Open-label Phase 3 Study With Mirabegron in Children From 3 to Less Than 18 Years of Age With Neurogenic Detrusor Overactivity

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

Population: The analysis population consisted of the full analysis set (FAS) which included all participants who took ≥ 1 dose of study drug and provided both valid (as by the central reviewer's assessment) nonmissing MCC measurements at baseline and at a postbaseline visit for the primary efficacy endpoint.

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.

Population: The analysis population consisted of the PKAS.

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.

Population: The analysis population consisted of the PKAS.

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.

Population: The analysis population consisted of the PKAS.

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

Population: The analysis population consisted of the FAS. Here, Overall Number of participants analyzed signifies number of participants evaluable for this outcome measure and number analyzed signifies number of participants with available data at each time point.

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

Population: The analysis population consisted of the FAS. Here, Overall Number of participants analyzed signifies number of participants evaluable for this outcome measure and number analyzed signifies number of participants with available data at each time point.

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

Population: The analysis population consisted of the FAS. Here, Overall Number of participants analyzed signifies number of participants evaluable for this outcome measure and number analyzed signifies number of participants with available data at each time point.

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

Population: The analysis population consisted of the FAS. Here, Overall Number of participants analyzed signifies number of participants evaluable for this outcome measure and number analyzed signifies number of participants with available data at each time point.

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

Population: The analysis population consisted of the FAS. Here, Overall Number of participants analyzed signifies number of participants evaluable for this outcome measure and number analyzed signifies number of participants with available data at each time point.

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

Population: The analysis population consisted of the FAS. Here, Overall Number of participants analyzed signifies number of participants evaluable for this outcome measure and number analyzed signifies number of participants with available data at each time point.

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

Population: The analysis population consisted of the FAS. Here, Overall Number of participants analyzed signifies number of participants evaluable for this outcome measure and number analyzed signifies number of participants with available data at each time point.

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

Population: The analysis population consisted of the FAS. Here, Overall Number of participants analyzed signifies number of participants evaluable for this outcome measure and number analyzed signifies number of participants with available data at each time point.

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

Population: The analysis population consisted of the FAS. Here, Overall Number of participants analyzed signifies number of participants evaluable for this outcome measure and number analyzed signifies number of participants with available data at each time point.

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

Population: The analysis population consisted of the FAS. Here, Overall Number of participants analyzed signifies those who where evaluable for this outcome measure.

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

Population: The analysis population consisted of the FAS. Here, Overall Number of participants analyzed signifies number of participants evaluable for this outcome measure and number analyzed signifies number of participants with available data at each time point.

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

Population: The analysis population consisted of the FAS. Here, Overall Number of participants analyzed signifies number of participants evaluable for this outcome measure and number analyzed signifies number of participants with available data at each time point.

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

Population: The analysis population consisted of the FAS. Here, Overall Number of participants analyzed signifies number of participants evaluable for this outcome measure and number analyzed signifies number of participants with available data at each time point.

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

Population: The analysis population consisted of the FAS. Here, Overall Number of participants analyzed signifies number of participants evaluable for this outcome measure and number analyzed signifies number of participants with available data at each time point.

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

Population: The analysis population consisted of the FAS. Here, Overall Number of participants analyzed signifies number of participants evaluable for this outcome measure and number analyzed signifies number of participants with available data at each time point.

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

Population: The analysis population consisted of the FAS. Here, Overall Number of participants analyzed signifies number of participants evaluable for this outcome measure and number analyzed signifies number of participants with available data at each time point.

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.

Population: The analysis population consisted of the pharmacokinetic analysis set (PKAS), which consisted of the subset of the SAF for whom plasma concentration data were available to facilitate derivation of ≥ 1 pharmacokinetic parameter and for whom the time of the last dose prior to sampling was known.

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)

Population: The analysis population consisted of the safety analysis set (SAF), which included of all participants who took at least 1 dose of study drug.

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

Population: The analysis population consisted of the FAS. Here, Overall Number of participants analyzed signifies number of participants evaluable for this outcome measure and number analyzed signifies number of participants with available data at each time point.

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

Population: The analysis population consisted of the FAS. Here, Overall Number of participants analyzed signifies number of participants evaluable for this outcome measure.

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

Population: The analysis population consisted of the FAS. Here, Overall Number of participants analyzed signifies number of participants evaluable for this outcome measure.

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

Population: The analysis population consisted of the FAS. Here, Overall Number of participants analyzed signifies number of participants evaluable for this outcome measure.

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

Population: The analysis population consisted of the FAS. Here, Overall Number of participants analyzed signifies number of participants evaluable for this outcome measure.

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

Population: The analysis population consisted of the FAS. Here, Overall Number of participants analyzed signifies number of participants evaluable for this outcome measure.

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

Population: The analysis population consisted of the FAS. Here, Overall Number of participants analyzed signifies number of participants evaluable for this outcome measure.

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.

Population: The analysis population consisted of the PKAS.

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.

Population: The analysis population consisted of the PKAS.