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    Clinical Trial Results:
    A multicentre, randomised, plcebo-controlled, double-blind study of the efficacy, safety, and pharmacekinetics of lubiprostone in paediatric subjects aged >=6 years to <18 years with functional constipation

    Summary
    EudraCT number
    		 2013-003468-30
    Trial protocol
    		 BE   GB   DE   ES   NL   PL   FR  
    Global end of trial date
    27 Jul 2016

    Results information
    Results version number
    		 v2(current)
    This version publication date
    06 Dec 2017
    First version publication date
    10 May 2017
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    • Changes to summary attachments
    We noted a number of errors included in this register, which we would need to correct.

    Trial information

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    Trial identification
    Sponsor protocol code
    SAG/0211PFC-1131
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02766777
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Sucampo AG
    Sponsor organisation address
    Baarerstrasse 22, Zug, Switzerland, 6300
    Public contact
    Hermann Schulze, PhD, Sucampo AG, 41 41-726-3030, hschulze@sucampo.com
    Scientific contact
    Hermann Schulze, PhD, Sucampo AG, 41 41-726-3030, hschulze@sucampo.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000245-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
    28 Mar 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Jul 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy, safety and pharmacokinetics of oral lubiprostone 12 or 24 mcg capsules dosed twice daily (based on subject body weight at baseline) as compared to matching placebo, when administered orally for 12 weeks in paediatric subjects with functional constipation. To evaluate the measurement characteristics of the paediatric functional constipation clinical outcome assessments, including observer-reported outcomes and patient-reported outcomes instruments.
    Protection of trial subjects
    No specific measures were put in place.
    Background therapy
    		 Background therapy was not allowed and had to be discontinued before randomisation. However, in the event that no bowel movement occurred within a 3-day period, the use of rescue medication was permitted as per the instructions of the investigator.
    Evidence for comparator
    		 No active comparator was use. This was a placebo-controlled study.
    Actual start date of recruitment
    25 Nov 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 9 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 46
    Country: Number of subjects enrolled
    Poland: 11
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    United States: 522
    Worldwide total number of subjects
    606
    EEA total number of subjects
    72
    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)
    279
    Adolescents (12-17 years)
    327
    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
    		 The total trial duration was 16 weeks, consisting of a screening phase (2 weeks), treatment phase (12 weeks) and a follow-up phase (2 weeks). Subjects had to be between 6 and 17 years old at the time of screening. Subjects had to fulfill the modified Rome III Diagnostic Criteria for Childhood Functional Constipation (Child/Adolescent; Section H3a)

    Pre-assignment
    Screening details
    		 Subjects fulfilling the inclusion criteria were screened 2 weeks prior to the treatment phase. During this time, subjects had to discontinue prior concomitant medications that would affect gastrointestinal motility. If subjects took a fibre supplement (Metamucil®, PerDiem®, Fybogel), usage must have been at a stable dose and schedule for 30 days.

    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, Data analyst, Carer
    Blinding implementation details
    None specific. The IMPs were all looking identical.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Verum
    Arm description
    		 Lubiprostone 12 or 24 mcg, depending on subject's body weight at baseline
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lubiprostone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects with a body weight <50 kg at baseline received Lubiprostone 12 mcg BID for 12 weeks. If the dose was safe but did not show any efficacy at Week 1, dosage was increased to 24 mcg BID. Subjects with a body weight >50 kg at baseline received Lubiprostone 24 mcg BID for 12 weeks. If the dose was unsafe at Week 1, dosage was decreased to 12 mcg BID.

    Arm title
    		 Placebo
    Arm description
    		 Matching placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to lubiprostone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    one placebo capsule BID for 12 weeks.

    Number of subjects in period 1
    		Verum Placebo
    Started
    404
    202
    Completed
    339
    166
    Not completed
    65
    36
         Physician decision
    7
    2
         Adverse event, non-fatal
    17
    6
         withdrawal by subject
    21
    16
         non-compliance with study drug
    2
    3
         Lost to follow-up
    9
    2
         Lack of efficacy
    4
    3
         terminated by sponsor
    2
    1
         not specified
    3
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Verum
    Reporting group description
    		 Lubiprostone 12 or 24 mcg, depending on subject's body weight at baseline

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo

    Reporting group values
    		 Verum Placebo Total
    Number of subjects
    		 404 202 606
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 196 95 291
        Adolescents (12-17 years)
    		 208 107 315
    Gender categorical
    Units: Subjects
        Female
    		 217 110 327
        Male
    		 187 92 279
    Body weight
    below and above 50 kg
    Units: Subjects
        <50 kg
    		 239 113 352
        >50 kg
    		 165 89 254
    Subject analysis sets

    Subject analysis set title
    mITT verum
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    mITT population receiving lubiprostone

