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    Clinical Trial Results:
    An Open-label, Randomized, Crossover, Reader-blinded Study To Investigate the Effect of Prucalopride and Polyethylene Glycol 3350 on Colon Motility with Intraluminal Manometry in Subjects with Chronic Constipation

    Summary
    EudraCT number
    		 2012-002495-13
    Trial protocol
    		 BE  
    Global end of trial date
    27 Nov 2013

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

    Trial information

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    Trial identification
    Sponsor protocol code
    SPD555-403
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01707667
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Shire Movetis NV
    Sponsor organisation address
    Veedijk 58(104), Turnhout, Belgium, 2300
    Public contact
    Medical Communications, Shire-Movetis, 0032 14404390, shire-movetis.clinicaltrials@shire.com
    Scientific contact
    Medical Communications, Shire-Movetis, 0032 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
    27 Nov 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Nov 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate differences in pharmacodynamic effects of prucalopride and polyethylene glycol (PEG 3350) + electrolytes on the number of colonic high amplitude propagating contractions (HAPC) during a 12-hour intraluminal manometry in chronically constipated subjects.
    Protection of trial subjects
    The subject's informed consent was a mandatory condition for taking part in the study. It was obtained in writing prior to the performance of any study-specific procedures. This study was conducted in accordance with International Conference on Harmonisation of 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
    27 Feb 2013
    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 States: 13
    Worldwide total number of subjects
    13
    EEA total number of subjects
    0
    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)
    13
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted in 1 center (United States).

    Pre-assignment
    Screening details
    		 Subjects were screened and entered a 10- to 19-day run in period, during which they recorded their bowel habits and rescue medication use in a daily diary and the existence of constipation was confirmed.

    Period 1
    Period 1 title
    Treatment Period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    To minimize bias, the study was reader-blinded: the tracings were read by an experienced gastroenterologist who received de-identified recordings that did not specify which treatment the subject had received.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Prucalopride-Polyethylene glycol (PEG)
    Arm description
    		 A single dose of prucalopride in the first period followed by 2 doses of PEG 3350 plus electrolytes in the second period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Prucalopride
    Investigational medicinal product code
    Other name
    Resolor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One 2mg tablet administered with 125ml of water on Day 1

    Arm title
    		 Polyethylene glycol (PEG)-Prucalopride
    Arm description
    		 Two doses of PEG 3350 plus electrolytes in the first period followed by a single dose of prucalopride in the second period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Polyethylene glycol (PEG) 3350
    Investigational medicinal product code
    Other name
    Movicol
    Pharmaceutical forms
    Powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    13.8g-sachets of PEG 3350 with sodium bicarbonate, sodium chloride, and potassium chloride as a solution in water (125ml). Administered twice on Day 1 (once in the morning and once prior to lunch).

    Number of subjects in period 1
    		Prucalopride-Polyethylene glycol (PEG) Polyethylene glycol (PEG)-Prucalopride
    Started
    7
    6
    Completed
    6
    6
    Not completed
    1
    0
         Expulsion of colonic sensor catheter
    1
    -
    Period 2
    Period 2 title
    Treatment Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    To minimize bias, the study was reader-blinded: the tracings were read by an experienced gastroenterologist who received de-identified recordings that did not specify which treatment the subject had received.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Prucalopride-Polyethylene glycol (PEG)
    Arm description
    		 A single dose of prucalopride in the first period followed by 2 doses of PEG 3350 plus electrolytes in the second period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Polyethylene glycol (PEG) 3350
    Investigational medicinal product code
    Other name
    Movicol
    Pharmaceutical forms
    Powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    13.8g-sachets of PEG 3350 with sodium bicarbonate, sodium chloride, and potassium chloride as a solution in water (125ml). Administered twice on Day 1 (once in the morning and once prior to lunch).

    Arm title
    		 Polyethylene glycol (PEG)-Prucalopride
    Arm description
    		 Two doses of PEG 3350 plus electrolytes in the first period followed by a single dose of prucalopride in the second period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Prucalopride
    Investigational medicinal product code
    Other name
    Resolor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One 2mg tablet administered with 125ml of water on Day 1

    Number of subjects in period 2
    		Prucalopride-Polyethylene glycol (PEG) Polyethylene glycol (PEG)-Prucalopride
    Started
    6
    6
    Completed
    6
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Prucalopride-Polyethylene glycol (PEG)
    Reporting group description
    		 A single dose of prucalopride in the first period followed by 2 doses of PEG 3350 plus electrolytes in the second period.

    Reporting group title
    Polyethylene glycol (PEG)-Prucalopride
    Reporting group description
    		 Two doses of PEG 3350 plus electrolytes in the first period followed by a single dose of prucalopride in the second period.

    Reporting group values
    		 Prucalopride-Polyethylene glycol (PEG) Polyethylene glycol (PEG)-Prucalopride Total
    Number of subjects
    		 7 6 13
    Age categorical
    Units: Subjects
        18-64 years
    		 7 6 13
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 40.3 ( 11.04 ) 35.2 ( 13.18 ) -
    Gender categorical
    Units: Subjects
        Female
    		 7 6 13
        Male
    		 0 0 0
    Region of Enrollment
    Units: Subjects
        United States
    		 7 6 13

    End points

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    End points reporting groups
    Reporting group title
    Prucalopride-Polyethylene glycol (PEG)
    Reporting group description
    		 A single dose of prucalopride in the first period followed by 2 doses of PEG 3350 plus electrolytes in the second period.

