 weeks after treatment is 
permanently stopped (total study duration 15 weeks) 
Inclusion Criteria: 
All subjects aged 18 to 70 will be eligible for inclusion in this study if all of the 
following criteria apply: 
1. 
Willing to provide written informed consent 
2. 
Have symptoms of urinary incontinence for at least 3 consecutive 
months 


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3. 
 
 
4. 
For male subjects: If subject has undergone any prostate procedure, this 
must have occurred at least 6 months prior to screening 
 
Have at least 7 incontinence episodes per week in the diary entries for 
the Screening Placebo Run In Period  
5. 
Subject is ambulatory and able to use the toilet independently 
6. 
If subjects use pelvic floor exercises, subjects must have been on a 
stable exercise and activity regime for at least 3 months prior to 
screening and that regime must remain stable during the treatment 
period 
7. 
Subject has a body mass index (BMI) ≥ 19 kg/m2 but ≤ 35 kg/m2 
BMI=weight [kg] / height [m2} 
8. 
Subjects must have a pre-dose mean systolic/diastolic blood pressure of 
≤ 140/90 mmHg before randomization can occur 
9. 
For female subjects: Must not be pregnant, lactating, or actively trying 
to become pregnant, Subjects who are premenopausal and of 
childbearing potential must have a negative pregnancy test at Screening 
(serum) and at Day 0 (urine) and must use a medically acceptable and 
effective method of birth control for the duration of the study, which 
can include: 
a. 
Having a male partner who is sterile prior to the female 
subject’s entry into the study and is the sole sexual partner for 
that female subject 
b. Use of double-barrier methods of contraception; condoms with 
the use of caps (with spermicide) and intra-uterine devices are 
acceptable 
c. 
Use of hormonal contraceptives (oral, depots, patches, etc.) 
with double-barrier methods of contraception as outlined 
above 
d. True abstinence: When this is in line with the preferred and 
usual lifestyle of the subject (period abstinence [eg, calendar, 
ovulation, symptothermal, post-ovulation methods] and 
withdrawal are not acceptable methods of contraception) 
10. 
Subjects taking oral contraceptives or hormone replacement therapy 
(women) or hormone adjuvant therapy (men) must have a stable dose 
and regimen for ≥ 3 months prior to entry into the study 
 
Exclusion Criteria: 
A subject will not be eligible to participate in the study if they meet any of the 
following criteria: 
1. 
History of anti-incontinence surgery in past 12 months 
2. 
Use of Botox for the treatment of urinary incontinence in the past 12 
months 


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3. 
 
4.  
Current or recent (3 months) use of any pharmacologic agent used to 
treat symptoms of urinary incontinence                                                       
For women: Grade III/IV pelvic organ prolapse; defined per clinical 
practice 
5. 
For women: History of pelvic prolapse repair or urethral 
diverticulectomy within 12 months of Screening   
For men: urethral surgery within 6 months of Screening.  
6. 
History of interstitial cystitis or bladder-related pain 
7. 
Subjects with concurrent (at Screening), recent (within 30 days), 
chronic, or recurrent (> 4 per year) urinary tract infections (positive 
dipstick for urinary tract infection and abnormal microscopic 
evaluation, signs and symptoms) or unevaluated microhematuria 
8. 
History of diagnosed gastrointestinal obstructive disorders 
9. 
Chronic severe constipation 
10. 
History of radiation cystitis or history of pelvic irradiation 
11. 
Electrostimulation, biofeedback, or bladder training therapy (behavioural 
therapy), during the previous month prior to Screening, or the intention to 
initiate such therapies during the study period. Pessaries and implants are 
also excluded. 
12. 
Postvoid residual (PVR) urine volume > 150 mL 
13. 
Diagnosis of dementia 
14. 
Diagnosis of epilepsy 
15. 
Diagnosis of acute narrow-angle glaucoma 
16. 
History of mania or diagnosis of bipolar disorder  and/or seizures 
17. 
Subjects with uncontrolled hypertension 
18. 
Documented history of myocardial infarction, unstable angina, and/or 
has undergone coronary artery bypass surgery and/or percutaneous 
transluminal coronary angioplasty in the past year 
19. 
Congestive heart failure (New York Heart Association Class III or IV 
heart failure; Appendix 3) 
20. 
Any concurrent condition or any clinically significant abnormality on the 
Screening physical examination, laboratory tests, electrocardiogram 
(ECG; including ischemic heart disease), Hepatitis B or C, which, in the 
opinion of the Investigator, may affect the interpretation of safety or 
efficacy data, or which otherwise contraindicates participation in a 
clinical study with litoxetine: 
a. 
Hypersensitivity to litoxetine or any of its ingredients 
b. History of clinically significant drug hypersensitivity  
c. 
Subjects with current (within 2 years) urogenital neoplasms or 
malignancies including bladder, uterine or cervical cancer (not 


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applicable to male subjects with prostate cancer in whom a 
prostatectomy has been performed) 
d. Subjects with neuropathology that could affect the lower 
urinary tract or nerve supply, including but not limited to 
multiple sclerosis, stroke, Parkinsonism, or spinal cord injury  
e. 
Subjects with diabetes insipidus  
f. 
Clinically significant or unstable, endocrine, hepatic, renal, 
immunologic, or lung disease (ie, active chronic obstructive 
pulmonary disease), or malignancy other than non-
melanomatous skin cancer  
21. 
Severe renal impairment (estimated glomerular filtration rate 
< 30 mL/min/1.73m2) 
22. 
Severe hepatic impairment (Child-Pugh B or greater) 
23. 
Current or recent (6 months) treatment for depression, or a current 
diagnosis of depression or have a state of depression or suicidality at 
Screening. 
24. 
 
25. 
 
 
26. 
History of current or recent (6 months) suicidal ideation and behaviour 
(SIB), or history of any suicide attempt in the past 12 months. 
History of an addiction to drugs or alcohol within 5 years prior to 
screening, or of alcohol or substance abuse within the past year, as 
determined by the Investigator.    
                                                                                                        
Current use of the following medications:, any serotonergic medication, 
nonselective irreversible monoamineoxidase inhibitors (MAOIs), 
cytochrome P450 (CYP)1A2 inhibitors (such as fluvoxamine, 
ciprofloxacin, or enoxacin), cytochrome P450 (CYP) 2D6 inhibitors 
(bupropion, fluoxetine, metoclopromide, paroxetine, quinidine), 
pimozide and thioridazine, and any other medication that would be 
considered a safety risk for co-administration with litoxetine (See 
Section 5.6.2 Prohibited Medications) 
27. 
Participation in a clinical study within the month prior to Screening, or 
exposure to an investigational drug which has not washed out for at least 
5 half-lives since its  last administration, prior to Screening 
28. 
In the opinion of the Investigator, is at risk of non-compliance with study 
procedures, or cannot read, understand, or complete study-related 
materials (including electronic diaries), particularly informed consent 
29. 
Participation in any clinical study of an investigational drug that may 
affect urinary function within 3 months prior to Screening 
 


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Number of Subjects: 
Approximately 95 subjects are expected to be enrolled into a 2-week, single-blind 
(subject blind), Screening Placebo Run-In Period. It is expected that 20% of 
subjects will not qualify for randomization after Screening Placebo Run-In.  
The study is expected to randomize approximately 78 subjects into the double-
blind treatment where subjects will be allocated to litoxetine (dose titration 10 mg, 
20 mg, 30 mg) or matched placebo BID in a 2:1 ratio. A post randomisation 
dropout rate of 30% has been estimated, resulting in 60 evaluable subjects.  
 
Countries/Number of 
Sites: 
Up to 15 sites in the US 
Investigational Medicinal 
Product: 
Litoxetine 10 mg, 20 mg,  
Batch number for active pharmaceutical ingredient: 100193-01 
Reference Therapy: 
Placebo  
Duration of Participation: 
The study will include a 2-week single-blind (subject blind) Screening Placebo 
Run-In Period; and a 8-week double-blind Treatment Period. The Treatment 
Period will be followed by a 1-week Dose-tapering Period. Subjects will be return 
to the clinic for a safety Follow-up Visit 4 weeks after treatment is completed, for 
a total study duration of 15 weeks. 
Criteria for Evaluation: 
Safety  Assessments: 
 
 
Efficacy  Assessments: 
 
Safety assessments will be conducted throughout the trial and will include 
physical examinations, vital signs, clinical laboratory evaluations, 12-lead 
electrocardiograms (ECGs), and adverse events (AEs). 
Efficacy will be assessed by numbers of urinary incontinence episodes and 
number of incontinence pads used 
Endpoints: 
Primary:  
• 
Incidence and severity of AEs and Adverse Events of interest (urinary 
retention, withdrawal symptoms) over the course of the study.  
• 
Adverse Events of special psychiatry interest (nervousness, anxiety, panic 
attacks, insomnia, aggression, mania, suicidal ideation, 
development/worsening of depression) over the course of the study 
• 
Suicidal Adverse Events and Adverse Events suggestive of abuse potential 
(described in Section 6.2.2.3) will be analysed, and detailed narratives 
provided 
• 
Haematology, chemistry, and urinalysis 
• 
Actual change from end of the Screening Placebo Run-In Period in ECG 
readings and Week 8. ECG parameters of interest include: ventricular rate, 
QT interval, corrected QT interval, PR interval, and QRS duration  
• 
Actual change from end of the Screening Placebo Run-In Period to each visit 
in standardised cuff systolic and diastolic blood pressure and radial heart rate 
Secondary:  
The following Efficacy endpoints will be explored 


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• 
Percentage change from end of the Screening Placebo Run-In Period to Week 
8 in the number of incontinence episodes/24 hours 
• 
Absolute change from end of the Screening Placebo Run-In Period to Week 8 
in the number of incontinence episodes/24 hours 
• 
Proportion of subjects who become continent at Week 8 
• 
Change from end of the Screening Placebo Run-In Period in the number of 
incontinence pads used per week 
Statistical Methods: 
Study Populations: 
The Safety Population (SP) is defined as all subjects who are randomised and 
receive the study drug, and undergo at least 1 visit. 
The intent-to-treat (ITT) population includes all subjects who are randomized 
The modified intent-to-treat (mITT) population includes all subjects who are 
randomized, receive at least 1 dose of study drug, and provide an end of study 
primary efficacy endpoint. 
The Per Protocol (PP) population is defined as those subjects who meet the ITT 
criteria and have completed the trial without a major protocol violation.  
The efficacy analysis will be performed on the ITT, mITT, and PP populations. The 
primary efficacy analysis will be performed on the ITT population with the analysis 
of the primary end-point on the mITT and PP populations as part of the secondary 
efficacy analysis. 
The efficacy analysis planned is a mixed effects model with repeated measure 
(MMRM). Percent reduction in incontinence episodes as the response variable is the 
first efficacy endpoint. The factor variable will be dose and centre. The covariate 
will be end of the Screening Placebo Run-In Period episodes of incontinence. Visits 
within subjects will provide the random effects of the mixed model. There is only 
one hypothesis so there will be no adjustment for multiplicity.  Further efficacy 
analysis will be conducted similarly, with appropriate baseline measures. There will 
not be an adjustment for multiple comparisons for these secondary endpoint 
analyses. 
Safety Analyses: Safety data will be presented and analysed using the Safety 
Population. 
• 
Serious adverse events (SAEs) will be listed and summarised in a table, 
including a description of each event, the time to onset, the severity, and the 
relationship to trial drug. 
• 
All AEs (excluding SAEs) will be listed, and their time to onset, frequency, 
severity, and relationship to the trial drug will be tabulated by treatment. 
Adverse events that occur before the time of the first treatment with the trial 
drug will be considered a non-treatment- emergent AE (non-TEAE), and all 
AEs that occur after the time of the first treatment with trial drug will be 
considered TEAEs. Non-TEAEs will be summarised separately from TEAEs. 
• 
Adverse Events of Special Interest (AESI) include urinary retention, psychiatric 
adverse events (nervousness, anxiety, panic attacks, insomnia, aggression, 
mania, suicidal ideation, development/worsening of depression) and withdrawal 
symptoms will be specifically summarized.  


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• 
Suicidal adverse events and abuse related events will be specifically 
summarized 
• 
Premature withdrawals from the trial will be displayed and summarised by 
primary reason and treatment. 
• 
Abnormal laboratory values will be listed and their incidence, severity and 
relationship to the trial drug will be tabulated by treatment. Change from 
Screening will be summarised by treatment. Individual changes (shift tables), 
individual clinically significant abnormalities, and modified World Health 
Organisation (WHO) ratings will also be presented. 
• 
While total white blood cell (WBC) count will be expressed in absolute values, 
differential count will be expressed as both absolute count and percentage of 
WBCs. 
• 
Abnormal physical examination findings will be summarised over time. 
• 
Concomitant medications will be presented in summary tables and listings. 
They will be classified according to whether they were taken before the trial 
(and ongoing into the trial), or started during the trial period. 
• 
Vital signs will be summarised by treatment group and listed by subject. 
• 
Any AE/SAE which occurs during the 30-day Follow-up Period or following 
discontinuation of treatment will be listed and summarized separately, and 
include a description of the event, time to onset, frequency, severity and 
relationship to treatment. 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS .................................................................................................. 6 
TABLE OF CONTENTS ................................................................................................ 13 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................. 16 
1 
INTRODUCTION ............................................................................................... 18 
1.1 
Background ..................................................................................................... 18 
1.1.1 
Urinary Incontinence ........................................................................... 18 
1.1.2 
Litoxetine for the Treatment of Urinary Incontinence ........................ 19 
1.2 
Risk/Benefit Assessment ................................................................................. 19 
1.3 
Rationale .......................................................................................................... 20 
2 
STUDY OBJECTIVES ....................................................................................... 21 
2.1 
Primary Objective ........................................................................................... 21 
2.2 
Secondary Objectives ..................................................................................... 21 
3 
OVERALL DESIGN AND PLAN OF THE STUDY ....................................... 22 
3.1 
Overview .......................................................................................................... 22 
3.2 
Discussion of Study Design ............................................................................. 23 
4 
STUDY POPULATION ...................................................................................... 25 
4.1 
Inclusion Criteria ............................................................................................ 25 
4.2 
Exclusion Criteria ........................................................................................... 26 
4.3 
Subject Withdrawal and Replacement ......................................................... 28 
4.4 
Subject Identification and Randomization ................................................... 29 
5 
STUDY DRUG ..................................................................................................... 30 
5.1 
Identity ............................................................................................................. 30 
5.2 
Administration ................................................................................................ 30 
5.3 
Packaging, Labelling and Storage ................................................................. 30 
5.4 
Blinding and Breaking the Blind ................................................................... 31 
5.5 
Drug Accountability ....................................................................................... 31 
5.6 
Concomitant Medications .............................................................................. 31 
5.6.1 
Allowed Medications ........................................................................... 32 
5.6.2 
Prohibited Medication ......................................................................... 32 
5.6.3 
Medications to be Used with Caution .................................................. 33 
6 
PARAMETERS AND METHODS OF ASSESSMENT .................................. 34 
6.1 
Safety Parameters ........................................................................................... 34 
6.1.1 
Demographics/Medical History ........................................................... 34 
6.1.2 
Adverse Events .................................................................................... 34 
6.1.2.1 
Definitions ..................................................................................... 34 
6.1.2.2 
Recording Adverse Events ............................................................. 38 
6.1.2.3 
Responsibilities of the Investigator ................................................ 38 
6.1.2.4 
Responsibilities of the Sponsor ...................................................... 40 
6.1.2.5 
Evaluation of Adverse Events ........................................................ 40 


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6.1.2.6 
Notifying of Adverse Events ........................................................... 41 
6.1.2.7 
Responsibilities of the Sponsor ...................................................... 42 
6.1.3 
Laboratory Parameters ......................................................................... 42 
6.1.4 
Vital Signs ........................................................................................... 43 
6.1.5 
Electrocardiograms .............................................................................. 44 
6.1.6 
Physical Examinations ......................................................................... 44 
6.1.7 
Prior and Concomitant Medication ...................................................... 44 
6.1.8 
Postvoid Residual Volume .................................................................. 44 
6.2 
Efficacy Parameters ........................................................................................ 45 
6.2.1 
Bladder Diary Questions ..................................................................... 45 
7 
STUDY CONDUCT ............................................................................................ 46 
7.1 
Observations by Visit ...................................................................................... 46 
7.1.1 
Screening/Placebo Run-In Visit – Visit 1 (Days 0) ............................. 46 
7.1.2 
Eligibility Assessment Visit – Visit 2 (Day 14) .................................. 46 
7.1.3 
One Week Post-randomisation Visit – Visit 3 (Day 21) ..................... 47 
7.1.4 
Two Weeks Post-randomisation Visit – Visit 4 (Day 28) ................... 48 
7.1.5 
Three  Weeks Post-randomisation Visit – Visit 5 (Day 35) ................ 48 
7.1.6 
Eight Weeks Post-randomisation/Early Termination Visit – Visit 6 
(Day70) ................................................................................................ 49 
7.1.7 
Post-treatment Visit/End of Study Visit – Visit 7 (Day 105) .............. 49 
8 
STATISTICAL METHODS ............................................................................... 51 
8.1 
General Considerations .................................................................................. 51 
8.2 
Analysis Populations ....................................................................................... 51 
8.3 
Disposition of Subjects .................................................................................... 51 
8.4 
Protocol Deviations ......................................................................................... 51 
8.5 
Demographics, Baseline Characteristics, and Concomitant Medications . 51 
8.6 
Treatment Compliance ................................................................................... 52 
8.7 
Safety Endpoints and Analyses ...................................................................... 52 
8.7.1 
Safety Endpoints .................................................................................. 52 
8.7.2 
Safety Analyses ................................................................................... 52 
8.8 
Efficacy Endpoints and Analyses .................................................................. 53 
8.8.1 
Efficacy Endpoints .............................................................................. 53 
8.8.2 
Efficacy Analyses ................................................................................ 53 
8.9 
Interim Analyses ............................................................................................. 54 
8.10 
Determination of Sample Size ........................................................................ 54 
8.11 
Missing Data .................................................................................................... 54 
9 
DATA MANAGEMENT ..................................................................................... 55 
9.1 
Data Collection ................................................................................................ 55 
9.2 
Data Correction ............................................................................................... 55 
9.3 
Data Handling ................................................................................................. 55 
9.3.1 
Deviations from the Protocol ............................................................... 56 
9.4 
Data Quality Assurance .................................................................................. 56 
10 
QUALITY CONTROL AND QUALITY ASSURANCE ................................ 57 


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10.1 
Study Initiation Activities .............................................................................. 57 
10.2 
Training of Site Staff ...................................................................................... 57 
10.3 
Documentation and Filing .............................................................................. 57 
10.3.1 
eCRF System ....................................................................................... 57 
10.3.2 
Bladder diary ....................................................................................... 57 
10.3.3 
List of Subjects (subject identification log) ......................................... 57 
10.3.4 
Source Data .......................................................................................... 57 
10.3.5 
Investigator Site File / Regulatory Binder ........................................... 58 
10.4 
Monitoring ....................................................................................................... 58 
10.5 
Audits and Inspections ................................................................................... 58 
11 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS ........................... 59 
11.1 
Good Clinical Practice .................................................................................... 59 
11.2 
Informed Consent ........................................................................................... 59 
11.3 
Protocol Approval and Amendment ............................................................. 59 
11.4 
Archiving Study Records ............................................................................... 59 
11.5 
Premature Termination of the Study ............................................................ 60 
11.6 
End of the Trial ............................................................................................... 60 
11.7 
Confidentiality ................................................................................................. 60 
11.8 
Liability and Insurance .................................................................................. 60 
11.9 
Publication Policy ........................................................................................... 61 
12 
REFERENCE LIST ............................................................................................ 62 
13 
APPENDICES ...................................................................................................... 63 
 
Tables in Text 
Table 5.1 Litoxetine and Placebo Ingredients ................................................................. 30 
Table 6.1: Laboratory Parameters ..................................................................................... 43 
Figures in Text 
Figure 1: Study Design ................................................................................................... 23 
List of Appendices 
Appendix 1: 
List of Institutions Involved in the Study ............................................ 64 
Appendix 2: 
Schedule of Assessments ..................................................................... 65 
Appendix 3: 
New York Heart Association Heart Failure Classification ................. 68 
Appendix 4: 
Psychiatric monitoring: Columbia-Suicide Severity Rating Scale (C-SSRS), 
Beck Depression Inventory-II (BDI-II), Beck Anxiety Inventory (BAI), Pittsburgh Sleep Quality 
Index (PSQI) 
69 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ACE inhibitors 
Angiotensin-converting-enzyme inhibitor 
AE 
AESI                   
Adverse event 
Adverse event of special interest 
BID 
Twice daily 
CRA 
Clinical Research Associate 
CYP 
Cytochrome P450 
DA 
Dopamine 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HDPE 
High-density polyethylene 
ICF 
Informed consent form 
ICH 
International Council on Harmonization 
ICS 
International Continence Society 
IRAE 
Immediately reportable adverse event 
IRB 
Institutional Review Board 
ISF 
Investigative site file 
ITT 
Intent-to-treat (population) 
IWR-IM 
Interactive Web-based Randomization and Inventory Management System 
MACR 
Missing completely at random 
MMRM 
Mixed-Effect Model for Repeated Measure 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat (population) 
MUI 
Mixed urinary incontinence 


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Abbreviation 
Definition 
NE 
Norepinephrine 
NHS 
National Health Service 
NSAID 
Non-steroidal anti-inflammatory drug 
PP 
Per Protocol (population) 
PVR 
Postvoid residual volume 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SNRI 
Selective norepinephrine reuptake inhibitor 
SSRI 
Selective serotonin reuptake inhibitor 
SUI 
Stress urinary incontinence 
TEAE 
Treatment-emergent adverse event 
UI 
Urinary incontinence 
UK 
United Kingdom 
US 
United States 
UUI 
Urge urinary incontinence 
WBC 
White blood cell (count) 
WHO 
World Health Organisation 
 


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1 
INTRODUCTION 
1.1 
Background 
1.1.1 Urinary Incontinence 
Urinary incontinence (UI) is a common and chronic condition affecting both males and females, 
although it is more commonly seen in women. For both genders, prevalence increases with age, 
occurring frequently in the geriatric population (65 years and older) (Adams P, 2010). 
While not life-threatening, urinary incontinence can have a significant negative impact on the 
psychological well-being, social functioning and overall quality of life of those affected. 
Prevalence varies greatly with age and the definition used, although not all affected patients are 
in need of medical treatment (Adams P, 2010). 
Women suffer most commonly from stress urinary incontinence (SUI) or a combination of SUI 
and urge urinary incontinence (UUI) ie, Mixed Urinary Incontinence (MUI). Men suffer 
primarily from urgency, due to obstruction from prostate hypertrophy, and have a higher 
incidence of ‘dry’ symptoms (urgency, frequency without urinary incontinence). Stress 
incontinence in men accounts for less than 10%, mainly occurring post prostate surgery 
(Adams P, 2010).  
Urinary incontinence is estimated to affect 400 million people worldwide (Fultz NH, Burgio K, 
Diokno AC et al. Burden of stress urinary incontinence for community dwelling women. Am J 
Obstet Gynaecol 2003; 189: 1275-1282.  
Global Forum on Incontinence). The prevalence is variable but has been reported to be as high as 
55%. 
The International Continence Society (ICS) defines incontinence as “involuntary loss of urine.” 
which leads to a significant impact on quality of life, social seclusion, psychological stress, and 
economic burden. This condition is often underreported since many people avoid discussing the 
problem with their doctor due to embarrassment, lack of knowledge about treatment options, or a 
belief that urinary incontinence is an inevitable part of ageing. The burden of urinary 
incontinence is high in financial terms, with the total annual cost of urinary incontinence in the 
United States (US) estimated to be as high as $32 billion (Wood LN, 2014), and similar costs 
have been described also in other countries;  Total cost of managing urinary incontinence in 
women over the age of 40 years in the United Kingdom (UK) in 2004 was £301 million, 0.3% of 
the total National Health Service (NHS) budget (Turner DA, 2004). Costs borne by women in 
out-of-pocket expenses was £230 million (Fultz NH, 2003) or £290 per woman per year 
(Papanicolaou S, 2005). 
Urinary incontinence can be managed initially by lifestyle modifications, with reduction of 
excessive fluid intake, timed voiding, weight loss if required, and bladder and pelvic floor 
muscle training. Drug treatments are available for over-active bladder, with anticholinergic drugs 
the mainstay of treatment for cases that do not respond to lifestyle modification. Several agents 


