国产A型肉毒毒素治疗膀胱过度活动症的有效性和安全性:多中心、随机、双盲、安慰剂平行对照研究

Efficacy and safety study of Chinese botulinum toxin A 100U in patients with overactive bladder:a prospective,multicenter,double-blind and randomized controlled trial

目的探讨国产A型肉毒毒素(BTX-A)100 U注射剂量治疗膀胱过度活动症(OAB)的疗效和安全性。方法2016年4月至2018年12月对17家三甲医院的OAB患者进行试验。本研究分为核心试验阶段和扩展试验阶段。核心试验阶段采用前瞻性、多中心、随机、双盲、安慰剂平行对照的试验方法进行研究。纳入标准:年龄18~75岁;口服抗胆碱能药物疗效不满意或不耐受;可自主排尿的患者。排除标准:过敏体质;严重的心、肾、肝脏疾病;6个月内接受过任何BTX制剂治疗;伴泌尿系感染、泌尿系结石、泌尿系肿瘤;糖尿病;有出血倾向者。按2∶1的比例将OAB患者分为试验组和安慰剂对照组。试验组将100 U的国产BTX-A用10 ml生理盐水复溶,于膀胱镜下分20个点注射入逼尿肌,注射位点分布于膀胱底部(5点)、膀胱三角区(3点)、两侧壁(各5点)及顶部(2点),避开膀胱颈,注射深度为黏膜下肌层。对照组同法注射不含注射用BTX-A的安慰剂。比较两组治疗前与治疗后2、6、12周的每24小时平均排尿次数、平均每日尿急次数和评分、平均每日尿失禁次数、平均每次排尿量、膀胱过度活动症症状评分(OABSS)及生活质量评分变化情况。主要疗效指标为第6周随访时排尿次数较基线的变化情况。次要疗效指标为2、12周两组每24小时平均排尿次数较基线的变化情况,以及2、6、12周两组患者OABSS和生活质量评分、平均每日尿急次数和评分、平均每日尿失禁次数、平均每次排尿量较基线的变化情况。治疗后12周记录不良事件。扩展试验阶段纳入标准:①受试者自愿接受BTX-A治疗;②第12周评估时,排尿日记显示每24小时排尿次数较基线下降<50%。进入扩展试验阶段两组患者在"第12周访视"时均注射1次100 U的国产BTX-A,然后随访12周,随访指标同核心试验阶段。结果本研究共纳入216例,试验组144例,对照组72例。试验组和对照组的年龄[(47.75±14.20)岁与(46.39±15.55)岁]、性别(男/女:25/117例与10/61例)、病程[0.51(0.08,1.89)年与0.60(0.18,2.23)年]比较差异无统计学意义(P>0.05)。核心试验阶段,试验组和对照组注射后6周的每24小时平均排尿次数较基线下降值分别为2.40(0.70,4.60)次和0.70(-1.00,3.30)次,数据变化率分别为(16±22)%和(8±25)%,组间差异均有统计学意义(P=0.003,P=0.014);两组注射前后数据差异均有统计学意义(P<0.001,P=0.008)。注射后2、12周的每24小时平均排尿次数较基线下降值,试验组分别为2.00(0.00,4.00)次和3.30(0.60,5.03)次,对照组分别为1.00(-1.00,3.00)次和1.70(-1.45,3.85)次,组间差异有统计学意义(P=0.038,P=0.012)。试验组和对照组注射后2、6、12周的平均每日尿急次数较基线变化值分别为2.00(0.00,4.30)次和2.40(0.30,5.00)次、3.00(0.30,5.70)次和0.70(-1.30,2.70)次、0.70(-1.30,3.00)次和1.35(-1.15,3.50)次,组间差异均有统计学意义(P=0.010,P=0.003,P=0.025)。试验组和对照组注射后6周的OABSS较基线下降值分别为1.00(0.00,4.00)分和0.50(-1.00,2.00)分,组间差异有统计学意义(P=0.003)。试验组和对照组分别有47例和34例进入扩展试验阶段,分别有40例和28例完成扩展试验。试验组和对照组12、14、18、24周的平均每次排尿量较基线变化值分别为-16.60(-41.60,-0.60)ml和-6.40(-22.40,13.30)ml、(-35.67±54.41)ml和(-1.76±48.69)ml、(-36.14±41.51)ml和(-9.28±44.59)ml、(-35.85±43.35)ml和(-10.41±40.29)ml,组间差异有统计学意义(P=0.010,P=0.006,P=0.012,P=0.016)。其他指标两组间差异无统计学意义(P>0.05)。不良反应包括残余尿量增加(试验组27例,对照组3例)、排尿困难(试验组21例,对照组6例)、尿路感染(试验组19例,对照组6例)、膀胱颈梗阻(试验组3例)、血尿(试验组3例,对照组1例)、丙氨酸氨基转移酶升高(试验组3例)等。除核心试验阶段两组的残余尿量增加例数差异有统计学意义(P<0.05)外,其他不良反应两组间差异均无统计学意义(P>0.05)。核心试验阶段,试验组和对照组分别有27例和3例残余尿量增加,其中仅试验组1例残余尿量>300 ml,所有患者残余尿量随注射后时间延长而改善或消失。结论膀胱壁注射国产BTX-A可减少OAB患者每24小时平均排尿次数、降低平均每日尿急次数、降低OABSS、增加平均每次排尿量,不良反应少。

Objective To assess the efficacy and safety of 100 units of botulinum toxin A(BTX-A)intradetrusor injection in patients with overactive bladder.Methods From April 2016 to December 2018,17 tertiary hospitals were selected to participate in this prospective,multicenter,randomized,double-blind,placebo-controlled study.Two phases of study were conducted:the primary phase and the extended phase.This study enrolled patients aged 18 to 75 years who had been inadequately managed by anticholinergic therapy(insufficient efficacy or intolerable side effects)and had spontaneous voiding with overactive bladder.Exclusion criteria included patients with severe cardiac,renal and hepatic disorders,patients with previous botulinum toxin treatment for 