A Study to Evaluate Mirabegron in Pediatric Participants From 5 to Less Than 18 Years of Age With Overactive Bladder (OAB)

Study Overview
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Brief Summary
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The purpose of this study was to evaluate the efficacy of mirabegron in children (5 to < 12 years of age) with OAB. This study will also evaluated the safety and tolerability of mirabegron in pediatric participants with OAB and evaluated the pharmacokinetics after multiple dose administration of mirabegron in pediatric participants with OAB.

Detailed Description
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The study consisted of 3 periods (Screening period/urotherapy (4 weeks); Double-blind, placebo-controlled period (12 weeks); Follow-up period (2 weeks)) for a total duration of 18 weeks.

Official Title
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A Phase 3, Double-blind, Randomized, Multicenter, Parallel Group, Placebo-controlled Sequential Dose Titration Study to Evaluate Efficacy, Safety and Pharmacokinetics of Mirabegron in Pediatric Subjects From 5 to < 18 Years of Age With Overactive Bladder

Conditions
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Overactive Bladder (OAB), Pharmacokinetics of Mirabegron

Intervention / Treatment
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* Drug: Mirabegron
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject has OAB defined according to the International Children's Continence Society (ICCS) criteria. Subject weighs at least 13 kg at screening. Subject is able to take the IP in accordance with the protocol. Subject agrees to drink an adequate fluid volume during urine collection weekends. Subject and subject's parent(s)/legal guardian(s) agree that the subject will not participate in another interventional study while participating in the present study. Subject and subject's parent(s)/legal guardian(s) are willing and able to comply with the study requirements and with the concomitant medication restrictions. Female subject is not pregnant and at least 1 of the following conditions apply: Not a female of childbearing potential Female of child bearing potential who agrees to follow the contraceptive guidance from the time of informed consent/assent through at least 30 days after final IP administration. Female subject must agree not to breastfeed starting at screening and throughout the study period and for 30 days after final IP administration. Female subject must not donate ova starting at first dose of IP and throughout the study period and for 30 days after final IP administration. Male subject with female partner(s) of childbearing potential (including breastfeeding partner[s]) must agree to use contraception throughout the treatment period and for 30 days after final IP administration. Male subject must agree not donate sperm during the treatment period and for 30 days after final IP administration. Male subject with pregnant partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy throughout the study period and for 30 days after final IP administration. Additional Inclusion at Visit 3/Week 0 (Baseline) Subject must have a micturition frequency of at least 8 times (on average) per day, in the 7 days prior to visit 3/week 0 (baseline), as recorded in the bladder e-diary. Subject must have at least 1 daytime incontinence episode (on average) per day, during the 7-day period before visit 3/baseline, as recorded in the bladder e-diary. Subject whose symptoms are not satisfactorily controlled with urotherapy and still fulfills the inclusion/exclusion criteria will enter the study. Exclusion Criteria: Exclusion at Visit 1/Week -4 (Screening) Subject has extraordinary daytime only urinary frequency according to the ICCS definition. This applies to a toilet-trained child who has the frequent need to void that is associated with small micturition volumes solely during the day. The daytime voiding frequency is at least once per hour with an average voided volume of < 50% of expected bladder capacity (EBC) (typically 10% to 15%). Incontinence is rare and nocturia is absent. Subject has an uroflow indicative of pathology other than OAB. Subject has monosymptomatic enuresis. Subject has dysfunctional voiding. Subject has bladder outlet obstruction, except if successfully treated. Subject has anatomical anomalies (surgically treated or untreated) that affect lower urinary tract function. Subject with hematuria on dipstick test. In the case of hematuria on dipstick test in a female during menstruation, the test can be repeated before randomization (after the end of menstruation). Subject with diabetes insipidus. Subject has kidney or bladder stones. Subject has suffered from chronic UTI or has had more than 3 UTIs