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    Clinical Trial Results:
    Trial Consisting of an 8-week Double-blind Placebo-controlled Part to Evaluate Efficacy, Safety, Tolerability and Pharmacokinetics of Prucalopride in Paediatric Subjects With Functional Constipation, Aged ≥6 Months to <18 Years, Followed by a 16-week Open-label Comparator (PEG) Controlled Part, to Document Safety and Tolerability up to 24 Weeks

    Summary
    EudraCT number
    		 2010-022402-40
    Trial protocol
    		 BE   NL   FR   GB   DE   HU   PL   IT  
    Global end of trial date
    01 Mar 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Sep 2018
    First version publication date
    25 Jan 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SPD555-303
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01330381
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Study number: M0001-C303
    Sponsors
    Sponsor organisation name
    Shire Development LLC
    Sponsor organisation address
    725 Chesterbrook Boulevard, Wayne, Pennsylvania, United States, 19087
    Public contact
    Study Physician, Shire, 1866 8425335,
    Scientific contact
    Study Physician, Shire, 1866 8425335,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000459-PIP01-08
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Mar 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Mar 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of prucalopride compared to placebo for the treatment of functional constipation in a paediatric population, aged greater than or equal to (≥) 6 months to less than (<) 18 years.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation-Good Clinical Practice, the principles of the Declaration of Helsinki, as well as other applicable local ethical and legal requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Apr 2011
    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
    Germany: 7
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Netherlands: 51
    Country: Number of subjects enrolled
    United Kingdom: 20
    Country: Number of subjects enrolled
    Poland: 48
    Country: Number of subjects enrolled
    Hungary: 74
    Worldwide total number of subjects
    215
    EEA total number of subjects
    215
    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)
    3
    Children (2-11 years)
    158
    Adolescents (12-17 years)
    54
    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
    		 -

    Pre-assignment
    Screening details
    		 Subjects who completed the 8-week double-blind treatment period and wished to continue were re-randomized after the double-blind treatment period to the 16-week open-label treatment period. Out of 215 subjects randomized in the study, 213 subjects received treatment and 2 subjects withdrew consent before treatment.

    Pre-assignment period milestones
    Number of subjects started
    		 215
    Intermediate milestone: Number of subjects
    Treated: 213
    Number of subjects completed
    		 213

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 2
    Period 1
    Period 1 title
    Double-blind Treatment Period (8 Weeks)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Carer, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Prucalopride
    Arm description
    		 Subjects with weight less than or equal to (≤) 50 kilogram (kg) received 0.04 milligram per kilogram (mg/kg) prucalopride once daily as oral solution of 0.4 mg/millilitre (mg/mL). Subjects with weight greater than (>) 50 kg received prucalopride 2 mg oral tablet once daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Prucalopride
    Investigational medicinal product code
    SPD555
    Other name
    Resolor
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects with weight ≤ 50 kg received 0.04 mg/kg prucalopride once daily as oral solution of 0.4 mg/mL.

    Investigational medicinal product name
    Prucalopride
    Investigational medicinal product code
    SPD555
    Other name
    Resolor
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects with weight > 50 kg received prucalopride 2 mg oral tablet once daily.

    Arm title
    		 Placebo
    Arm description
    		 Subjects with weight ≤ 50 kg received placebo matching to prucalopride oral solution. Subjects with weight >50 kg received placebo matching prucalopride oral tablet.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects with weight ≤ 50 kg received placebo matching to prucalopride oral solution.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects with weight >50 kg received placebo matching prucalopride oral tablet.

    Number of subjects in period 1 [1]
    		Prucalopride Placebo
    Started
    106
    107
    Completed
    96
    101
    Not completed
    10
    6
         Consent withdrawn by subject
    4
    3
         Non-compliance
    2
    1
         Did not fulfill inclusion/exclusion
    1
    -
         Adverse event
    1
    1
         Lost to follow-up
    1
    -
         Lack of efficacy
    1
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Not all enrolled subjects were treated with study drugs. Since baseline included treated subjects only, the worldwide number enrolled in the trial differs with the number of subjects reported in the baseline period.
    Period 2
    Period 2 title
    Open-label Treatment Period (16 Weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Prucalopride
    Arm description
    		 Subjects with weight ≤ 50 kg received 0.04 mg/kg prucalopride once daily as oral solution of 0.4 mg/mL. Subjects with weight > 50 kg received prucalopride 2 mg oral tablet once daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Prucalopride
    Investigational medicinal product code
    SPD555
    Other name
    Resolor
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects with weight ≤ 50 kg received 0.04 mg/kg prucalopride once daily as oral solution of 0.4 mg/mL.

