DBPC Trial to Evaluate the Safety, Tolerability and Efficacy of Oral Litoxetine in Subjects With Urinary Incontinence

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

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

3. For male subjects: Undergone prostatectomy at least 6 months prior to inclusion

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:

1. 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

2. Use of double-barrier methods of contraception; condoms with the use of caps
(with spermicide) and intra-uterine devices are acceptable

3. Use of hormonal contraceptives (oral, depots, patches, etc.) with double-barrier
methods of contraception as outlined above

4. 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

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

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:

1. Hypersensitivity to litoxetine or any of its ingredients

2. History of clinically significant drug hypersensitivity

3. 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)

4. 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

5. Subjects with diabetes insipidus

6. 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.
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 (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 5.7.2 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