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    Clinical Trial Results:
    An Open-Label, Long-Term Extension, Multi-center, Sequential Dose Titration Study to Assess Safety and Efficacy of Solifenacin Succinate Suspension in Pediatric Subjects with Overactive Bladder (OAB)

    Summary
    EudraCT number
    2011-002047-10
    Trial protocol
    GB   BE   NL   DE   DK   SE   NO   FR  
    Global end of trial date
    08 Oct 2014

    Results information
    Results version number
    v2(current)
    This version publication date
    24 Feb 2018
    First version publication date
    22 Apr 2015
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    905-CL-077
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01655069
    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-000573-PIP01-09
    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
    08 Oct 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Oct 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and efficacy of solifenacin oral suspension once daily in children and adolescents with overactive bladder (OAB).
    Protection of trial subjects
    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
    04 Oct 2012
    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
    Norway: 4
    Country: Number of subjects enrolled
    Poland: 21
    Country: Number of subjects enrolled
    Sweden: 8
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Belgium: 34
    Country: Number of subjects enrolled
    Denmark: 20
    Country: Number of subjects enrolled
    Brazil: 9
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    Mexico: 8
    Country: Number of subjects enrolled
    Philippines: 2
    Country: Number of subjects enrolled
    Serbia: 16
    Country: Number of subjects enrolled
    South Africa: 5
    Country: Number of subjects enrolled
    Turkey: 2
    Country: Number of subjects enrolled
    Ukraine: 3
    Country: Number of subjects enrolled
    United States: 2
    Country: Number of subjects enrolled
    Korea, Republic of: 7
    Worldwide total number of subjects
    148
    EEA total number of subjects
    89
    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)
    119
    Adolescents (12-17 years)
    29
    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
    Participants recruited for this study were children (5 to less than 12 years old) and adolescents (12 to less than 18 years old) with overactive bladder (OAB), who completed the 2-week placebo run-in period and 12-week treatment period of Study 905-CL-076.

    Pre-assignment
    Screening details
    Children and adolescents with OAB, who completed study 905-CL-076, consented to enter this study and fulfilled all the eligibility criteria were enrolled at Week 12/13 (2-3 days after last dose was received during the 905-CL-076 study). The age of participant at informed consent signing in 905-CL-076 determined the age group in this study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    All participants in this extension study received open-label solifenacin. However, the treatment which they received (solifenacin or placebo) in Study 905-CL-076 has been reflected to provide clarity on the baseline status of the participants.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Children Treated With Placebo in 905-CL-076
    Arm description
    Male and female children aged 5 to less than 12 years old who received placebo in Study 905-CL-076 and received open-label solifenacin once daily in this study. The mean time on study drug in this study was 247.9 days in children.
    Arm type
    Experimental

    Investigational medicinal product name
    Solifenacin succinate suspension
    Investigational medicinal product code
    YM905
    Other name
    solifenacin succinate
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Children were given solifenacin liquid suspension once a day orally via syringe along with the completion of a 7-day diary prior to study visit (start of 905-CL-076 to end of 905-CL-077, 14 visits). The initial dose started with the equivalent of 5 mg in adults (referred to as PED5) except for participants who finished Study 905-CL-076 with PED2.5 (active or placebo), who could start at this dose for this study. Doses were calculated per weight determined at the first visit of this study, targeting to have equivalent doses of 2.5, 5, 7.5 and 10 mg doses of solifenacin once daily in adults (referred to as PED2.5, PED5, PED7.5 and PED10). There was a titration period of up to 12 weeks during which the participants would be up or down-titrated based on a combination of efficacy and safety parameters followed by a fixed dose period during which no dose adjustments were allowed.

    Arm title
    Children Treated With Solifenacin in 905-CL-076
    Arm description
    Male and female children aged 5 to less than 12 years old who received solifenacin in Study 905-CL-076 and received open-label solifenacin once daily in this study. The mean time on study drug in this study was 247.9 days in children.
    Arm type
    Experimental

    Investigational medicinal product name
    Solifenacin succinate suspension
    Investigational medicinal product code
    YM905
    Other name
    solifenacin succinate
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Children were given solifenacin liquid suspension once a day orally via syringe along with the completion of a 7-day diary prior to study visit (start of 905-CL-076 to end of 905-CL-077, 14 visits). The initial dose started with the equivalent of 5 mg in adults (referred to as PED5) except for participants who finished Study 905-CL-076 with PED2.5 (active or placebo), who could start at this dose for this study. Doses were calculated per weight determined at the first visit of this study, targeting to have equivalent doses of 2.5, 5, 7.5 and 10 mg doses of solifenacin once daily in adults (referred to as PED2.5, PED5, PED7.5 and PED10). There was a titration period of up to 12 weeks during which the participants would be up or down-titrated based on a combination of efficacy and safety parameters followed by a fixed dose period during which no dose adjustments were allowed.

