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    Clinical Trial Results:
    Onabotulinum toxin-A versus extended release tolterodine in the management of idiopathic overactive bladder in children: A pilot randomised controlled trial (OVERT)

    Summary
    EudraCT number
    2014-001068-36
    Trial protocol
    GB  
    Global end of trial date
    06 Mar 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Mar 2019
    First version publication date
    13 Mar 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    R03465
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    RfPB: PB-PG-0712-28094
    Sponsors
    Sponsor organisation name
    Manchester University NHS Foundation Trust
    Sponsor organisation address
    1st Floor Nowgen Building, 29 Grafton Street, Manchester, United Kingdom, M13 9WU
    Public contact
    Lynne Webster, Manchester University NHS Foundation Trust, +44 01612764125, lynne.webster@mft.nhs.uk
    Scientific contact
    Lynne Webster, Manchester University NHS Foundation Trust, +44 01612764125, lynne.webster@mft.nhs.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    06 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Jun 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The principle objective of the pilot study is to ensure that a full randomised control trial (RCT) is logistically feasible and acceptable to patients. We will collect the following information to allow us to plan the main trial: 1. Eligibility rate of the patients screened - how many meet the eligibility criteria. 2. Recruitment rate of the eligible patients - how many consent to take part in the study. 3. Acceptability of randomisation to those patients consenting - how many are actually randomised, and of those randomised how many receive the treatment allocated. 4. Primary outcome data for the power calculation. 5. Loss to follow up rate of the patients randomised how many children will continue to be willing to participate throughout the study 6. Acceptability and suitability of urodynamic studies to assess secondary outcome measures
    Protection of trial subjects
    A urodynamic study will be done as part of baseline assessment. This is a routine practice in patients who are not responding to standard medical treatment as is the case with our participants. Urodynamic study requires a general anaesthetic as a standard procedure. Parental feelings were explored at the focus group meeting and in the questionnaire with regard to the requirement for a general anaesthetic. While this is of some concern they accept that this is necessary. The study design requires a urodynamic study under general anaesthetic at 6 weeks after initiation of treatment which is not always performed in routine clinical practice. The urodynamic study is felt to be necessary to assess the response to treatment in an objective way. Parental feelings were explored at the focus group meeting and in the questionnaire with regard to the requirement for a second general anaesthetic and urodynamic study. Parents and patients with experience of having a urodynamic study reported minimal concerns. Parents accepted that urodynamic data was required to objectively measure any improvement in bladder function. The study group considered all options before formulating the current research plan. While a double blind randomised study is ideal, in our view performing a blinded study comparing onaBtA with placebo injections at cystoscopy would be unethical considering the general anaesthetic involved. Hence we are proposing this as a non blinded study comparing onaBtA with extended release tolterodine. Extended release tolterodine is dispensed as a capsule. Younger children may not be able to swallow a capsule. We have checked with the pharmacist and the capsules can be opened and granules can be taken with fluid/yoghurt/jelly making it feasible for all age groups to have the medication.
    Background therapy
    none
    Evidence for comparator
    The decision to compare the effectiveness of Botox® with Tolterodine XL (extended release tolterodine) was taken, as most patients would either have not been commenced on Tolterodine XL or may have had tolterodine at a lower dose. However there would be a tiny proportion that may have had Tolterodine XL at 4mg dose. A 4mg dose would be applicable to all children in the study group and in children who cannot swallow a capsule it is possible to open the capsule without affecting the pharmacokinetics (2010, The NEWT Guidelines for Administration of Medication to Patients with Enteral Feeding Tubes or Swallowing Difficulties).
    Actual start date of recruitment
    11 Feb 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 46
    Worldwide total number of subjects
    46
    EEA total number of subjects
    46
    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)
    35
    Adolescents (12-17 years)
    11
    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
    Recruitment took place at Manchester Royal Infirmary. PIC sites were added in an amendment however this came in too late to have an impact as only one patient was recruited through the PICs. Recruitment to screening phase began in February 2015 and the first patient was randomised in August 2015; 46 patients were randomised in total.

    Pre-assignment
    Screening details
    There were a total of 98 patients assessed for eligibility. Eighty-five patients (87%) were eligible to proceed to the screening phase and the parents of 62 of these patients (73%) were willing to provide consent. Forty-six patients remained eligible at the end of the screening stage (74%) and went on to be randomised.

