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    Clinical Trial Results:
    A 12-week, Randomised, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy, Quality of Life, Safety and Tolerability of Prucalopride in Male Subjects With Chronic Constipation

    Summary
    EudraCT number
    2009-015719-42
    Trial protocol
    BE   DE   CZ   GB   FR   NL   BG   DK  
    Global end of trial date
    25 Oct 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
    SPD555-302
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01147926
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Study Number: M0001-C302
    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)
    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
    25 Oct 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Oct 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of prucalopride versus placebo over 12 weeks of treatment in male subjects with chronic constipation.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation of Good Clinical Practice (GCP), 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
    23 Sep 2010
    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
    United Kingdom: 24
    Country: Number of subjects enrolled
    Belgium: 20
    Country: Number of subjects enrolled
    Bulgaria: 18
    Country: Number of subjects enrolled
    Czech Republic: 29
    Country: Number of subjects enrolled
    Denmark: 41
    Country: Number of subjects enrolled
    France: 41
    Country: Number of subjects enrolled
    Germany: 21
    Country: Number of subjects enrolled
    Netherlands: 10
    Country: Number of subjects enrolled
    Poland: 56
    Country: Number of subjects enrolled
    Romania: 114
    Worldwide total number of subjects
    374
    EEA total number of subjects
    374
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    222
    From 65 to 84 years
    145
    85 years and over
    7

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Out of a total of 553 subjects screened, 374 were randomized and 370 were treated with study drug. Reasons for 4 'randomized subjects but not treated': 2 subjects withdrew consent (1 each in placebo and prucalopride groups), 1 subject was non-compliant in prucalopride group, and 1 subject did not meet selection criteria in prucalopride group.

    Pre-assignment period milestones
    Number of subjects started
    374
    Number of subjects completed
    370

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Consent withdrawn by subject: 2
    Reason: Number of subjects
    Non-compliance: 1
    Reason: Number of subjects
    Did not meet selection criteria: 1
    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Placebo matched to Prucalopride tablet orally once daily.
    Arm type
    Placebo

    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 received oral dose of placebo matching with prucalopride once daily.

    Arm title
    Prucalopride
    Arm description
    Prucalopride 2 milligram (mg) tablet orally once daily for subjects greater than or equal to (≥) 18 to less than (<) 65 years; 1 mg once daily orally for subjects ≥65 years, and in case of insufficient response, increased to 2 mg once daily orally at Week 2 or Week 4.
    Arm type
    Experimental

    Investigational medicinal product name
    Prucalopride
    Investigational medicinal product code
    M0001, SPD555
    Other name
    Resolor®
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received prucalopride 2 mg once daily orally (subjects ≥18 to <65 years); 1 mg once daily orally (subjects ≥65 years), and in case of insufficient response, increased to 2 mg once daily orally at Week 2 or Week 4.

    Number of subjects in period 1 [1]
    Placebo Prucalopride
    Started
    186
    184
    Completed
    160
    158
    Not completed
    26
    26
         Sponsor's Decision
    -
    1
         Too busy, no time for study
    1
    -
         Lack of efficacy
    1
    -
         Selection criteria not met
    3
    -
         Subject non-compliant
    5
    3
         Consent withdrawn by subject
    8
    9
         Adverse Event
    7
    6
         Principal investigator left hospital
    1
    3
         Colonoscopy result
    -
    1
         Went on holiday
    -
    1
         Lost to follow-up
    -
    2
    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 period included only treated subjects, the worldwide number enrolled in the trial differs with the number of subjects reported in the baseline period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo matched to Prucalopride tablet orally once daily.

    Reporting group title
    Prucalopride
    Reporting group description
    Prucalopride 2 milligram (mg) tablet orally once daily for subjects greater than or equal to (≥) 18 to less than (<) 65 years; 1 mg once daily orally for subjects ≥65 years, and in case of insufficient response, increased to 2 mg once daily orally at Week 2 or Week 4.

    Reporting group values
    Placebo Prucalopride Total
    Number of subjects
    186 184 370
    Age categorical
    Safety population was defined as all subjects randomized into the study, who took at least 1 dose of investigational product based on information from the e-diary and/or tablet count (compliance) documented on the electronic case report form (eCRF). The Safety Population is equivalent to an Intent-to-treat (ITT) Population.
    Units: Subjects
        Less than 65 years
    115 104 219
        Between 65 and 75 years
    39 43 82
        75 years and above
    32 37 69
    Age continuous
    Safety population was defined as all subjects randomized into the study, who took at least 1 dose of investigational product based on information from the e-diary and/or tablet count (compliance) documented on the eCRF. The Safety Population is equivalent to an ITT Population.
    Units: years
        arithmetic mean (standard deviation)
    58.5 ± 16.28 58.4 ± 17.57 -
    Gender categorical
    Safety population was defined as all subjects randomized into the study, who took at least 1 dose of investigational product based on information from the e-diary and/or tablet count (compliance) documented on the eCRF. The Safety Population is equivalent to an ITT Population.
    Units: Subjects
        Male
    186 184 370

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo matched to Prucalopride tablet orally once daily.