    Arm title
    Adolescents Treated With Placebo in 905-CL-076
    Arm description
    Male and female adolescents aged 12 to less than 18 years old who received placebo in Study 905-CL-076 and received open-label solifenacin once daily in this study. The mean time on study drug in this study was 240.1 days in adolescents.
    Arm type
    Experimental

    Investigational medicinal product name
    Solifenacin succinate suspension
    Investigational medicinal product code
    YM905
    Other name
    solifenacin succinate
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Adolescents were given solifenacin liquid suspension once a day orally via syringe along with the completion of a 7-day diary prior to study visit (start of 905-CL-076 to end of 905-CL-077, 14 visits). The initial dose started with the equivalent of 5 mg in adults (referred to as PED5) except for participants who finished Study 905-CL-076 with PED2.5 (active or placebo), who could start at this dose for this study. Doses were calculated per weight determined at the first visit of this study, targeting to have equivalent doses of 2.5, 5, 7.5 and 10 mg doses of solifenacin once daily in adults (referred to as PED2.5, PED5, PED7.5 and PED10). There was a titration period of up to 12 weeks during which the participants would be up or down-titrated based on a combination of efficacy and safety parameters followed by a fixed dose period during which no dose adjustments were allowed.

    Arm title
    Adolescents Treated With Solifenacin in 905-CL-076
    Arm description
    Male and female adolescents aged 12 to less than 18 years old who received solifenacin in Study 905- CL-076 and received open-label solifenacin once daily in this study. The mean time on study drug in this study was 240.1 days in adolescents.
    Arm type
    Experimental

    Investigational medicinal product name
    Solifenacin succinate suspension
    Investigational medicinal product code
    YM905
    Other name
    solifenacin succinate
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Adolescents were given solifenacin liquid suspension once a day orally via syringe along with the completion of a 7-day diary prior to study visit (start of 905-CL-076 to end of 905-CL-077, 14 visits). The initial dose started with the equivalent of 5 mg in adults (referred to as PED5) except for participants who finished Study 905-CL-076 with PED2.5 (active or placebo), who could start at this dose for this study. Doses were calculated per weight determined at the first visit of this study, targeting to have equivalent doses of 2.5, 5, 7.5 and 10 mg doses of solifenacin once daily in adults (referred to as PED2.5, PED5, PED7.5 and PED10). There was a titration period of up to 12 weeks during which the participants would be up or down-titrated based on a combination of efficacy and safety parameters followed by a fixed dose period during which no dose adjustments were allowed.

    Number of subjects in period 1
    Children Treated With Placebo in 905-CL-076 Children Treated With Solifenacin in 905-CL-076 Adolescents Treated With Placebo in 905-CL-076 Adolescents Treated With Solifenacin in 905-CL-076
    Started
    61
    58
    14
    15
    Safety Analysis Set (SAF)
    61
    57
    14
    15
    Full Analysis Set (FAS)
    60
    57
    14
    15
    Completed
    53
    46
    12
    11
    Not completed
    8
    12
    2
    4
         Withdrawal by Subject
    2
    3
    -
    -
         No Treatment Needed
    -
    1
    -
    -
         Lack of Efficacy
    -
    1
    -
    -
         Physician Decision
    -
    -
    -
    1
         Adverse Event
    6
    7
    2
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Children Treated With Placebo in 905-CL-076
    Reporting group description
    Male and female children aged 5 to less than 12 years old who received placebo in Study 905-CL-076 and received open-label solifenacin once daily in this study. The mean time on study drug in this study was 247.9 days in children.

    Reporting group title
    Children Treated With Solifenacin in 905-CL-076
    Reporting group description
    Male and female children aged 5 to less than 12 years old who received solifenacin in Study 905-CL-076 and received open-label solifenacin once daily in this study. The mean time on study drug in this study was 247.9 days in children.

    Reporting group title
    Adolescents Treated With Placebo in 905-CL-076
    Reporting group description
    Male and female adolescents aged 12 to less than 18 years old who received placebo in Study 905-CL-076 and received open-label solifenacin once daily in this study. The mean time on study drug in this study was 240.1 days in adolescents.

    Reporting group title
    Adolescents Treated With Solifenacin in 905-CL-076
    Reporting group description
    Male and female adolescents aged 12 to less than 18 years old who received solifenacin in Study 905- CL-076 and received open-label solifenacin once daily in this study. The mean time on study drug in this study was 240.1 days in adolescents.

    Reporting group values
    Children Treated With Placebo in 905-CL-076 Children Treated With Solifenacin in 905-CL-076 Adolescents Treated With Placebo in 905-CL-076 Adolescents Treated With Solifenacin in 905-CL-076 Total
    Number of subjects
    61 58 14 15
    Age categorical
    Units: Subjects
    Age continuous
    The analysis population is Safety Analysis Set (SAF), which consisted of all participants who received at least 1 dose of open-label solifenacin and had any safety data reported after the first dose of open-label solifenacin. The baseline values measured for study 905-CL-076 were used as the baseline values for the present study.
    Units: years
        arithmetic mean (standard deviation)
    7.2 ± 1.6 7.5 ± 1.5 13.9 ± 1.6 14.5 ± 1.8 -
    Gender categorical
    Units:
        Male
    34 23 1 4 62
        Female
    27 34 13 11 85
        Not recorded
    0 1 0 0 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    7 7 2 1 17
        Not Hispanic or Latino
    54 50 12 14 130
        Unknown or Not Reported
    0 1 0 0 1
    Race
    Units: Subjects
        American Indian or Alaska Native
    3 3 1 0 7
        Asian
    4 5 1 1 11
        Native Hawaiian or Other Pacific Islander
    0 0 0 0 0
        Black or African American
    2 2 1 2 7
        White
    49 47 11 12 119
        More than one race
    0 0 0 0 0
        Other
    3 0 0 0 3
        Unknown or Not Reported
    0 1 0 0 1

