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    Clinical Trial Results:
    Clinical Trial to Evaluate the Efficacy and Safety of MACRORANGE® in Patients Suffering from Functional Constipation

    Summary
    EudraCT number
    		 2018-001914-13
    Trial protocol
    		 BE  
    Global end of trial date
    26 Mar 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 May 2021
    First version publication date
    15 May 2021
    Other versions
    Summary report(s)
    		 Summary

    Trial information

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    Trial identification
    Sponsor protocol code
    MACR001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Salsarulo Pharma
    Sponsor organisation address
    8, rue de l'Est, Boulogne-Billancourt, France, 92100
    Public contact
    Gilles Salsarulo, Salsarulo Pharma, +33 618920881, gilles.salsarulo@salsapharma.com
    Scientific contact
    Gérard Salsarulo, Salsarulo Pharma, +33 148257764, gerard.salsarulo@wanadoo.fr
    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
    30 Apr 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Mar 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Mar 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of MACRORANGE® in patients with functional constipation (according to Rome III criteria) after daily administration of MACRORANGE® up to 14 days.
    Protection of trial subjects
    The study was conducted in accordance with International Conference on Harmonisation, Good Clinical Practice (ICH-GCP E6R2), the ethical principles that have their origins in the Declaration of Helsinki (revised Edinburgh, 2000), and applicable national and local regulatory requirements. Prior to the performance of any study-specific procedures, written informed consent was obtained from each patient. The patient was informed about the nature and purpose of the study, as well as of its risks and benefits. It was explained that the patient could withdraw from the study at any time for any reason and that this would not have any effect on potential future medical care.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Nov 2018
    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
    Belgium: 30
    Worldwide total number of subjects
    30
    EEA total number of subjects
    30
    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)
    30
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at a single site at Advanced Technology Corporation (ATC) Pharma S.A., Liège, Belgium. The first patient was screened and signed informed consent document on 05 November 2018 (first patient / first visit).

    Pre-assignment
    Screening details
    		 Patients attended the site to enter the screening period within 21 days prior to dosing (Day 1). 40 patients were screened to get 30 patients enrolled. The main reasons for screen failure consisted either in the inclusion/exclusion criteria that were not fulfilled (e.g. Irritable Bowel Syndrome) or a consent withdrawal for personal reasons.

    Period 1
    Period 1 title
    Wash-out
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 wash-out
    Arm description
    		 wash-out
    Arm type
    		 wash-out

    Investigational medicinal product name
    none
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral paste in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    no product - wash-out period

    Number of subjects in period 1
    		wash-out
    Started
    30
    Completed
    30
    Period 2
    Period 2 title
    Macrorange
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Macrorange
    Arm description
    		 MACRORANGE® was administered as 12 g single dose stick-pack, corresponding to a dosage of 5.04 g of Macrogol 4000. The dose regimen started with a fixed dose of MACRORANGE® for 2 days, with 3 stick packs on Day 1 and 2 stick-packs on Day 2, and then was flexible from Day 3 to Day 14 (with 1 to 2 stick-pack per day), as decided by the patient and based on the number of defecations per day. The patient was instructed to take one single dose stick-pack of MACRORANGE® per day if he/she defecated at least once during that day, or two single dose stick-packs of MACRORANGE® per day if he/she did not defecate at all during that day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Macrorange
    Investigational medicinal product code
    MACROGOL 4000
    Other name
    Pharmaceutical forms
    Oral paste in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    MACRORANGE® was administered as 12 g single dose stick-pack, corresponding to a dosage of 5.04 g of Macrogol 4000. The dose regimen started with a fixed dose of MACRORANGE® for 2 days, with 3 stick packs on Day 1 and 2 stick-packs on Day 2, and then was flexible from Day 3 to Day 14 (with 1 to 2 stick-pack per day), as decided by the patient and based on the number of defecations per day. The patient was instructed to take one single dose stick-pack of MACRORANGE® per day if he/she defecated at least once during that day, or two single dose stick-packs of MACRORANGE® per day if he/she did not defecate at all during that day.

