Back to resultsOpen-label Phase 3 Study With Mirabegron in Children From 3 to Less Than 18 Years of Age With Neurogenic Detrusor Overactivity (Crocodile)
Primary Purpose
Neurogenic Detrusor Overactivity
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Mirabegron
Sponsored by
About this trial
This is an interventional treatment trial for Neurogenic Detrusor Overactivity focused on measuring Pediatrics, Urodynamics, Mirabegron, Phase 3, Neurogenic Detrusor Overactivity
Eligibility Criteria
Inclusion Criteria:
- 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
Exclusion Criteria:
- 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 5.
- 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.
Sites / Locations
- Site AU61002
- Site BE32004
- Site BE32001
- Site HR38501
- Site HR38503
- Site DK45001
- Site DK45002
- Site IL97202
- Site JO96202
- Site JO96201
- Site KR82001
- Site KR82002
- Site LV37101
- Site LT37002
- Site LT37001
- Site MY60001
- Site MY60002
- Site MX52002
- Site NO47001
- Site PH63001
- Site PL48003
- Site PL48001
- Site PL48002
- Site RO40002
- Site RO40001
- Site RS38102
- Site RS38101
- Site SK42101
- Site TW88601
- Site TR90002
- Site TR90006
- Site TR90008
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Children (3 to < 12 Years)
Adolescents (12 to < 18 Years)
Arm Description
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).
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.
Outcomes
Primary Outcome Measures
Change From Baseline in Maximum Cystometric Capacity (MCC) at 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).
Secondary Outcome Measures
Change From Baseline in Bladder Compliance (ΔV/ΔP)
Bladder compliance was an indication of the elasticity of the bladder wall and was calculated by dividing the change in volume by the change in detrusor pressure during the filling of the bladder. Change from baseline in bladder compliance (change in volume/change in pressure) was assessed by the independent central reviewers and reported as annotations on the urodynamic trace and in an external database. 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.
Change From Baseline in Maximum Cystometric Capacity at Week 4
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.
Change From Baseline in Number of Overactive Detrusor Contractions (> 15 cm H20) Until End of Filling
Detrusor overactivity is the occurrence of involuntary detrusor contractions during filling cystometry. 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.
Change From Baseline in Detrusor Pressure at End of Filling
Detrusor pressure was defined as bladder pressure minus intra-abdominal pressure as assessed by urodynamics. Filling was stopped (end of filling) when the detrusor pressure exceeded 100 cm H2O or was considered dangerously high by the investigator or urodynamicist (for instance, a prolonged passive detrusor pressure > 40 cm H2O). 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.
Change From Baseline in Filling Bladder Volume Until First Overactive Detrusor Contraction (> 15 cm H20)
Detrusor overactivity is the occurrence of involuntary detrusor contractions during filling cystometry. 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. If no detrusor contraction of > 15 cm H2O occurred, the bladder volume was imputed with maximum cystometric capacity.
Change From Baseline in Filling Bladder Volume Until First Overactive Detrusor Contraction (> 15 cm H20): Wilcoxon Signed-rank Test Updated Analysis
Detrusor overactivity is the occurrence of involuntary detrusor contractions during filling cystometry. 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. If no detrusor contraction of > 15 cm H2O occurred, the bladder volume was imputed with maximum cystometric capacity. This updated analysis is presented as the original analysis of bladder volume until first detrusor contraction (> 15 cm H2O) did not impute missing bladder volume data with the maximum cystometric capacity (MCC) value at that visit according to the statistical analysis plan (SAP). This analysis was updated to impute missing values for volume at first contraction with respective MCC values.
Change From Baseline in Filling Bladder Volume Until First Overactive Detrusor Contraction (> 15 cm H20): Paired T-test
Detrusor overactivity is the occurrence of involuntary detrusor contractions during filling cystometry. 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. If no detrusor contraction of > 15 cm H2O occurred, the bladder volume was imputed with maximum cystometric capacity.
Change From Baseline in Average Catheterized Volume Per Catheterization
For each participant, the average catheterized volume per catheterization was calculated as the sum of all available/non-missing catheterized volumes recorded over 2 measuring days in the weekend diary, whether or not the 2 days were consecutive divided by the number of catheterizations with non-missing volumes. If volumes were recorded on 1 single day of the weekend diary, the average catheterized volume per catheterization was calculated using all available/non-missing catheterized volumes recorded that day. If no volumes were recorded on any day of the weekend diary, the average catheterized volume per catheterization was missing. A valid bladder diary day in the weekend diary was any e-diary day for which ≥1 catheterized volume >0 mL was recorded with complete date and time.