    End points

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    End points reporting groups
    Reporting group title
    Children Treated With Placebo in 905-CL-076
    Reporting group description
    Male and female children aged 5 to less than 12 years old who received placebo in Study 905-CL-076 and received open-label solifenacin once daily in this study. The mean time on study drug in this study was 247.9 days in children.

    Reporting group title
    Children Treated With Solifenacin in 905-CL-076
    Reporting group description
    Male and female children aged 5 to less than 12 years old who received solifenacin in Study 905-CL-076 and received open-label solifenacin once daily in this study. The mean time on study drug in this study was 247.9 days in children.

    Reporting group title
    Adolescents Treated With Placebo in 905-CL-076
    Reporting group description
    Male and female adolescents aged 12 to less than 18 years old who received placebo in Study 905-CL-076 and received open-label solifenacin once daily in this study. The mean time on study drug in this study was 240.1 days in adolescents.

    Reporting group title
    Adolescents Treated With Solifenacin in 905-CL-076
    Reporting group description
    Male and female adolescents aged 12 to less than 18 years old who received solifenacin in Study 905- CL-076 and received open-label solifenacin once daily in this study. The mean time on study drug in this study was 240.1 days in adolescents.

    Subject analysis set title
    Children (aged 5 to less than 12 years) - FAS
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Children aged 5 to less than 12 years old with OAB who received placebo or solifenacin in 905-CL-076, received a weight-based dose of open-label solifenacin oral suspension once daily for 40 weeks in this study. At the start of the 12-week titration period, the dose was adjusted according to the weight of the participant in order to deliver a plasma drug exposure equivalent to the 2.5 mg, 5 mg, 7.5 mg and 10 mg once daily oral tablet dose of solifenacin in adults. The full analysis set (FAS) consisted of participants who received at least one dose of open-label solifenacin and for at least 1 efficacy variable had a valid baseline value (from 905-CL-076 study) and a valid postbaseline value from diary data completed after the first dose of open-label solifenacin (in 905-CL-077 study).

    Subject analysis set title
    Adolescents (Aged 12 to Less Than 18 Years) - FAS
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Adolescents aged 12 to less than 18 years old with OAB who received placebo or solifenacin in 905-CL-076, received a weight-based dose of open-label solifenacin oral suspension once daily for 40 weeks in this study. At the start of the 12-week titration period, the dose was adjusted according to the weight of the participant in order to deliver a plasma drug exposure equivalent to the 2.5 mg, 5 mg, 7.5 mg and 10 mg once daily oral tablet dose of solifenacin in adults. This group is part of the FAS.

    Subject analysis set title
    Children (aged 5 to less than 12 years old) - SAF
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Children aged 5 to less than 12 years old with OAB who received placebo or solifenacin in 905-CL-076, received a weight-based dose of open-label solifenacin oral suspension once daily for 40 weeks in this study. At the start of the 12-week titration period, the dose was adjusted according to the weight of the participant in order to deliver a plasma drug exposure equivalent to the 2.5 mg, 5 mg, 7.5 mg and 10 mg once daily oral tablet dose of solifenacin in adults. The safety analysis set (SAF) consisted of all participants who received at least 1 dose of open-label solifenacin and had any safety data reported after the first dose of open-label solifenacin.

    Subject analysis set title
    Adolescents (Aged 12 to Less Than 18 Years) - SAF
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Adolescents aged 12 to less than 18 years old with OAB who received placebo or solifenacin in 905-CL-076, received a weight-based dose of open-label solifenacin oral suspension once daily for 40 weeks in this study. At the start of the 12-week titration period, the dose was adjusted according to the weight of the participant in order to deliver a plasma drug exposure equivalent to the 2.5 mg, 5 mg, 7.5 mg and 10 mg once daily oral tablet dose of solifenacin in adults. This group is part of the SAF.

