| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 16.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10059617 |
| E.1.2 | Term | Overactive bladder |
| E.1.2 | System Organ Class | 100000004857 |
|
| 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 solifenacin 5 mg plus mirabegron 50 mg versus solifenacin 5 mg monotherapy |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the safety and tolerability of combination therapy versus solifenacin 5mg and solifenacin 10mg monotherapy
- To evaluate the efficacy of combination therapy versus solifenacin 10mg monotherapy |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
At screening (visit 1):
1. Subject is male or female and at least 18 years of age;
2. Subject has symptoms of OAB (urinary frequency and urgency
with urgency incontinence) for > 3 months prior to the screening visit;
3. Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved written Informed Consent (IC) and
privacy language as per national regulations has been obtained
from the subject or legally authorized representative prior to any study-related procedures (including discontinuation of prohibited medication, if applicable);
4. Female subject must be either:
• Of non child bearing potential:
• post-menopausal (defined as at least 1 year without any
menses in the absence of other plausible aetiology) prior to
Screening or
• documented surgically sterile or status post hysterectomy
(at least 1 month prior to Screening)
• Or, if of childbearing potential,
•must have a negative serum pregnancy test at Screening and
must use a highly effective method of birth control, which
include established use of oral, injected or implanted hormonal
methods of contraception, placement of an intrauterine device
(IUD) or intrauterine system (IUS), or barrier methods of
contraception: condom or occlusive cap (diaphragm or
cervical/vault caps) with spermicidal
foam/gel/film/cream/suppository. Birth control must be
practiced from the Screening visit, throughout the study period
and for 28 days after final study drug administration;
5. Female subject must not be breastfeeding at Screening or
during the study period and for 28 days after final study drug
administration;
6. Female subject must not donate ova starting at Screening and
throughout the study period and for 28 days after final study
drug administration;
7. Male subjects and their female spouse/partners who are of
childbearing potential must be using highly effective contraception starting at Screening and continue throughout the study period and for 90 days after final study drug administration;
8. Male subject must not donate sperm starting at Screening and
throughout the study period and for at least 90 days after final
study drug administration;
9. Subject is willing and able to complete the micturition diary
and questionnaires correctly, including collection and
measurement of urine output for 3 days prior to each visit;
10. Subject has symptoms of “wet” OAB (urinary frequency and
urgency with incontinence or mixed incontinence with
predominant urgency incontinence), and reports an average of
at least 2 incontinence episodes per 24 hour period.
At run-in (visit 2):
11. Subject experiences on average at least 1 episode of urgency
(grade 3 or 4) with or without incontinence per 24-hour period
during the 3-day micturition diary period.
12. Subject experiences on average at least 2 incontinence
episodes per 24-hour period during the 3-day micturition diary
period.
13. Subject experiences on average at least 8 micturitions
(excluding incontinence episodes) per 24-hour period during
the 3-day micturition diary period.
At randomization (visit 3):
14. Subject experiences at least 1 incontinence episode during the
3-day micturition diary period and wishes to increase their
treatment for OAB symptoms. |
|
| E.4 | Principal exclusion criteria |
Subjects will be excluded from participation if any of the
following apply:
At screening (visit 1):
1. Subject in the opinion of the investigator has clinically
significant Bladder Outlet Obstruction (BOO).
2. Subject has significant PVR volume (PVR > 150 ml).
3. Subject has significant stress incontinence or mixed
stress/urgency incontinence where stress is the predominant
factor as determined by the investigator
4. Subject has an indwelling catheter or practices intermittent
self-catheterization.
5. Subject has evidence of a Urinary Tract Infection (UTI). If a
urine dipstick shows positive for nitrite, this must be followed
up with a urine sediment and then culture (if the sediment is
positive). The subject should be treated with an appropriate
course of antibiotics. The subject can be enrolled into the study
after successful treatment of the UTI, which is confirmed by a
dipstick test negative for nitrites. If more than 28 days has
passed since the initial screening visit, the subject must repeat
the screening assessments.
