| 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 | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10059617 |
| E.1.2 | Term | Overactive bladder |
| E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
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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 |
(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.
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| E.2.2 | Secondary objectives of the trial |
(1.) After 8 weeks of dosing, to assess the effect of MK-4618 compared with the effect of placebo on:
• the average number of urge incontinence episodes in patients with OAB wet
• the average number of total incontinence episodes in patients with OAB wet
• the average number of 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 weeks of dosing, to assess the effect of concomitant dosing with MK-4618 and tolterodine ER compared with the effect of the selected dose of MK-4618 monotherapy and with the effect of tolterodine ER monotherapy on the average number of daily micturitions.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient is male or female of non-childbearing potential between 40 and 75 years of age inclusive on day of signing informed consent.
2. 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.
3. 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, which will be provided by the SPONSOR.
4. Patient meets either the OAB wet or OAB dry criteria described below based on the screening diary returned at Visit 2 and the placebo run-in diary returned at Visit
3:
• OAB wet criteria: An average of ≥ 8 micturitions/day and average number of urge incontinence episodes is ≥ 1 per diary day AND the total number of urge incontinence episodes exceeds the total number of stress incontinence episodes from the screening diary.
OR
• OAB dry criteria: An average of ≥ 8 micturitions/day and the average number of strong urge episodes is ≥ 3 per diary day from the screening diary. |
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| E.4 | Principal exclusion criteria |
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 systolic blood pressure > 160 mmHg or diastolic blood pressure >90 mmHg or resting heart rate (by pulse) > 100 beats per minute at Visit 1.
3.Patient has evidence from current history of symptomatic orthostatic hypotension.
4.Patient has a history of cerebral vascular accident, transient ischemic attack, unstable angina, or myocardial infarction within the previous 6 months.
5.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 stress incontinence, urolithiasis, interstitial cystitis, urothelial tumor, prostatitis, and clinically relevant benign prostatic hypertrophy or bladder outlet obstruction as judged by the investigator.
6.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.
7.Patient has a history of continual urine leakage or patient is unaware of urine leakage.
8.Patient has a history of surgery to correct stress urinary incontinence or prolapsed uterus within 6 months.
9.Patient has a known history of elevated postvoid residual defined per the investigator's local standard of care.
10.Patient has undergone bladder training or electrostimulation within 2 weeks prior to Visit 1 or plans to initiate either during the study.
11.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.
12.Patient has hematuria, including microscopic hematuria (> 5 RBCs/hpf).
13.Patient has a requirement for an indwelling catheter or intermittent catheterization.
14.Patient has a history of fecal incontinence.
15.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 including but not limited to oxybutynin, tolterodine, trospium, darifenacin, solifenacin, fesoterodine, hyoscyamine, and propantheline.
•Smooth muscle relaxants including but not limited to flavoxate, dicyclomine, propiverine.
•Beta 2 adrenergic agonists used for the treatment of stress urinary incontinence including but not limited to clenbuterol.
•Synthetic antidiuretic hormones, including but not limited to desmopressin.
16. 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 including but not limited to amitiptyline, imipramine, and doxepin.
• Serotonin and/or norepinephrine reuptake inhibitors including but limited to fluoxetine, paroxetine, and duloxetine.
• Alpha-adrenergic agonists, including nonspecific sympathomimetic amines, such as but not limited to ephedrine, pseudoephedrine, and phenylephrine.
• Angiotensin converting enzyme (ACE) inhibitors, including but not limited to enalapril, linsinopril, and captopril.
• Angiotensin II receptor antagonists, also known as angiotensin receptor blockers (ARBs) including but not limited to losartan and valsartan.
• Diuretic therapy including but not limited to furosemide and hydrochlorothiazide.
• Hormone replacement therapy, systemic or topical, including but not limited to estrogen and estrogen/progesterone combination products.
• Inhaled anticholinergics including but not limited to tiotropium bromide and ipratropium bromide.
17. Patient is currently taking beta-adrenergic blocking agents (beta blockers), including but not limited to atenolol, metaprolol, and propranolol.
18. Patient is currently taking a calcium channel blocker including but not limited to amlodipine, verapamil, nimodipine and nifedipine.
19. Patient is currently taking direct acting vasodilators including but not limited to hydralazine and alpha-1 adrenergic receptor antagonists such as tamsulosin or terazosin.
20. 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 Protocol for exclusions 21 through 25 |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in average number of daily micturitions. |
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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 | 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) | 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 | 13 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 54 |
| 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 | 1 |
| 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 | 1 |
| 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 |
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