    Period 1
    Period 1 title
    Full trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Tolterodine
    Arm description
    Extended-release Tolterodine XL 4mg orally
    Arm type
    Active comparator

    Investigational medicinal product name
    Tolterodine XL
    Investigational medicinal product code
    Other name
    Tolterodine, Extended-release Tolterodine
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    4mg extended-release Tolterodine XL to be taken once daily via oral administration for the duration of the trial

    Arm title
    Botox
    Arm description
    Single administration of Onabotulinum Toxin A (onaBtA; 5 IU/Kg, maximum 150 IU) into the bladder
    Arm type
    Experimental

    Investigational medicinal product name
    Onabotulinum toxin A
    Investigational medicinal product code
    Other name
    Botox
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravesical use
    Dosage and administration details
    A single dose of 5 IU/kg up to a maximum of 150 IU constituted in 0.9% saline to a dilution of 10 IU per ml. Under general anaesthetic multiple injections are given intravesically in the submucosal layer of the bladder. A trigone sparing technique under the guidance of rigid cystoscopy is used.

    Number of subjects in period 1
    Tolterodine Botox
    Started
    24
    22
    Completed
    24
    20
    Not completed
    0
    2
         Lost to follow-up
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tolterodine
    Reporting group description
    Extended-release Tolterodine XL 4mg orally

    Reporting group title
    Botox
    Reporting group description
    Single administration of Onabotulinum Toxin A (onaBtA; 5 IU/Kg, maximum 150 IU) into the bladder

    Reporting group values
    Tolterodine Botox Total
    Number of subjects
    24 22 46
    Age categorical
    Units: Subjects
        Children (2-11 years)
    17 18 35
        Adolescents (12-17 years)
    7 4 11
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    10.2 ( 2.6 ) 10.2 ( 2.1 ) -
    Gender categorical
    Units: Subjects
        Female
    16 13 29
        Male
    8 9 17
    Previous bladder training
    Units: Subjects
        Yes
    22 21 43
        No
    2 1 3
    Urinalysis
    Units: Subjects
        Normal
    18 18 36
        Abnormal
    6 4 10
    Urodynamic study: presence of detrusor overactivity
    Units: Subjects
        Yes
    21 19 40
        No
    3 3 6
    Prescribed prophylactic antibiotics
    Units: Subjects
        Yes
    23 22 45
        No
    1 0 1
    Overall assessment: reduced capacity
    Units: Subjects
        Yes
    17 14 31
        No
    7 8 15
    Overall assessment: reduced compliance
    Units: Subjects
        Yes
    11 10 21
        No
    13 12 25
    Overall assessment: presence of detrusor overactivity
    Units: Subjects
        Yes
    21 19 40
        No
    3 3 6
    SAQ: did nocturnal enuresis occur?
    Units: Subjects
        Yes
    19 15 34
        No
    3 2 5
        Missing
    2 5 7
    Height
    Units: cm
        arithmetic mean (standard deviation)
    136.4 ( 15.3 ) 138.1 ( 12.9 ) -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    35.7 ( 15.8 ) 36.9 ( 17.2 ) -
    Uroflowmetry 1: maximum voided volume
    Units: ml
        arithmetic mean (standard deviation)
    147.9 ( 95.0 ) 130.2 ( 70.1 ) -
    Uroflowmetry 1: post-void residual volume
    Units: ml
        arithmetic mean (standard deviation)
    21.5 ( 27.8 ) 23.7 ( 26.0 ) -
    Uroflowmetry 2: maximum voided volume
    Units: ml
        arithmetic mean (standard deviation)
    156.9 ( 105.4 ) 146.0 ( 109.0 ) -
    Uroflowmetry 2: post-void residual volume
    Units: ml
        arithmetic mean (standard deviation)
    34.5 ( 39.0 ) 15.9 ( 22.8 ) -
    Uroflowmetry 3: maximum voided volume
    Units: ml
        arithmetic mean (standard deviation)
    165.2 ( 104.6 ) 110.3 ( 76.5 ) -
    Uroflowmetry 3: post-void residual volume
    Units: ml
        arithmetic mean (standard deviation)
    13.5 ( 24.4 ) 8.5 ( 15.0 ) -
    Urodynamic study: maximum cystometric capacity
    Units: ml
        arithmetic mean (standard deviation)
    218.0 ( 104.0 ) 246.2 ( 105.8 ) -
    Urodynamic study: maximum detrusor pressure during detrusor overactivity
    Units: cm of water
        arithmetic mean (standard deviation)
    53.4 ( 43.5 ) 35.1 ( 16.5 ) -
    Urodynamic study: number of overactive contractions
    Units: contractions
        arithmetic mean (standard deviation)
    6.2 ( 3.7 ) 7.3 ( 5.5 ) -
    Urodynamic study: maximum detrusor pressure during storage phase
    Units: cm of water
        arithmetic mean (standard deviation)
    14.9 ( 7.5 ) 17.1 ( 11.1 ) -
    Urodynamic study: bladder compliance
    Units: ml/cm water
        arithmetic mean (standard deviation)
    21.6 ( 20.8 ) 19.6 ( 15.6 ) -
    Urodynamic study: post-void residual urine
    Units: ml
        arithmetic mean (standard deviation)
    7.0 ( 17.7 ) 10.0 ( 22.4 ) -
    SAQ: number of wetting episodes per day
    Units: wetting episodes per day
        arithmetic mean (standard deviation)
    2.6 ( 1.3 ) 2.7 ( 2.0 ) -
    SAQ: number of wees per day
    Units: wees per day
        arithmetic mean (standard deviation)
    8.4 ( 2.8 ) 7.6 ( 1.6 ) -
    SAQ: number of episodes of urinary urgency per day
    Units: episodes per day
        arithmetic mean (standard deviation)
    4.2 ( 2.0 ) 3.7 ( 1.9 ) -
    SAQ: number of episodes of nocturia per day
    Units: episodes per day
        arithmetic mean (standard deviation)
    0.6 ( 0.8 ) 0.4 ( 0.7 ) -

