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    Clinical Trial Results:
    Mucosal immune regulation by high dose vitamin D treatment in Crohn’s disease

    Summary
    EudraCT number
    		 2013-000971-34
    Trial protocol
    		 DK  
    Global end of trial date
    22 Nov 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Jun 2020
    First version publication date
    24 Jun 2020
    Other versions
    Summary report(s)
    		 summary

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    01052013
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aarhus University Hospital
    Sponsor organisation address
    Palle Juul Jensens boulevard 99, Aarhus N, Denmark, 8200
    Public contact
    Jørgen Agnholt, Hepatology and Gastroenterology department, Aarhus University Hospital, joeragnh@rm.dk
    Scientific contact
    Jørgen Agnholt, Hepatology and Gastroenterology department, Aarhus University Hospital, joeragnh@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
    30 May 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Nov 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    We hypotheses that treatment with high dose vitamin D alone or combined with infliximab to Crohn's disease patients with disease activity increases the anti-inflammatory response in the intestinal mucosa. This would result in changed VDR expression in mucosa together with changed expression of IL17A, Il17F, IL22 and IL4 in mucosa compared to placebo. Secondary vitamin D treatment decreases the disease activity measured by inflammatory markers and endoscopic score. Other pro- and anti-inflammatory mucosal cytokines will also be affected by vitamin D treatment. The intervention was 7 weeks. Afterwards all patients were admitted to open infliximab treatment as standard treatment and was followed 52 weeks or until their infliximab treatment was stopped. 10 healthy were included to test if high dose vitamin D also had impact on healthy intestinal mucosa. The results from the healthy is already published (N. F: Bak 2018, Eur J Nutr)
    Protection of trial subjects
    Laboratory analyses for adverse reactions related to the Infliximab and Cholecalciferol treatment will be carried out at baseline, week 2 and 6. Safety markers are collected at screening. Chest X-ray is performed at screening if this has not been done within the last year – or if participants have been exposed to TB-endemic areas after prior TB screening. Blood samples were done the day of the control visit to minimise the number of hospitalvisits. Colonoscopy/sigmideoscopy When the endoscope is moved forward it can cause a slight to moderate discomfort like a feeling like too much air in the intestines. To reduce this, patients were offered treatment with midazolam and fentanyl during the examination. There are no pain sensing nerves in the intestinal mucosa and therefore, the biopsy procedure is usually not associated with pain. There is a minor risk of bleeding and perforation of the intestine during colonoscopy. The risk is approximately 1:1000 in elderly with intestinal disease (inflammation, ischemia or tumour). The risk is estimated to be less than 1:1000 in healthy individuals. The risks will be minimised since experienced physicians will perform all colonoscopies.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jul 2014
    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: 40
    Worldwide total number of subjects
    40
    EEA total number of subjects
    40
    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)
    40
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Patients with colon or/and ilieoceacal Crohn’s disease with active disease assessed by HBI score recruited. Patients were screened with blood samples, urine examinations, x-ray and finally colonoscopy according to in- and exclusion criteria.

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    patients are blinded until week 7 . afterwards all patients in follow up are treated with open infliximab

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Infliximab+vitamin D
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    infliximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate and solution for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/kg infused over 3 hours

    Investigational medicinal product name
    dekristol
    Investigational medicinal product code
    Other name
    Vitamin D3
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    5 mg as a bolus and afterwards 0.5 mg daily in 7 weeks

    Arm title
    		 Infliximab+placebo vitamin D
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    infliximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate and solution for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/kg infused over 3 hours

    Investigational medicinal product name
    placebo dekristol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    placebo capsules, same amount as the active drug

    Arm title
    		 Placebo infliximab+Vitamin D
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    dekristol
    Investigational medicinal product code
    Other name
    Vitamin D3
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    5 mg as a bolus and afterwards 0.5 mg daily in 7 weeks

    Investigational medicinal product name
    natriumchloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    placebo infliximab same amount was given as the active drug