    Primary: Number of Participants With and Severity of Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    Number of Participants With and Severity of Treatment-Emergent Adverse Events (TEAEs) [1]
    End point description
    The investigator assessed the severity of AEs, including abnormal clinical laboratory values, electrocardiogram (ECG), vital signs, as follows: (1) Mild: No disruption of normal daily activities; (2) Moderate: Affect normal daily activities; (3) Severe: Inability to perform daily activities. In participants treated with placebo in Study 905-CL-076, a TEAE was defined as an AE that started/worsened after the first dose of open-label solifenacin in Study 905-CL-077 up to 7 days after the last dose of solifenacin. In participants treated with solifenacin in Study 905-CL-076, a TEAE was defined as an AE that started/worsened after the first dose of double-blind solifenacin in Study 905-CL-076 up to 7 days after last dose of open-label solifenacin in Study 905-CL-077. The analysis population was the SAF. Participants who received placebo and participants who received solifenacin in Study 905-CL-076 are combined for analyses of efficacy and safety in this study.
    End point type
    Primary
    End point timeframe
    From first dose of solifenacin (in Study 905-CL-076 or in current study) up to 7 days after last dose of open-label solifenacin (41 weeks for participants who received placebo in 076 and 53 weeks for those who received solifenacin in 076)
    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: As this was simply an open-label, long-term safety study, there were no statistical analyses performed for the primary safety endpoint. However, statistical analyses were performed for the secondary efficacy endpoints, which used a repeated measures model to provide adjusted means per study period (window) and data is seen in the summary results. There were no comparisons and no p-values that resulted from these analyses.
    End point values
    Children (aged 5 to less than 12 years old) - SAF Adolescents (Aged 12 to Less Than 18 Years) - SAF
    Number of subjects analysed
    118
    29
    Units: participants
    number (not applicable)
        TEAE - Mild
    72
    10
        TEAE - Moderate
    20
    8
        TEAE - Severe
    1
    2
        Any TEAE
    93
    20
        Drug-related TEAEs
    41
    11
        Deaths
    0
    0
        Serious TEAEs
    1
    1
        Drug-related serious TEAEs
    0
    0
        TEAEs leading to discontinuation
    12
    5
        Drug related TEAEs leading to permanent discont.
    12
    4
    No statistical analyses for this end point

    Secondary: Change From Baseline in Mean Number of Incontinence Episodes Per 24 Hours

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    End point title
    Change From Baseline in Mean Number of Incontinence Episodes Per 24 Hours
    End point description
    The mean number of incontinence episodes was based on 7-day diary data completed by participants prior to each visit from the start of 905-CL-076 to the end of 905-CL-077. An Incontinence episode is defined as an episode with any involuntary loss of urine. Data are reported by duration of solifenacin treatment based on the number of days from the date of first dose of solifenacin in either study 905-CL-076 or 905-CL-077 up to and including the study visit. Using equivalent treatment duration periods, data were combined for participants who received placebo and solifenacin in study 905-CL-076 within each age group. The analysis population was the FAS. N indicates the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline (of 905-CL-076 study) and after 3, 6, 9, 12, 24, 40, and 52 weeks of solifenacin treatment
    End point values
    Children (aged 5 to less than 12 years) - FAS Adolescents (Aged 12 to Less Than 18 Years) - FAS
    Number of subjects analysed
    117
    29
    Units: Incontinence episodes
    arithmetic mean (standard error)
        3 weeks solifenacin treatment [N=114, 28]
    -0.92 ± 0.18
    -1.05 ± 0.34
        6 weeks solifenacin treatment [N=116, 26]
    -1.11 ± 0.17
    -1.40 ± 0.33
        9 weeks solifenacin treatment [N=115, 29]
    -1.28 ± 0.19
    -1.48 ± 0.38
        12 weeks solifenacin treatment [N=111, 29]
    -1.39 ± 0.20
    -1.66 ± 0.39
        24 weeks solifenacin treatment [N=108, 27]
    -1.61 ± 0.19
    -1.73 ± 0.39
        40 weeks solifenacin treatment [N=97, 23]
    -1.66 ± 0.23
    -1.49 ± 0.36
        52 weeks solifenacin treatment [N=44, 11]
    -1.56 ± 0.22
    -1.34 ± 0.38
    No statistical analyses for this end point

    Secondary: Change from Baseline in Mean Number of Incontinence Episodes per 24 Hours – Repeated Measures ANCOVA

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    End point title
    Change from Baseline in Mean Number of Incontinence Episodes per 24 Hours – Repeated Measures ANCOVA
    End point description
    Repeated measures ANCOVA (analysis of covariance) was used in this analysis, which included double-blind and/or open-label solifenacin treatment duration, gender, geographic region and randomized treatment group in Study 905-CL-076 as fixed effects, baseline as a covariate and "duration" repeated within participant. The analysis population was the FAS. N indicates the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline (of 905-CL-076 study) and after 3, 6, 9, 12, 24, 40, and 52 weeks of solifenacin treatment
    End point values
    Children (aged 5 to less than 12 years) - FAS Children (aged 5 to less than 12 years old) - SAF
    Number of subjects analysed
    117
    29
    Units: Incontinence episodes
    least squares mean (standard error)
        3 weeks solifenacin treatment [N=114, 28]
    -0.95 ± 0.12
    -0.93 ± 0.35
        6 weeks solifenacin treatment [N=116, 26]
    -1.11 ± 0.12
    -1.38 ± 0.36
        9 weeks solifenacin treatment [N=115, 29]
    -1.26 ± 0.13
    -1.40 ± 0.35
        12 weeks solifenacin treatment [N=111, 29]
    -1.39 ± 0.12
    -1.58 ± 0.35
        24 weeks solifenacin treatment [N=108, 27]
    -1.54 ± 0.11
    -1.80 ± 0.35
        40 weeks solifenacin treatment [N=97, 23]
    -1.56 ± 0.13
    -1.57 ± 0.36
        52 weeks solifenacin treatment [N=44, 11]
    -1.93 ± 0.13
    -2.00 ± 0.42
    No statistical analyses for this end point