    Investigational medicinal product name
    Prucalopride
    Investigational medicinal product code
    SPD555
    Other name
    Resolor
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects with weight > 50 kg received prucalopride 2 mg oral tablet once daily.

    Arm title
    		 PEG 4000 (Polyethylene Glycol)
    Arm description
    		 Subjects received PEG 4000 oral solution at a dose of 4 gram to 20 gram once daily.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Polyethylene glycol 4000
    Investigational medicinal product code
    PEG 4000
    Other name
    Forlax Junior, Forlax
    Pharmaceutical forms
    Powder for oral solution in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects with age ≥6 months to <1 year, received PEG 4000 oral solution at a dose of 4 gram once daily. Subjects with age ≥1 year to <4 years, received PEG 4000 oral solution at a dose of 8 gram once daily. Subjects with age ≥4 years to <8 years, received PEG 4000 oral solution at a dose of 12 gram once daily. Subjects with age ≥8 year to <18 years, received PEG 4000 oral solution at a dose of 20 gram once daily.

    Number of subjects in period 2
    		Prucalopride PEG 4000 (Polyethylene Glycol)
    Started
    98
    99
    Completed
    88
    81
    Not completed
    10
    18
         Sponsor's decision
    1
    1
         Consent withdrawn by subject
    7
    16
         Adverse event
    2
    -
         Non-compliance
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Prucalopride
    Reporting group description
    		 Subjects with weight less than or equal to (≤) 50 kilogram (kg) received 0.04 milligram per kilogram (mg/kg) prucalopride once daily as oral solution of 0.4 mg/millilitre (mg/mL). Subjects with weight greater than (>) 50 kg received prucalopride 2 mg oral tablet once daily.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects with weight ≤ 50 kg received placebo matching to prucalopride oral solution. Subjects with weight >50 kg received placebo matching prucalopride oral tablet.

    Reporting group values
    		 Prucalopride Placebo Total
    Number of subjects
    		 106 107 213
    Age categorical
    Safety Set was defined as all subjects who were randomized and used the investigational product at least once.
    Units: Subjects
        ≤ 18 years
    		 106 107 213
        Between 18 and 65 years
    		 0 0 0
        ≥ 65 years
    		 0 0 0
    Age continuous
    Safety Set was defined as all subjects who were randomized and used the investigational product at least once.
    Units: years
        arithmetic mean (standard deviation)
    		 8.3 ( 4.54 ) 8.2 ( 4.69 ) -
    Gender categorical
    Safety Set was defined as all subjects who were randomized and used the investigational product at least once.
    Units: Subjects
        Female
    		 60 58 118
        Male
    		 46 49 95

    End points

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    End points reporting groups
    Reporting group title
    Prucalopride
    Reporting group description
    		 Subjects with weight less than or equal to (≤) 50 kilogram (kg) received 0.04 milligram per kilogram (mg/kg) prucalopride once daily as oral solution of 0.4 mg/millilitre (mg/mL). Subjects with weight greater than (>) 50 kg received prucalopride 2 mg oral tablet once daily.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects with weight ≤ 50 kg received placebo matching to prucalopride oral solution. Subjects with weight >50 kg received placebo matching prucalopride oral tablet.
    Reporting group title
    Prucalopride
    Reporting group description
    		 Subjects with weight ≤ 50 kg received 0.04 mg/kg prucalopride once daily as oral solution of 0.4 mg/mL. Subjects with weight > 50 kg received prucalopride 2 mg oral tablet once daily.

    Reporting group title
    PEG 4000 (Polyethylene Glycol)
    Reporting group description
    		 Subjects received PEG 4000 oral solution at a dose of 4 gram to 20 gram once daily.

