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    Clinical Trial Results:
    A 12-week, randomised, double-blind, placebo-controlled trial to evaluate the efficacy and safety of prucalopride in subjects with chronic non-cancer pain suffering from opioid induced constipation

    Summary
    EudraCT number
    2009-015652-20
    Trial protocol
    BE   PL   DE   CZ   FR   NL   BG   GB   ES   HU  
    Global end of trial date
    13 Aug 2012

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

    Trial information

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    Trial identification
    Sponsor protocol code
    M0001-C301/SPD555-301
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01117051
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Shire-Movetis NV
    Sponsor organisation address
    B-2300 Turnhout, Veedijk, Belgium, 58 (1004)
    Public contact
    Shire-Movetis Clinical Trials, Shire-Movetis NV, +32 14404390, Shire-Movetis.clinicaltrials@shire.com
    Scientific contact
    Shire-Movetis Clinical Trials, Shire-Movetis NV, +32 14404390, Shire-Movetis.clinicaltrials@shire.com
    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
    13 Aug 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Aug 2012
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of prucalopride versus placebo over 12 weeks of treatment in subjects aged 18 years and older with chronic non-cancer pain, suffering from opioid-induced constipation (OIC).
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice. The subject’s informed consent was obtained in writing prior to performing any study-related procedures. Subjects were allowed to take a laxative (bisacodyl DULCOLAX®; Boehringer-Ingelheim) as rescue medication throughout the study, but only if they had not had a bowel movement (BM) in the preceding 48 hours.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    19 May 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
    Netherlands: 1
    Country: Number of subjects enrolled
    Poland: 11
    Country: Number of subjects enrolled
    Romania: 11
    Country: Number of subjects enrolled
    United Kingdom: 27
    Country: Number of subjects enrolled
    Belgium: 17
    Country: Number of subjects enrolled
    Bulgaria: 9
    Country: Number of subjects enrolled
    Czech Republic: 78
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Hungary: 3
    Worldwide total number of subjects
    174
    EEA total number of subjects
    174
    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)
    132
    From 65 to 84 years
    42
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Subjects were screened and entered a 2-week Run-in Period (or a 3-week Run-in Period if the subject was using agents that influence bowel habit) during which the presence and severity of opioid-induced constipation (OIC) was documented (the subject completed an e-diary).

    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
    Blinding implementation details
    Placebo matched investigational product.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Subjects received placebo once daily before breakfast for up to 12 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo was administered once daily before breakfast for 12 weeks. Adult subjects ≥18 to <65 years of age took a placebo tablet matching a 2mg prucalopride tablet. Elderly subjects ≥65 years took a placebo tablet matching a 1mg prucalopride tablet. In case of insufficient response, defined as an average of <3 spontaneous bowel movements (SBM)/week during the preceding 2 weeks of treatment at Week 2 or Week 4, the daily dose had to be increased to one placebo tablet matching a 2mg prucalopride tablet. Once the placebo dose was increased to match 2mg once daily the subject stayed on this dose for the remainder of the study. Further increases or decreases in dose were not permitted, ie, no changes in dose occurred at the Week 8 visit or thereafter.

    Arm title
    Prucalopride
    Arm description
    Participants received prucalopride once daily before breakfast for up to 12 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Prucalopride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prucalopride was administered once daily before breakfast for 12 weeks. Adult subjects ≥18 to <65 years of age took one 2mg tablet. Elderly subjects ≥65 years took one 1mg tablet. In case of insufficient response, defined as an average of <3 spontaneous bowel movements (SBM)/week during the preceding 2 weeks of treatment at Week 2 or Week 4, the daily dose had to be increased to one 2mg tablet. Once the dose was increased to 2mg once daily the subject stayed on this dose for the remainder of the study. Further increases or decreases in dose were not permitted, ie, no changes in dose occurred at the Week 8 visit or thereafter.

    Number of subjects in period 1
    Placebo Prucalopride
    Started
    86
    88
    Completed
    73
    77
    Not completed
    13
    11
         Sponsor's decision
    3
    1
         Convenience issue
    1
    -
         Adverse event
    4
    3
         Withdrawal by subject
    5
    3
         Did not meet in-/exclusion criteria
    -
    1
         Randomised by mistake
    -
    1
         Surgical procedure
    -
    1
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo once daily before breakfast for up to 12 weeks.

