Title: Onabotulinum toxin-A versus extended release tolterodine in the management of idiopathic overactive bladder in children: A pilot randomised controlled trial
Funder: Department of Health and Social Care

Abstract: Idiopathic overactive bladder (IOAB) is the commonest cause of urinary incontinence, urgency and bed wetting in children with a prevalence of 5-7%. The management of this condition includes bladder training and anti-cholinergic medication. Eighty percent of children with severe symptoms and daily wetting have a suboptimal response to standard therapy (Van Arendonk, 2006). The aim of this trial is to assess the effectiveness of botulinum toxin-A(BtA) as a treatment for paediatric IOAB compared to extended release tolterodine, a standard second line anti-cholinergic agent. Inclusion Criteria Children of both sexes between the age of 7 and 16 years with clinical symptoms of IOAB. Symptoms must include episodes of daytime urinary incontinence Incomplete resolution of symptoms after 6 months of bladder training and anticholinergic therapy. Absence of any neurological pathology that could cause incontinence, on physical examination. Urodynamic studies demonstrating either detrusor overactivity and/or reduced bladder compliance and/or reduced bladder capacity. Ultrasound of the renal tract showing no structural abnormality which could account for the symptoms. Exclusion Criteria Recurrent urinary tract infection not controlled with antibiotic prophylaxis. The presence of a neurological pathology which could account for incontinence, on physical examination. Normal urodynamic study or evidence of significant dysfunctional voiding. Structural abnormality which could account for the symptoms or a post void residual greater than 20% of predicted capacity. Previous treatment with BtA within 12 months of the recruitment date. Allergy to BtA or tolterodine. Positive pregnancy test in menstruating girls. Plan of Investigation: After identification, provision of study information to the family and informed consent, children will be asked to stop any IOAB medication for 2 weeks. This washout period will allow a clear assessment of baseline bladder function. The urodynamic studies will be conducted and clinical assessment will be performed using a bladder diary. Quality of life will be assessed using PedsQL and PinQ. Eligible children will then be randomly assigned electronically into two arms. The first study arm will be given extended release tolterodine 4 mg orally once a day. The second study arm will have treatment with BtA in a dosage of 5 IU/Kg (maximum dose of 150 IU) under general anaesthesia. The study will not be blinded so children in the first arm will be spared unnecessary general anaesthesia. Primary Outcome measure: 1. Mean number of episodes of daytime urinary incontinence per day at 6 weeks Secondary outcome measures: 1. Urodynamic study data at 6 weeks a. maximum cystometric capacity b. presence or absence of detrusor overactivity c. maximum detrusor pressure during storage phase d. bladder compliance e. post void residual urine 2. Bladder diary analysis at 6 weeks, 3 and 6 months: a. daytime urinary frequency corrected for fluid intake b. episodes of urinary urgency over a 24 hour period c. minimum, median and maximum voided volumes over a 24 hour period d. nocturia or nocturnal enuresis 3. Quality of life score (PedsQL/PinQ) at 6 weeks, 3 and 6 months 4. Adverse events Children who have not had good therapeutic response to treatment at 6 weeks or have experienced side effects will be given the option of having the therapy in the alternative study arm. Participant safety is paramount and if we or the families feel the need to withdraw participants we will do so. This trial will help to evaluate the effectiveness of BtA in children with IOAB, compared to tolterodine.

Lay abstract: Idiopathic overactive bladder (IOAB) is the commonest cause of urinary incontinence in children with a prevalence of 5-7%. IOAB results in reduced self-esteem and has a detrimental effect on academic performance. Untreated IOAB in childhood is associated with persisting urinary symptoms in adulthood. The social and economic impact of IOAB in adults is well documented with resultant anxiety, depression and increased healthcare usage. The initial management is bladder training. Anticholinergic medication is the next step but has only a 20% success rate in children with severe daily wetting. Botulinum toxin-A (BtA) is used in adults with IOAB with good results. Published experience in children is limited to 3 observational studies of 91 patients. We have been using BtA in the treatment of selected children with IOAB for two years with good results. The aim of this study is to compare the effectiveness of intravesical BtA with extended release tolterodine, a second line anticholinergic drug in children with IOAB aged 7-16 years. One-hundred patients who are still symptomatic after initial bladder training and at least 6 months of anticholinergic medication will be recruited. Patients will be randomly allocated to two arms of treatment. The first will receive tolterodine once per day. The second arm will receive a single treatment with intravesical BtA under general anaesthetic. Patients will be followed up after 6 weeks with a bladder diary, quality of life questionnaires, uroflow studies and urodynamic study. Further follow-up will be at 3 and 6 months with bladder diary and quality of life questionnaires. Those with no response to one arm of the treatment will be withdrawn from the study and offered rescue treatment with other modality. Our hypothesis is that treatment with BtA will result in significant improvement in the mean number of daytime incontinence episodes per day compared to tolterodine.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: RENAL AND UROGENITAL