    Primary: Percent of Responders in the Last Four Weeks of the Double-Blind Treatment Period

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    End point title
    		 Percent of Responders in the Last Four Weeks of the Double-Blind Treatment Period
    End point description
    Responders are defined as subjects with an average spontaneous defecation frequency is ≥3 times per week AND the average number of fecal incontinence episodes per 2 weeks is ≤1 episode (only for subjects after acquisition of toileting skills). Full Analysis Set includes all subjects who were randomized and received at least 1 dose of investigational product.
    End point type
    Primary
    End point timeframe
    Last 4 weeks of double-blind treatment period
    End point values
    		 Prucalopride Placebo
    Number of subjects analysed
    106
    107
    Units: percentage of subjects
        number (not applicable)
    17
    17.8
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Prucalopride v Placebo
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9002
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Percent of Subjects With Bowel Frequency of 3 or More Spontaneous Bowel Movements (SBM) Per Week in the Last Four Weeks of the Double-Blind Treatment Period

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    End point title
    		 Percent of Subjects With Bowel Frequency of 3 or More Spontaneous Bowel Movements (SBM) Per Week in the Last Four Weeks of the Double-Blind Treatment Period
    End point description
    Spontaneous Bowel Movements defined as a bowel movement that is not preceded within a period of 24 hours by the intake of a laxative agent or by the use of an enema. Full Analysis Set includes all subjects who were randomized and received at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Last 4 weeks of double-blind treatment period
    End point values
    		 Prucalopride Placebo
    Number of subjects analysed
    106
    107
    Units: percentage of subjects
        number (not applicable)
    29.2
    35.5
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Prucalopride v Placebo
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.352
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Percent of Subjects With Fecal Incontinence Episodes of 1 or Less Per 2 Weeks in the Last Four Weeks of the Double-Blind Treatment Period

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    End point title
    		 Percent of Subjects With Fecal Incontinence Episodes of 1 or Less Per 2 Weeks in the Last Four Weeks of the Double-Blind Treatment Period
    End point description
    Fecal incontinence is a lack of control over defecation, leading to involuntary loss of bowel contents (only for subjects after acquisition of toileting skills). Full Analysis Set includes all subjects who were randomized and received at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Last 4 weeks of double-blind treatment period
    End point values
    		 Prucalopride Placebo
    Number of subjects analysed
    93 [1]
    93 [2]
    Units: percentage of subjects
        number (not applicable)
    43
    43
    Notes
    [1] - Not all subjects in the Full Analysis Set had data for this outcome.
    [2] - Not all subjects in the Full Analysis Set had data for this outcome.
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Prucalopride v Placebo
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5228
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Number of Retentive Posturing or Excessive Volitional Stool Retention in the Double-Blind Treatment Period

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    End point title
    		 Number of Retentive Posturing or Excessive Volitional Stool Retention in the Double-Blind Treatment Period
    End point description
    Purposefully avoiding defecation. Full Analysis Set includes all subjects who were randomized and received at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Over the 8 week double blind treatment period
    End point values
    		 Prucalopride Placebo
    Number of subjects analysed
    105 [3]
    107
    Units: retentions/week
        arithmetic mean (standard deviation)
    1.1 ( 1.82 )
    1.2 ( 1.71 )
    Notes
    [3] - Not all subjects in the Full Analysis Set had data for this outcome.
    No statistical analyses for this end point

    Secondary: Painful Bowel Movements Score in the Double-Blind Treatment Period

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    End point title
    		 Painful Bowel Movements Score in the Double-Blind Treatment Period
    End point description
    Pain was rated on a 6-point scale (0=no hurt, 1=hurts little bit, 2=hurts little more, 3=hurts even more, 4=hurts whole lot, 5=hurts worst) in subjects of 3 years and older. Lower scores represent less pain. Full Analysis Set includes all subjects who were randomized and received at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Over the 8 week double blind treatment period
    End point values
    		 Prucalopride Placebo
    Number of subjects analysed
    98 [4]
    100 [5]
    Units: units on a scale
        arithmetic mean (standard deviation)
    1.3 ( 1.25 )
    1.7 ( 1.34 )
    Notes
    [4] - Not all subjects in the Full Analysis Set had data for this outcome.
    [5] - Not all subjects in the Full Analysis Set had data for this outcome.
    No statistical analyses for this end point

    Secondary: Stool Consistency Per SBM Score in Children Without Diapers in the Double-Blind Treatment Period

