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    Clinical Trial Results:
    Monocentric, open-label, phase III study that compares the efficiency and tolerance between intravesical oxybutynin and oral fesoterodine in children (5-16y) with neurogenic detrusor overactivity.

    Summary
    EudraCT number
    		 2012-005295-33
    Trial protocol
    		 BE  
    Global end of trial date
    01 Jul 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Feb 2023
    First version publication date
    23 Feb 2023
    Other versions
    Summary report(s)
    		 Publication 22MAY2019

    Trial information

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    Trial identification
    Sponsor protocol code
    S54913
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UZ Leuven- Department of Urology
    Sponsor organisation address
    Herestraat 49, Leuven, Belgium, 3000
    Public contact
    Guy Bogaert, UZ Leuven-Department of Urology, +32 16346930, guy.bogaert@uzleuven.be
    Scientific contact
    Guy Bogaert, UZ Leuven-Department of Urology, +32 16346930, guy.bogaert@uzleuven.be
    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
    01 Dec 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Jul 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jul 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Efficiency and tolerance of fesoterodine in comparison with intravesical oxybutynin +/- tolterodine in children with neurogenic detrusor overactivity.
    Protection of trial subjects
    The Clinical Trial Center of UZ Leuven, the Medical Ethics Committee and the Federal Agency for Medicines and Health Products approved this study. The children needed to be older than 4 years of age because they had to be able to swallow an entire tablet, so that the prolonged release formula could work. Based on previous studies with tolterodine, which has the same active metabolite as fesoterodine, and the results of the pharmacokinetic behaviour of fesoterodine in a study with paediatric subjects, we calculated that a maximal dose of fesoterodine of 0.2 mg/kg/24 h would be safe. The child’s body weight had to be at least 20 kg because fesoterodine is available in 4 and 8 mg slow release tablets.
    Background therapy
    		 A low-pressure bladder in children with neuropathic bladder dysfunction can be achieved using anticholinergic medication. Due to the significant side effects of oral oxybutynin, our patients are treated with daily intravesical oxybutynin instillations. Newer oral anticholinergic medication, such as fesoterodine, claim to have fewer side effects in a once daily formulation. Because once-daily oral intake is easier than performing twice-daily intravesical instillations, we studied the effects of switching from intravesical oxybutynin to oral fesoterodine and compared the clinical response, urodynamic parameters and side effects.
    Evidence for comparator
    		 Anticholinergic medication lowers the frequency of involuntary bladder contractions, can lower the intravesical pressure, prevents the development of a hypertrophic bladder and augments the bladder capacity. However, anticholinergics cause side effects due to concomitant suppression of the muscarinic receptors in the rest of the body. The oldest and most well-known anticholinergic used to suppress detrusor overactivity is oxybutynin, a mild muscarinic-3 receptor selective antagonist. It is registered for the use in children and adults with neuropathic and non-neuropathic bladder disturbances.
    Actual start date of recruitment
    03 Dec 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
    Belgium: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    20
    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)
    10
    Adolescents (12-17 years)
    10
    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
    		 Twenty children with a body weight of at least 20 kg were enrolled and all completed the study. All children had NDO and sphincter overactivity proved by a UDS for which they performed CIC (4–6 times a day) and used intravesical oxybutynin. Out of 20 children, 12 (60%) took concom prophylactic AB. Monocentric, open-label, pilot study with 1 arm.

    Pre-assignment
    Screening details
    		 Children with NDO and sphincter overactivity (DSD) proved by a urodynamic study (UDS) performing daily CIC taking intravesical oxybutynin hydrochloride (0.3–0.6 mg/kg/24 h divided over 2–3 instillations a day) were included. The children needed to be older than 4 years of age because they had to be able to swallow an entire tablet.

    Pre-assignment period milestones
    Number of subjects started
    		 20
    Intermediate milestone: Number of subjects
    Part 1: 20
    Intermediate milestone: Number of subjects
    Part 2: 20
    Intermediate milestone: Number of subjects
    Part 3: 20
    Number of subjects completed
    		 20

    Period 1
    Period 1 title
    Part 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    N/A, as it's an academic, monocentric, open-label, pilot study with 1 study-arm.

