| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Urge 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 general objective of this study is to determine the efficacy and safety of cizolirtine citrate 300 mg bid (600 mg/d) and 400 mg bid (800 mg/d) after 12 weeks treatment/ at treatment termination in patients with urge urinary incontinence (UUI).
The primary objective is to investigate the effect of the study medication on
•Number of incontinence episodes (per 24 hours, change from baseline to end of study) and
•Responder rate, defined as improvement of one point or more of a six point Likert scale (patient’s assessment of incontinence problems)
The primary and co-primary variables are specified in Section 5.5.2.1.of the protocol
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| E.2.2 | Secondary objectives of the trial |
Secondary objectives are to investigate the effect of the study medication on the following efficacy and safety parameters:
Efficacy
•Number of voluntary micturitions (per 24 hours)
•Number of incontinence episodes (per 24 hours, change from Baseline (Visit 3) to Visits 4, 5, 6)
•Number of urgency episodes (per 24 hours)
•Intensity of urgency episodes
•Nocturia
•Volume of the first micturition per day
•Proportion of patients achieving both
o less than 8 micturitions/ 24 hours and
o complete dryness (no incontinence episode)
during the last available diary period
•Cystometry (in a subgroup of patients at selected sites)
•Patient assessment of treatment benefit
•Clinical global impression (CGI) by the investigator
Quality of Life (QoL): King's Health Questionnaire/SF-36
Safety: Adverse Events, Lab parameters, urological examination, residual urinary volume, physical examination including vital signs and ECG findings.
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
Criteria for inclusion in the run-in period at Visit 1 (Week -3, Day -21 plus or minus 3 days)
Patients who meet the following criteria are considered for inclusion in the run-in period
•Outpatients
•Both genders
•Age 18 to 80 years
•Premenopausal female patients:
Adequate contraception (in the investigator's opinion) or no childbearing potential (i.e. medically confirmed infertility, operative sterilisation, hysterectomy)
•Urge urinary incontinence for a duration of at least 6 months confirmed by medical history and documented in the patient’s file i.e.
o Involuntary leakage of urine immediately preceded or accompanied by the feeling of urgency,
o Often associated with increased frequency of micturition and/or episodes of urgency not leading to incontinence
•Urge urinary incontinence confirmed by cystometric results in patients having agreed in this examination. If no cystometry is available from within 4 months prior to Visit 1, cystometry will be performed between Visit 1 and Visit 3. At least one of the following criteria must be present:
o Phasic increases in the bladder pressure with an amplitude of 15 mm H2O during medium fill cystometry (filling rate between 10 and 100 ml/min) that, in the investigator’s judgement, are caused by detrusor contractions
o Volume at first desire to micturate below normal range (150 ml – 200 ml; to be judged by investigator individually for each patient)
o Maximal cystometric capacity below normal range (400 ml – 500 ml; to be judged by investigator individually for each patient)
• Patient has given informed consent according to GCP
• Patient is willing and able to comply with all trial requirements
Criteria for inclusion in the randomised, double-blind period at Visit 3 (Day 0):
After completion of the run-in period, patients must meet the following criteria:
•Presence of
o A minimum of 1 episode of the feeling of urgency (strong desire to micturate)
and at least one of the following
o A minimum of 8 micturitions/24 hours, on average
o A minimum of 1 incontinence episode/24 hours, on average, during 7 days prior to the randomisation visit
• Normal basic urinalysis
•Negative urine culture |
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| E.4 | Principal exclusion criteria |
Criteria for exclusion from the run-in period at Visit 1 (Week -3, Day -21 plus or minus 3 days) and from the randomised, double-blind period at Visit 3 (day 0)
The following criteria are to be checked at screening and to be re-checked at the baseline visit:
• Evidence of mixed incontinence with prevailing obstructive component or stress component according to the investigator’s opinion, or treatment (current or within the last week) with any of the following drugs: alpha adrenergic agonists (e.g. phenylpropanolamine) or antagonists (e.g. prazosine, tamsulosine, or terazosine)
• Lower tract urological pathology in the investigator's opinion potentially responsible for incontinence known from medical history for the last 3 months
• Urinary tract infection defined in terms of clinical signs and symptoms
e.g. urgency and/or frequency associated with fever, dysuria, suprapubic pain
with or without microbiological confirmation, within two weeks prior to randomisation
• Any obstructive condition affecting the urethra or any clinically significant prostatic disease requiring therapy
• Mechanical obstructive uropathy known from medical history and/or shown by residual urine volume >200 ml at screening and/or the randomisation visit
•Polyuria (>2500 ml/24h) known from medical history and confirmed during run-in
•Increased frequency and/or nocturia only due to renal or cardiac insufficiency known from medical history
•Neurological disease influencing bladder function (e.g. multiple sclerosis, Parkinson's disease, spinal cord injuries, spina bifida)
•Urogenital surgeryin the patient’s history,
e.g. prostatectomy, or a surgical procedure for the treatment of incontinence
• Known allergy or hypersensitivity to any components of the study medication or structurally related drugs
•Pregnancy or lactation period
•Respiratory, renal (serum creatinine >2.5 mg/dl or >211 µmol/l), hepatic (ALAT >3-fold ULN), gastrointestinal, haematological, endocrine, psychiatric, or any other disease or condition that, in the opinion of the investigator, could affect the evaluation of the study medication
•Obstructive disease of the gastrointestinal tract, paralytic ileus, intestinal atony, megacolon (including toxic), chronic inflammatory bowel disease known from medical history
•Myasthenia gravis
•Untreated narrow angle glaucoma
•In general any clinically significant heart disease
•Known severe or malignant hypertension
•Mild to moderate hypertension not controlled satisfactorily
•Uncontrolled diabetes
•Previous participation in this study (participation in former cizolirtine studies is allowed)
•Participation in another study of an investigational drug within the last 30 days or current participation in another study of an investigational drug
•Chronic alcohol or drug abuse within the last 6 months
•Any condition which, in the opinion of the investigator, can jeopardize or would compromise the subject's ability to participate in this study
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy variable
• Number of incontinence episodes (per 24 hours, change from Baseline to end of study)
Co-primary efficacy variable
• Responder rate
Percentage of patients with improvement of one point or more of the six point Likert scale
My urinary incontinence causes me
o No problems
o Very minor problems
o Minor problems
o Moderate problems
o Severe problems
o Very severe problems
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Information not present in EudraCT |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Information not present in EudraCT |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| 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 | Information not present in EudraCT |
| 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 | 1 |
| 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 | 1 |
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