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    End point title
    		 Stool Consistency Per SBM Score in Children Without Diapers in the Double-Blind Treatment Period
    End point description
    Measured using the 7-point Bristol scale where 1-2 indicate constipation, 3-4 are ideal stools, and 5-7 tending toward diarrhea. Full Analysis Set includes all subjects who were randomized and received at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Over the 8 week double blind treatment period
    End point values
    		 Prucalopride Placebo
    Number of subjects analysed
    92 [6]
    93 [7]
    Units: units on a scale
        arithmetic mean (standard deviation)
    3.8 ( 0.96 )
    3.6 ( 1.17 )
    Notes
    [6] - Not all subjects in the Full Analysis Set had data for this outcome.
    [7] - Not all subjects in the Full Analysis Set had data for this outcome.
    No statistical analyses for this end point

    Secondary: Stool Consistency Per SBM Score in Children With Diapers in the Double-Blind Treatment Period

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    End point title
    		 Stool Consistency Per SBM Score in Children With Diapers in the Double-Blind Treatment Period
    End point description
    Measured on a 4-point scale where 1 is constipation, 2-3 is ideal, and 4 is diarrhea. Full Analysis Set includes all subjects who were randomized and received at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Over the 8 week double blind treatment period
    End point values
    		 Prucalopride Placebo
    Number of subjects analysed
    13 [8]
    14 [9]
    Units: units on a scale
        arithmetic mean (standard deviation)
    2.1 ( 0.47 )
    2 ( 0.59 )
    Notes
    [8] - Not all subjects in the Full Analysis Set had data for this outcome.
    [9] - Not all subjects in the Full Analysis Set had data for this outcome.
    No statistical analyses for this end point

    Secondary: Large Diameter Stools in the Double-Blind Treatment Period

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    End point title
    		 Large Diameter Stools in the Double-Blind Treatment Period
    End point description
    Large diameter stools make defecation more difficult. Small diameter stools are better. Full Analysis Set includes all subjects who were randomized and received at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Over the 8 week double blind treatment period
    End point values
    		 Prucalopride Placebo
    Number of subjects analysed
    105 [10]
    107
    Units: large diameter stools/week
        arithmetic mean (standard deviation)
    1.7 ( 1.67 )
    1.7 ( 1.2 )
    Notes
    [10] - Not all subjects in the Full Analysis Set had data for this outcome.
    No statistical analyses for this end point

    Secondary: Abdominal Pain Score in Double-Blind Treatment Period

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    End point title
    		 Abdominal Pain Score in Double-Blind Treatment Period
    End point description
    Pain was rated on a 6-point scale (0=no hurt, 1=hurts little bit, 2=hurts little more, 3=hurts even more, 4=hurts whole lot, 5=hurts worst) in subjects of 3 years and older. Lower scores represent less pain. Full Analysis Set includes all subjects who were randomized and received at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Over the 8 week double blind treatment period
    End point values
    		 Prucalopride Placebo
    Number of subjects analysed
    96 [11]
    95 [12]
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.9 ( 1.18 )
    1.1 ( 1.15 )
    Notes
    [11] - Not all subjects in the Full Analysis Set had data for this outcome.
    [12] - Not all subjects in the Full Analysis Set had data for this outcome.
    No statistical analyses for this end point

    Secondary: Frequency of Toilet Training in the Double-Blind Treatment Period

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    End point title
    		 Frequency of Toilet Training in the Double-Blind Treatment Period
    End point description
    Only for subjects after acquisition of toileting skills. Full Analysis Set includes all subjects who were randomized and received at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Over the 8 week double blind treatment period
    End point values
    		 Prucalopride Placebo
    Number of subjects analysed
    82 [13]
    75 [14]
    Units: toilet trainings/week
        arithmetic mean (standard deviation)
    4.9 ( 2.47 )
    5.1 ( 2.47 )
    Notes
    [13] - Not all subjects in the Full Analysis Set had data for this outcome.
    [14] - Not all subjects in the Full Analysis Set had data for this outcome.
    No statistical analyses for this end point

    Secondary: Number of Rescue Medications Taken in the Double-Blind Treatment Period

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    End point title
    		 Number of Rescue Medications Taken in the Double-Blind Treatment Period
    End point description
    Full Analysis Set includes all subjects who were randomized and received at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Over the 8 week double blind treatment period
    End point values
    		 Prucalopride Placebo
    Number of subjects analysed
    105 [15]
    107
    Units: rescue medications/week
        arithmetic mean (standard deviation)
    1.2 ( 1.25 )
    1.3 ( 1.09 )
    Notes
    [15] - Not all subjects in the Full Analysis Set had data for this outcome.
    No statistical analyses for this end point