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are currently available including oxybutynin, tolterodine, fesoterodine, trospium, solifenacin, and 
darifenacin (Adams P, 2010). 
Many women are unable to tolerate anticholinergic drugs and 30-91% discontinue them after 
1 year. If patients do not respond to a treatment attempt of anticholinergic drugs, beta3 agonists 
or minimally invasive treatment options are available, with intravesical injection of 
onabotulinum toxin A, sacral neuromodulation, and posterior tibial nerve stimulation available as 
potential options (Adams P, 2010). 
1.1.2 Litoxetine for the Treatment of Urinary Incontinence 
Serotonin plays an important role in centrally modulating the reflexes of continence/micturition; 
5-HT potentiates the guarding reflex which allows continence by increasing urethral pressure and 
inhibits the micturition reflex responsible for voiding. Animal studies have shown that increased 
levels of 5-HT and norepinephrine (NE), in the sacral spinal cord, lead to increased urethral tone 
via enhanced pudendal nerve stimulation to the urethral striated sphincter muscle during the 
storage phase of the micturition cycle. Studies with duloxetine support a similar mechanism in 
women, believed to result in stronger urethral closure during urine storage with physical stress.  
Animal studies have confirmed that litoxetine increases the urethral sphincter pressure, and also 
demonstrated that litoxetine improves bladder capacity through a relaxation effect of the 
detrusor. Taken together these effects suggest that litoxetine could have therapeutic benefit in 
Urinary Incontinence, a condition for which there remain an unmet medical need. 
The 5-HT selectivity of litoxetine, and the weaker affinity for NE and epinephrine (E) as well as 
for dopamine (DA) transporters has the potential to provide a good cardiovascular safety profile, 
and reduce the risk of nausea which is the most frequent side effect following treatment with 
5-HT reuptake inhibitors.  
Further details can be found in the Investigator's Brochure (edition 2), which contains 
comprehensive information on the investigational product. 
1.2 
Risk/Benefit Assessment 
To date, 10 Phase 1 studies and 3 Phase 2 studies have been performed with litoxetine. 
Litoxetine has been evaluated in 154 healthy subjects and 445 patients with depression either as 
a capsule or a tablet containing litoxetine drug substance with excipients. Clinical pharmacology 
data has shown that doses up to 50 mg BID were acceptable, the open-label Phase 2 study in 
depression explored doses up to 100 mg daily, and subsequent double-blind, placebo-controlled 
studies explored doses up to 60 mg daily for a duration of 6 weeks. While study effects were 
observed in subjects with depression, the efficacy of litoxetine compared to placebo was 
negligible. In these studies, litoxetine safety information did not show any negative 
cardiovascular effects. The most common AEs were headache, nausea, and dyspepsia. The safety 
profile of litoxetine is acceptable and in line with the known and well established safety profile 
of 5-HT reuptake inhibitors. No AEs in the clinical studies have been reported which would 


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preclude development of litoxetine in the new indication of Urinary Incontinence and Adverse 
Events will continue to be monitored throughout the study, including AEs of special interest (i.e., 
urinary retention, psychiatric adverse events and withdrawal effects). 
Non-clinical studies have demonstrated effects of litoxetine on urethral sphincter and bladder 
capacity, which are key features for micturition and continence. The “dual action”-inhibitory 
effect on detrusor muscle activity and excitatory effect on urethral sphincter- provides a 
scientific rationale to evaluate whether litoxetine treatment may be a treatment option for 
subjects with UI. One phase 2 study is currently ongoing with litoxetine in women suffering 
from MUI, and, while early in its conduct, the adverse events reported to date confirm the data 
previously reported.  
The safety and tolerability of  litoxetine was mainly determined on data from 445 subjects 
included in depression studies, receiving daily doses up to 100 mg daily, up to 6 weeks duration, 
to support the current use of litoxetine at doses 20, 40, and 60 mg daily (10, 20 and 30 BID) for 
the currently proposed 8-week treatment period, while the non- clinical pharmacology supports 
the scientific rationale to evaluate litoxetine in the indication of UI. The safety data from the 
comprehensive nonclinical study program support the proposed Phase I/IIa study. Further details 
can be found in the Investigator's Brochure (edition 1). 
Taken together the Risk/Benefit for the use of litoxetine in the proposed study phase 1/2a is 
considered acceptable. 
1.3 
Rationale 
Urinary incontinence is a condition which can have a significant negative impact on the 
psychological well-being, social functioning and overall quality of life of those affected. There 
remains an unmet medical need to identify treatment options for patients suffering from UI. The 
“dual action”-inhibitory effect on detrusor muscle activity and excitatory effect on urethral 
sphincter- provides a scientific rationale to evaluate whether litoxetine treatment may be a 
treatment option for UI. 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to evaluate the safety and tolerability of litoxetine (dose 
titration 10 mg, 20 mg, 30 mg) compared to placebo administered orally twice daily (BID) for 8 
weeks in subjects with a diagnosis of UI. 
2.2 
Secondary Objectives 
The secondary objective of this study is to explore efficacy of litoxetine (dose titration 10 mg, 
20 mg, 30 mg) compared to placebo administered orally twice daily (BID) for 8 weeks in 
subjects with a diagnosis of UI. 


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3 
OVERALL DESIGN AND PLAN OF THE STUDY 
3.1 
Overview 
This is a Phase 1/2a, double-blind, randomised, placebo-controlled, parallel-group study in 
subjects 18 to 70 years old diagnosed with UI.  
The study will include a 2-week, single-blind (subject blind) Screening Placebo Run-In Period 
and an 8-week double-blind Treatment Period. The Treatment Period will be followed by a 
1-week Dose-tapering Period. Subjects will return to the clinic for a safety Follow-up Visit 
4 weeks after treatment is completed for a total study duration of 15 weeks. No interim analysis 
is planned. 
All subjects will enter the Screening Placebo Run-In Period during which eligibility will be 
assessed and placebo run in medication will be provided. During this period, 7 days daily diary 
symptoms will be collected. Subjects who continue to meet eligibility criteria after the Screening 
Placebo Run-In period, including collection of diary data will enter the Treatment Period and be 
randomly assigned (2:1) to receive study drug (litoxetine 10 mg, 20 mg, 30mg, or placebo) BID.  
Litoxetine treatment will be provided with dose titration, starting with 10 mg BID for 1 week, 
escalated to 20 mg BID for 1 week, and subsequently escalated to 30 mg BID for 6 weeks’ 
duration (for a total litoxetine treatment period of 8 weeks). Placebo treatment will be matched.  
If the subject does not tolerate the last dose level escalation (ie cannot tolerate 30 mg BID), the 
dose can be reduced to the previous dose level (20 mg BID). If the patient does not tolerate the 
lower dose level (20 mg BID) s/he will be discontinued from the study. After 8 weeks of 
treatment, doses will be reduced by 50% over 1 week to taper off treatment. A safety follow up 
visit will occur 4 weeks after treatment is permanently stopped (total study duration 15 weeks) 
Safety assessments will be conducted throughout the trial and will include physical 
examinations, vital signs, evaluation of psychiatric status (suicidality, depression symptoms, 
anxiety and sleep related symptoms), clinical laboratory evaluations, 12-lead electrocardiograms 
(ECGs), and adverse events (AEs).  
Efficacy will be assessed by number of urinary incontinence episodes and the number of 
incontinence pads used. 
A schedule of assessments is provided in Appendix 2. A schematic of the study design is 
presented in Figure 1. 
 


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Figure 1: Study Design 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BID = twice daily 
3.2 
Discussion of Study Design 
Litoxetine’ s initial development as an antidepressant (discontinued in the 1990’s due to absence 
of effect) has included 12 phase 1 studies in HVs.  The current development in Urinary 
Single-blind Screening Placebo Run-In Period 
(subject blind)  
Day 0-14 
Double-blind Period 
Randomization (2:1) 
(Day 14)
Treatment Period 
8 weeks duration 
Taper Period (study drug will be administered ONCE daily in the morning) 
(Week 11) 
Follow-up Visit 
(Week 15) 
Litoxetine; 
10 mg BID, 1 week 
20 mg BID, 1 week 
30 mg BID, 6 weeks 
 
dose escalation 
Placebo 
Matching to litoxetine 
dose escalation 


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Incontinence (UI) is based on the scientific rationale and preclinical data showing effect on both 
detrusor and sphincter, and the definition of the condition used in this protocol adheres to clinical 
practice and ICS guidelines. The present study, for which safety is the primary endpoint, will 
include patients diagnosed with UI and is designed as a phase 1/2a study. The inclusion of a 
placebo arm is based on recent European Medicines Agency (EMA) guidelines for the 
development of medications for UI (European Medicines Agency, UI Guideline 2013).  The dose 
titration posology serves to explore safety and tolerability following a sequential increase in 
dose, rather than as a fixed dose regimen. The selection of safety parameters for determination of 
subject eligibility and for safety analysis reflect the FDA’s recommendation for evaluation of 
SSRIs, including attention to psychiatric adverse events and events indicative of abuse potential. 
Inclusion of subjects in the age range 18-70 is reflective of the expectation that UI may affect all 
age groups, with increasing prevalence with age (FDA Guidance General Consideration for the 
Clinical Evaluation of Drugs). The choice of efficacy endpoint (percentage change from end of 
the Placebo Run-in Period to Week 8 in the number of incontinence episodes/24 hours) is a 
clinical measure to explore whether litoxetine has a clinically relevant treatment effect on 
patients’ reported symptomatology and patient reported outcome measures in a clinical practice 
setting. The 2-week Screening Placebo Run-In Period serves to control for the placebo effect 
which is anticipated to be relatively large. 
 
 


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4 
STUDY POPULATION 
The study population will consist of subjects with UI. Subjects must be able to provide written 
consent and meet all the inclusion criteria and none of the exclusion criteria. 
In addition, to assess any potential impact on subject eligibility with regard to safety, the 
Investigator must refer to the litoxetine Investigator Brochure for detailed information regarding 
warnings, precautions, contraindications, AEs, and other significant data pertaining to the 
investigational products being used in the study. 
4.1 
Inclusion Criteria 
Subjects aged 18 to 70 will be eligible for inclusion in this study if all the following criteria 
apply: 
 
1. Willing to provide written informed consent 
2. Have symptoms of urinary incontinence for at least 3 consecutive months 
3. For male subjects: If subject has undergone any prostate procedure, this must 
have occurred at least 6 months prior to screening                                                       
4. Have at least 7 incontinence episodes per week in the diary entries for the 
Screening Placebo Run-In Period  
5. Subject is ambulatory and able to use the toilet independently 
6. If subjects use pelvic floor exercises, subjects must have been on a stable exercise 
and activity regime for at least 3 months prior to screening and that regime must 
remain stable during the treatment period 
7. Subject has a body mass index (BMI) ≥ 19 kg/m2 but ≤ 35 kg/m2  (BMI=weight 
[kg] / height [m2}) 
8. Subjects must have a pre-dose mean systolic/diastolic blood pressure of 
≤ 140/90 mmHg before randomization can occur 
9. For female subjects: Must not be pregnant, lactating, or actively trying to become 
pregnant. Subjects who are premenopausal and of childbearing potential must 
have a negative pregnancy test at Screening (serum) and at Day 0 (urine) and must 
use a medically acceptable and effective method of birth control for the duration 
of the study, which can include: 
a. Having a male partner who is sterile prior to the female subject’s entry into 
the study and is the sole sexual partner for that female subject 
b. Use of double-barrier methods of contraception; condoms with the use of 
caps (with spermicide) and intra-uterine devices are acceptable 
c. Use of hormonal contraceptives (oral, depots, patches, etc.) with double-
barrier methods of contraception as outlined above 


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d. True abstinence: When this is in line with the preferred and usual lifestyle 
of the subject (period abstinence [eg, calendar, ovulation, symptothermal, 
post-ovulation methods] and withdrawal are not acceptable methods of 
contraception) 
10. Subjects taking oral contraceptives or hormone replacement therapy (women) or 
hormone adjuvant therapy (men) must have a stable dose and regimen for 
≥ 3 months prior to entry into the study 
 
 
4.2 
Exclusion Criteria 
Individuals who meet any of the following criteria are not eligible to participate in the study. 
 
1. History of anti-incontinence surgery in past 12 months 
2. Use of Botox for the treatment of urinary incontinence in the past 12 months 
3. Current or recent (3 months) use of any pharmacologic agent used to treat 
symptoms of urinary incontinence   
                                                                   
4. For women: Grade III/IV pelvic organ prolapse; defined per clinical practice 
5. For women: History of pelvic prolapse repair or urethral diverticulectomy within 
12 months of Screening.                                                                                            
For men: urethral surgery within 6 months of Screening. 
6. History of interstitial cystitis or bladder-related pain 
7. Subjects with concurrent (at Screening), recent (within 30 days), chronic, or 
recurrent (> 4 per year) urinary tract infections (positive dipstick for urinary tract 
infection and abnormal microscopic evaluation, signs and symptoms) or 
unevaluated microhematuria 
8. History of diagnosed gastrointestinal obstructive disorders 
9. Chronic severe constipation 
10. History of radiation cystitis or history of pelvic irradiation 
11. Electrostimulation, biofeedback, or bladder training therapy (behavioural therapy), 
during the previous month prior to Screening, or the intention to initiate such 
therapies during the study period. Pessaries and implants are also excluded. 
12. Postvoid residual (PVR) urine volume > 150 mL 
13. Diagnosis of dementia 
14. Diagnosis of epilepsy 


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15. Diagnosis of acute narrow-angle glaucoma 
16. History of mania or diagnosis of bipolar disorder  and/or seizures 
17. Subjects with uncontrolled hypertension 
18. Documented history of myocardial infarction, unstable angina, and/or has 
undergone coronary artery bypass surgery and/or percutaneous transluminal 
coronary angioplasty in the past year 
19. Congestive heart failure (New York Heart Association Class III or IV heart failure; 
Appendix 3) 
20. Any concurrent condition or any clinically significant abnormality on the Screening 
physical examination, laboratory tests, electrocardiogram (ECG; including ischemic 
heart disease), Hepatitis B or C, which, in the opinion of the Investigator, may affect 
the interpretation of safety or efficacy data, or which otherwise contraindicates 
participation in a clinical study with litoxetine: 
a. Hypersensitivity to litoxetine or any of its ingredients 
b. History of clinically significant drug hypersensitivity  
c. Subjects with current (within 2 years) urogenital neoplasms or 
malignancies including bladder, uterine or cervical cancer (not applicable 
to male subjects with prostate cancer in whom a prostatectomy has been 
performed) 
d. Subjects with neuropathology that could affect the lower urinary tract or 
nerve supply, including but not limited to multiple sclerosis, stroke, 
Parkinsonism, or spinal cord injury  
e. Subjects with diabetes insipidus  
f. Clinically significant or unstable, endocrine, hepatic, renal, immunologic, 
or lung disease (ie, active chronic obstructive pulmonary disease), or 
malignancy other than non-melanomatous skin cancer  
21. Severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73m2) 
22. Severe hepatic impairment (Child-Pugh B or greater) 
23. Current or recent (6 months) treatment for depression, or a current diagnosis of 
depression or have a state of depression or suicidality at Screening  
24. History of current or recent (6 months) suicidal ideation and behaviour (SIB), or 
history of any suicide attempt in the past 12 months. 
25. History of an addiction to drugs or alcohol within 5 years prior to screening, or of 
alcohol or substance abuse within the past year, as determined by the Investigator 
 


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26. Current use of the following medications:, any serotonergic medication, nonselective 
irreversible monoamineoxidase inhibitors (MAOIs) , cytochrome P450 (CYP)1A2 
inhibitors (such as fluvoxamine, ciprofloxacin, or enoxacin), cytochrome P450 
(CYP) 2D6 inhibitors (buproprion, fluoxetine, metoclopramide, paroxetine, 
quinidine), pimozide and thioridazine, and any other medication that would be 
considered a safety risk for co-administration with litoxetine (See Section 5.6.2 
Prohibited Medications) 
27. Participation in a clinical study within the month prior to Screening, or exposure to 
an investigational drug which has not washed out for at least 5 half-lives since its  
last administration, prior to Screening 
28. In the opinion of the Investigator, is at risk of non-compliance with study 
procedures, or cannot read, understand, or complete study-related materials 
(including electronic diaries), particularly informed consent 
29. Participation in any clinical study of an investigational drug that may affect urinary 
function within 3 months prior to Screening 
 
4.3 
Subject Withdrawal and Replacement 
The participation of an individual subject may be discontinued prematurely for reasons such as: 
• Withdrawal of written informed consent 
• Required treatment with any medication known or suspected to interfere with the study drug 
• Pregnancy 
• Lack of study compliance 
• Treatment unblinding (treatment unblinding for the purpose of expedite reporting of 
SUSARs will not by default lead to withdrawal of subjects from the study) 
• Any other condition which in the opinion of the Investigator no longer permits safe 
participation in the study 
A subject may discontinue participation in the clinical study at their own request at any time 
without stating a reason.  
The Investigator can stop a subject's participation in the study at any time if continuation could 
lead to disadvantages for the subject which cannot be justified by the Investigator. 
The reason for withdrawal of the subject must be documented by the Investigator. All data 
collected until the day of premature study discontinuation including laboratory results and 
assessment of AEs will be evaluated. AEs will be followed up until resolution of the symptoms 
or until they reach a stable chronic condition.  


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Abrupt discontinuation of litoxetine should be avoided; the dose should be reduced over a period 
of 1 week to reduce the risk of withdrawal reactions. If intolerable symptoms occur following 
this decrease in dose or upon discontinuation of treatment, then resuming the previously 
prescribed dose may be considered. Subsequently, the Investigator may continue decreasing the 
dose. Withdrawal symptoms when treatment is discontinued are common, particularly if 
discontinuation is abrupt. The risk of withdrawal symptoms seen with selective serotonin 
reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs) may be 
dependent on several factors including the duration and dose of therapy and the rate of dose 
reduction. Generally, these symptoms are mild to moderate; however, in some subjects they may 
be severe in intensity. They usually occur within the first few days of discontinuing treatment, 
but there have been very rare reports of such symptoms in patients who have inadvertently 
missed a dose. Generally, these symptoms are self-limiting and usually resolve within 2 weeks, 
though in some individuals they may be prolonged (2-3 months or more).  
Subjects who withdraw from the study will be asked to taper the dose of study drug. If they 
refuse, that refusal will be recorded. The subject will be asked to return for the Post-treatment 
Follow-up Visit and if symptomatic of withdrawal, will be followed up until the resolution of 
such symptoms or until they reach a stable chronic condition. 
4.4 
Subject Identification and Randomization 
Each country will be assigned a 3-digit country code. Each participating investigative study 
centre will be assigned a 2-digit investigative study centre number (eg, 01, 02, 03, and up) on 
enrolment. Each subject will receive a 3-digit Screening number in sequential order at the 
Screening Visit after the consent form is signed (eg, 001, 002, 003), regardless of the 
investigative study centre at which the subject is enrolled.  
Enrolled subjects who fail Screening or discontinue study participation early, regardless of 
whether treatment was received or not, will retain their Screening number and a new number will 
be assigned to the next enrolled subject. 
Randomization numbers will be assigned by the Interactive Response Randomization System, 
which is integrated into the Electronic Data Capture (EDC) system. Details of assignment of 
subject numbers will be provided as a separate document. 
Subjects will be randomly assigned to receive litoxetine or matched placebo BID in a 2:1 ratio. 
See Section 5.4 for information on blinding and breaking the blind.  


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5 
STUDY DRUG 
5.1 
Identity 
Litoxetine is a selective inhibitor of serotonin (5-HT) reuptake. Litoxetine is formulated as an 
immediate release capsule. The formulated product is a dry-blend containing either 10 mg or 20 
mg litoxetine (free base equivalents) in orange hard gelatine capsules. The composition of 
litoxetine is presented in Table 5.1. The batch number for active pharmaceutical ingredient is 
100193-01. 
Table 5.1 
Composition of Litoxetine and Placebo Capsules 
Ingredient 
mg/capsule 
10 mg Free Base 
Equivalents 
20 mg Free Base 
Equivalents 
Placebo 
Litoxetine benzoate a 
15.1 
30.2 
– 
Microcrystalline cellulose 
272.9 
257.8 
288.00 
Sodium starch glycolate 
9.00 
9.00 
9.00 
Magnesium stearate 
3.00 
3.00 
3.00 
Total fill weight 
300.0 
300.0 
300.0 
a Conversion factor from base to benzoate salt is 1.51. 
 
Matching placebo capsules will be manufactured without the active ingredient. 
5.2 
Administration 
Study drug will be administered orally BID with 240 mL water.  
During the tapering period, the study drug will be administered ONCE daily in the morning with 
240 mL water. 
5.3 
Packaging, Labelling and Storage 
Litoxetine benzoate capsules (10 and 20 mg of free base equivalents) are packaged in high-
density polyethylene (HDPE) jars with tamper evident and child-resistant closures.  
Study drug will be packaged according to local legal requirements. Study drug will be labelled in 
accordance with applicable regulatory requirements.  
All study drug supplies must be stored in accordance with the manufacturer’s instructions 
(between 15 and 25ºC). Temperature excursions between 8ºC to 15ºC and 30ºC to 25ºC are 
allowed for up to 3 days.  This is a conservative estimate based on accelerated stability 
data.  Until dispensed to the subjects, the study drug will be stored in a securely locked area, 
accessible to authorized personnel only. 


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Packaging and labelling of study drug will comply with Good Manufacturing Practice (GMP), 
Good Clinical Practice (GCP) rules, Annex 13, and country specific regulatory requirements. 
5.4 
Blinding and Breaking the Blind 
The study will be performed in a single-blind ([subject blind] Screening Placebo Run-In Period) 
and a double-blind (Treatment Period) manner. All study drugs will be supplied in identical 
HDPE bottles and will be similar in colour, smell, taste, and appearance, thereby enabling single- 
and double-blind conditions. 
During the Treatment Period, the study blind should not be broken except in a medical 
emergency (where knowledge of the study drug received is essential for the treatment of the 
emergency) or due to a regulatory requirement (eg, expedited reporting). If required for medical 
emergency, the EDC system will be used to break the blind. 
If the blind is broken, the date, time and reason will automatically be recorded in the subject’s 
electronic case report form (eCRF). An automated email notification from EDC will be sent to 
the Sponsor/Medical Monitor in the event that the blind is broken. 
If an Investigator, site personnel performing assessments, or subject, is unblinded, the subject 
must be withdrawn from the study and procedures accompanying withdrawal are to be 
performed. In cases where there are ethical reasons for the subject to remain in the study, the 
Investigator must obtain specific approval from the appointed CRO for the subject to continue in 
the study.  
The overall randomization code will be broken only for reporting purposes. This will occur once 
all interim/final (as appropriate) clinical data have been entered onto the database and all data 
queries have been resolved and database lock has been approved. 
5.5 
Drug Accountability 
The Investigator is responsible for maintaining accurate study drug accountability records 
throughout the study. 
Each dispensing of study drug will be documented in the eCRF. 
At the end of the study, the Investigator is responsible for return or destruction of all unused or 
partially used study drugs, as agreed with the Sponsor and must verify that all unused or partially 
used drug supplies have been returned by the subject and that no remaining supplies are in the 
Investigator’s possession. Destruction will only be performed in accordance with the 
Investigators institutional procedures, by authorised personnel who are aware of any possible 
hazardous effects and following receipt and written approval from the Sponsor. The procedure 
should be documented in full, in writing.  
5.6 
Concomitant Medications 
Any medication the subject takes other than the study drug is considered a concomitant 
medication. All concomitant medications must be recorded in the eCRF. The following 
information must be recorded in the eCRF for each concomitant medication: generic name, route 


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of administration, start date, stop date, dosage, and indication. Any changes in the dosage or 
regimen of a concomitant medication must be recorded in the eCRF. 
Detailed medication history will be collected during Screening. Details regarding concomitant 
medications taken since previous visit will be collected at every study visit. 
5.6.1 Allowed Medications 
Chronic medications, other than those listed as Prohibited Medications (Section 5.6.2), are 
permitted. However, dosages changes in these medications should, if medically appropriate, not 
occur while the subject is enrolled in the study. If a dosage change in medication is necessary, 
information pertaining to the change must be documented in the eCRF. Conventional once-daily 
multivitamins, acetylsalicylic acid (aspirin) and acetaminophen (Tylenol®), or occasional over-
the-counter non-steroidal anti-inflammatory drug (NSAID) compounds (ibuprofen) are permitted 
during the study.  
If a subject is receiving anti-hypertensive medication, then their blood pressure must have been 
stable over the last 4 weeks on the same dose of anti-hypertensives including, but not limited to, 
angiotensin-converting enzyme (ACE) inhibitors, diuretics, or ß-blockers. If a subject does not 
meet blood pressure eligibility at Screening, but is otherwise eligible to participate in the study, 
medication may be added or the dose of medication may be modified if medically appropriate, 
and the subject rescreened 1 month after the dose adjustment. The change in dosage must be 
documented according to the instructions in the previous paragraph.  
While in the study, doses of anti-hypertensives therapy must not be changed. The only exception 
to this is a change in dosage that occurs between initial Screening and rescreening as discussed 
above (ie, the subject’s dose of medication changed a month before officially entering the study). 
The subject should be withdrawn if doses of antihypertensive and/or lipid lowering medications 
are changed during the study.  
Women are permitted to take oestrogen if the dose has been stable over the last 3 months. Men 
are permitted to take hormone adjuvant therapy if the dose has been stable dose over the last 3 
months. 
5.6.2 Prohibited Medication 
The following medications are prohibited during the study and within 30 days prior to study 
entry: 
• Nonselective, irreversible monoamine oxidase inhibitors: eg, moclobemide or linezolid 
• CYP1A2 inhibitors like fluvoxamine, ciprofloxacin, or enoxacin since the combination 
may result in elevated plasma concentrations of litoxetine 
•  CYP2D6 inhibitors like bupropion, fluoxetine, metoclopromide, paroxetine or quinidine 
since the combination may result in elevated plasma concentrations of litoxetine 
 


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• Pimozide and thioridazine since the combination with litoxetine may result in elevated 
plasma concentration of these compounds 
• Medicinal products containing duloxetine 
• St John’s wort or herbal preparations containing St John’s wort (Hypericum perforatum) 
• Other serotonergic agents: SSRIs, SNRIs, tricyclic antidepressants like clomipramine or 
amitriptyline, triptans, tramadol, pethidine, and tryptophan 
• Administration of any other medication that would be considered a safety risk for 
co-administration with litoxetine 
• Any pharmacologic agent used to treat symptoms of urinary incontinence 
 
5.6.3 Medications to be Used with Caution 
The following medications should be used with caution during the study: 
• Warfarin or digoxin 
• Benzodiazepines, morphinomimetics, antipsychotics, phenobarbital, sedative 
antihistamines 
• 1c antiarrhythmics (propafenone, flecainide) and metoprolol 
• Herbal preparations (other than St John’s wort mentioned above). However, subjects who 
have been on a stable dose of these preparations prior to entering the study may continue 
to take these drugs. No new herbal preparations may be introduced or dosage changes 
initiated while participating in the study. 
 