6 months or allergic to BTX-A,patients with urinary tract infections,patients with urinary stones,urinary tract tumors,diabetes mellitus,and bleeding tendency.Eligible patients were randomly assigned to BTX-A group and placebo control group in a ratio of 2∶1.Two groups of patients received 20 intradetrusor injections of BTX-A 100U or placebo at the depth of the submucosal muscle layer respectively under cystoscope,including 5 injections at the base of the bladder,3 injections to the bladder triangle,5 injections each to the left and right walls and 2 injections to the top,sparing the bladder neck.As a placebo control group,patients received same volume of placebo containing no BTX-A and only adjuvant freeze-dried preparations for injection with the same method.A combination of gelatin,sucrose,and dextran served as adjuvants.Average micturition times per 24 hours,urinary incontinence(UI)episodes per day,average micturition volume per day,OAB symptom score(OABSS),and quality of life(QOL)score were recorded at baseline and the 2nd,6th and 12th week after treatment.The primary efficacy endpoint was the change from baseline in the average micturition times per 24 hours at the 6th week after treatment.The secondary efficacy endpoints included the change from baseline in the average micturition times per 24 hours at 2nd and 12th week,as well as the change from baseline in the OABSS,QOL score,average frequency of urgency and UI episodes per day,urgency score,average micturition volume per day at 2nd,6th and 12th week after treatment.Patients were followed for 12 weeks to assess adverse events(AEs).After assessed at week 12,if the micturition times has decreased less than 50%compared to baseline and the patient is willing to receive retreatment,then patients could enter the extended trial phase.In that phase,patients in both groups were injected with 100 units BTX-A from 12th week onwards and then followed up the same indicators for 12 weeks.Results 216 patients were enrolled in this trial(144 cases in the BTX-A group and 72 cases in the placebo control group).Baseline characteristics such as age(47.75±14.20 in the BTX-A group and 46.39±15.55 in the control group),sex(25 male/117 female in the BTX-A group and 10/61 in the control group),and disease duration(0.51 years in the BTX-A group and 0.60 years in the control group)were balanced between the two groups(P>0.05).A marked reduction from baseline in average micturition times per 24 hours was observed in all treatment groups at the 6th week and the reduction of the two groups was statistically different(P<0.001 and P=0.008 respectively).Compared with the baseline,the average micturition times per 24 hours at the 6th week decreased from baseline by 2.40(0.70,4.60)times for the BTX-A group and 0.70(-1.00,3.30)times for the placebo control group respectively,and the difference between the two groups was considered to be statistically significant(P=0.003).The change rates of average micturition times per 24 hours from baseline at the 6th week of