6. Subject has chronic inflammation such as interstitial cystitis,
bladder stones, previous pelvic radiation therapy, or previous
or current malignant disease of the pelvic organs (i.e., within
the confines of the pelvis including the bladder and rectum in
both sexes, the prostate in males and the uterus, ovaries, and
fallopian tubes in females; organs of the lower gastrointestinal
tract are not necessarily considered pelvic organs as the distal
ascending colon, the full transverse colon and proximal portion
of the descending colon are in the abdomen).
7. Subject has received intravesical treatment in the past 12
months with e.g., botulinum toxin, resiniferatoxin, capsaicin.
8. Subject has uncontrolled narrow angle glaucoma, urinary or
gastric retention, severe ulcerative colitis, toxic megacolon,
myasthenia gravis or any other medical condition which in the
opinion of the investigator makes the use of anticholinergics
contraindicated.
9. Subject receives non-drug treatment including sacral nerve
stimulation therapy (a bladder training program or pelvic floor
exercises which started more than 30 days prior to entry into
the study can be continued).
10. Subject has moderate to severe hepatic impairment defined as
Child-Pugh Class B or C.
11. Subject has severe renal impairment or End Stage Renal
disease defined as eGFR < 30 ml/min/1.73 m2.
12. 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.
13. Subject has severe uncontrolled hypertension, which is defined
as a sitting average systolic blood pressure ≥ 180 mmHg
and/or average diastolic blood pressure ≥ 110 mmHg.
14. Subject has a QTcF interval > 450 ms for males or > 470 ms
for females or is at risk of QT prolongation (e.g., family
history of long QT syndrome, hypokalaemia).
15. Subject has a clinically significant abnormal ECG.
16. Subject has a known or suspected hypersensitivity to
solifenacin, mirabegron or any of the inactive ingredients. This
includes subjects with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency or glucose-galactose
malabsorbtion.
17. Subject has any other clinically significant condition, which in
the opinion of the investigator makes the subject unsuitable for
the study.
18. Subject has been treated with an experimental device within
30 days or received an experimental agent within 30 days or
five half-lives whichever is longer, prior to study drug
administration. If local regulations stipulate a longer period, such local regulations should take precedence.
19. Subject has a concurrent malignancy or history of cancer
(except noninvasive skin cancer) within the last 5 years prior
to screening. Subjects with a history of cancer are considered
eligible if the subject has undergone therapy and the subject
has been considered disease free for at least 5 years.
20. Subject is using prohibited medications which cannot be
stopped safely at the Screening Visit (these include potent
CYP3A4 inhibitors (e.g. ketoconazole, ritonavir, nelfinavir,
itraconazole).
21. Subject is an employee of the Astellas Group, third parties
associated with the study, or the clinical study site team.
At randomization (visit 3):
22. Subject has achieved 100% continence from Visit 2 to Visit 3
(no incontinence episodes are recorded in the 3 day diary
administered for 3 days prior to Visit 3).
23. Subject does not desire an increase in study medication.
24. Subject has an average total daily urine volume > 3000ml as
recorded in the micturition diary.
25. Subject has severe uncontrolled hypertension, which is defined
as a sitting average systolic blood pressure ≥ 180 mmHg
and/or average diastolic blood pressure ≥ 110 mmHg.
26. Subject has a clinically significant abnormal ECG |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from Baseline in mean number of incontinence episodes. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Baseline visit (Visit 3/Randomization) to End of Treatment (Visit 6). |
|
| E.5.2 | Secondary end point(s) |
1. Change from Baseline in mean number of micturitions per 24 hours.
2. Number of incontinence episodes reported over 3-day diary. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Baseline Visit (Visit 3/Randomization) to end of Treatment (Visit 6). |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 165 |
| 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 |
| Algeria |
| Armenia |
| Australia |
| Canada |
| Egypt |
| Georgia |
| Israel |
| Jordan |
| Kazakhstan |
| Korea, Republic of |
| Lebanon |
| New Zealand |
| Russian Federation |
| Taiwan |
| Turkey |
| Ukraine |
| United States |
|
| 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
|
|
| 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 | 4 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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