in the 2 months prior to visit 1/week -4 (screening). Subject has stage 2 hypertension or subject has stage 1 hypertension that is not well controlled, as defined by the 2017 American Academy of Pediatrics Clinical Practice Guidelines. Subject has QT interval using Fridericia's correction formula (QTcF) > 440 msec on screening ECG, risk of QT prolongation (e.g., hypokalemia, long QT syndrome [LQTS] or family history of LQTS or exercise-induced syncope) or is currently taking medication known to prolong the QT interval. Subject's aspartate aminotransferase (AST) or alanine aminotransferase (ALT) is ≥ 2 × upper limit of normal (ULN) or total bilirubin (TBL) is ≥ 1.5 × ULN according to age and sex (subjects with Gilbert's syndrome are excepted from the bilirubin threshold). Subject has mild or moderate renal impairment (estimated glomerular filtration rate according to the modified Schwartz of < 60 mL/min per 1.73 m^2). Subject has a symptomatic (symptoms can include pain, fever, hematuria, new onset foul-smelling urine) UTI. Note: if the UTI is treated successfully (clinical recovery: confirmed by dipstick test and repeated dipstick test after 14 days [both should be negative]), the subject can be rescreened. Subject has a history or presence of any malignancy. Subject uses any drugs that are sensitive cytochrome P450 2D6 (CYP2D6) substrates with a narrow therapeutic index or sensitive P-glycoprotein (P-gp) substrates, or moderate or strong cytochrome CYP3A4/5 or P-gp inhibitors or inducers after the start of washout. Subject is using or has used prohibited prior and/or concomitant medication(s) that cannot be discontinued. Subject has known or suspected hypersensitivity to mirabegron or any components of the formulations used. Subject has participated in another clinical study (and/or subject has received any investigational therapy within 30 days (or 5 half-lives of the drug, or the limit set by national law, whichever is longer) prior to visit 1/week -4 (screening). Subject received urinary catheterization within 2 weeks prior to screening. Subject has constipation as defined by the Rome IV criteria that cannot be successfully treated prior to study entry. Female subject who has been pregnant within 6 months prior to screening or breastfeeding within 3 months prior to screening. Subject has any condition that makes the subject unsuitable for study participation. Additional Exclusion at Visit 3/Week 0 (Baseline) Subject has extraordinary daytime only urinary frequency according to the ICCS definition based on the bladder e-diary. Subject has monosymptomatic enuresis confirmed by the bladder e-diary. Subject has a maximum voided volume (morning volume excluded) > expected bladder capacity (EBC) for age ([age +1] × 30) in mL, based on the bladder e-diary. Subject has polyuria defined as voided urine volumes of > 40 mL/kg baseline body weight during 24 hours or > 2.8 L urine for a child weighing ≥ 70 kg (ICCS definition), based on bladder e-diary. Subject has PVR volume > 20 mL (lowest PVR volume result) as measured by ultrasonography. Subject suffers from a symptomatic (symptoms can include pain, fever, hematuria, new onset foul-smelling urine) urinary tract infection (UTI). Note: if a symptomatic UTI is present, all visit 3/week 0 (baseline) assessments must be postponed until the UTI is successfully treated (clinical recovery: confirmed by dipstick test and repeated dipstick test after 14 days [both should be negative]), and the urotherapy should continue. The postponed visit 3/week 0 (baseline) should be within 14 days of the intended visit 3/week 0 (baseline). Subject with hematuria on dipstick test. In the case of hematuria on dipstick test in a female during menstruation, the test can be repeated before randomization (after the end of menstruation). Subject has a pulse > 99th percentile for age. Subject has stage 2 hypertension or subject has stage 1 hypertension that is not well controlled, as defined by the 2017 American Academy of Pediatrics Clinical Practice Guidelines. Any reason that makes the subject unsuitable for study participation.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mirabegron (5 to <12 Years)<br>Participants aged 5 to < 12 years received initial dose of 25 milligram (mg) of mirabegron orally once daily based on weight (pediatric equivalent dose of 25 mg [PED25]) on day 1. Participants with a body weight ≥ 35 kilogram (kg) received tablet and participants with a body weight< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the pediatric equivalent dose of 50 mg [PED50] based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12. | Drug: Mirabegron<br>* Oral/ Oral Suspension: Participants with a body weight of ≥ 35 kg are to receive the tablet form of IP unless unable to swallow tablets and will be provided the oral suspension as an alternative. Participants with a body weight < 35 kg or those who cannot be dosed with the tablet will receive oral suspension.<br>* Other names: YM178;|
