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    Clinical Trial Results:
    Intestinal Inflammation in Ankylosing Spondylitis assessed by Fecal Calprotectin, Capsular Endoscopy and Colonoscopy and the effects of Adalimumab on mucosal healing

    Summary
    EudraCT number
    2009-018085-35
    Trial protocol
    DK  
    Global end of trial date
    11 Mar 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    26 Mar 2016
    First version publication date
    26 Mar 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    4682724
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01174186
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Regionshospitalet Silkeborg
    Sponsor organisation address
    Falkevej 1, Silkeborg, Denmark, 8220
    Public contact
    Studieledelse, Regionshospitalet Silkeborg, +45 87222360, henngler@rm.dk
    Scientific contact
    Studieledelse, Regionshospitalet Silkeborg, +45 87222360, henngler@rm.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
    09 Mar 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Mar 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Mar 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To establish the proportion of otherwise intestinally low-symptomatic patients with intestinal ulcers in patients diagnosed with active spondyloarthritis and to illustrate the healing rate following treatment with the TNF-alpha inhibitor adalimumab
    Protection of trial subjects
    The patients were informed orally and in writing. During the trial the patients could call a phone number day and night with questions.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Oct 2010
    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
    Denmark: 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
    Patients were recruited from the rheumatologic outpatient clinics in the Central and North Denmark Regions on the basis of SpA activity. Patients ≥18 years with active SpA defined by expert opinion and a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥4 (and thus candidates for anti-TNF treatment) were eligible for inclusion and were a

    Pre-assignment
    Screening details
    Because NSAID can elevate fecal calprotectin, patients were subjected to a 4-week NSAID washout period, after which fecal calprotectin was measured. Depending on the fecal calprotectin level the patients were grouped into either a “calprotectin normal” (<50 mg/kg) or “calprotectin high” (≥100 mg/kg) category.

    Pre-assignment period milestones
    Number of subjects started
    31 [1]
    Number of subjects completed
    30

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Consent withdrawn by subject: 1
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: One patient gave consent to join the study but withdrew his consent before completing NSAID wash-out period
    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Calprotectin high
    Arm description
    calprotectin high: Fecal calprotectin ≥100 mg/kg after NSAID wash-out period
    Arm type
    Experimental

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    PR1
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled injector, Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Loading dose of 80 mg. Hereafter 40 mg every other week

    Arm title
    Calprotectin normal
    Arm description
    Faecal calprotectin <50 mg/kg after wash-out period
    Arm type
    Active comparator

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    PR1
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled injector, Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    40 mg every other week

    Number of subjects in period 1
    Calprotectin high Calprotectin normal
    Started
    15
    15
    Repeat endoscopy
    15
    15
    Follow-up
    15
    15
    Completed
    15
    12
    Not completed
    0
    3
         Lost to follow-up
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Calprotectin high
    Reporting group description
    calprotectin high: Fecal calprotectin ≥100 mg/kg after NSAID wash-out period

    Reporting group title
    Calprotectin normal
    Reporting group description
    Faecal calprotectin <50 mg/kg after wash-out period

    Reporting group values
    Calprotectin high Calprotectin normal Total
    Number of subjects
    15 15 30
    Age categorical
    Age at baseline
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    15 15 30
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    34 (18 to 45) 32 (18 to 43) -
    Gender categorical
    Units: Subjects
        Female
    3 4 7
        Male
    12 11 23
    HLA-B27 positive
    Positive meaning having MHC-class 1 allele B27
    Units: Subjects
        Positive
    15 10 25
        Negative
    0 5 5
    Disease duration
    Time from first symptom to inclusion
    Units: Years
        median (full range (min-max))
    7 (1 to 24) 7 (1 to 26) -
    Subject analysis sets

    Subject analysis set title
    Follow-up baseline
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Follow-up endoscopy in patients with intestinal inflammation or elevated calprotectin at baseline

    Subject analysis set title
    Follow-up 20 weeks
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Patients with either elevated calprotectin at baseline or intestinal inflammation after 20 weeks of treatment

    Subject analysis set title
    Follow-up 12 weeks
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Patients with elevated calprotectin at baseline or intestinal inflammation at endoscopy

    Subject analysis sets values
    Follow-up baseline Follow-up 20 weeks Follow-up 12 weeks
    Number of subjects
    16
    16
    16
    Age categorical
    Age at baseline
    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
    16
        85 years and over
    0
    Age continuous
    Units: years
        median (full range (min-max))
    Gender categorical
    Units: Subjects
        Female
        Male
    HLA-B27 positive
    Positive meaning having MHC-class 1 allele B27
    Units: Subjects
        Positive
        Negative
    Disease duration
    Time from first symptom to inclusion
    Units: Years
        median (full range (min-max))

    End points

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    End points reporting groups
    Reporting group title
    Calprotectin high
    Reporting group description
    calprotectin high: Fecal calprotectin ≥100 mg/kg after NSAID wash-out period

    Reporting group title
    Calprotectin normal
    Reporting group description
    Faecal calprotectin <50 mg/kg after wash-out period