    End points

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    End points reporting groups
    Reporting group title
    Tolterodine
    Reporting group description
    Extended-release Tolterodine XL 4mg orally

    Reporting group title
    Botox
    Reporting group description
    Single administration of Onabotulinum Toxin A (onaBtA; 5 IU/Kg, maximum 150 IU) into the bladder

    Primary: Six-week SAQ: number of wetting episodes per day

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    End point title
    Six-week SAQ: number of wetting episodes per day [1]
    End point description
    End point type
    Primary
    End point timeframe
    Week 6 post-randomisation
    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: Pilot trial - descriptive statistics only
    End point values
    Tolterodine Botox
    Number of subjects analysed
    22
    15
    Units: episodes per day
        arithmetic mean (standard deviation)
    1.6 ( 1.0 )
    1.4 ( 1.7 )
    No statistical analyses for this end point

    Secondary: Six-week urodynamic study: maximum cystometric capacity

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    End point title
    Six-week urodynamic study: maximum cystometric capacity
    End point description
    End point type
    Secondary
    End point timeframe
    Week 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    18
    17
    Units: ml
        arithmetic mean (standard deviation)
    252.9 ( 97.7 )
    336.4 ( 166.4 )
    No statistical analyses for this end point

    Secondary: Six-week urodynamic study: detrusor overactivity

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    End point title
    Six-week urodynamic study: detrusor overactivity
    End point description
    End point type
    Secondary
    End point timeframe
    Week 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    18
    17
    Units: patients
        Present
    16
    8
        Absent
    2
    9
    No statistical analyses for this end point

    Secondary: Six-week urodynamic study: maximum detrusor pressure during storage phase

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    End point title
    Six-week urodynamic study: maximum detrusor pressure during storage phase
    End point description
    End point type
    Secondary
    End point timeframe
    Week 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    18
    17
    Units: cm of water
        arithmetic mean (standard deviation)
    15.3 ( 11.4 )
    16.2 ( 8.8 )
    No statistical analyses for this end point

    Secondary: Six-week urodynamic study: bladder compliance

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    End point title
    Six-week urodynamic study: bladder compliance
    End point description
    End point type
    Secondary
    End point timeframe
    Week 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    18
    17
    Units: ml/cm water
        arithmetic mean (standard deviation)
    26.9 ( 40.8 )
    28.9 ( 25.1 )
    No statistical analyses for this end point

    Secondary: Six-week urodynamic study: post-void residual urine

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    End point title
    Six-week urodynamic study: post-void residual urine
    End point description
    End point type
    Secondary
    End point timeframe
    Week 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    18
    17
    Units: ml
        arithmetic mean (standard deviation)
    16.6 ( 23.8 )
    61.2 ( 54.0 )
    No statistical analyses for this end point

    Secondary: Three-month SAQ: number of wetting episodes per day

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    End point title
    Three-month SAQ: number of wetting episodes per day
    End point description
    End point type
    Secondary
    End point timeframe
    Month 3 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    19
    13
    Units: episodes per day
        arithmetic mean (standard deviation)
    1.5 ( 1.1 )
    1.9 ( 1.8 )
    No statistical analyses for this end point

    Secondary: Six-month SAQ: number of wetting episodes per day

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    End point title
    Six-month SAQ: number of wetting episodes per day
    End point description
    End point type
    Secondary
    End point timeframe
    Month 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    17
    10
    Units: episodes per day
        arithmetic mean (standard deviation)
    1.0 ( 0.6 )
    2.0 ( 1.8 )
    No statistical analyses for this end point