Change From Baseline in Maximum Catheterized Volume
For each participant, the maximum catheterized volume per day was calculated using all available/non-missing catheterized volumes recorded for the 2 measuring days in the weekend e-diary, whether or not these 2 days were consecutive. Maximum value was calculated separately for each measuring day and the mean of the two values was used. If volumes recorded on 1 single day of the weekend e-diary, the maximum catheterized volume per day was calculated using all available/non-zero catheterized volumes recorded that day. If no volumes were recorded on any day of the weekend e-diary, the maximum catheterized volume per day was missing. A valid bladder diary day in the weekend diary was any e-diary day for which >=1 catheterized volume >0 mL was recorded with complete date and time.
Change From Baseline in Maximum Catheterized Daytime Volume (MCDV)
For each participant, the MCDV was calculated using all available/non-missing catheterized daytime volumes for the 2 measuring days in the weekend e-diary, whether or not the 2 days were consecutive. Maximum value was calculated separately for each measuring day and the mean of the 2 values was used. If volumes were recorded on 1 single day of the weekend e-diary, the MCDV was calculated using all available/non-zero catheterized daytime volumes recorded that day. If no volumes were recorded on any day of the weekend e-diary, the MCDV was missing. Daytime was defined as the time between wake-up time (minus 30 min) & time to sleep (plus 29 min) recorded in the e-diary. A valid bladder diary day in the weekend diary was any e-diary day for which >=1 catheterized volume >0 mL was recorded with complete date and time.
Change From Baseline in Average Morning Catheterized Volume
The first morning catheterized volume was the first recorded non-zero volume within or after the hour of the wake-up time on a volume-measuring day in the e-diary. The average first morning catheterized volume was calculated as the average of the available first morning catheterized volumes recorded for the 2 measuring days in the weekend e-diary, whether or not these 2 days were consecutive. If the first morning catheterized volume was recorded on 1 single day of the weekend e-diary, the average morning catheterized is the first morning catheterized that day. If no first morning catheterized volumes are recorded on any day of the weekend e-diary, the average first morning catheterized volume was missing. A valid bladder diary day in the weekend diary was any e-diary day for which >=1 catheterized volume >0 mL was recorded with complete date and time.
Change From Baseline in Mean Number of Leakage Episodes Per Day
For each participant, the mean number of leakage episodes per day (during day & night time) was calculated using all available/non-missing number of leakage episodes for the 2 measuring days in the weekend diary during day & night time. If the number of leakage episodes was recorded on 1 single day in the 7-day diary during day & night time, the mean number of leakage episodes per day during day & night time is equal to the total number of leakage episodes recorded that day during day & night time. If no leakage episodes were recorded on any day of the weekend diary during day & night time, the mean number of leakage episodes per day was zero. Participants who did not report any leakage episode during the visit were imputed with a '0' for that visit. A valid bladder diary day in the weekend diary was any e-diary day for which ≥1 catheterized volume >0 mL was recorded with complete date and time.
Change From Baseline in Mean Number of Leakage Episodes Per Day: Updated Analysis
For each participant, the mean number(no.) of leakage episodes per day (during day & night time) was calculated using all available/non-missing no. of leakage episodes for the 2 measuring days in the weekend diary during day & night time. If the no. of leakage episodes was recorded on 1 single day in the 7-day diary during day & night time, the mean no. of leakage episodes per day during day & night time is equal to the total no. of leakage episodes recorded that day during day & night time. If no leakage episodes were recorded on any day of the weekend diary during day & night time, the mean no. of leakage episodes per day was zero. Participants who did not report leakage episode during the visit were imputed with a '0' for that visit. A valid bladder diary day in weekend diary was any e-diary day for which ≥1 catheterized volume >0 mL was recorded with complete date and time. Updated analysis is presented because one participant entered weight of leakage instead of no. of leakages.
Change From Baseline in Number of Dry Days Per 7 Days (Day and Night Time)
Dry days were defined as leakage-free days, this included day and night time. Participants recorded dry days in the 7-day diary. Dry days were calculated as follows: Ddry was the number of valid diary days where the response to the question 'Did you leak between this catheterization and the last one' was 'No' each time a new catheterization was entered in the e-diary during the day & night time period. Dwet was the number of valid diary days where the response to the question 'Did you leak between this catheterization and the last one' was 'Yes' for at least one catheterization entered during the day and night time period. If (Ddry + Dwet) > 3, the number of dry days per 7 days was calculated as Ddry/(Ddry + Dwet) x 7, otherwise the value was missing.
