E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Mixed Urinary Incontinence |
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E.1.1.1 | Medical condition in easily understood language |
Stress and Urge Incontinence |
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E.1.1.2 | Therapeutic area | Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare the efficacy of 3 doses of litoxetine (10 mg, 20 mg, 40 mg) versus placebo administered orally twice daily (BID) for 12 weeks in female subjects with a diagnosis of MUI |
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of 3 doses of litoxetine (10 mg, 20 mg, 40 mg BID) compared to placebo in female subjects with a diagnosis of MUI. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Willing to provide written informed consent 2. Have symptoms of urinary incontinence for at least 3 consecutive months 3. Have at least 7 incontinence episodes per week in the diary entries for the Screening Period of which at least 3 episodes per week are defined as stress urinary incontinence. The PPIUS will be completed when subjects report an event in the electronic diary (e-diary) 4. Have an Investigator-confirmed urinary leakage from the urethral meatus synchronous with effort, eg, coughing or straining as an objective evidence of the stress component of incontinence. The urge incontinence component must be confirmed by the subject diaries during the Screening Period, using the PPIUS 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 ≥ 19 kg/m2 but < 31 kg/m2 8. Subjects must have a pre-dose mean systolic/diastolic blood pressure of ≤ 140/90 mmHg before randomization can occur 9. 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 outline 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 must have a stable dose and regimen for ≥ 3 months prior to entry into the study |
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E.4 | Principal exclusion criteria |
1. History of anti-incontinence surgery in past 12 months 2. Use of Botox for urge urinary incontinence in the past 12 months 3. Grade III/IV pelvic organ prolapse; defined per clinical practice 4. History of interstitial cystitis or bladder-related pain 5. History of pelvic prolapse repair (cystocele or rectocele) or urethral diverticulectomy within 12 months of Screening 6. 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 7. History of diagnosed gastrointestinal obstructive disorders 8. Chronic severe constipation 9. History of radiation cystitis or history of pelvic irradiation 10. 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. Pessaries and implants are also excluded. 11. Postvoid residual (PVR) urine volume > 150 mL 12. Diagnosis of dementia 13. Diagnosis of epilepsy 14. Diagnosis of acute narrow-angle glaucoma 15. History of mania or diagnosis of bipolar disorder, and/or seizures 16. Subjects with uncontrolled hypertension 17. 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 18. Congestive heart failure (New York Heart Association Class III or IV heart failure 19. 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 efficacy or safety 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 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, active seasonal allergic rhinitis), or malignancy other than nonmelanomatous skin cancer 20. Severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73m2) 21. Severe hepatic impairment (Child-Pugh B or greater) 22. Subjects who are on current treatment for depression 23. Use of the following medications: nonselective irreversible monoamineoxidase inhibitors, cytochrome P450 (CYP)1A2 inhibitors (such as fluvoxamine, ciprofloxacin, or enoxacin), pimozide and thioridazine, and any other medication that would be considered a safety risk for co-administration with litoxetine 24. Use of any pharmacologic agent used to treat symptoms of urinary incontinence 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. 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 the last administration prior to Screening 27. 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 28. Participation in any clinical study of an investigational drug that may affect urinary function within 3 months prior to Screening |
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E.5 End points |
E.5.1 | Primary end point(s) |
Percentage change from the end of the Placebo Run-in Period to Week 12 in the weekly average of 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) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• Absolute change from the end of the Placebo Run-in Period to Week 12 in the number of incontinence episodes/24 hours • Dose response of study drug on the primary endpoint • Proportion of subjects who become continent at Week 4, Week 8, and Week 12 • Change in the Kings Health Questionnaire total score and 3 sub-domain scores at Week 12 • Change from end of the Placebo Run-in Period in subject’s rating of improvement using the PGI-I at Week 12 • Change from end of the Placebo Run-in Period in PPBC score at Weeks 4, 8, and 12 • Percentage change from end of the Placebo Run-in Period to Week 4 and Week 8 in incontinence episodes/24 hours • Percentage change from end of the Placebo Run-in Period to Week 4, Week 8, and Week 12 in: - Weekly average of number of stress incontinence episodes/24 hours - Weekly average of number of urge incontinence episodes/24 hours - Weekly average of number of micturitions/24 hours - Weekly average of number of nocturia episodes/24 hours • Proportion of subjects with at least a 50% reduction from end of the Placebo Run-in Period to Week 4, Week 8, and Week 12 in weekly average incontinence episodes/24 hours • Proportion of subjects with at least a 50% reduction from end of the Placebo Run-in Period to Week 12 in weekly average stress incontinence episodes/24 hours • Proportion of subjects with at least a 50% reduction from end of the Placebo Run-in Period to Week 12 in weekly average urge incontinence episodes/24 hours • Proportion of subjects with < 8 micturitions/24 hours at Week 12 • Proportion of subjects with no urgency at Week 12 • Proportion of subjects reporting nocturia at end of the Placebo Run-in Period with no nocturia at Week 4, Week 8, and Week 12 • Responder analysis based on the established within-treatment minimal clinically important difference established for the Kings Health Questionnaire • Change from end of the Placebo Run-in Period in the number of incontinence pads used per week |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
2-week single-blind Run-in Period, will be followed by 12-week double blind Treatment Period |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
France |
Georgia |
Poland |
Ukraine |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of trial is defined as the date of the final clinical database lock |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 14 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |