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    Clinical Trial Results:
    Treatment effect of colesevelam for bile acid diarrhoea

    Summary
    EudraCT number
    		 2016-001452-22
    Trial protocol
    		 DK  
    Global end of trial date
    14 Feb 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Oct 2023
    First version publication date
    07 Oct 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SJ-641
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Zealand University Hospital
    Sponsor organisation address
    Lykkebaekvej 1, Koege, Denmark, 4600
    Public contact
    Department of Medicine, Zealand University Hosipital, 0045 47322400, chrbo@regionsjaelland.dk
    Scientific contact
    Department of Medicine, Zealand University Hosipital, 0045 47322400, chrbo@regionsjaelland.dk
    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
    14 Feb 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Feb 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Feb 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the efficacy and safety of treating bile acid diarrhoea with colesevelam.
    Protection of trial subjects
    No SAEs in the trial
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 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
    Denmark: 168
    Worldwide total number of subjects
    168
    EEA total number of subjects
    168
    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)
    139
    From 65 to 84 years
    29
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 All patients referred for clinical routine SeHCAT scintigraphy were identified and patient charts prescreened for eligibility data. At the first of two hospital visits needed for the SeHCAT test, eligible patients were recruited baseline assessment (pre-screening/pre-assignment)

    Pre-assignment
    Screening details
    		 6 day diary of stool habits. Only patients fulfilling at least one criterion (A or B) for diarrhea were eligible for randomization. the criteria were on mean number of bowel movements; means over the baseline period A. Mean total bowel movements of3 or more per day B. Mean number sum of watery (Bristol stool type 6 and 7) of 1 or more per day

    Pre-assignment period milestones
    Number of subjects started
    		 168
    Intermediate milestone: Number of subjects
    Bile acid diarrhea or not: 41
    Number of subjects completed
    		 41

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Not bile acid diarrhea: 127
    Period 1
    Period 1 title
    Treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Colesevelamhydrochloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablets of 625mg; starting dose 2 tablets twice daily. Titrated to effect (taper or increase dose). three doses allowed: 1 tablet twice daily (bid), 2 tablets bid. 3 tablets bid.

    Arm title
    		 Colesevelam
    Arm description
    		 Active treatment
    Arm type
    		 Experimental

    Investigational medicinal product name
    Colesevelamhydrochloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablets of 625mg; starting dose 2 tablets twice daily. Titrated to effect (taper or increase dose). three doses allowed: 1 tablet twice daily (bid), 2 tablets bid. 3 tablets bid.

    Number of subjects in period 1 [1]
    		Placebo Colesevelam
    Started
    19
    22
    Completed
    17
    22
    Not completed
    2
    0
         Consent withdrawn by subject
    1
    -
         Lack of efficacy
    1
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: We enrolled all patients attending the nuclear medicine SeHCAT test for suspected bile acid diarrhea (BAD). All patients were tested with an alternative biochemical test called C4. Only patients with a positive C4 test (n=41) were eligible in the primary outcome population. Several diagnostic ROC analyses were done comparing C4 and SeHCAT positive vs negative ; however, these secondary and tertiary analyses were not the primary focus of the RCT

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Colesevelam
    Reporting group description
    		 Active treatment

    Reporting group values
    		 Placebo Colesevelam Total
    Number of subjects
    		 19 22 41
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 64 (53 to 69) 45 (37 to 59) -
    Gender categorical
    Units: Subjects
        Female
    		 14 16 30
        Male
    		 5 6 11

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Colesevelam
    Reporting group description
    		 Active treatment

    Primary: Remission of C4-defined bile acid diarrhea

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    End point title
    		 Remission of C4-defined bile acid diarrhea
    End point description
    Remission of both Hjortswang diarrhea criteria (A and B) of daily bowel habit means over the seven treatment days (6-12)
    End point type
    Primary
    End point timeframe
    Treatment days 6-12
    End point values
    		 Placebo Colesevelam
    Number of subjects analysed
    19 [1]
    22
    Units: Adjusted remission rate
        arithmetic mean (confidence interval 95%)
    17 (5 to 44)
    65 (41 to 83)
    Notes
    [1] - 2 missing values were defined as treatment failure (in a sensitivity analysis we imputed missing val
    Statistical analysis title
    		 Logistic regression
    Comparison groups
    Placebo v Colesevelam
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.011
    Method
    		 Regression, Logistic
    Parameter type
    		 Log odds ratio
    Point estimate
    9.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.9
         upper limit
    		 62.8

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From treatment start (randomization) until 72 hours after treatment end
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 SNOMED CT
    Dictionary version
    2022MAR31
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Colesevelam
    Reporting group description
    		 Active treatment

    Serious adverse events
    		 Placebo Colesevelam
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 22 (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: 1%
    Non-serious adverse events
    		 Placebo Colesevelam
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 19 (57.89%)
    14 / 22 (63.64%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 19 (5.26%)
    2 / 22 (9.09%)
         occurrences all number
    3
    3
    Migraine
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    General disorders and administration site conditions
    Malaise
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    Fatigue
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 22 (0.00%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Bloated abdomen
         subjects affected / exposed
    4 / 19 (21.05%)
    5 / 22 (22.73%)
         occurrences all number
    9
    9
    Abdominal pain
         subjects affected / exposed
    4 / 19 (21.05%)
    5 / 22 (22.73%)
         occurrences all number
    9
    9
    Nausea
         subjects affected / exposed
    1 / 19 (5.26%)
    4 / 22 (18.18%)
         occurrences all number
    5
    5
    Constipation
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    2
    2
    Flatulence
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 22 (4.55%)
         occurrences all number
    2
    2
    heartburn
         subjects affected / exposed
    1 / 19 (5.26%)
    2 / 22 (9.09%)
         occurrences all number
    3
    3
    Increased intestinal sounds
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 22 (4.55%)
         occurrences all number
    2
    2
    Appetite disorder
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    Belching
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    Epigastric discomfort
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 22 (0.00%)
         occurrences all number
    1
    1
    Hepatobiliary disorders
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jan 2019
    Exclusion Criteria: added 1) Acute suspected or proven viral gastroenteritis within the recent 4 weeks 2) Acute non-viral gastroenteritis within the recent 8 weeks
    25 Nov 2020
    Changed the C4 cut-off defining the primary endpoint from 15.4 to > 30 ng/mL. (Note all blood samples till in freezer biobank)
    10 Feb 2022
    Changed the cut-off value of 30 to 46 ng/mL. Other analyses had shown an analytical error in determining the C4 threshold in the previous reference lab (Paris). Measuring the samples originally used to determine the threshold again at two new labs (Copenhagen and Stockholm) showed agreement between these two new measurements. The trial reference lab was changed to Copenhagen

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    13 Mar 2020
    Due to COVID-19 lockdown and termination of research activities at affected hospitals
    05 May 2020

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/36758570
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