    Reporting group title
    Prucalopride
    Reporting group description
    Participants received prucalopride once daily before breakfast for up to 12 weeks.

    Reporting group values
    Placebo Prucalopride Total
    Number of subjects
    86 88 174
    Age categorical
    Units: Subjects
        Between >=18 and <65 years
    65 67 132
        Between >=65 and <75 year
    11 11 22
        >=75 years
    10 10 20
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    57.5 ± 11.49 56 ± 12.25 -
    Gender categorical
    Units: Subjects
        Female
    63 64 127
        Male
    23 24 47
    Region of enrollment
    Units: Subjects
        Belgium
    8 9 17
        Bulgaria
    4 5 9
        Czech Republic
    40 38 78
        Germany
    6 7 13
        France
    2 2 4
        United Kingdom
    13 14 27
        Hungary
    2 1 3
        Netherlands
    0 1 1
        Poland
    6 5 11
        Romania
    5 6 11

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo once daily before breakfast for up to 12 weeks.

    Reporting group title
    Prucalopride
    Reporting group description
    Participants received prucalopride once daily before breakfast for up to 12 weeks.

    Primary: Percent of Subjects With an Average Frequency of >=3 Spontaneous Bowel Movements (SBM) Per Week

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    End point title
    Percent of Subjects With an Average Frequency of >=3 Spontaneous Bowel Movements (SBM) Per Week
    End point description
    A bowel movement (BM) was defined as spontaneous if no laxatives were taken in the 24 hours preceding that BM. This end point analysed the Intent-to-Treat (ITT) population, defined as all subjects who were randomised into the study and who had received at least 1 dose of investigational medication.
    End point type
    Primary
    End point timeframe
    12 weeks
    End point values
    Placebo Prucalopride
    Number of subjects analysed
    83
    86
    Units: percent of subjects
        number (not applicable)
    39.8
    48.8
    Statistical analysis title
    Analysis of SBM
    Comparison groups
    Placebo v Prucalopride
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.305
    Method
    Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Plasma Concentration of Prucalopride at Week 2

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    End point title
    Plasma Concentration of Prucalopride at Week 2 [1]
    End point description
    This end point analysed the ITT population, defined as all subjects who were randomised into the study and who had received at least 1 dose of investigational medication. Subjects in the ITT whose post-dose samples were collected outside the 5-hour sampling window were not used in the plasma concentration calculation.
    End point type
    Secondary
    End point timeframe
    Week 2
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a subgroup analysis of the Prucalopride treatment arm. Prucalopride concentration was not assessed for subjects who received placebo.
    End point values
    Prucalopride
    Number of subjects analysed
    62
    Units: ng/ml
    arithmetic mean (standard deviation)
        Pre-dose
    2.827 ± 1.5989
        5 hours post-dose
    6.107 ± 2.8839
    No statistical analyses for this end point

    Secondary: Plasma Concentration of Prucalopride at Week 8

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    End point title
    Plasma Concentration of Prucalopride at Week 8 [2]
    End point description
    This end point analysed the ITT population, defined as all subjects who were randomised into the study and who had received at least 1 dose of investigational medication. Subjects in the ITT whose post-dose samples were collected outside the 5-hour sampling window were not used in the plasma concentration calculation.
    End point type
    Secondary
    End point timeframe
    Week 8
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a subgroup analysis of the Prucalopride treatment arm. Prucalopride concentration was not assessed for subjects who received placebo.
    End point values
    Prucalopride
    Number of subjects analysed
    53
    Units: ng/ml
    arithmetic mean (standard deviation)
        Pre-dose
    3.179 ± 1.9066
        5 hours post-dose
    6.615 ± 2.5758
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    12 weeks
    Adverse event reporting additional description
    AEs were assessed for the Safety Population, defined as all subjects who were randomised into the study and who had received at least 1 dose of investigational product.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo once daily before breakfast for up to 12 weeks.

    Reporting group title
    Prucalopride
    Reporting group description
    Participants received prucalopride once daily before breakfast for up to 12 weeks.