    Secondary: Six-week SAQ: number of wees per day

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    End point title
    Six-week SAQ: number of wees per day
    End point description
    End point type
    Secondary
    End point timeframe
    Week 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    22
    19
    Units: wees per day
        arithmetic mean (standard deviation)
    7.2 ( 2.1 )
    6.7 ( 1.9 )
    No statistical analyses for this end point

    Secondary: Three-month SAQ: number of wees per day

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    End point title
    Three-month SAQ: number of wees per day
    End point description
    End point type
    Secondary
    End point timeframe
    Month 3 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    19
    16
    Units: wees per day
        arithmetic mean (standard deviation)
    7.7 ( 3.2 )
    6.8 ( 1.9 )
    No statistical analyses for this end point

    Secondary: Six-month SAQ: number of wees per day

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    End point title
    Six-month SAQ: number of wees per day
    End point description
    End point type
    Secondary
    End point timeframe
    Month 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    18
    13
    Units: wees per day
        arithmetic mean (standard deviation)
    7.1 ( 2.1 )
    7.8 ( 1.8 )
    No statistical analyses for this end point

    Secondary: Six-week SAQ: number of episodes of urinary urgency per day

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    End point title
    Six-week SAQ: number of episodes of urinary urgency per day
    End point description
    End point type
    Secondary
    End point timeframe
    Week 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    22
    19
    Units: episodes per day
        arithmetic mean (standard deviation)
    3.2 ( 2.0 )
    2.8 ( 1.7 )
    No statistical analyses for this end point

    Secondary: Three-month SAQ: number of episodes of urinary urgency per day

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    End point title
    Three-month SAQ: number of episodes of urinary urgency per day
    End point description
    End point type
    Secondary
    End point timeframe
    Month 3 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    19
    14
    Units: episodes per day
        arithmetic mean (standard deviation)
    3.5 ( 2.4 )
    2.7 ( 1.7 )
    No statistical analyses for this end point

    Secondary: Six-month SAQ: number of episodes of urinary urgency per day

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    End point title
    Six-month SAQ: number of episodes of urinary urgency per day
    End point description
    End point type
    Secondary
    End point timeframe
    Month 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    18
    12
    Units: episodes per day
        arithmetic mean (standard deviation)
    2.4 ( 1.6 )
    3.2 ( 2.6 )
    No statistical analyses for this end point

    Secondary: Six-week SAQ: number of episodes of nocturia per day

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    End point title
    Six-week SAQ: number of episodes of nocturia per day
    End point description
    End point type
    Secondary
    End point timeframe
    Week 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    19
    15
    Units: episodes per day
        arithmetic mean (standard deviation)
    0.5 ( 0.5 )
    0.5 ( 0.6 )
    No statistical analyses for this end point

    Secondary: Three-month SAQ: number of episodes of nocturia per day

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    End point title
    Three-month SAQ: number of episodes of nocturia per day
    End point description
    End point type
    Secondary
    End point timeframe
    Month 3 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    16
    13
    Units: episodes per day
        arithmetic mean (standard deviation)
    0.7 ( 0.7 )
    0.6 ( 0.6 )
    No statistical analyses for this end point

    Secondary: Six-month SAQ: number of episodes of nocturia per day

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    End point title
    Six-month SAQ: number of episodes of nocturia per day
    End point description
    End point type
    Secondary
    End point timeframe
    Month 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    16
    11
    Units: episodes per day
        arithmetic mean (standard deviation)
    0.6 ( 0.7 )
    0.7 ( 0.8 )
    No statistical analyses for this end point

    Secondary: Six-week SAQ: did nocturnal enuresis occur?

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    End point title
    Six-week SAQ: did nocturnal enuresis occur?
    End point description
    End point type
    Secondary
    End point timeframe
    Week 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    22
    17
    Units: patients
        Yes
    19
    13
        No
    3
    4
    No statistical analyses for this end point

    Secondary: Three-month SAQ: did nocturnal enuresis occur?

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    End point title
    Three-month SAQ: did nocturnal enuresis occur?
    End point description
    End point type
    Secondary
    End point timeframe
    Month 3 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    20
    15
    Units: patients
        Yes
    16
    11
        No
    4
    4
    No statistical analyses for this end point

    Secondary: Six-month SAQ: did nocturnal enuresis occur?