    Arm title
    		 PLacebo infliximab+placebo vitamin D
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo dekristol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    placebo capsules, same amount as the active drug

    Investigational medicinal product name
    natriumchloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    placebo infliximab same amount was given as the active drug

    Number of subjects in period 1
    		Infliximab+vitamin D Infliximab+placebo vitamin D Placebo infliximab+Vitamin D PLacebo infliximab+placebo vitamin D
    Started
    8
    8
    16
    8
    Completed
    7
    8
    16
    8
    Not completed
    1
    0
    0
    0
         Adverse event, non-fatal
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Infliximab+vitamin D
    Reporting group description
    		 -

    Reporting group title
    Infliximab+placebo vitamin D
    Reporting group description
    		 -

    Reporting group title
    Placebo infliximab+Vitamin D
    Reporting group description
    		 -

    Reporting group title
    PLacebo infliximab+placebo vitamin D
    Reporting group description
    		 -

    Reporting group values
    		 Infliximab+vitamin D Infliximab+placebo vitamin D Placebo infliximab+Vitamin D PLacebo infliximab+placebo vitamin D Total
    Number of subjects
    		 8 8 16 8 40
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 8 8 16 8 40
    Age continuous
    Units: years
        median (full range (min-max))
    		 28 (21 to 49) 26 (20 to 53) 35 (20 to 59) 30 (22 to 48) -
    Gender categorical
    Units: Subjects
        Female
    		 4 4 8 5 21
        male
    		 4 4 8 3 19
    Family history of CD or UC
    Units: Subjects
        Family history of CD or UC
    		 1 2 3 1 7
        no family history
    		 7 6 13 7 33
    smoking
    Units: Subjects
        smoking
    		 3 1 1 3 8
        non smoking
    		 5 7 15 5 32
    Former or present stenosis
    Units: Subjects
        Former or present stenosis
    		 3 3 1 3 10
        no stenosis
    		 5 5 15 5 30
    Former abdominal surgery
    Units: Subjects
        Former abdominal surgery
    		 1 0 3 1 5
        no surgery
    		 7 8 13 7 35
    Former or present fistula
    Units: Subjects
        former or present fistula
    		 0 1 1 0 2
        no fistula
    		 8 7 15 8 38
    Former or present abcess
    Units: Subjects
        Former or present abcess
    		 0 2 2 1 5
        no abcess
    		 8 6 14 7 35
    Former or present fissure
    Units: Subjects
        dormer or present fissure
    		 0 0 1 0 1
        no fissure
    		 8 8 15 8 39
    Other autoimmune diseases
    Units: Subjects
        other autoimmune diseases
    		 0 2 2 1 5
        no autoimmune diseases
    		 8 6 14 7 35
    Extra intestinal manifestations
    Units: Subjects
        EIM
    		 2 2 5 0 9
        no EIM
    		 6 6 11 8 31
    Fatigue
    Units: Subjects
        Fatigue
    		 4 5 13 4 26
        no fatigue
    		 4 3 3 4 14
    Former infliximab treatment
    Units: Subjects
        former infliximab treatment
    		 2 3 4 1 10
        no former infliximab
    		 6 5 12 7 30
    Former Adalimumab treatment
    Units: Subjects
        former adalimumab treatment
    		 0 0 2 1 3
        no former adalimumab
    		 8 8 14 7 37
    Former treatment with other biologicals
    Units: Subjects
        former treatment with other biologicals
    		 0 0 1 0 1
        no former other biologicals
    		 8 8 15 8 39
    budesonide users (3 mg/day)
    Units: Subjects
        budesonide users
    		 0 1 0 0 1
        no budesonide
    		 8 7 16 8 39
    azathioprine users
    Units: Subjects
        azathioprine users
    		 3 6 3 1 13
        no azathioprine
    		 5 2 13 7 27
    BMI
    Units: kg/m2
        median (full range (min-max))
    		 25 (21.5 to 29.9) 22.8 (20.5 to 44.3) 24.8 (18.7 to 32.9) 28.8 (23.1 to 34.2) -
    Harvey-Bradshaw index
    Units: score
        median (full range (min-max))
    		 7 (5 to 14) 6.5 (5 to 16) 7 (5 to 11) 5 (5 to 10) -
    Calprotectin
    Units: mg/kg
        median (full range (min-max))
    		 884 (114 to 2174) 718 (163 to 3366) 895 (113 to 2094) 714 (256 to 6000) -
    25-hydroxyviatmin D
    Units: nmol/l
        median (full range (min-max))
    		 45 (11 to 83) 73 (33 to 88) 66.5 (32 to 94) 72.5 (21 to 90) -
    CRP
    Units: mg/l
        median (full range (min-max))
    		 5.3 (0.6 to 25.6) 16.5 (0.6 to 38.5) 8.8 (0.3 to 25) 6.3 (0.8 to 45.9) -
    Leucocytes
    Units: 10^9/l
        median (full range (min-max))
    		 7.67 (5 to 11.6) 7.1 (5.6 to 9.4) 7.6 (5 to 11.5) 8.2 (3.7 to 15.8) -
    Haemoglobin
    Units: mmol/l
        median (full range (min-max))
    		 8.7 (7.5 to 10.2) 8.6 (6.4 to 9.5) 8.5 (6.9 to 9.7) 8.5 (6.6 to 10) -
    Short health score
    Units: score
        median (full range (min-max))
    		 21 (11 to 32) 20 (3 to 33) 14.5 (4 to 36) 21 (5 to 33) -
    Endoscopic CDEIS score
    Units: score
        median (full range (min-max))
    		 13 (11 to 32) 18 (7 to 33) 14 (6 to 29) 19 (6 to 49) -
    years since diagnosis
    Units: years
        median (full range (min-max))
    		 2.3 (0 to 4.7) 3.3 (0 to 16.2) 1.2 (0 to 23.9) 1.9 (0.1 to 7.8) -

