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    Clinical Trial Results:
    A Multicentre, Open-label, Single Dose, Phase 1 Study to Evaluate the Pharmacokinetics, Safety and Tolerability of Mirabegron Oral Suspension in Pediatric Subjects from 3 to Less than 12 Years of Age with Neurogenic Detrusor Overactivity (NDO) or Overactive Bladder (OAB)

    Summary
    EudraCT number
    2015-000700-26
    Trial protocol
    DK  
    Global end of trial date
    30 Sep 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    05 Apr 2017
    First version publication date
    05 Apr 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    178-CL-203
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Astellas Pharma Europe B.V.
    Sponsor organisation address
    Sylviusweg 62, Leiden, Netherlands, 2333 BE
    Public contact
    Clinical Trial Disclosure, Astellas Pharma Europe B.V., astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma Europe B.V., astellas.resultsdisclosure@astellas.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000597-PIP02-10, EMEA-000597-PIP03-15
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Sep 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the pharmacokinetics of mirabegron oral suspension after single dose administration in children with NDO or OAB.
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the fed ral, national and/or regional legislation related to the privacy and protection of personal information.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    17 Dec 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 5
    Country: Number of subjects enrolled
    Poland: 4
    Worldwide total number of subjects
    9
    EEA total number of subjects
    9
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    9
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Children were enrolled in sites in Denmark and Poland.

    Pre-assignment
    Screening details
    Children with NDO aged 3 to less than 12 years of age and with OAB aged 5 to less than 12 years of age who gave assent or whose parents/legal guardians consented to enter this study and fulfilled all the eligibility criteria were enrolled. A wash-out of prohibited medication for 5 half-lives was performed if a participant was using them.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Total (All participants)
    Arm description
    Participants received a single, weight-based dose of mirabegron on day 1.
    Arm type
    Experimental

    Investigational medicinal product name
    Mirabegron
    Investigational medicinal product code
    YM178
    Other name
    Myrbetriq®, Betmiga™
    Pharmaceutical forms
    Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a single, weight-based dose of mirabegron, resulting in an exposure equivalent to steady state exposure to 50 mg prolonged-release tablets given once daily to adults. Participants were dosed under fed conditions (within 1 hour after completion of the light breakfast and were allowed to have a light lunch > 2 hours after dosing). Mirabegron was provided as granules and reconstituted with vehicle in bottle and was prepared into a modified release oral suspension 2 mg/mL.

    Number of subjects in period 1
    Total (All participants)
    Started
    9
    Completed
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Total (All participants)
    Reporting group description
    Participants received a single, weight-based dose of mirabegron on day 1.

    Reporting group values
    Total (All participants) Total
    Number of subjects
    9
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    7.3 ± 2.2 -
    Gender categorical
    Units:
        Male
    4 4
        Female
    5 5
    Diagnosis
    Units: Subjects
        NDO
    6 6
        OAB
    3 3

    End points

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    End points reporting groups
    Reporting group title
    Total (All participants)
    Reporting group description
    Participants received a single, weight-based dose of mirabegron on day 1.

    Primary: Maximum Concentration (Cmax) of Mirabegron

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    End point title
    Maximum Concentration (Cmax) of Mirabegron [1]
    End point description
    The analysis population was the Pharmacokinetic Analysis Set (PKAS) which consisted of participants from the Safety Analysis Set (SAF; consisted of all participants who took the dose of study medication) population for whom sufficient plasma concentration data were available to facilitate derivation of at least 1 pharmacokinetic parameter and for whom date and time of dosing and sampling were known.
    End point type
    Primary
    End point timeframe
    Day 1: 0.5-2, 3-5, 6-8 hours (h) postdose, Day 2: 24-32 h, Day 3: 48-56 h, Day 4: 72-80 h, Day 5: 96-104 h, Day 6: 120-128 h, Day 7: 144-152 h (2 samples only for Day 3-7)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study was written with no planned statistical analyses (inferential) to be performed for any end points due to the simple design and purpose of the study.
    End point values
    Total (All participants)
    Number of subjects analysed
    9
    Units: ng/mL
        arithmetic mean (standard deviation)
    18.41 ± 11.72
    No statistical analyses for this end point

    Primary: Area Under the Concentration-time Curve from Time Zero to Infinity (AUCinf) for Mirabegron