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    End point title
    Six-month SAQ: did nocturnal enuresis occur?
    End point description
    End point type
    Secondary
    End point timeframe
    Month 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    18
    12
    Units: patients
        Yes
    14
    9
        No
    4
    3
    No statistical analyses for this end point

    Secondary: Three-month bladder capacity

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    End point title
    Three-month bladder capacity
    End point description
    End point type
    Secondary
    End point timeframe
    Month 3 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    21
    18
    Units: ml
        arithmetic mean (standard deviation)
    211.7 ( 138.0 )
    208.8 ( 106.9 )
    No statistical analyses for this end point

    Secondary: Six-month bladder capacity

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    End point title
    Six-month bladder capacity
    End point description
    End point type
    Secondary
    End point timeframe
    Month 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    19
    16
    Units: ml
        arithmetic mean (standard deviation)
    225.4 ( 118.1 )
    230.4 ( 100.2 )
    No statistical analyses for this end point

    Secondary: Three-month post-void residual urine

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    End point title
    Three-month post-void residual urine
    End point description
    End point type
    Secondary
    End point timeframe
    Month 3 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    21
    18
    Units: ml
        arithmetic mean (standard deviation)
    18.2 ( 23.3 )
    27.3 ( 27.4 )
    No statistical analyses for this end point

    Secondary: Six-month post-void residual urine

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    End point title
    Six-month post-void residual urine
    End point description
    End point type
    Secondary
    End point timeframe
    Month 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    19
    16
    Units: ml
        arithmetic mean (standard deviation)
    42.0 ( 33.0 )
    19.4 ( 24.9 )
    No statistical analyses for this end point

    Secondary: Six-week PedsQL: Physical functioning (parent report)

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    End point title
    Six-week PedsQL: Physical functioning (parent report)
    End point description
    End point type
    Secondary
    End point timeframe
    Week 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    6
    6
    Units: score
        arithmetic mean (standard deviation)
    91.1 ( 8.0 )
    77.1 ( 20.7 )
    No statistical analyses for this end point

    Secondary: Six-week PedsQL: Physical functioning (patient report)

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    End point title
    Six-week PedsQL: Physical functioning (patient report)
    End point description
    End point type
    Secondary
    End point timeframe
    Week 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    16
    13
    Units: score
        arithmetic mean (standard deviation)
    80.5 ( 17.5 )
    87.7 ( 12.5 )
    No statistical analyses for this end point

    Secondary: Three-month PedsQL: Physical functioning (parent report)

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    End point title
    Three-month PedsQL: Physical functioning (parent report)
    End point description
    End point type
    Secondary
    End point timeframe
    Month 3 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    5
    3
    Units: score
        arithmetic mean (standard deviation)
    70.0 ( 33.7 )
    89.6 ( 4.8 )
    No statistical analyses for this end point

    Secondary: Three-month PedsQL: Physical functioning (patient report)

    Close Top of page
    End point title
    Three-month PedsQL: Physical functioning (patient report)
    End point description
    End point type
    Secondary
    End point timeframe
    Month 3 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    20
    13
    Units: score
        arithmetic mean (standard deviation)
    79.1 ( 23.9 )
    80.5 ( 19.1 )
    No statistical analyses for this end point

    Secondary: Six-month PedsQL: Physical functioning (parent report)

    Close Top of page
    End point title
    Six-month PedsQL: Physical functioning (parent report)
    End point description
    End point type
    Secondary
    End point timeframe
    Month 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    3
    2
    Units: score
        arithmetic mean (standard deviation)
    80.2 ( 34.3 )
    78.1 ( 13.3 )
    No statistical analyses for this end point

    Secondary: Six-month PedsQL: Physical functioning (patient report)

    Close Top of page
    End point title
    Six-month PedsQL: Physical functioning (patient report)
    End point description
    End point type
    Secondary
    End point timeframe
    Month 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    14
    13
    Units: score
        arithmetic mean (standard deviation)
    79.5 ( 19.4 )
    83.7 ( 19.0 )
    No statistical analyses for this end point

    Secondary: Six-week PedsQL: Emotional functioning (parent report)

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    End point title
    Six-week PedsQL: Emotional functioning (parent report)
    End point description
    End point type
    Secondary
    End point timeframe
    Week 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    7
    6
    Units: score
        arithmetic mean (standard deviation)
    63.6 ( 20.6 )
    60.0 ( 23.9 )
    No statistical analyses for this end point

    Secondary: Six-week PedsQL: Emotional functioning (patient report)

    Close Top of page
    End point title
    Six-week PedsQL: Emotional functioning (patient report)
    End point description
    End point type
    Secondary
    End point timeframe
    Week 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    16
    13
    Units: score
        arithmetic mean (standard deviation)
    69.7 ( 28.6 )
    70.0 ( 30.2 )
    No statistical analyses for this end point

    Secondary: Three-month PedsQL: Emotional functioning (parent report)