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6 
PARAMETERS AND METHODS OF ASSESSMENT 
 
6.1 
Safety Parameters 
6.1.1 Demographics/Medical History 
The medical history should include demographic information, urinary and incontinence history 
(with date of onset), past treatment(s) for incontinence, current co-morbidities, relevant past 
illnesses, surgical procedures performed within the prior 6 months, all current medications 
(including those taken within 30 days prior to Screening), and smoking history (including current 
usage, if applicable).  
At the screening visit and at each study visit, the Investigator must conduct the following 
psychiatric monitoring: 
• suicide monitoring through the use of  Columbia-Suicide Severity Rating Scale (C-
SSRS) 
• monitor for depression symptoms through the use of the Beck Depression Inventory-II 
(BDI-II) 
• monitor for anxiety and sleep-related symptoms through the use of Beck Anxiety 
Inventory (BAI) and Pittsburgh Sleep Quality Index (PSQI) 
In addition to the visit assessments detailed above, suicide monitoring using the C-SSRS will 
also be performed by a telephone contact with the subject 4 weeks post randomization (study day 
42). 
6.1.2 Adverse Events 
6.1.2.1 Definitions 
Per the International Council on Harmonization (ICH), an AE is defined as any untoward 
medical occurrence in a patient or clinical investigation subject administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this treatment. An AE can 
therefore be any unfavourable or 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. The AE may be any of the 
following: 
• A new illness 
• An exacerbation of a sign or symptom or of the underlying condition or of a concomitant 
illness under treatment  
• Unrelated to participation in the clinical study or an effect of the study medication or 
comparator drug 


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• A combination of 1 or more of the above factors 
No causal relationship with the study medication is implied by the use of the term AE. 
Planned or elective surgical or invasive procedures for pre-existing conditions that have not 
worsened are not AEs. However, any complication that occurs during a planned or elective 
surgery is an AE. Conditions leading to unplanned surgical procedures may be AEs.  
When an AE occurs after written consent has been obtained but before the first dose of study 
drug, the AE will be considered a non-treatment emergent AE. An AE that occurs from the time 
the subject receives their first dose of study drug until their last study visit will be considered a 
treatment-emergent AE (TEAE) regardless of the assessed relationship to the administration of 
the study drug.  
For the recording of pregnancy and relevant laboratory data see Section 6.1.2.2. 
6.1.2.1.1 Immediately Reportable Adverse Event 
Immediately reportable AEs (IRAEs) are AEs that must be reported to the Sponsor within 
24 hours of the study site being informed of the IRAE (reporting requirements are detailed in 
Section 6.1.2.3).  
Immediately reportable AEs include:  
• All SAEs 
• Overdose  
• Pregnancy  
• AEs that result in a subject's withdrawal from the study 
 
6.1.2.1.2 Serious Adverse Event  
A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose: 
• Results in death 
• Is life-threatening 
• Requires hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect  
• Is another medically important condition  
 


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An important medical event that is not immediately life-threatening or will result in death or 
hospitalization, but which may jeopardize the subject or may require medical intervention to 
prevent 1 of the outcomes listed above, should be reported as “serious” as well. 
Medical and scientific judgment should be exercised in deciding whether a case is serious. 
“Occurring at any dose” does not imply that the subject is receiving study drug at the time of the 
event.  
6.1.2.1.3 Severity of Adverse Event 
The severity of an AE refers to the extent to which an AE affects the subject's daily activities. 
Severity will be categorized according to the following criteria:  
Mild: 
The AE does not interfere with the subject’s routine activities. 
Moderate: 
The AE interferes with the subject’s daily routine, but usual routine 
activities can still be carried out. 
Severe: 
The AE results in the inability to perform routine activities. 
The term “severity” is used to describe the intensity of an event. This is not the same as 
“serious.” Seriousness, not severity, refers to results or consequences of an adverse event and 
serves as the guide for defining regulatory reporting obligations. The highest severity grade 
attained should be reported, for AEs with divergent severities. 
6.1.2.1.4 Causality of Adverse Event 
The causality of an AE refers to the relationship of the AE to study drug. Causality will be 
categorized according to the following criteria: 
Certain: 
A clinical event, including laboratory test abnormality, occurring in a 
plausible time relationship to drug administration, and which cannot be 
explained by concurrent disease or other drugs or chemicals. The response 
to withdrawal of the drug (dechallenge) should be clinically plausible. The 
event must be definitive pharmacologically or phenomenologically, using a 
satisfactory rechallenge procedure if necessary. 
Probably/ 
Likely: 
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and which follows a 
clinically reasonable response on withdrawal (dechallenge). Rechallenge 
information is not required to fulfil this definition. 
Possible: 
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, but which could also be 


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explained by concurrent disease or other drugs or chemicals. Information 
on drug withdrawal may be lacking or unclear. 
Unlikely: 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration which makes a causal relationship 
improbable, and in which other drugs, chemicals, or underlying disease 
provide plausible explanations.  
6.1.2.1.5 Action Taken Regarding Adverse Events 
The Investigator must assess the action taken with regards to each AE as: 
• None 
• Dosing interrupted 
• Dose reduction 
• Use of concomitant medication 
• Discontinuation from the study drug 
 
6.1.2.1.6 Outcome of Adverse Events 
The Investigator must assess the outcome of each AE as:  
• Unresolved 
• Resolving 
• Resolved 
• Resolved with sequelae 
• Death 
• Unknown 
 
Every effort should be made to determine the outcome of any AE that occurs at any point in the 
study. 
6.1.2.1.7 Overdose 
An overdose is defined as administration of a quantity of a medicinal product given per 
administration or per day, which is above the maximal recommended dose according to the 
authorised product information. This shall also take into account cumulative effects due to 
overdose. Therefore, for litoxetine in the current study and with the current posology, an 
overdose should be considered as any dose above 60 mg taken per day, since the maximum dose 
in this study will be 30 mg BID. 


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6.1.2.2 Recording Adverse Events 
Period – Subject Enrolment to the First Administration of Study Drug: Non-treatment 
emergent AEs will be recorded from the time when the subject is enrolled into the study (date of 
signature of the informed consent) until first administration of study drug.  
Period – First Administration of Study Drug to Subject's Last Study Visit: In this period, all 
AEs are TEAEs (see Definitions, Section 6.1.2.1) and will be recorded until the final Follow-up 
Visit has been performed. 
Period – After Last Study Visit: Any SAE occurring after the subject's last study visit but 
considered by the Investigator to be related to the study drug will be recorded. 
If an AE (serious or not) started during the study but did not end before the final Follow-up Visit, 
the Investigator should make a reasonable effort to establish the outcome (resolution of 
symptoms, stable condition) and the end date. If this is not possible, the outcome recorded at the 
final Follow-up Visit will be assumed to be the final outcome. 
If an event stops and later restarts, all the occurrences must be reported. Adverse events assessed 
as related to study medication by the Investigator and all SAEs must be followed up until 
resolution, or until they reach a stable chronic condition. 
Signs/symptoms should be documented if a definite diagnosis cannot be established. The 
Investigator should attempt to establish a diagnosis of the event based on signs, symptoms and/or 
other clinical information. In such cases, the diagnosis should be documented as the AE and/or 
SAE and not the individual signs/symptoms. If a diagnosis is accompanied by unusual 
symptoms, the diagnosis itself and the symptoms have to be reported separately. 
In addition to the definition as given, the following special types of events should be recorded: 
a) Pregnancy - Occurrence of pregnancy in a subject during a clinical study must be recorded.  
b) Laboratory values that are outside the normal range and if, in the opinion of the 
Investigator, these values represent a clinically relevant change versus pre-treatment values 
are also defined as AEs. 
If abnormal laboratory values are signs of an AE (eg, an infection) that has already been 
recorded, the respective abnormal laboratory value does not constitute a separate AE. 
Wherever reasonable the reporting Investigator will use the clinical term rather than the 
laboratory term (eg, anaemia versus low haemoglobin value). 
6.1.2.3 Responsibilities of the Investigator 
Adverse event data should be obtained through observation of the subject, from any information 
volunteered by the subject, or through subject questioning. The general type of question asked 
could be similar to: “Do you have any health problems?” or “Have you had any health problems 
since your last clinic visit?”  


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Specific emphasis should be given to explore the occurrence of psychiatric events (nervousness, 
anxiety, panic attacks, insomnia, aggression, mania, suicidal ideation, development/worsening of 
depression). The patient should be routinely monitored by the C-SSRS, BDI-II, BAI and PSQI, 
as laid out in section 6.1.1. 
If any patient experience suggestive suicidal ideation/behaviour as per the C-SSRS s/he will be 
submitted for psychiatric evaluation. The outcome of the psychiatric evaluation will determine 
the patient’s suicidal state and whether the patient will continue in the study or prematurely 
withdrawn from participation. 
 
Adverse Event terms such as euphoria, dissociative effects, hallucinosis, psychosis, impaired 
cognition, attention, mood and psychomotor effects, inappropriate affect, patient dropouts, 
overdoses, misuse and lost or unaccounted for medication and unjustified dose increases will 
result in detailed narratives, as they may be indicative of abuse potential. 
Adverse events are to be documented/recorded accurately and completely on the AE pages of the 
respective eCRF and in the subject's source data.  
All non-treatment and treatment-emergent AEs will be recorded. This is true even if the study 
drug was not administered according to study protocol. 
For conditions leading to unplanned surgical procedures, the underlying condition, but not the 
procedure, should be documented as an AE.  
Reporting Immediately Reportable Adverse Events (IRAEs):  
For AEs that are “serious” (SAEs) additional separate documentation is required using the 
electronic SAE Forms.  
The following variables will be recorded on the electronic SAE Form and on the eCRFs provided 
in accordance to the eCRF completion guidelines:  
• Description of the event, including its duration (date of onset and resolution),  
• Whether the event constitutes a SAE or not (if yes, see event seriousness criteria in 
Section 6.1.2.1.2) 
• Any action taken (eg, changes to study treatment, other treatment given, and follow up tests) 
• Outcome of the event 
• Investigator’s assessment of causality (the relationship to the study treatment and study 
procedures)  
• Severity 
For all SAEs where important or relevant information is missing, active follow-up should be 
undertaken. 


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The assumption of a causal relationship between the study medication/study conduct and the AE 
is irrelevant to the obligation to record AEs and notifying IRAEs to the Sponsor. 
For subject withdrawal due to AEs the eCRF page "Study completion / Study termination 
Form" and a copy of the eCRF AE page needs to be completed and forwarded to INC Research’s 
Pharmacovigilance Department. 
Pregnancy Reporting: Patients who become pregnant during the study must be withdrawn from 
study medication and Early Termination visit assessments should be performed. Each pregnancy 
that starts during the study must be reported by the Investigator to INC Research’s 
Pharmacovigilance Department within 24 hours of the Investigator’s knowledge of the 
pregnancy by using the Pregnancy Reporting Form. Any adverse outcome of the pregnancy must 
be recorded and notified on the “Drug Exposure via Parent Report Form.” The Investigator 
should make any reasonable effort to follow any pregnancy until birth of the child.  
Overdose needs to be reported to INC Research’s Pharmacovigilance Department following the 
criteria for SAE reporting.  
If additional information is required by INC Research’s Pharmacovigilance Department, then as 
a representative of the Sponsor. INC Research must be granted access to the medical records.  
After subject's last study visit:  
The Investigator records and forwards to the Sponsor all SAEs that she or he becomes aware of 
and she or he considers related to the study drug. 
6.1.2.4 Responsibilities of the Sponsor 
For purposes of safety analyses, all AEs will be recorded in the clinical database. To ensure 
expedited and periodic notification of authorities, SAEs will also be recorded in the drug safety 
database. 
6.1.2.5 Evaluation of Adverse Events 
6.1.2.5.1 Responsibilities of the Investigator 
The Investigator will assess the seriousness, severity, and causality of each AE in accordance 
with the definitions in Section 6.1.2.1. Notification of IRAEs must follow the procedure 
described in Section 6.1.2.3. 
Causality of AE:  
For all AEs a causality assessment must be provided and documented on the respective form 
(eCRF AE page for all AEs, SAE form for SAEs and eCRF page “Study completion / 
termination Form” for withdrawals due to AEs) even if it is preliminary information.  


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6.1.2.5.2 Responsibilities of the Sponsor 
The Sponsor will not downgrade the causality assessment provided by the Investigator. If the 
Sponsor disagrees with the Investigator’s causality assessment, both the opinion of the 
Investigator and the Sponsor will be recorded. 
6.1.2.6 Notifying of Adverse Events 
6.1.2.6.1 Responsibilities of the Investigator 
For IRAEs (SAEs, overdose, pregnancy, and AEs leading to withdrawal), the Investigator must 
inform the INC Research’s Pharmacovigilance Department via e-mail or fax using the SAE 
report/eCRF page within 24 hours of the study site being informed of the IRAE. At a later date, 
the INC Research Safety Contact will report to IXALTIS, the INC Research Clinical Study 
Manager, and the INC Research Medical Monitor.  
For any new SAE, the following minimum information is required as initial notification: 
• Clear identification of the Investigator/Reporter with full contact information, 
• Subject identification details (study number, site number, date of birth), 
• Investigational Medicinal Product administration details (dates), 
• Diagnosis of the event with the description (or a brief description of signs/symptoms/clinical 
course if the diagnosis is not available) and the date of onset, 
• Reason(s) for considering the event serious, and 
• Relationship of the event with the Investigational Medicinal Product or with the trial 
procedure (eg, the causality according to the Investigator). 
In addition, the Investigator/Reporter must respond to any request for follow-up information or 
questions the Sponsor may have regarding the AE within the same timelines as for initial reports. 
Adverse Event Reporting Contact: 
INC Research Pharmacovigilance 
Fax: 1-877-464-7787 
E-mail: INCDrugSafety@incresearch.com 
For questions regarding IRAEs, or to provide information that cannot be provided electronically, 
or to notify the Sponsor of an IRAE in the event of technical failure, the Investigator should 
contact INC Research’s Pharmacovigilance Department. Details for contacting the 
Pharmacovigilance Department if this occurs will be provided in the Safety Plan.  
Investigators or other site personnel should inform INC Research’s Pharmacovigilance 
Department of any follow-up information that becomes available for a previously reported SAE 
immediately but no later than 24 hours of becoming aware of the information. Follow-up reports 
(as many as required) should be completed and faxed or e-mailed following the same procedure 


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above. Any requested supporting documentation (eg, ECG, laboratory results, autopsy report) 
should be sent to the INC Research’s Pharmacovigilance Department. 
Prior to forwarding any personal data for safety reporting, the documents need to be coded in a 
way that keeps the subject's identity confidential (eg, by using the subject's identification code, 
randomization number, etc.). 
For fatal and life-threatening SAEs, INC Research’s Pharmacovigilance Department will work 
with the Investigator to ensure that any additional information is provided by the Investigator 
within 1 business day. The Investigator will ensure that all the necessary information for all other 
SAEs will be provided within the timelines stipulated by the Sponsor when the request for 
information is made. 
If required, the Investigator is responsible for informing local Independent Ethics Committees 
(IECs)/Institutional Review Boards (IRBs) of safety reports in compliance with applicable 
regulatory requirements. Copies of all correspondence relating to reporting of any safety reports 
to the IEC/IRB should be maintained in the Investigator Site File (ISF)/Regulatory Binder.  
Subject Enrolment to the First Administration of Study Drug: 
Only serious procedure-related AEs will be reported to the Sponsor using the IRAE reporting 
process (SAE report form) as described above.  
After Subject's Last Study Visit: 
The Investigator will notify INC Research’s Pharmacovigilance Department of any SAE that she 
or he becomes aware of and considers related to the study drug. 
Following-up AEs / SAEs: 
At the subject's last study visit (including Early Termination Visit, if applicable), a Safety 
Follow-up Visit should be scheduled up to 30 days after the final examination only for those 
subjects who experienced not resolved related AEs, laboratory parameters showing not 
normalized clinical relevant changes, or SAEs. The assessments measured will be determined by 
the Investigator. All data must be documented in the eCRF. 
6.1.2.7 Responsibilities of the Sponsor 
The Sponsor is responsible for fulfilling all obligations regarding notification of Regulatory 
Authorities and IECs/IRBs according to applicable regulatory requirements (eg, expedited and 
periodic reporting, serious unexpected suspected adverse reactions, Development Safety Update 
Report). In addition, the Sponsor will provide safety information to Investigators according to 
the current regulations.  
6.1.3 Laboratory Parameters 
Laboratory assessments will be performed by a central laboratory, as identified in the List of 
Study Personnel (Appendix 1) at the time points outlined in Appendix 2. 


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The tests listed in Table 6.1 will be conducted on samples collected and analysed by standard 
laboratory procedures at the time points outlined on the Schedule of Assessments (Appendix 2). 
Blood draws that are not done must be reported as such on the eCRFs.  
Table 6.1: 
Laboratory Parameters 
Haematology 
 
 
Haemoglobin 
Haematocrit 
Red blood cell count 
Platelets 
White blood cell count with 
differential(neutrophils,neutrophil 
bands, lymphocytes, monocytes, 
eosinophils, basophils) 
Mean corpuscular volume 
Mean corpuscular haemoglobin 
 concentration 
Red cell morphology 
Chemistry 
 
 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate aminotransferase 
Total bilirubin  
Total protein 
Blood urea nitrogen 
Albumin 
Glucosea  
 
Creatinine 
Gamma glutamyl transpeptidase 
Electrolytes (sodium, potassium, 
chloride) 
Cholesterol (total, HDL, LDL) 
Urine b 
 
 
Appearance 
Specific gravity 
pH 
Glucose 
Ketones 
 
Occult blood 
 
Macroscopic haematuria  
Other Tests 
 
 
Pregnancy tests for women of childbearing potential: Serum at Screening (Visit 1), the ET Visit (if the 
subject is discontinuing from the study), or the End of Study Visit (Visit 7) and urine (at all other visits)  
AE = adverse event; ET = early termination; HDL = high-density lipoprotein; LDL = low-density 
lipoprotein 
a 
Glucose should be measured fasting. If for any reason a subject is not able to follow this 
recommendation, then there should be a 2-hour gap between a meal and the blood sample. 
b 
Microscopic evaluations will be performed if dipstick is positive. At Screening, if dipstick is positive 
and microscopic evaluation is abnormal, the subject must be excluded from participating in the study. If 
during the study, the dipstick is positive and the microscopic evaluation is abnormal these results will 
be recorded as an AE with the follow-up of the AE reported to the Medical Monitor. 
 
6.1.4 Vital Signs 
Vital signs will be measured and recorded at the time points outlined on the Schedule of 
Assessments (Appendix 2). The following measurements must be performed: systolic/diastolic 
blood pressure, heart rate, and body temperature. Vital signs will be measured after the subject 
has been in the supine position for at least 5 minutes. At the Randomization Visit (Visit 3), vital 
signs will be measured 3 times in order to determine the mean blood pressure. All measurements 
will be recorded on the vital signs eCRF. Abnormal test results may be repeated at the discretion 


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of the Investigator and must be reported on the corresponding eCRF. When vital signs and ECGs 
occur at the same time, vital signs should be performed before ECGs. 
6.1.5 Electrocardiograms 
During the study, 12-lead ECGs will be performed at the time points designated on the Schedule 
of Assessments (Appendix 2). 
The subject must be in a supine position in a rested and calm state for at least 5 minutes before 
ECG assessment is conducted. If the subject is unable to be in the supine position, the subject 
should be in the most recumbent position possible. All ECGs should be performed in a 
standardized method, in triplicate, and approximately 30 seconds apart, prior to blood draws or 
other invasive procedures. Each ECG must include the following measurements: ventricular rate, 
QRS, QT, corrected QT, RR, and PR intervals.  
The Investigator or designated site physician will review and sign all ECGs. Results must be 
summarized in writing and classified as normal; abnormal; abnormal, clinically relevant; or 
abnormal, not clinically relevant. Once signed, the original ECG tracing will be retained with the 
subject’s source documents. At the request of the Sponsor, a copy of the original ECG will be 
made available. 
6.1.6 Physical Examinations 
The Investigator or qualified designee will perform a complete physical examination at the time 
points outlined on the Schedule of Assessments (Appendix 2). Pre-dose abnormal findings will 
be reported on the medical history eCRF. Any adverse change from the baseline physical 
examination (Day 0 examination) will be documented on the AE eCRF. Weight will be 
measured at Screening, at Visit 6 (Eight weeks Postrandomization/ Early Termination Visit) and 
Visit 7 (Week 15, Post-Treatment Safety Follow-up Visit). 
A full physical examination will include examination of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, heart, lungs, abdomen, lymph nodes, extremities, 
urinary system, musculoskeletal system, and nervous system, (including the central nervous 
system).  
6.1.7 Prior and Concomitant Medication 
Prior and concomitant medication will be recorded at the time points outlined on the Schedule of 
Assessments (Appendix 2). All prior and concomitant medications taken by the subject will be 
recorded in the appropriate eCRF along with dose, dates of administration, and reason for use. 
6.1.8 Postvoid Residual Volume 
Bladder scans (ultrasound) for postvoid residual volume will be recorded at the time points 
outlined on the Schedule of Assessments (Appendix 2). Measurements should be performed 
within 15 minutes of the void. The time of the bladder scan and the time of the preceding void 
will also be recorded. Subjects who demonstrate a PVR >150 mL at Screening or at Day 0 


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(Visit 3), will require a repeat bladder scan. If the PVR is >150 mL, the subject will be ineligible 
for study.  
Catheterization should not be used to capture post void residual volume.  
6.2 
Efficacy Parameters  
6.2.1 Bladder Diary Questions 
The bladder diary will be completed daily for the 7 days prior to visit 2 and visit 6, to record the 
number of incontinence episodes and whether these were nocturia events. If a subject has 
multiple events in 1 day, each event will preferably be entered separately. The number of 
incontinence pads used will also be recorded in the diary. 
 
Subjects will be instructed on how to use the bladder diary and complete the assessments.  
 


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7 
STUDY CONDUCT 
7.1 
Observations by Visit 
Visits should occur within ±2 days of the scheduled visit. All times should be recorded using the 
24-hour clock (eg, 23:20, not 11:20 PM). 
7.1.1 Screening/Placebo Run-In Visit – Visit 1 (Days 0) 
The following procedures are to be completed during the Screening/washout period at time 
points outlined on the Schedule of Assessments (Appendix 2). 
• Provide informed consent and request informed consent form (ICF) signature 
• Record demographic data including sex, age, race, and ethnicity 
• Record medical/surgical history (including urinary and incontinence history and symptoms); 
record smoking history and current usage, if applicable) 
• Record previous and current medications 
• Measure and record vital signs (blood pressure, heart rate, and body temperature) 
• Complete full physical examination (including height and weight) 
• Complete the C-SSRS, BDI-II, BAI, PSQI 
• Determine subject’s PVR 
• Draw blood for pregnancy test in women of childbearing potential 
• Collect urine for dipstick test (If test is positive for nitrates and leukocyte esterase, take 
history of signs and symptoms of urinary tract infection and perform urine culture. If urine 
culture and clinical signs and symptoms are positive, the subject cannot be enrolled in the 
study, but can be re-screened at a later date, as long as s/he does not meet exclusion 
criterion 11 [chronic, or recurrent (> 4 per year) urinary tract infections]. Microscopic 
evaluations will be performed if the dipstick test is positive. If the dipstick test is positive at 
Screening, the subject must be excluded from the study.) 
• Draw blood for haematology and biochemistry tests 
• Perform 12-lead ECG 
• Verify eligibility (inclusion/exclusion criteria) 
• Dispense single-blind study drug for Placebo Run-In Period 
• Dispense bladder diary and instruct subject in its use 
7.1.2 Eligibility Assessment Visit – Visit 2 (Day 14) 
The following procedures are to be completed during the Eligibility Assessment Visit at time 
points outlined on the Schedule of Assessments (Appendix 2). 


