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    Clinical Trial Results:
    A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Sequential, Ascending, Multidose Study to Evaluate the Safety and Efficacy of Linaclotide in Pediatric Participants (Age 2 to 5 Years) with Functional Constipation

    Summary
    EudraCT number
    		 2019-002126-75
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    20 Apr 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Nov 2021
    First version publication date
    04 Nov 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LIN-MD-67
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04110145
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Allergan
    Sponsor organisation address
    1st Floor, Marlow International, The Parkway, Marlow Buckinghamshire, United Kingdom, SL7 1YL
    Public contact
    Therapeutic Area, Head, Allergan, 001 714-246-4500, IR-CTRegistration@Allergan.com
    Scientific contact
    Therapeutic Area, Head, Allergan, 001 714-246-4500, IR-CTRegistration@Allergan.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000927-PIP01-10
    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
    20 Apr 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Apr 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study was to evaluate the dose response, safety, and efficacy of linaclotide when compared with placebo in pediatric participants, 2 to 5 years of age, with Functional Constipation.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Oct 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 35
    Worldwide total number of subjects
    35
    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)
    35
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants were randomized in a 3:1 ratio to receive ascending dose of linaclotide Cohorts 1-3 (18/36/72 μg) to determine the highest dose to be safe or placebo and in a 5:1 ratio for the Final Cohort (72 μg) safe dose or placebo.

    Period 1
    Period 1 title
    Double-Blind Treatment Period (4 weeks)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1 (Linaclotide 18 μg)
    Arm description
    		 Linaclotide 18 microgram (μg), capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Linaclotide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Linaclotide 18 μg, capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal).

    Arm title
    		 Cohort 2 (Linaclotide 36 μg)
    Arm description
    		 Linaclotide 36 μg, capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Linaclotide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Linaclotide 36 μg, capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal).

    Arm title
    		 Cohort 3 (Linaclotide 72 μg)
    Arm description
    		 Linaclotide 72 μg, capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Linaclotide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Linaclotide 72 μg, capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal).

    Arm title
    		 Final Cohort (Linaclotide 72 μg)
    Arm description
    		 Linaclotide at the highest dose tested/determined to be safe (72 μg), capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Linaclotide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Linaclotide 72 μg, capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal).

    Arm title
    		 Placebo Pooled
    Arm description
    		 Matching placebo, orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period pooled from Cohorts 1, 2, 3, and Final Cohort.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo-matching linaclotide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo, orally, once daily in fasted state (30 minutes before any meal).

    Number of subjects in period 1
    		Cohort 1 (Linaclotide 18 μg) Cohort 2 (Linaclotide 36 μg) Cohort 3 (Linaclotide 72 μg) Final Cohort (Linaclotide 72 μg) Placebo Pooled
    Started
    7
    7
    6
    7
    8
    Completed
    7
    7
    6
    6
    8
    Not completed
    0
    0
    0
    1
    0
         Site Terminated by the Sponsor
    -
    -
    -
    1
    -
    Period 2
    Period 2 title
    Post-treatment Period (1 week)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1 (Linaclotide 18 μg)
    Arm description
    		 Linaclotide 18 μg, capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Linaclotide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Linaclotide 18 μg, capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal).

    Arm title
    		 Cohort 2 (Linaclotide 36 μg)
    Arm description
    		 Linaclotide 36 μg, capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Linaclotide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Linaclotide 36 μg, capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal)

    Arm title
    		 Cohort 3 (Linaclotide 72 μg)
    Arm description
    		 Linaclotide 72 μg, capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Linaclotide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Linaclotide 72 μg, capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal).

    Arm title
    		 Final Cohort (Linaclotide 72 μg)
    Arm description
    		 Linaclotide at the highest dose tested/determined to be safe (72 μg), capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Linaclotide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Linaclotide 72 μg, capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal).

    Arm title
    		 Placebo Pooled
    Arm description
    		 Matching placebo, orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period pooled from Cohorts 1, 2, 3, and Final Cohort.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo-matching linaclotide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo, orally, once daily in fasted state (30 minutes before any meal).

    Number of subjects in period 2 [1]
    		Cohort 1 (Linaclotide 18 μg) Cohort 2 (Linaclotide 36 μg) Cohort 3 (Linaclotide 72 μg) Final Cohort (Linaclotide 72 μg) Placebo Pooled
    Started
    7
    7
    5
    6
    8
    Completed
    7
    7
    5
    6
    8
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 1 participant in the Cohort 3 (Linaclotide 72 μg) arm group completed Period 1 but did not participate in Period 2.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1 (Linaclotide 18 μg)
    Reporting group description
    		 Linaclotide 18 microgram (μg), capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.