| Placebo Comparator: Placebo (5 to <12 Years)<br>Participants aged 5 to < 12 years received placebo matched to mirabegron orally once daily based on weight PED25 on day 1. Participants with a body weight ≥ 35 kg received tablet and participants with a body weight< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the PED50 based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12. | Drug: Placebo<br>* Oral/ Oral Suspension<br>|
| Experimental: Mirabegron (12 to <18 Years)<br>Participants aged 12 to < 18 years received initial dose of 25 mg of mirabegron orally once daily based on weight PED25 on day 1. Participants with a body weight ≥ 35 kg received tablet and participants with a body weight< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the PED50 based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12. | Drug: Mirabegron<br>* Oral/ Oral Suspension: Participants with a body weight of ≥ 35 kg are to receive the tablet form of IP unless unable to swallow tablets and will be provided the oral suspension as an alternative. Participants with a body weight < 35 kg or those who cannot be dosed with the tablet will receive oral suspension.<br>* Other names: YM178;|
| Placebo Comparator: Placebo (12 to <18 Years)<br>Participants aged 12 to < 18 years received placebo matched to mirabegron orally once daily based on weight PED25 on day 1. Participants with a body weight ≥ 35 kg received tablet and participants with a body weight< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the PED50 based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12. | Drug: Placebo<br>* Oral/ Oral Suspension<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 12/EoT in Mean Number of Micturitions Per 24 Hours for Age Group 5 to <12 Years | A micturition was defined as any voluntary act of passing urine (excluding incontinence only episodes). The mean number of micturitions per 24 hours was calculated as the average number of times a participant urinated per day during the 7-day micturition diary period. The analysis was performed with imputation of missing visit 7/week 12 data using the last observation carried forward (LOCF) method. | Baseline, week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 12/EoT in Mean Volume Voided Per 24 Hours for Age Group 5 to <12 Years | Mean volume voided was derived from Pee Volume of the 2-day Weekend Episodic Diary. Mean volume voided per day was calculated as the sum of the volumes voided on that (valid diary) day divided by the number of times a volume was recorded on that day in the 2-day Weekend Episodic Diary. The analysis was performed with LOCF and without LOCF method. | Baseline, week 12 | 
| Change From Baseline to Week 12/EoT in Maximum Volume Voided (MVV) for Age Group 5 to <12 Years | MVV data was derived from Pee Volume of the 2-day Weekend Episodic Diary. The MVV was the largest (non-zero) volume recorded over both of the 2 (valid) measuring days in the diary. The analysis was performed with LOCF and without LOCF method. | Baseline, week 12 | 
| Change From Baseline to Week 12/EoT in Mean Number of Daytime Incontinence Episodes Per 24 Hours for Age Group 5 to <12 Years | A daytime incontinence episode was defined as the complaint of any involuntary leakage of urine during daytime hours. Daytime was defined as time between waking up in the morning and going to sleep later the same day or next day. The mean number of daytime incontinence episodes per 24 hours was calculated by taking the sum of all daytime urinary incontinence episodes recorded in the participant diary, divided by the number of valid diary days. The analysis was performed with LOCF and without LOCF method. | Baseline, week 12 | 
| Change From Baseline to Week 12/EoT in Mean Number of Nighttime Incontinence Episodes Per 24 Hours for Age Group 5 to <12 Years | A nighttime incontinence episode was defined as the complaint of any involuntary leakage of urine during nighttime hours. Nightime was defined as time between between going to sleep on a day and waking up on the same or next day. The mean number of nighttime incontinence episodes per 24 hours was calculated by taking the sum of all nighttime urinary incontinence episodes recorded in the participant diary, divided by the number of valid diary days. The analysis was performed with LOCF and without LOCF method. | Baseline, week 12 | 
