Safety and efficacy of litoxetine in women with urinary incontinence

• Register: EUCTR
• Last refreshed on: 30 April 2019
• Main ID: EUCTR2016-004307-30-PL
• Date of registration: 24/03/2017
• Prospective Registration: Yes
• Primary sponsor: IXALTIS
• Public title: Safety and efficacy of litoxetine in women with urinary incontinence
• Scientific title: A Double-Blind, Randomised, Placebo-Controlled, Parallel Group, Phase II, Dose Ranging Trial to Evaluate the Efficacy, Safety and Tolerability of oral Litoxetine 10mg, 20mg and 40mg Twice Daily (BID) versus placebo in women with Mixed Urinary Incontinence
• Date of first enrolment: 30/03/2017
• Target sample size: 240
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-004307-30
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: yes; Other trial design description: 2-week single-blind Run-in Period, will be followed by 12-week double blind Treatment Period; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 4
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Canada, France, Georgia, Poland, Ukraine, United Kingdom

Contacts

• Name: Elisabeth Svanberg
• Affiliation: IXALTIS

• Name: Elisabeth Svanberg
• Affiliation: IXALTIS

Key inclusion & exclusion criteria

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
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 190
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 50

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

Age minimum:
Age maximum:
Gender:
Female: yes
Male: no

Health Condition(s) or Problem(s) studied

Mixed Urinary Incontinence

Therapeutic area: Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13]

Intervention(s)

Product Name: Litoxetine
Product Code: Litoxetine
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: LITOXETINE
CAS Number: 86811-09-8
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Product Name: Litoxetine
Product Code: Litoxetine
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: LITOXETINE
CAS Number: 86811-09-8
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Primary Outcome(s)

Secondary Objective: 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.

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)

Timepoint(s) of evaluation of this end point: Week 12

Main Objective: 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

Secondary Outcome(s)

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

Timepoint(s) of evaluation of this end point: specified above

Secondary ID(s)

IXA-CSP-001

Source(s) of Monetary Support

IXALTIS

Ethics review

Status: Approved
Approval date:
Contact:

Results

• Results available: Yes
• Date Posted: 31/05/2019
• Date Completed: 13/03/2019
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-004307-30/results