NCT02751931已完成3 期
An Open-label, Baseline-controlled, Multicenter, Phase 3 Dose-titration Study Followed by a Fixed-dose Observation Period to Evaluate Efficacy, Safety and Pharmacokinetics of Mirabegron in Children and Adolescents From 3 to Less Than 18 Years of Age With Neurogenic Detrusor Overactivity (NDO) on Clean Intermittent Catheterization (CIC)
适应症
干预措施
相关药物
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 91
- 试验地点
- 32
- 主要终点
- Change From Baseline in Maximum Cystometric Capacity (MCC) at Week 24
研究概览
简要总结
The objective of the study was to evaluate the efficacy, safety, tolerability and pharmacokinetics of mirabegron after multiple-dose administration in the pediatric population.
详细描述
This was a phase 3, open-label, baseline-controlled, multicenter study. The study consisted of 3 periods: Pretreatment period: for a maximum of 28 days before baseline, including screening, washout (if applicable) and baseline.
Efficacy treatment period: beginning the day after baseline and continuing to week 24. Long-term safety period: beginning after week 24 and continuing to week 52 (end of study [EOS]), or to the end of treatment (EOT).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 3 Years 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subject has a body weight of greater than or equal to 11 kg.
- •Subject suffers from NDO confirmed by urodynamic investigation at baseline. The diagnosis of NDO must be confirmed by the presence of at least 1 involuntary detrusor contraction > 15 cm H2O from baseline detrusor pressure, and/or a decrease in compliance leading to an increase in baseline detrusor pressure of > 20 cm H2O.
- •Subject has been using CIC for at least 4 weeks prior to visit 1/screening.
- •Subject has a current indication for drug therapy to manage NDO.
- •Subject is able to take the study drug in accordance with the protocol
排除标准
- •Subject has a known genitourinary condition (other than NDO) that may cause overactive contractions or incontinence or kidney/bladder stones or another persistent urinary tract pathology that may cause symptoms.
- •Subject has one of the following gastrointestinal problems: partial or complete obstruction, decreased motility such as paralytic ileus, subjects at risk of gastric retention.
- •Subject has a urinary indwelling catheter within 4 weeks prior to visit 1/screening.
- •Subject has a surgically treated underactive urethral sphincter
- •Subject has vesico-ureteral reflux grade 3 to
- •Subject has undergone bladder augmentation surgery.
- •Subject receives electrostimulation therapy, if started within 30 days before visit 1/screening or is expected to start during the study period. Subjects who are on an established regimen may remain on this for the duration of the study.
- •Subject suffers from a symptomatic urinary tract infection (UTI) at baseline (symptomatic is defined as pain, fever, hematuria, new onset foul-smelling urine). If present at visit 1/screening or diagnosed between visit 1/screening and visit 3/baseline, the UTI should be treated successfully (clinical recovery) prior to baseline. If a symptomatic UTI is present at baseline, all baseline assessments are allowed to be postponed for a maximum of 7 days until the UTI is successfully treated (clinical recovery).
- •Subject has a (mean) resting pulse rate > 99th percentile [Fleming et al, 2011].
- •Subject has an established hypertension and a systolic or diastolic blood pressure greater than the 99th percentile of the normal range determined by sex, age and height, plus 5mmHg [NIH 2005].
- •Subject has a risk of QT prolongation (e.g., hypokalemia, long QT syndrome [LQTS]; or family history of LQTS, exercise-induced syncope).
- •Subject has severe renal impairment (eGFR according to Larsson equation < 30 mL/min).
- •Subject's aspartate aminotransferase (AST) or alanine aminotransferase (ALT) is greater than or equal to 2 times the upper limit of normal (ULN) or total bilirubin (TBL) greater than or equal to 1.5 times the ULN according to age and sex.
- •Subject has a history or presence of any malignancy prior to visit 1/screening.
