| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| Overactive bladder is not a disease but a condition characterized by the following symptoms: urgency, to void, with or without urinary leakage, usually with frequent voiding also at night. |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Physical Phenomena [G01] |
| 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 |
| To evaluate the efficacy of four combinations of solifenacin succinate (2.5 mg or 5 mg) plus mirabegron (25 mg or 50 mg) vs. solifenacin succinate 5 mg monotherapy. |
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| E.2.2 | Secondary objectives of the trial |
To investigate the dose-response surface of combinations of solifenacin succinate (0 mg, 2.5 mg, 5 mg and 10 mg) and mirabegron (0 mg, 25 mg and 50 mg) doses;
To compare the safety and tolerability of six combinations of solifenacin succinate and mirabegron vs. solifenacin succinate monotherapy, mirabegron monotherapy, and placebo;
To investigate the population pharmacokinetics (PK) and PK/pharmacodynamic (PD) relationship of six combinations of solifenacin succinate and mirabegron and the mirabegron and solifenacin succinate monotherapies.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The PK substudy is part of this protocol.
Subjects will be asked to participate in an addtional PK substudy, which will involve additional PK profiling at one visit. It is planned for 120 subjects (10 subjects per treatment arm) to participate in this substudy. |
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| E.3 | Principal inclusion criteria |
Inclusion Criteria at Visit 1/Screening
1.Subject is male or female and at least 18 years of age;
2.Subject has a Body Mass Index (BMI) of between 18 and 35 kg/m2 and a total body weight between 50 and 95 kg;
3.Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent and privacy language as per national regulations has been obtained from the subject prior to any study-related procedures (including discontinuation of prohibited medication, if applicable);
4.Subject is willing and able to complete the micturition diary and questionnaires correctly and is willing and able to measure his/her vital signs at home at stipulated time points, using the device provided by the study personnel, and to adequately record the readings;
5.Subject has symptoms of OAB (urinary frequency, urgency and/or urgency incontinence) for at least 3 months.
Inclusion Criteria at Visit 2/Placebo Run-In
6. Subject must still fulfill all inclusion criteria and none of the exclusion criteria for Visit 1;
7.Subject is willing and able to complete the micturition diary correctly and is willing and able to measure his/her vital signs at home at stipulated time points, using the device provided by the study personnel, and to adequately record the readings.
Inclusion Criteria at Visit 3/Baseline
8.Subject continues to meet all inclusion criteria and none of the exclusion criteria for Visit 1;
9.Subject has experienced frequency of micturition on average ≥ 8 times per 24-hour period during the 3-day micturition diary period (incontinence episode should not be counted as a micturition);
10.Subject must experience at least 1 episode of urgency (grade 3 or 4) per 24-hour period (with or without urgency incontinence) during the 3 day micturition diary period.
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|
| E.4 | Principal exclusion criteria |
1.Subject is breastfeeding, pregnant or intends to become pregnant during the study. The pregnancy test (β-HCG in serum) at Screening must be negative in women of childbearing potential;
2.Female subjects of childbearing potential and not using a highly effective method of birth control during the study and for 30 days after final study drug administration.Male subjects (unless surgically sterile) with female spouses/partners who are of childbearing potential, and not using a barrier method of contraception during the study and for 30 days after final study drug administration.
3.Subject has significant PVR volume (> 150 mL);
4.Subject has significant stress incontinence or mixed stress/urgency incontinence where stress is the predominant factor as determined by the Investigator 6.Subject has a neurological cause for detrusor overactivity;
5.Subject has an indwelling catheter or practices intermittent self-catheterization;
6.Subject has diabetic neuropathy;
7.Subject has chronic inflammation such as interstitial cystitis, bladder stones, previous pelvic radiation therapy or previous or current malignant disease of the pelvic organs;
8.Subject has had previous lower urinary tract or pelvic floor surgery (except cystoscopy);
9.Subject has had intravesical treatment in the past 12 months with e.g., botulinum toxin, resiniferatoxin, capsaicin;
10.Subject has uncontrolled narrow angle glaucoma, urinary or gastric retention, severe ulcerative colitis or Crohn’s Disease, toxic megacolon, myasthenia gravis or any other condition which makes the use of anticholinergics contraindicated;
11.Subject has clinically significant cardiovascular or cerebrovascular diseases within 6 months prior to Screening, such as myocardial infarction, uncontrolled angina, significant ventricular arrhythmias, heart failure and stroke;
12.Subject is receiving current non-drug treatment including electro-stimulation therapy 15.Subject is using medications intended to treat OAB or prohibited medications. Subject is excluded if using restricted medications under conditions different to those specified in the 'Concomitant Medication' section;
13.Subject has known or suspected hypersensitivity to solifenacin succinate, mirabegron or any of their excipients;
14.Subject has any significant neurological disease or defect affecting bladder function
15.Subject has severe hypertension 19.Subject has any clinically significant condition which in the opinion of the Investigator makes the subject unsuitable for the study;
16.Subject who participated in any clinical study or who has been treated with any investigational drug or device within 30 days (90 days in the UK) or the period stipulated by local regulations, whichever is longer, prior to Screening;
Exclusion Criteria at Visit 2/Placebo Run-In
17.Subject has evidence of a UTI (urine culture containing > 100,000 cfu/mL). The subject can be enrolled into the study after successful treatment of the UTI (confirmed by a laboratory result of negative urine culture). However, the subject must be re-screened if the initial screening visit (Visit 1b) was > 28 days;
18.Subject has a QT interval > 450 ms or is at risk of QT prolongation (e.g., family history of long QT syndrome, hypokalaemia) or is on drug treatment known to be associated with QT prolongation;
19.Subject has clinically significant abnormalities on the 12-lead ECG;
20.Subject has serum creatinine > 150 µmol/L, AST and/or ALT > 2x upper limit of normal (ULN), γ-GT > 3x ULN, or total bilirubin > 2x ULN, as assessed in Screening samples;
Exclusion Criteria at Visit 3/Baseline
21.Subject had an average total daily urine volume > 3000 mL as recorded in the micturition diary period;
22.Subject has severe hypertension |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in mean volume voided per micturition after 12 weeks of treatment |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After 12 weeks of treatment |
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| E.5.2 | Secondary end point(s) |
Change from baseline in mean number of micturitions/24 h
Change from baseline in mean number of incontinence episodes/24 h
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 12 |
| 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 | 132 |
| 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 | No |
| 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 |
| Belarus |
| Russian Federation |
| Ukraine |
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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 | 9 |
| 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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