    Serious adverse events
    Placebo Prucalopride
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 83 (2.41%)
    2 / 86 (2.33%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal obstruction
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Hepatitis A
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 86 (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: 2%
    Non-serious adverse events
    Placebo Prucalopride
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 83 (22.89%)
    20 / 86 (23.26%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 83 (2.41%)
    0 / 86 (0.00%)
         occurrences all number
    2
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 83 (1.20%)
    2 / 86 (2.33%)
         occurrences all number
    1
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 83 (2.41%)
    4 / 86 (4.65%)
         occurrences all number
    2
    4
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    4 / 83 (4.82%)
    2 / 86 (2.33%)
         occurrences all number
    6
    3
    Abdominal Pain Upper
         subjects affected / exposed
    2 / 83 (2.41%)
    3 / 86 (3.49%)
         occurrences all number
    2
    3
    Diarrhoea
         subjects affected / exposed
    4 / 83 (4.82%)
    3 / 86 (3.49%)
         occurrences all number
    4
    3
    Flatulence
         subjects affected / exposed
    1 / 83 (1.20%)
    4 / 86 (4.65%)
         occurrences all number
    1
    4
    Nausea
         subjects affected / exposed
    5 / 83 (6.02%)
    9 / 86 (10.47%)
         occurrences all number
    8
    11
    Rectal Haemorrhage
         subjects affected / exposed
    2 / 83 (2.41%)
    1 / 86 (1.16%)
         occurrences all number
    3
    1
    Vomiting
         subjects affected / exposed
    3 / 83 (3.61%)
    2 / 86 (2.33%)
         occurrences all number
    3
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 83 (0.00%)
    2 / 86 (2.33%)
         occurrences all number
    0
    2
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    1 / 83 (1.20%)
    4 / 86 (4.65%)
         occurrences all number
    1
    4
    Pain In Extremity
         subjects affected / exposed
    2 / 83 (2.41%)
    0 / 86 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    Influenza
         subjects affected / exposed
    1 / 83 (1.20%)
    2 / 86 (2.33%)
         occurrences all number
    1
    2
    Nasopharyngitis
         subjects affected / exposed
    2 / 83 (2.41%)
    1 / 86 (1.16%)
         occurrences all number
    2
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Apr 2010
    The following changes were made to the protocol: * Exclusion criterion 4: Intestinal perforation was added as an organic disorder of the large bowel * Exclusion criterion 10: In the following phrase “serum creatinine concentration greater than 2mg/dL (<180micromole/L)”, the “180micromole/L” was deleted * The following was added to the list of prohibitions and restrictions “Women of childbearing potential should be instructed that in case of severe diarrhoea, the efficacy of oral contraceptives may be reduced and the use of an additional contraceptive method is recommended to prevent possible failure of oral contraception (see the prescribing information of the oral contraceptive).”
    19 May 2011
    Protocol Amendment 2: The pharmacovigilance reporting methods were changed in order to be in line with the sponsor’s procedures.
    13 Jan 2012
    Protocol Amendment 3:The main reason for this protocol amendment was the lowering of the planned number of subjects to be included in the study from 510 (255 in each treatment arm) to 342 (171 in each treatment arm). Furthermore, several changes were made in order to clarify that it should be included in the subject’s medical history in case he/she was lactose intolerant. All subjects with lactose intolerance had to strictly adhere to their diet during the entire study (added to the list of prohibitions and restrictions in Section 3.9) since in subjects with lactose intolerance low doses of lactose could lead to diarrhea (added to Exclusion Criterion 14). In addition, the following changes were made: * Exclusion criterion 4: the wording was changed to clarify that subjects with “insulin-dependent diabetes mellitus, even if adequately controlled” were excluded * Exclusion criterion 10: the serum creatinine lower limit concentration was changed from 2mg/dL to 180micromole/L and the calculated creatinine clearance was changed from 50 to </= 30mL/min * Additional exclusion criterion 16 “subjects who previously used prucalopride” was added * It was clarified in the section on screening failures that these subjects could not be rescreened without prior approval from the sponsor * A paragraph was added to the section on dose regimen and administration period (Section 4.5.1) on what subjects had to do in case they forgot to take their daily dose of investigational product in the morning * The definition of overdose was added to the section of overdose management (Section 4.5.5) * In the section on sample size (Section 6.1), the 2-sided significance level was changed from 1 to 5%.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    13 Aug 2012
    This study was terminated early due to slow recruitment and the fact that the sponsor is no longer pursuing the opioid-induced constipation (OIC) indication.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to the early termination of the study, results should be interpreted with caution.
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