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• Record current medications 
• Measure and record vital signs (blood pressure, heart rate, and body temperature) 
• Complete full physical examination 
• Complete the C-SSRS, BDI-II, BAI, PSQI 
• Determine subject’s PVR 
• Collect urine for pregnancy test in women of childbearing potential 
• Collect urine for dipstick test (If test is positive for nitrates and leukocyte esterase, take 
history of signs and symptoms of urinary tract infection and perform urine culture. If urine 
culture and clinical signs and symptoms are positive, the subject cannot be enrolled in the 
study, but can be re-screened at a later date, as long as s/he does not meet exclusion 
criterion 11 [chronic, or recurrent (> 4 per year) urinary tract infections]. Microscopic 
evaluations will be performed if the dipstick test is positive. If the dipstick test is positive and 
the microscopic evaluation is abnormal these results will be recorded as an AE with the 
follow-up of the AE reported to the Medical Monitor.) 
• Draw blood for haematology and biochemistry tests 
• Perform 12-lead ECG 
• Review bladder diary  
• Verify eligibility (inclusion/exclusion criteria) 
• Randomise subject 
• Collect single-blind study drug for Run-in Period and perform drug accountability 
• Dispense double-blind study drug 
• Query for AEs 
7.1.3 One Week Post-randomisation Visit – Visit 3 (Day 21) 
The following procedures are to be completed during the 1 Week Post-randomisation Visit at 
time points outlined on the Schedule of Assessments (Appendix 2). 
• Record current medications 
• Measure and record vital signs (blood pressure, heart rate, and body temperature) 
• Complete full physical examination 
• Complete the C-SSRS, BDI-II, BAI, PSQI 
• Collect urine for pregnancy test in women of childbearing potential 
• Draw blood for analysis of electrolytes (including sodium) 


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• Perform 12-lead ECG 
• Collect unused study drug and perform drug accountability 
• Dispense study drug 
• Query for AEs, including adverse events of special psychiatric interest 
7.1.4 Two Weeks Post-randomisation Visit – Visit 4 (Day 28) 
The following procedures are to be completed during the 2 Weeks Post-randomisation Visit at 
time points outlined on the Schedule of Assessments (Appendix 2). 
• Record current medications 
• Measure and record vital signs (blood pressure, heart rate, and body temperature) 
• Complete full physical examination 
• Complete the C-SSRS, BDI-II, BAI, PSQI 
• Collect urine for pregnancy test in women of childbearing potential 
• Draw blood for analysis of electrolytes (including sodium) 
• Perform 12-lead ECG 
• Collect unused study drug and perform drug accountability 
• Dispense study drug 
• Query for AEs including adverse events of special psychiatric interest 
7.1.5 Three  Weeks Post-randomisation Visit – Visit 5 (Day 35) 
The following procedures are to be completed during the 3 Weeks Post-randomisation Visit at 
time points outlined on the Schedule of Assessments (Appendix 2). 
• Record current medications 
• Measure and record vital signs (blood pressure, heart rate, and body temperature) 
• Complete full physical examination 
• Complete the C-SSRS, BDI-II, BAI, PSQI 
• Collect urine for pregnancy test in women of childbearing potential 
• Draw blood for analysis of electrolytes (including sodium) 
• Perform 12-lead ECG 
• Collect unused study drug and perform drug accountability 
• Dispense study drug 


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• Query for AEs including adverse events of special psychiatric interest 
 
7.1.6 Eight Weeks Post-randomisation/Early Termination Visit – Visit 6 (Day70) 
The following procedures are to be completed during the 8 Weeks Post-randomisation/Early 
Termination Visit at time points outlined on the Schedule of Assessments (Appendix 2). 
If this is the Early Termination Visit, the Investigator should use every effort to encourage the 
subject to taper study medication for 1 week and to return for the Safety Follow-up Visit 
(Visit 7). 
• Record current medications 
• Measure and record vital signs (blood pressure, heart rate, and body temperature) 
• Complete full physical examination (including weight) 
• Complete the C-SSRS, BDI-II, BAI, PSQI 
• Determine subject’s PVR 
• Collect urine for pregnancy test in women of childbearing potential if the subject is 
continuing in the study or collect blood for the pregnancy test if this is the ET Visit 
• Draw blood for haematology and biochemistry tests 
• Perform 12-lead ECG 
• Collect unused study drug and perform drug accountability 
• Dispense study drug for the 1-week tapering period (half of the dose to which the subject is 
randomized) 
• Review and collect bladder diary  
• Query for AEs including adverse events of special psychiatric interest 
7.1.7 Post-treatment Visit/End of Study Visit – Visit 7 (Day 105) 
The following procedures are to be completed during the Post-treatment Visit at time points 
outlined on the Schedule of Assessments (Appendix 2). 
• Measure and record weight 
• Record current medications 
• Measure and record vital signs (blood pressure, heart rate, and body temperature) 
• Complete full physical examination (including weight) 
• Complete the C-SSRS, BDI-II, BAI, PSQI 


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• Draw blood for pregnancy test in women of childbearing potential 
• Draw blood for haematology and biochemistry tests (only if abnormal values were seen at 
Visit 6) 
• Perform 12-lead ECG (only if any abnormality seen at Visit 6 represents a clinically 
significant worsening from baseline) 
• Collect unused study drug and perform drug accountability 
• Query for AEs including adverse events of special psychiatric interest 
 
7.2 Monitoring by telephone contact 
• In addition to the visit assessments detailed above, suicide monitoring using the C-SSRS 
will also be performed by a telephone contact with the subject 4 weeks post 
randomization (study day 42). 
 


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8 
STATISTICAL METHODS 
8.1 
General Considerations 
The general objectives of this study are to establish the safety, tolerability and efficacy of 
litoxetine in men and women who suffer from UI. The primary analyses will focus on safety, 
describing the adverse events with point estimates and Clopper Pearson 95% confidence 
intervals. Efficacy will be explored with regards to number of incontinence episodes and will use 
a mixed effects model with repeated measure (MMRM). Additional statistical considerations will 
be addressed in the Statistical Analysis Plan (SAP). 
8.2 
Analysis Populations 
There are 4 analysis populations for this study: 
Safety population: 
Defined as all subjects who are randomised, receive study drug, and 
undergo at least 1 visit 
Intent-to-Treat (ITT) 
population: 
Defined as all subjects who are randomized 
Modified Intent-to-
Treat (mITT) 
population: 
Defined as all subjects who are randomised, receive at least 1 dose of 
study drug, and provide an end of study primary efficacy endpoint 
Per Protocol (PP) 
population: 
Defined as those subjects who meet the ITT criteria and have 
completed the study without a major protocol deviation 
8.3 
Disposition of Subjects 
Subjects randomised and who receive study drug will be identified as completing the study or 
withdrawn from the study. Reasons for withdrawal will include: AE, failure to return, protocol 
deviation, subject request, and other. 
8.4 
Protocol Deviations 
In addition to clinical and study conduct protocol deviations, subjects that fail to provide valid 
measurements of the bladder diary at the end of the Placebo Run-In Period and at the end of the 
Treatment Period will be considered protocol deviations. Additionally, subjects that do not meet 
compliance criteria will be considered protocol deviations. 
8.5 
Demographics, Baseline Characteristics, and Concomitant Medications 
Demographics, baseline characteristics (including smoking history and current usage, if 
applicable), medical history, and concomitant medications will be reported for the subjects in the 
study. 


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8.6 
Treatment Compliance 
Treatment compliance will be defined as all subjects that take at least 80% of the study drug 
during the Treatment Period of the study. 
8.7 
Safety Endpoints and Analyses 
8.7.1 Safety Endpoints 
• Incidence and severity of AEs and Adverse Events of interest (urinary retention, withdrawal 
symptoms) over the course of the study.  
• Adverse Events of special psychiatry interest (nervousness, anxiety, panic attacks, insomnia, 
aggression, mania, suicidal ideation, development/worsening of depression) over the course 
of the study 
• Suicidal Adverse Events and Adverse Events suggestive of abuse potential will be analysed, 
and detailed narratives provided 
• Haematology, chemistry, and urinalysis 
• Actual change from end of the Screening Placebo Run-In Period in ECG readings and Week 
8. ECG parameters of interest include: ventricular rate, QT interval, corrected QT interval, 
PR interval, and QRS duration  
• Actual change from end of the Placebo Run-In Period to each visit in standardised cuff 
systolic and diastolic blood pressure and radial heart rate 
 
8.7.2 Safety Analyses 
• SAEs will be listed and summarised in a table, including a description of each event, the time 
to onset, the severity, and the relationship to trial drug. 
• All AEs (excluding SAEs) will be listed, and their time to onset, frequency, severity, and 
relationship to the trial drug will be tabulated by treatment. Adverse events that occur before 
the time of the first treatment with the trial drug will be considered a non-treatment- 
emergent AE (non-TEAE), and all AEs that occur after the time of the first treatment with 
trial drug will be considered TEAEs. Non-TEAEs will be summarised separately from 
TEAEs. 
• AEs of Special Interest include urinary retention, psychiatric adverse events ((nervousness, 
anxiety, panic attacks, insomnia, aggression, mania, suicidal ideation, 
development/worsening of depression) and withdrawal symptoms will be specifically 
summarized by treatment 
• Suicidal adverse events and abuse related adverse events will be specifically summarized by 
treatment 
• Premature withdrawals from the trial will be displayed and summarised by primary reason 
and treatment. 


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• Abnormal laboratory values will be listed and their incidence, severity, and relationship to 
the trial drug will be tabulated by treatment. Change from Screening will be summarised by 
treatment. Individual changes (shift tables), individual clinically significant abnormalities, 
and modified World Health Organization (WHO) ratings will also be presented. 
• While total white blood cell (WBC) count will be expressed in absolute values, differential 
count will be expressed as both absolute count and percentage of WBCs. 
• Abnormal physical examination findings will be summarised over time. 
• Concomitant medications will be presented in summary tables and listings. They will be 
classified according to whether they were taken before the trial (and ongoing into the trial), 
or started during the trial period. 
• Vital signs will be summarised by treatment group and listed by subject. 
• Any AE/SAE which occurs during the 30-day Follow-up Period or following discontinuation 
of treatment will be listed and summarized separately, and include a description of the event, 
time to onset, frequency, severity and relationship to treatment. 
8.8 
Efficacy Endpoints and Analyses  
8.8.1 Efficacy Endpoints 
Baseline for all efficacy endpoints will be defined as the last week of the Screening Placebo Run-
In Period. 
• Percentage change from the end of the Screening Placebo Run-In Period to Week 8 in the 
number of incontinence episodes/24 hours 
• Absolute change from the end of the Screening Placebo Run-In Period to Week 8 in the 
number of incontinence episodes/24 hours 
Number of incontinence episodes/24 hours will be computed as Total Number of incontinence 
episodes recorded over the 7 days/7. 
• Proportion of subjects who become continent at Week 8 
• Change from end of the Screening Placebo Run-In Period to Week 8 in the number of 
incontinence pads used per week 
8.8.2 Efficacy Analyses 
The efficacy analysis will be performed on the ITT, mITT, and PP populations. The efficacy 
analysis will be performed on the ITT population, with the analysis on the mITT and PP 
populations as part of secondary efficacy analysis. 
The efficacy analysis planned is a mixed effects model with repeated measures (MMRM). 
Percent reduction in incontinence episodes as the response variable is the first efficacy endpoint. 
The factor variable will be dose and the covariate will be baseline episodes (end of placebo run 


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in) of incontinence. Visits within subjects will provide the random effects of the mixed model. 
There is only one hypothesis so there will be no adjustment for multiplicity. Further efficacy 
analysis will be conducted similarly, with appropriate baseline measure. There will not be an 
adjustment for multiple comparisons for these secondary analyses. 
8.9 
Interim Analyses 
No interim analyses are planned for this study. 
8.10 Determination of Sample Size 
Approximately 95 subjects are expected to be enrolled into the 2-week, single-blind (subject 
blind) Screening Placebo Run-In Period. It is expected that 20% of subjects will not qualify for 
randomization after Screening Placebo Run-In.  
The study is expected to randomize approximately 78 subjects into the double-blind treatment 
where subjects will be allocated to litoxetine (dose titration over 10 mg, 20 mg, 30mg) or 
matched placebo BID in a 2:1 ratio. A post randomisation dropout rate of 30% has been 
estimated, resulting in 60 evaluable subjects.  
This sample size will provide confidence intervals for the rate of safety events that are +/- 14% 
for the widest observed intervals in the treatment arm. 
8.11 Missing Data 
As a sensitivity analysis, missing data will be addressed with a multiple imputation method for 
the efficacy endpoints only. Details of the imputation method will be identified in the SAP prior 
to unblinding the data which will include the seed for the imputation, the number of imputations, 
and how the imputations will be randomly selected. As the only term in the efficacy analysis that 
should be missing is the change from baseline, the imputation will be a simple imputation on this 
variable with no covariates. In the event other values are missing, they too will be imputed using 
simple multiple imputation methods with no covariates in the imputation algorithm. This is 
consistent with an assumption of missing completely at random (MCAR). This method is 
selected over single imputation methods as the anticipated placebo effect is expected to be 
considerable. 
 


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9 
DATA MANAGEMENT 
9.1 
Data Collection 
The trained Investigator site staff will enter the data required by the protocol into the eCRFs 
from source documents (eg, medical records and study-specific data capture tools as needed) 
directly into the study database on a central server. All information in the eCRFs must be 
traceable to these source documents. Data recorded directly into the eCRFs will be defined 
before study start and the eCRFs will be considered the source data. Clinical Research 
Associates (CRAs) and a Data Manager will review eCRFs entered by investigational staff for 
completeness and accuracy. Automatic quality programs check for data discrepancies in the 
eCRFs and the resulting queries will be notified to the investigational site using an electronic 
data query process within the EDC system. Designated Investigator site staff are required to 
respond to queries and make any necessary changes to the data. Details of the data correction 
process will be specified in the Data Quality Check specification.  
A validated, electronic database will be employed from the EDC system. An audit trail of all 
changes to this database, including the date, reason for the data change and who made the 
change, will be maintained within the same database. The audit trail will be part of the archived 
data at the end of the study. 
The complete data management process (data capture, data entry, data validation, checks on 
plausibility, query handling, data editing after entry, coding, data base closure, etc.) will be 
defined in advance within a Data Management Plan together with a description of the personnel 
responsible for data entry. 
The bladder diary will be used to collect daily bladder information (incontinence episodes, pad 
usage) for 7 days prior to visit 2 and visit 6.  
9.2 
Data Correction 
Automatic and manual queries will be defined according to the Data Quality Check specification. 
These queries will be generated by the INC Research Data Management Department and CRAs 
and sent through the EDC system for clarification. Corrections will be entered directly into the 
system. This procedure will be repeated until all queries are resolved. All query forms will be 
linked to the eCRF in the EDC system. 
9.3 
Data Handling 
The final data will be transferred to the SAS-system for data analyses in accordance with the 
SAP. The Medical Dictionary for Regulatory Activities (MedDRA) will be used for coding of 
AEs and concomitant diseases. Concomitant medication will be coded using the WHO Drug 
Dictionary Anatomical Therapeutic Chemical code. 


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9.3.1 Deviations from the Protocol 
Deviations from the protocol will be judged during the study and/or when an individual subject’s 
eCRF is completed (monitored).  
9.4 
Data Quality Assurance 
INC Research will conduct a site visit to verify the qualifications of each Investigator, inspect the 
site facilities, and inform the Investigator of responsibilities and the procedures for ensuring 
adequate and correct documentation. 
The Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. All information recorded on the eCRFs for this study must be consistent with the 
subjects’ source documentation (ie, medical records). 
 


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10 QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 Study Initiation Activities 
The Investigator(s) are informed about study objectives and methods, the inclusion and exclusion 
criteria, the time-schedule, and study procedures at a Pre-Study Visit by the CRA (if necessary), 
an Investigators’ meeting, or during the Site Initiation Visit by the CRA. 
10.2 Training of Site Staff 
The Investigator will ensure that everyone assisting with the clinical study is adequately 
informed about the protocol, the study drugs, and their study-related duties and functions. 
Furthermore, the Investigator will maintain a list of qualified persons to whom the Investigator 
has delegated study-related duties. 
10.3 Documentation and Filing 
10.3.1 eCRF System 
The Investigator and persons authorized by the Investigator will be instructed about how to 
complete the eCRF. Entries in the eCRF must only be made by the Investigator or persons 
authorized by the Investigator. A list of all persons who are allowed to make entries in the eCRF 
must be available in each study site. 
The Investigator must verify that all data entries in the eCRF are accurate and correct. Entries 
will be checked against appropriate source documentation by the monitor. 
10.3.2 Bladder diary 
Bladder diary data are uploaded into the EDC at visit 2 and visit 6.  
10.3.3 List of Subjects (subject identification log) 
The Investigator will keep a confidential list of names of all subjects participating in the study, 
so that the subjects' records can be identified if necessary.  
In addition, the Investigator will keep a list of all subjects screened on a Screening log to 
document identification of subjects who entered pre-study Screening. If a subject is not eligible 
to participate in the study, a reason must be provided. 
10.3.4 Source Data 
Per ICH, source data are defined as all information in original records and certified copies of 
original records of clinical findings, observations, or other activities in a clinical study necessary 
for the reconstruction and evaluation of the study. Source data are contained in source documents 
which comprise clinical documentation, data, and records (eg, hospital records, clinical and 
office charts, laboratory notes, memoranda, subjects' diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions certified 
after verification as being accurate copies, microfiches, photographic negatives, microfilm or 


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magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at 
medico-technical departments involved in the clinical study). 
10.3.5 Investigator Site File / Regulatory Binder 
Before site initiation INC Research will provide an ISF/Regulatory Binder to each site. The ISF 
will include essential documents as defined by the ICH GCP guideline and applicable local 
requirements. 
The Investigator will be responsible for the update and maintenance of the ISF, which will be 
reviewed periodically by the CRA. These documents will be reviewed during an audit by the 
Sponsor or an inspection by the Regulatory Authorities. 
All study-related documents are to be archived and stored according to legal requirements. 
Prior to destruction of study-related documents, the Investigator will contact IXALTIS for 
approval and confirmation. 
10.4 Monitoring 
The monitor is responsible for checking the quality of data and ensuring that the investigative 
site is adhering to the study protocol. Additionally, the monitor ensures that the site is following 
the legal and ethical requirements as stated in local laws and the principles of GCP. 
The interval between monitoring visits will depend on the recruitment rate and the site needs. 
Source data verification is an essential part of the monitoring process and the Investigator must 
grant direct access to the subject’s source data. 
The extent and nature of monitoring will be described in detail in the monitoring plan. 
10.5 Audits and Inspections 
Audits will be performed according to the corresponding audit program. Audits may also be 
performed by contract auditors who will be instructed about the timing and extent of the audits. 
In the event of an audit at the investigational site, the CRA will usually accompany the 
auditor(s).  
Inspections by Regulatory Authority representatives and IECs/IRBs are possible at any time, 
even after the end of study. The Investigator is to notify the Sponsor immediately of any such 
inspection. The Investigator and institution will permit study-related monitoring, audits, reviews 
by the IEC/IRB and/or Regulatory Authorities, and will allow direct access to source data and 
source documents for monitoring, audits, and inspections. 


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11 ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS 
11.1 Good Clinical Practice 
The procedures set out in this study protocol are designed to ensure that the Sponsor and 
Investigator abide by the principles of the GCP guidelines of the ICH, and of the current version 
of the Declaration of Helsinki. The study also will be carried out in keeping with local legal 
requirements.  
11.2 Informed Consent 
Before each subject is admitted to the study, informed consent will be obtained from the subject 
(or their legally authorized representative) according to the regulatory and legal requirements of 
the participating country and the current version of the Declaration of Helsinki. This consent 
form must be dated and retained by the Investigator as part of the study records. The Investigator 
will not undertake any investigation specifically required only for the clinical study until valid 
consent has been obtained. The terms of the consent and when it was obtained must also be 
documented in the eCRF. 
The explicit wish of a mentally incapacitated adult, who is capable of forming an opinion and 
assessing the study information, to refuse participation in or to be withdrawn from the study at 
any time will be considered by the Investigator. 
If a protocol amendment is required, the informed consent form may need to be revised to reflect 
the changes to the protocol. If the consent form is revised, it must be reviewed and approved by 
the appropriate IEC/IRB, and signed by all subjects subsequently enrolled in the study as well as 
those currently enrolled in the study. 
11.3 Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be approved 
by the IEC/IRB/Competent Authorities, in accordance with local legal requirements. The 
Sponsor must ensure that all ethical and legal requirements have been met before the first subject 
is enrolled in the study. 
This protocol is to be followed exactly. To alter the protocol, amendments must be written, 
receive approval from the appropriate personnel, and receive IEC/IRB/Competent Authority 
approval prior to implementation (if appropriate).  
Administrative changes (not affecting the subject benefit/risk ratio) may be made without the 
need for a formal amendment. All amendments will be distributed to all protocol recipients, with 
appropriate instructions. 
11.4 Archiving Study Records 
According to ICH guidelines, essential documents should be retained for a minimum of 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. However, these 


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documents should be retained for a longer period if required by the applicable legal 
requirements. 
11.5 Premature Termination of the Study 
If the Investigator, the Sponsor, or the Medical Monitor becomes aware of conditions or events 
that suggest a possible hazard to subjects if the study continues, the study may be temporarily or 
permanently discontinued after appropriate consultation between the relevant parties. The study 
may also be terminated early at the Sponsor’s discretion in the absence of such a finding. 
Conditions that may warrant termination include, but are not limited to: 
• The discovery of an unexpected, significant, or unacceptable risk to the subjects enrolled in 
the study 
• Failure to enrol subjects at an acceptable rate 
• A decision on the part of the Sponsor to suspend or discontinue development of the drug 
 
11.6 End of the Trial 
For administrative and safety reporting purposes, the end of the trial will be defined as the date 
of the final clinical database lock. This provides for a single and conservative definition across 
all trial sites. 
11.7 Confidentiality 
All study findings and documents will be regarded as confidential. The Investigator and 
members of his/her research team must not disclose such information without prior written 
approval from the Sponsor. 
The anonymity of participating subjects must be maintained. Subjects will be identified on 
eCRFs and other documents by their subject number, and/or birth date, not by name. Documents 
that identify the subject (eg, the signed informed consent) must be maintained in confidence by 
the Investigator.  
11.8 Liability and Insurance 
The Sponsor will take out reasonable third-party liability insurance cover in accordance with all 
local legal requirements. The civil liability of the Investigator, the persons instructed by him and 
the hospital, practice, or institute in which they are employed and the liability of the Sponsor 
with respect to financial loss due to personal injury and other damage that may arise as a result of 
the carrying out of this study are governed by the applicable law. 
The Sponsor will arrange for subjects participating in this study to be insured against financial 
loss due to personal injury caused by the pharmaceutical products being tested or by medical 
steps taken in the course of the study.  


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11.9 Publication Policy 
By signing the study protocol, the Investigator agrees with the use of results of the study for the 
purposes of national and international registration, publication, and information for medical and 
pharmaceutical professionals. If necessary, the authorities will be notified of the Investigator's 
name, address, qualifications, and extent of involvement. 
An Investigator shall not publish any data (poster, abstract, paper, etc.) without having consulted 
with the Sponsor in advance. 


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12 REFERENCE LIST 
Adams P, Andersson KE, Birder L, et al. Fourth International Consultation on Incontinence 
Recommendations of the International Scientific Committee: Evaluation and treatment of urinary 
incontinence, pelvic organ prolapse, and fecal incontinence. Neurourl Urodyn. 
2010; 29:213-240. 
European Medicines Agency, Committee for Medicinal Products for Human Use. Guideline on 
the Clinical Investigation of Medicinal Products for the Treatment of Urinary Incontinence. 
27 June 2013. 
Fultz NH, Burgio K, Diokno AC et al. Burden of stress urinary incontinence for community 
dwelling women. Am J Obstet Gynaecol 2003; 189: 1275-1282.  
Global Forum on Incontinence resources page. About incontinence. Available at: 
http://www.gfiforum.com/incontinence. Accessed 28 October 2016. 
Papanicolaou S. Pons ME, Hampel C et al. Medical resource utilization and cost of care for 
women seeking treatment for urinary incontinence in an outpatient setting. Examples from three 
countries in the PURE study. Maturitas 2005; 52. Suppl 2:S35-47.  
Turner DA, Shaw C, McGrother DW et al. The cost of clinically significant urinary storage 
symptoms in community dwelling adults in the UK. BJUI 2004; 93:1246-1252. 
Wood LN, Anger JT. Urinary incontinence in women. BMJ: 2014;349: g4531.  
 