Change From Baseline in Pediatric Incontinence Questionnaire (PIN-Q) Score
PIN-Q measured quality of life via an e-diary. Total score ranged from 0 (no effect) to 80 (worst effect); decrease in score indicated improvement. Total score was 20x average of individual PinQ items, the 20 Likert scales were converted to a score: Items 6 & 17; 0: "No" to 4: "Definitely" was used; & For the other 18 items; 0: "No" to 4: "All the time" was used. Expectation that questionnaires had limited missing values; if answers >2 questions were missing, total score was not calculated & was missing. Individual item scores were directly imputed. Change from baseline to each post-baseline visit in the total score was post-baseline visit value minus baseline value. If either baseline or post-baseline visit value was missing, change from baseline was missing. If change was: <0, improvement between 2 time-points; =0, no change between 2 time points; >0, worsening between 2 time points.
Change From Baseline in Patient Global Impression of Severity Scale (PGI-S)
The PGI-S was an answer to the question: "How did you feel about your bladder condition during the past 3 days?" Participants evaluated their recent condition as "Really Bad"(0), "Bad" (1), "Not Bad, Not Good" (2), "Good" (3) &"Really Good" (4). An increase indicated improvement. The total score ranged from 0 to 4, where higher scores indicated improvement.The change from baseline to each postbaseline visit in the PGI-S score is the value at the post-baseline visit minus the value at the baseline visit. If either the baseline or the post-baseline visit value is missing, the change from baseline was missing. A positive change indicated an improvement while a negative change indicated a worsening.
Number of Participants With Clinician Global Impression of Change (CGI-C)
The Clinician Global Impression of Change (CGI-C) is a 7 point scale that required the clinician to assess how much the participant's overall bladder symptoms since the start of the study on day 1 has improved or worsened and rated as: very much improved (1); much improved (2); minimally improved (3); no change (4); minimally worse (5); much worse (6); or very much worse (7). The total score range from 1-7, where lower scores indicated improvement.
Number of Participants With Study Drug Acceptability for Tablets at Week 4
Participants evaluated the taste of the study medication/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 medication/tablets by ticking one of the following categories: "Really Difficult" (0), "Difficult" (1), "Not Difficult, Not Easy" (2), "Easy" (3) and "Really Easy" (4).
Number of Participants With Study Drug Acceptability for Tablets at Week 24
Participants evaluated the taste of the study medication/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 medication/tablets by ticking one of the following categories: "Really Difficult" (0), "Difficult" (1), "Not Difficult, Not Easy" (2), "Easy" (3) and "Really Easy" (4).
Number of Participants With Study Drug Acceptability for Tablets at Week 52
Participants evaluated the taste of the study medication/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 medication/tablets by ticking one of the following categories: "Really Difficult" (0), "Difficult" (1), "Not Difficult, Not Easy" (2), "Easy" (3) and "Really Easy" (4).
Number of Participants With Study Drug Acceptability for Oral Suspension at Week 4
Participants evaluated the taste of the study medication/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 medication/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 and the preparation of the study medication/oral suspension by ticking 1 of the following categories: "Really Difficult" (0),"Difficult" (1), "Not Difficult, Not Easy" (2), "Easy" (3) & "Really Easy" (4).
Number of Participants With Study Drug Acceptability for Oral Suspension at Week 24
Participants evaluated the taste of the study medication/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 medication/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 and the preparation of the study medication/oral suspension by ticking 1 of the following categories: "Really Difficult" (0),"Difficult" (1), "Not Difficult, Not Easy" (2), "Easy" (3) & "Really Easy" (4).
Number of Participants With Study Drug Acceptability for Oral Suspension at Week 52
Participants evaluated the taste of the study medication/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 medication/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 and the preparation of the study medication/oral suspension by ticking 1 of the following categories: "Really Difficult" (0),"Difficult" (1), "Not Difficult, Not Easy" (2), "Easy" (3) & "Really Easy" (4).
Number of Participants With Adverse Events (AEs)
An AE was defined as any untoward medical occurrence in a participant who was given the study drug or who had undergone study procedures and did not necessarily have a causal relationship with this treatment. An AE could therefore be any unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A treatment-emergent adverse event (TEAE) was defined as any AE with date of onset occurring on or after the first dose of study medication and up to the end of study.
Maximum Plasma Concentration (Cmax) of Mirabegron
Cmax was defined as the maximum plasma concentration of mirabegron.
