Clinical trial NCT05621616: A Study to Learn How Effective and Safe the Drug 'Mirabegron' is and How Long it Stays in the Body of Children Aged 6 Months to Less Than 3 Years of Age With Neurogenic Detrusor Overactivity
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Neurogenic Detrusor Overactivity
Keywords: Neurogenic Detrusor Overactivity
Pediatric acceptability
Bladder capacity
Pharmacokinetics of mirabegron
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2022-11-18
Enrollment: 10
Sex: ALL
Minimum age (years): 6
Maximum age (years): 3
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: People with neurogenic detrusor overactivity (NDO) have poor bladder control because of how their nerves to the bladder are wired. This can cause high pressure in the bladder, causing it to leak urine by accident (incontinence). Mirabegron has already been approved for adults with bladder problems and for children 3 years and older. This study will learn if mirabegron can help young children with NDO. The children will be from 6 months to up to 3 years old.

The main aim of this study is to learn if mirabegron increases how much urine the bladder holds (maximum cystometric capacity, or Maximum Cystometric Capacity \[MCC\]) in young children with NDO. An increase in MCC will prevent high pressure in the bladder.

Children from 6 months to up to 3 years old who have NDO can take part. They must weigh 9 kilograms (kg) or more. They will already be fitted with a tube (catheter) in their bladder. They will use this to drain urine from their bladder regularly during the day. This is called clean intermittent catheterization (CIC).

There will be 2 groups in the study. Young children who aren't taking certain medicines for NDO will be in group A. Young children who are taking certain medicines for NDO will be in group B. Children in group B will stop taking these medicines before they start taking mirabegron. Treatment in group B will be delayed to allow the medicines to be cleared from the body before they start taking mirabegron. Both groups (A and B) will have the same treatment and dose of mirabegron and will have the same checks throughout the study.

Mirabegron will be squirted from a syringe into the children's mouths, followed by a sip of water. This will happen once a day for up to 52 weeks (1 year). They will start on a low dose, adjusted for their weight. The dose may be increased to a higher dose if the study doctor thinks the child will benefit from the higher dose.

Children will have safety checks throughout the study. Other tests will include checking how the bladder fills and empties plus an ultrasound of the bladder area.

There will be several clinic visits during the study. There will be fewer clinic visits if a child stays on the low dose of mirabegron. Then, the clinic will phone the caregiver about 1 month after the last dose of mirabegron to check if there are any further medical problems.


Eligibility criteria: Inclusion Criteria:

* Participant's weight is a minimum of 9 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 receiving study intervention 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 ≥ 2 × ULN, with ULN defined as 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, hematology or coagulation.
* 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.

Primary outcomes:
measure: Change From Baseline to Week 24 in Maximum Cystometric Capacity (MCC)
timeFrame: Baseline and week 24
Secondary outcomes:
measure: Change from baseline in bladder compliance
timeFrame: Baseline and weeks 4 and 24
measure: Change from baseline in filling volume until first detrusor contraction (>15cm H2O)
timeFrame: Baseline and weeks 4 and 24
measure: Change from baseline in number of uninhibited detrusor contractions until leakage or until maximum 135% of age-related bladder capacity
timeFrame: Baseline and weeks 4 and 24
measure: Change from baseline in maximum catheterized daytime volume
timeFrame: Baseline and up to week 52
measure: Change from baseline in average catheterized daytime volume
timeFrame: Baseline and up to week 52
measure: Change from baseline in average morning catheterized volume
timeFrame: Baseline and up to week 52
measure: Change from baseline in number of leakage episodes per 24 hours
timeFrame: Baseline and up to week 52
measure: Change from baseline in number of dry days per 7 days
timeFrame: Baseline and up to week 52
measure: Acceptability by pediatric oral medicine acceptability questionnaire for caregivers (P-OMAQ-C)
timeFrame: Baseline and weeks 4, 24 and 52
measure: Frequency of adverse events (AE)
timeFrame: Up to week 54
measure: Number of Participants With Vital Sign Abnormalities and/or AEs
timeFrame: Up to week 54
measure: Number of participants with laboratory value abnormalities and/or AEs
timeFrame: Up to week 52
measure: Number of participants with electrocardiogram (ECG) abnormalities and/or AEs
timeFrame: Up to week 54
measure: Number of participants with upper urinary tract ultrasound abnormalities and/or AEs
timeFrame: Up to week 52
measure: PK of mirabegron in plasma: Area under the concentration-time curve per 24 hours (AUC24)
timeFrame: Up to week 52
measure: PK of mirabegron in plasma: Concentration immediately prior to dosing (Ctrough)
timeFrame: Up to week 52
measure: PK of mirabegron in plasma: Apparent clearance (CL/F)
timeFrame: Up to week 52
measure: PK of mirabegron in plasma: Apparent volume of distribution (VzF)
timeFrame: Up to week 52
measure: PK of mirabegron in plasma: Maximum concentration (Cmax)
timeFrame: Up to week 52
measure: PK of mirabegron in plasma: Time of maximum concentration (Tmax)
timeFrame: Up to week 52
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford Hospital
state: California
city: Orlando
country: United States
facility: Nemours Children's Clinic
state: Florida
city: Salt Lake City
country: United States
facility: Intermountain Primary Children
state: Utah
city: Edegem
country: Belgium
facility: Site BE32001
city: Aarhus Region Midtjylland
country: Denmark
facility: Site DK45001
city: Frankfurt
country: Germany
facility: Site DE49003
city: Hannover
country: Germany
facility: Site DE49002
city: Quezon City
country: Philippines
facility: Site PH63002
city: Quezon
country: Philippines
facility: Site PH63001
city: Gdansk
country: Poland
facility: Site PL48001
city: Ankara
country: Turkey
facility: Site TR90002
city: Antalya
country: Turkey
facility: Site TR90003
city: Mersin
country: Turkey
facility: Site TR90001
Study officials:
affiliation: Astellas Pharma Global Development, Inc.
name: Medical Director
role: STUDY_DIRECTOR
References: