Flexibly adding-on Second Antimuscarinic Agent to the First Antimuscarinics for Refractory Overactive Bladder Syndrome
Flexibly adding-on Second Antimuscarinic Agent to the First Antimuscarinics for Refractory Overactive Bladder Syndrome
To investigate if oxybutynin ER adding on antimuscarinics is more effective than
 mono-antimuscarinic treatment for patients with refractory OAB
-  Introduction:Overactive bladder (OAB) is a symptom syndrome characterized by urgency
 frequency with or without urgency incontinence. Usually no metabolic or anatomical
 disorders can be found in patients with OAB, and the condition may have a great impact
 on quality of life. Antimuscarinics are the first line treatment and yield a success
 rate of more than 70%. Urothelial dysfunction and abnormalities of sensory receptor
 expression or transmitter release in the suburothelial nerves might contribute to OAB
 which is refractory to antimuscarinics. In patients who failed current antimuscarinic
 treatment, intravesical botulinum toxin A (BoNT-A) injection provides an chance of
 improvement. Previous studies reported success rates of BoNT-A injection for OAB ranged
 from 60 to 80%. Intravesical treatment to inhibit abnormal receptor expression or
 transmitter release in the sensory nerve terminals of the suburothelial space can
 provide good therapeutic effects in the treatment of OAB. However, patients might
 develop large postvoid residual (PVR) and subsequent urinary tract infection (UTI) after
 BoNT-A injections, therefore, this treatment is usually left for patients who are
 refractory to antimuscarinic therapy. However, how to define antimuscarinic refractory
 OAB remains controversial. How many different types of antimuscarinics should be
 prescribed before we call the case failure has not been elucidated. The aim of this
 study is to evaluate the effect of flexibly adding-on oxybutynin ER (5mg QD) in patients
 with OAB who were refractory to monotherapy with the first antimuscarinic agent
 (tolterodine 4mg QD).

 -  Methods: A total of 200 patients with refractory OAB will be included in this
 prospective, open label protocol. Inclusion criteria are persistent OAB symptoms
 (frequency urgency with/without urgency urinary incontinence) after behaviour therapy
 and an optimized dose of one antimuscarinic agent (Tolterodine 4mg) for at least 3
 months. Patients with neurogenic diseases, untreated bladder outlet obstruction,
 recurrent UTI, large PVR (>150ml) will be excluded from this study. Patients will be
 randomized to allocate in the treatment group (receiving tolterodine 4mg QD and
 oxybutynin 5mg to 15mg QD) or control group (tolterodine 4mg QD) in 1:1 ratio based on
 the permuted block randomization code. Oxybutynin ER 5mg to 15 mg once daily will be
 flexibly adding-on from baseline to the third month in the treatment group, depending on
 patient's effectiveness and tolerability to adverse events. At the baseline, 1 and 3
 months after oxybutynin ER adding-on, we will assess the International Prostate Symptom
 Score (IPSS), Overactive Bladder Symptom Score (OABSS), Patient Perception of Bladder
 Condition (PPBC), the Urgency Severity Scale (USS) questionnaires, uroflowmetry and PVR.
 The therapeutic effect will be considered as successful if there was a reduction of PPBC
 of 2 from baseline and a reduction of USS of 1 from baseline, or the USS value is 0 at 3
 months. The adverse events and tolerability of this combined therapy will also be
 assessed.

 -  Expected Results: Compared with baseline, total IPSS, IPSS storage subscore, quality of
 life indexes, OABSS, USS and PPBC will be expected to significantly decrease at 1 and 3
 months. PVR might be increased at 3 months after adding-on treatment. The changes of
 IPSS voiding subscore, peak urinary flow rate and voided volume might be increased or
 comparable to the control group during the follow-up. We expect at least one-third of
 patients can have a successful therapeutic effect without significantly increased
 adverse events. However, the other patients might withdraw from the study due to adverse
 events such as severe dry mouth, constipation, large PVR, UTI, severe difficult
 urination or acute urinary retention.

 Adverse events should be cautiously monitored during the treatment course.
Inclusion Criteria:

 -  Patients aged ≥20 years of male or female gender with OAB refractory to one
 antimuscarinics therapy

 -  Patient or his/her legally acceptable representative has signed the written informed
 consent form

 Exclusion Criteria:

 -  Patients with untreated bladder outlet obstruction, intrinsic sphincter deficiency,
 pelvic organ prolapse

 -  Patients with history of urethral injury or transurethral surgery for prostate or
 bladder

 -  Patients with severe cardiopulmonary disease and such as congestive heart failure,
 arrhythmia, poorly controlled hypertension, not able to receive regular follow-up

 -  Patients with known active urinary tract infection, urinary stone or malignancy

 -  Patients have laboratory abnormalities at screening including:

 1. Aspartate aminotransferase (AST) > 3 x upper limit of normal range.

 2. Alanine aminotransferase (ALT) > 3 x upper limit of normal range.

 3. Patients have abnormal serum creatinine level > 2 x upper limit of normal range.

 -  Patients with urinary retention, PVR≥250 ml

 -  Patients with any other serious disease or condition considered by the investigator
 not suitable for entry into the trial

 -  Patients participated investigational drug trial within 1 month before entering this
 study

 -  Patients with major psychiatric illness or drug abuse