Time to Reach Maximum Plasma Concentration of Mirabegron Following Drug Administration (Tmax)
Tmax was defined as the time to reach maximum plasma concentration following drug administration.
Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC24) for Mirabegron
AUC (0-24) is the area under the plasma concentration versus time curve from time zero (pre-dose) to 24 hours post-dose.
Plasma Concentration of Mirabegron at the End of a Dosing Interval at Steady State (Ctrough)
Ctrough was defined as the measured plasma concentration of mirabegron at the end of a dosing interval at steady state.
Apparent Total Clearance of Mirabegron From Plasma After Oral Administration (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.
Apparent Volume of Distribution After Non-intravenous Administration (Vz/F) of Mirabegron
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. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.
Full Information
NCT ID
NCT02751931
First Posted
April 22, 2016
Last Updated
September 21, 2022
Sponsor
Astellas Pharma Europe B.V.
1. Study Identification
Unique Protocol Identification Number
NCT02751931
Brief Title
Open-label Phase 3 Study With Mirabegron in Children From 3 to Less Than 18 Years of Age With Neurogenic Detrusor Overactivity
Acronym
Crocodile
Official Title
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)
Study Type
Interventional
2. Study Status
Record Verification Date
September 2022
Overall Recruitment Status
Completed
Study Start Date
June 17, 2016 (Actual)
Primary Completion Date
November 5, 2018 (Actual)
Study Completion Date
May 6, 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Astellas Pharma Europe B.V.
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The objective of the study was to evaluate the efficacy, safety, tolerability and pharmacokinetics of mirabegron after multiple-dose administration in the pediatric population.
Detailed Description
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).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neurogenic Detrusor Overactivity
Keywords
Pediatrics, Urodynamics, Mirabegron, Phase 3, Neurogenic Detrusor Overactivity
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
91 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Children (3 to < 12 Years)
Arm Type
Experimental
Arm Description
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).
Arm Title
Adolescents (12 to < 18 Years)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Mirabegron
Other Intervention Name(s)
YM178, Myrbetriq, Betanis, Betmiga
Intervention Description
Participants received initial dose of 25 mg of mirabegron PED25 orally once daily. At weeks 2, 4 or 8, participants were up-titrated to PED50 based on the given dose titration criteria. Following week 24, participants stayed on their individual dose level until week 52 EOS or EOT. Participants with a body weight >=35 kg received mirabegron tablets or body weight <35 kg received mirabegron oral suspension. At week 24, participants on mirabegron oral suspension could switch to tablets if the body weight became >=35 kg or participants on mirabegron tablets could switch to oral suspension if the body weight became <35 Kg or participants could switch to either of the dosage form for acceptability reasons after sponsor's prior approval and on a case-by-case basis. Mirabegron extended-release granules were reconstituted with water to prepare a mirabegron oral suspension of 8 mg/mL. Administration was via an oral syringe with a sip of water afterwards.
Primary Outcome Measure Information:
Title
Change From Baseline in Maximum Cystometric Capacity (MCC) at Week 24
Description
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).
Time Frame
Baseline and week 24
Secondary Outcome Measure Information:
Title
Change From Baseline in Bladder Compliance (ΔV/ΔP)
Description
Bladder compliance was an indication of the elasticity of the bladder wall and was calculated by dividing the change in volume by the change in detrusor pressure during the filling of the bladder. Change from baseline in bladder compliance (change in volume/change in pressure) was assessed by the independent central reviewers and reported as annotations on the urodynamic trace and in an external database. 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.
Time Frame
Baseline and weeks 4 and 24
Title
Change From Baseline in Maximum Cystometric Capacity at Week 4
Description
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.
Time Frame
Baseline and week 4
Title
Change From Baseline in Number of Overactive Detrusor Contractions (> 15 cm H20) Until End of Filling
Description
Detrusor overactivity is the occurrence of involuntary detrusor contractions during filling cystometry. 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.
Time Frame
Baseline and weeks 4 and 24
Title
Change From Baseline in Detrusor Pressure at End of Filling
Description
Detrusor pressure was defined as bladder pressure minus intra-abdominal pressure as assessed by urodynamics. Filling was stopped (end of filling) when the detrusor pressure exceeded 100 cm H2O or was considered dangerously high by the investigator or urodynamicist (for instance, a prolonged passive detrusor pressure > 40 cm H2O). 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.