    End points

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    End points reporting groups
    Reporting group title
    Infliximab+vitamin D
    Reporting group description
    		 -

    Reporting group title
    Infliximab+placebo vitamin D
    Reporting group description
    		 -

    Reporting group title
    Placebo infliximab+Vitamin D
    Reporting group description
    		 -

    Reporting group title
    PLacebo infliximab+placebo vitamin D
    Reporting group description
    		 -

    Primary: VDR expression

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    End point title
    		 VDR expression
    End point description
    End point type
    Primary
    End point timeframe
    VDR mRNA expression given week 0 and 7.
    End point values
    		 Infliximab+vitamin D Infliximab+placebo vitamin D Placebo infliximab+Vitamin D PLacebo infliximab+placebo vitamin D
    Number of subjects analysed
    7 [1]
    8 [2]
    14 [3]
    8 [4]
    Units: relative quantification
    median (confidence interval 95%)
        week 0
    0.079 (0.015 to 0.14)
    0.25 (0.054 to 0.43)
    0.11 (0.048 to 0.17)
    0.13 (0.029 to 0.23)
        week 7
    0.055 (0.004 to 0.11)
    0.2 (0.013 to 0.39)
    0.15 (0.055 to 0.25)
    0.092 (0 to 0.19)
    Notes
    [1] - 7 week 0 and 7 week 7
    [2] - 8 week 0 and 7 week 7
    [3] - 14 week 0 and 16 week 7
    [4] - 8 w 0 and 5 week 7
    Statistical analysis title
    		 mixed model
    Statistical analysis description
    All mRNA expression were tested with mixed model and data was logarithm transformed. Within every group changes from week 7 to week 0 was tested and median ratios are used to describe changes within the groups. afterwards these changes were compared the following way: infliximab+vitamin D versus infliximab+placebovitamin D and placebo infliximab+ vitamin D versus placebo infliximab+ placebo vitamin D. This description fits all mRNA measurements.
    Comparison groups
    Infliximab+placebo vitamin D v Placebo infliximab+Vitamin D v Infliximab+vitamin D v PLacebo infliximab+placebo vitamin D
    Number of subjects included in analysis
    37
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Confidence interval