    Reporting group title
    Cohort 2 (Linaclotide 36 μg)
    Reporting group description
    		 Linaclotide 36 μg, capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.

    Reporting group title
    Cohort 3 (Linaclotide 72 μg)
    Reporting group description
    		 Linaclotide 72 μg, capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.

    Reporting group title
    Final Cohort (Linaclotide 72 μg)
    Reporting group description
    		 Linaclotide at the highest dose tested/determined to be safe (72 μg), capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.

    Reporting group title
    Placebo Pooled
    Reporting group description
    		 Matching placebo, orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period pooled from Cohorts 1, 2, 3, and Final Cohort.

    Reporting group values
    		 Cohort 1 (Linaclotide 18 μg) Cohort 2 (Linaclotide 36 μg) Cohort 3 (Linaclotide 72 μg) Final Cohort (Linaclotide 72 μg) Placebo Pooled Total
    Number of subjects
    		 7 7 6 7 8 35
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 7 7 6 7 8 35
    Age Continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 3.6 (2 to 5) 3.3 (2 to 5) 4.0 (3 to 5) 3.6 (2 to 5) 3.5 (3 to 4) -
    Sex: Female, Male
    Units: participants
        Female
    		 4 3 5 0 4 16
        Male
    		 3 4 1 7 4 19
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 2 3 4 5 5 19
        Black or African American
    		 5 4 2 2 3 16
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    		 1 2 4 4 3 14
        Not Hispanic or Latino
    		 6 5 2 3 5 21

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1 (Linaclotide 18 μg)
    Reporting group description
    		 Linaclotide 18 microgram (μg), capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.

    Reporting group title
    Cohort 2 (Linaclotide 36 μg)
    Reporting group description
    		 Linaclotide 36 μg, capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.

    Reporting group title
    Cohort 3 (Linaclotide 72 μg)
    Reporting group description
    		 Linaclotide 72 μg, capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.

    Reporting group title
    Final Cohort (Linaclotide 72 μg)
    Reporting group description
    		 Linaclotide at the highest dose tested/determined to be safe (72 μg), capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.

    Reporting group title
    Placebo Pooled
    Reporting group description
    		 Matching placebo, orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period pooled from Cohorts 1, 2, 3, and Final Cohort.
    Reporting group title
    Cohort 1 (Linaclotide 18 μg)
    Reporting group description
    		 Linaclotide 18 μg, capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.

    Reporting group title
    Cohort 2 (Linaclotide 36 μg)
    Reporting group description
    		 Linaclotide 36 μg, capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.

    Reporting group title
    Cohort 3 (Linaclotide 72 μg)
    Reporting group description
    		 Linaclotide 72 μg, capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.

    Reporting group title
    Final Cohort (Linaclotide 72 μg)
    Reporting group description
    		 Linaclotide at the highest dose tested/determined to be safe (72 μg), capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.

    Reporting group title
    Placebo Pooled
    Reporting group description
    		 Matching placebo, orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period pooled from Cohorts 1, 2, 3, and Final Cohort.

    Primary: Change from Baseline in 4-week Overall Spontaneous Bowel Movement (SBM) Frequency Rate (SBMs/week) During the Study Intervention Period of Each Cohort

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    End point title
    		 Change from Baseline in 4-week Overall Spontaneous Bowel Movement (SBM) Frequency Rate (SBMs/week) During the Study Intervention Period of Each Cohort [1]
    End point description
    A SBM was defined as a bowel movement (BM) that occurred in the absence of laxative, suppository, or enema use on the calendar day of the BM or the calendar day before the BM. Each day caregiver recorded the number of SBMs in the last 24 hours in an electronic diary(eDiary). The SBM frequency rate(SBMs/week) during the analysis period for each participant were calculated as [(total number of SBMs in the analysis period/number of days in the analysis period)*7]. Baseline value was based on values collected 14 days before randomization up to randomization. Change from Baseline was calculated as the SBM frequency rate during the 4-week treatment period - SBM frequency rate at Baseline. A positive change from Baseline indicates improvement. Modified-intent-to-treat (mITT) Population included all Randomized Population who received at least 1 dose of double-blind study intervention and who had at least 1 postbaseline entry on BM characteristic assessments that determine occurrences of SBMs.
    End point type
    Primary
    End point timeframe
    Baseline (14 days prior to randomization) to Day 29
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses are reported for this endpoint.
    End point values
    		 Cohort 1 (Linaclotide 18 μg) Cohort 2 (Linaclotide 36 μg) Cohort 3 (Linaclotide 72 μg) Final Cohort (Linaclotide 72 μg) Placebo Pooled
    Number of subjects analysed
    7
    7
    6
    7
    8
    Units: SBMs per week
    arithmetic mean (standard deviation)
        Baseline
    1.379 ± 1.095
    0.621 ± 0.365
    0.724 ± 0.953
    1.034 ± 0.809
    1.267 ± 1.062
        Change from Baseline at Day 29
    3.100 ± 5.251
    0.032 ± 0.508
    3.603 ± 2.867
    1.574 ± 1.933
    0.482 ± 0.773
    No statistical analyses for this end point