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    End point title
    Area Under the Concentration-time Curve from Time Zero to Infinity (AUCinf) for Mirabegron [2]
    End point description
    The analysis population was the PKAS.
    End point type
    Primary
    End point timeframe
    Day 1: 0.5-2, 3-5, 6-8 hours (h) postdose, Day 2: 24-32 h, Day 3: 48-56 h, Day 4: 72-80 h, Day 5: 96-104 h, Day 6: 120-128 h, Day 7: 144-152 h (2 samples only for Day 3-7)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study was written with no planned statistical analyses (inferential) to be performed for any end points due to the simple design and purpose of the study.
    End point values
    Total (All participants)
    Number of subjects analysed
    9
    Units: ng*h/mL
        arithmetic mean (standard deviation)
    464.1 ± 288.9
    No statistical analyses for this end point

    Primary: Time After Dosing When Cmax Occurs (tmax) for Mirabegron

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    End point title
    Time After Dosing When Cmax Occurs (tmax) for Mirabegron [3]
    End point description
    The analysis population was the PKAS.
    End point type
    Primary
    End point timeframe
    Day 1: 0.5-2, 3-5, 6-8 hours (h) postdose, Day 2: 24-32 h, Day 3: 48-56 h, Day 4: 72-80 h, Day 5: 96-104 h, Day 6: 120-128 h, Day 7: 144-152 h (2 samples only for Day 3-7)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study was written with no planned statistical analyses (inferential) to be performed for any end points due to the simple design and purpose of the study.
    End point values
    Total (All participants)
    Number of subjects analysed
    9
    Units: hours
        median (full range (min-max))
    3.93 (1.25 to 6.5)
    No statistical analyses for this end point

    Primary: Apparent Terminal Elimination Half-life (t1/2) of Mirabegron

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    End point title
    Apparent Terminal Elimination Half-life (t1/2) of Mirabegron [4]
    End point description
    The analysis population was the PKAS.
    End point type
    Primary
    End point timeframe
    Day 1: 0.5-2, 3-5, 6-8 hours (h) postdose, Day 2: 24-32 h, Day 3: 48-56 h, Day 4: 72-80 h, Day 5: 96-104 h, Day 6: 120-128 h, Day 7: 144-152 h (2 samples only for Day 3-7)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study was written with no planned statistical analyses (inferential) to be performed for any end points due to the simple design and purpose of the study.
    End point values
    Total (All participants)
    Number of subjects analysed
    9
    Units: hours
        arithmetic mean (standard deviation)
    25.99 ± 5.8
    No statistical analyses for this end point

    Primary: Area Under the Concentration-time Curve from the Time of Dosing (Time Zero) to 24 Hours (AUC24) for Mirabegron

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    End point title
    Area Under the Concentration-time Curve from the Time of Dosing (Time Zero) to 24 Hours (AUC24) for Mirabegron [5]
    End point description
    The analysis population was the PKAS.
    End point type
    Primary
    End point timeframe
    Day 1: 0.5-2, 3-5, 6-8 hours (h) postdose, Day 2: 24-32 h, Day 3: 48-56 h, Day 4: 72-80 h, Day 5: 96-104 h, Day 6: 120-128 h, Day 7: 144-152 h (2 samples only for Day 3-7)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study was written with no planned statistical analyses (inferential) to be performed for any end points due to the simple design and purpose of the study.
    End point values
    Total (All participants)
    Number of subjects analysed
    9
    Units: ng*h/mL
        arithmetic mean (standard deviation)
    226.9 ± 136.2
    No statistical analyses for this end point

    Primary: Area Under the Concentration-time Curve from Time Zero to Last Measurable Concentration (AUClast) for Mirabegron

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    End point title
    Area Under the Concentration-time Curve from Time Zero to Last Measurable Concentration (AUClast) for Mirabegron [6]
    End point description
    The analysis population was the PKAS.
    End point type
    Primary
    End point timeframe
    Day 1: 0.5-2, 3-5, 6-8 hours (h) postdose, Day 2: 24-32 h, Day 3: 48-56 h, Day 4: 72-80 h, Day 5: 96-104 h, Day 6: 120-128 h, Day 7: 144-152 h (2 samples only for Day 3-7)
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study was written with no planned statistical analyses (inferential) to be performed for any end points due to the simple design and purpose of the study.
    End point values
    Total (All participants)
    Number of subjects analysed
    9
    Units: ng*h/mL
        arithmetic mean (standard deviation)
    414.3 ± 263.6
    No statistical analyses for this end point