Time Frame
Baseline and weeks 4 and 24
Title
Change From Baseline in Filling Bladder Volume Until First Overactive Detrusor Contraction (> 15 cm H20)
Description
Detrusor overactivity is the occurrence of involuntary detrusor contractions during filling cystometry. 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. If no detrusor contraction of > 15 cm H2O occurred, the bladder volume was imputed with maximum cystometric capacity.
Time Frame
Baseline and weeks 4 and 24
Title
Change From Baseline in Filling Bladder Volume Until First Overactive Detrusor Contraction (> 15 cm H20): Wilcoxon Signed-rank Test Updated Analysis
Description
Detrusor overactivity is the occurrence of involuntary detrusor contractions during filling cystometry. 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. If no detrusor contraction of > 15 cm H2O occurred, the bladder volume was imputed with maximum cystometric capacity. This updated analysis is presented as the original analysis of bladder volume until first detrusor contraction (> 15 cm H2O) did not impute missing bladder volume data with the maximum cystometric capacity (MCC) value at that visit according to the statistical analysis plan (SAP). This analysis was updated to impute missing values for volume at first contraction with respective MCC values.
Time Frame
Baseline and weeks 4 and 24
Title
Change From Baseline in Filling Bladder Volume Until First Overactive Detrusor Contraction (> 15 cm H20): Paired T-test
Description
Detrusor overactivity is the occurrence of involuntary detrusor contractions during filling cystometry. 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. If no detrusor contraction of > 15 cm H2O occurred, the bladder volume was imputed with maximum cystometric capacity.
Time Frame
Baseline and weeks 4 and 24
Title
Change From Baseline in Average Catheterized Volume Per Catheterization
Description
For each participant, the average catheterized volume per catheterization was calculated as the sum of all available/non-missing catheterized volumes recorded over 2 measuring days in the weekend diary, whether or not the 2 days were consecutive divided by the number of catheterizations with non-missing volumes. If volumes were recorded on 1 single day of the weekend diary, the average catheterized volume per catheterization was calculated using all available/non-missing catheterized volumes recorded that day. If no volumes were recorded on any day of the weekend diary, the average catheterized volume per catheterization was missing. A valid bladder diary day in the weekend diary was any e-diary day for which ≥1 catheterized volume >0 mL was recorded with complete date and time.
Time Frame
Baseline and weeks 2, 4, 8, 12, 24, 36 and 52
Title
Change From Baseline in Maximum Catheterized Volume
Description
For each participant, the maximum catheterized volume per day was calculated using all available/non-missing catheterized volumes recorded for the 2 measuring days in the weekend e-diary, whether or not these 2 days were consecutive. Maximum value was calculated separately for each measuring day and the mean of the two values was used. If volumes recorded on 1 single day of the weekend e-diary, the maximum catheterized volume per day was calculated using all available/non-zero catheterized volumes recorded that day. If no volumes were recorded on any day of the weekend e-diary, the maximum catheterized volume per day was missing. A valid bladder diary day in the weekend diary was any e-diary day for which >=1 catheterized volume >0 mL was recorded with complete date and time.
Time Frame
Baseline and weeks 2, 4, 8, 12, 24, 36 and 52
Title
Change From Baseline in Maximum Catheterized Daytime Volume (MCDV)
Description
For each participant, the MCDV was calculated using all available/non-missing catheterized daytime volumes for the 2 measuring days in the weekend e-diary, whether or not the 2 days were consecutive. Maximum value was calculated separately for each measuring day and the mean of the 2 values was used. If volumes were recorded on 1 single day of the weekend e-diary, the MCDV was calculated using all available/non-zero catheterized daytime volumes recorded that day. If no volumes were recorded on any day of the weekend e-diary, the MCDV was missing. Daytime was defined as the time between wake-up time (minus 30 min) & time to sleep (plus 29 min) recorded in the e-diary. A valid bladder diary day in the weekend diary was any e-diary day for which >=1 catheterized volume >0 mL was recorded with complete date and time.
Time Frame
Baseline and weeks 2, 4, 8, 12, 24, 36 and 52
Title
Change From Baseline in Average Morning Catheterized Volume
Description
The first morning catheterized volume was the first recorded non-zero volume within or after the hour of the wake-up time on a volume-measuring day in the e-diary. The average first morning catheterized volume was calculated as the average of the available first morning catheterized volumes recorded for the 2 measuring days in the weekend e-diary, whether or not these 2 days were consecutive. If the first morning catheterized volume was recorded on 1 single day of the weekend e-diary, the average morning catheterized is the first morning catheterized that day. If no first morning catheterized volumes are recorded on any day of the weekend e-diary, the average first morning catheterized volume was missing. A valid bladder diary day in the weekend diary was any e-diary day for which >=1 catheterized volume >0 mL was recorded with complete date and time.
