A Study of Mirabegron in Young Children With Neurogenic Detrusor Overactivity

Study Overview
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Brief Summary
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People with neurogenic detrusor overactivity have poor bladder control because of how their nerves to the bladder are wired. This can cause high pressure in the bladder. It can also cause the bladder to leak by accident (incontinence). In this study, the researchers are studying whether a medicine, mirabegron, can help young children with neurogenic detrusor overactivity. The children will be from 6 months to under 3 years old. Mirabegron has already been approved for adults with bladder problems. The main aim of this study is to learn if mirabegron increases the maximum bladder capacity (to prevent high pressure in the bladder) in young children after 24 weeks of treatment. Maximum bladder capacity is the maximum amount of urine that the bladder can hold before it releases urine or starts to leak. There will be 2 groups in the study. Young children who are not taking certain medicines for their condition will be in group A. Young children who are already taking certain medicines for this condition will be in group B. Children in group B will stop taking these medicines before taking mirabegron. Their treatment will be delayed by 2 weeks to allow the other medicines to be cleared from the body before treatment. Both groups (A and B) will take the same treatment and have the same checks throughout the study. Children will have their vital signs checked (blood pressure, heart rate and body temperature). They will also have an ECG to check their heart rhythm and give urine samples for laboratory tests. Other tests will include checking how the bladder fills and empties plus an ultrasound of the bladder area. The caregivers will be shown how to check their child's blood pressure. They will be given an electronic diary to record the blood pressure, as well as any other medicines taken. They will do this every day for 7 days before each visit. Mirabegron will be stirred into water, making it easier for children to drink. Children will drink mirabegron once a day for up to 52 weeks. They will start on a low dose, adjusted for their weight. If children are taking other medicines for this condition, they will wait an extra 2 weeks before starting mirabegron. At weeks 2, 4 and 8, the dose may be increased once to a higher dose if the study doctor thinks the child will benefit from the higher dose. The children and their caregivers will visit the clinic at 2, 4, 8, 12, 24, 52, and 54 weeks. There will be fewer clinic visits if a child stays on the lower dose of mirabegron. In this case, the clinic will phone the caregiver instead to check the information in the diary. During each visit, the children will have their vital signs checked and have an ECG. The caregiver will be asked if their child has had any medical problems. At some visits, the children will give urine and blood samples for laboratory tests. Other tests will include checking how the bladder fills and empties. 36 weeks after treatment starts, the clinic will phone the caregiver to ask if their child has had any medical problems, and will check the information in the diary. The children and their caregivers will visit the clinic 52 weeks after treatment starts. The caregiver will be asked if their child has had any medical problems. The children will have a physical exam and have their vital signs checked. Also, they will have an ECG and have urine and blood samples taken for laboratory tests. Other tests will include an ultrasound of the bladder area. There will be a final clinic visit at 54 weeks. The caregiver will be asked if their child has had any medical problems. The children will have a physical exam and will have their vital signs checked. They will also have an ECG. The caregiver will be asked to complete a survey on their child's experience with taking mirabegron. They will do this at 4, 24 and 52 weeks after their child starts treatment. Finally, the clinic will phone the caregiver 30 days after the last dose of mirabegron to check if there were any further medical problems. No other visits are planned during this study.

Official Title
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A Phase 3, Open Label, Multicenter, Baseline-Controlled Sequential Dose Titration Study Followed by a Fixed Dose Observation Period to Evaluate Pharmacokinetics, Efficacy and Safety of Mirabegron Prolonged-Release Microgranula-Based Suspension in Children From 6 Months to Less Than 3 Years of Age With Neurogenic Detrusor Overactivity

Conditions
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Neurogenic Detrusor Overactivity

Intervention / Treatment
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* Drug: mirabegron