    Reporting group title
    Polyethylene glycol (PEG)-Prucalopride
    Reporting group description
    		 Two doses of PEG 3350 plus electrolytes in the first period followed by a single dose of prucalopride in the second period.
    Reporting group title
    Prucalopride-Polyethylene glycol (PEG)
    Reporting group description
    		 A single dose of prucalopride in the first period followed by 2 doses of PEG 3350 plus electrolytes in the second period.

    Reporting group title
    Polyethylene glycol (PEG)-Prucalopride
    Reporting group description
    		 Two doses of PEG 3350 plus electrolytes in the first period followed by a single dose of prucalopride in the second period.

    Subject analysis set title
    Prucalopride
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    A single dose of 2mg prucalopride, administered orally as tablets with 125mL of water on Day 1.

    Subject analysis set title
    PEG 3350
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    13.8g polyethylene glycol (PEG) 3350 with sodium bicarbonate, sodium chloride, and potassium chloride as a solution in water. Administered twice orally on Day 1 (once in the morning and once prior to lunch).

    Primary: The Number of High-Amplitude Propagating Contractions (HAPC)

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    End point title
    		 The Number of High-Amplitude Propagating Contractions (HAPC)
    End point description
    Manometry recordings were read by an experienced gastroenterologist who was blinded to the treatment each subject received. The tracings were analyzed using computer-based validated software. HAPC and manometry data were available for every sensor as well as average values for each HAPC and manometry time point. The primary outcome analysis of HAPC data used the following threshold: Mean amplitude ≥100mmHg and extension ≥20cm (9 sensors). This end point analyzed the Pharmacodynamic Analysis Set, which consisted of all randomized subjects who had taken at least 1 dose of investigational product and who had 1 evaluable manometry assessment (minimum of 4 hours of manometry recordings from the intake of investigational product) for each treatment period.
    End point type
    Primary
    End point timeframe
    Over 12 hours post-dose
    End point values
    		 Prucalopride PEG 3350
    Number of subjects analysed
    12
    12
    Units: Number of HAPC with amplitude ≥100mmHg
        least squares mean (standard error)
    8.7 ( 2.06 )
    2.9 ( 2.06 )
    Statistical analysis title
    		 Analysis of HPACs
    Comparison groups
    PEG 3350 v Prucalopride
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.012
    Method
    		 Linear Mixed-Effect Models Analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    5.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.6
         upper limit
    		 9.9

    Secondary: Area Under The Concentration Curve (AUC) of All HAPCs

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    End point title
    		 Area Under The Concentration Curve (AUC) of All HAPCs
    End point description
    The AUC of all HAPCs during the first 12 hours after treatment was calculated as the sum of the AUC at all sensors of each HAPC at the ≥100mmHg and ≥20cm threshold. This end point analyzed the Pharmacodynamic Analysis Set, which consisted of all randomized subjects who had taken at least 1 dose of investigational product and who had 1 evaluable manometry assessment (minimum of 4 hours of manometry recordings from the intake of investigational product) for each treatment period.
    End point type
    Secondary
    End point timeframe
    Over 12 hours post-dose
    End point values
    		 Prucalopride PEG 3350
    Number of subjects analysed
    9
    6
    Units: mmHg.sec
        least squares mean (standard error)
    110204.1 ( 28279.91 )
    41152.7 ( 34432.61 )
    Statistical analysis title
    		 Analysis of AUC of All HAPCs
    Comparison groups
    PEG 3350 v Prucalopride
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.079
    Method
    		 Linear Mixed-Effect Models Analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    69051.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12004.5
         upper limit
    		 150107.3

    Secondary: The Mean Amplitude of HAPC

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    End point title
    		 The Mean Amplitude of HAPC
    End point description
    The mean amplitude of all HAPCs was calculated as the sum of the mean amplitude for each HAPC divided by the number of HAPCs. This end point analyzed the Pharmacodynamic Analysis Set, which consisted of all randomized subjects who had taken at least 1 dose of investigational product and who had 1 evaluable manometry assessment (minimum of 4 hours of manometry recordings from the intake of investigational product) for each treatment period.
    End point type
    Secondary
    End point timeframe
    Over 12 hours post-dose
    End point values
    		 Prucalopride PEG 3350
    Number of subjects analysed
    9
    6
    Units: mmHg
        least squares mean (standard error)
    199 ( 15.15 )
    189.8 ( 19.56 )
    Statistical analysis title
    		 Analysis of Mean Amplitude of HAPC
    Comparison groups
    Prucalopride v PEG 3350
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.717
    Method
    		 Linear Mixed-Effect Models Analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    9.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -45.3
         upper limit
    		 63.7

    Secondary: Time to First HAPC

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    End point title
    		 Time to First HAPC
    End point description
    The median (95% confidence interval) time to first HAPC after administration of investigational product with amplitude ≥100mmHg and extension ≥20cm. This end point analyzed the Pharmacodynamic Analysis Set, which included all subjects in the Safety Analysis Set who had 1 evaluable manometry assessment (minimum of 4 hours of manometry recordings from the intake of investigational product) for each treatment period. In the PEG 3350 group, the median time to first HAPC after administration of investigational product with amplitude ≥100mmHg and extension ≥20cm could not be calculated as only 6 subjects had HAPCs that met this threshold.
    End point type
    Secondary
    End point timeframe
    Over 12 hours post-dose
    End point values
    		 Prucalopride
    Number of subjects analysed
    9
    Units: hours
        median (confidence interval 95%)
    4.5 (1.5 to 9.3)
    No statistical analyses for this end point

    Secondary: Propagation Velocity of HAPC

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    End point title
    		 Propagation Velocity of HAPC
    End point description
    Propagation velocity was calculated as the extension divided by the duration for each HAPC. Mean propagation velocity is the sum of the propagation velocities divided by the number of HAPCs. This end point analyzed the Pharmacodynamic Analysis Set, which consisted of all randomized subjects who had taken at least 1 dose of investigational product and who had 1 evaluable manometry assessment (minimum of 4 hours of manometry recordings from the intake of investigational product) for each treatment period.
    End point type
    Secondary
    End point timeframe
    Over 12 hours post-dose
    End point values
    		 Prucalopride PEG 3350
    Number of subjects analysed
    9
    6
    Units: cm/sec
        least squares mean (standard error)
    0.467 ( 0.0803 )
    0.646 ( 0.1074 )
    Statistical analysis title
    		 Analysis of Propagation Velocity of HAPC
    Comparison groups
    Prucalopride v PEG 3350
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.18
    Method
    		 Linear Mixed-Effect Models Analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.179
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.465
         upper limit
    		 0.107

    Secondary: Duration of HAPC

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    End point title
    		 Duration of HAPC
    End point description
    The mean duration of all HAPCs was calculated as the sum of the duration of each HAPC divided by the number of HAPCs. This end point analyzed the Pharmacodynamic Analysis Set, which consisted of all randomized subjects who had taken at least 1 dose of investigational product and who had 1 evaluable manometry assessment (minimum of 4 hours of manometry recordings from the intake of investigational product) for each treatment period.
    End point type
    Secondary
    End point timeframe
    Over 12 hours post-dose
    End point values
    		 Prucalopride PEG 3350
    Number of subjects analysed
    9
    6
    Units: sec
        least squares mean (standard error)
    84.9 ( 8.05 )
    69.1 ( 10.75 )
    Statistical analysis title
    		 Analysis of Duration of HAPC
    Comparison groups
    Prucalopride v PEG 3350
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.225
    Method
    		 Linear Mixed-Effect Models Analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    15.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.6
         upper limit
    		 44.3

    Secondary: Motility Index

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    End point title
    		 Motility Index
    End point description
    Motility index (mmHg) was summarized for the following 3 time points: pre-dose, 0-5 hours post-dose, and 5-12 hours post-dose. The motility index is defined as the natural logarithm of all peak amplitudes of every contraction +1. This end point analyzed the Pharmacodynamic Analysis Set, which consisted of all randomized subjects who had taken at least 1 dose of investigational product and who had 1 evaluable manometry assessment (minimum of 4 hours of manometry recordings from the intake of investigational product) for each treatment period.
    End point type
    Secondary
    End point timeframe
    Over 12 hours post-dose
    End point values
    		 Prucalopride PEG 3350
    Number of subjects analysed
    9
    11
    Units: mmHg
    least squares mean (standard error)
        Pre-dose
    9.467 ( 0.4668 )
    8.312 ( 0.4403 )
        0-5 hours post-dose
    13.661 ( 0.3221 )
    13.349 ( 0.352 )
        5-12 hours post-dose
    14.208 ( 0.2976 )
    14.39 ( 0.2489 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 35 days
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Prucalopride
    Reporting group description
    		 A single dose of 2mg prucalopride, administered orally as tablets with 125mL of water on Day 1.

    Reporting group title
    Polyethylene Glycol
    Reporting group description
    		 13.8g polyethylene glycol (PEG) 3350 with sodium bicarbonate, sodium chloride, and potassium chloride as a solution in water. Administered twice orally on Day 1 (once in the morning and once prior to lunch).

    Serious adverse events
    		 Prucalopride Polyethylene Glycol
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Prucalopride Polyethylene Glycol
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 13 (23.08%)
    0 / 12 (0.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    Diarrhoea
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Sep 2012
    The general amendment included the following changes: 1-The medical monitor was changed 2-Due to concerns regarding the original lengthy fasting period between Day -2 and Day 1, dinner was added to Day -2 and Day -1, and an afternoon snack was added to Day -1 3-The original text on the packaging of the investigational product was corrected 4-Additional wording was added on the timing of colonic multiple sensor catheter placement 5-The original text on the reporting period for SAEs was changed from "must occur within one business day" to "must occur within 24 hours" 5-Minor editorial changes were performed

    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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