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13 APPENDICES 
 


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Appendix 1: 
List of Institutions Involved in the Study 
 
Sponsor 
IXALTIS 
Archamps Technopole 
Acti’Tech 6 
60 avenue Marie Curie 
74160 Archamps, France 
Principal Scientific Advisor 
Pr. Roger Dmochowski  
Vanderbilt University 
Nashville, TN 
 
Contract Research 
Organization 
INC Research  International 
 
Adverse Event Reporting 
INC Research Pharmacovigilance 
Fax: 1-877-464-7787 
E-mail: INCDrugSafety@incresearch.com 
 
Central Laboratory 
 
TBD 


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Appendix 2: 
Schedule of Assessments 
Visit Number 
Visit 1(1) 
Visit 2(1) 
Visit 3 
Visit 4 
Visit 5 
Telephone 
contact 
Visit 6 
Visit 7 
Visit Name 
Screening/ 
Placebo 
Run In  
Eligibility 
assessment/ 
Randomization  
(start 10 mg 
litoxetine or 
Placebo BID) 
1 week 
Post 
Randomization 
First dose 
escalation 
(start 20 mg or 
Placebo BID) 
2 weeks Post 
Randomization 
Second dose 
escalation 
(start 30 mg or 
Placebo BID) 
3 weeks Post 
Randomization 
 
 
8 weeks post 
Randomization 
Final Treatment 
Visit(4) 
(ET Visit) 
13 weeks po
Randomizat
Post-Treatm
Safety F/U(3
(End of Stud
Visit) 
Study Day 
Day 0 
Day 14  
Day 21 
Day 28 
Day 35 
Day 42 
Day 70 
Day 105 
Signed informed consent 
X 
 
 
 
 
 
 
 
Demographics (incl body 
weight and height, BMI) 
X 
 
 
 
 
 
X(13) 
X(13) 
Complete C-SSRS, BDI-
II, BAI, PSQI16 
X 
X 
X 
X 
X 
X (C-SSRS only) 
X 
X 
Medical / surgical/ 
smoking history  
X 
 
 
 
 
 
 
 
Urinary and incontinence 
history 
X 
 
 
 
 
 
 
 
Prior and concomitant 
medication recording 
X 
X 
X 
X 
 
 
X 
X 
Vital signs(11) 
X 
X 
X 
X 
X 
 
X 
X 
Physical examination  
X 
X 
X 
X 
X 
 
X 
X 
PVR 
X 
X 
 
 
 
 
X 
 
Pregnancy test(5,6) 
X 
X 
X 
X 
 
 
X 
X 
Urinalysis (dipstick)(10) 
X 
X 
 
 
 
 
 
 
Haematology and 
biochemistry(8) 
X 
X 
X(15) 
X(15)  
 X(15) 
 
X 
X(9) 
ECG (resting, 12-lead)  
X 
X 
X 
X 
X 
 
X 
X(7) 


IXALTIS 
 
IXA-CSP-002 amendment 2  
 
CONFIDENTIAL 
Page 66 of 70 
October 10,  2018 
 
Appendix 2: 
Schedule of Assessments 
Visit Number 
Visit 1(1) 
Visit 2(1) 
Visit 3 
Visit 4 
Visit 5 
Telephone 
contact 
Visit 6 
Visit 7 
Visit Name 
Screening/ 
Placebo 
Run In  
Eligibility 
assessment/ 
Randomization  
(start 10 mg 
litoxetine or 
Placebo BID) 
1 week 
Post 
Randomization 
First dose 
escalation 
(start 20 mg or 
Placebo BID) 
2 weeks Post 
Randomization 
Second dose 
escalation 
(start 30 mg or 
Placebo BID) 
3 weeks Post 
Randomization 
 
 
8 weeks post 
Randomization 
Final Treatment 
Visit(4) 
(ET Visit) 
13 weeks po
Randomizat
Post-Treatm
Safety F/U(3
(End of Stud
Visit) 
Study Day 
Day 0 
Day 14  
Day 21 
Day 28 
Day 35 
Day 42 
Day 70 
Day 105 
Evaluation of 
eligibility/randomization 
X 
X 
 
 
 
 
 
 
Dispensing/collection of 
trial drug 
X 
X 
X 
X 
 
 
X(14) 
X 
Patient bladder diary 
review/collection(12)  
X 
X 
 
 
 
 
X 
 
Recording of AEs 
 
X 
X 
X 
X 
 
X 
X 
Abbreviations: AEs = adverse events; BMI = body mass index; ECG = electrocardiogram; ET = early termination; PVR = postvoid residual urine volume; UTI = 
urinary tract infection 
(1) 
Eligible subjects will undergo a 2-week Screening Placebo Run-In Period with 7 days bladder daily diary symptom collection (e-diaries). Subjects who 
continue to be eligible after the Screening Placebo Run-In Period will be randomised (Treatment Period). 
(2) 
Visit window ± 2 days 
(3) 
AEs must be followed for a minimum of 30 days and until complete resolution or stabilization of the event, or as deemed appropriate by the Investigator 
on consultation with the Sponsor medical responsible. 
(4) 
If a subject is withdrawn prematurely from the trial, all procedures indicated for the Week 8 (Visit 6) visit must be performed. The Investigator should use 
every effort to encourage the subject to taper study medication for 1 week and to return for the Safety Follow-up Visit (Visit 7). 
(5) 
Serum pregnancy tests will be performed prior to entry into the trial (Visit 1), the ET Visit (Visit 6; if the subject is discontinuing the study) and at the End 
of Study Visit (Visit 7) for all female subjects of childbearing potential. Only those female subjects with a negative pregnancy test at Visit 1 will receive 
trial medication. 
(6) 
Urine (dipstick) pregnancy tests will be performed at Visits 2, 3, 4, 5, and 6 (if it is not the ET Visit) for all female subjects of childbearing potential. Only 
those female subjects with a negative pregnancy test will receive trial medication. 


IXALTIS 
 
IXA-CSP-002 amendment 2  
 
CONFIDENTIAL 
Page 67 of 70 
October 10,  2018 
(7) 
ECG at Follow-up (Visit 7) is only required if ECG was abnormal at Week 8 (Visit 6) and the abnormality represents a clinically significant worsening 
from baseline. 
(8) 
Blood samples will be taken in a fasting state at Screening, Day 14 (Visit 2) and Week 8 (Visit 6). 
(9) 
Laboratory tests at Follow-up (Visit 7) are only required if labs were abnormal at Week 8 (Visit 6) and the abnormality represents a clinically significant 
worsening from baseline. 
(10) If Urine Dipstick is positive for nitrates and leukocyte esterase, take history of signs and symptoms of UTI, and perform urine culture. If urine culture and 
clinical signs and symptoms are positive, the subject cannot be included, but can be re-screened at a later date as long as the subject does not meet 
exclusion criterion 3 (4 or more UTIs in the past 12 months). 
(11) Vital signs include blood pressure, heart rate, and body temperature. 
(12) At Visit 1, the patient is in formed how to use the bladder diary. During the 7 days prior to Visit 2 and Visit 6 the following urinary incontinence 
information will be recorded in the bladder diary: the number of incontinence episodes/pads used daily.  
(13) Weight only. 
(14) Dispense study drug for the 1-week tapering period (half of the dose to which the subject is randomized). 
(15) Electrolytes (including sodium) only. 
(16)  In addition to the visit assessments detailed above, suicide monitoring using the C-SSRS will also be performed by a telephone contact with the subject 4 
weeks post randomization (study day 42). 


IXALTIS 
IXA-CSP-002 amendment 2 
 
CONFIDENTIAL 
Page 68 of 70 
October 10, 2018 
Appendix 3: 
New York Heart Association Heart Failure Classification 
 
Class 
Patient Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnoea (shortness of breath). 
II 
Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity 
results in fatigue, palpitation, dyspnoea (shortness of breath). 
III 
Marked limitation of physical activity. Comfortable at rest. Less than ordinary 
activity causes fatigue, palpitation, or dyspnoea. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of heart 
failure at rest. If any physical activity is undertaken, discomfort increases. 
 


IXALTIS 
IXA-CSP-002 amendment 2 
 
CONFIDENTIAL 
Page 69 of 70 
October 10, 2018 
Appendix 4: 
Psychiatric monitoring: Columbia-Suicide Severity Rating Scale (C-SSRS), 
Beck Depression Inventory-II (BDI-II), Beck Anxiety Inventory (BAI), Pittsburgh Sleep 
Quality Index (PSQI) 


IXALTIS 
IXA-CSP-002 amendment 2 
 
CONFIDENTIAL 
Page 70 of 70 
October 10, 2018 
 
 

SAP_001.pdf: 
Statistical Analysis Plan 
CONFIDENTIAL 
Date: 2nd April 2019 
Study code: IXA-CSP-002 
 
 
 
Final 
 
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Statistical Analysis Plan 
 
 
Study Title 
A 
Double-Blind, 
Randomised, 
Placebo-
Controlled, Phase I/IIa, Dose Titration Trial to 
Evaluate the Safety, Tolerability and Efficacy of 
Oral Litoxetine up to 30 mg versus Placebo BID 
in subjects with Urinary Incontinence 
 
 
Protocol No.: 
IXA-CSP-002 
 
 
 
Original SAP: 
Version 0.1, 8th November 2018 
 
Current Version: 
Version 1.3, 2nd April 2019 
 
 
 
Prepared by: 
Gloria Crispino 
 
 
 
StatisticaMedica 
 
Dublin 
 
Ireland 


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 2nd April 2019 
Study code: IXA-CSP-002 
 
 
 
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Approval SIGNATURE(S) 
A Double-Blind, Randomised, Placebo-Controlled, Phase I/IIa, Dose 
Titration Trial to Evaluate the Safety, Tolerability and Efficacy of Oral 
Litoxetine up to 30 mg versus Placebo BID in subjects with Urinary 
Incontinence 
 
Protocol No. IXA-CSP-002 
I have read this SAP and confirm that to the best of my knowledge it accurately describes the statistical 
analyses for this study. 
 
Sponsor Signatory: 
 
 .......................................................................................................  
 ......................................  
 
Date 
 
 
 
Statistician Signatory: 
 
 .......................................................................................................  
 ......................................  
 
Date 
Gloria Crispino, CEO and Director of Biostatistics 
 
 
02/APR/2019
April 2, 2019


Statistical Analysis Plan 
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Date: 2nd April 2019 
Study code: IXA-CSP-002 
 
 
 
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Table of Contents 
Approval SIGNATURE(S) .......................................................................................................................... 2 
List of abbreviations and definitions of terms ........................................................................................ 5 
1. 
Introduction .................................................................................................................................... 7 
1.1 
Background ............................................................................................................................. 7 
1.2 
Risk/Benefit Assessment ......................................................................................................... 8 
1.3 
Rationale ................................................................................................................................. 9 
1.4 
Statistical Analysis Plan Summary (SAP) ................................................................................. 9 
1.5 
Clarifications from Protocol .................................................................................................... 9 
1.6 
Study Summary ....................................................................................................................... 9 
1.7 
Version History ...................................................................................................................... 10 
2. 
Study Objectives ........................................................................................................................... 11 
2.1 
Primary Objective.................................................................................................................. 11 
2.2 
Secondary Objective ............................................................................................................. 11 
2.3 
Primary Endpoint(s) .............................................................................................................. 11 
2.4 
Secondary Endpoints(s) ........................................................................................................ 11 
3. 
Study Design.................................................................................................................................. 11 
3.1 
Sample Size ........................................................................................................................... 18 
3.2 
Randomisation ...................................................................................................................... 18 
4. 
Analysis Sets .................................................................................................................................. 19 
4.1 
Study Populations ................................................................................................................. 19 
4.2 
Disposition of Subjects .......................................................................................................... 19 
4.3 
Protocol Deviations ............................................................................................................... 19 
5. 
Definitions and Data Conventions ................................................................................................ 20 
5.1 
General, demographic and baseline characteristics ............................................................. 20 
5.2 
Compliance ........................................................................................................................... 21 
5.3 Safety variables ........................................................................................................................... 22 
5.4 
Efficacy Variables .................................................................................................................. 24 
5.4.1 
Sensitivity Efficacy Variables ............................................................................................. 25 
5.4.2 
Exploratory Efficacy Variables ........................................................................................... 25 
5.5 
Baseline ................................................................................................................................. 25 
6. 
Statistical Methodology ................................................................................................................ 25 
6.1 
Handling of Missing Data ...................................................................................................... 25 
6.2 
Covariate and Subgroups ...................................................................................................... 26 


Statistical Analysis Plan 
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Date: 2nd April 2019 
Study code: IXA-CSP-002 
 
 
 
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6.3 
General Methodology ........................................................................................................... 26 
6.4 
Patient Disposition ................................................................................................................ 27 
6.5 
Demographic and Screening/Baseline Characteristics ......................................................... 27 
6.6 
Compliance ........................................................................................................................... 28 
6.7 
Safety Analysis ...................................................................................................................... 28 
6.8 
Additional Safety Analyses .................................................................................................... 30 
6.9 
Efficacy Analyses ................................................................................................................... 34 
6.9.1 
Sensitivity Efficacy Analyses .............................................................................................. 36 
6.9.2 
Exploratory Efficacy Analyses............................................................................................ 37 
7. 
General Considerations ................................................................................................................. 38 
7.1 
Software to be used .............................................................................................................. 38 
7.2 
Programs and Tables Quality Control ................................................................................... 38 
8. 
Data Storage .................................................................................................................................. 38 
9. 
References .................................................................................................................................... 38 
10. 
Appendix 1 ................................................................................................................................ 39 
11. 
Appendix 2 ................................................................................................................................ 39 
12. 
Appendix 3 ................................................................................................................................ 39 
13. 
Appendix 4 ................................................................................................................................ 39 
14. 
Appendix 5 ................................................................................................................................ 39 
 
 
 


Statistical Analysis Plan 
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Date: 2nd April 2019 
Study code: IXA-CSP-002 
 
 
 
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List of abbreviations and definitions of terms 
Abbreviation 
Definition 
AE 
AESI                   
Adverse event 
Adverse event of special interest 
BID 
Twice daily 
CYP 
Cytochrome P450 
DA 
Dopamine 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ICS 
International Continence Society 
IRAE 
Immediately reportable adverse event 
ITT 
Intent-to-treat (population) 
MACR 
Missing completely at random 
MMRM 
Mixed-Effect Model for Repeated Measure 
MedDRA 
Medical Dictionary for Regulatory Activities 
MUI 
Mixed urinary incontinence 
NE 
Norepinephrine 
NHS 
National Health Service 
PP 
Per Protocol (population) 
PVR 
Postvoid residual volume 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SNRI 
Serotonin and  norepinephrine reuptake inhibitor 
SSRI 
Selective serotonin reuptake inhibitor 
SUI 
Stress urinary incontinence 
TEAE 
Treatment-emergent adverse event 
UI 
Urinary incontinence 
UK 
United Kingdom 


Statistical Analysis Plan 
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Date: 2nd April 2019 
Study code: IXA-CSP-002 
 
 
 
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Abbreviation 
Definition 
US 
United States 
UUI 
Urge urinary incontinence 
WBC 
White blood cell (count) 
WHO 
World Health Organisation 
 
 


Statistical Analysis Plan 
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Date: 2nd April 2019 
Study code: IXA-CSP-002 
 
 
 
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1. Introduction 
This Statistical Analysis Plan (SAP) describes the statistical analysis for IXA-CSP-002 study based on 
study protocol IXA-CSP-002-protocol amendment 2 issued Oct 10, 2018. 
1.1 Background 
Urinary incontinence (UI) is a common and chronic condition affecting both males and females, 
although it is more commonly seen in women. For both genders, prevalence increases with age, 
occurring frequently in the geriatric population (65 years and older) (Adams P, 2010). Urinary 
incontinence, which is defined by the International Continence Society (ICS) as involuntary loss of 
urine”, is estimated to affect 400 million people worldwide (Fultz NH, 2003; Global Forum on 
Incontinence). Prevalence varies greatly with age and the definition used, and has been reported to be 
as high as 55%. Not all affected need medical treatment. 
 
This condition is often underreported since many people avoid discussing the problem with their doctor 
due to embarrassment, lack of knowledge about treatment options, or a belief that urinary incontinence 
is an inevitable part of ageing. 
 
While not life-threatening, urinary incontinence can have a significant negative impact on the 
psychological well-being, social functioning and overall quality of life of those affected, resulting in 
social reclusion and also an economic burden. 
 
The burden of urinary incontinence is high in financial terms, with the total annual cost of urinary 
incontinence in the United States (US) estimated to be as high as $32 billion (Wood LN, 2014). Total 
cost of managing urinary incontinence in women over the age of 40 years in the United Kingdom (UK) 
in 2004 was £301 million, 0.3% of the total National Health Service (NHS) budget (Turner DA, 2004). 
Costs borne by women in out-of-pocket expenses was £230 million (Fultz NH, 2003) or £290 per 
woman per year (Papanicolaou S, 2005). 
 
Women suffer most commonly from stress urinary incontinence (SUI) or a combination of SUI and 
urge urinary incontinence (UUI) i.e. Mixed Urinary Incontinence (MUI). Men suffer primarily from 
urgency, due to obstruction from prostate hypertrophy, and have a higher incidence of ‘dry’ symptoms 
(urgency, frequency without urinary incontinence). Stress incontinence in men accounts for less than 
10%, mainly occurring post prostate surgery (Adams P, 2010). 
 
Urinary incontinence can be managed initially by lifestyle modifications, with reduction of excessive 
fluid intake, timed voiding, weight loss if required, and bladder and pelvic floor muscle training. Drug 
treatments are available for over-active bladder, with anticholinergic drugs the mainstay of treatment 
for cases that do not respond to lifestyle modification. Several agents are currently available including 
oxybutynin, tolterodine, fesoterodine, trospium, solifenacin, and darifenacin. 
 
Many women are unable to tolerate anticholinergic drugs and 30-91% discontinue them after 1 year. If 
patients do not respond to a treatment attempt of anticholinergic drugs, minimally invasive treatment 
options are available, with intravesical injection of onabotulinum toxin A, sacral neuromodulation, and 
posterior tibial nerve stimulation available as potential options. 
 
Serotonin plays an important role in centrally modulating the reflexes of continence/micturition; 5-HT 
potentiates the guarding reflex which allows continence by increasing urethral pressure and inhibits the 
micturition reflex responsible for voiding. Animal studies have shown that increased levels of 5-HT 
and norepinephrine (NE), in the sacral spinal cord, lead to increased urethral tone via enhanced pudendal 
nerve stimulation to the urethral striated sphincter muscle during the storage phase of the micturition 
cycle. Studies with duloxetine support a similar mechanism in women, believed to result in stronger 
urethral closure during urine storage with physical stress. 


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 2nd April 2019 
Study code: IXA-CSP-002 
 
 
 
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Animal studies have confirmed that litoxetine increases the urethral sphincter pressure, and also 
demonstrated that litoxetine improves bladder capacity through a relaxation effect of the detrusor. 
Taken together these effects suggest that litoxetine could have therapeutic benefit in Urinary 
Incontinence, a condition for which there is a high unmet medical need.  
 
The 5-HT selectivity of litoxetine, and the weaker affinity for NE and epinephrine (E) as well as for 
dopamine (DA) transporters has the potential to provide a good cardiovascular safety profile, and reduce 
the risk of nausea which is the most frequent side effect following treatment with 5-HT reuptake 
inhibitors. 
 
Further details can be found in the Investigator's Brochure (Edition 3, Feb 2018), which contains 
comprehensive information on the investigational product. 
 
1.2 Risk/Benefit Assessment 
To date, 11 Phase 1 studies in healthy volunteers and 3 Phase 2 studies in subjects suffering from 
depression have been performed with litoxetine. One in vitro study in human blood has been performed 
to evaluate plasma protein binding in humans. 
Litoxetine has been evaluated in 154 healthy subjects and 445 patients with depression either as a 
capsule or a tablet containing litoxetine drug substance with excipients. Clinical pharmacology data has 
shown that doses up to 50 mg BID were acceptable, the open-label Phase 2 study in depression explored 
doses up to 100 mg daily, and subsequent double-blind, placebo-controlled studies explored doses up 
to 60 mg daily for a duration of 6 weeks. While study effects were observed in subjects with depression, 
the efficacy of litoxetine compared to placebo was negligible. In these studies, litoxetine safety 
information did not show any negative cardiovascular effects. The most common AEs were headache, 
nausea, and dyspepsia. The safety profile of litoxetine is acceptable and in line with the known and well 
established safety profile of 5-HT reuptake inhibitors. No AEs in the clinical studies have been reported 
which would preclude development of litoxetine in the new indication of Urinary Incontinence and 
Adverse Events will continue to be monitored throughout the study, including AEs of special interest 
(i.e., urinary retention, psychiatric adverse events and withdrawal effects). 
 
Non-clinical studies have demonstrated effects of litoxetine on urethral sphincter and bladder capacity, 
which are key features for micturition and continence. The “dual action”-inhibitory effect on detrusor 
muscle activity and excitatory effect on urethral sphincter- provides a scientific rationale to evaluate 
whether litoxetine treatment may be a treatment option for subjects with UI. One phase 2 study is 
currently ongoing with litoxetine in women suffering from MUI, and, while early in its conduct, the 
adverse events reported to date confirm the data previously reported.  
 
The safety and tolerability of  litoxetine was mainly determined on data from 445 subjects included in 
depression studies, receiving daily doses up to 100 mg daily, up to 6 weeks duration, to support the 
current use of litoxetine at doses 20, 40, and 60 mg daily (10, 20 and 30 BID) for the currently proposed 
8-week treatment period, while the non- clinical pharmacology supports the scientific rationale to 
evaluate litoxetine in the indication of UI. The safety data from the comprehensive nonclinical study 
program support the proposed Phase I/IIa study. Further details can be found in the Investigator's 
Brochure (Edition 3, Feb 2018). 
 
Serotonin plays an important role in centrally modulating the reflexes of continence/micturition; 5-HT 
potentiates the guarding reflex which allows continence by increasing urethral pressure and inhibits the 
micturition reflex responsible for voiding. Animal studies have shown that increased levels of 5-HT 
and norepinephrine (NE), in the sacral spinal cord, lead to increased urethral tone via enhanced pudendal 
nerve stimulation to the urethral striated sphincter muscle during the storage phase of the micturition 


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 2nd April 2019 
Study code: IXA-CSP-002 
 
 
 
Final 
 
Page 9 of 39
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cycle. Studies with duloxetine support a similar mechanism in women, believed to result in stronger 
urethral closure during urine storage with physical stress.  
 
Animal studies have confirmed that litoxetine increases the urethral sphincter pressure, and also 
demonstrated that litoxetine improves bladder capacity through a relaxation effect of the detrusor. 
Taken together these effects suggest that litoxetine could have therapeutic benefit in Urinary 
Incontinence, a condition for which there remain an unmet medical need. 
 
The 5-HT selectivity of litoxetine, and the weaker affinity for NE and epinephrine (E) as well as for 
dopamine (DA) transporters has the potential to provide a good cardiovascular safety profile, and reduce 
the risk of nausea which is the most frequent side effect following treatment with 5 HT reuptake 
inhibitors. 
 
Further details can be found in the Investigator's Brochure (Edition 3, Feb 2018), which contains 
comprehensive information on the investigational product. 
 
Taken together the Risk/Benefit for the use of litoxetine in the proposed study phase 1/2a is considered 
acceptable. 
 
1.3 Rationale 
Urinary incontinence is a condition which can have a significant negative impact on the psychological 
well-being, social functioning and overall quality of life of those affected. There remains an unmet 
medical need to identify treatment options for patients suffering from UI. The “dual action”-inhibitory 
effect on detrusor muscle activity and excitatory effect on urethral sphincter- provides a scientific 
rationale to evaluate whether litoxetine treatment may be a treatment option for UI. 
 
1.4 Statistical Analysis Plan Summary (SAP) 
This Statistical Analysis Plan (SAP) describes the statistical analysis for the IXA-CSP-002 study. The 
SAP provides full details of the analyses, the data displays and the algorithms to be used for data 
derivations. The analysis will be done using the statistical software SAS version 9.4 or higher. 
 
1.5 Clarifications from Protocol 
a. Efficacy analysis of nocturia events has been added, although not specifically laid out in the 
protocol, since this data is captured in the bladder diary and nocturia episodes are of relevance 
for the wellbeing of the patient. 
b. The protocol includes an mITT population, which has been omitted from analyses since it was 
determined that the ITT and PP population will adequately describe the data. 
c. The methodology described in the protocol for the efficacy analyses is a mixed model with 
repeated measures (MMRM). In light of the fact that the efficacy measurements were recorded 
at visit 2 and visit 6 only, there are no repeated measures. Therefore, the MMRM model 
described in the protocol cannot be applied to these analyses. The efficacy analyses will be 
conducted as an analysis of covariance (ANCOVA). 
d. The description of the efficacy endpoints in the protocol in clarified to be: 
a. Percentage change in number of incontinence episodes that a subject had in a week 
This analysis is consistent with the analysis conducted for the phase 2 study IXA CSP 
001 
 
1.6 Study Summary 
This is a Phase 1/2a, double-blind, randomised, placebo-controlled, parallel-group study in subjects, 
male and female, 18 to 70 years old diagnosed with UI.  


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 2nd April 2019 
Study code: IXA-CSP-002 
 
 
 
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The study will include a 2-week, single-blind (subject blind) Screening Placebo Run-In Period and an 
8-week double-blind Treatment Period. The treatment period is a dose titration posology starting with 
10 mg BID for 1 week, escalated to 20 mg BID for 1 week, and subsequently escalated to 30 mg BID 
for 6 weeks for a total treatment duration of 8 weeks. The Treatment Period will be followed by a 1week 
Dose-tapering Period and subjects will return to the clinic for a safety Follow up Visit 4 weeks after 
treatment is completed. This provides a total study duration of 15 weeks. 
 