Time Frame
Baseline and weeks 2, 4, 8, 12, 24, 36 and 52
Title
Change From Baseline in Mean Number of Leakage Episodes Per Day
Description
For each participant, the mean number of leakage episodes per day (during day & night time) was calculated using all available/non-missing number of leakage episodes for the 2 measuring days in the weekend diary during day & night time. If the number of leakage episodes was recorded on 1 single day in the 7-day diary during day & night time, the mean number of leakage episodes per day during day & night time is equal to the total number of leakage episodes recorded that day during day & night time. If no leakage episodes were recorded on any day of the weekend diary during day & night time, the mean number of leakage episodes per day was zero. Participants who did not report any leakage episode during the visit were imputed with a '0' for that visit. A valid bladder diary day in the weekend diary was any e-diary day for which ≥1 catheterized volume >0 mL was recorded with complete date and time.
Time Frame
Baseline and weeks 2, 4, 8, 12, 24, 36 and 52
Title
Change From Baseline in Mean Number of Leakage Episodes Per Day: Updated Analysis
Description
For each participant, the mean number(no.) of leakage episodes per day (during day & night time) was calculated using all available/non-missing no. of leakage episodes for the 2 measuring days in the weekend diary during day & night time. If the no. of leakage episodes was recorded on 1 single day in the 7-day diary during day & night time, the mean no. of leakage episodes per day during day & night time is equal to the total no. of leakage episodes recorded that day during day & night time. If no leakage episodes were recorded on any day of the weekend diary during day & night time, the mean no. of leakage episodes per day was zero. Participants who did not report leakage episode during the visit were imputed with a '0' for that visit. A valid bladder diary day in weekend diary was any e-diary day for which ≥1 catheterized volume >0 mL was recorded with complete date and time. Updated analysis is presented because one participant entered weight of leakage instead of no. of leakages.
Time Frame
Baseline and weeks 2, 4, 8, 12, 24, 36 and 52
Title
Change From Baseline in Number of Dry Days Per 7 Days (Day and Night Time)
Description
Dry days were defined as leakage-free days, this included day and night time. Participants recorded dry days in the 7-day diary. Dry days were calculated as follows: Ddry was the number of valid diary days where the response to the question 'Did you leak between this catheterization and the last one' was 'No' each time a new catheterization was entered in the e-diary during the day & night time period. Dwet was the number of valid diary days where the response to the question 'Did you leak between this catheterization and the last one' was 'Yes' for at least one catheterization entered during the day and night time period. If (Ddry + Dwet) > 3, the number of dry days per 7 days was calculated as Ddry/(Ddry + Dwet) x 7, otherwise the value was missing.
Time Frame
Baseline and weeks 2, 4, 8, 12, 24, 36 and 52
Title
Change From Baseline in Pediatric Incontinence Questionnaire (PIN-Q) Score
Description
PIN-Q measured quality of life via an e-diary. Total score ranged from 0 (no effect) to 80 (worst effect); decrease in score indicated improvement. Total score was 20x average of individual PinQ items, the 20 Likert scales were converted to a score: Items 6 & 17; 0: "No" to 4: "Definitely" was used; & For the other 18 items; 0: "No" to 4: "All the time" was used. Expectation that questionnaires had limited missing values; if answers >2 questions were missing, total score was not calculated & was missing. Individual item scores were directly imputed. Change from baseline to each post-baseline visit in the total score was post-baseline visit value minus baseline value. If either baseline or post-baseline visit value was missing, change from baseline was missing. If change was: <0, improvement between 2 time-points; =0, no change between 2 time points; >0, worsening between 2 time points.
Time Frame
Baseline and weeks 24 and 52
Title
Change From Baseline in Patient Global Impression of Severity Scale (PGI-S)
Description
The PGI-S was an answer to the question: "How did you feel about your bladder condition during the past 3 days?" Participants evaluated their recent condition as "Really Bad"(0), "Bad" (1), "Not Bad, Not Good" (2), "Good" (3) &"Really Good" (4). An increase indicated improvement. The total score ranged from 0 to 4, where higher scores indicated improvement.The change from baseline to each postbaseline visit in the PGI-S score is the value at the post-baseline visit minus the value at the baseline visit. If either the baseline or the post-baseline visit value is missing, the change from baseline was missing. A positive change indicated an improvement while a negative change indicated a worsening.
