Efficacy of Intravesical Oxybutynin in Children With Neurogenic Bladder Dysfunction: A Randomized, Prospective Controlled Multi-center Trial
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 60
- 试验地点
- 30
- 主要终点
- Evolution of maximal bladder capacity at 4 weeks of treatment (end of follow-up)
研究概览
简要总结
Malformation of the lumbosacral region (spina bifida) affects the innervation of the bladder in children. The usual evolution leads to a neurological bladder with small capacity, poor compliancy and overactivity, exposing to incontinence and obstruction to the evacuation of urine. It is responsible for renal failure requiring dialysis and transplantation. Current therapeutics aim to evacuate urine and reduce intravesical pressure. It gradually combines 1) intermittent catheterization, 2) anticholinergics, 3) botulinum toxin (Botox®) injection into the detrusor (bladder muscle) by cystoscopy and 4) surgery (vesicostomy, Bricker, enterocystoplasty). Oxybutynin relaxes the detrusor, improves continence and reduces intravesical pressure. It is usually administered per os, but there are contraindications (glaucoma, myasthenia), side effects (constipation, dry mouth). It can be difficult to swallow for children, and drug resistance may develop. It can lead to ineffective treatment requiring therapeutic escalation. The next step, intradetrusor Botox® injection, is invasive (cystoscopy), has a limited duration of action (6 months) and must be performed under general anesthesia in children.
Surgical treatments are effective but irreversible and responsible for morbidity and mortality. A randomized study was performed demonstrating the efficacy of intravesical oxybutynin compared to oral administration in adult patients. This study found a significant increase in bladder capacity and a significant decrease in side effects in the intravesical oxybutynin group. Due to the relative difficulties of intravesical oxybutynin delivery (preparation, cost) and the more invasive nature, it is not used as an alternative to oral oxybutynin.
The hypothesis of this study is that this treatment may have a legitimate place in the treatment of neurogenic bladder in patients with failure of anticholinergic treatment before a therapeutic escalation requiring an invasive procedure (Botox®, enterocystoplasty) especially in children for whom repeated general anesthesia for Botox® injection may interfere with brain development. In this way, the investigators aim to extend the time to therapeutic escalation in the pediatric population.
The main objective of the trial is to compare the efficacy on maximal bladder capacity of intravesical oxybutynin instillation versus placebo in the treatment of children with overactive neurogenic bladder (spina bifida), performing intermittent catheterization, for whom oral anticholinergic treatment is ineffective or poorly tolerated.
详细描述
Secondary objectives of the trial :
- Secondary efficacy objectives will be analyzed following a fixed sequence in a priori ordered hypotheses: to evaluate after treatment with intravesical oxybutynin (IVO) or placebo instillation: maximum bladder pressure evolution; incontinence: time to clinical treatment failure perceived by the patient. These parameters are considered by experts to be objective markers of neurological bladder improvement, in addition to the primary urodynamic objective.
- Evaluate and compare between groups the tolerance and adverse effects of treatment.
- Evaluate and compare between groups the number of responders and continent patients after treatment
- Evaluate and compare between groups the usability of Intravesical Oxybutynin.
- Evaluate and compare between groups the evolution of quality of life.
- Evaluate and compare between groups the evolution of bladder diary data.
- Evaluate and compare between groups the evolution of other urodynamic parameters.
- Evaluate and compare between groups the evolution of renal ultrasonography parameters.
- Identify factors, among the patient's characteristics, associated with a greater probability to be a responder or non-responder to intravesical oxybutynin
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 6 Years 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Person affiliated to or beneficiary of a social security plan
- •In failure of treatment with one or more anticholinergics defined by a response considered insufficient by the investigator after at least 4 weeks of optimal dose treatment, unable to take oral oxybutynin or intolerable adverse events
- •Having performed renal ultrasonography less than 2 months ago
- •Having performed cystomanometry less than 6 months ago including maximal bladder capacity and maximal bladder pressure (preferably not under oral oxybutynin treatment)
- •Age between 6 and 17 years old
- •Informed about study organization, having given consent to participate and each legal representative have signed the informed consent
- •Having undergone the medical examination adapted to research
- •Presenting overactive bladder due to spina bifida confirmed by urodynamic check-up of less than 6 months. Overactive bladder is defined according to International Children's Continence Society, (ICCS): "a urodynamic observation characterized by involuntary detrusor contractions during the filling phase which may be spontaneous or provoked"
- •Carrying out intermittent catheterization for at least 6 weeks and at least three times a day
- •Able and volunteer to perform intravesical catheterization and instillation (patient or parents).
排除标准
- •Person displaying known allergy to one of the components of evaluated product (notably oxybutynin).