Safety assessments will be conducted throughout the trial and will include physical examinations, vital 
signs, evaluation of psychiatric status (suicidality, depression symptoms, anxiety and sleep related 
symptoms), clinical laboratory evaluations, 12-lead electrocardiograms (ECGs), and adverse events 
(AEs).  
Efficacy will be assessed by number of urinary incontinence episodes and the number of incontinence 
pads used at the end of the Placebo Run In period and after 8 weeks of double blind study treatment. 
 
Approximately 95 subjects are expected to be enrolled into a 2 week, single-blind (subject blind), 
Screening Placebo Run-In Period. It is expected that 20% of subjects will not qualify for randomization 
after Screening Placebo Run-In.  
The study is expected to randomize approximately 78 subjects into the double-blind treatment where 
subjects will be allocated to litoxetine (dose titration 10 mg, 20 mg, 30 mg) or matched placebo BID in 
a 2:1 ratio. A post randomisation dropout rate of 30% has been estimated, resulting in 60 evaluable 
subjects. This sample size is expected to provide confidence intervals for the most conservative rate of 
safety events (50%) that are +/- 14% for the widest observed intervals in the treatment arm. 
 
The present study, for which safety is the primary endpoint, will include patients diagnosed with UI and 
is designed as a phase 1/2a study. The inclusion of a placebo arm is based on recent European Medicines 
Agency (EMA) guidelines for the development of medications for UI (European Medicines Agency, 
UI Guideline 2013).  The dose titration posology serves to explore safety and tolerability following a 
sequential increase in dose, rather than as a fixed dose regimen. The selection of safety parameters for 
determination of subject eligibility and for safety analysis reflect the FDA’s recommendation for 
evaluation of SSRIs, including attention to psychiatric adverse events and events indicative of abuse 
potential. Inclusion of subjects in the age range 18-70 is reflective of the expectation that UI may affect 
all age groups, with increasing prevalence with age (FDA Guidance General Consideration for the 
Clinical Evaluation of Drugs). The choice of efficacy endpoint (percentage change from end of the 
Placebo Run-in Period to Week 8 in the number of incontinence episodes/24 hours) is a clinical measure 
to explore whether litoxetine has a clinically relevant treatment effect on patients’ reported 
symptomatology and patient reported outcome measures in a clinical practice setting. The 2-week 
Screening Placebo Run-In Period serves to control for the placebo effect which is anticipated to be 
relatively large. 
 
1.7 Version History 
SAP version history: 
SAP v1.3 – Final (2nd April 2019).  
SAP v1.2 – Draft 4 (25th March 2019). 
SAP v1.1 – Draft 3 (21th February 2019). 
SAP v1.0 – Draft 2 (18th February 2019). 
SAP v0.1 – Draft version (8 November 2018). 
 
Study protocol version history:  
Version 1 Final Sep 14, 2017 
Version 2 Amendment 1, June 28, 2018 


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 2nd April 2019 
Study code: IXA-CSP-002 
 
 
 
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Version 3 Amendment 2, October 10, 2018 
 
2. Study Objectives 
2.1 Primary Objective 
The primary objective of this study is to evaluate the safety and tolerability of litoxetine (dose titration 
10 mg for 1 week - 20 mg for 1 week - 30 mg for 6 weeks BID) compared to corresponding placebo in 
subjects with a diagnosis of UI. 
 
2.2 Secondary Objective 
The secondary objective of this study is to explore efficacy of litoxetine (dose titration 10 mg for 1 
week - 20 mg for 1 week - 30 mg for 6 weeks BID) compared to corresponding placebo in subjects 
with a diagnosis of UI. 
 
2.3 Primary Endpoint(s) 
Safety: 
1. Incidence and severity of AEs and Adverse Events of interest (urinary retention, withdrawal 
symptoms) over the course of the study. AEs are recorded at visits 2,3,4,5,6 and 7. 
2. Adverse Events of special psychiatry interest (nervousness, anxiety, panic attacks, insomnia, 
aggression, mania, suicidal ideation, development/worsening of depression) over the course of 
the study 
3. Suicidal Adverse Events and Adverse Events suggestive of abuse potential will be analysed, 
and detailed narratives provided  
4. Lab parameters: Haematology and chemistry recorded at visit 1,2,6 and 7. Urinalysis recorded 
at visit 1 and 2. 
5. Absolute change from end of the Screening Placebo Run-In Period in ECG readings and Week 
8 (Visit 6). ECG parameters of interest include: ventricular rate, QT interval, corrected QT 
interval, PR interval, and QRS duration  
6. Absolute change from end of the Screening Placebo Run-In Period to each visit in standardised 
cuff systolic and diastolic blood pressure and radial heart rate 
 
2.4 Secondary Endpoints(s) 
Efficacy: 
1. Percentage change from end of the Screening Placebo Run-In Period to Week 8 (Visit 6) in the 
number of incontinence episodes in a week  
2. Absolute change from end of the Screening Placebo Run-In Period to Week 8 (Visit 6) in the 
number of incontinence episodes/24 hours (daily average) 
3. Proportion of subjects who become continent at Week 8 (Visit 6) 
4. Change from end of the Screening Placebo Run-In Period to Week 8 (Visit 6) in the total 
number of incontinence pads used per week 
5. Percentage  change from end of the Screening Placebo Run-In Period to Week 8 (Visit 6) in the 
number of nocturia episodes in a week. 
 
3. Study Design 
This is a Phase 1/2a, double-blind, randomised, placebo-controlled, parallel-group study in subjects 18 
to 70 years old diagnosed with UI.  
 
The study will include a 2-week, single-blind (subject blind) Screening Placebo Run-In Period and an 
8-week double-blind Treatment Period. The Treatment Period will be followed by a 1 week Dose-
tapering Period and subjects will return to the clinic for a safety Follow up Visit 4 weeks after treatment 
is completed. This provides a total study duration of 15 weeks. No interim analysis is planned. 


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 2nd April 2019 
Study code: IXA-CSP-002 
 
 
 
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All subjects will enter the Screening Placebo Run-In Period during which eligibility will be assessed 
and single blind placebo run-in medication will be provided. In the latter half of this period, the subject 
will complete 7 days of bladder diary to capture incontinence events and pad usage. Subjects who 
continue to meet eligibility criteria after the Screening Placebo Run-In period, will enter the Treatment 
Period and be randomly assigned (2:1) to receive study drug (litoxetine10 mg, 20 mg, 30mg) or 
matching placebo BID.  
Litoxetine or placebo treatment will be provided with dose titration, starting with 10 mg BID for 1 
week, escalated to 20 mg BID for 1 week, and subsequently escalated to 30 mg BID for 6 weeks’ 
duration (for a total treatment period of 8 weeks).  
If the subject does not tolerate the last dose level escalation (i.e. cannot tolerate 30 mg BID), the dose 
can be reduced to the previous dose level (20 mg BID). If the patient does not tolerate the lower dose 
level (20 mg BID) s/he will be discontinued from the study. After 8 weeks of treatment, doses will be 
reduced by 50% over 1 week to taper off treatment. A safety follow up visit will occur 4 weeks after 
treatment is permanently stopped (total study duration 15 weeks). 
 
Safety assessments will be conducted throughout the trial and will include physical examinations, vital 
signs, evaluation of psychiatric status (suicidality, depression symptoms, anxiety and sleep related 
symptoms), clinical laboratory evaluations, 12-lead electrocardiograms (ECGs), and adverse events 
(AEs).  
 
Efficacy will be assessed by number of urinary incontinence episodes and the number of incontinence 
pads used, recorded at Baseline (V2) and endpoint (V6). 
 
A schedule of assessments is provided in Figure 1.  
A schematic of the study design is presented in Figure 2. 
 
 
 


Statistical Analysis Plan 
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Date: 2nd April 2019 
Study code: IXA-CSP-002 
 
 
 
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Figure 1: Schedule of Assessment 
Visit Number 
Visit 1(1) 
Visit 2(1) 
Visit 3 
Visit 4 
Visit 5 
Telephone 
contact 
Visit 6 
Visit 7 
Visit Name 
Screening/ 
Placebo 
Run In  
Eligibility 
assessment/ 
Randomization  
(start 10 mg 
litoxetine or 
Placebo BID) 
1 week 
Post 
Randomization 
First dose 
escalation 
(start 20 mg or 
Placebo BID) 
2 weeks Post 
Randomization 
Second dose 
escalation 
(start 30 mg or 
Placebo BID) 
3 weeks Post 
Randomization 
 
 
8 weeks post 
Randomization 
Final Treatment 
Visit(4) 
(ET Visit) 
13 weeks post 
Randomization 
Post-Treatment 
Safety F/U(3) 
(End of Study 
Visit) 
Study Day (2) 
Day 0 
Day 14  
Day 21 
Day 28 
Day 35 
Day 42 
Day 70 
Day 105 
Signed informed 
consent 
X 
 
 
 
 
 
 
 
Demographics (incl 
body weight and height, 
BMI) 
X 
 
 
 
 
 
X(13) 
X(13) 
Complete C-SSRS, BDI-II, 
BAI, PSQI16 
X 
X 
X 
X 
X 
X (C-SSRS 
only) 
X 
X 
Medical / surgical/ 
smoking history  
X 
 
 
 
 
 
 
 
Urinary and 
incontinence history 
X 
 
 
 
 
 
 
 
Prior and concomitant 
medication recording 
X 
X 
X 
X 
 
 
X 
X 


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Figure 1: Schedule of Assessment 
Visit Number 
Visit 1(1) 
Visit 2(1) 
Visit 3 
Visit 4 
Visit 5 
Telephone 
contact 
Visit 6 
Visit 7 
Visit Name 
Screening/ 
Placebo 
Run In  
Eligibility 
assessment/ 
Randomization  
(start 10 mg 
litoxetine or 
Placebo BID) 
1 week 
Post 
Randomization 
First dose 
escalation 
(start 20 mg or 
Placebo BID) 
2 weeks Post 
Randomization 
Second dose 
escalation 
(start 30 mg or 
Placebo BID) 
3 weeks Post 
Randomization 
 
 
8 weeks post 
Randomization 
Final Treatment 
Visit(4) 
(ET Visit) 
13 weeks post 
Randomization 
Post-Treatment 
Safety F/U(3) 
(End of Study 
Visit) 
Study Day (2) 
Day 0 
Day 14  
Day 21 
Day 28 
Day 35 
Day 42 
Day 70 
Day 105 
Vital signs(11) 
X 
X 
X 
X 
X 
 
X 
X 
Physical examination  
X 
X 
X 
X 
X 
 
X 
X 
PVR 
X 
X 
 
 
 
 
X 
 
Pregnancy test(5,6) 
X 
X 
X 
X 
 
 
X 
X 
Urinalysis (dipstick)(10) 
X 
X 
 
 
 
 
 
 
Haematology and 
biochemistry(8) 
X 
X 
X(15) 
X(15)  
 X(15) 
 
X 
X(9) 
ECG (resting, 12-lead)  
X 
X 
X 
X 
X 
 
X 
X(7) 
Evaluation of 
eligibility/randomization
X 
X 
 
 
 
 
 
 
Dispensing/collection of 
trial drug 
X 
X 
X 
X 
 
 
X(14) 
X 


Statistical Analysis Plan 
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Date: 2nd April 2019 
Study code: IXA-CSP-002 
 
 
 
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Figure 1: Schedule of Assessment 
Visit Number 
Visit 1(1) 
Visit 2(1) 
Visit 3 
Visit 4 
Visit 5 
Telephone 
contact 
Visit 6 
Visit 7 
Visit Name 
Screening/ 
Placebo 
Run In  
Eligibility 
assessment/ 
Randomization  
(start 10 mg 
litoxetine or 
Placebo BID) 
1 week 
Post 
Randomization 
First dose 
escalation 
(start 20 mg or 
Placebo BID) 
2 weeks Post 
Randomization 
Second dose 
escalation 
(start 30 mg or 
Placebo BID) 
3 weeks Post 
Randomization 
 
 
8 weeks post 
Randomization 
Final Treatment 
Visit(4) 
(ET Visit) 
13 weeks post 
Randomization 
Post-Treatment 
Safety F/U(3) 
(End of Study 
Visit) 
Study Day (2) 
Day 0 
Day 14  
Day 21 
Day 28 
Day 35 
Day 42 
Day 70 
Day 105 
Patient bladder diary 
review/collection(12)  
X 
X 
 
 
 
 
X 
 
Recording of AEs 
 
X 
X 
X 
X 
 
X 
X 
Abbreviations: AEs = adverse events; BMI = body mass index; ECG = electrocardiogram; ET = early termination; PVR = postvoid residual urine volume; UTI = 
urinary tract infection 
(1) 
Eligible subjects will undergo a 2-week Screening Placebo Run-In Period with 7 days bladder daily diary symptom collection. Subjects who continue 
to be eligible after the Screening Placebo Run-In Period will be randomised (Treatment Period). 
(2) 
Visit window ± 2 days 
(3) 
AEs must be followed for a minimum of 30 days and until complete resolution or stabilization of the event, or as deemed appropriate by the 
Investigator on consultation with the Sponsor medical responsible. 
(4) 
If a subject is withdrawn prematurely from the trial, all procedures indicated for the Week 8 (Visit 6) visit must be performed. The Investigator 
should use every effort to encourage the subject to taper study medication for 1 week and to return for the Safety Follow-up Visit (Visit 7). 
(5) 
Serum pregnancy tests will be performed prior to entry into the trial (Visit 1), the ET Visit (Visit 6; if the subject is discontinuing the study) and at the 
End of Study Visit (Visit 7) for all female subjects of childbearing potential. Only those female subjects with a negative pregnancy test at Visit 1 will receive 
trial medication. 


Statistical Analysis Plan 
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(6) 
Urine (dipstick) pregnancy tests will be performed at Visits 2, 3, 4, 5, and 6 (if it is not the ET Visit) for all female subjects of childbearing potential. 
Only those female subjects with a negative pregnancy test will receive trial medication. 
(7) 
ECG at Follow-up (Visit 7) is only required if ECG was abnormal at Week 8 (Visit 6) and the abnormality represents a clinically significant worsening 
from baseline. 
(8) 
Blood samples will be taken in a fasting state at Screening, Day 14 (Visit 2) and Week 8 (Visit 6). 
(9) 
Laboratory tests at Follow-up (Visit 7) are only required if labs were abnormal at Week 8 (Visit 6) and the abnormality represents a clinically 
significant worsening from baseline. 
(10) 
If Urine Dipstick is positive for nitrates and leukocyte esterase, take history of signs and symptoms of UTI, and perform urine culture. If urine culture 
and clinical signs and symptoms are positive, the subject cannot be included, but can be re-screened at a later date as long as the subject does not meet 
exclusion criterion 3 (4 or more UTIs in the past 12 months). 
(11) 
Vital signs include blood pressure, heart rate, and body temperature. 
(12) 
At Visit 1, the patient is in formed how to use the bladder diary. During the 7 days prior to Visit 2 and Visit 6 the following urinary incontinence 
information will be recorded in the bladder diary: the number of incontinence episodes/pads used daily.  
(13) 
Weight only. 
(14) 
Dispense study drug for the 1-week tapering period (half of the dose to which the subject is randomized). 
(15) 
Electrolytes (including sodium) only. 
(16)  In addition to the visit assessments detailed above, suicide monitoring using the C-SSRS will also be performed by a telephone contact with the subject 
4 weeks post randomization (study day 42). 
 


Statistical Analysis Plan 
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Figure 2: Study Design 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BID = twice daily 
 
 
Single-blind Screening Placebo Run-In 
Period 
(subject blind)  
Day 0-14 
Double-blind Period 
Randomization (2:1) 
(Day 14) 
Treatment Period 
8 weeks duration
Taper Period (study drug will be administered ONCE daily in the morning) 
(Week 11)
Follow-up Visit 
(Week 15)
Litoxetine; 
10 mg BID, 1 week 
20 mg BID, 1 week 
30 mg BID, 6 weeks 
 
dose escalation 
Placebo 
Matching to 
litoxetine  
dose escalation 


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3.1 Sample Size 
Approximately 95 subjects are expected to be enrolled into the 2-week, single-blind (subject blind) 
Screening Placebo Run-In Period. It is expected that 20% of subjects will not qualify for randomization 
after Screening Placebo Run-In.  
 
The study is expected to randomize approximately 78 subjects into the double-blind treatment where 
subjects will be allocated to litoxetine (dose titration over 10 mg, 20 mg, 30mg) or matched placebo 
BID in a 2:1 ratio. A post randomisation dropout rate of 30% has been estimated, resulting in 60 
evaluable subjects.  
 
A sample size of 60 subjects is expected to provide a 95% confidence interval for a rate of safety events 
of 50% with a width +/- 14%. The sample size calculation is based on the precision of the estimate of 
the primary outcome, safety events, using a rate of  50% which would provide the most conservative 
sample size. 
 
3.2 Randomisation 
The patient number will be an 8 digits code: 3 digits country code (the study is only conducted in the 
US, US Country Code is 840), 2 digits site number and 3 digits patient number. Each participating 
investigative study centre will be assigned a 2 digit investigative study centre number (eg, 01, 02, 03, 
and up) on enrolment.  
 
Each subject will receive a 3 digit Screening number in sequential order at the Screening Visit after the 
consent form is signed (eg, 001, 002, 003), regardless of the investigative study centre at which the 
subject is enrolled.   
 
Enrolled subjects who fail Screening or discontinue study participation early, regardless of whether 
treatment was received or not, will retain their Screening number and a new number will be assigned to 
the next enrolled subject. 
 
For subjects who remain eligible after the Screening Placebo Run-In period, randomization numbers 
(which are separate from the screening numbers) will be assigned by the Interactive Response 
Randomization System, which is integrated into the Electronic Data Capture (EDC) system. Details of 
assignment of subject numbers will be provided as a separate document. 
 
Subjects will be randomly assigned to receive litoxetine or matched placebo BID in a 2:1 ratio. 
 
 


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4. Analysis Sets 
4.1 Study Populations 
The study population will consist of subjects with UI. Subjects must be able to provide written consent 
and meet all the inclusion criteria and none of the exclusion criteria. 
A valid efficacy measurement is defined as a valid number of incontinence episodes as recorded in the 
bladder diary and uploaded in the eCRF at Visit 2 and Visit 6, i.e. either as 0 or greater than 0. 
 
There are 4 analysis populations for this study: 
Randomised population: 
Defined as all subjects randomised to treatment (Visit 2). 
 
Safety population:  
Defined as all subjects who are randomised to treatment (Visit 2), receive study drug, and undergo at 
least 1 visit. 
 
Intent-to-Treat (ITT) population:  
Defined as all subjects who are randomized to treatment (Visit 2), receive at least one dose of study 
drug and have a valid efficacy measurement at Baseline (Visit 2).  
 
Per Protocol (PP) population:  
Defined as those subjects who are randomised, receive at least one dose of study drug, provide a valid 
efficacy measurement at Baseline (Visit 2) and a valid end of study primary efficacy endpoint (Visit 6), 
and have completed the study without a major protocol deviation. 
 
The following populations are defined for analysis purposes: 
1. Enrolled Population: each subject that signed the Informed Consent form and entered the 
Screening Period. 
2. Completers Population: each subject that completed the trial, per protocol. 
3. Full Analysis Set Population: each subject which is in either ITT or PP population. 
  
4.2 Disposition of Subjects 
Subjects randomised and who receive study drug will be identified as completing the study or 
withdrawn from the study. 
 
The participation of an individual subject may be discontinued prematurely for reasons such as: 
1. Withdrawal of written informed consent 
2. Required treatment with any medication known or suspected to interfere with the study drug 
3. Pregnancy 
4. Lack of study compliance 
5. Treatment unblinding (treatment unblinding for the purpose of expedite reporting of SUSARs 
will not by default lead to withdrawal of subjects from the study) 
6. Any other condition which in the opinion of the Investigator no longer permits safe participation 
in the study 
7. Protocol Deviation 
8. AE 
9. Other 
 
4.3 Protocol Deviations 
In addition to clinical and study conduct protocol deviations which may include deviations to visit 
procedure, lab testing and patient safety, the following criteria will be considered as protocol deviations: 


Statistical Analysis Plan 
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1. Study drug compliance less than 80% during Treatment Period of the study 
2. Not valid efficacy Endpoint value: Number of incontinence episodes not available at Visit 6 
(Endpoint). 
3. Not valid efficacy Baseline value: Number of incontinence episodes not available at Visit 2 
(Baseline).  
4. Prohibited medication and medications to be used with caution taken 30 days prior to study 
entry (Visit 1) onwards. During the Blinded Data Review meeting the Sponsor will evaluate 
the medications taken from each patient on a case by case basis, determining if major protocol 
deviations are found, and if so exclude such subject from the ITT or PP population analysis. 
The adjudication of prohibited and to be used with caution medications will be provided by the 
Medical monitor. They include: 
a. Prohibited medications: 
o Nonselective, irreversible monoamine oxidase inhibitors: eg, moclobemide or 
linezolid 
o CYP1A2 inhibitors like fluvoxamine, ciprofloxacin, or enoxacin since the 
combination may result in elevated plasma concentrations of litoxetine 
o CYP2D6 inhibitors like bupropion, fluoxetine, metoclopromide, paroxetine 
or quinidine since the combination may result in elevated plasma 
concentrations of litoxetine 
o Pimozide and thioridazine since the combination with litoxetine may result in 
elevated plasma concentration of these compounds 
o Medicinal products containing duloxetine 
o St John’s wort or herbal preparations containing St John’s wort (Hypericum 
perforatum) 
o Other serotonergic agents: SSRIs, SNRIs, tricyclic antidepressants like 
clomipramine or amitriptyline, triptans, tramadol, pethidine, and tryptophan 
o Administration of any other medication that would be considered a safety risk 
for co administration with litoxetine 
o Any pharmacologic agent used to treat symptoms of urinary incontinence 
b. Medications to be used with caution: 
o Warfarin or digoxin 
o Benzodiazepines, morphinomimetics, antipsychotics, phenobarbital, sedative 
antihistamines 
o 1c antiarrhythmics (propafenone, flecainide) and metoprolol 
o Herbal preparations (other than St John’s wort mentioned above). However, 
subjects who have been on a stable dose of these preparations prior to 
entering the study may continue to take these drugs. No new herbal 
preparations may be introduced or dosage changes initiated while 
participating in the study. 
5. Days outside the protocol timeframe (protocol allowed time window is ±2 days) at Visit 6 
greater or equal to 8 days will be considered a major protocol deviation. If the number of days 
outside the protocol timeframe is smaller or equal to 7 the deviation is considered minor. 
 
5. Definitions and Data Conventions  
This section contains definitions and conventions that will be used for analysis. 
5.1 General, demographic and baseline characteristics 
Age (years) 


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The age will not be recalculated. The values automatically derived in the CRF will be used in the 
analysis. 
 
Body Mass Index (BMI) (kg/m2) 
BMI will not be recalculated. The values automatically derived in the CRF will be used in the analysis. 
 
Previous and Concomitant Medication 
Any medication the subject takes from the signature of informed consent and through the duration of 
the study, other than the study drug, is considered a concomitant medication. 
The CRF records all concomitant medications and all medications taken within 30 days prior to 
Screening. 
The medications labelled as ‘ongoing’ in the ‘Prior and Concomitant Medications and Procedures’ page 
in the eCRF will be considered concomitant medications. All other medications are evaluated based on 
the date: all records with start or end date after the date of signature of the informed consent are labelled 
as concomitant, other medications are labelled as past. 
 
Past and Concomitant disease  
Medical history will be recorded in the CRF. A disease is concomitant if ongoing at Screening visit (i.e. 
it ended after Screening visit).  
A disease is considered as past if it ended prior to the Screening visit.  
The diseases labelled as ‘ongoing’ in the ‘Medical and Surgical procedure history’ page in the eCRF 
will be considered concomitant diseases, all other diseases will be defined as past. 
 
Study drug intake 
Each dispensing of study drug will be documented in the eCRF. 
 
Date of first randomised study drug intake is the Study Visit 2 date, at which the trial drug is dispensed. 
 
Date of last randomised study drug intake is the date of study visit 6. If this date is missing, the last 
Study Visit date available will be considered (excluding Visit 1 and Visit 7 dates). The tapering period 
will not be included to assess the last intake. 
 
5.2 Compliance 
 
All subjects will enter the Screening Placebo Run-In Period (2 weeks) during which they will receive 
the placebo treatment twice daily. 
After randomisation, subjects are instructed to take the study drug or the matched Placebo orally twice 
daily (BID) for 8 weeks. Study treatment (litoxetine or placebo) will be provided with dose titration, 
starting with 10 mg BID for 1 week, escalated to 20 mg BID for 1 week, and subsequently escalated to 
30 mg BID for 6 weeks for a total litoxetine treatment duration of 8 weeks.  
After 8 weeks of treatment, doses will be reduced by 50% over 1 week to taper off treatment. 
 
Compliance will be computed for treatment period only, ie. from Visit 2 to Visit 6 (8 weeks). 
 
During the treatment period, patients are instructed to take two capsules in the morning and two capsules 
in the evening. The two capsules will be taken as follows: one from jar A and one from jar B.  
The CRF captures the actual medication taken based on quantitative pill count at the site. The CRF 
data is therefore to be used as the source to determine patient treatment compliance. 
 
