A Double-Blind, Randomized, Parallel Group, Multi-Centre Study to Evaluate the Efficacy and Safety of Mirabegron Compared to Solifenacin in Subjects with Overactive Bladder (OAB) Treated with Antimuscarinics and Dissatisfied due to Lack of Efficacy

Overactive bladder (OAB) syndrome is defined by the International Continence
Society (ICS) as urgency with or without urgency incontinence, usually with
increased daytime frequency and nocturia. The fundamental symptom is urgency,
which is widely considered to be the driver of other urological symptoms .
Urgency is a sudden compelling desire to pass urine, which is difficult to
defer. These urological symptoms can have a considerable negative impact on a
subject*s quality of life, typically resulting in embarrassment and loss of
dignity, which might affect relationships, intimacy and self-image.
Population-based surveys have shown that OAB is a common disorder. In a
cross-sectional survey of 19165 adults in Canada, Germany, Italy, Sweden and
the United Kingdom (the EPIC study) the overall prevalence of OAB was reported
to be 11.8%. The overall rates were similar between men and women, and
increased with age; urgency was reported in 19.1% of men and 18.3% of women
aged 60 years or over.

The correct functioning of the urinary bladder requires a balanced and
sequential involvement of smooth muscle activity in the various bladder
elements, controlled in part by the sympathetic autonomic nervous system
(involving the hypogastric nerve) and the parasympathetic system (via the
pelvic nerve). Regulation of these nerves is mainly via adrenergic and
muscarinic receptors, controlled by the pontine micturition center in the
brain. Stimulation of muscarinic receptors facilitates urine voiding through
contracting of the detrusor, whereas activation of Beta-Adrenoreceptors (AR's)
in the bladder facilitates urine storage through flattening and lengthening of
the bladder base

The main treatment options for OAB are conservative management (e.g. bladder
training) and pharmacotherapy, or a combination of both. The main
pharmacological treatment for OAB is the use of antimuscarinic agents. The
pathophysiology of OAB is not fully understood, but it is likely that
antimuscarinic drugs act by inhibiting the M3 subtype of muscarinic receptors
in the urinary bladder, leading to a decrease in involuntary detrusor
contractions and increased bladder filling, thereby reducing storage symptoms
(frequency, nocturia, urgency and urgency incontinence). Solifenacin,
oxybutynin and tolterodine are the most common muscarinic receptor antagonists
used in the treatment of OAB. Muscarinic receptors are also found in other
tissues such as the salivary gland, intestine and eye, which mean that the use
of antimuscarinic agents can give rise to anticholinergic-type adverse events
such as dry mouth, constipation and blurred vision. Of these, dry mouth is
reported most frequently and is the main reason for discontinuation of these
agents. Development of drugs with a different mode of action to the muscarinic
receptor antagonists may therefore result in treatment options with a better
benefit/risk ratio than the currently available compounds.

In vitro organ bath studies using pig tissue showed that smooth muscle
relaxation of the trigone and bladder body areas was mediated by activation of
Beta-ARs. Beta-ARs have been shown to play a role in the relaxation of the
urinary bladder detrusor smooth muscle [9]. However, this pharmacological
effect could not be therapeutically exploited at the time due to incomplete
knowledge of the heterogeneity of Beta-ARs, the abundance of Beta 1- and Beta
2-ARs in pivotal organs like the heart, bronchi and blood vessels, and the lack
of drug selectivity.
The Beta 3-AR subtype is dominant in the human detrusor muscle as demonstrated
by the fact that the relaxation of detrusor muscle strips by the Beta-AR
agonist isoprenaline could be blocked by Beta 3-AR antagonists but not by Beta
1- or Beta 2-AR antagonists [11]. Based on these findings, it is considered
that in humans, detrusor relaxation by activation of sympathetic nerves is
mediated primarily via the Beta 3-AR [13]. These data support a likely role for
Beta 3-ARs in promoting urine storage in the bladder and suggest a therapeutic
potential for drugs acting at Beta 3-ARs

Mirabegron (the medication under investigation in this trial) is a selective
agonist for the human beta 3-adrenoreceptor (AR) that is currently being
assessed by the registration-authorities for the treatment of patients with
OAB. It is the first of a new class of compounds with a distinct mode of action
as compared with the current standard of care, primarily antimuscarinics, in
the treatment of patients with OAB.

To assess the efficacy of Mirabegron 50mg versus Solifenacin 5mg in the
treatment of subjects with OAB who were dissatisfied with their treatment due
to lack of efficacy.

A Double-Blind, Randomized, Parallel Group, Multi-Centre Study to Evaluate the
Efficacy and Safety of Mirabegron Compared to Solifenacin. Phase III study.

During the first two weeks (Placebo Run-in; Single blind study period) all
patients will receive two placebo tablets, once daily.

During the 12 week; Double blind study period (Directly starting after the
Placebo Run-in period)
One treatment group will receive one tablet of 5 mg Solifenacin and 1 placebo
tablet, once daily for 12 weeks.
The other treatment group will receive one tablet of 50 mg Mirabegron and 1
placebo tablet, once daily for 12 weeks.
The participants will be randomised in ratio of 1:1 into one of the mentioned
treatmentgroups.

During the visits the following assessments will be performed:
- Interview about medical history and OAB: Visit 1
- Asked to stop taking any medications patients are taking to treat their OAB:
Bezoek 1
- Test for stress-incontinence for female only (cough provocation): Bezoek 1
- Physical Examination: Visit 1 and 5
- Bloodsampling 20-30 mL: Visit 1 and 5
- ECG: Visit 1 and 5
- Provision of urine sample to test on infections: Visit 1, 2 and 5.
- Urine Pregnancytest (for female subject): All visits (1-5)
- Bloodpressure and pulsrate measurement: All visits (1-5)
- Bladderscan: Visit 1
- Explanation/Instruction for diary completion: Visit 1
- Diary Completion; during 14 weeks (whole study duration) to record/confirm
intake of study medication every day. In addition subjects needs to record
three days before hospital visits the time for every occasion that he/she
urinates, experiences incontinence or urgency.
- Questionnaires: One questionnaire at visit 1; Four questionnaires at visit 2
and 5; and three questionnaires at visit 3 and 4. Questionnaires are regarding
the patients OAB condition and impact it has on the daily living/Quality of
life.
- General Health status check; patients will be asked about their general
health status and possible side effects (adverse reactions) during all visits
(1-5).

The adverse reactions of the study medication and the standard bloodsampling
could cause a risk for the subjects during the study.

Adverse reactions Solifenacine;
- dry mouth (very often), constipation, blurred vision, nausea and other
intestinal complaints.
- At the dosage of 5 mg o.d. (used during this study) there are no severe
adverse reactions expected.

Adverse reactions Mirabegron;
Important potential risks include QT prolongation with supratherapeutic doses
or in high-risk populations, increased heart rate with supratherapeutic doses,
increased blood pressure with supratherapeutic doses, nonimmediate cutaneous
hypersensitivity reactions, urinary tract infections, indigestion and joint
swelling. During the clinical develpment phase several dosages were tested. The
proposed therapeutic dose of mirabegron based on the overall risk benefit is 50
mg once daily