Time Frame
Baseline and weeks 24 and 52
Title
Number of Participants With Clinician Global Impression of Change (CGI-C)
Description
The Clinician Global Impression of Change (CGI-C) is a 7 point scale that required the clinician to assess how much the participant's overall bladder symptoms since the start of the study on day 1 has improved or worsened and rated as: very much improved (1); much improved (2); minimally improved (3); no change (4); minimally worse (5); much worse (6); or very much worse (7). The total score range from 1-7, where lower scores indicated improvement.
Time Frame
Weeks 24 and 52
Title
Number of Participants With Study Drug Acceptability for Tablets at Week 4
Description
Participants evaluated the taste of the study medication/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 medication/tablets by ticking one of the following categories: "Really Difficult" (0), "Difficult" (1), "Not Difficult, Not Easy" (2), "Easy" (3) and "Really Easy" (4).
Time Frame
Week 4
Title
Number of Participants With Study Drug Acceptability for Tablets at Week 24
Description
Participants evaluated the taste of the study medication/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 medication/tablets by ticking one of the following categories: "Really Difficult" (0), "Difficult" (1), "Not Difficult, Not Easy" (2), "Easy" (3) and "Really Easy" (4).
Time Frame
Week 24
Title
Number of Participants With Study Drug Acceptability for Tablets at Week 52
Description
Participants evaluated the taste of the study medication/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 medication/tablets by ticking one of the following categories: "Really Difficult" (0), "Difficult" (1), "Not Difficult, Not Easy" (2), "Easy" (3) and "Really Easy" (4).
Time Frame
Week 52
Title
Number of Participants With Study Drug Acceptability for Oral Suspension at Week 4
Description
Participants evaluated the taste of the study medication/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 medication/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 and the preparation of the study medication/oral suspension by ticking 1 of the following categories: "Really Difficult" (0),"Difficult" (1), "Not Difficult, Not Easy" (2), "Easy" (3) & "Really Easy" (4).
Time Frame
Week 4
Title
Number of Participants With Study Drug Acceptability for Oral Suspension at Week 24
Description
Participants evaluated the taste of the study medication/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 medication/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 and the preparation of the study medication/oral suspension by ticking 1 of the following categories: "Really Difficult" (0),"Difficult" (1), "Not Difficult, Not Easy" (2), "Easy" (3) & "Really Easy" (4).
Time Frame
Week 24
Title
Number of Participants With Study Drug Acceptability for Oral Suspension at Week 52
Description
Participants evaluated the taste of the study medication/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 medication/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 and the preparation of the study medication/oral suspension by ticking 1 of the following categories: "Really Difficult" (0),"Difficult" (1), "Not Difficult, Not Easy" (2), "Easy" (3) & "Really Easy" (4).
Time Frame
Week 52
Title
Number of Participants With Adverse Events (AEs)
Description
An AE was defined as any untoward medical occurrence in a participant who was given the study drug or who had undergone study procedures and did not necessarily have a causal relationship with this treatment. An AE could therefore be any unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A treatment-emergent adverse event (TEAE) was defined as any AE with date of onset occurring on or after the first dose of study medication and up to the end of study.
Time Frame
From the first dose of study drug administration up to end-of-treatment (EoT) (up to week 52)
Title
Maximum Plasma Concentration (Cmax) of Mirabegron
Description
Cmax was defined as the maximum plasma concentration of mirabegron.
Time Frame
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.
Title
Time to Reach Maximum Plasma Concentration of Mirabegron Following Drug Administration (Tmax)
Description
Tmax was defined as the time to reach maximum plasma concentration following drug administration.
Time Frame
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.
Title
Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC24) for Mirabegron
Description
AUC (0-24) is the area under the plasma concentration versus time curve from time zero (pre-dose) to 24 hours post-dose.
Time Frame
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.
Title
Plasma Concentration of Mirabegron at the End of a Dosing Interval at Steady State (Ctrough)
Description
Ctrough was defined as the measured plasma concentration of mirabegron at the end of a dosing interval at steady state.
Time Frame
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.
Title
Apparent Total Clearance of Mirabegron From Plasma After Oral Administration (CL/F)
Description
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.
Time Frame
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.
Title
Apparent Volume of Distribution After Non-intravenous Administration (Vz/F) of Mirabegron
Description
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. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.
Time Frame
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.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
3 Years
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
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
Exclusion Criteria:
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 5.
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Monitor
Organizational Affiliation
Astellas Pharma Europe B.V.