The Investigational Site personnel will collect the study drug containers and will count and record 
unused study drug. This information will be used to compute compliance according to the following 
formula:   


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𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒= ൬
𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝐶𝑎𝑝𝑠𝑢𝑙𝑒𝑠 𝑡𝑎𝑘𝑒𝑛
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑑𝑎𝑦𝑠 𝑏𝑒𝑡𝑤𝑒𝑒𝑛 𝑉𝑖𝑠𝑖𝑡 2 𝑎𝑛𝑑 𝐿𝑎𝑠𝑡 𝑠𝑡𝑢𝑑𝑦 𝑑𝑟𝑢𝑔 𝑖𝑛𝑡𝑎𝑘𝑒 × 4൰× 100 
The above formula takes into account the fact that four capsules are taken each day (number of days × 
4). 
If the date of last study drug intake is not available, the date of the latest available visit will be considered 
in the formula above (excluding Visit 1 and Visit 7 dates). 
 
To compute the compliance for Jar A and Jar B separately, the following formula will be used: 
𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒 𝐽𝑎𝑟 𝑖= ൬
𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝐶𝑎𝑝𝑠𝑢𝑙𝑒𝑠 𝑡𝑎𝑘𝑒𝑛 𝑓𝑟𝑜𝑚 𝐽𝑎𝑟 𝑖
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑑𝑎𝑦𝑠 𝑏𝑒𝑡𝑤𝑒𝑒𝑛 𝑉𝑖𝑠𝑖𝑡 2 𝑎𝑛𝑑 𝐿𝑎𝑠𝑡 𝑠𝑡𝑢𝑑𝑦 𝑖𝑛𝑡𝑎𝑘𝑒 × 2൰× 100 
Where i = A, B.  
The formula takes into account that two capsules from each Jar are taken at each day. 
 
The total number of capsules taken during the treatment period will be derived from the eCRF as: 
𝐶𝑎𝑝𝑠𝑢𝑙𝑒𝑠 𝑡𝑎𝑘𝑒𝑛= 𝑐𝑎𝑝𝑠𝑢𝑙𝑒𝑠 𝑑𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑−𝑐𝑎𝑝𝑠𝑢𝑙𝑒𝑠 𝑟𝑒𝑡𝑢𝑟𝑛𝑒𝑑−𝑐𝑎𝑝𝑠𝑢𝑙𝑒𝑠 𝑛𝑜𝑡 𝑡𝑎𝑘𝑒𝑛/𝑛𝑜𝑡 𝑟𝑒𝑡𝑢𝑟𝑛𝑒𝑑 
Treatment duration will be calculated as:  
 
𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛= 𝐷𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑠𝑡𝑢𝑑𝑦 𝑑𝑟𝑢𝑔 𝑖𝑛𝑡𝑎𝑘𝑒−𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑟𝑢𝑔 𝑖𝑛𝑡𝑎𝑘𝑒 
 
The date of the first study drug intake is the date of Visit 2, after randomisation to treatment (it 
excludes the Placebo Run-in period). Date of last randomised study drug intake is the date of Study 
Visit 6. If this date is missing, the date of last Study Visit available will be considered (excluding 
Visit 1 and Visit 7 dates). 
 
5.3 Safety variables 
All safety variables will be derived from the eCRF. 
 
Adverse Event (AE) An AE is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have a 
causal relationship with this treatment.  
 
Non-Treatment-Emergent Adverse Event (non-TEAE) 
When an AE occurs after written consent has been obtained but before the first dose of treatment study 
drug (Visit 2 date), the AE will be considered a non-treatment emergent AE. Adverse Events, related 
to abnormal laboratory parameters, that were identified at Visit 2, when blood samples were collected 
before the first dose of the study drug, are considered non- TEAEs. 
 
Treatment-Emergent Adverse Event (TEAE) 
An AE that occurs from the time the subject receives his first dose of treatment study drug (Visit 2 date) 
until his last study visit (Follow-up Visit date) will be considered a treatment-emergent AE (TEAE) 
regardless of the assessed relationship to the administration of the study drug. 
 
Immediately Reportable Adverse Event (IRAE) 
Immediately reportable AEs (IRAEs) are AEs that must be reported to the Sponsor within 24 hours of 
the study site being informed of the IRAE. 
 
Immediately reportable AEs include: 


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 
All SAEs 
 
Overdose 
 
Pregnancy 
 
AEs that result in a subject's withdrawal from the study 
 
For litoxetine in the current study and with the current posology, an overdose should be considered as 
any dose above 60 mg taken per day. 
 
Serious Adverse Event (SAE) 
A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose: 
 
Results in death 
 
Is life threatening  
 
Requires hospitalisation or prolongation of existing hospitalisation 
 
Results in persistent or significant disability or incapacity 
 
Is a congenital anomaly or birth defect 
 
Is another medically important condition 
 
An important medical event that is not immediately life-threatening or will result in death or 
hospitalisation, but which may jeopardize the subject or may require medical intervention to 
prevent 1 of the outcomes listed above, should be reported as “serious” as well. 
 
Adverse Event of Special Interest (AESI) 
Adverse events of special interest are: 
1. Adverse Events of Interest include urinary retention and withdrawal symptoms. 
2. Adverse Events of Special Psychiatric Interest include nervousness, anxiety, panic attacks, 
insomnia, aggression, mania, suicidal ideation and development/worsening of depression. 
 
Suicidal Adverse Event 
Suicidal Adverse Events and Adverse Events suggestive of abuse potential will be recorded. 
Adverse Events suggestive of abuse potential are the events listed in the FDA Guidance for Industry 
(see Appendix 6). In particular, the following AEs are defined as adverse events suggestive of abuse 
potential: 
1. Euphoria-related terms (Euphoric mood; Elevated mood; Feeling abnormal; Feeling drunk; 
Feeling of relaxation; Dizziness; Thinking abnormal; Hallucination; Inappropriate affect) 
2. Terms indicative of impaired attention, cognition, and mood (Somnolence; Mood disorders 
and disturbances) 
3. Dissociative/psychotic terms (Psychosis; Aggression; Confusion and disorientation) 
4. Related terms not captured elsewhere (Drug tolerance; Habituation; Drug withdrawal 
syndrome; Substance-related disorders) 
 
 
The following special types of events should be recorded as AEs: 
1. Pregnancy - Occurrence of pregnancy in a subject during a clinical study must be recorded. 
2. Laboratory values that are outside the normal range and if, in the opinion of the Investigator, 
these values represent a clinically relevant change versus pre-treatment values are also 
defined as AEs. 
 
12-lead ECG 
All ECGs should be performed in a standardized method, in triplicate, and approximately 30 seconds 
apart, prior to blood draws or other invasive procedures. Each ECG must include the following 
measurements: ventricular rate, QRS duration, QT, corrected QT, RR, and PR intervals. 


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Physical examination 
A full physical examination will include examination of general appearance, skin, neck (including 
thyroid), eyes, ears, nose, throat, heart, lungs, abdomen, lymph nodes, extremities, urinary system, 
musculoskeletal system, and nervous system, (including the central nervous system). 
 
Psychiatric monitoring 
The following psychiatric monitoring will be conducted at the screening visit and at each study visit: 
1. suicide monitoring through the use of Columbia-Suicide Severity Rating Scale (C-SSRS) 
2. monitor for depression symptoms through the use of the Beck Depression Inventory-II (BDI-
II) 
3. monitor for anxiety and sleep-related symptoms through the use of Beck Anxiety Inventory 
(BAI) and Pittsburgh Sleep Quality Index (PSQI) 
In addition to the visit assessments detailed above, suicide monitoring using the C-SSRS will also be 
performed by a telephone contact with the subject 4 weeks post randomization (study day 42). 
 
5.4 Efficacy Variables 
Bladder Diary Questions 
The bladder diary will be completed daily for the 7 days prior to visit 2 and visit 6, to record the number 
of incontinence episodes and whether these were nocturia events. If a subject has multiple events in 1 
day, each event will preferably be entered separately. The number of incontinence pads used will also 
be recorded in the diary. 
 
Percentage change in number of incontinence episodes in a week 
The number of incontinence episodes entered into the eCRF is the total number of events a subject 
recorded during the 7day period prior to visit 2 and visit 6. This number will be directly used in the 
calculation of % change in number of incontinence episodes in a week 
 
Number of Incontinence Episodes/24 hours (daily average) 
The number of incontinence episodes entered in the eCRF will be divided by 7 to compute the number 
of episodes/24 hours (daily average). This consideration follows the assumption that the bladder diary 
will be filled by the subject for the 7 days prior to Visit 2 and Visit 6 and that the patient entered all 
episodes occurred in this period. Therefore, the following formula will be used: 
 
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝐼𝑛𝑐𝑜𝑛𝑡𝑖𝑛𝑒𝑛𝑐𝑒 𝑒𝑝𝑖𝑠𝑜𝑑𝑒𝑠 / 24 ℎ𝑜𝑢𝑟𝑠= 𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑖𝑛𝑐𝑜𝑛𝑡𝑖𝑛𝑒𝑛𝑐𝑒 𝑒𝑝𝑖𝑠𝑜𝑑𝑒𝑠 𝑟𝑒𝑐𝑜𝑟𝑑𝑒𝑑
7
 
 
Number of Nocturia Episodes in a week 
The number of nocturia episodes entered in the eCRF is the total number of nocturia episodes a subject 
recorded during the 7day period prior to Visit 2 and Visit 6. The value entered in the eCRF will be used 
in the efficacy analysis of nocturia episodes without any adjustment. 
 
Number of Incontinence Pads per week 
The number of incontinence pads entered in the diary represents the number of pads used in a week, 
therefore the value entered in the eCRF will be used in the analysis without any adjustment. 
 
This consideration follows the assumption that the bladder diary is completed by the subject for the 7 
days prior to Visit 2 and Visit 6 and that the patient entered all pads used in this period. 
 
Proportion of subjects who become continent 
A subject is defined as continent if he/she has no incontinence episodes. 


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5.4.1 Sensitivity Efficacy Variables 
Sensitivity Analyses will be performed on the number of incontinence episodes in a week as defined 
in section 5.4. 
 
One set of sensitivity analysis runs efficacy analyses without imputation.  
 
A second set of sensitivity analysis compares the placebo group with the patients in the litoxetine arm 
at 30 mg who did not have a dose reduction. 
 
A third set of tables will analyse the absolute change of the number of incontinence episodes in a week 
and the percentage change in the number of incontinence episodes/24 hours. 
 
5.4.2 Exploratory Efficacy Variables 
Exploratory Analyses will be performed on the number of incontinence episodes in a week and on the 
number of incontinence episodes/24 hours as defined in section 5.4. 
 
Based on previous study results with litoxetine, an exploratory analysis will be conducted in subjects 
with less and more severe UI. Less severe is defined as the population who has incontinence episode 
frequency below the study median at baseline, while more severe is defined as the population who has 
incontinence episode frequency above the study median at baseline.  
 
5.5 Baseline 
Baseline for all Safety variables including the laboratory parameters will be defined as Visit 2 date.  
Baseline for all efficacy endpoints will be defined as the last week of the Screening Placebo Run-in 
Period. 
 
6. Statistical Methodology 
6.1 Handling of Missing Data 
Missing Data for the Safety Analysis 
Partial dates for medications will be imputed. In case of incomplete date, if day and month are missing 
the first of January is imputed, if only the day is missing the first of the month will be imputed. 
Completely missing dates will not be imputed. 
No other imputation methods are used for missing values in safety variables. 
 
Missing Data for the Efficacy Analysis 
The cases where the total number of incontinence episodes is missing will be addressed prior to 
unblinding with the following multiple imputation process: 
1. The imputation method will be applied to the total number of incontinence episodes missing at 
Visit 6 only. 
2. The imputation method will be applied to the number of incontinence episodes only, it will not 
be applied to the number of pads or to the number of nocturia episodes. 
3. The number of imputations will be based on the percentage of missing data. 
4. The seed will be set to 1. 
5. The imputation process will be applied to the ITT population. 
 
The method of Predictive Mean Matching is proposed for the imputation process. The method imputes 
the total number of incontinence episodes for each subject with missing value at visit 6. This method 
does not make an assumption about the distribution of the variables, thereby minimising the risk of 
assuming normality when not applicable.  


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With this method a predictive value is computed via a regression model using a set of observed values 
from cases deemed to be similar to the missing case based on a set of covariates. This methodology is 
consistent with an assumption of Missing at Random. 
 
For all analyses where the imputation method is used, analyses without imputation will also be 
performed as sensitivity analyses.  
 
6.2 Covariate and Subgroups 
Safety 
Age (under 65, over 65) is used as subgroup for the analysis of treatment emergent adverse event. 
 
Efficacy 
The methodology described in the protocol for the efficacy analyses is a mixed model with repeated 
measures (MMRM). In light of the fact that the efficacy measurements were recorded at visit 2 and visit 
6 only, there are no repeated measures. Therefore, the MMRM model described in the protocol cannot 
be applied to these analyses. The efficacy analyses will be conducted as an analysis of covariance 
(ANCOVA). 
The model will include Baseline values as a covariate and dose and site as factor variables. 
 
Baseline is defined as end of Screening Placebo Run-in for all efficacy analyses (Visit 2). 
 
Exploratory efficacy analysis will be performed based on the baseline severity of incontinence episodes, 
as defined in section 5.4.2. Patients will be divided in 2 groups according to the median number of 
incontinence episodes. 
 
6.3 General Methodology 
Safety 
Safety data will be presented and analysed using the Safety Population. 
The primary safety analyses include all treatment emergent adverse events defined as any AE started 
after Visit 2. The analysis will be carried out with point estimates and Clopper Pearson 95% confidence 
intervals. 
 
Descriptive statistics will be provided for all variables in the summary tables by treatment group 
according to the type of variable summarised. 
 
Quantitative variables will be summarised by using n (number of subjects per group), arithmetic mean, 
standard deviation (SD), median and range (minimum and maximum).  
 
Categorical variables will be summarised by using frequency distributions and percentages. 
The number of Adverse Events and the number and the percentage of patients experiencing those 
events, will be summarised by treatment group. Differences between groups will be evaluated using 
Chi-square test or Fisher’s exact test. Subgroup analysis of differences between groups of AEs will be 
performed separately for patients who had an adverse event while on the 10mg dose (AE started from 
Visit 2 and Visit 3), 20 mg dose (AE started from Visit 3 and Visit 4) and 30 mg dose (AE started from 
Visit 4 and Visit 6). Subjects with adverse events who deviated from the protocol dosage will be 
highlighted in the footnotes. 
Shift tables will be used to describe the evaluation of clinical significance for laboratory values, 12-
Lead ECG and physical examination. 
 


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For all analyses, hypothesis testing will be carried out at the alpha = 0.05 level (two-sided) when 
comparing treatments. P-values will be rounded to three decimal places. Statistical significance will be 
declared if the rounded p-value will be less than or equal to 0.05. 
 
Efficacy 
For the PP efficacy analysis of incontinence episodes, only valid efficacy endpoints at Visit 6 will be 
used. For the ITT efficacy analysis of incontinence episodes, valid and imputed endpoints at Visit 6 
will be used. The imputation method is described in section 6.1. No LOCF from baseline will be used 
for any efficacy analysis. 
 
Descriptive statistics will be provided for all variables in the summary tables by treatment group 
according to the type of variable summarised. 
  
Quantitative variables will be summarised by using n (number of subjects per group), arithmetic mean, 
standard deviation (SD), median and range (minimum and maximum).  
 
Categorical variables will be summarised by using frequency distributions and percentages. 
 
For all analyses, hypothesis testing will be carried out at the alpha = 0.05 level (two-sided) when 
comparing treatments. P-values will be rounded to three decimal places. Statistical significance will be 
declared if the rounded p-value will be less than or equal to 0.05. 
 
6.4 Patient Disposition 
Disposition of patients will be presented by treatment group and overall for all patients. 
 
The number of patients included in each of the randomised, safety, ITT, and PP populations will be 
summarised for each treatment group and overall. 
Randomised patients who discontinued from the study prematurely will also be presented with a 
breakdown of the reasons for discontinuation by treatment group and overall for the randomised 
population. 
 
Major and minor protocol violations will be presented in the listings only.  
 
The number of patients who need a dose reduction will be presented with means of descriptive statistics. 
Frequencies and percentages will be used to describe the number of subjects who took a given amount 
of study drug (10/20/30 mg) at each visit. 
 
6.5 Demographic and Screening/Baseline Characteristics 
The baseline demographic characteristics recorded during Screening visit (Visit 1) will be 
summarised by treatment group and overall by means of descriptive statistics. 
The following characteristics will be provided for the Safety population: 
1. Age (years) 
2. Sex 
3. Race (White, Black or African American, Asian, Native Hawaiian or Pacific Islander, Other) 
4. Weight (kg) 
5. Height (m) 
6. BMI (kg/m2)  
7. Vital sign – blood pressure (systolic and diastolic), heart rate, Temperature (C) 
8. ECG result at Screening visit (Normal, Abnormal NCS, Abnormal CS) 
9. Smoking history and current usage, if applicable 
 


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Demographic characteristics will also be summarised by site. 
 
Prior and Concomitant medications 
Medications will be coded using WHO Drug Dictionary, B3 WHO DDE-March17, using the following 
Anatomical Therapeutic Classification (ATC) codes; 
1. Anatomical Main Group (ATC 1st level code); 
2. Chemical subgroup (ATC 4th level code); 
3. Preferred name.  
Prior and concomitant medications will be summarised separately for safety population by anatomical 
main group, chemical subgroup and preferred name by treatment group. 
Subjects experiencing more than one previous (or concomitant) medication within the same anatomical 
main group, chemical subgroup and preferred name will be counted only once. 
 
Past disease and concomitant disease 
Past disease and concomitant diseases will be coded using Medical Dictionary for regulatory activities 
(MedDRA) dictionary (version 20.1) and frequency distributions and percentages will be summarised 
by treatment group for the safety population by System Organ Class (SOC) and PT. 
 
6.6 Compliance 
Overall compliance to study treatment during the treatment period will be summarised using descriptive 
statistics by treatment group. Compliance will also be presented separately for jars A and B. 
Total number of capsules taken from each jar and overall, as well as the treatment duration will also be 
summarised by treatment group. 
Compliance will be analysed in the safety population. 
 
6.7 Safety Analysis 
The general objectives of this study are to establish the safety, tolerability and efficacy of litoxetine in 
men and women who suffer from UI. The primary analyses will focus on safety, describing the adverse 
events with point estimates and Clopper Pearson 95% confidence intervals. All safety analyses will be 
conducted on the safety population. 
 
All AEs will be coded using the MedDRA dictionary (version 20.1).  
 
1. Incidence and severity of Treatment Emergent Adverse Events and Treatment Emergent 
Adverse Events of interest (urinary retention, withdrawal symptoms) over the course of the 
study.  
The Treatment Emergent Adverse Events (TEAEs) and the TEAEs of Interest will be summarised by 
treatment group. The SOCs and PTs will be used for tabulation. The number of TEAEs/TEAEs of 
interest and the number and the percentage of patients with at least one AE will be presented by SOC 
and PT for each treatment group. Within each SOC and PT, the highest severity grade attained will be 
reported, for AEs with divergent severities. 
 
TEAEs/TEAEs of interest will be described with point estimates and Clopper Pearson 95% confidence 
intervals. 
The analysis of treatment emergent adverse events is the primary safety endpoint, the analysis of TEAEs 
of interest is considered as part of the secondary safety analysis. 
 
2. Treatment Emergent Adverse Events of special psychiatry interest (nervousness, anxiety, 
panic attacks, insomnia, aggression, mania, suicidal ideation, development/worsening of 
depression) over the course of the study 


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The Treatment Emergent Adverse Events of special psychiatry interest will be summarised by treatment 
group. The SOCs and PTs will be used for tabulation. The number of AEs and the number and the 
percentage of patients with at least one AE will be presented by SOC and PT for each treatment group. 
Within each SOC and PT, the highest severity grade attained will be reported, for AEs with divergent 
severities. 
Adverse events will be described with point estimates and Clopper Pearson 95% confidence intervals. 
 
3. Treatment Emergent Suicidal Adverse Events and Adverse Events suggestive of abuse potential 
 
Suicidal Adverse Events and Adverse Events suggestive of abuse potential will be summarised by 
treatment group. The SOCs and PTs will be used for tabulation. The number of AEs and the number 
and the percentage of patients with at least one AE will be presented by SOC and PT for each treatment 
group. Within each SOC and PT, the highest severity grade attained will be reported, for AEs with 
divergent severities. 
Adverse events will be described with point estimates and Clopper Pearson 95% confidence intervals. 
 
4. Laboratory parameters (Haematology, chemistry, and urinalysis) 
Abnormal laboratory values will be listed and their incidence, severity, and relationship to the trial drug 
will be tabulated by treatment. Change from baseline will be summarised by treatment. Individual 
changes (shift tables) and individual clinically significant abnormalities will also be presented. 
 
While total white blood cell (WBC) count will be expressed in absolute values, differential count will 
be expressed as both absolute count and percentage of WBCs. 
Haematology and chemistry parameters will be summarised by treatment at each visit (visit 2 and visit 
6) by means of descriptive statistics. At each visit, mean of the change from baseline will be calculated 
by treatment group. For Electrolytes only, values at visit 3, visit 4 and visit 5 will also be summarised. 
In special cases, other parameters may be collected at visit 3, visit 4 and visit 5. In that case the results 
will be included in the summary statistics. 
 
Shift tables presenting the number and the percentage of patients in each bivariate category (Baseline 
(Visit 2) versus Endpoint (Visit 6)) with regards to normal range (Low, Normal, High) will be provided 
for all laboratory parameters (Haematology and chemistry) by treatment group. 
 
For liver enzymes (ALT, AST) and total bilirubin additional analysis will be performed with values 
expressed in ULN (upper limit of normal) in incidence tables (>3xULN, >5xULN, and >10xULN for 
aminotransferase activities, and for total bilirubin >2xULN). 
 
The pregnancy test and the urinalysis will be listed only. In particular, the serum pregnancy test is 
performed at visit 1, visit 6 and visit 7, while the urine (dipstick) pregnancy test is performed at visit 2, 
visit 3, visit 4,visit 5 and visit 6. Urinalysis is performed at visit 1 and 2. 
 
5. Absolute change from end of the Screening Placebo Run-In Period in ECG readings and Week 
8. ECG parameters of interest include: ventricular rate, QT interval, corrected QT interval, PR 
interval, and QRS duration 
 
Absolute values and also change from baseline (Screening Placebo Run-In Period) in ECG readings at 
Week 8 (Visit 6) will be summarised by descriptive statistics. 
ECG parameters of interest include:  
a. Ventricular rate 
b. QT interval 


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c. Corrected QT interval 
d. PR interval 
e. RR interval 
f. QRS duration. 
 
6. Absolute change from end of the Placebo Run-In Period to each visit in standardised cuff 
systolic and diastolic blood pressure and radial heart rate 
 
Absolute change form baseline (Visit 2) to each visit (Visits 3, 4, 5 and 6) for Systolic and Diastolic 
blood pressure will be summarised by treatment group. The average value of 3 recordings will be 
considered in the analysis. 
A t-test will be used to test a difference between arms only for the change of systolic and diastolic blood 
pressure from Baseline (Visit 2) to Endpoint (Visit 6). Hypothesis testing will be carried out at the alpha 
= 0.05 level (two-sided) when comparing treatments. P-value and 95% Confidence Interval will be 
reported. Statistical significance will be declared if the rounded p-value will be less than or equal to 
0.05. 
 
6.8 Additional Safety Analyses 
Adverse Events 
The number of treatment-emergent AEs, non-TEAEs, AEs occurring during follow-up or following 
discontinuation, AEs leading to death, AEs leading to discontinuation and SAEs, and the number and 
the percentage of patients experiencing those events, will be summarised by treatment group. 
Differences between groups will be evaluated using Chi-square test or Fisher’s exact test (if more than 
20% of the cells in a contingency table have counts less than 5). 
 
The following adverse events will be specifically summarized by treatment: 
1. TEAEs of Special Interest include urinary retention, psychiatric adverse events (nervousness, 
anxiety, panic attacks, insomnia, aggression, mania, suicidal ideation, development/worsening 
of depression) and withdrawal symptoms 
2. Treatment Emergent Suicidal Adverse Events and Adverse Events suggestive of abuse 
potential 
3. SAEs 
4. TEAEs 
5. Non-TEAEs 
6. AEs/SAEs which occurred during the 30-day Follow-up Period or following discontinuation 
 
The SOCs and PTs will be used for tabulation. The number of AEs and the number and the percentage 
of patients with at least one AE will be presented by SOC and PT for each treatment group. Within each 
SOC and PT, the highest severity grade attained will be reported, for AEs with divergent severities. 
 
A comparison of treatment-emergent AE rates between litoxetine and placebo will be performed using 
an exact logistic regression model with the treatment-emergent AE (“1”=At least one treatment-
emergent AE occurred for the patient; “0”=otherwise) as dependent variable and litoxetine dose as fixed 
effects. The probability modelled will be treatment-emergent AE=”1”. 
The number of patients and the number of patients considered in the model will be provided. The exact 
odds ratio of the fixed effects will be calculated as the number of patients with/without AEs in all arms. 
If the omnibus test is significant, comparisons between arms will be tested individually, with the relative 
95% CI and p-value. 
The same model will be repeated by considering SAE (“1”=At least one SAE occurred for the patient; 
“0”=otherwise) as dependent variable. 
 