    Subject analysis set title
    Follow-up baseline
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Follow-up endoscopy in patients with intestinal inflammation or elevated calprotectin at baseline

    Subject analysis set title
    Follow-up 20 weeks
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Patients with either elevated calprotectin at baseline or intestinal inflammation after 20 weeks of treatment

    Subject analysis set title
    Follow-up 12 weeks
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Patients with elevated calprotectin at baseline or intestinal inflammation at endoscopy

    Primary: Intestinal inflammation

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    End point title
    Intestinal inflammation
    End point description
    Number of subjects at baseline with any intestinal ulceration
    End point type
    Primary
    End point timeframe
    Baseline
    End point values
    Calprotectin high Calprotectin normal
    Number of subjects analysed
    15
    15
    Units: Subject
        Present
    12
    1
        Absent
    3
    14
    Statistical analysis title
    Intestinal inflammation between groups
    Comparison groups
    Calprotectin high v Calprotectin normal
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    < 0.001
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Lewis score at follow-up

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    End point title
    Lewis score at follow-up
    End point description
    Follow-up endoscopy in patients with intestinal inflammation or elevated faecal calprotectin at baseline
    End point type
    Primary
    End point timeframe
    After 20 weeks of treatment
    End point values
    Follow-up baseline Follow-up 20 weeks
    Number of subjects analysed
    16
    16
    Units: unit(s)
        arithmetic mean (full range (min-max))
    398 (112 to 608)
    33 (0 to 180)
    Statistical analysis title
    Follow-up endoscopy
    Statistical analysis description
    Comparison of Lewis score from baseline to 20 weeks after treatment onset
    Comparison groups
    Follow-up baseline v Follow-up 20 weeks
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    < 0.01
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Fecal calprotectin changes

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    End point title
    Fecal calprotectin changes
    End point description
    Changes in koncentration of calprotectin in faces
    End point type
    Primary
    End point timeframe
    Baseline, 12 weeks and 20 weeks of treatment
    End point values
    Follow-up baseline Follow-up 20 weeks Follow-up 12 weeks
    Number of subjects analysed
    16
    16
    16
    Units: mg/kg
        arithmetic mean (standard deviation)
    285 ± 186
    48 ± 33
    83 ± 67
    Attachments
    Untitled (Filename: F-calpro.png)
    Statistical analysis title
    Faecal calprotectin
    Statistical analysis description
    Change in calprotectin koncentration over time
    Comparison groups
    Follow-up baseline v Follow-up 20 weeks v Follow-up 12 weeks
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    < 0.001
    Method
    ANOVA
    Confidence interval

    Secondary: MRI inflammation

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    End point title
    MRI inflammation
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 52 weeks of follow-up
    End point values
    Calprotectin high Calprotectin normal
    Number of subjects analysed
    15
    12
    Units: units
        arithmetic mean (inter-quartile range (Q1-Q3))
    6.6 (2 to 12)
    3.5 (0 to 4)
    Attachments
    Untitled (Filename: MRI intasah.png)
    Statistical analysis title
    MRI score between groups
    Statistical analysis description
    Analysis of MRI scores between groups
    Comparison groups
    Calprotectin normal v Calprotectin high
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    < 0.05
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    MRI score over time
    Statistical analysis description
    Comparison of MRI scores before and after treatment
    Comparison groups
    Calprotectin high v Calprotectin normal
    Number of subjects included in analysis
    27
    Analysis specification
    Post-hoc
    Analysis type
    equivalence
    P-value
    < 0.05
    Method
    ANOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Report for serious adverse events made annually. Here reported for entire study period
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    ICD
    Dictionary version
    10
    Reporting groups
    Reporting group title
    Calprotectin high
    Reporting group description
    calprotectin high: Fecal calprotectin ≥100 mg/kg after NSAID wash-out period

    Reporting group title
    Calprotectin normal
    Reporting group description
    Faeacal calprotectin <50 mg/kg after wash-out period

    Serious adverse events
    Calprotectin high Calprotectin normal
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 15 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Dizziness
    Additional description: 10 days after the start she gets dizziness and malaise. The patient goes to the family doctor, who admits patient. At the hospital examined with blood tests and physical examination. Discharged after 4 hours of stay in hospital.
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastro intestinal bleeding
    Additional description: 20 year old man wknown previous episodes that bleeding episodes from the gut hospitalized with nausea and dizziness. At the hospital found bleeding from the intestine surgically burned.
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (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: 5%
    Non-serious adverse events
    Calprotectin high Calprotectin normal
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 15 (20.00%)
    2 / 15 (13.33%)
    Skin and subcutaneous tissue disorders
    Dry skin
    Additional description: Patients reporting dryness of skin after use of adalimumab
         subjects affected / exposed
    3 / 15 (20.00%)
    2 / 15 (13.33%)
         occurrences all number
    3
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 May 2011
    A comparator group (calprotectin normal) was added to the study. Based on included subjects inclusion number was changed to n=15 in each group

    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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