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant's weight is a minimum of 6 kg. Participant has a previous myelomeningocele (documented at the screening visit). Participant has a diagnosis of neurogenic detrusor overactivity (NDO) confirmed by urodynamic investigation at baseline (day 1). The diagnosis of NDO should be confirmed by the presence of ≥ 1 involuntary detrusor contraction > 15 cm H2O from baseline detrusor pressure, and/or a decrease in bladder compliance leading to an increase in baseline detrusor pressure of > 20 cm H2O. Participant has a diagnosis of detrusor sphincter dyssynergia (DSD). Participant is using clean intermittent catheterization (CIC). Participant is suitable for a regimen of 4 to 6 CICs per day, fixed for the duration of the study using the 7-day baseline e-diary. Participant is able to swallow the study drug. Participant's legally authorized representative (LAR) is willing and able to comply with the study requirements (including compliant use of the e-diary) and with the concomitant medication restrictions. Participant's LAR agree not to allow participant to participate in another interventional study while on treatment and throughout the pretreatment period. Exclusion Criteria: Participant has a bladder capacity less than 25% of expected age-related capacity, confirmed by urodynamic investigation at baseline (day 1). Participant has vesicoureteral reflux grade 3 to 5. Participant has a known genitourinary condition, other than NDO, that may cause overactive contractions and/or incontinence (e.g., bladder exstrophy, urinary tract obstruction, urethral diverticulum or fistula) or kidney/bladder stones or another persistent local pathology that may cause urinary symptoms. Participant has had an indwelling urinary catheter within 4 weeks prior to the baseline visit. Participant has undergone bladder augmentation surgery. Participant with surgically corrected underactive sphincter. Participant receives electrostimulation therapy, if started within 30 days before visit 1 screening or is expected to start during the study period. Participants who are on an established regimen (defined as starting more than 30 days before visit 1 screening) may remain on this for the duration of the study. Participant has been administered intravesical botulinum toxin; except if given > 4 months prior to visit 1 screening and the participant experiences symptoms comparable to those existing prior to the botulinum toxin injections. Participant has a current symptomatic urinary tract infection (UTI) confirmed by urinalysis (urine culture containing > 100,000 cfu/mL) at baseline. If at screening and start of washout a UTI is present, the participant will be eligible for enrollment if the UTI has been treated successfully prior to baseline. If a symptomatic UTI is present at baseline, all baseline assessments should be postponed for a maximum of 7 days until the UTI is successfully treated. Successful treatment is defined as a symptom free patient with a white blood cell count in the urine < 100/microliter and urine culture below 100,000 cfu/mL. Participant is using prohibited medications. Participant has a diagnosis of central or congenital nephrogenic diabetes insipidus. Participant with severe gastrointestinal (GI) condition (including toxic megacolon) or any of the following GI conditions: partial or complete obstruction, decreased motility like paralytic ileus or at risk for gastric retention. Participant suffers from malnutrition or is severely overweight. Participant has an average QT interval corrected by Bazett's formula (QTcB) > 440 ms (based on the QTcB mean from the screening and baseline ECG triplicates), history of QTc prolongation or risk of QT prolongation (e.g., hypokalemia, Long QT Syndrome (LQTS), or family history of LQTS, exercise induced syncope). Participant has severe renal impairment (estimated glomerular filtration rate (eGFR) < 30 mL/min per 1.73 m^2 for participants 1 year of age and older; serum creatinine ≥ 97.5th percentile for participants 6 to < 12 months of age.). Participant's aspartate aminotransferase (AST) or alanine aminotransferase (ALT) is ≥ 2 × upper limit of normal (ULN) or total bilirubin (TBL) greater than or equal to 1.5 × ULN. Participant has a current or previous history of epilepsy. Participant has a history or presence of any malignancy prior to visit 1 screening. Participant has any other clinically significant out of range results of urinalysis, biochemistry or hematology. Participant has an established hypertension and systolic or diastolic blood pressure greater than the 99th percentile of their normal range determined by gender, body size and age, plus 5 mmHg. Participant has a (median) resting heart rate > 99th percentile. Participant has any clinically significant or unstable medical condition or disorder which precludes the participant from participating in the study. Participant has known or suspected hypersensitivity to mirabegron, any of the excipients used in the current formulation or previous severe hypersensitivity to any drug. Participant 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. Participant is being breast-fed by a woman taking any prohibited medication or fed with a milk product in which the presence of prohibited medication ingredients cannot be excluded.