    Reporting group title
    Prucalopride
    Reporting group description
    Prucalopride 2 milligram (mg) tablet orally once daily for subjects greater than or equal to (≥) 18 to less than (<) 65 years; 1 mg once daily orally for subjects ≥65 years, and in case of insufficient response, increased to 2 mg once daily orally at Week 2 or Week 4.

    Primary: The Percentage of Subjects With an Average of ≥3 Spontaneous Complete Bowel Movements (SCBM) Per Week

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    End point title
    The Percentage of Subjects With an Average of ≥3 Spontaneous Complete Bowel Movements (SCBM) Per Week
    End point description
    Spontaneous Bowel Movements defined as a bowel movement that was not preceded within a period of 24 hours by the intake of a laxative agent or by the use of an enema. Modified Intent-to-treat Population (mITT) included all subjects randomized into the study except those excluded due to a major GCP breach at one site, who took at least 1 dose of the investigational product.
    End point type
    Primary
    End point timeframe
    Over 12-week treatment period
    End point values
    Placebo Prucalopride
    Number of subjects analysed
    181
    177
    Units: percentage of subjects
        number (not applicable)
    17.7
    37.9
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Placebo v Prucalopride
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Percentage of Subjects With an Average Weekly Frequency of at Least 3 SCBM Per Week and an Increase of ≥ 1 SCBM Per Week for ≥ 75% of the 12-week Treatment Period and ≥ 75% of the Last Third of the 12-week Treatment Period

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    End point title
    Percentage of Subjects With an Average Weekly Frequency of at Least 3 SCBM Per Week and an Increase of ≥ 1 SCBM Per Week for ≥ 75% of the 12-week Treatment Period and ≥ 75% of the Last Third of the 12-week Treatment Period
    End point description
    mITT population included all subjects randomized into the study except those excluded due to a major GCP breach at one site, who took at least 1 dose of the investigational product.
    End point type
    Secondary
    End point timeframe
    Over 12-week treatment period
    End point values
    Placebo Prucalopride
    Number of subjects analysed
    181
    177
    Units: percentage of subjects
        number (not applicable)
    12.2
    27.7
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With an Increase of at Least 1 SCBM Per Week

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    End point title
    Percentage of Subjects With an Increase of at Least 1 SCBM Per Week
    End point description
    mITT population included all subjects randomized into the study except those excluded due to a major GCP breach at one site, who took at least 1 dose of the investigational product.
    End point type
    Secondary
    End point timeframe
    Over 12-week treatment period
    End point values
    Placebo Prucalopride
    Number of subjects analysed
    181
    177
    Units: percentage of subjects
        number (not applicable)
    45.3
    53.7
    No statistical analyses for this end point

    Secondary: SCBM Per Week

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    End point title
    SCBM Per Week
    End point description
    mITT population included all subjects randomized into the study except those excluded due to a major GCP breach at one site, who took at least 1 dose of the investigational product.
    End point type
    Secondary
    End point timeframe
    Over 12-week treatment period
    End point values
    Placebo Prucalopride
    Number of subjects analysed
    172 [1]
    170 [2]
    Units: SCBM per week
        arithmetic mean (standard deviation)
    1.8 ± 1.91
    2.6 ± 2.4
    Notes
    [1] - Not all subjects in the mITT population had data for this outcome.
    [2] - Not all subjects in the mITT population had data for this outcome.
    No statistical analyses for this end point

    Secondary: Percent spontaneous bowel movements (SBM) With a Consistency of Normal and Hard/Very Hard