    Primary: Apparent Oral Clearance (CL/F) for Mirabegron

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    End point title
    Apparent Oral Clearance (CL/F) for Mirabegron [7]
    End point description
    The analysis population was the PKAS.
    End point type
    Primary
    End point timeframe
    Day 1: 0.5-2, 3-5, 6-8 hours (h) postdose, Day 2: 24-32 h, Day 3: 48-56 h, Day 4: 72-80 h, Day 5: 96-104 h, Day 6: 120-128 h, Day 7: 144-152 h (2 samples only for Day 3-7)
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study was written with no planned statistical analyses (inferential) to be performed for any end points due to the simple design and purpose of the study.
    End point values
    Total (All participants)
    Number of subjects analysed
    9
    Units: L/h
        arithmetic mean (standard deviation)
    338 ± 281.5
    No statistical analyses for this end point

    Primary: Apparent volume of Distribution (Vz/F) of Mirabegron

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    End point title
    Apparent volume of Distribution (Vz/F) of Mirabegron [8]
    End point description
    The analysis population was the PKAS.
    End point type
    Primary
    End point timeframe
    Day 1: 0.5-2, 3-5, 6-8 hours (h) postdose, Day 2: 24-32 h, Day 3: 48-56 h, Day 4: 72-80 h, Day 5: 96-104 h, Day 6: 120-128 h, Day 7: 144-152 h (2 samples only for Day 3-7)
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study was written with no planned statistical analyses (inferential) to be performed for any end points due to the simple design and purpose of the study.
    End point values
    Total (All participants)
    Number of subjects analysed
    9
    Units: liters
        arithmetic mean (standard deviation)
    13726 ± 14036
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events

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    End point title
    Number of Participants with Adverse Events
    End point description
    Safety was assessed by collecting AEs, which included abnormalities identified during a medical test (e.g. laboratory tests, vital signs, electrocardiogram, PVR volume, etc.) if the abnormality induced clinical signs or symptoms, needed active intervention, interruption or discontinuation of study medication or was clinically significant. A serious AE (SAE) was an event resulting in death, persistent or significant disability/incapacity or congenital anomaly or birth defect, was life-threatening, required or prolonged hospitalization or was considered medically important A treatment-emergent adverse event (TEAE) was defined as an AE observed after starting administration of the test drug, and no later than 7 days after the last dose of study drug received over the whole investigational period. The analysis population was the SAF.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to 30 days after last dose of study drug (up to 37 days)
    End point values
    Total (All participants)
    Number of subjects analysed
    9
    Units: participants
        Any TEAE
    1
        Drug-related TEAEs
    0
        Deaths
    0
        Serious TEAEs
    0
        Drug-related Serious TEAEs
    0
    No statistical analyses for this end point

    Secondary: Acceptability and Palatability of Mirabegron using a Visual Analog Scale (VAS): Taste

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    End point title
    Acceptability and Palatability of Mirabegron using a Visual Analog Scale (VAS): Taste
    End point description
    Acceptability (drug intake) and palatability (taste and smell) of mirabegron (oral suspension) was assessed using a 5-point VAS questionnaire, which was completed by the participant (or by parent/guardian based on input from the participant). The taste assessment scales ranged from "really bad" to "really good". Not available was regarded as response not available. The analysis population was the SAF.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    Total (All participants)
    Number of subjects analysed
    9
    Units: participants
        Really bad
    4
        Bad
    1
        Not bad, not good
    1
        Good
    2
        Really Good
    1
        Not available
    0
    No statistical analyses for this end point

    Secondary: Acceptability and Palatability of Mirabegron using a Visual Analog Scale (VAS): Smell

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    End point title
    Acceptability and Palatability of Mirabegron using a Visual Analog Scale (VAS): Smell
    End point description
    Acceptability (drug intake) and palatability (taste and smell) of mirabegron was assessed using a 5-point VAS questionnaire, which was completed by the participant (or by parent/guardian based on input from the participant). The smell assessment scales ranged from "really bad" to "really good". Not available was regarded as response not available. The analysis population was the SAF.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    Total (All participants)
    Number of subjects analysed
    8
    Units: participants
        Really bad
    1
        Bad
    1
        Not bad, not good
    4
        Good
    2
        Really good
    0
        Not available
    1
    No statistical analyses for this end point