- •Subject has known or suspected hypersensitivity to mirabegron, any of the excipients used in the current formulations or previous severe hypersensitivity to any drug.
- •Subject has participated in another clinical trial (and/or has taken an investigational drug within 30 days (or 5 half-lives of the drug, or the limit set by national law, whichever is longer) prior to visit 1/screening.
- •Subject uses any of the following prohibited medications (after start of washout):
- •Any medication, other than the study drug used, for the management of NDO;
- •Any drugs that are sensitive CYP2D6 substrates with a narrow therapeutic index or sensitive P-glycoprotein (P-gp) substrates
- •Any strong CYP3A4 inhibitors if the subject has a mild to moderate renal impairment (eGFR 30 - 89 mL/min).
- •Subject has been administered intravesical botulinum toxin; except if given > 4 months prior to visit 1/screening and the subject experiences symptoms comparable to those existing prior to the botulinum toxin injections.
研究组 & 干预措施
Children (3 to < 12 Years)
Experimental
Participants aged 3 to < 12 years received initial dose of 25 milligram (mg) of mirabegron orally once daily based on weight (pediatric equivalent dose of 25 mg (milligram) [PED25]) on day 1. At weeks 2, 4 or 8, participant's were up-titrated to the pediatric equivalent dose of 50 mg in adults [PED50], orally once daily based on the given dose titration criteria. Following week 24, participants stayed on their individual dose level until week 52 end-of-study (EOS) or end-of-treatment (EOT).
干预措施: Mirabegron (Drug)
Adolescents (12 to < 18 Years)
Experimental
Participants aged 12 to < 18 years received initial dose of 25 mg of mirabegron orally once daily based on weight [PED25] on day 1. At weeks 2, 4 or 8, participant's were up-titrated to the pediatric equivalent dose of 50 mg in adults [PED50] orally once daily based on the given dose titration criteria. Following week 24, participants stayed on their individual dose level until week 52 EOS or EOT.
干预措施: Mirabegron (Drug)
结局指标
主要结局
Change From Baseline in Maximum Cystometric Capacity (MCC) at Week 24
时间窗: Baseline and week 24
Change from baseline in MCC was based on filling urodynamics (volume at the end of filling). During urodynamic assessments, the bladder was filled until voiding/leakage began, or until the participant experienced pain or discomfort, or because dangerous high detrusor pressure, or 135% of maximum catheterized volume for age had been reached. A valid urodynamic assessment was confirmed valid by the central reviewers. Missing MCC observations at week 24 were imputed using last observation carried forward (LOCF).
次要结局
- Change From Baseline in Bladder Compliance (ΔV/ΔP)(Baseline and weeks 4 and 24)
- Change From Baseline in Number of Overactive Detrusor Contractions (> 15 cm H20) Until End of Filling(Baseline and weeks 4 and 24)
- Number of Participants With Clinician Global Impression of Change (CGI-C)(Weeks 24 and 52)
- Change From Baseline in Maximum Cystometric Capacity at Week 4(Baseline and week 4)
- Number of Participants With Study Drug Acceptability for Oral Suspension at Week 4(Week 4)
- Number of Participants With Study Drug Acceptability for Oral Suspension at Week 24(Week 24)
- Change From Baseline in Detrusor Pressure at End of Filling(Baseline and weeks 4 and 24)
- Change From Baseline in Filling Bladder Volume Until First Overactive Detrusor Contraction (> 15 cm H20)(Baseline and weeks 4 and 24)
- Change From Baseline in Average Catheterized Volume Per Catheterization(Baseline and weeks 2, 4, 8, 12, 24, 36 and 52)
- Change From Baseline in Maximum Catheterized Volume(Baseline and weeks 2, 4, 8, 12, 24, 36 and 52)