the two groups were(16±22)%and(8±25)%respectively,and the difference between the two groups was statistically significant(P=0.014).Compared with the baseline,the average micturition times per 24 hours at 2nd and 12th week decreased by 2.00(0.00,4.00)and 3.30(0.60,5.03)for the BTX-A group,1.00(-1.00,3.00)and 1.70(-1.45,3.85)for the placebo control group respectively.The difference between two groups was considered to be statistically significant(P=0.038 and P=0.012);the changes of average urgency times per day for the BTX-A group and the control group at the 2nd,6th and 12th week were 2.00(0.00,4.30)and 2.40(0.30,5.00),3.00(0.30,5.70)and 0.70(-1.30,2.70),0.70(-1.30,3.00)and 1.35(-1.15,3.50),respectively.There were significant differences between two groups at the 2nd,6th and 12th week,(P=0.010,P=0.003 and P=0.025,respectively).The OABSS of the BTX-A group and the control group at the 6th week decreased by 1.00(0.00,4.00)and 0.50(-1.00,2.00)compared with the baseline,and the difference between the two groups was statistically significant(P=0.003).47 cases of BTX-A group and 34 cases of placebo control group entered the extended trial phase,and 40 and 28 cases completed the extended trial phase,respectively.The average micturition volume per 24 hours changed by-16.60(-41.60,-0.60)ml and-6.40(-22.40,13.30)ml,(-35.67±54.41)ml and(-1.76±48.69)ml,(-36.14±41.51)ml and(-9.28±44.59)ml,(-35.85±43.35)ml and(-10.41±40.29)ml for two groups at the 12th,14th,18th and 24th week,and the difference between two groups was statistically significant at each follow-up time(P=0.01,0.006,0.012 and 0.016,respectively).There was no significant difference in other parameters(P>0.05).However,adverse reactions after intradetrusor injection included increased residual urine volume(27 in the BTX-A group and 3 in the control group),dysuria(21 in the BTX-A group and 6 in the control group),urinary infection(19 in the BTX-A group and 6 in the control group),bladder neck obstruction(3 in the BTX-A group and 0 in the control group),hematuria(3 in the BTX-A group and 1 in the control group),elevated alanine aminotransferase(3 in the BTX-A group and 0 in the control group),etc.During the follow-up period,there was no significant difference in the other adverse events between two groups except the increase of residual urine volume(P<0.05).In the primary trial phase,among the 27 cases with increased residual urine volume in BTA group,only 1 case(3.70%)with PVR more than 300 ml;the PVR of 3 patients in the placebo group was less than 100 ml.The increase of residual urine volume caused by the injection could be improved or disappeared with the passage of time.Conclusions Intradetrusor injection of Chinese BTX-A improved the average micturition times per 24 hours,the average daily urgent micturition times,OABSS,and average micturition volume per time,and reduced the adverse effects in patients with overactive bladder.Chinese BTX-A at dose of 100U demonstrated durable efficacy and safety in the management of overactive bladder.