    Primary: Change from Baseline in 4-week Stool Consistency Reported by the Caregiver During the Study Intervention Period of Each Cohort

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    End point title
    		 Change from Baseline in 4-week Stool Consistency Reported by the Caregiver During the Study Intervention Period of Each Cohort [2]
    End point description
    The caregiver rated and recorded in an eDiary the consistency of the stool for each bowel movement using the Bristol Stool Form 7-point scale where: 1=Separate hard lumps, like nuts (hard to pass); 2=Sausage-shaped, but lumpy; 3=Like a sausage but with cracks on its surface; 4=Like a sausage or snake, smooth and soft; 5=Soft blobs with clear cut edges (easy to pass); 6=Fluffy pieces with ragged edges, a mushy stool; 7=Watery, no solid pieces. Entirely liquid. Baseline value was based on values collected 14 days before randomization up to randomization. A participant’s stool consistency score for the treatment period was the average of the nonmissing consistency scores from the BMs recorded by the caregiver during the 4-week treatment period. mITT Population. Number of subjects analysed is the number of participants with data available for analyses.
    End point type
    Primary
    End point timeframe
    Baseline (14 days prior to randomization) to Day 29
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses are reported for this endpoint.
    End point values
    		 Cohort 1 (Linaclotide 18 μg) Cohort 2 (Linaclotide 36 μg) Cohort 3 (Linaclotide 72 μg) Final Cohort (Linaclotide 72 μg) Placebo Pooled
    Number of subjects analysed
    5
    5
    3
    7
    7
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline
    1.633 ± 0.461
    1.700 ± 0.447
    2.733 ± 1.079
    2.021 ± 0.793
    2.024 ± 0.641
        Change From Baseline to Day 29
    0.917 ± 1.360
    1.600 ± 1.294
    1.687 ± 2.779
    1.716 ± 1.689
    0.596 ± 0.937
    No statistical analyses for this end point

    Primary: Change from Baseline in 4-week Straining Reported by the Caregiver During the Study Intervention Period of Each Cohort

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    End point title
    		 Change from Baseline in 4-week Straining Reported by the Caregiver During the Study Intervention Period of Each Cohort [3]
    End point description
    The caregiver rated and recorded in an eDiary the amount of straining they observed when the child passed the BM (1=Not at all; 2=Yes a little; 3=Yes a lot; 99=I don’t know). Baseline value was based on values collected 14 days before randomization up to randomization. A participant’s straining score for the treatment period was the average of the nonmissing straining scores from the BMs recorded by the caregiver during the 4-week treatment period. A negative change from Baseline indicates improvement. mITT Population included all Randomized Population who received at least 1 dose of double-blind study intervention and who had at least 1 postbaseline entry on BM characteristic assessments that determine occurrences of SBMs. Number of subjects analysed is the number of participants with data available for analyses.
    End point type
    Primary
    End point timeframe
    Baseline (14 days prior to randomization) to Day 29
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses are reported for this endpoint.
    End point values
    		 Cohort 1 (Linaclotide 18 μg) Cohort 2 (Linaclotide 36 μg) Cohort 3 (Linaclotide 72 μg) Final Cohort (Linaclotide 72 μg) Placebo Pooled
    Number of subjects analysed
    5
    5
    3
    7
    7
    Units: straining score
    arithmetic mean (standard deviation)
        Baseline
    2.310 ± 0.410
    2.600 ± 0.379
    2.600 ± 0.361
    2.571 ± 0.426
    2.548 ± 0.658
        Change From Baseline to Day 29
    -0.370 ± 0.631
    -0.320 ± 0.325
    -0.769 ± 0.884
    -0.996 ± 0.759
    -0.334 ± 0.360
    No statistical analyses for this end point

    Primary: Percentage of Days with Fecal Incontinence During the Study Intervention Period (for Participants who have Acquired Toileting Skills During the Daytime and Nighttime or Acquired Toileting Skills During Daytime Only) Within Each Cohort