    Number of subjects in period 2
    		Macrorange
    Started
    30
    Completed
    30

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Wash-out
    Reporting group description
    		 -

    Reporting group values
    		 Wash-out Total
    Number of subjects
    		 30 30
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 30 30
    Age continuous
    Units: years
        median (full range (min-max))
    		 37 (23 to 63) -
    Gender categorical
    Units: Subjects
        Female
    		 21 21
        Male
    		 9 9

    End points

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    End points reporting groups
    Reporting group title
    wash-out
    Reporting group description
    		 wash-out
    Reporting group title
    Macrorange
    Reporting group description
    		 MACRORANGE® was administered as 12 g single dose stick-pack, corresponding to a dosage of 5.04 g of Macrogol 4000. The dose regimen started with a fixed dose of MACRORANGE® for 2 days, with 3 stick packs on Day 1 and 2 stick-packs on Day 2, and then was flexible from Day 3 to Day 14 (with 1 to 2 stick-pack per day), as decided by the patient and based on the number of defecations per day. The patient was instructed to take one single dose stick-pack of MACRORANGE® per day if he/she defecated at least once during that day, or two single dose stick-packs of MACRORANGE® per day if he/she did not defecate at all during that day.

    Primary: Average number of complete spontaneous defecations for the treatment period

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    End point title
    		 Average number of complete spontaneous defecations for the treatment period
    End point description
    End point type
    Primary
    End point timeframe
    The average number of complete spontaneous defecations for the 2-week treatment with MACRORANGE®
    End point values
    		 Macrorange wash-out
    Number of subjects analysed
    30
    30
    Units: number per week
        arithmetic mean (standard deviation)
    5.44 ± 2.08
    2.95 ± 1.90
    Statistical analysis title
    		 Change from Baseline in Defecations
    Comparison groups
    Macrorange v wash-out
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Average number of complete spontaneous defecations (Week 1)

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    End point title
    		 Average number of complete spontaneous defecations (Week 1)
    End point description
    End point type
    Secondary
    End point timeframe
    The average number of complete spontaneous defecations during the treatment periods from Day 1 (post-dose) to Day 8 (pre-dose)
    End point values
    		 Macrorange
    Number of subjects analysed
    30
    Units: number per week
        arithmetic mean (standard error)
    5.43 ± 2.28
    No statistical analyses for this end point

    Secondary: Average number of complete spontaneous defecations (Week 2)

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    End point title
    		 Average number of complete spontaneous defecations (Week 2)
    End point description
    End point type
    Secondary
    End point timeframe
    The average number of complete spontaneous defecations during the treatment periods from from Day 8 (post-dose) to Day 14.
    End point values
    		 Macrorange
    Number of subjects analysed
    30
    Units: number per week
        arithmetic mean (standard error)
    5.44 ± 2.46
    No statistical analyses for this end point

    Secondary: Average of daily dosage of MACRORANGE (Week 1)

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    End point title
    		 Average of daily dosage of MACRORANGE (Week 1)
    End point description
    End point type
    Secondary
    End point timeframe
    The average daily dosage of MACRORANGE® as grams of macrogol 4000 from Day 1 to Day 8 pre-dose (Week 1)
    End point values
    		 Macrorange
    Number of subjects analysed
    30
    Units: grams of macrogol 4000
        arithmetic mean (standard error)
    8.54 ± 0.92
    No statistical analyses for this end point

    Secondary: Average of daily dosage of MACRORANGE (Week 2)

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    End point title
    		 Average of daily dosage of MACRORANGE (Week 2)
    End point description
    End point type
    Secondary
    End point timeframe
    The average daily dosage of MACRORANGE® as grams of macrogol 4000 from Day 8 (post-dose) to Day 14 (Week 2)
    End point values
    		 Macrorange
    Number of subjects analysed
    30
    Units: grams of macrogol 4000
        arithmetic mean (standard error)
    6.89 ± 1.39
    No statistical analyses for this end point