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    End point title
    Percent spontaneous bowel movements (SBM) With a Consistency of Normal and Hard/Very Hard
    End point description
    Consistency measured using the 7-point Bristol scale where 1-2 indicate constipation (=hard/very hard), 3-4 are ideal stools (=normal), and 5-7 tending toward diarrhea. mITT population included all subjects randomized into the study except those excluded due to a major GCP breach at one site, who took at least 1 dose of the investigational product.
    End point type
    Secondary
    End point timeframe
    Over 12-week treatment period
    End point values
    Placebo Prucalopride
    Number of subjects analysed
    167 [3]
    170 [4]
    Units: percentage of SBM
    arithmetic mean (standard deviation)
        Normal consistency
    50.8 ± 30.21
    47.5 ± 31.7
        Hard/Very hard consistency
    31.9 ± 29.86
    26.9 ± 28.27
    Notes
    [3] - Not all subjects in the mITT population had data for this outcome.
    [4] - Not all subjects in the mITT population had data for this outcome.
    No statistical analyses for this end point

    Secondary: Percent SCBM With No Straining and Severe/Very Severe Straining

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    End point title
    Percent SCBM With No Straining and Severe/Very Severe Straining
    End point description
    Straining was evaluated on a 5-point scale (0=none, 1=mild, 2=moderate, 3=severe, or 4=very severe). mITT population included all subjects randomized into the study except those excluded due to a major GCP breach at one site, who took at least 1 dose of the investigational product.
    End point type
    Secondary
    End point timeframe
    Over 12 week treatment period
    End point values
    Placebo Prucalopride
    Number of subjects analysed
    167 [5]
    170 [6]
    Units: percentage of SBM
    arithmetic mean (standard deviation)
        No straining
    9.5 ± 16.23
    9.7 ± 17.4
        Severe/Very severe straining
    23.7 ± 27.62
    20.6 ± 27.33
    Notes
    [5] - Not all subjects in the mITT population had data for this outcome.
    [6] - Not all subjects in the mITT population had data for this outcome.
    No statistical analyses for this end point

    Secondary: Percent SBM With Sensation of Complete Evacuation

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    End point title
    Percent SBM With Sensation of Complete Evacuation
    End point description
    mITT population included all subjects randomized into the study except those excluded due to a major GCP breach at one site, who took at least 1 dose of the investigational product.
    End point type
    Secondary
    End point timeframe
    Over 12 week treatment period
    End point values
    Placebo Prucalopride
    Number of subjects analysed
    167 [7]
    170 [8]
    Units: percentage of SBM
        arithmetic mean (standard deviation)
    43.2 ± 32.9
    46.7 ± 34.19
    Notes
    [7] - Not all subjects in the mITT population had data for this outcome.
    [8] - Not all subjects in the mITT population had data for this outcome.
    No statistical analyses for this end point

    Secondary: Time to First SCBM After Investigational Product Intake on Day 1

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    End point title
    Time to First SCBM After Investigational Product Intake on Day 1
    End point description
    mITT population included all subjects randomized into the study except those excluded due to a major GCP breach at one site, who took at least 1 dose of the investigational product.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    Placebo Prucalopride
    Number of subjects analysed
    181
    177
    Units: hours
        median (confidence interval 95%)
    218.9 (143.93 to 291.43)
    110.3 (70.8 to 172.77)
    No statistical analyses for this end point

    Secondary: Bisacodyl Tablets Taken Per Week

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    End point title
    Bisacodyl Tablets Taken Per Week
    End point description
    mITT population included all subjects randomized into the study except those excluded due to a major GCP breach at one site, who took at least 1 dose of the investigational product.
    End point type
    Secondary
    End point timeframe
    Over 12 week treatment period
    End point values
    Placebo Prucalopride
    Number of subjects analysed
    172 [9]
    170 [10]
    Units: tablets/week
        arithmetic mean (standard deviation)
    1 ± 1.76
    0.6 ± 1.56
    Notes
    [9] - Not all subjects in the mITT population had data for this outcome.
    [10] - Not all subjects in the mITT population had data for this outcome.
    No statistical analyses for this end point

    Secondary: Days With Rescue Medication Taken Per Week

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    End point title
    Days With Rescue Medication Taken Per Week
    End point description
    mITT population included all subjects randomized into the study except those excluded due to a major GCP breach at one site, who took at least 1 dose of the investigational product.
    End point type
    Secondary
    End point timeframe
    Over 12-week treatment period
    End point values
    Placebo Prucalopride
    Number of subjects analysed
    172 [11]
    170 [12]
    Units: days/week
        arithmetic mean (standard deviation)
    0.6 ± 0.94
    0.3 ± 0.69
    Notes
    [11] - Not all subjects in the mITT population had data for this outcome.
    [12] - Not all subjects in the mITT population had data for this outcome.
    No statistical analyses for this end point

    Secondary: Percent of Subjects With an Improvement of ≥ 1 Point on the Patient Assessment of Constipation – Symptom (PAC-SYM) Questionnaire Total Score at Final On-Treatment Assessment