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    End point title
    Three-month PedsQL: Emotional functioning (parent report)
    End point description
    End point type
    Secondary
    End point timeframe
    Month 3 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    5
    3
    Units: score
        arithmetic mean (standard deviation)
    59.0 ( 35.2 )
    45.0 ( 39.7 )
    No statistical analyses for this end point

    Secondary: Three-month PedsQL: Emotional functioning (patient report)

    Close Top of page
    End point title
    Three-month PedsQL: Emotional functioning (patient report)
    End point description
    End point type
    Secondary
    End point timeframe
    Month 3 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    20
    13
    Units: score
        arithmetic mean (standard deviation)
    74.0 ( 23.5 )
    61.5 ( 31.6 )
    No statistical analyses for this end point

    Secondary: Six-month PedsQL: Emotional functioning (parent report)

    Close Top of page
    End point title
    Six-month PedsQL: Emotional functioning (parent report)
    End point description
    End point type
    Secondary
    End point timeframe
    Month 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    3
    2
    Units: score
        arithmetic mean (standard deviation)
    75.0 ( 43.3 )
    45.0 ( 49.5 )
    No statistical analyses for this end point

    Secondary: Six-month PedsQL: Emotional functioning (patient report)

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    End point title
    Six-month PedsQL: Emotional functioning (patient report)
    End point description
    End point type
    Secondary
    End point timeframe
    Month 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    14
    13
    Units: score
        arithmetic mean (standard deviation)
    68.9 ( 24.5 )
    67.7 ( 25.1 )
    No statistical analyses for this end point

    Secondary: Six-week PedsQL: Social functioning (parent report)

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    End point title
    Six-week PedsQL: Social functioning (parent report)
    End point description
    End point type
    Secondary
    End point timeframe
    Week 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    7
    6
    Units: score
        arithmetic mean (standard deviation)
    78.6 ( 22.5 )
    50.0 ( 27.4 )
    No statistical analyses for this end point

    Secondary: Six-week PedsQL: Social functioning (patient report)

    Close Top of page
    End point title
    Six-week PedsQL: Social functioning (patient report)
    End point description
    End point type
    Secondary
    End point timeframe
    Week 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    16
    13
    Units: score
        arithmetic mean (standard deviation)
    75.3 ( 22.3 )
    88.1 ( 17.9 )
    No statistical analyses for this end point

    Secondary: Three-month PedsQL: Social functioning (parent report)

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    End point title
    Three-month PedsQL: Social functioning (parent report)
    End point description
    End point type
    Secondary
    End point timeframe
    Month 3 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    5
    3
    Units: score
        arithmetic mean (standard deviation)
    75.0 ( 30.6 )
    41.7 ( 38.2 )
    No statistical analyses for this end point

    Secondary: Three-month PedsQL: Social functioning (patient report)

    Close Top of page
    End point title
    Three-month PedsQL: Social functioning (patient report)
    End point description
    End point type
    Secondary
    End point timeframe
    Month 3 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    20
    13
    Units: score
        arithmetic mean (standard deviation)
    72.3 ( 30.5 )
    88.1 ( 19.7 )
    No statistical analyses for this end point

    Secondary: Six-month PedsQL: Social functioning (parent report)

    Close Top of page
    End point title
    Six-month PedsQL: Social functioning (parent report)
    End point description
    End point type
    Secondary
    End point timeframe
    Month 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    3
    2
    Units: score
        arithmetic mean (standard deviation)
    91.7 ( 14.4 )
    37.5 ( 17.7 )
    No statistical analyses for this end point

    Secondary: Six-month PedsQL: Social functioning (patient report)

    Close Top of page
    End point title
    Six-month PedsQL: Social functioning (patient report)
    End point description
    End point type
    Secondary
    End point timeframe
    Month 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    14
    13
    Units: score
        arithmetic mean (standard deviation)
    80.0 ( 28.9 )
    88.8 ( 14.2 )
    No statistical analyses for this end point

    Secondary: Six-week PedsQL: School functioning (parent report)

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    End point title
    Six-week PedsQL: School functioning (parent report)
    End point description
    End point type
    Secondary
    End point timeframe
    Week 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    7
    6
    Units: score
        arithmetic mean (standard deviation)
    68.6 ( 23.4 )
    50.0 ( 21.9 )
    No statistical analyses for this end point

    Secondary: Six-week PedsQL: School functioning (patient report)

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    End point title
    Six-week PedsQL: School functioning (patient report)
    End point description
    End point type
    Secondary
    End point timeframe
    Week 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    16
    13
    Units: score
        arithmetic mean (standard deviation)
    66.3 ( 21.3 )
    66.2 ( 22.7 )
    No statistical analyses for this end point

    Secondary: Three-month PedsQL: School functioning (parent report)