    Primary: IL22 expression

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    End point title
    		 IL22 expression
    End point description
    End point type
    Primary
    End point timeframe
    mRNA IL22 expression week 0 and 7.
    End point values
    		 Infliximab+vitamin D Infliximab+placebo vitamin D Placebo infliximab+Vitamin D PLacebo infliximab+placebo vitamin D
    Number of subjects analysed
    6 [5]
    8 [6]
    14 [7]
    8 [8]
    Units: relative quantification
    median (confidence interval 95%)
        week 0
    0.0011 (0 to 0.0029)
    0.00067 (0 to 0.0016)
    0.00065 (0 to 0.0013)
    0.00038 (0 to 0.0009)
        week 7
    0.00003 (0 to 0.00006)
    0.00007 (0 to 0.00018)
    0.00031 (0.00004 to 0.00057)
    0.00022 (0 to 0.00053)
    Notes
    [5] - w7=7
    [6] - w7=7
    [7] - w7=15
    [8] - w7=5
    Statistical analysis title
    		 mixed model
    Comparison groups
    Infliximab+vitamin D v Infliximab+placebo vitamin D v Placebo infliximab+Vitamin D v PLacebo infliximab+placebo vitamin D
    Number of subjects included in analysis
    36
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 median ratio
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Primary: IL17F expression

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    End point title
    		 IL17F expression
    End point description
    End point type
    Primary
    End point timeframe
    mRNA IL17F expression week 0 and 7
    End point values
    		 Infliximab+vitamin D Infliximab+placebo vitamin D Placebo infliximab+Vitamin D PLacebo infliximab+placebo vitamin D
    Number of subjects analysed
    7 [9]
    8 [10]
    14
    8 [11]
    Units: relative quantification
    median (confidence interval 95%)
        week 0
    0.00034 (0 to 0.00071)
    0.00017 (0 to 0.00035)
    0.00019 (0.00004 to 0.00033)
    0.00022 (0 to 0.00045)
        week 7
    0.00008 (0 to 0.00017)
    0.00006 (0 to 0.00012)
    0.00017 (0.00005 to 0.00029)
    0.00021 (0 to 0.00044)
    Notes
    [9] - w7= 7
    [10] - w7= 7
    [11] - w7 = 5
    Statistical analysis title
    		 mixed model
    Comparison groups
    Infliximab+placebo vitamin D v Infliximab+vitamin D v Placebo infliximab+Vitamin D v PLacebo infliximab+placebo vitamin D
    Number of subjects included in analysis
    37
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 median ratio
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Primary: IL17A expression

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    End point title
    		 IL17A expression
    End point description
    End point type
    Primary
    End point timeframe
    mRNA IL17A mucosa expression week 0 and 7.
    End point values
    		 Infliximab+vitamin D Infliximab+placebo vitamin D Placebo infliximab+Vitamin D PLacebo infliximab+placebo vitamin D
    Number of subjects analysed
    7
    8 [12]
    14 [13]
    8 [14]
    Units: relative quantification
    median (confidence interval 95%)
        week 0
    0.00088 (-0.00005 to 0.0018)
    0.0007 (-0.0000007 to 0.0014)
    0.0014 (0.00035 to 0.0024)
    0.00052 (-0.000005 to 0.001)
        week 7
    0.00017 (-0.000008 to 0.00034)
    0.00027 (-0.00001 to 0.00056)
    0.00063 (0.00018 to 0.0011)
    0.00032 (-0.00006 to 0.00069)
    Notes
    [12] - w7=7
    [13] - w7=15
    [14] - w7=5
    Statistical analysis title
    		 mixed model
    Comparison groups
    Infliximab+vitamin D v Infliximab+placebo vitamin D v Placebo infliximab+Vitamin D v PLacebo infliximab+placebo vitamin D
    Number of subjects included in analysis
    37
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 median ratio
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Secondary: TGFbeta expression