    Secondary: Change from Baseline in Number of Dry (Incontinence-free) Days per 7 Days

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    End point title
    Change from Baseline in Number of Dry (Incontinence-free) Days per 7 Days
    End point description
    The number of dry (incontinence-free) days was based on 7-day diary data completed by participants prior to each visit from start of 905-C L-076 to end of 905-C L-077. An incontinence-free day is a day without any incontinence episodes. Data are reported by duration of solifenacin treatment based on the number of days from the date of first dose of solifenacin in either study 905-CL-076 or 905-CL-077 up to and including the study visit. Using equivalent treatment duration periods, data were combined for participants who received placebo and solifenacin in study 905-CL-076 within each age group. The analysis population was the FAS. N indicates the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline (of 905-CL-076 study) and after 3, 6, 9, 12, 24, 40, and 52 weeks of solifenacin treatment
    End point values
    Children (aged 5 to less than 12 years) - FAS Adolescents (Aged 12 to Less Than 18 Years) - FAS
    Number of subjects analysed
    117
    29
    Units: days
    arithmetic mean (standard error)
        3 weeks solifenacin treatment [N=114, 28]
    1.17 ± 0.16
    1.69 ± 0.53
        6 weeks solifenacin treatment [N=116, 26]
    1.28 ± 0.19
    2.21 ± 0.56
        9 weeks solifenacin treatment [N=115, 29]
    1.59 ± 0.21
    1.94 ± 0.50
        12 weeks solifenacin treatment [N=111, 29]
    1.60 ± 0.21
    2.89 ± 0.51
        24 weeks solifenacin treatment [N=108, 27
    2.09 ± 0.22
    3.19 ± 0.51
        40 weeks solifenacin treatment [N=97, 23]
    2.15 ± 0.25
    2.71 ± 0.59
        52 weeks solifenacin treatment [N=44, 11]
    2.57 ± 0.40
    3.27 ± 0.73
    No statistical analyses for this end point

    Secondary: Change from Baseline in Number of Dry (Incontinence-free) Days per 7 Days – Repeated Measures ANCOVA

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    End point title
    Change from Baseline in Number of Dry (Incontinence-free) Days per 7 Days – Repeated Measures ANCOVA
    End point description
    Repeated measures ANCOVA (analysis of covariance) was used in this analysis, which included double-blind and/or open-label solifenacin treatment duration, gender, geographic region and randomized treatment group in Study 905-CL-076 as fixed effects, baseline as a covariate and "duration" repeated within participant. The analysis population was the FAS. N indicates the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline (of 905-CL-076 study) and after 3, 6, 9, 12, 24, 40, and 52 weeks of solifenacin treatment
    End point values
    Children (aged 5 to less than 12 years) - FAS Adolescents (Aged 12 to Less Than 18 Years) - FAS
    Number of subjects analysed
    117
    29
    Units: days
    least squares mean (standard error)
        3 weeks solifenacin treatment [N=114, 28]
    1.35 ± 0.19
    1.53 ± 0.69
        6 weeks solifenacin treatment [N=116, 26]
    1.43 ± 0.20
    1.90 ± 0.70
        9 weeks solifenacin treatment [N=115, 29]
    1.72 ± 0.22
    1.75 ± 0.69
        12 weeks solifenacin treatment [N=111, 29]
    1.80 ± 0.22
    2.69 ± 0.69
        24 weeks solifenacin treatment [N=108, 27]
    2.21 ± 0.23
    3.07 ± 0.69
        40 weeks solifenacin treatment [N=97, 23]
    2.28 ± 0.25
    2.45 ± 0.71
        52 weeks solifenacin treatment [N=44, 11]
    2.84 ± 0.33
    3.93 ± 0.81
    No statistical analyses for this end point

    Secondary: Change from Baseline in Mean Number of Micturitions per 24 Hours

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    End point title
    Change from Baseline in Mean Number of Micturitions per 24 Hours
    End point description
    The mean number of micturitions (urinations) was based on 7-day diary data completed by participants prior to each visit from start of 905-CL-076 to end of 905-CL-077. Data are reported by duration of solifenacin treatment based on the number of days from the date of first dose of solifenacin in either study 905-CL-076 or 905-CL-077 up to and including the study visit. Using equivalent treatment duration periods, data were combined for participants who received placebo and solifenacin in study 905-CL-076 within each age group. The analysis population was the FAS. N indicates the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline (of 905-CL-076 study) and after 3, 6, 9, 12, 24, 40, and 52 weeks of solifenacin treatment
    End point values
    Children (aged 5 to less than 12 years) - FAS Adolescents (Aged 12 to Less Than 18 Years) - FAS
    Number of subjects analysed
    117
    29
    Units: Micturitions
    arithmetic mean (standard error)
        3 weeks solifenacin treatment [N=114, 28]
    -0.78 ± 0.18
    -1.29 ± 0.39
        6 weeks solifenacin treatment [N=116, 26]
    -0.96 ± 0.20
    -1.38 ± 0.63
        9 weeks solifenacin treatment [N=115, 29]
    -1.15 ± 0.20
    -1.15 ± 0.61
        12 weeks solifenacin treatment [N=111, 29]
    -1.09 ± 0.21
    -1.24 ± 0.49
        24 weeks solifenacin treatment [N=108, 27]
    -1.42 ± 0.21
    -1.01 ± 0.49
        40 weeks solifenacin treatment [N=97, 23]
    -1.43 ± 0.24
    -1.39 ± 0.75
        52 weeks solifenacin treatment [N=44, 11]
    -1.80 ± 0.43
    -0.81 ± 0.34
    No statistical analyses for this end point