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    End point title
    		 Percentage of Days with Fecal Incontinence During the Study Intervention Period (for Participants who have Acquired Toileting Skills During the Daytime and Nighttime or Acquired Toileting Skills During Daytime Only) Within Each Cohort [4]
    End point description
    Each day the caregiver recorded in an eDiary if the child had a bowel movement accident (Yes; No; I don’t know). The percentage of days with fecal incontinence for the treatment period was the average of the nonmissing incidences of fecal incontinence recorded by the caregiver during the 4-week treatment period. mITT Population included all Randomized Population who received at least 1 dose of double-blind study intervention and who had at least 1 postbaseline entry on BM characteristic assessments that determine occurrences of SBMs. Number of subjects analysed is the number of participants with data available for analyses.
    End point type
    Primary
    End point timeframe
    29 days
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses are reported for this endpoint.
    End point values
    		 Cohort 1 (Linaclotide 18 μg) Cohort 2 (Linaclotide 36 μg) Cohort 3 (Linaclotide 72 μg) Final Cohort (Linaclotide 72 μg) Placebo Pooled
    Number of subjects analysed
    5
    6
    5
    5
    6
    Units: percentage of days
        arithmetic mean (standard deviation)
    0.007 ± 0.016
    0.065 ± 0.107
    0.091 ± 0.063
    0.009 ± 0.019
    0.000 ± 0.000
    No statistical analyses for this end point

    Primary: Percentage of Participants with Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

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    End point title
    		 Percentage of Participants with Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) [5]
    End point description
    An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease. A serious adverse event (SAE) is defined as any untoward medical occurrence that: results in death, is immediately life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, and/or causes a congenital anomaly/birth defect. A TEAE is an AE that begins or worsens after receiving study drug. Safety Population included all participants in the Randomized Population who received at least 1 dose of double-blind study intervention.
    End point type
    Primary
    End point timeframe
    First dose of study drug intervention to within 1 week of last dose (Up to 45 days)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses are reported for this endpoint.
    End point values
    		 Cohort 1 (Linaclotide 18 μg) Cohort 2 (Linaclotide 36 μg) Cohort 3 (Linaclotide 72 μg) Final Cohort (Linaclotide 72 μg) Placebo Pooled
    Number of subjects analysed
    7
    7
    6
    7
    8
    Units: percentage of participants
    number (not applicable)
        TEAEs
    28.6
    0.0
    0.0
    28.6
    12.5
        TESAE
    0.0
    0.0
    0.0
    0.0
    0.0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose of study drug intervention to within 1 week of last dose (Up to 45 days)
    Adverse event reporting additional description
    All-Cause Mortality: All randomized participants. Serious Adverse Events and Other Adverse Events: Safety Population included all participants in the Randomized Population who received at least 1 dose of double-blind study intervention.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Cohort 2 (Linaclotide 36 μg)
    Reporting group description
    		 Linaclotide 36 μg, capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.

    Reporting group title
    Cohort 1 (Linaclotide 18 μg)
    Reporting group description
    		 Linaclotide 18 μg, capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.

    Reporting group title
    Final Cohort (Linaclotide 72 μg)
    Reporting group description
    		 Linaclotide at the highest dose tested/determined to be safe (72 μg), capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.

    Reporting group title
    Placebo Pooled
    Reporting group description
    		 Matching placebo once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period pooled from Cohorts 1, 2, 3, and Final Cohort.

    Reporting group title
    Cohort 3 (Linaclotide 72 μg)
    Reporting group description
    		 Linaclotide 72 μg, capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period.

    Serious adverse events
    		 Cohort 2 (Linaclotide 36 μg) Cohort 1 (Linaclotide 18 μg) Final Cohort (Linaclotide 72 μg) Placebo Pooled Cohort 3 (Linaclotide 72 μg)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Cohort 2 (Linaclotide 36 μg) Cohort 1 (Linaclotide 18 μg) Final Cohort (Linaclotide 72 μg) Placebo Pooled Cohort 3 (Linaclotide 72 μg)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    2 / 7 (28.57%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Developmental delay
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Infections and infestations
    Otitis media
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Ear infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 May 2020
    The purpose of Global Protocol Amendment 1 was to include an assessment of modified Rome III criteria at the end of treatment as an ‘other’ efficacy endpoint, to include a fecal impaction assessment prior to randomization and dosing, and to provide additional clarification and updates to the LIN-MD-67 protocol (dated 01 May 2019); European Union (EU) sites would not be included in the study; Information was provided on study conduct during the novel coronavirus pandemic; Appendix: Liver Safety was added.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    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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