Official's Role
Study Director
Facility Information:
Facility Name
Site AU61002
City
Randwick
State/Province
New South Wales
ZIP/Postal Code
2031
Country
Australia
Facility Name
Site BE32004
City
Edegem
ZIP/Postal Code
B-2650
Country
Belgium
Facility Name
Site BE32001
City
Gent
ZIP/Postal Code
9000
Country
Belgium
Facility Name
Site HR38501
City
Zagreb
ZIP/Postal Code
10000
Country
Croatia
Facility Name
Site HR38503
City
Zagreb
ZIP/Postal Code
10000
Country
Croatia
Facility Name
Site DK45001
City
Aarhus N
ZIP/Postal Code
DK-8200
Country
Denmark
Facility Name
Site DK45002
City
Copenhagen
ZIP/Postal Code
2100
Country
Denmark
Facility Name
Site IL97202
City
Jerusalem
ZIP/Postal Code
91090
Country
Israel
Facility Name
Site JO96202
City
Amman
ZIP/Postal Code
11183
Country
Jordan
Facility Name
Site JO96201
City
Irbid
ZIP/Postal Code
22110
Country
Jordan
Facility Name
Site KR82001
City
Seoul
ZIP/Postal Code
03722
Country
Korea, Republic of
Facility Name
Site KR82002
City
Seoul
ZIP/Postal Code
110744
Country
Korea, Republic of
Facility Name
Site LV37101
City
Riga
ZIP/Postal Code
LV-1004
Country
Latvia
Facility Name
Site LT37002
City
Kaunas
ZIP/Postal Code
LT-50009
Country
Lithuania
Facility Name
Site LT37001
City
Vilnius
ZIP/Postal Code
LT-08406
Country
Lithuania
Facility Name
Site MY60001
City
Georgetown
ZIP/Postal Code
10990
Country
Malaysia
Facility Name
Site MY60002
City
Kuala Lumpur
ZIP/Postal Code
50586
Country
Malaysia
Facility Name
Site MX52002
City
Mexico City
ZIP/Postal Code
06700
Country
Mexico
Facility Name
Site NO47001
City
Bergen
ZIP/Postal Code
5021
Country
Norway
Facility Name
Site PH63001
City
Quezon City
ZIP/Postal Code
1100
Country
Philippines
Facility Name
Site PL48003
City
Gdansk
ZIP/Postal Code
80-952
Country
Poland
Facility Name
Site PL48001
City
Gdansk
ZIP/Postal Code
80803
Country
Poland
Facility Name
Site PL48002
City
Warszawa
ZIP/Postal Code
04-730
Country
Poland
Facility Name
Site RO40002
City
Bucuresti
ZIP/Postal Code
021495
Country
Romania
Facility Name
Site RO40001
City
Bucuresti
ZIP/Postal Code
22328
Country
Romania
Facility Name
Site RS38102
City
Nis
Country
Serbia
Facility Name
Site RS38101
City
Novi Sad
ZIP/Postal Code
21000
Country
Serbia
Facility Name
Site SK42101
City
Bratislava
ZIP/Postal Code
83301
Country
Slovakia
Facility Name
Site TW88601
City
New Taipei City
ZIP/Postal Code
23142
Country
Taiwan
Facility Name
Site TR90002
City
Ankara
ZIP/Postal Code
06100
Country
Turkey
Facility Name
Site TR90006
City
Bursa
Country
Turkey
Facility Name
Site TR90008
City
Mersin
ZIP/Postal Code
33343
Country
Turkey
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as compounds terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.
IPD Sharing Time Frame
Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
IPD Sharing Access Criteria
Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.
IPD Sharing URL
https://www.clinicalstudydatarequest.com/
Citations:
PubMed Identifier
34058027
Citation
Baka-Ostrowska M, Bolong DT, Persu C, Tondel C, Steup A, Lademacher C, Martin N. Efficacy and safety of mirabegron in children and adolescents with neurogenic detrusor overactivity: An open-label, phase 3, dose-titration study. Neurourol Urodyn. 2021 Aug;40(6):1490-1499. doi: 10.1002/nau.24657. Epub 2021 May 31.
Results Reference
derived
Links:
URL
https://astellasclinicalstudyresults.com/patientStudySearch.aspx?RID=;;;178-CL-206A
Description
Link to results on the Astellas Clinical Study Results website.
Learn more about this trial
Open-label Phase 3 Study With Mirabegron in Children From 3 to Less Than 18 Years of Age With Neurogenic Detrusor Overactivity
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