    Arms
    Arm title
    		 Intravesical oxybutynin instillation
    Arm description
    		 During the first 2 patient contacts in part 1, the current urinary tract status was collected while on intravesical oxybutynin treatment by filling out 2 voiding diaries and urodynamics.
    Arm type
    		 Intravesical oxybutynin

    Investigational medicinal product name
    Oxybutynin Hydrochloride
    Investigational medicinal product code
    SUB03581MIG
    Other name
    1508-65-2
    Pharmaceutical forms
    Intravesical solution
    Routes of administration
    Intravesical use
    Dosage and administration details
    40g oxybutynin hydrochloride is solved into 40 liters of physiological solution, it is filtrated, then 5ml solution is put in an ampule. (0.3–0.6 mg/kg/24 h divided over 2–3 instillations a day)

    Number of subjects in period 1
    		Intravesical oxybutynin instillation
    Started
    20
    Completed
    20
    Period 2
    Period 2 title
    Part 2
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    N/A, as it's an academic, monocentric, open-label, pilot study with 1 study-arm.

    Arms
    Arm title
    		 Stop oxybutynin
    Arm description
    		 In the second part of the study, intravesical oxybutynin instillations were stopped for 4 days as a washout of the medication. During this washout, the child and parents were asked to fill a third voiding diary.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Stop oxybutynin
    Started
    20
    Completed
    20
    Period 3
    Period 3 title
    Part 3
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    N/A, as it's an academic, monocentric, open-label, pilot study with 1 study-arm.

    Arms
    Arm title
    		 Oral Fesoterodine
    Arm description
    		 The third part of the study consisted of 40 days of oral fesoterodine administration, a slow release tablet every morning, instead of intravesical oxybutynin, and the CIC was continued. Children with a body weight 20–40 kg took 4 mg per day, children with a body weight of more than 40 kg a day took 8 mg per day. They had to contain their normal life style but had to avoid grapefruit because this fruit interferes with the metabolism of fesoterodine.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fesoterodine
    Investigational medicinal product code
    G04BD11
    Other name
    SUB25383
    Pharmaceutical forms
    Prolonged-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Based on previous studies with tolterodine, which has the same active metabolite as fesoterodine, and the results of the pharmacokinetic behaviour of fesoterodine in a study with paediatric subjects, we calculated that a maximal dose of fesoterodine of 0.2 mg/kg/24 h would be safe. The child’s body weight had to be at least 20 kg because fesoterodine is available in 4 and 8 mg slow release tablets, taken orally. Children with a body weight 20–40 kg took 4 mg per day, children with a body weight of more than 40 kg a day took 8 mg per day.

    Number of subjects in period 3
    		Oral Fesoterodine
    Started
    20
    Completed
    20

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1
    Reporting group description
    		 -

    Reporting group values
    		 Part 1 Total
    Number of subjects
    		 20 20
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Twenty children (11 girls, 9 boys, 4–17 years) with neuropathic bladder dysfunction who perform clean intermittent catheterization and use intravesical oxybutynin instillations twice daily were included in this prospective study.
    Units: years
        median (full range (min-max))
    		 13 (4 to 17) -
    Gender categorical
    Twenty children (11 girls, 9 boys, 4–17 years) with neuropathic bladder dysfunction who perform clean intermittent catheterization and use intravesical oxybutynin instillations twice daily were included in this prospective study.
    Units: Subjects
        Female
    		 11 11
        Male
    		 9 9
    Neurogenic detrusor overactivity (NDO)
    Neurogenic detrusor overactivity (NDO) is seen in children with congenital neuropathic bladder disturbance like spinal dysraphism. In the long term, secondary pathological-anatomical changes can occur with consequent vesico-ureteral reflux, hydronephrosis, an increased risk of urinary tract infections, renal damage and renal insufficiency. 58% of untreated patients develop renal damage after 3 years. The primary treatment goal in this patient group is to keep the intravesical detrusor pressure low from birth in order to preserve kidney function.
    Units: Subjects
        Spina bifida
    		 15 15
        Tethered cord
    		 2 2
        Caudal regression syndrome
    		 1 1
        Transverse myelitis
    		 1 1
        Traumatic spinal cord injury
    		 1 1
    Number of patients applying CIC
    The primary treatment goal in this patient group is to keep the intravesical detrusor pressure low from birth in order to preserve kidney function. This can be achieved by frequent emptying of the bladder by clean intermittent catheterization (CIC) in combination with anticholinergic medication. All children had NDO and sphincter overactivity proved by a UDS for which they performed CIC (4–6 times a day) and used intravesical oxybutynin.
    Units: Subjects
        Clean intermittent catheterization
    		 20 20
    Number of patients applying intravesical oxybutynin at start
    Due to the significant side effects of oral oxybutynin, our patients are treated with daily intravesical oxybutynin instillations. Twenty children with neuropathic bladder dysfunction who perform CIC catheterization and use intravesical oxybutynin instillations twice daily were included in this prospective study.
    Units: Subjects
        Intravesical oxybutynin
    		 20 20
    Subject analysis sets

    Subject analysis set title
    Patient Characteristics
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Twenty children with a body weight of at least 20 kg were enrolled and all completed the study. All children had NDO and sphincter overactivity proved by a UDS for which they performed CIC (4–6 times a day) and used intravesical oxybutynin. Out of 20 children, 12 (60%) took concomitant prophylactic antibiotics (nitrofurantoin) of whom 1 patient (5%) used erythromycin for acne, which was stopped at informed consent because it could interact with the metabolism of fesoterodine.

    Subject analysis sets values
    		 Patient Characteristics
    Number of subjects
    20
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Twenty children (11 girls, 9 boys, 4–17 years) with neuropathic bladder dysfunction who perform clean intermittent catheterization and use intravesical oxybutynin instillations twice daily were included in this prospective study.
    Units: years
        median (full range (min-max))
    13 (4 to 17)
    Gender categorical
    Twenty children (11 girls, 9 boys, 4–17 years) with neuropathic bladder dysfunction who perform clean intermittent catheterization and use intravesical oxybutynin instillations twice daily were included in this prospective study.
    Units: Subjects
        Female
    11
        Male
    9
    Neurogenic detrusor overactivity (NDO)
    Neurogenic detrusor overactivity (NDO) is seen in children with congenital neuropathic bladder disturbance like spinal dysraphism. In the long term, secondary pathological-anatomical changes can occur with consequent vesico-ureteral reflux, hydronephrosis, an increased risk of urinary tract infections, renal damage and renal insufficiency. 58% of untreated patients develop renal damage after 3 years. The primary treatment goal in this patient group is to keep the intravesical detrusor pressure low from birth in order to preserve kidney function.
    Units: Subjects
        Spina bifida
    15
        Tethered cord
    1
        Caudal regression syndrome
    1
        Transverse myelitis
    1
        Traumatic spinal cord injury
    1
    Number of patients applying CIC
    The primary treatment goal in this patient group is to keep the intravesical detrusor pressure low from birth in order to preserve kidney function. This can be achieved by frequent emptying of the bladder by clean intermittent catheterization (CIC) in combination with anticholinergic medication. All children had NDO and sphincter overactivity proved by a UDS for which they performed CIC (4–6 times a day) and used intravesical oxybutynin.
    Units: Subjects
        Clean intermittent catheterization
    20
    Number of patients applying intravesical oxybutynin at start
    Due to the significant side effects of oral oxybutynin, our patients are treated with daily intravesical oxybutynin instillations. Twenty children with neuropathic bladder dysfunction who perform CIC catheterization and use intravesical oxybutynin instillations twice daily were included in this prospective study.
    Units: Subjects
        Intravesical oxybutynin
    20

    End points

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    End points reporting groups
    Reporting group title
    Intravesical oxybutynin instillation
    Reporting group description
    		 During the first 2 patient contacts in part 1, the current urinary tract status was collected while on intravesical oxybutynin treatment by filling out 2 voiding diaries and urodynamics.
    Reporting group title
    Stop oxybutynin
    Reporting group description
    		 In the second part of the study, intravesical oxybutynin instillations were stopped for 4 days as a washout of the medication. During this washout, the child and parents were asked to fill a third voiding diary.
    Reporting group title
    Oral Fesoterodine
    Reporting group description
    		 The third part of the study consisted of 40 days of oral fesoterodine administration, a slow release tablet every morning, instead of intravesical oxybutynin, and the CIC was continued. Children with a body weight 20–40 kg took 4 mg per day, children with a body weight of more than 40 kg a day took 8 mg per day. They had to contain their normal life style but had to avoid grapefruit because this fruit interferes with the metabolism of fesoterodine.

    Subject analysis set title
    Patient Characteristics
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Twenty children with a body weight of at least 20 kg were enrolled and all completed the study. All children had NDO and sphincter overactivity proved by a UDS for which they performed CIC (4–6 times a day) and used intravesical oxybutynin. Out of 20 children, 12 (60%) took concomitant prophylactic antibiotics (nitrofurantoin) of whom 1 patient (5%) used erythromycin for acne, which was stopped at informed consent because it could interact with the metabolism of fesoterodine.

    Primary: Maximum tolerable cystometric capacity

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    End point title
    		 Maximum tolerable cystometric capacity [1]
    End point description
    The primary efficacy variable, change from baseline in mean maximum cystometric capacity was 18.4 mL, which did not represent a significant increase (Wilcoxonmatched pairs test, p = 0.196). Maximum tolerable cystometric capacity until voiding, until leaking and at 40cmH2O.
    End point type
    Primary
    End point timeframe
    Week 1 and 7 before and after admission of fesoterodine.
    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: The included population is too small for statistical analysis; to obtain significant results re the efficacy, more pts should be included. We anticipated including 20 children as an initial pilot study to study the trend of efficiency, safety and tolerance rather than a formal statistical analysis. Results are given in %, average and range; no formal statistical testing of these results was performed. Shapiro Wilk test was performed to identify between parametric and non-parametric distribution.
    End point values
    		 Intravesical oxybutynin instillation Oral Fesoterodine
    Number of subjects analysed
    20
    20
    Units: in mililitres
        arithmetic mean (standard error)
    353.4 ( 0.196 )
    371.8 ( 0.196 )
    Attachments
    		 Table 2
    No statistical analyses for this end point

    Secondary: Secondary efficacy variables

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    End point title
    		 Secondary efficacy variables
    End point description
    Secondary variables were other UDS parameters like detrusor pressure at maximum cystometric capacity in cm H20. In case of involuntary loss of urine, the UDS parameters detrusor leak point pressure in cm H20 as well as the filling volume of the bladder during urine loss in mLs was assessed. The voiding diary parameters that were analyzed were the average catheterized urine volume in mLs, the percentage of pads that were dry during 3 days and the average incontinence volume per day in grams.
    End point type
    Secondary
    End point timeframe
    During intravesical oxybutynin administration (Baseline) and after 40 days of fesoterodine oral administration.
    End point values
    		 Intravesical oxybutynin instillation Oral Fesoterodine
    Number of subjects analysed
    20
    20
    Units: cm H2O
    median (standard error)
        Maximum detrusor pressure (UDS)
    28.2 ( 0.563 )
    30.6 ( 0.563 )
        Bladder filling volume during urine loss (UDS)
    217.9 ( 0.038 )
    353.4 ( 0.038 )
        Detrusor leak point pressure (UDS)
    18.8 ( 0.674 )
    22.0 ( 0.674 )
        Catheterized urine volume (bladder diary)
    147.5 ( 0.247 )
    139.5 ( 0.247 )
        Volume urine incontinence per day (bladder diary)
    121.0 ( 0.657 )
    132.9 ( 0.657 )
        Dry pads during 3 days (bladder diary)
    53.3 ( 0.215 )
    45.1 ( 0.215 )
    Attachments
    		 Table 2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Study duration was 12 weeks, starting from ICF signing. Written ICF was obtained from at least one of the parents and from the children themselves if they were older than 12 years old. In those 12w, pt contacts were done, either clinic visit by phone.
    Adverse event reporting additional description
    Safety+tolerability of fesoterodine were compared with those of intravesical oxybutynin based on data of anamnesis during 3 clinical contacts and 4 phone calls, vital signs (BP, HR, temperature and weight), clinical examination, behavioural checklists, lab evaluations (blood, urine). We specifically asked for the development of poss side effects.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 unknown
    Dictionary version
    1
    Reporting groups
    Reporting group title
    All enrollend subjects
    Reporting group description
    		 Safety and tolerability of fesoterodine were compared with those of intravesical oxybutynin based on data of anamnesis during 3 clinical contacts and 4 telephone interviews, vital signs (blood pressure, heart rate, axillary temperature and body weight), clinical examination, behavioural checklists, laboratory evaluations like blood and urine samples. There were no remarkable differences seen between the vital functions and clinical examination during both treatments.

    Serious adverse events
    		 All enrollend subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 20 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 All enrollend subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 20 (40.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    Dry mouth
    Additional description: Light-moderate dry mouth
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    4
    Nausea
    Additional description: Nausea and hot flushes
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Psychiatric disorders
    Behaviour disorder
    Additional description: Behavioral changes (reversible)
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Appetite disorder
    Additional description: Increased appetite
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    The results of this study have to be interpreted with their limitations. The included population is too small for statistical analysis; moreover, in order to obtain significant results about the efficacy, more patients should be included.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31117096
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