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    End point title
    Percent of Subjects With an Improvement of ≥ 1 Point on the Patient Assessment of Constipation – Symptom (PAC-SYM) Questionnaire Total Score at Final On-Treatment Assessment
    End point description
    The PAC-SYM is a validated 12-item questionnaire for the evaluation of severity of symptoms of constipation in subjects with constipation. Items were rated on a 5-point Likert scale: 0=absent, 1=mild, 2=moderate, 3=severe, 4=very severe. Total score ranged from 0 to 48. Lower scores indicate improvement in symptoms. A 1-point improvement in PAC-SYM total score was considered clinically meaningful. mITT population included all subjects randomized into the study except those excluded due to a major GCP breach at one site, who took at least 1 dose of the investigational product.
    End point type
    Secondary
    End point timeframe
    Over 12-week treatment period
    End point values
    Placebo Prucalopride
    Number of subjects analysed
    171 [13]
    169 [14]
    Units: percentage of subjects
        number (not applicable)
    30.4
    34.9
    Notes
    [13] - Not all subjects in the mITT population had data for this outcome.
    [14] - Not all subjects in the mITT population had data for this outcome.
    No statistical analyses for this end point

    Secondary: Percent of Subjects With an Improvement of ≥ 1 Point on the Patient Assessment of Constipation - Quality of Life (PAC-QOL) Total Score at Final On-Treatment Assessment

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    End point title
    Percent of Subjects With an Improvement of ≥ 1 Point on the Patient Assessment of Constipation - Quality of Life (PAC-QOL) Total Score at Final On-Treatment Assessment
    End point description
    The PAC-QOL is a validated 28-item questionnaire for the evaluation of quality of life in subjects with constipation. Items were rated on a 5-point Likert scale: 0=not at all/none of the time, 1=a little bit/a little bit of the time, 2=moderately/some of the time, 3=quite a bit/most of the time, 4=extremely/all of the time. Total score ranged from 0-112. Lower scores indicate improvement in symptoms. A 1-point improvement in PAC-QOL total score was considered clinically meaningful. mITT population included all subjects randomized into the study except those excluded due to a major GCP breach at one site, who took at least 1 dose of the investigational product.
    End point type
    Secondary
    End point timeframe
    Over 12-week treatment period
    End point values
    Placebo Prucalopride
    Number of subjects analysed
    171 [15]
    169 [16]
    Units: percentage of subjects
        number (not applicable)
    32.7
    40.2
    Notes
    [15] - Not all subjects in the mITT population had data for this outcome.
    [16] - Not all subjects in the mITT population had data for this outcome.
    No statistical analyses for this end point

    Secondary: Percent of Subjects on the Subject Global Evaluation on Severity of Constipation Score Rating Constipation as Severe to Very Severe at Final On-Treatment Assessment

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    End point title
    Percent of Subjects on the Subject Global Evaluation on Severity of Constipation Score Rating Constipation as Severe to Very Severe at Final On-Treatment Assessment
    End point description
    Subject was asked to rate the severity of his constipation using a 5-point Likert scale: 0=absent, 1=mild, 2=moderate, 3=severe, 4=very severe. mITT population included all subjects randomized into the study except those excluded due to a major GCP breach at one site, who took at least 1 dose of the investigational product.
    End point type
    Secondary
    End point timeframe
    Over 12-week treatment period
    End point values
    Placebo Prucalopride
    Number of subjects analysed
    171 [17]
    169 [18]
    Units: percentage of subjects
        number (not applicable)
    30.4
    21.9
    Notes
    [17] - Not all subjects in the mITT population had data for this outcome.
    [18] - Not all subjects in the mITT population had data for this outcome.
    No statistical analyses for this end point

    Secondary: Percent of Subjects on the Subject Global Evaluation on Efficacy of Treatment Score Rating Treatment as Quite a Bit to Extremely Effective at Final On-Treatment Assessment

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    End point title
    Percent of Subjects on the Subject Global Evaluation on Efficacy of Treatment Score Rating Treatment as Quite a Bit to Extremely Effective at Final On-Treatment Assessment
    End point description
    The subject was asked to rate his global evaluation of the efficacy of treatment using the following 5-point scale: 0=not at all effective 1=a little bit effective 2=moderately effective 3=quite a bit effective 4=extremely effective. mITT population included all subjects randomized into the study except those excluded due to a major GCP breach at one site, who took at least 1 dose of the investigational product.
    End point type
    Secondary
    End point timeframe
    Over 12-week treatment period
    End point values
    Placebo Prucalopride
    Number of subjects analysed
    171 [19]
    169 [20]
    Units: percentage of subjects
        number (not applicable)
    30.4
    46.7
    Notes
    [19] - Not all subjects in the mITT population had data for this outcome.
    [20] - Not all subjects in the mITT population had data for this outcome.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Week 12
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo matched to Prucalopride tablet orally once daily.