    Secondary: Change from Baseline in Mean Number of Micturitions per 24 Hours – Repeated Measures ANCOVA

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    End point title
    Change from Baseline in Mean Number of Micturitions per 24 Hours – Repeated Measures ANCOVA
    End point description
    Repeated measures ANCOVA (analysis of covariance) was used in this analysis, which included double-blind and/or open-label solifenacin treatment duration, gender, geographic region and randomized treatment group in Study 905-CL-076 as fixed effects, baseline as a covariate and "duration" repeated within participant. The analysis population was the FAS. N indicates the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline (of 905-CL-076 study) and after 3, 6, 9, 12, 24, 40, and 52 weeks of solifenacin treatment
    End point values
    Children (aged 5 to less than 12 years) - FAS Adolescents (Aged 12 to Less Than 18 Years) - FAS
    Number of subjects analysed
    117
    29
    Units: Micturitions
    least squares mean (standard error)
        3 weeks solifenacin treatment [N=114, 28]
    -0.98 ± 0.15
    -0.93 ± 0.39
        6 weeks solifenacin treatment [N=116, 26]
    -1.15 ± 0.15
    -0.94 ± 0.26
        9 weeks solifenacin treatment [N=115, 29]
    -1.31 ± 0.15
    -0.81 ± 0.31
        12 weeks solifenacin treatment [N=111, 29]
    -1.22 ± 0.15
    -0.91 ± 0.30
        24 weeks solifenacin treatment [N=108, 27]
    -1.50 ± 0.15
    -0.71 ± 0.52
        40 weeks solifenacin treatment [N=97, 23]
    -1.52 ± 0.16
    -1.18 ± 0.36
        52 weeks solifenacin treatment [N=44, 11]
    -1.83 ± 0.20
    -1.79 ± 0.38
    No statistical analyses for this end point

    Secondary: Change from Baseline in Mean Number of Grade 3 or 4 Urgency Episodes per 24 Hours in Adolescents

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    End point title
    Change from Baseline in Mean Number of Grade 3 or 4 Urgency Episodes per 24 Hours in Adolescents
    End point description
    Adolescent participants were also asked to record urgencies for at least 2 of the 7 diary days using the Perception of Intensity of Urgency Scale (PPIUS): (0 - no urgency, 1 - mild urgency, 2 - moderate urgency, 3 - severe urgency, 4 - urge incontinence). This data is based on 7-day diary data completed by participants prior to each visit from the start of 905-CL-076 to the end of 905-CL-077. Data are reported by duration of solifenacin treatment based on the number of days from the date of first dose of solifenacin in either study 905-CL-076 or 905-CL-077 up to and including the study visit. Using equivalent treatment duration periods, data were combined for participants who received placebo and solifenacin in study 905-CL-076 within each age group. The analysis population was the FAS. N indicates the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline (of 905-CL-076 study) and after 3, 6, 9, 12, 24, 40, and 52 weeks of solifenacin treatment
    End point values
    Adolescents (Aged 12 to Less Than 18 Years) - FAS
    Number of subjects analysed
    29
    Units: Urgency episodes
    arithmetic mean (standard error)
        3 weeks solifenacin treatment [N=27]
    -0.79 ± 0.26
        6 weeks solifenacin treatment [N=25]
    -1.36 ± 0.53
        9 weeks solifenacin treatment [N=27]
    -1.15 ± 0.54
        12 weeks solifenacin treatment [N=28]
    -1.31 ± 0.38
        24 weeks solifenacin treatment [N=26]
    -1.11 ± 0.47
        40 weeks solifenacin treatment [N=22]
    -2.18 ± 0.81
        52 weeks solifenacin treatment [N=10]
    -1.87 ± 0.44
    No statistical analyses for this end point

    Secondary: Change from Baseline in Mean Number of Grade 3 or 4 Urgency Episodes per 24 Hours in Adolescents – Repeated Measures ANCOVA