    Secondary: Global Efficacy (Patient’s evaluation)

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    End point title
    		 Global Efficacy (Patient’s evaluation)
    End point description
    End point type
    Secondary
    End point timeframe
    Global efficacy of MACRORANGE® was assessed by the patient at the end of the 2-week treatment period.
    End point values
    		 Macrorange
    Number of subjects analysed
    30
    Units: number
        Poor
    6
        Moderate
    5
        Good
    15
        Very Good
    4
    No statistical analyses for this end point

    Secondary: Taste of MACRORANGE

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    End point title
    		 Taste of MACRORANGE
    End point description
    End point type
    Secondary
    End point timeframe
    Taste of MACRORANGE® was assessed by the patient at the end of the 2-week treatment period.
    End point values
    		 Macrorange
    Number of subjects analysed
    30
    Units: number
        Dislike very much
    0
        Dislike slightly
    1
        Like slightly
    20
        Like very much
    9
    No statistical analyses for this end point

    Secondary: Global Efficacy (Independent rater’s evaluation)

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    End point title
    		 Global Efficacy (Independent rater’s evaluation)
    End point description
    End point type
    Secondary
    End point timeframe
    Global efficacy of MACRORANGE® were assessed by independent reader at the end of the 2-week treatment period.
    End point values
    		 Macrorange
    Number of subjects analysed
    30
    Units: number
        Poor
    4
        Moderate
    8
        Good
    12
        Very Good
    6
    No statistical analyses for this end point

    Secondary: Global Tolerance (Independent rater’s evaluation)

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    End point title
    		 Global Tolerance (Independent rater’s evaluation)
    End point description
    End point type
    Secondary
    End point timeframe
    Global Tolerance of MACRORANGE® were assessed by independent reader at the end of the 2-week treatment period.
    End point values
    		 Macrorange
    Number of subjects analysed
    30
    Units: number
        Poor
    0
        Moderate
    4
        Good
    15
        Ver Good
    11
    No statistical analyses for this end point

    Secondary: Stool Consistency

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    End point title
    		 Stool Consistency
    End point description
    Stool consistency as assessed by the patient by using the Bristol scale
    End point type
    Secondary
    End point timeframe
    during wash-out period and from Day 8, post-dose to Day 14
    End point values
    		 Macrorange wash-out
    Number of subjects analysed
    30 [1]
    30 [2]
    Units: number
        Separate hard lumps, like nuts
    3
    17
        Sausage-shaped but lumpy
    9
    26
        Like a sausage but with cracks on its surface
    29
    29
        Like a sausage or snake, smooth and soft
    74
    15
        Soft blobs with clear-cut edges (passed easily)
    17
    4
        : Fluffy pieces with ragged edges, a mushy stool
    8
    9
        Watery, no solid pieces, entirely liquid
    0
    1
    Notes
    [1] - n=140 stools
    [2] - n=101 stools
    Statistical analysis title
    		 Chi-test
    Statistical analysis description
    chi-squared test
    Comparison groups
    Macrorange v wash-out
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Chi-squared
    Confidence interval

    Other pre-specified: Average number of complete spontaneous defecations (at baseline)

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    End point title
    		 Average number of complete spontaneous defecations (at baseline)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Average number of complete spontaneous defecations at the end of baseline period (7 days wash-out)
    End point values
    		 wash-out
    Number of subjects analysed
    30
    Units: number per week
        arithmetic mean (standard deviation)
    2.95 ± 1.90
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Collection of adverse event was performed from screening to end of trial, during on-site visits.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21
    Reporting groups
    Reporting group title
    Safety population
    Reporting group description
    		 all subjects who received at least one dose of IMP

    Serious adverse events
    		 Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 30 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 30 (43.33%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    4
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    9 / 30 (30.00%)
         occurrences all number
    15
    Abdominal pain
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Vomiting
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Flatulence
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Abdominal distension
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    2
    Pharyngitis
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Infections and infestations
    Cystitis
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Furuncle
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    Open label study - no comparator
    For support, Contact us.
    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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