Study to Test the Efficacy and Safety of YM178 in Subjects With Symptoms of Overactive Bladder

A Randomized, Double-blind, Parallel Group, Proof of Concept Study of YM178 in Comparison With Placebo and Tolterodine in Patients With Symptomatic Overactive Bladder

The study is intended to test efficacy, safety and tolerability of two doses of YM178 against placebo and tolterodine to treat patients with symptoms of over active bladder.

This is a multinational, multicenter, double-blind, double-dummy,

randomized, parallel group, placebo and active controlled phase II proof-of concept study. Patients are enrolled into a single-blind, 2-week placebo run in

period after which they are randomized to 4 weeks of double-blind

treatment with YM178 (low dose and high dose), placebo or tolterodine. Subsequently patients will be followed for an additional 2 weeks

with single-blind placebo treatment. There are 6 visits in total: visit 1 at

enrolment, visit 2 (baseline) after the 2-week placebo run-in, visits 3, 4 and 5

after 1, 2 and 4 weeks of double-blind treatment respectively, and visit 6

after a 2-week follow-up.

Inclusion Criteria:

• Patient is willing and able to complete the micturition diary correctly.
• Symptoms of overactive bladder (urinary frequency and urgency with or without incontinence) for ≥ 3 months

At randomization:

• Patient must experience frequency of micturition on average ≥ 8 times per 24-hour period during the 3-day micturition diary period
• Patient must experience at least 3 episodes of urgency (grade 3 or 4) with or without incontinence, during the 3-day micturition diary period

Exclusion Criteria:

• Pregnant women or women who intend to become pregnant during the study or women of childbearing potential who are sexually active and practicing an unreliable method of birth control or will be lactating during the study. Reliable contraceptive methods are intra-uterine devices, contraceptive pills of combination type, hormonal implants, contraceptive patches and injectable contraceptives
• Clinically significant outflow obstruction (at the discretion of the investigator)
• Significant post void residual volume (PVR>200ml)
• Significant stress incontinence or mixed stress/urge incontinence where stress is the predominant factor as determined by the investigator (for female patients confirmed by a cough provocation test)
• Patients with a neurological cause for abnormal detrusor activity
• Diabetic neuropathy
• Evidence of a symptomatic urinary tract infection, chronic inflammation such as interstitial cystitis, bladder stones, previous pelvic radiation therapy or previous or current malignant disease of the pelvic organs
• Uncontrolled narrow angle glaucoma, urinary or gastric retention, colitis ulcerosa, toxic megacolon, myasthenia gravis or any other medical condition which in the opinion of the investigator makes the use of anticholinergics contra-indicated
• Non-drug treatment including electrostimulation therapy

(a bladder training program or pelvic floor exercises which started more than 1 month prior to entry into the study can be continued)

• Use of medications intended to treat urinary incontinence or listed in Appendix 1 Part A. Part B lists medications that are restricted but accepted under certain conditions
• Known or suspected hypersensitivity to tolterodine, other anticholinergics, ß-adrenoceptor agonists, or lactose or any of the other inactive ingredients
• Any clinically significant cardiovascular complication including CVA, recent myocardial infarction and uncontrolled hypertension, indicated by a sitting systolic blood pressure ≥ 180 mmHg and/or diastolic blood pressure ≥ 110 mmHg
• Any clinically significant condition, which in the opinion of the investigator makes the patient unsuitable for the trial
• Participation in any clinical trial within 30 (90 in the UK) days prior to randomization
• Employees of the sponsor, third parties associated with the study, or the study site

At randomization:

• Patient who did not complete the micturition diary according to the instructions
• Average total daily urine volume > 3000 ml as recorded in the micturition diary
• Clinically significant elevation of serum creatinine or liver enzymes as evidenced by creatinine >150 mmol/L, ASAT or ALAT > 2x upper limit of normal range (ULN), γ-GT > 3x ULN and/or abnormal serum total bilirubin (as assessed in visit 1 samples or alternative sampling within 4 weeks prior to visit 1)