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    End point title
    Change from Baseline in Mean Number of Grade 3 or 4 Urgency Episodes per 24 Hours in Adolescents – Repeated Measures ANCOVA
    End point description
    Repeated measures ANCOVA (analysis of covariance) was used in this analysis, which included double-blind and/or open-label solifenacin treatment duration, gender, geographic region and randomized treatment group in Study 905-CL-076 as fixed effects, baseline as a covariate and "duration" repeated within participant. The analysis population was the FAS. N indicates the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline (of 905-CL-076 study) and after 3, 6, 9, 12, 24, 40, and 52 weeks of solifenacin treatment
    End point values
    Adolescents (Aged 12 to Less Than 18 Years) - FAS
    Number of subjects analysed
    28
    Units: Urgency episodes
    least squares mean (standard error)
        3 weeks solifenacin treatment [N=27]
    -0.74 ± 0.46
        6 weeks solifenacin treatment [N=25]
    -1.30 ± 0.47
        9 weeks solifenacin treatment [N=27]
    -1.14 ± 0.47
        12 weeks solifenacin treatment [N=28]
    -1.28 ± 0.46
        24 weeks solifenacin treatment [N=26]
    -1.04 ± 0.46
        40 weeks solifenacin treatment [N=22]
    -1.96 ± 0.49
        52 weeks solifenacin treatment [N=10]
    -2.20 ± 0.65
    No statistical analyses for this end point

    Secondary: Change from Baseline to Final Visit in Postvoid Residual (PVR) Volume

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    End point title
    Change from Baseline to Final Visit in Postvoid Residual (PVR) Volume
    End point description
    PVR volume was assessed by ultrasonography or bladder scan during 905-CL-076 and 905-CL-077. The value reported is the last PVR volume value after first dose of solifenacin up to 52 weeks.
    End point type
    Secondary
    End point timeframe
    Baseline (of 905-CL-076 study) to final visit (the most recent value after first dose of solifenacin up to 40 weeks for participants who received placebo in 076 and 52 weeks for those who received solifenacin in 076)
    End point values
    Children (aged 5 to less than 12 years old) - SAF Adolescents (Aged 12 to Less Than 18 Years) - SAF
    Number of subjects analysed
    118
    29
    Units: mL
        arithmetic mean (standard error)
    1.3 ± 11.9
    0.7 ± 8.8
    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 solifenacin (in Study 905-CL-076 or in current study) up to 7 days after last dose of open-label solifenacin (41 weeks for participants who received placebo in 076 and 53 weeks for those who received solifenacin in 076).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    Children (Aged 5 to Less Than 12 Years)
    Reporting group description
    Children aged 5 to less than 12 years old with OAB who received placebo or solifenacin in 905-CL-076, received a weight-based dose of open-label solifenacin oral suspension once daily for 40 weeks in this study. At the start of the 12-week titration period, the dose was adjusted according to the weight of the participant in order to deliver a plasma drug exposure equivalent to the 2.5 mg, 5 mg, 7.5 mg and 10 mg once daily oral tablet dose of solifenacin in adults.

    Reporting group title
    Adolescents (Aged 12 to Less Than 18 Years)
    Reporting group description
    Adolescents aged 12 to less than 18 years old with OAB who received placebo or solifenacin in 905-CL-076, received a weight-based dose of open-label solifenacin oral suspension once daily for 40 weeks in this study. At the start of the 12-week titration period, the dose was adjusted according to the weight of the participant in order to deliver a plasma drug exposure equivalent to the 2.5 mg, 5 mg, 7.5 mg and 10 mg once daily oral tablet dose of solifenacin in adults.

