| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Urge Urinary Incontinence (UUI) | |
| 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 determine the efficacy of duloxetine, 40mg twice daily compared with placebo for up to 12 weeks in women with predominant UUI, as measured by 1) the reduction in the number of incontinence episodes per week and 2) the patient’s global perception of treatment effect. | |
| E.2.2 | Secondary objectives of the trial | The secondary objectives of the study are:
1. To compare the effects of duloxetine with those of placebo on bladder function as measured by other parameters derived from the patient completed 1-week urinary diary
2. To compare the effects of duloxetine with those of placebo on Patient Reported Outcomes (PRO) as measured by validated quality of life scales and symptom scores 3. To compare the effects of tolterodine, 4mg once daily with those of placebo, utilising all the efficacy measures outlined above for duloxetine, including the primary endpoints.
4. To compare the safety of duloxetine and tolterodine with that of placebo
5. To collect data for a future integrated analysis of two pivotal trials (1208.15 and 1208.16) on the efficacy of duloxetine compared with tolterodine during acute treatment measured by the mean change in IEF from baseline to endpoint.
| |
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria | 1. Is a female outpatient 18 years of age or over.
2. Have predominant urge urinary incontinence (UUI) defined as involuntary loss of urine immediately preceded by or accompanied by urgency (the complaint of a sudden compelling desire to pass urine, which is difficult to defer) without predominant SUI symptoms for 3 consecutive months prior to Visit 1.
3. Predominant UUI will be defined as at least 7 UUI episodes and at least twice as many UUI as SUI episodes recorded on the Stress Urge Incontinence Questionnaire (S/UIQ) at Visit 1 AND by at least 7 urge incontinence episodes per week on the screening diary completed prior to Visit 2 (see Section 11.1).
4. At least 10 voids per 24 hours (on a screening diary prior to Visit 2).
5. A urine output of less than 3000mL per 24 hours, as measured and recorded on a screening frequency volume chart (prior to Visit 2).
6.A negative cough stress test with a bladder volume of at least 150mL.
7. Is ambulatory and able to use a toilet independently and without difficulty.
8. Has a PVR volume less than or equal to 100mL within 15 minutes of a spontaneous void at Visit 1 documented either by ultrasound or catheterisation.
9. Has no language or cognitive barriers, agrees to comply with the requirements of the protocol, and has signed a written informed consent document prior to any study specific examinations/interactions are performed.
10. Have responded appropriately to all screening questions at Visit 1.
| |
| E.4 | Principal exclusion criteria | 1. Pre-menopausal women (last menstruation less than 1 year prior to signing informed consent) who are:
a. Pregnant or have been pregnant in the last 6 months
b. Currently breastfeeding or have not resumed normal menstruation for 3 months due to breastfeeding
c. Of child-bearing potential and are NOT practicing acceptable methods of birth control.
2. Had continence surgery or received bladder neck bulking agent therapy, including collagen injections for incontinence, within 6 months prior to randomisation.
3. Has a current diagnosis ureteric, bladder, urethral, or rectal fistula, uncorrected congenital abnormality leading to urinary incontinence, voiding difficulty, including significant hesitancy or history of retention.
4.Has pelvic organ prolapse with protrusion of any vaginal segment greater than 1cm (> 1cm) beyond the hymen.
5. Had any major surgery within 3 months prior to randomisation.
6. Currently has, or has a history of, invasive urogenital cancer.
7. A history of mania or bipolar disorder.
8. Are judged clinically prior to randomisation to be at suicidal risk identified as a score of 2 or greater on question 9 of the BDI-II.
9. Active seizure disorder.
10. Unstable diabetes mellitus.
11. Known neurologic lesions or conditions or local lesions (for example, bladder stones, tumours) that could cause bladder overactivity.
12. Uncontrolled narrow angle glaucoma or a risk of acute narrow angle glaucoma.
13. Currently has, or history of ulcerative colitis or toxic mega-colon.
14. History of severe allergies requiring emergency medical treatment or multiple adverse drug reactions.
15. Risk of increased bleeding or full anticoagulation.
16. Monoamine oxidase inhibitors (MAOIs), SSRIs, SNRIs, tricyclic antidepressants or any other excluded medication intake within 14 days prior to randomisation.
17. On a medication regimen, including diuretics, where dose and/or frequency have not been stable for at least 12 weeks prior to randomisation.
18. Taken any medication for urge incontinence within 1 month prior to randomisation.
19. Currently uses any anti-incontinence device including tampons used to prevent incontinence, vaginal pessaries for prolapse or incontinence.
20. Had any nonpharmacologic intervention for incontinence or prolapse within 3 months of randomisation.
21. Known active substance abuse disorder within the 5 years prior to randomisation or reports regular consumption of 21 or more units of alcohol per week.
22. Any active cardiac ischaemic condition, including myocardial infarction within 6 months prior to randomisation.
23. Uncontrolled or poorly controlled hypertension.
24. A symptomatic arrhythmia despite antiarrhythmic medication, uncontrolled angina, or a significant abnormality on ECG
25. Acute liver injury or severe cirrhosis (Child-Pugh Class C).
26. Hepatic dysfunction as defined by the following laboratory parameters:
a. SGPT (ALT) or SGOT (AST) greater than or equal to 3 times upper limit of normal (ULN)
or
b. Bilirubin greater than or equal to 1.5 times ULN
27. A positive urine culture (> 100,000 cfu/mL) at Visit 1, or a history of 4 or more urinary tract infections (UTIs) in the preceding year as determined by the clinical investigator.
28. Known severe renal impairment as defined by creatinine clearance < 30mL/min.
29. Known hypersensitivity to duloxetine, tolterodine or any of its inactive ingredients.
| |
| E.5 End points |
| E.5.1 | Primary end point(s) | • The mean change from baseline to endpoint in the number of IEF as recorded in the patient diary (The patient diary is the Subject 24-Hour Diary and frequency volume chart)
• The Patient Global Impression of Incontinence Improvement (PGI-II) rating
| |
| 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 | Information not present in EudraCT |
| 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) | Yes |
| 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| 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 | No |
| 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 | |
| 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 | | End of trial is the last visit of the last subject. | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