    Secondary: Time to First SBM in the Double-Blind Treatment Period

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    End point title
    		 Time to First SBM in the Double-Blind Treatment Period
    End point description
    After intake of the trial medication on Day 1. Full Analysis Set includes all subjects who were randomized and received at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Day 1 onwards
    End point values
    		 Prucalopride Placebo
    Number of subjects analysed
    106
    107
    Units: hours
        median (confidence interval 95%)
    67 (49.42 to 101.17)
    99.75 (73.75 to 204)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Prucalopride v Placebo
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.377
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Number of SBM Per Week in the Double-Blind Treatment Period

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    End point title
    		 Number of SBM Per Week in the Double-Blind Treatment Period
    End point description
    Full Analysis Set includes all subjects who were randomized and received at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Over the 8 week double blind treatment period
    End point values
    		 Prucalopride Placebo
    Number of subjects analysed
    105 [16]
    107
    Units: SBM/week
        arithmetic mean (standard deviation)
    2.3 ( 2.35 )
    2.1 ( 1.74 )
    Notes
    [16] - Not all subjects in the Full Analysis Set had data for this outcome.
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Number of SBM Per Week Over the 8 Week Double Blind Treatment Period

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    End point title
    		 Change From Baseline in the Number of SBM Per Week Over the 8 Week Double Blind Treatment Period
    End point description
    Full Analysis Set includes all subjects who were randomized and received at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Baseline and over the 8 week double blind treatment period
    End point values
    		 Prucalopride Placebo
    Number of subjects analysed
    105 [17]
    107
    Units: SBM/week
        arithmetic mean (standard deviation)
    1.5 ( 2.35 )
    1 ( 1.78 )
    Notes
    [17] - Not all subjects in the Full Analysis Set had data for this outcome.
    No statistical analyses for this end point

    Secondary: Severity of Constipation Over the Past 2 Weeks for the Final On Treatment Assessment in the Double-Blind Treatment Period

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    End point title
    		 Severity of Constipation Over the Past 2 Weeks for the Final On Treatment Assessment in the Double-Blind Treatment Period
    End point description
    Full Analysis Set includes all subjects who were randomized and received at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    2 weeks
    End point values
    		 Prucalopride Placebo
    Number of subjects analysed
    103 [18]
    107
    Units: percentage of subjects
    number (not applicable)
        Absent
    15.5
    5.6
        Mild
    21.4
    18.7
        Moderate
    19.4
    27.1
        Severe
    27.2
    24.3
        Very severe
    16.5
    24.3
    Notes
    [18] - Not all subjects in the Full Analysis Set had data for this outcome.
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Prucalopride v Placebo
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1599
    Method
    		 Van Elteren test
    Confidence interval

    Secondary: Severity of Constipation Over the Past 2 Weeks for the Final On Treatment Assessment in the Open-Label Treatment Period

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    End point title
    		 Severity of Constipation Over the Past 2 Weeks for the Final On Treatment Assessment in the Open-Label Treatment Period
    End point description
    Full Analysis Set includes all subjects who were randomized and received at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    2 weeks
    End point values
    		 Prucalopride PEG 4000 (Polyethylene Glycol)
    Number of subjects analysed
    97 [19]
    93 [20]
    Units: percentage of subjects
    number (not applicable)
        Absent
    24.7
    46.2
        Mild
    17.5
    16.1
        Moderate
    17.5
    9.7
        Severe
    15.5
    15.1
        Very severe
    24.7
    12.9
    Notes
    [19] - Not all subjects in the Full Analysis Set had data for this outcome.
    [20] - Not all subjects in the Full Analysis Set had data for this outcome.
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Prucalopride v PEG 4000 (Polyethylene Glycol)
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003
    Method
    		 Van Elteren test
    Confidence interval

    Secondary: Efficacy of Treatment for Final On Treatment Assessment in Double-Blind Treatment Period

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    End point title
    		 Efficacy of Treatment for Final On Treatment Assessment in Double-Blind Treatment Period
    End point description
    Full Analysis Set includes all subjects who were randomized and received at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Over the 8 week double blind treatment period
    End point values
    		 Prucalopride Placebo
    Number of subjects analysed
    103 [21]
    107
    Units: percentage of subjects
    number (not applicable)
        Not at all effective
    33
    32.7
        Little bit effective
    14.6
    18.7
        Moderately effective
    15.5
    25.2
        Quite a bit effective
    22.3
    14
        Extremely effective
    14.6
    9.3
    Notes
    [21] - Not all subjects in the Full Analysis Set had data for this outcome.
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Placebo v Prucalopride
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4647
    Method
    		 Van Elteren test
    Confidence interval