    Serious adverse events
    Children (Aged 5 to Less Than 12 Years) Adolescents (Aged 12 to Less Than 18 Years)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 118 (0.85%)
    1 / 29 (3.45%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Children (Aged 5 to Less Than 12 Years) Adolescents (Aged 12 to Less Than 18 Years)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    93 / 118 (78.81%)
    29 / 29 (100.00%)
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    10 / 118 (8.47%)
    4 / 29 (13.79%)
         occurrences all number
    10
    4
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    1 / 118 (0.85%)
    2 / 29 (6.90%)
         occurrences all number
    1
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 118 (13.56%)
    1 / 29 (3.45%)
         occurrences all number
    21
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    9 / 118 (7.63%)
    0 / 29 (0.00%)
         occurrences all number
    11
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    7 / 118 (5.93%)
    1 / 29 (3.45%)
         occurrences all number
    10
    1
    Constipation
         subjects affected / exposed
    16 / 118 (13.56%)
    1 / 29 (3.45%)
         occurrences all number
    19
    1
    Diarrhoea
         subjects affected / exposed
    7 / 118 (5.93%)
    2 / 29 (6.90%)
         occurrences all number
    7
    3
    Abdominal pain
         subjects affected / exposed
    3 / 118 (2.54%)
    2 / 29 (6.90%)
         occurrences all number
    3
    2
    Nausea
         subjects affected / exposed
    3 / 118 (2.54%)
    3 / 29 (10.34%)
         occurrences all number
    4
    3
    Infections and infestations
    Escherichia urinary tract infection
         subjects affected / exposed
    7 / 118 (5.93%)
    2 / 29 (6.90%)
         occurrences all number
    9
    4
    Gastroenteritis
         subjects affected / exposed
    11 / 118 (9.32%)
    2 / 29 (6.90%)
         occurrences all number
    11
    2
    Nasopharyngitis
         subjects affected / exposed
    16 / 118 (13.56%)
    4 / 29 (13.79%)
         occurrences all number
    21
    4
    Urinary tract infection
         subjects affected / exposed
    6 / 118 (5.08%)
    2 / 29 (6.90%)
         occurrences all number
    8
    2
    Influenza
         subjects affected / exposed
    4 / 118 (3.39%)
    3 / 29 (10.34%)
         occurrences all number
    4
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Apr 2012
    Several changes to dose, risk-benefit assessment and other statistical analyses were made to align the current protocol with the updated opinion of the Paediatric Committee (PDCO) of the EMA (published as: opinion of the PDCO on the acceptance of a modification of an agreed PIP (EMEA-000573-PIP01-09-M01). Other changes were: increase in number of sites, inclusion criterion 3 was updated to reflect differences in national legislation with regard to informed consent (IC) for adolescents in clinical studies, inclusion criterion 4 was updated to provide more clarity on who should be subject to birth control, the discontinuation criterion relating to the QT interval was updated to reflect the use of QT interval corrected for heart rate by Bazett formula (QTcB), acute urinary retention (AUR) was defined as “urinary retention for which an intervention is required or has taken place” to provide clarification to investigators, it was added that no important identified risks for solifenacin had been captured in a pediatric population to date, a requirement for leucocyturia, defined as white blood cell (WBC) count > 100/mcL as a prior step to urine culture was added, Tri- and tetracyclic antidepressants were added to the list of restricted medication, the recording of the urgency grade in adolescents according to the PPIUS was reduced from 7 days per diary period to 2 days, the requirement of a sitting position of the patient for these assessments and the use of the same arm for every blood pressure measurement was specified to further standardize the measurement, instructions were changed to repeat the PVR volume assessment only once when the initial PVR volume was > 20 mL, specifications (comparison to age-appropriate norms) were added to aid data interpretation and ensure consistency in the assessment and evaluation of vital signs, laboratory results and height and weight, the SAE reporting instruction was slightly rephrased to provide better guidance to investigators.
    19 Jul 2012
    After finalization and first regulatory submissions of Substantial Amendment 1 dated 20 Apr 2012 (Protocol version 2.0), inconsistencies were identified in the changes made to the respective paragraphs across the protocol (e.g., changes made only in the synopsis part of the protocol, but not in the body text of the protocol). These were corrected in Protocol version 2.1, including Substantial Amendment 1 dated 20 Apr 2012.
    07 Sep 2012
    Germany country-specific amendment: A local substantial Amendment 1 dated 7 Sep 2012 was issued. This amendment corresponds to the global substantial Amendment 2 dated 30 Oct 2012. In addition, the pharmacokinetic samples scheduled to be taken in Study 905-CL-076 were instead to be taken in this unblinded extension Study 905-CL-077. No patients were enrolled at the study sites in Germany.
    24 Sep 2012
    The Netherlands country-specific amendment: A local substantial Amendment 1 dated 24 Sep 2012 was issued. This amendment corresponds to the global substantial Amendment 2 dated 30 Oct 2012. No patients were enrolled at the study sites in the Netherlands before this amendment was implemented.
    17 Oct 2012
    UK country-specific amendment: A local substantial Amendment 1 dated 17 Oct 2012 was issued. This amendment corresponds to the global substantial Amendment 2 dated 30 Oct 2012. No patients were enrolled at the study sites in the UK before this amendment was implemented.
    30 Oct 2012
    This global amendment was prepared and submitted after approval of the country specific amendments. The sections “Study Design”,“Dose Rationale”, “Discontinuation Criteria for Individual Subjects”, “Dose/Dose Regimen and Administration Period”, and “Increase or Reduction in Dose of the Study Drugs” were updated to reflect the inclusion of the possibility to down titrate to “no treatment” (i.e., interruption of treatment) for a period of 3 weeks and the subsequent possibility to discontinue the study in case no symptoms of OAB occur in this period. This amendment was developed to limit unnecessary exposure to solifenacin in patients who did no longer require treatment with OAB medication. The objective was to identify patients who did not require treatment with OAB medication.
    23 Sep 2013
    Several changes were made to align current protocol with the updated opinion of the PDCO of the EMA regarding solifenacin (published as: opinion of the Paediatric Committee on the acceptance of a modification of an agreed PIP [EMEA-000573-PIP01-09-M04]). Other changes were: the number of patients was changed from at least 120 patients (at least 60 children and 60 adolescents) to at least 120 patients (at least 100 children and at least 20 adolescents) evaluable for the primary endpoint, an additional inclusion criterion was added “Subject agrees not to participate in another interventional study while on treatment”, as well as the main analyses of safety and efficacy, which were performed separately in both children and adolescent cohorts, further statistical methods were described that used the data from the patients in this study together with data from adults in the solifenacin phase 3 program, to interpolate between children and adults, and provide estimates of treatment effects in adolescents based on an extensive data set, in assessing the PVR volume, the instruction that the bladder was to be emptied when it was initially filled > 50% of the bladder capacity for age was changed such that the bladder should only be emptied when it was initially filled with preferably > 50% of the bladder capacity for age, the calculation of the baseline QTcB mean was revised to use the average of the QTcB means of the ECG triplicates from the 2 prerandomization visits (i.e., visits 2 and 3) of Study 905-CL-076 instead of using the QTcB mean from visit 3 ECG triplicates only, the definition of SAE was reworded for clarification and the events of interest that may require expedited reporting and/or safety evaluation were defined and categorized.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    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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