E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10059617 |
E.1.2 | Term | Overactive bladder |
E.1.2 | System Organ Class | 100000004857 |
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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 |
Base Study:
(1) To investigate a dose-related reduction in average number of daily micturitions compared with placebo at Week 8
(2) To assess the safety and tolerability of treatment with the selected MK-4618 doses either alone or dosed concomitantly with tolterodine ER
52 week extension:
(1) To assess the long-term safety and tolerability of treatment with MK-4618 compared to tolterodine ER
(2) To assess the long-term safety profile of MK-4618 dosed concomitantly with tolterodine ER, relative to MK-4618 monotherapy and/or tolterodine ER monotherapy |
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E.2.2 | Secondary objectives of the trial |
Base study: 1) After 8 wks of dosing, to assess the effect of MK-4618 compared with placebo on average number of: a) urge incontinence episodes in patients with OAB wet b) total incontinence episodes in patients with OAB wet c) strong urge episodes in all patients with OAB
2) To investigate whether there is a lower incidence of dry mouth when treated with MK-4618 compared with tolterodine ER
3) After 4 wks of dosing, to assess the effect of concomitant dosing with MK-4618 and tolterodine ER compared with the selected dose of MK-4618 monotherapy and with the tolterodine ER monotherapy on the average number of daily micturitions
52 wk extension: To assess the efficacy profile of MK-4618 compared with tolterodine ER after 52 wks of treatment on average number of: a) daily micturitions in all patients with OAB b) urge incontinence episodes in patients with OAB wet c) total incontinence episodes in patients with OAB wet d) strong urge episodes in all patients with OAB |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Base study:
1. Patient is male or female between 18 and 75 years of age inclusive on day of signing informed consent.
2. A female patient who is of reproductive potential agrees to remain abstinent or use (or have their partner use) 2 acceptable methods of birth control within the projected duration of the study.
3. Patient has a clinical history of OAB (may be verbal per patient) for at least 3 months prior to Visit 1. OAB is defined as urgency, with or without urge incontinence, usually associated with frequency and nocturia. Urodynamic evaluation is not required.
4. Patient is able to read, understand and complete questionnaires and voiding diaries as well as collect, measure and record voided volume by herself/himself using a graduated beaker, and toilet seat hat (if needed), which will be provided by the SPONSOR.
5. Patient meets either the OAB wet or OAB dry (patients with no or minimal incontinence of any type) criteria described below based on the screening diary returned at Visit 2 (averages should not be rounded up to the whole number):
• OAB wet criteria: An average of ≥8.0 micturitions per diary day; and an average of ≥1.0 urge incontinence episodes per diary day; and the total number of urge incontinence episodes must be greater than the total number of stress incontinence episodes from the screening diary.
Or
•OAB dry criteria: An average of ≥8.0 micturitions per diary day; and,
an average of ≥3.0 strong urge episodes per diary day; and an average of < 1.0 urge incontinence episode per diary day; and the total number of urge incontinence episodes must be greater than the total number of stress incontinence episodes from the screening diary.
52 week extension:
Patient completed either Part 1 or Part 2 of the base study. |
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E.4 | Principal exclusion criteria |
Base study:
1.Patient has evidence of diabetes insipidus, uncontrolled hyperglycemia (fasting blood glucose >150 mg/dL or 8.33 mmol/l and/or non fasting blood glucose >180 mg/dL or 10.0 mmol/l), or uncontrolled hypercalcemia (blood total calcium >11 mg/dL or 2.75 mmol/l).
2.Patient has a resting systolic blood pressure > 160 mmHg or resting diastolic blood pressure >90 mmHg or resting heart rate (by pulse) > 100 beats per minute at Visit 1.
3.Patient has a history of cerebral vascular accident, transient ischemic attack, unstable angina, or myocardial infarction within the previous 6 months.
4.Patient has lower urinary tract pathology that could, in the opinion of the investigator, be responsible for urgency, frequency, or incontinence; including but not limited to urolithiasis, interstitial cystitis, urothelial tumor, prostatitis, and clinically relevant benign prostatic hypertrophy or bladder outlet obstruction as judged by the investigator.
5.Patient has a history of injury, surgery, or neurodegenerative diseases (e.g., multiple sclerosis) that could affect the lower urinary tract or its nerve supply.
6.Patient has a history of continual urine leakage or patient is unaware of urine leakage.
7. Patient has a history of surgery to correct stress urinary incontinence or pelvic organ prolapse within 6 months.
8.Patient has a known history of elevated postvoid residual defined per the investigator's local standard of care.
9.Patient has undergone bladder training or electrostimulation within 2 weeks prior to Visit 1 or plans to initiate either during the study.
10.Patient has active or recurrent (>6 episodes per year) urinary tract infections by clinical history, clinical symptoms, or laboratory criteria (≥ 5 WBC or ≥ 26 bacteria (moderate) per high-powered field in a spun specimen and/or a positive urine culture defined as ≥ 104 colony forming units (CFU)/mL in 1 specimen.
11.Patient has hematuria, including microscopic hematuria (> 5 RBCs/hpf).
12.Patient has a requirement for an indwelling catheter or intermittent catheterization.
13.Patient has a history of fecal incontinence.
14.Patient is not willing to discontinue use of the following therapies at least 2 weeks prior to completing the screening voiding diary and remain off these therapies for the duration of the study:
•Anticholinergics
•Smooth muscle relaxants
•Beta 2 adrenergic agonists used for the treatment of stress urinary incontinence
•Synthetic antidiuretic hormones
•Phosphodiesterase type 5 (PDE 5) inhibitors, including but not limited to tadalafil, sidenafil and vardenafil.
• Beta 3 adrenergic agonists, including but not limited to mirabegron.
15. Patient is receiving therapy with any of the following medications for less than 8 weeks prior to Visit 1 or plans to initiate or change therapy during the study.
• Tricyclic antidepressants or combinations
• Serotonin and/or norepinephrine reuptake inhibitors
• Alpha-adrenergic agonists, including nonspecific sympathomimetic amines
• Diuretic therapy
• Hormone replacement therapy, systemic or topical
• Inhaled anticholinergics
16. Patient is currently taking or has taken within the past 6 months 5-alpha reductase inhibitors or herbal remedies for the treatment of benign prostatic hypertrophy.
Refer to base protocol for complete list of exclusions
Additional criteria for 52 week extension:
• serious, drug-related or unresolved adverse events that in the Investigator's medical judgement may preclude the patient from continuing in the extension study
• patient meets the discontinuation criteria for the study
• patient has experienced clinically significant changes to their medical condition since enrolling in the study that in the Investigator's medical judgement may preclude them from continuing
• patient has been off the base study drug for more than 14 days prior to entering the extension study |
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E.5 End points |
E.5.1 | Primary end point(s) |
Base study:
Change from baseline in average number of daily micturitions.
52 week extension:
Safety and tolerability will be assessed via clinical review of all relevant safety parameters including clinical adverse experiences and laboratory variables related to blood chemistry and heamatology and vital signs that occurred during the extension. |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
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 | 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 | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 47 |
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 | Yes |
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 | 2 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |