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    Clinical Trial Results:
    The effect of melatonin on nocturnal enuresis

    Summary
    EudraCT number
    		 2011-004138-33
    Trial protocol
    		 DK  
    Global end of trial date
    06 May 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 May 2021
    First version publication date
    13 May 2021
    Other versions
    Summary report(s)
    		 Supplementary info EudraCT 2011-004138-33

    Trial information

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    Trial identification
    Sponsor protocol code
    EnuMel-11
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01575678
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aarhus University Hospital
    Sponsor organisation address
    Palle Juul Jensen Boulevard 99, Aarhus N, Denmark, 8200
    Public contact
    Britt Borg, Aarhus University Hospital, 0045 22740973, bborg@clin.au.dk
    Scientific contact
    Britt Borg, Aarhus University Hospital, 0045 22740973, bborg@clin.au.dk
    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
    12 Apr 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 May 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    06 May 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To investigate the effect of melatonin in fixed dosage before bedtime in children with monosymtomatic nocturnal enuresis on the number of wet nights per week compared with placebo.
    Protection of trial subjects
    Blood- and urinesamples obtained at every follow up to monitor adverse events
    Background therapy
    		 none
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Oct 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 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)
    16
    Adolescents (12-17 years)
    4
    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
    		 All subject recruited from the outpatient clinic Center for Child Incontinence, Pediatric Department, Aarhus University Hospital

    Pre-assignment
    Screening details
    		 Patients from Centre for Child Incontinence was screened bases on their previous hospital records. If records were in accordance with inclusion and exclusion criteria, the patient was screened in person by investigators. Number of screenet patients: 69

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    active and placebo tablets were encapsulated in in grey DB Caps(R) size B

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Melatonin (Circadin, Neurim 2mg)
    Arm description
    		 Subjects receives treatment with Melatonin (Circadin, Neurim 2mg) every evening for four weeks. Study design was cross over. So subjects were randomized to treatment start with either melatonin or placebo for four weeks, then one week of wash out, and finally four weeks of the treatment they did not receive initially
    Arm type
    		 Experimental

    Investigational medicinal product name
    Circadin
    Investigational medicinal product code
    N05CH01o
    Other name
    Pharmaceutical forms
    Prolonged-release capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2 mg once every evening for four weeks

    Arm title
    		 Placebo
    Arm description
    		 Subjects received treatment with placebo every evening for four weeks. Study design was cross over. So subjects were randomized to treatment start with either melatonin or placebo for four weeks, then one week of wash out, and finally four weeks of the treatment they did not receive initially.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet once every evening for four weeks

    Number of subjects in period 1
    		Melatonin (Circadin, Neurim 2mg) Placebo
    Started
    20
    20
    Completed
    18
    18
    Not completed
    2
    2
         Consent withdrawn by subject
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 Correction: n=20

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 20 20
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 16 16
        Adolescents (12-17 years)
    		 4 4
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 9.70 ( 1.69 ) -
    Gender categorical
    Units: Subjects
        Female
    		 3 3
        Male
    		 17 17
    Previous desmopressin treatment
    Units: Subjects
        Yes
    		 18 18
        No
    		 2 2
    Previous alarm treatment
    Units: Subjects
        Yes
    		 10 10
        No
    		 10 10
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 40.20 ( 10.03 ) -
    Height
    Units: centimeter
        arithmetic mean (standard deviation)
    		 146.65 ( 11.88 ) -
    Percentage of nights with enuresis
    Units: percent
        arithmetic mean (standard deviation)
    		 88.57 ( 15.96 ) -
    Nocturnal urine production/expected bladder capacity
    Units: percent
        arithmetic mean (standard deviation)
    		 124.49 ( 54.16 ) -
    Maximal voided volume/Expected bladder capacity
    Units: percent
        arithmetic mean (standard deviation)
    		 74.70 ( 26.49 ) -

    End points

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    End points reporting groups
    Reporting group title
    Melatonin (Circadin, Neurim 2mg)
    Reporting group description
    		 Subjects receives treatment with Melatonin (Circadin, Neurim 2mg) every evening for four weeks. Study design was cross over. So subjects were randomized to treatment start with either melatonin or placebo for four weeks, then one week of wash out, and finally four weeks of the treatment they did not receive initially

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received treatment with placebo every evening for four weeks. Study design was cross over. So subjects were randomized to treatment start with either melatonin or placebo for four weeks, then one week of wash out, and finally four weeks of the treatment they did not receive initially.

    Primary: frequency of nights with enuresis

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    End point title
    		 frequency of nights with enuresis
    End point description
    End point type
    Primary
    End point timeframe
    registered for each night during the course of four weeks allocated treatment , and the same procedure after cross over to the other treatment allocation
    End point values
    		 Melatonin (Circadin, Neurim 2mg) Placebo
    Number of subjects analysed
    18
    18
    Units: percent
        arithmetic mean (standard deviation)
    81.39 ( 25.68 )
    80.82 ( 26.46 )
    Statistical analysis title
    		 paired t-test
    Comparison groups
    Melatonin (Circadin, Neurim 2mg) v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.83
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.14
         upper limit
    		 6.29
    Variability estimate
    Standard deviation
    Dispersion value
    11.49

