Kitta Takeya, Darekar Amanda, Malhotra Bimal, Shahin Mohamed H, Jones Philip, Lindsay Monica, Mallen Sharon, Nieto Alejandra, Crook Tim J
Department of Renal and Urologic Surgery, Asahikawa Medical University Hospital, Asahikawa, Japan.
Pfizer R&D UK Ltd, Walton Oaks, UK.
J Pediatr Urol. 2023 Apr;19(2):175.e1-175.e10. doi: 10.1016/j.jpurol.2022.11.020. Epub 2022 Nov 29.
Neurogenic detrusor overactivity (NDO) can damage the upper urinary tract leading to chronic renal impairment. Antimuscarinic therapy is used to improve urinary incontinence and protect the upper urinary tract in patients with NDO.
This study investigated safety and efficacy of fesoterodine, a muscarinic receptor antagonist, in 6‒<18-year-old patients with NDO (NCT01557244).
This open-label phase 3 study included 2 pediatric cohorts. Patients in Cohort 1 (bodyweight >25 kg) were randomized to fesoterodine 4 or 8 mg extended-release tablets or oxybutynin XL tablets administered over the 12-week active comparator-controlled phase. The safety extension phase evaluated fesoterodine 4 and 8 mg for a further 12 weeks, with patients in the oxybutynin arm allocated to fesoterodine 4 or 8 mg. Patients in Cohort 2 (bodyweight ≤25 kg) were randomized to fesoterodine 2 or 4 mg extended-release beads-in-capsule (BIC) administered over a 12-week efficacy phase and 12-week safety extension phase. Patients with stable neurologic disease and clinically or urodynamically proven NDO were included. The primary endpoint was change from baseline to Week 12 in maximum cystometric bladder capacity (MCC). Secondary efficacy endpoints included detrusor pressure at maximum bladder capacity, bladder volume at first involuntary detrusor contraction, bladder compliance, and incontinence episodes. Safety endpoints included adverse event incidence, and specific assessments of cognition, behavior and vision. The pharmacokinetics of 5-hydroxymethyl tolterodine (5-HMT; fesoterodine's active metabolite) was determined using population-pharmacokinetic analysis.
In Cohort 1 (n = 124), fesoterodine 4 and 8 mg treatment resulted in significant increases from baseline in the primary endpoint of MCC at Week 12. In Cohort 2 (n = 57), fesoterodine 2 and 4 mg BIC treatment resulted in improvements in MCC from baseline. Fesoterodine 4 and 8 mg and fesoterodine 4 mg BIC led to improvements in some secondary efficacy endpoints. The most common treatment-related adverse reactions were gastrointestinal effects, such as dry mouth, which occurred more frequently with oxybutynin than fesoterodine. No detrimental effects on visual accommodation or acuity, or on cognitive function or behavior were observed.
These safety and efficacy results are consistent with limited published data on fesoterodine treatment in pediatric populations with overactive bladder or NDO. Study limitations include the lack of placebo control and the small sample size, which limits the ability to make formal efficacy comparisons and detect rare adverse reactions.
Fesoterodine has a favorable benefit-risk profile in 6‒<18-year-old patients with NDO and may represent an additional option for pediatric NDO treatment.
神经源性逼尿肌过度活动（NDO）可损害上尿路，导致慢性肾功能损害。抗毒蕈碱疗法用于改善NDO患者的尿失禁并保护上尿路。
本研究调查了毒蕈碱受体拮抗剂非索罗定在6至<18岁NDO患者中的安全性和有效性（NCT01557244）。
这项开放标签的3期研究包括2个儿科队列。队列1（体重>25 kg）的患者在为期12周的活性对照药物对照阶段被随机分配至非索罗定4或8 mg缓释片或奥昔布宁控释片。安全性延长期对非索罗定4和8 mg进行了为期12周的进一步评估，奥昔布宁组的患者被分配至非索罗定4或8 mg。队列2（体重≤25 kg）的患者在为期12周的疗效期和12周的安全性延长期被随机分配至非索罗定2或4 mg胶囊内缓释微丸（BIC）。纳入患有稳定神经疾病且经临床或尿动力学证实为NDO的患者。主要终点是最大膀胱测压容量（MCC）从基线到第12周的变化。次要疗效终点包括最大膀胱容量时的逼尿肌压力、首次逼尿肌不自主收缩时的膀胱容量、膀胱顺应性和尿失禁发作次数。安全性终点包括不良事件发生率，以及对认知、行为和视力的特定评估。使用群体药代动力学分析确定5-羟甲基托特罗定（5-HMT；非索罗定的活性代谢物）的药代动力学。
在队列1（n = 124）中，非索罗定4和8 mg治疗使第12周时MCC的主要终点较基线有显著增加。在队列2（n = 57）中，非索罗定2和4 mg BIC治疗使MCC较基线有所改善。非索罗定4和8 mg以及非索罗定4 mg BIC使一些次要疗效终点得到改善。最常见的与治疗相关的不良反应是胃肠道效应，如口干，奥昔布宁比非索罗定更常出现。未观察到对视觉调节或视力、认知功能或行为的有害影响。
这些安全性和有效性结果与已发表的关于非索罗定治疗小儿膀胱过度活动症或NDO的有限数据一致。研究局限性包括缺乏安慰剂对照和样本量小，这限制了进行正式疗效比较和检测罕见不良反应的能力。
非索罗定在6至<18岁的NDO患者中具有良好的效益风险比，可能是小儿NDO治疗的另一种选择。
