| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| stress urinary incontinence and stress predominant mixed urinary incontinence |
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| 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 |
| The primary objective of this study is to assess the efficacy of duloxetine given orally as 40 mg twice daily for up to 12 weeks, compared to placebo, in community dwelling women 65 years of age with symptoms of pure stress urinary incontinence (SUI) or stress-predominant mixed urinary incontinence (MUI) as measured by the change in total incontinence episode frequency (IEF) from baseline to endpoint as measured by the 24-hour Subject Diary. |
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| E.2.2 | Secondary objectives of the trial |
1.To compare the efficacy of duloxetine 40 mg twice daily with that of placebo in the treatment of SUI and stress-predominant MUI )(
2. To compare the efficacy of duloxetine 40 mg twice daily with that of placebo as measured by the percent change in IEF from baseline to endpoint using diaries in the subgroups of SUI and stress-predominant MUI separately.
3. To assess the impact of treatment with duloxetine 40 mg twice daily and placebo on the development of suicidal ideation using question 9 of the Beck Depression Inventory-II (BDI-II).
4. To assess the impact of treatment with duloxetine 40 mg twice daily and placebo on cognition as measured by the change in the Modified Mini-Mental State Exam (3MS) score.
5. To assess the impact of treatment with duloxetine 40mg twice daily and placebo as measured by changes in the Beck Depression Inventory-II (BDI-II) total score from baseline to endpoint.
6. To compare the safety of duloxetine compared with placebo
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Is a female outpatient >65 years of age.
2. Have symptoms of SUI or stress-predominant MUI for at least 3 consecutive months prior to visit 1.
3. Have at least 7 incontinence episodes per week as determined by the S/UIQ at Visit 1. For subjects with MUI, at least 50% of the IEF must be due to stress recorded on the S/UIQ at Visit 1 (see section 11.1).
4. Fit the definition of community dwelling women. A community dwelling subject is defined as a subject sufficiently autonomous to live in society at large on her own.
5. Is ambulatory and able to use a toilet independently and without difficulty.
6. Have a post void residual (PVR) volume of <100 mL identified either by catheterisation or a bladder scan within 15 minutes of a spontaneous void.
7. Have no language or significant cognitive barriers (as determined by the Modified Mini-Mental State Exam 3MS score of >80), agree to comply with the requirements of the protocol and has signed a written informed consent document prior to any study procedures.
8. Have responded appropriately to all screening questions at visit 1.
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| E.4 | Principal exclusion criteria |
1. At Visit 1 have a positive urine culture (>100,000 cfu/mL) or a history of four or more (>4) urinary tract infections (UTIs) in the preceding year.
2. Suffer from severe constipation (for example have impacted rectum at time of physical examination) at study entry.
3. Are on a regimen of a chronically administered medication where dose and/or frequency has not been stable for at least 3 months prior to study entry or is anticipated to change during the course of the study.
4. Have had continence surgery or received bladder neck bulking agent therapy, including collagen injections for incontinence, within 3 months prior to study entry.
5.Have pelvic organ prolapse greater than stage II (>2); that is, protrusion of any vaginal segment greater than 1 cm (>1 cm) beyond the hymen at study entry.
6. Have had any major surgery within 3 months prior to study entry.
7. Have a current diagnosis of any of the following conditions, disorders or diseases of the genitourinary tract:
a) Ureteric, bladder, urethral or rectal fistula
b) Uncorrected congenital abnormality leading to urinary incontinence
c) Voiding difficulty including significant hesitancy or history of retention
8. Have had any non-pharmacologic intervention for incontinence or prolapse (for example, electrostimulation, vaginal cones, pessaries, tampons, bladder training) within 3 months prior to study entry or throughout the study.
9. Began pelvic floor muscle exercises (for example, Kegel or biofeedback) within 3 months prior to study entry or at any time during the study. Subjects who regularly perform pelvic floor muscle exercises cannot change their exercise regimen during the course of the study.
10. Have neurologic lesions or conditions (for example, multiple sclerosis, spinal cord lesions or Parkinson’s disease) or local lesions (for example, bladder stones present or tumors) that affect the lower urinary tract.
11. Have any condition, limitation, disease or abnormal laboratory value that could, in the judgment of the investigator, preclude evaluation of response to duloxetine.
12. Are judged prior to randomisation (visit 1, 2, 3) to be at suicidal risk, identified as a score of 2 or greater on question 9 of the Beck Depression Inventory-II (BDI-II) (see section 11.3).
13. Have any active substance abuse disorders within the 5 years prior to study entry.
14. Have a history of mania or bipolar disorder.
15. Have active seizure disorder.
16. Have a symptomatic arrhythmia despite antiarrhythmic medication, uncontrolled angina or a significant abnormality on ECG within the six months prior to randomisation, that in the opinion of the investigator, requires investigation or intervention
17. Are prone to syncopal episodes
18. Have any active cardiac ischaemic condition, including myocardial infarction, within 6 months prior to randomisation
19. Have hepatic dysfunction .by the following laboratory parameters:
SGPT (ALT) or SGOT (AST) > 3 times upper limit of normal (ULN), or
Bilirubin > 1.5 times ULN.
20. Have known severe renal impairment as defined by creatinine clearance <30 mL/min.
21. Intake of monoamine oxidase inhibitors (MAOIs) or any other excluded medication within 14 days prior to randomisation or at any time during the study.
22 Have current urogenital cancer.
23. Have abnormal thyroid-stimulating hormone (TSH) concentration.
24. Have uncontrolled narrow-angle glaucoma.
25. Have a history of severe allergies, including drug allergies, requiring emergency medical treatment or have multiple and/or severe adverse drug reactions.
26. Have a hypersensitivity to duloxetine or any of the inactive ingredients.
27. Have acute liver injury (such as hepatitis) or severe (Child-Pugh Class C) cirrhosis.
28. On physical examination, neurological, and/or vaginal examination or on historical review have results (including hematuria or diagnosis of female urethral syndrome or interstitial cystitis) that, in the opinion of the investigator, should exclude the subject. The female urethral syndrome is a condition characterised by a lack of objective findings, but with subjective complaints of urethral pain or irritation that prompts voiding, but is not relieved by voiding.
29. Have previously taken study medication in any study investigating duloxetine or are currently being treated with commercially available duloxetine or are treated in the past with commercially available duloxetine (Cymbalta®, Xeristar®, Yentreve®, Ariclaim®).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The change (percent) in total incontinence episode frequency (IEF) from baseline to endpoint. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| 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 | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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 | No |
| 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.8.3 |
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.8.5 | The trial involves multiple Member States | Yes |
| 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 | Information not present in EudraCT |
| 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 |
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| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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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| 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 | 2 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 2 |
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