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AEs leading to study drug discontinuation and AEs leading to death will be presented in the listings 
only.  
 
SAEs will be listed and summarised in a table, including a description of each event, the time to onset, 
the severity, and the relationship to trial drug. 
 
All AEs (excluding SAEs) will be listed, and their time to onset, frequency, severity, and relationship 
to the trial drug will be tabulated by treatment. Non-TEAEs will be summarised separately from TEAEs. 
 
A subgroup analysis of TEAEs will be presented. Subjects will be divided according to age (under 65, 
over 65). The SOCs and PTs will be used for tabulation. The number of TEAEs and the number and the 
percentage of patients with at least one TEAE will be presented by SOC and PT for each treatment 
group and according to the patient’s age. 
 
An additional analysis will explore the TEAEs that lead to study drug reduction. Results will be 
presented as listings as well as with means of descriptive statistics. 
 
Withdrawals 
Premature withdrawals from the trial will be displayed and summarised by primary reason and 
treatment. 
 
Physical examination 
Abnormal physical examination findings will be summarised. For each physical examination a shift 
table presenting the number and the percentage of patients in each bivariate category (baseline versus 
Week 8 (Visit 6)) with regards to investigator’s interpretation (Normal, Abnormal NCS, Abnormal CS, 
Not done) will be provided by treatment group. 
The other results of targeted physical examination will be only listed. 
 
Concomitant Medications 
Concomitant medications will be presented in summary tables and listings. They will be classified 
according to whether they were taken before the trial (and ongoing into the trial), or started during the 
trial period. A medication will be defined as concomitant if taken after the date of informed consent. 
The following information will be reported for each concomitant medication: generic name, route of 
administration, start date, stop date, frequency, dosage, and indication. 
 
Prior Medications 
Prior medications will be presented in summary tables and listings. Medications will be classified as 
prior medications if taken before the date of informed consent. 
 
Vital signs 
Vital signs will be summarised by treatment group at each visit (Baseline, Visit 3, Visit 4, Visit 5, Visit 
6) by means of descriptive statistics and listed by subject. 
Parameters collected include: 
1. Heart Rate (bpm) 
2. Body Temperature (Degree Centigrade) 
 
An additional analysis will be performed also on radial heart rate. The actual change from baseline to 
each visit (Visit 3, Visit 4, Visit 5, Visit 6) in radial heart rate will be computed. 
 
Past and Concomitant Diseases 
The medical history should include demographic information, urinary and incontinence history (with 
date of onset), past treatment(s) for incontinence, current co morbidities, relevant past illnesses, surgical 


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procedures performed within the prior 6 months, all current medications (including those taken within 
30 days prior to Screening), and smoking history (including current usage, if applicable). 
 
Past and concomitant diseases will be coded using MedDRA dictionary (version 20.1) and frequency 
distributions and percentages will be summarised by treatment group for the safety population by 
SOC and PT. 
Counts will be given for both SOC and PT by subject.  Subjects experiencing more than one past 
disease (or concomitant disease) event within a given SOC category will be counted only once within 
that SOC.  Similarly, subjects experiencing more than one past disease (or concomitant disease) event 
fitting a given PT will be counted only once for that PT. 
Summary tabulations for the Safety Population, including the number and percentage of subjects with 
past and concomitant diseases by SOC and PT, and further categorised by treatment arm will be 
added. 
12-Lead ECG 
Actual values and also change from baseline in ECG readings at Visit 2 (baseline), Visit 3, Visit 4, Visit 
5, Visit 6 will be summarised by descriptive statistics. 
ECG parameters of interest include:  
1. Ventricular rate 
2. QT interval 
3. Corrected QT interval 
4. PR interval 
5. RR interval 
6. QRS duration. 
 
All three measurements for each parameter will be reported. A shift table presenting the number and 
the percentage of patients in each bivariate category (Baseline to Endpoint) with regards to 
investigator’s interpretation (Normal, Abnormal NCS, Abnormal CS, Not done) will be provided by 
treatment group. 
 
QT will be corrected for HR using the following formulas:  
- 
Fridericia’s correction (QTc=QT/RR0.33),  
- 
Bazett’s correction (QTc=QT/RR0.5)  
- 
Framingham correction (QTc=QT+0.154(1-RR)) 
 
Change in QT and QTc for each correction method, will be analysed by central tendency and as 
categorical analyses. The mean of the QT and HR (obtained in triplicate) will be used. 
 
Central tendency analysis will include: 
- 
Change from baseline (V2) at all time points.  
- 
The change from baseline to Visit 6 in active treatment group will be compared to placebo with 
a two-sided t-test. The level of significance alpha will be set equal to 5%. 
- 
Results will be reported by 95% CI 
 
Categorical analysis will be conducted based on predetermined thresholds (Visit 2, Visit 3, Visit 4, Visit 
5, Visit 6): 
- 
Number of subjects with 450 < QT <= 480 ms, 480 ms < QT <= 500 ms and QT > 500 ms 
- 
Number of subjects with 450 < QTc <= 480 ms, 480 ms < QTc <= 500 ms and QTc > 500 ms  


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- 
Number of subjects with increase in QT from baseline >30 ms and <= 60 ms, as well as >60 
ms 
- 
Number of subjects with increase in average QTc from baseline >30 ms and <= 60 ms, as well 
as >60 ms 
 
Tabulation of the results will follow Appendix 1, Guide for the analysis and review of QT and QTc 
Interval data, Health Canada, 2010. 
 
Psychiatric monitoring 
Answers of the questionnaires for psychiatric monitoring will be listed.  
In particular, answers for the following questionnaires will be reported: 
1. Columbia-Suicide Severity Rating Scale (C-SSRS) 
2. Beck Depression Inventory-II (BDI-II) 
3. Beck Anxiety Inventory (BAI) 
4. Pittsburgh Sleep Quality Index (PSQI) 
 
For the Columbia-Suicide Severity Rating Scale (C-SSRS), summary tables will be used to present the 
results at visit 1, visit 2, visit 3, visit 4, visit 5, telephone contact at day 42, visit 6 and visit 7. Patients 
will be classified into 3 categories of subjects with suicidal behaviour, suicidal ideation and suicidal 
ideation or behaviour according to the Columbia Scoring and Data Analysis Guide (see Appendix 2). 
Subcategories will also be included. A subject has a suicidal ideation if she/he reports “yes” answer at 
any time during treatment to any one of the five suicidal ideation questions (Categories 1-5) on the C-
SSRS; a suicidal behaviour if there is a “yes” answer to any one of the five suicidal behaviour questions 
(Categories 6-10); a suicidal ideation or behaviour is the subject has either suicidal ideation or 
behaviour. 
The Suicidal Ideation Score corresponds to the ‘Most severe Ideation’ score reported in the eCRF and 
it will be presented as listings. A missing suicidal ideation score means  no ideation is present. A shift 
table will be provided to demonstrate changes in C-SSRS categories from Baseline to Visit 6. 
 
The BDI-II is a widely used 21-item self-report inventory measuring the severity of depression in 
adolescents and adults. BDI-II items are rated on a 4-point scale ranging from 0 to 3 based on the 
severity of each item. The maximum total score is 63. The total score derived in the eCRF will be 
summarized. Patients will also be classified according to the following rules: total scores of 0 to 13 
indicates minimal depression, 14 to 19 indicates mild depression, 20 to 28 indicates moderate 
depression, and 29 to 63 indicates severe depression. A summary table will be used to describe the 
results at visit 1, visit 2, visit 3, visit 4, visit 5, visit 6 and visit 7. See Appendix 3 for more details on 
this questionnaire. A shift table will be provided to demonstrate changes in BDI-II categories from 
Baseline (Visit 2) to end of study (Visit 6). 
 
The Beck Anxiety Inventory (BAI) is a widely used 21-item self-reported inventory used to assess 
anxiety levels in adults and adolescents. Summary tables will be used to present the total score at visit 
1, visit 2, visit 3, visit 4, visit 5, visit 6 and visit 7. The total score will be computed summing up the 
score to each question.  
The total score ranges from 0–63. The following categories for the interpretation of scores will be used: 
0–7, minimal; 8-15, mild; 16-25, moderate; and 26–63, severe anxiety. A shift table will be provided to 
demonstrate changes in BAI categories from Baseline (Visit 2) to end of study (Visit 6). 
See Appendix 4 for more details on this questionnaire. 
 
The Pittsburgh Sleep Quality Index (PSQI) is an effective instrument used to measure the quality and 
patterns of sleep in adults. It differentiates “poor” from “good” sleep quality by measuring seven areas 
(components): subjective sleep quality (question 6), sleep latency (question 2 and 5A), sleep duration 


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(question 4), habitual sleep efficiency (questions 1, 3, 4), sleep disturbances (question 5B to 5J 
inclusive), use of sleeping medications (question 7), and daytime dysfunction over the last month 
(questions 8 and 9). In scoring the PSQI, seven component scores are derived, each scored 0 (no 
difficulty) to 3 (severe difficulty). The component scores are summed to produce a global score (range 
0 to 21). Higher scores indicate worse sleep quality. The global score reported in the eCRF will be 
summarized at visit 1, visit 2, visit 3, visit 4, visit 5, visit 6 and visit 7. A global sum greater than “5” 
indicates a “poor” sleeper, therefore patients will be classified according to the global score into “good” 
or “poor” sleepers, a summary table will be provided to describe those results. A shift table will be 
provided to demonstrate changes in PSQI categories from Baseline to end of study (Visit 6). 
See Appendix 5 for more details on this questionnaire. 
 
6.9 Efficacy Analyses 
Efficacy will be assessed by the number of urinary incontinence episodes. There is only one hypothesis 
so there will be no adjustment for multiplicity.   
 
The efficacy analysis will be performed on the ITT and PP populations.  
There will not be an adjustment for multiple comparisons for these efficacy analyses. 
Baseline for all efficacy endpoints will be defined as the last week of the Screening Placebo Run-In 
Period (Visit 2). The final measurement (endpoint) will be defined as Week 8 (Visit 6). 
 
1. 
Percentage change from end of the Screening Placebo Run-In Period to Week 8 in the 
number of incontinence episodes in a week   
 
The efficacy analysis planned is an analysis of covariance model (ANCOVA). Percentage change in 
the number incontinence episodes/week is the response variable. The factor variables will be dose and 
centre. If the center effect is significant, summary statistics will be presented to describe the effect. The 
covariate will be end of the Screening Placebo Run-In Period episodes of incontinence. 
 
The percentage change, %UIEi, for subjects in each arm, is expressed as the ratio of the total number 
of urinary incontinence episodes in a week between final measurement (UIEi, end) and baseline (UIEi, 
base)  
 
%𝑈𝐼𝐸୧ = 𝑈𝐼𝐸୧,௘௡ௗ 
𝑈𝐼𝐸୧,௕௔௦௘
 
 
Since percentage change from baseline does not have the properties of additivity and symmetry, it will 
be log-transformed, and the response variable will be the natural logarithm of the ratio of Week 8 (Visit 
6) to Baseline, as shown below:  
 
 
log(%𝑈𝐼𝐸୧ ) = log ቆ𝑈𝐼𝐸௜,௘௡ௗ  
𝑈𝐼𝐸௜,௕௔௦௘
ቇ 
 
The hypothesis test being conducted is as follows:  
 
H0: log (%UIELitoxetine) – log (%UIEPlacebo ) =  0   
H1: log (%UIELitoxetine) – log (%UIEPlacebo )  ≠ 0, 
 
 
This is equivalent to testing the hypothesis:  


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H0: log ቀ
%௎ூாై౟౪౥౮౛౪౟౤౛  
%௎ூாౌౢ౗ౙ౛ౘ౥ቁ= 0 
 
 
The result of the ANCOVA model will be expressed as log % and then back transformed to percentage 
change. Therefore, H0 can be interpreted as: 
 
 H0: 
%௎ூாಽ೔೟೚ೣ೐೟೔೙೐
%௎ூாౌౢ౗ౙ౛ౘ౥= 1 
 
This makes the actual statistics: 
𝛿 =   log (%𝑈𝐼𝐸𝐿𝑖𝑡𝑜𝑥𝑒𝑡𝑖𝑛𝑒 )–  log (%𝑈𝐼𝐸𝑃𝑙𝑎𝑐𝑒𝑏𝑜 ) = log ቆ%𝑈𝐼𝐸𝐿𝑖𝑡𝑜𝑥𝑒𝑡𝑖𝑛𝑒 
%𝑈𝐼𝐸Placebo
ቇ 
When back-transformed, this is expressed as follows: 
 
 
 
Δ= exp ቀlog ቀ
%௎ூாಽ೔೟೚ೣ೐೟೔೙೐ 
%௎ூாౌౢ౗ౙ౛ౘ౥ቁቁ=
%௎ூாಽ೔೟೚ೣ೐೟೔೙೐
%௎ூாౌౢ౗ౙ౛ౘ౥ 
 
%UIEi  is the ratio of the total number of urinary incontinence episodes in a week at endpoint (Visit 6) 
(UIEi,end) to the total number of urinary incontinence episodes in a week at baseline (UIEi,base) for arm 
i, with i equal to Litoxetine or Placebo.  
 
An ANCOVA will be performed to compare 𝛿 to 0; the test will provide an appropriate p-value with a 
significance level alpha equal to 0.05. This p-value will be computing the probability of observing a 
difference among arms. 
 
Numbers of incontinence episodes equal to 0 (not missing) will be imputed as 0.4 to allow for the log 
transformation. 
 
2. 
Absolute change from end of the Screening Placebo Run-In Period to Week 8 in the 
number of incontinence episodes/24 hours (daily average) 
 
The analysis planned is an analysis of covariance model (ANCOVA). Absolute change in the total 
number of incontinence episodes/24  hours is the response variable. The factor variables will be dose 
and centre. The covariate will be end of the Screening Placebo Run-In Period episodes of incontinence. 
 
Number of incontinence episodes/24 hours will be computed as Total Number of incontinence 
episodes recorded during the 7-day period and entered in the eCRF divided by 7, as defined in Section 
5.4. 
 
The hypothesis test being conducted is as follows: 
 
H0: ∆UIELitoxetine – ∆UIEPlacebo = 0 
H1: ∆UIELitoxetine – ∆UIEPlacebo ≠ 0 
 
Where ∆UIEi is the absolute change, for subjects in arm i, in the number of incontinence episodes/24 
hoursas defined above from baseline (UIEi,base) to the final measurement (UIEi,end): 
∆𝑈𝐼𝐸௜= 𝑈𝐼𝐸௜,௘௡ௗ− 𝑈𝐼𝐸௜,௕௔௦௘ . 
 
Where i goes from 1 to 2 and it represents the 2 arms: Litoxetine and Placebo. 
 
3. 
Proportion of subjects who become continent at Week 8  


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A subject is defined as continent if s/he has no incontinence episodes at Visit 6 (Week 8). Frequencies 
will be used to describe the proportion of subjects who are continent at Week 8. The proportion will be 
computed on the total number of subjects for each arm at baseline. The category Missing will be 
included in the analysis, to consider subjects who do not attend the visit or who have missing values for 
that visit. 
 
Differences between groups will be evaluated using Chi-square test or Fisher’s exact test (if more than 
20% of the cells in a contingency table have counts less than 5). 
 
4. 
Change from end of the Screening Placebo Run-In Period to Week 8 in the number of 
incontinence pads used per week 
The analysis planned is an analysis of covariance model (ANCOVA). Absolute change in the number 
of incontinence pads used per week is the response variable. The factor variables will be dose and 
centre. The covariate will be the number of pads used at the end of the Screening Placebo Run-In Period. 
 
Number of incontinence pads used per week will be derived for the eCRF, as defined in Section 5.4. 
 
The hypothesis test being conducted is as follows: 
 
H0: ∆Pads Litoxetine – ∆Pads Placebo = 0 
H1: ∆Pads Litoxetine – ∆Pads Placebo ≠ 0 
 
Where ∆Padsi is the absolute change, for subjects in arm i, in the number of incontinence pads used per 
week from baseline (Padsi,base) to the final measurement (Padsi,end): 
∆Pads௜= Pads௜,௘௡ௗ− Pads௜,௕௔௦௘ . 
 
Where i goes from 1 to 2 and it represents the 2 arms: Litoxetine and Placebo. 
 
5. 
Percentage change from end of the Screening Placebo Run-In Period to Week 8 in the 
number of nocturia episodes in a week 
 
The analysis planned is an analysis of covariance model (ANCOVA). Percentage change in the total 
number of nocturia episodes in a week is the response variable. The factor variables will be dose and 
centre. The covariate will be end of the Screening Placebo Run-In Period episodes of incontinence. 
 
The number of nocturia episodes in a week is the total number of nocturia episodes recorded over the 
7-day period and entered in the eCRF, as defined in Section 5.4. 
 
The analysis will be carried out as described in section 6.9 point 1. 
 
6.9.1 Sensitivity Efficacy Analyses 
 
For the Efficacy Analyses relating to the number of incontinence episodes, a sensitivity analysis without 
imputation will be performed.  
The sensitivity analyses will be performed on the ITT only, since the imputation method is not used in 
the PP population.  
As with the Efficacy Analysis, baseline for all sensitivity endpoints will be defined as the last week of 
the Screening Placebo Run-In Period. The final measurement (endpoint) will be defined as Week 8 
(Visit 6). 
 


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A second set of sensitivity analysis compares the placebo group with the patients in the litoxetine arm 
at 30 mg who did not have a dose reduction. 
 
A third set of tables will analyse the absolute change of the number of incontinence episodes in a week 
and the percentage change in the number of incontinence episodes/24 hours. 
 
 
1. Percentage change from end of the Screening Placebo Run-In Period to Week 8 (Visit 6) in the 
number of incontinence episodes in a week (without imputation) 
This sensitivity analysis will use an ANCOVA model. It will follow the efficacy analysis described in 
section 6.9 point 1. 
The imputation method will not be applied. 
 
2. Change from end of the Screening Placebo Run-In Period to Week 8 (Visit 6) in the number 
of incontinence episodes/24 hours (daily average) (without imputation) 
The change in the total number of incontinence episodes in a week will be analysed with an ANCOVA 
model. It will follow the efficacy analysis described in section 6.9 point 2. 
The imputation method will not be applied. 
 
3. Percentage change from end of the Screening Placebo Run-In Period to Week 8 (Visit 6) in 
the number of incontinence episodes in a week for patients without a dose reduction 
The percentage change in the total number of incontinence episodes in a week will be analysed with an 
ANCOVA model. It will follow the efficacy analysis described in section 6.9 point 1. In the litoxetine 
group, only patients who did not have a dose reduction will be considered. Therefore, subjects who are 
dispensed the 30 mg dose at visit 5 will be considered in the litoxetine group. 
 
4. Change from end of the Screening Placebo Run-In Period to Week 8 (Visit 6) in the number 
of incontinence episodes/24 hours (daily average) for patients without a dose reduction 
The change in the total number of incontinence episodes/24 hours will be analysed with an ANCOVA 
model. It will follow the efficacy analysis described in section 6.9 point 2. In the litoxetine group, only 
patients who did not have a dose reduction will be considered. Therefore, subjects who took the 30 mg 
dose at visit 6 will be considered in the litoxetine group. 
 
5. Percentage change from end of the Screening Placebo Run-In Period to Week 8 (Visit 6) in the 
number of incontinence episodes/24 hours (daily average) 
This exploratory analysis will use an ANCOVA model. It will follow the efficacy analysis described in 
section 6.9 point 1. 
The number of incontinence episodes/24 hours (daily average) will be used as endpoint. 
 
6. Change from end of the Screening Placebo Run-In Period to Week 8 (Visit 6) in the number 
of incontinence episodes in a week 
The change in incontinence episodes in a week will be analysed with an ANCOVA model. It will follow 
the efficacy analysis described in section 6.9 point 2. 
The total number of incontinence episodes in a week will be used as endpoint. 
 
6.9.2 Exploratory Efficacy Analyses 
 
The severity of incontinence episodes will be explored dividing the population in subjects with 
less/more severe UI. Less severe is defined as the population who has incontinence episode frequency 
below the study median at baseline, while more severe is defined as the population who has incontinence 
episode frequency above the study median at baseline.  


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Based on the assessment of the variability of the data and the size of each subgroup, the efficacy analysis 
will be performed on the subgroups. 
Baseline severity threshold is defined as the median value of incontinence episodes at baseline.  
 
These analyses will be performed on the PP population only. 
 
1. Percentage change from end of the Screening Placebo Run-In Period to Week 8 (Visit 6) in the 
number of incontinence episodes in a week as a function of degree of incontinence 
The percentage change in the total number of incontinence episodes in a week will be analysed with an 
ANCOVA model. It will follow the efficacy analysis described in section 6.9 point 1. Patients will be 
divided in two groups depending on the baseline severity of incontinence episodes. 
The median number of incontinence episodes at baseline will be computed on the randomised 
population. Two analyses will be performed, one on subjects whose baseline number of incontinence 
episodes is less than the median, and the other on subjects whose baseline number of incontinence 
episodes is greater than or equal to the median. 
 
2. Change from end of the Screening Placebo Run-In Period to Week 8 (Visit 6) in the number 
of incontinence episodes/24 hours (daily average) as a function of degree of incontinence.  
The change in the number of incontinence episodes/24 hours (daily average) will be analysed with an 
ANCOVA model. It will follow the efficacy analysis described in section 6.9 point 2. Patients will be 
divided in two groups depending on the baseline severity of incontinence episodes. 
The median number of incontinence episodes at baseline will be computed on the randomised 
population. Two analyses will be performed, one on subjects whose baseline number of incontinence 
episodes is less than the median, and the other on subjects whose baseline number of incontinence 
episodes is greater than or equal to the median. 
 
7. General Considerations 
7.1 Software to be used 
All statistical analyses and data processing will be performed using SAS version 9.4 or higher. 
7.2 Programs and Tables Quality Control 
The following procedures will be implemented as quality control measures: 
 
Double-blind programming, ensuring that the code gives the required output and the 
programming is in compliance with any applicable specifications from the analysis plan 
 
Check for errors and warning messages 
 
Check of the layout of the listings and tables 
 
Additionally, in the course of data collection, eCRF data will be reviewed and queries raised if needed. 
 
8. Data Storage 
Relevant study documentation will be stored in the “Buncro” – private StatisticaMedica cloud hosted 
by Radix Technologies, in IXA2-Ixaltis Prostate and SUI/Programming for the scripts and IXA2-Ixaltis 
Prostate and SUI/Reports for the delivered documentation, in the corresponding subfolders for the SAP, 
TFLs and CSR. 
 
9. References 
1. Adams P, Andersson KE, Birder L, et al. Fourth International Consultation on Incontinence 
Recommendations of the International Scientific Committee: Evaluation and treatment of 
urinary incontinence, pelvic organ prolapse, and fecal incontinence. Neurourl Urodyn. 
2010; 29:213-240. 


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2. European Medicines Agency, Committee for Medicinal Products for Human Use. Guideline on 
the Clinical Investigation of Medicinal Products for the Treatment of Urinary Incontinence. 27 
June 2013. 
3. Fultz NH, Burgio K, Diokno AC et al. Burden of stress urinary incontinence for community 
dwelling women. Am J Obstet Gynaecol 2003; 189: 1275-1282.  
4. Turner DA, Shaw C, McGrother DW et al. The cost of clinically significant urinary storage 
symptoms in community dwelling adults in the UK. BJUI 2004; 93:1246-1252. 
5. Wood LN, Anger JT. Urinary incontinence in women. BMJ: 2014;349: g4531. 
6. Papanicolaou S. Pons ME, Hampel C et al. Medical resource utilization and cost of care for 
women seeking treatment for urinary incontinence in an outpatient setting. Examples from three 
countries in the PURE study. Maturitas 2005; 52. Suppl 2:S35-47. 
 
10. Appendix 1 
Guide for the analysis and review of QT and QTc Interval data, Health Canada, 2010. 
11. Appendix 2 
Nilsson, Mary E., et al. "Columbia–Suicide Severity Rating Scale Scoring and Data Analysis 
Guide." CSSRS Scoring Version 2 (2013): 1-13. 
12. Appendix 3 
Beck Depression Inventory-Second Edition published on The National Child Traumatic Stress 
Network (Source URL: https://www.nctsn.org/measures/beck-depression-inventory-second-edition) 
13. Appendix 4 
Beck, Aaron T., et al. "An inventory for measuring clinical anxiety: psychometric properties." Journal 
of consulting and clinical psychology 56.6 (1988): 893. 
Clinical Psychology, 56, 893–897. Beck, A. T., & Steer, R. A. (1990). Manual for the Beck Anxiety 
Inventory. San Antonio, TX: Psychological Corporation. Jolly, J. 
Beck Anxiety Inventory published on The National Child Traumatic Stress Network (Source URL: 
https://www.nctsn.org/measures/beck-anxiety-inventory) 
14. Appendix 5 
Buysse, Daniel J., et al. "The Pittsburgh Sleep Quality Index: a new instrument for psychiatric 
practice and research." Psychiatry research 28.2 (1989): 193-213. 
15. Appendix 6 
Food and Drug Administration Center for Drugs Evaluation Research, Guidance for Industry: 
Assessment of Abuse Potential of Drugs (2017)