- Change From Baseline in Maximum Catheterized Daytime Volume (MCDV)(Baseline and weeks 2, 4, 8, 12, 24, 36 and 52)
- Change From Baseline in Mean Number of Leakage Episodes Per Day(Baseline and weeks 2, 4, 8, 12, 24, 36 and 52)
- Change From Baseline in Filling Bladder Volume Until First Overactive Detrusor Contraction (> 15 cm H20): Wilcoxon Signed-rank Test Updated Analysis(Baseline and weeks 4 and 24)
- Change From Baseline in Filling Bladder Volume Until First Overactive Detrusor Contraction (> 15 cm H20): Paired T-test(Baseline and weeks 4 and 24)
- Change From Baseline in Average Morning Catheterized Volume(Baseline and weeks 2, 4, 8, 12, 24, 36 and 52)
- Change From Baseline in Mean Number of Leakage Episodes Per Day: Updated Analysis(Baseline and weeks 2, 4, 8, 12, 24, 36 and 52)
- Number of Participants With Study Drug Acceptability for Tablets at Week 24(Week 24)
- Change From Baseline in Number of Dry Days Per 7 Days (Day and Night Time)(Baseline and weeks 2, 4, 8, 12, 24, 36 and 52)
- Change From Baseline in Pediatric Incontinence Questionnaire (PIN-Q) Score(Baseline and weeks 24 and 52)
- Change From Baseline in Patient Global Impression of Severity Scale (PGI-S)(Baseline and weeks 24 and 52)
- Number of Participants With Study Drug Acceptability for Tablets at Week 4(Week 4)
- Number of Participants With Study Drug Acceptability for Tablets at Week 52(Week 52)
- Number of Participants With Study Drug Acceptability for Oral Suspension at Week 52(Week 52)
- Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC24) for Mirabegron(A total of 4 samples were collected over 2 sampling days at 2 separate visits at any of week 4, 8, 12, 24, 36, or 52, at the following time points: Sampling day 1- Predose; Sampling day 2- Predose and 2 samples 2-5 hours postdose more than 1 hour apart.)
- Number of Participants With Adverse Events (AEs)(From the first dose of study drug administration up to end-of-treatment (EoT) (up to week 52))
- Maximum Plasma Concentration (Cmax) of Mirabegron(A total of 4 samples were collected over 2 sampling days at 2 separate visits at any of week 4, 8, 12, 24, 36, or 52, at the following time points: Sampling day 1- Predose; Sampling day 2- Predose and 2 samples 2-5 hours postdose more than 1 hour apart.)
- Time to Reach Maximum Plasma Concentration of Mirabegron Following Drug Administration (Tmax)(A total of 4 samples were collected over 2 sampling days at 2 separate visits at any of week 4, 8, 12, 24, 36, or 52, at the following time points: Sampling day 1- Predose; Sampling day 2- Predose and 2 samples 2-5 hours postdose more than 1 hour apart.)
- Plasma Concentration of Mirabegron at the End of a Dosing Interval at Steady State (Ctrough)(A total of 4 samples were collected over 2 sampling days at 2 separate visits at any of week 4, 8, 12, 24, 36, or 52, at the following time points: Sampling day 1- Predose; Sampling day 2- Predose and 2 samples 2-5 hours postdose more than 1 hour apart.)
- Apparent Total Clearance of Mirabegron From Plasma After Oral Administration (CL/F)(A total of 4 samples were collected over 2 sampling days at 2 separate visits at any of week 4, 8, 12, 24, 36, or 52, at the following time points: Sampling day 1- Predose; Sampling day 2- Predose and 2 samples 2-5 hours postdose more than 1 hour apart.)
- Apparent Volume of Distribution After Non-intravenous Administration (Vz/F) of Mirabegron(A total of 4 samples were collected over 2 sampling days at 2 separate visits at any of week 4, 8, 12, 24, 36, or 52, at the following time points: Sampling day 1- Predose; Sampling day 2- Predose and 2 samples 2-5 hours postdose more than 1 hour apart.)
研究者
研究点 (32)
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