    Secondary: Nocturnal urine production on enuretic nights

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    End point title
    		 Nocturnal urine production on enuretic nights
    End point description
    End point type
    Secondary
    End point timeframe
    registered for each night during the last week of allocated treatment , and the same procedure after cross over to the other treatment allocation
    End point values
    		 Melatonin (Circadin, Neurim 2mg) Placebo
    Number of subjects analysed
    18
    18
    Units: millilitre(s)
        arithmetic mean (standard deviation)
    356 ( 109 )
    355 ( 106 )
    Statistical analysis title
    		 paired t-test
    Comparison groups
    Melatonin (Circadin, Neurim 2mg) v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.95
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -28.78
         upper limit
    		 30.4
    Variability estimate
    Standard deviation
    Dispersion value
    55.52

    Secondary: Adherence to treatment

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    End point title
    		 Adherence to treatment
    End point description
    End point type
    Secondary
    End point timeframe
    Same as for the primary endpoint of enuresis frequency: (registered for each night during the course of four weeks allocated treatment , and the same procedure after cross over to the other treatment allocation)
    End point values
    		 Melatonin (Circadin, Neurim 2mg) Placebo
    Number of subjects analysed
    18
    18
    Units: percent
        arithmetic mean (standard deviation)
    97.0 ( 4.4 )
    96.9 ( 3.3 )
    Statistical analysis title
    		 paired t-test
    Comparison groups
    Melatonin (Circadin, Neurim 2mg) v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.92
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.2
         upper limit
    		 2.4
    Variability estimate
    Standard deviation
    Dispersion value
    4.6

    Secondary: Maximal voided volume (MVV)

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    End point title
    		 Maximal voided volume (MVV)
    End point description
    End point type
    Secondary
    End point timeframe
    registered each urine output for two days during the last week of allocated treatment, the largest was considered as the MVV(excluding first morning void). The same procedure after cross over to the other treatment allocation
    End point values
    		 Melatonin (Circadin, Neurim 2mg) Placebo
    Number of subjects analysed
    18
    18
    Units: millilitre(s)
        arithmetic mean (standard deviation)
    219.8 ( 105.8 )
    235.7 ( 95.8 )
    Statistical analysis title
    		 paired t-test
    Comparison groups
    Placebo v Melatonin (Circadin, Neurim 2mg)
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.42
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -15.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -57.1
         upper limit
    		 25.3
    Variability estimate
    Standard deviation
    Dispersion value
    71.4

    Secondary: Daytime fluid intake

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    End point title
    		 Daytime fluid intake
    End point description
    End point type
    Secondary
    End point timeframe
    Same period as for secondary endpoint MVV
    End point values
    		 Melatonin (Circadin, Neurim 2mg) Placebo
    Number of subjects analysed
    18
    18
    Units: millilitre(s)
        arithmetic mean (standard deviation)
    1100 ( 545 )
    1216 ( 411 )
    Statistical analysis title
    		 paired t-test
    Comparison groups
    Melatonin (Circadin, Neurim 2mg) v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.23
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -117
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -315
         upper limit
    		 81
    Variability estimate
    Standard deviation
    Dispersion value
    344

    Secondary: Daytime urine output

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    End point title
    		 Daytime urine output
    End point description
    End point type
    Secondary
    End point timeframe
    Same period as for secondary endpoint MVV
    End point values
    		 Melatonin (Circadin, Neurim 2mg) Placebo
    Number of subjects analysed
    18
    18
    Units: millilitre(s)
        arithmetic mean (standard deviation)
    804 ( 531 )
    876 ( 362 )
    Statistical analysis title
    		 paired t-test
    Comparison groups
    Melatonin (Circadin, Neurim 2mg) v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.47
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -288
         upper limit
    		 144
    Variability estimate
    Standard deviation
    Dispersion value
    302

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Systematically during the trial after each treatment period. No systematic registration after trial participation.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Own basic dictionary
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Melatonin (Circadin, Neurim 2mg)
    Reporting group description
    		 Adverse event during treatment with melatonin

    Reporting group title
    Placebo
    Reporting group description
    		 Adverse event during treatment with placebo

    Serious adverse events
    		 Melatonin (Circadin, Neurim 2mg) Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 18 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Melatonin (Circadin, Neurim 2mg) Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 18 (27.78%)
    3 / 18 (16.67%)
    Nervous system disorders
    Headache
    Additional description: headache for two days, treated with paracetamol
         subjects affected / exposed
    5 / 18 (27.78%)
    3 / 18 (16.67%)
         occurrences all number
    0
    1
    Tiredness
    Additional description: Tiredness during daytime. Tiredness in evening shortly after ingestion of studytreatment not included
         subjects affected / exposed
    5 / 18 (27.78%)
    3 / 18 (16.67%)
         occurrences all number
    3
    1
    Insomnia
    Additional description: Harder to fall asleep in the evening for two days
         subjects affected / exposed
    5 / 18 (27.78%)
    3 / 18 (16.67%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Appetite disorder
    Additional description: Less appetite for four days
         subjects affected / exposed
    5 / 18 (27.78%)
    3 / 18 (16.67%)
         occurrences all number
    1
    0
    Constipation
    Additional description: mild for two weeks
         subjects affected / exposed
    5 / 18 (27.78%)
    3 / 18 (16.67%)
         occurrences all number
    1
    0

    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? Yes
    Date
    Interruption
    Restart date
    01 Oct 2014
    Lack of resources for personnel to run the trial
    02 Jul 2018

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    -Early termination leads to small number of subjects for statistical analysis. -Technical problems with armbands leading to a big amount of missing data for the following endpoints: activity, skin temperature, galvanic skin response. Data not shown
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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