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    End point title
    Three-month PedsQL: School functioning (parent report)
    End point description
    End point type
    Secondary
    End point timeframe
    Month 3 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    5
    3
    Units: score
        arithmetic mean (standard deviation)
    60.0 ( 42.3 )
    65.0 ( 10.0 )
    No statistical analyses for this end point

    Secondary: Three-month PedsQL: School functioning (patient report)

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    End point title
    Three-month PedsQL: School functioning (patient report)
    End point description
    End point type
    Secondary
    End point timeframe
    Month 3 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    20
    13
    Units: score
        arithmetic mean (standard deviation)
    62.0 ( 30.5 )
    66.2 ( 25.1 )
    No statistical analyses for this end point

    Secondary: Six-month PedsQL: School functioning (parent report)

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    End point title
    Six-month PedsQL: School functioning (parent report)
    End point description
    End point type
    Secondary
    End point timeframe
    Month 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    3
    2
    Units: score
        arithmetic mean (standard deviation)
    71.7 ( 32.1 )
    65.0 ( 14.1 )
    No statistical analyses for this end point

    Secondary: Six-month PedsQL: School functioning (patient report)

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    End point title
    Six-month PedsQL: School functioning (patient report)
    End point description
    End point type
    Secondary
    End point timeframe
    Month 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    14
    13
    Units: score
        arithmetic mean (standard deviation)
    67.5 ( 23.0 )
    67.7 ( 23.0 )
    No statistical analyses for this end point

    Secondary: Six-week PedsQL: Psychosocial health (parent report)

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    End point title
    Six-week PedsQL: Psychosocial health (parent report)
    End point description
    End point type
    Secondary
    End point timeframe
    Week 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    7
    6
    Units: score
        arithmetic mean (standard deviation)
    70.2 ( 14.8 )
    53.3 ( 22.4 )
    No statistical analyses for this end point

    Secondary: Six-week PedsQL: Psychosocial health (patient report)

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    End point title
    Six-week PedsQL: Psychosocial health (patient report)
    End point description
    End point type
    Secondary
    End point timeframe
    Week 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    16
    13
    Units: score
        arithmetic mean (standard deviation)
    70.4 ( 21.4 )
    74.7 ( 20.0 )
    No statistical analyses for this end point

    Secondary: Three-month PedsQL: Psychosocial health (parent report)

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    End point title
    Three-month PedsQL: Psychosocial health (parent report)
    End point description
    End point type
    Secondary
    End point timeframe
    Month 3 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    5
    3
    Units: score
        arithmetic mean (standard deviation)
    64.7 ( 35.1 )
    50.6 ( 28.3 )
    No statistical analyses for this end point

    Secondary: Three-month PedsQL: Psychosocial health (patient report)

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    End point title
    Three-month PedsQL: Psychosocial health (patient report)
    End point description
    End point type
    Secondary
    End point timeframe
    Month 3 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    20
    13
    Units: score
        arithmetic mean (standard deviation)
    69.4 ( 26.3 )
    71.9 ( 22.6 )
    No statistical analyses for this end point

    Secondary: Six-month PedsQL: Psychosocial health (parent report)

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    End point title
    Six-month PedsQL: Psychosocial health (parent report)
    End point description
    End point type
    Secondary
    End point timeframe
    Month 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    3
    2
    Units: score
        arithmetic mean (standard deviation)
    79.4 ( 29.9 )
    49.2 ( 17.7 )
    No statistical analyses for this end point

    Secondary: Six-month PedsQL: Psychosocial health (patient report)

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    End point title
    Six-month PedsQL: Psychosocial health (patient report)
    End point description
    End point type
    Secondary
    End point timeframe
    Month 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    14
    13
    Units: score
        arithmetic mean (standard deviation)
    72.1 ( 21.5 )
    74.7 ( 18.7 )
    No statistical analyses for this end point

    Secondary: Six-week PedsQL: Total score (parent report)

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    End point title
    Six-week PedsQL: Total score (parent report)
    End point description
    End point type
    Secondary
    End point timeframe
    Week 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    7
    6
    Units: score
        arithmetic mean (standard deviation)
    75.3 ( 14.8 )
    61.6 ( 19.6 )
    No statistical analyses for this end point

    Secondary: Six-week PedsQL: Total score (patient report)

    Close Top of page
    End point title
    Six-week PedsQL: Total score (patient report)
    End point description
    End point type
    Secondary
    End point timeframe
    Week 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    16
    13
    Units: score
        arithmetic mean (standard deviation)
    73.9 ( 18.0 )
    79.3 ( 15.1 )
    No statistical analyses for this end point