    Secondary: Efficacy of Treatment for Final On Treatment Assessment in Open-Label Treatment Period

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    End point title
    		 Efficacy of Treatment for Final On Treatment Assessment in Open-Label Treatment Period
    End point description
    Full Analysis Set includes all subjects who were randomized and received at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Over the 16 week open label treatment period
    End point values
    		 Prucalopride PEG 4000 (Polyethylene Glycol)
    Number of subjects analysed
    97 [22]
    93 [23]
    Units: percentage of subjects
    number (not applicable)
        Not at all effective
    29.9
    15.1
        Little bit effective
    10.3
    5.4
        Moderately effective
    20.6
    11.8
        Quite a bit effective
    18.6
    21.5
        Extremely effective
    20.6
    46.2
    Notes
    [22] - Not all subjects in the Full Analysis Set had data for this outcome.
    [23] - Not all subjects in the Full Analysis Set had data for this outcome.
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    PEG 4000 (Polyethylene Glycol) v Prucalopride
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Van Elteren test
    Confidence interval

    Secondary: Convenience of Treatment for Final On Treatment Assessment in Open-Label Treatment Period

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    End point title
    		 Convenience of Treatment for Final On Treatment Assessment in Open-Label Treatment Period
    End point description
    Full Analysis Set includes all subjects who were randomized and received at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Over the 16 week open label treatment period
    End point values
    		 Prucalopride PEG 4000 (Polyethylene Glycol)
    Number of subjects analysed
    97 [24]
    90 [25]
    Units: percentage of subjects
    number (not applicable)
        Neutral
    16.5
    15.6
        Very difficult
    1
    2.2
        Quite difficult
    0
    5.6
        Quite easy
    27.8
    28.9
        Very easy
    54.6
    47.8
    Notes
    [24] - Not all subjects in the Full Analysis Set had data for this outcome.
    [25] - Not all subjects in the Full Analysis Set had data for this outcome.
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Prucalopride v PEG 4000 (Polyethylene Glycol)
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3044
    Method
    		 Van Elteren test
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Week 24
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    Prucalopride (Double-blind Period)
    Reporting group description
    		 Subjects with weight ≤ 50 kg received 0.04 mg/kg prucalopride once daily as oral solution of 0.4 mg/mL. Subjects with weight > 50 kg received prucalopride 2 mg oral tablet once daily.

    Reporting group title
    Placebo (Double-blind Period)
    Reporting group description
    		 Subjects with weight ≤ 50 kg received placebo matching to prucalopride oral solution. Subjects with weight >50 kg received placebo matching prucalopride oral tablet.

    Reporting group title
    Prucalopride (Open-label Period)
    Reporting group description
    		 Subjects with weight ≤ 50 kg received 0.04 mg/kg prucalopride once daily as oral solution of 0.4 mg/mL. Subjects with weight > 50 kg received prucalopride 2 mg oral tablet once daily.

    Reporting group title
    PEG 4000 (Open-label Period)
    Reporting group description
    		 Subjects received PEG 4000 oral solution at a dose of 4 gram to 20 gram once daily.