    Reporting group title
    Prucalopride
    Reporting group description
    Prucalopride 2 mg tablet orally once daily for subjects ≥18 to <65 years; 1 mg once daily orally for subjects ≥65 years, and in case of insufficient response, increased to 2 mg once daily orally at Week 2 or Week 4.

    Serious adverse events
    Placebo Prucalopride
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 186 (2.15%)
    1 / 184 (0.54%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    LOWER LIMB FRACTURE
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    GLOTTIS CARCINOMA
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    ATRIAL FIBRILLATION
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYOCARDIAL ISCHAEMIA
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ATELECTASIS
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 184 (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
    Placebo Prucalopride
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 186 (11.29%)
    37 / 184 (20.11%)
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    7 / 186 (3.76%)
    17 / 184 (9.24%)
         occurrences all number
    8
    18
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    11 / 186 (5.91%)
    8 / 184 (4.35%)
         occurrences all number
    12
    11
    DIARRHOEA
         subjects affected / exposed
    3 / 186 (1.61%)
    12 / 184 (6.52%)
         occurrences all number
    3
    16
    NAUSEA
         subjects affected / exposed
    4 / 186 (2.15%)
    11 / 184 (5.98%)
         occurrences all number
    4
    12

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Apr 2011
    1. A colonoscopy/sigmoidoscopy was added at the Screening Visit (Visit 1) in subjects for which organic disorders needed to be ruled out (these subjects had a 4-week Run-in Period) 2. Study duration was prolonged up to 16 weeks to allow for a possible 4-week Run-in Period 3. Inclusion criterion was reworded to specify that subjects with a history of on average less than or equal to 2 SBM/week that resulted in a feeling of complete evacuation were to be excluded 4. Subjects with insulin-dependent diabetes mellitus should always be excluded, also if they were under appropriate medical therapy. In addition, for all other conditions listed in this exclusion criterion, the following was added: if a subject was experiencing chronic constipation prior to the onset of the condition and the constipation had not been worsened by the condition, the subject was eligible for screening. However, if the constipation had started after the onset of the condition and the relation between both could not be excluded (it was not certain whether it was secondary to it or not), or when the constipation had worsened after the onset of 1 of the above conditions, the subject was not allowed to be screened for this study 5. Summarized information on excluded conditions of the gastrointestinal tract. In addition, it was specified in which circumstances an endoscopy or radiologic bowel evaluation was required 6. An exclusion criterion was added to exclude subjects who previously used prucalopride 7. It was clarified that serious adverse events needed to be reported within 1 working day (instead of within 24 hours)
    11 Aug 2011
    1. Exclusion Criterion was reworded to reflect clinical practice and to allow for clinical judgment in those instances when a repeat procedure would be indicated. Colonoscopy and/or sigmoidoscopy with or without barium enema (depending on age) was performed in this study to prevent subjects from being randomized into the study with primarily obstructive or inflammatory disease as the cause of constipation. A procedure within 5 years was sufficient to screen subjects for serious colonic disease and to remove polyps. In clinical practice, removal of a polyp would not warrant repeat colonoscopy prior to a 5-year time point unless there were special circumstances 2. Updated from milligram per deciliter to micromole per liter, to reflect the current International System of Units for serum creatinine concentration. Also, the creatinine clearance cut-off was changed from 50 milliliter per minute (mL/min) to 30 mL/min to be in line with the Summary of Product Characteristics which mentions that subjects with severe renal impairment (creatinine clearance less than or equal to 30mL/min) had to start at a dose of 1 mg 3. Subjects could not be rescreened without prior approval from the sponsor 4. It was clarified that subjects received 1 package of bisacodyl at the Screening Visit (Visit 1) and from then on, they received bisacodyl as required 5. The timing of dosing was specified in Dose Regimen and Administration Period and instructions were added on what to do in case of a missed dose 6. The relatedness categories were updated to the dichotomized categories “related” (includes very likely, probably, and possibly related) and “not related” (includes doubtful and not related) 6. The time period prior to the start of investigational product during which no bisacodyl could be used was changed from “48 hours before the start of the Double-blind Treatment (Visit)” to “24 hours before the start of Double-blind Treatment (morning after Visit 2)"

    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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