    Secondary: Three-month PedsQL: Total score (parent report)

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    End point title
    Three-month PedsQL: Total score (parent report)
    End point description
    End point type
    Secondary
    End point timeframe
    Month 3 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    5
    3
    Units: score
        arithmetic mean (standard deviation)
    66.5 ( 34.1 )
    64.1 ( 20.1 )
    No statistical analyses for this end point

    Secondary: Three-month PedsQL: Total score (patient report)

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    End point title
    Three-month PedsQL: Total score (patient report)
    End point description
    End point type
    Secondary
    End point timeframe
    Month 3 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    20
    13
    Units: score
        arithmetic mean (standard deviation)
    72.8 ( 24.2 )
    74.9 ( 20.7 )
    No statistical analyses for this end point

    Secondary: Six-month PedsQL: Total score (parent report)

    Close Top of page
    End point title
    Six-month PedsQL: Total score (parent report)
    End point description
    End point type
    Secondary
    End point timeframe
    Month 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    3
    2
    Units: score
        arithmetic mean (standard deviation)
    79.7 ( 31.4 )
    59.2 ( 16.1 )
    No statistical analyses for this end point

    Secondary: Six-month PedsQL: Total score (patient report)

    Close Top of page
    End point title
    Six-month PedsQL: Total score (patient report)
    End point description
    End point type
    Secondary
    End point timeframe
    Month 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    14
    13
    Units: score
        arithmetic mean (standard deviation)
    74.7 ( 19.5 )
    77.8 ( 17.5 )
    No statistical analyses for this end point

    Secondary: Six-week PinQ

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    End point title
    Six-week PinQ
    End point description
    End point type
    Secondary
    End point timeframe
    Week 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    20
    16
    Units: score
        arithmetic mean (standard deviation)
    1.7 ( 0.8 )
    1.6 ( 0.9 )
    No statistical analyses for this end point

    Secondary: Three-month PinQ

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    End point title
    Three-month PinQ
    End point description
    End point type
    Secondary
    End point timeframe
    Month 3 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    20
    17
    Units: score
        arithmetic mean (standard deviation)
    1.5 ( 0.8 )
    1.7 ( 1.0 )
    No statistical analyses for this end point

    Secondary: Six-month PinQ

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    End point title
    Six-month PinQ
    End point description
    End point type
    Secondary
    End point timeframe
    Month 6 post-randomisation
    End point values
    Tolterodine Botox
    Number of subjects analysed
    16
    15
    Units: score
        arithmetic mean (standard deviation)
    1.5 ( 0.8 )
    1.5 ( 0.8 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Twenty-eight days from last dose or last trial follow-up
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21
    Reporting groups
    Reporting group title
    Tolterodine
    Reporting group description
    Extended-release Tolterodine XL 4mg orally

    Reporting group title
    Botox
    Reporting group description
    Single administration of Onabotulinum Toxin A (onaBtA; 5 IU/Kg, maximum 150 IU) into the bladder

    Serious adverse events
    Tolterodine Botox
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 22 (4.55%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Tolterodine Botox
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 24 (37.50%)
    8 / 22 (36.36%)
    Injury, poisoning and procedural complications
    Abdominal injury
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Malaise
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    Pyrexia
         subjects affected / exposed
    1 / 24 (4.17%)
    2 / 22 (9.09%)
         occurrences all number
    1
    2
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    3 / 24 (12.50%)
    1 / 22 (4.55%)
         occurrences all number
    4
    1
    Anal incontinence
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Constipation
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    Diarrhoea
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Wheezing
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    2
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    3
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    4 / 24 (16.67%)
    3 / 22 (13.64%)
         occurrences all number
    9
    4
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jun 2015
    Protocol version 5.0 - Following Trial Steering Committee (TSC), Data monitoring committee (DMC), and trial management group (TMG) meetings there were elements of the protocol that were deemed to be ambiguous. Based on these conversations, clarifications were provided in the protocol and associated documents. The most substantial change is the clarification of the measurement of the primary outcome. The protocol was changed to detail a seven day symptom assessment questionnaire instead of a two day one as this was unclear. The protocol stated that the DMC would advise on interim analyses which the committee said was not possible so this was removed. The TMG discussed a number of more minor changes to the protocol which were implemented as well.
    11 May 2016
    Protocol version 6.0 - The main purpose of this amendment was to increase recruitment by the addition of patient identification centres. In addition the Children's Continence Service, Children's Community Services and Central Manchester University Hospitals NHS Foundation Trust (CMFT) will identify potential participants on behalf of the CMFT and if a potential participant is interested, we will request a clinical referral from the GP.
    05 Feb 2018
    Change of sponsor amendment

    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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