    Subject analysis set title
    mITT Placebo
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    mITT population receiving placebo

    Subject analysis sets values
    		 mITT verum mITT Placebo
    Number of subjects
    399
    195
    Age categorical
    Units: Subjects
        Children (2-11 years)
    193
    92
        Adolescents (12-17 years)
    206
    103
    Age continuous
    Units:
        
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    216
    106
        Male
    183
    89
    Body weight
    below and above 50 kg
    Units: Subjects
        <50 kg
    236
    109
        >50 kg
    163
    86

    End points

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    End points reporting groups
    Reporting group title
    Verum
    Reporting group description
    		 Lubiprostone 12 or 24 mcg, depending on subject's body weight at baseline

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo

    Subject analysis set title
    mITT verum
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    mITT population receiving lubiprostone

    Subject analysis set title
    mITT Placebo
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    mITT population receiving placebo

    Primary: Change in rate of spontaneous bowel movements (SBM)

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    End point title
    		 Change in rate of spontaneous bowel movements (SBM)
    End point description
    The primary efficacy endpoint was the overall SBM response rate of subjects who received oral lubiprostone capsules 12 mcg or 24 mcg BID compared with matching placebo BID administered orally for 12 weeks to subjects with PFC aged ≥6 years to <18 years in the mITT Population.
    End point type
    Primary
    End point timeframe
    at Week 12
    End point values
    		 Verum Placebo mITT verum mITT Placebo
    Number of subjects analysed
    404
    202
    399
    195
    Units: percent
        number (not applicable)
    19
    14.4
    19
    14.4
    Statistical analysis title
    		 Cochran-Mantel-Haenzel
    Statistical analysis description
    For the primary efficacy endpoint of overall SBM response, the Cochran-Mantel-Haenzel (CMH) test stratifying by, baseline SBM frequency (<1.5 or ≥1.5) was to be used for the comparison between the placebo group and the overall lubiprostone group.
    Comparison groups
    Placebo v Verum
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.1609 [1]
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -1.56
         upper limit
    		 10.94
    Variability estimate
    Standard deviation
    Notes
    [1] - primary endpoint was not met.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    14 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Verum
    Reporting group description
    		 this group received Lubiprostone 12 or 24 mcg.

    Reporting group title
    Placebo arm
    Reporting group description
    		 this group received placebo

    Serious adverse events
    		 Verum Placebo arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 404 (2.72%)
    7 / 202 (3.47%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Faecaloma
         subjects affected / exposed
    4 / 404 (0.99%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Hand-foot-and-mouth disease
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Verum Placebo arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    239 / 404 (59.16%)
    114 / 202 (56.44%)
    Investigations
    Investigation
         subjects affected / exposed
    37 / 404 (9.16%)
    14 / 202 (6.93%)
         occurrences all number
    37
    14
    Nervous system disorders
    Headache
         subjects affected / exposed
    34 / 404 (8.42%)
    10 / 202 (4.95%)
         occurrences all number
    34
    10
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    57 / 404 (14.11%)
    14 / 202 (6.93%)
         occurrences all number
    57
    14
    Vomiting
         subjects affected / exposed
    45 / 404 (11.14%)
    12 / 202 (5.94%)
         occurrences all number
    45
    12
    Abdominal pain
         subjects affected / exposed
    42 / 404 (10.40%)
    23 / 202 (11.39%)
         occurrences all number
    42
    23
    Diarrhoea
         subjects affected / exposed
    28 / 404 (6.93%)
    6 / 202 (2.97%)
         occurrences all number
    28
    6
    Abdominal pain upper
         subjects affected / exposed
    20 / 404 (4.95%)
    6 / 202 (2.97%)
         occurrences all number
    20
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Oct 2013
    • Update in Biostatistician and Medical Monitor personnel; • Update in contact information for SAE reporting; • Update to the eligibility criteria associated with bowel movement characteristics; • Change in the primary endpoint to overall SBM response based on FDA’s recommendation; and • Addition of events of special interest (chest pain, dyspnea, hepatotoxicity/liver enzyme increased, anaphylaxis).
    26 Nov 2013
    • Clarification of contraception specifications.
    15 Apr 2014
    • Added evaluation of measurement characteristics of the PFC clinical outcome measure assessments; and • Clarified eligibility to DXA subgroup;
    14 Apr 2015
    • Update to Medical Monitor personnel information in Europe; and • Eligibility update to allow subjects with a concurrent diagnosis of IBS.
    02 Sep 2015
    • Eligibility update to exclude subjects with concurrent diagnosis of IBS.
    25 Sep 2015
    • Revision of dose escalation instructions to require dose escalation by Investigator for subjects who may benefit from a higher dose of study medication.

    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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    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
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