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 3 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: mirabegron<br>Participants will receive mirabegron prolonged-release microgranula-based oral suspension. | Drug: mirabegron<br>* Participants will receive mirabegron prolonged-release microgranula-based oral suspension once daily. The initial dose of mirabegron will be based on the participant's weight. The initial low dose will be up-titrated to a higher dose at weeks 2, 4 or 8 unless the participant is determined to be effectively treated with the low dose, based on urodynamics and the participants'e-diary.<br>* Other names: YM178;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 24 in Maximum Cystometric Capacity (MCC) | MCC is maximum bladder capacity reached at end of filling cytometry. | Baseline and week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in bladder compliance | Bladder compliance is calculated by change in volume divided by change in pressure during filling of the bladder. | Baseline and weeks 4 and 24 | 
| Change from baseline in filling volume until first detrusor contraction (>15cm H2O) | Change in bladder volume calculated by urodynamic assessments. | Baseline and weeks 4 and 24 | 
| Change from baseline in number of uninhibited detrusor contractions until leakage or until maximum 135% of age-related bladder capacity | Change in number of of uninhibited detrusor contractions is calculated by urodynamic assessments. | Baseline and weeks 4 and 24 | 
| Change from baseline in maximum catheterized daytime volume | Based on participant e-diary. | Baseline and up to week 52 | 
| Change from baseline in average catheterized daytime volume | Based on participant e-diary. | Baseline and up to week 52 | 
| Change from baseline in average morning catheterized volume | E-diary measure based on first catheterization after participant wakes up. | Baseline and up to week 52 | 
| Change from baseline in number of leakage episodes per 24 hours | Based on participant e-diary. | Baseline and up to week 52 | 
| Change from baseline in number of dry days per 7 days | Based on participant e-diary, dry defined as leakage-free. | Baseline and up to week 52 | 
| Acceptability by pediatric oral medicine acceptability questionnaire for caregivers (P-OMAQ-C) | The P-OMAQ-C uses a 5-point numerical rate scale to measure acceptability of use of the tablet formulation with questions related to taste, smell and administration of study medication. Acceptability questionnaires to be completed by caregivers on an electronic device. | Baseline and weeks 4, 24 and 52 | 
| Frequency of adverse events (AE) | An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study IP, whether or not considered related to the study investigational product (IP). An AE can 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 IP. This includes events related to the comparator and events related to the (study) procedures. | Up to week 54 | 
| Number of Participants With Vital Sign Abnormalities and/or AEs | Number of participants with potentially clinically significant vital sign values. | Up to week 54 | 
| Number of participants with laboratory value abnormalities and/or AEs | Number of participants with potentially clinically significant laboratory values. | Up to week 52 | 
| Number of participants with electrocardiogram (ECG) abnormalities and/or AEs | Number of participants with potentially clinically significant ECG values. | Up to week 54 | 
| Number of participants with upper urinary tract ultrasound abnormalities and/or AEs | Number of participants with potentially clinically significant upper urinary tract ultrasounds. | Up to week 52 | 
| PK of mirabegron in plasma: Area under the concentration-time curve per 24 hours (AUC24) | AUC24 will be recorded from the PK plasma samples collected. | Up to week 52 | 
| PK of mirabegron in plasma: Concentration immediately prior to dosing (Ctrough) | Ctrough will be recorded from the PK plasma samples collected. | Up to week 52 | 
| PK of mirabegron in plasma: Apparent clearance (CL/F) | CL/F will be recorded from the PK plasma samples collected. | Up to week 52 | 
| PK of mirabegron in plasma: Apparent volume of distribution (VzF) | VzF will be recorded from the PK plasma samples collected. | Up to week 52 | 
| PK of mirabegron in plasma: Maximum concentration (Cmax) | Cmax will be recorded from the PK plasma samples collected. | Up to week 52 | 
| PK of mirabegron in plasma: Time of maximum concentration (Tmax) | Tmax will be recorded from the PK plasma samples collected. | Up to week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neurogenic Detrusor Overactivity, Pediatric acceptability, Bladder capacity, Pharmacokinetics of mirabegron