    Secondary: Acceptability and Palatability of Mirabegron using a Visual Analog Scale (VAS): Drug Intake

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    End point title
    Acceptability and Palatability of Mirabegron using a Visual Analog Scale (VAS): Drug Intake
    End point description
    Acceptability (drug intake) and palatability (taste and smell) of mirabegron was assessed using a 5-point VAS questionnaire, which was completed by the participant (or by parent/guardian based on input from the participant). The smell assessment scales ranged from "really bad" to "really good". Not available was regarded as response not available. The analysis population was the SAF.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    Total (All participants)
    Number of subjects analysed
    9
    Units: participants
        Really difficult
    2
        Difficult
    1
        Not difficult, not easy
    2
        Easy
    2
        Really easy
    2
        Not available
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to 30 days after last dose of study drug (up to 37 days)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Total (All participants)
    Reporting group description
    Participants received a single, weight-based dose of mirabegron on day 1.

    Serious adverse events
    Total (All participants)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 9 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Total (All participants)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 9 (11.11%)
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Nov 2015
    In this global amendment, changes include: (1) The exclusion criterion for pulse rate has been amended to exclude subjects with a (mean) resting pulse rate > 99th percentile. The age-specific centiles used for heart rate in children were based on a systematic review of all studies, which measured these vital signs in healthy children. Taking into account the high variability in pulse rate in children, inclusion would become more feasible if this criterion was followed; (2) The exclusion criteria on systolic blood pressure (SBP) and diastolic blood pressure (DBP) have been combined and amended to exclude subjects with established hypertension and a SBP or DBP greater than the 99th percentile of their normal range determined by sex, age and height, plus 5 mmHg. The previous criteria on blood pressure rates were based on normal ranges in healthy children. However, children with spina bifida have a higher prevalence of hypertension. Therefore, the exclusion criteria had to be amended to allow inclusion of NDO subjects, but still exclude subjects with established hypertension; (3) It was amended that a serious adverse event (SAE) had to be reported to INC Research LCC and not to Astellas Pharma Europe BV; (4) The contact details for the Medical Monitor and the Medical Expert were updated; (5) The list of references was updated; (6) Minor administrative-type changes were implemented.
    08 Jul 2016
    In this global amendment, changes include: (1) The age range for the study population was expanded to include male and female children with NDO from 3 years to less than 12 years of age to enter the study, in order to fulfill the FDA Written Request requirement regarding age range for this study; (2) The protocol was amended to allow a total of 6 subjects with NDO in the study to fulfill an FDA Written Request stipulating that Study 178-CL-203 should include a total of 6 subjects with NDO. By allowing a total of 6 subjects with NDO (adding 3 NDO subjects to the already recruited group of subjects [3 NDO and 3 OAB]), this study was designed to fulfill both the Pediatric Investigation Plan and the FDA Written Request, without the need to setup a new study and expose more subjects. The total number of 9 subjects as indicated in the initially approved protocol was not exceeded. A subgroup analysis for the 6 subjects with NDO was added to the protocol to allow for separate reporting of the NDO data. Because subjects with NDO are more difficult to recruit, the planned study period was also prolonged; (3) The calculation of the estimated glomerular filtration rate (eGFR) according to the modified Schwartz formula was added to the protocol in line with the Advice/Information Request, dated 14 Mar 2016, which was received a few days before the FDA Written Request. The eGFR calculated using the Larsson equation was erroneously not listed amongst the laboratory parameters, but only mentioned in the exclusion criterion for the determination of the eGFR. This omission was corrected; (4)The procedure of reporting of expedited safety reports was updated to reflect the actual process.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    22 Dec 2015
    Recruitment of Study 178-CL-203 was temporarily halted after an abnormal postdose ECG without symptoms, had been observed in 1 subject that caused concern to the investigator. After review of patient data and all available information, the abnormal ECG was attributed to artifacts that render the ECG nonevaluable. No safety concerns had been identified for this subject; therefore, APEB considered it acceptable to resume recruitment in Study 178-CL-203.
    08 Feb 2016

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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