| Change From Baseline to Week 12/EoT in Mean Number of Daytime Micturitions Per 24 Hours for Age Group 5 to <12 Years | For a week day the daytime micturitions was derived from Number of Times using the Toilet During the Day was entered into the 5-day Week Diary. For a weekend day the daytime micturitions was derived from the number of times a Pee in Toilet or a Pee in Toilet and Leakage was entered into the 2-day Weekend Episodic Diary between the time the participant woke-up (exclusive). The total number of micturitions per weekend day was equal to the total number of times, in the diary, an amount of pee was recorded during daytime for that day. For each participant, the mean number of daytime micturitions was calculated as: Sum of the Number of Daytime Micturitions (per day) over the Valid Diary Days prior to Visit/Number of Valid Diary Days. The analysis was performed with LOCF and without LOCF method. | Baseline, week 12 | 
| Change From Baseline to Week 12/EoT in Number of Dry (Incontinence-free) Days Per 7 Days for Age Group 5 to <12 Years | A dry (incontinence free) day was defined as a day where the response is Dry to the question How was your Day and to How was your Night. For a weekend day a Dry (incontinence free) Day was defined a day where no New pee or leakage was reported. Let Ddry be the number of valid diary days where the response to both questions was Dry. Let Dwet be the number of valid diary days where the response to one of the two questions or to both questions was Wet. If (Ddry + Dwet) > 3, the number of dry days per 7 days was calculated as Ddry/(Ddry + Dwet)* 7, otherwise the value was missing. The analysis was performed with LOCF and without LOCF method. | Baseline, week 12 | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | An AE was any untoward medical occurrence in a participant administered a study drug and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study drug whether or not considered related to the study drug. A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, resulted a congenital anomaly/birth defect or other medically important event. A TEAE was defined as an AE observed after starting administration of the study drug until 30 days after last dose. | From first dose up to week 14 | 
| Change From Baseline in Post Void Residual (PVR) Volume | PVR was assessed by ultrasonography. | Baseline, weeks 4, 12, 14 | 
| Number of Participants With Study Drug Acceptability and Palatability for Tablets | Participants evaluated the taste of the study drug/tablets by ticking 1 of the following categories: Really Bad (0), Bad (1), Not Bad, Not Good (2), Good (3) & Really Good (4). Participants evaluated the swallow of the study drug/tablets by ticking one of the following categories: Really Difficult (0), Difficult (1), Not Difficult, Not Easy (2), Easy (3) and Really Easy (4). | Week 12 | 
| Number of Participants With Study Drug Acceptability and Palatability for Oral Suspension | Participants evaluated the taste of the study drug/oral suspension by ticking 1 of the following categories: Really Bad (0), Bad (1), Not Bad, Not Good (2), Good (3) & Really Good (4). Participants evaluated the smell of the study drug/oral suspension by ticking 1 of the following categories: Really Bad (0), Bad (1),Not Bad, Not Good (2), Good (3) & Really Good (4). Participants evaluated the consumption of the study drug/oral suspension by ticking 1 of the following categories: Really Difficult (0),Difficult (1), Not Difficult, Not Easy (2), Easy (3) & Really Easy (4). Participants evaluated the preparation of the study drug/oral suspension by ticking 1 of the following categories: Really Difficult (0), Difficult (1), Not Difficult, Not Easy (2), Easy (3) & Really Easy (4). | Week 12 | 
| Pharmacokinetic (PK) of Mirabegron in Plasma: Maximum Concentration (Cmax) | Maximum observed plasma concentration (Cmax). | Predose (1 hour prior) at weeks 4 and 12 | 
| PK of Mirabegron in Plasma: Time of the Maximum Concentration (Tmax) | Time taken to reach Cmax (Tmax). | Predose (1 hour prior) at weeks 4 and 12 | 
| PK of Mirabegron in Plasma: Area Under Concentration-time Curve Over Dosing Interval (AUCtau) | AUCtau is the measure of the plasma drug concentration from time zero to end of dosing interval. It is used to characterize drug absorption. | Predose (1 hour prior) at weeks 4 and 12 | 
| PK of Mirabegron in Plasma: Concentration Immediately Prior to Dosing (Ctrough) | Trough level or trough concentration (Ctrough) in the concentration reached by the drug immediately before the next dose is administered. | Predose (1 hour prior) at weeks 4 and 12 | 
| PK of Mirabegron in Plasma: Apparent Total Clearance (CL/F) | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | Predose (1 hour prior) at weeks 4 and 12 | 
| PK of Mirabegron in Plasma: Apparent Volume of Distribution (Vz/F) | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vz/F is influenced by the fraction absorbed. | Predose (1 hour prior) at weeks 4 and 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pediatrics, mirabegron