    Serious adverse events
    		 Prucalopride (Double-blind Period) Placebo (Double-blind Period) Prucalopride (Open-label Period) PEG 4000 (Open-label Period)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 106 (4.72%)
    2 / 107 (1.87%)
    4 / 98 (4.08%)
    1 / 99 (1.01%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 107 (0.00%)
    1 / 98 (1.02%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (0.00%)
    0 / 98 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (0.00%)
    0 / 98 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 107 (0.93%)
    0 / 98 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
    2 / 98 (2.04%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (0.00%)
    1 / 98 (1.02%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhea
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (0.00%)
    0 / 98 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (0.00%)
    0 / 98 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 107 (0.00%)
    0 / 98 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anorectal discomfort
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
    0 / 98 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (0.00%)
    0 / 98 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (0.00%)
    0 / 98 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (0.00%)
    0 / 98 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 107 (0.00%)
    1 / 98 (1.02%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Prucalopride (Double-blind Period) Placebo (Double-blind Period) Prucalopride (Open-label Period) PEG 4000 (Open-label Period)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    53 / 106 (50.00%)
    50 / 107 (46.73%)
    44 / 98 (44.90%)
    44 / 99 (44.44%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    17 / 106 (16.04%)
    9 / 107 (8.41%)
    3 / 98 (3.06%)
    7 / 99 (7.07%)
         occurrences all number
    24
    11
    3
    7
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    15 / 106 (14.15%)
    3 / 107 (2.80%)
    5 / 98 (5.10%)
    7 / 99 (7.07%)
         occurrences all number
    18
    4
    5
    7
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 106 (1.89%)
    2 / 107 (1.87%)
    6 / 98 (6.12%)
    2 / 99 (2.02%)
         occurrences all number
    3
    2
    8
    2
    Vomiting
         subjects affected / exposed
    14 / 106 (13.21%)
    5 / 107 (4.67%)
    9 / 98 (9.18%)
    5 / 99 (5.05%)
         occurrences all number
    16
    5
    10
    6
    Abdominal pain
         subjects affected / exposed
    13 / 106 (12.26%)
    12 / 107 (11.21%)
    9 / 98 (9.18%)
    11 / 99 (11.11%)
         occurrences all number
    17
    21
    9
    12
    Diarrhea
         subjects affected / exposed
    5 / 106 (4.72%)
    6 / 107 (5.61%)
    3 / 98 (3.06%)
    12 / 99 (12.12%)
         occurrences all number
    5
    6
    5
    13
    Nausea
         subjects affected / exposed
    9 / 106 (8.49%)
    6 / 107 (5.61%)
    4 / 98 (4.08%)
    1 / 99 (1.01%)
         occurrences all number
    11
    6
    4
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    6 / 106 (5.66%)
    2 / 107 (1.87%)
    4 / 98 (4.08%)
    6 / 99 (6.06%)
         occurrences all number
    6
    2
    4
    6
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 106 (1.89%)
    7 / 107 (6.54%)
    5 / 98 (5.10%)
    3 / 99 (3.03%)
         occurrences all number
    2
    8
    5
    3
    Nasopharyngitis
         subjects affected / exposed
    3 / 106 (2.83%)
    2 / 107 (1.87%)
    6 / 98 (6.12%)
    5 / 99 (5.05%)
         occurrences all number
    3
    2
    6
    6
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 106 (1.89%)
    5 / 107 (4.67%)
    5 / 98 (5.10%)
    5 / 99 (5.05%)
         occurrences all number
    4
    7
    6
    7
    Viral infection
         subjects affected / exposed
    6 / 106 (5.66%)
    5 / 107 (4.67%)
    3 / 98 (3.06%)
    4 / 99 (4.04%)
         occurrences all number
    6
    5
    4
    5
    Pharyngitis
         subjects affected / exposed
    3 / 106 (2.83%)
    6 / 107 (5.61%)
    5 / 98 (5.10%)
    4 / 99 (4.04%)
         occurrences all number
    3
    6
    5
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Dec 2010
    The volumes of blood to be taken for biochemistry and hematology panels were corrected.
    27 Jan 2011
    Upon request of the Competent Authorities, the following changes were made: 1. Severe renal insufficiency was added to the exclusion criteria 2. “The rescue medication products have to be used in respect to the contraindications, warnings and precautions of use, and interactions of their Summary of Product Characteristics” was added as a warning for rescue medication 3. “Prucalopride should be used with caution in subjects receiving concomitant drugs known to cause QTc prolongation” was added as a warning for prucalopride
    18 Apr 2011
    1. The sponsor’s name was changed from Movetis to Shire-Movetis 2. SAE reporting procedures were changed from Movetis to Shire procedures 3. It was indicated that a paper medication intake form was to be used in the Open-label Treatment Period
    19 Dec 2011
    1. The Shire study number (SPD555-303) was added to the front page of the protocol 2. Measurement of Tanner stages for sexual maturation was added 3. In response to scientific input of experienced clinicians at an investigator follow-up meeting, some sections in the protocol were slightly reworded and clarified to be in line with clinical practice Apart from the above, minor editorial changes were performed
    31 Jul 2012
    Reference to a proposed study for the follow-up of growth and sexual maturation was removed.

    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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