- •Person with congestive cardiac failure
- •Person with cardiac arrhythmia
- •Person with tachycardia
- •Person with uncontrolled hypertension
- •Person under one of the following treatments : Bisphosphonates; Cytochrome P450 Inhibitors (such as ketoconazole and Erythromycin); Cholinesterase inhibitors.
- •Person displaying a contraindication to evaluated product, in particular: Hypersensitivity to oxybutynin; Myasthenia; Angle-closure glaucoma; Functional or organic gastrointestinal obstruction including pyloric stenosis, paralytic ileus and intestinal atony; Serious gastro-intestinal disorders (e.g., severe ulcerative colitis and toxic megacolon); Patients who have undergone ileostomy, colostomy, severe hemorrhagic colectasis or rectocolitis; Subvesical obstruction (urethral stenosis, posterior urethra valve); Ongoing treatment with anticholinergic drugs for another indication that could not be stopped; Patient with polyuria of other origin (renal, heart, potomania); Concomitant oxygenotherapy.
- •Woman of childbearing age without highly effective contraception (Sexual abstinence OR combined contraception by oral, intravaginal or transdermal ovulation inhibition OR progestin-only contraception by oral, injectable or implantable ovulation inhibition OR Intrauterine device or hormonal IUD).
- •Pregnant, parturient or breastfeeding woman.
- •Person deprived of liberty for judicial or administrative decision.
- •Person under psychiatric care as referred in articles L. 3212-1 and L. 3213-
- •Intradetrusor injection of botulinum toxin less than 6 months before.
- •Person with hyperthyroidism
- •Person with coronary cardiac disease.
研究组 & 干预措施
IntraVesical Placebo (PCB)
Instillation of saline solution conditioned in 10 mL ready-to-use syringes at the end of the evacuation catheterization. Dose equivalent to IVO in ml, i.e. always 0.4mg/kg/day, i.e. a maximum of 10 mL per instillation. Maximum dose: 20mL/day for patients aged 6-11 years and 11 months, and 30mL/day for patients aged 12 to 17 years.
干预措施: Placebo (Drug)
IntraVesical Oxybutynin (IVO)
Instillation of oxybutynin conditioned in VESOXX® 10mg/10mL ready-to-use syringes (1mg/mL) at the end of the evacuation catheterization.
Dose: 0.4mg/kg/day in 2 to 3 instillations per day, i.e. a maximum of 10mg per instillation. Maximum dose: 20mg/day for patients aged 6-11 years and 11 months, and 30mg/day for patients aged 12-17 years.
干预措施: Oxybutynin Hydrochloride (Drug)
结局指标
主要结局
Evolution of maximal bladder capacity at 4 weeks of treatment (end of follow-up)
时间窗: 4 weeks
This parameter is considered by experts to be an objective marker of improvement in neurological bladder, in addition to the secondary clinical objective. It was used as the primary objective in the only prospective study in the literature. It is obtained by cystomanometry and is defined by the maximum volume (in mL) measured at the moment when permission to urinate is given to the patient, after filling via urethral catheter. In younger patients, urination occurs spontaneously, and this value is obtained a posteriori by curve analysis. If treatment is successful, maximum bladder capacity should increase.
次要结局
- Evolution of maximal bladder pressure at 4 weeks of treatment (end of follow-up)(4 weeks)
- Urinary incontinence(4 weeks)
- Evaluation of the number of side effects(4 weeks)
- Proportion of responders at 4 weeks of treatment(4 weeks)
- Proportion of continent patients at 4 weeks of treatment(4 weeks)
- Product usability measured with usability questionnaire(4 weeks)
- Standardized difference in patient quality of life calculated according to the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI-SF) score between the beginning and the end of the study.(4 weeks)
- Standardized difference in patient quality of life calculated according to the KIDSCREEN-10 score between the beginning and the end of the study.(4 weeks)
- Evolution of the number of urinary catheterizations at 4 weeks of treatment(4 weeks)
- Evolution of the volume of urinary catheterizations at 4 weeks of treatment(4 weeks)
- Evolution of the bladder compliance at 4 weeks of treatment(4 weeks)
- Evolution of the minimum filling volume causing uninhibited detrusor contraction at 4 weeks of treatment(4 weeks)
- Evolution of the Detrusor leak point pressure at 4 weeks of treatment(4 weeks)
- Evolution of the volume of bladder filling during urine loss at 4 weeks of treatment(4 weeks)
- Evolution of renal ultrasonography at 4 weeks of treatment(4 weeks)
研究者
Nicolas BERTE
Principal investigator, pediatric surgeon
Central Hospital, Nancy, France