A RANDOMISED, MULTI-CENTRE, DOUBLE-BLIND, PLACEBO- AND ACTIVE-CONTROLLED, 5-WAY, PARALLEL GROUP STUDY TO INVESTIGATE THE EFFICACY, SAFETY AND TOLERABILITY OF ONO-8539 IN PATIENTS WITH OVERACTIVE BLADDER

Overactive bladder (OAB) is defined as urgency, with or without urgency
incontinence, usually with frequency and nocturia if there is no proven
infection or other obvious pathology. It is a commonly occurring complex of
symptoms that affects about 16% of the adult population in Europe and the US.
The prevalence of OAB increases with age and is similar in men and women. It
is estimated that there are approximately 22 million adults (> 40 years old)
affected by OAB in Europe.
The current treatment for OAB focuses on the use of anticholinergic drugs which
are contraindicated in patients with bladder outlet obstruction and glaucoma.
Dry mouth also seems to be a cause of patient non-compliance to chronic
anticholinergic treatment. Thus EP1 receptor antagonists, may offer efficacious
treatment for OAB, without the adverse effects or contraindications seen with
anticholinergic drugs.

The hypothesis for this study is that one or more of the investigative doses of
ONO-8539 will lead to a mean relative decrease in the number of micturitions
per 24 hrs of at least 1.5 compared to placebo at 12 weeks and controlling for
baseline.

The primary objective of this trial is to compare the effect of three different
doses of ONO-8539 with placebo in the mean change of the number of micturitions
per 24 hrs from baseline to 12 weeks.

The secondary objectives of this trial will be:
*To compare the effect of three different doses of ONO-8539 and Tolterodine
(Detrusitol XL) versus placebo on the number of micturitions per 24 hrs,
frequency of urinary urgency incontinence episodes per 24 hrs, number of
urgency episodes per 24 hrs, severity of urgency, mean volume voided per
micturition, number of micturitions during daytime, number of micturitions
during sleeping time, and number of continent days (among incontinent patients)
during the course of treatment.
*To compare the effect of three different doses of ONO-8539 and Tolterodine
(Detrusitol XL) versus placebo on subjective scales of treatment effect and
Quality of Life during the course of treatment.
*To compare the safety and tolerability of three different doses of ONO-8539
and Tolterodine (Detrusitol XL) versus placebo.

In addition, the exploratory objectives of this trial will be:
*To investigate the dose response of ONO-8539.
*To investigate the plasma concentration of ONO-8539 and its glucuronide.
*To investigate the association between the changes in efficacy parameters of
ONO-8539 and the plasma concentrations of ONO-8539.
*To investigate the association between the changes in efficacy parameters of
ONO-8539 and baseline level/post-treatment level of PGE2 in urine.
*To compare the efficacy and safety between the three different doses of
ONO-8539 versus Tolterodine (Detrusitol XL).
*To undertake subgroup analyses using appropriate clinical and biological
factors.

Randomised, double-bllind, placebo- and active-controlled, 5-way parallel
group.

Patients will take their morning dose (six tablets of ONO-8539 and/or matching
placebo, and one capsule of Tolterodine or matching placebo) after breakfast
and take their evening dose (six tablets of ONO-8539 and/or matching placebo)
after dinner.

Patients will receive the following:
One of three possible treatment doses of ONO-8539 - either 30mg twice a day,
100 mg twice a day or 300mg twice a day- or Tolterodine 4mg once daily or
Placebo. ONO-8539 is available in tablets of 10 mg and 50 mg. This results in
the following:

- Placebo group: Twice a day 6 placebo tablets of ONO and once a day
Tolterodine placebo capsule.
- Ono 30 mg group: Twice a day 3 tablets of 10 mg and 3 placebo tablets and
once a day Tolterodine placebo capsule.
- Ono 100 mg group: Twice a day 2 tablets of 50 mg and 4 placebo tablets and
once a day Tolterodine placebo capsule.
- Ono 300 mg group: Twice a day 6 tablets of 50 mg and once a day Tolterodine
placebo capsule.
- Tolterodine 4 mg group: Twice a day 6 placebo tablets of ONO and once a day
Tolterodine capsule.

Burden for the patient:
- Patients have to come in 7 times.
- Patients have to complete a bladder diary 3 days before every visit.
- Every day a compliance diary must be completed
- 3 times a physical examination
- 2 times completion of questionnaire
- 3 times uro-flow (Qmax) for all man and for women only if there is a
clinical relevance.
- 4 times ECG
- Blood will be drawn 7 times 20 ml.

Gastrointestinal side effects such as nausea, diarrhoea, heartburn and
abdominal pain were reported occasionally. Other side effects are headache,
decreased appetite, urinary frequency, sweating, rash and sleepiness.