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    End point title
    		 TGFbeta expression
    End point description
    End point type
    Secondary
    End point timeframe
    mRNA expression week 0 an 7
    End point values
    		 Infliximab+vitamin D Infliximab+placebo vitamin D Placebo infliximab+Vitamin D PLacebo infliximab+placebo vitamin D
    Number of subjects analysed
    7
    8 [15]
    14 [16]
    8 [17]
    Units: relative quantification
    median (confidence interval 95%)
        week 0
    0.015 (0.0043 to 0.026)
    0.011 (0.0033 to 0.0186)
    0.017 (0.0084 to 0.026)
    0.017 (0.0052 to 0.03)
        week 6
    0.013 (0.0025 to 0.023)
    0.008 (0.0016 to 0.014)
    0.012 (0.0054 to 0.019)
    0.02 (0.0024 to 0.038)
    Notes
    [15] - w7=7
    [16] - w7=16
    [17] - w7=5
    Statistical analysis title
    		 mixed model
    Comparison groups
    Infliximab+vitamin D v Infliximab+placebo vitamin D v Placebo infliximab+Vitamin D v PLacebo infliximab+placebo vitamin D
    Number of subjects included in analysis
    37
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 median ratio
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Secondary: IL10 expression

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    End point title
    		 IL10 expression
    End point description
    End point type
    Secondary
    End point timeframe
    IL10 mRNA expression week 0 and 7.
    End point values
    		 Infliximab+vitamin D Infliximab+placebo vitamin D Placebo infliximab+Vitamin D PLacebo infliximab+placebo vitamin D
    Number of subjects analysed
    7
    8 [18]
    14 [19]
    8 [20]
    Units: relative quantification
    median (confidence interval 95%)
        week 0
    0.00049 (0.00015 to 0.00083)
    0.00048 (0.00016 to 0.00079)
    0.00056 (0.00028 to 0.00083)
    0.00032 (0.00011 to 0.00054)
        week 7
    0.00024 (0.00005 to 0.00042)
    0.00036 (0.00008 to 0.00063)
    0.00035 (0.00017 to 0.00054)
    0.0003 (0.00004 to 0.00054)
    Notes
    [18] - w7=7
    [19] - w7=16
    [20] - w7=5
    No statistical analyses for this end point

    Secondary: IFNgamma

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    End point title
    		 IFNgamma
    End point description
    End point type
    Secondary
    End point timeframe
    mRNA IFNgamma expression week 0 an 7. logarithmic transformed data.
    End point values
    		 Infliximab+vitamin D Infliximab+placebo vitamin D Placebo infliximab+Vitamin D PLacebo infliximab+placebo vitamin D
    Number of subjects analysed
    7
    8 [21]
    14 [22]
    8 [23]
    Units: relative quantification
    median (confidence interval 95%)
        week 0
    0.00049 (0 to 0.001)
    0.0011 (0 to 0.0022)
    0.00076 (0.00019 to 0.0013)
    0.00052 (0 to 0.0011)
        week 7
    0.0001 (0 to 0.00021)
    0.0004 (0 to 0.00085)
    0.00036 (0.00009 to 0.00063)
    0.0005 (0 to 0.0011)
    Notes
    [21] - w7=7
    [22] - w7=16
    [23] - w7=5
    No statistical analyses for this end point

    Secondary: TNFalpha expression

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    End point title
    		 TNFalpha expression
    End point description
    End point type
    Secondary
    End point timeframe
    mRNA expression week 0 and 7
    End point values
    		 Infliximab+vitamin D Infliximab+placebo vitamin D Placebo infliximab+Vitamin D PLacebo infliximab+placebo vitamin D
    Number of subjects analysed
    7
    8 [24]
    14 [25]
    8 [26]
    Units: relative quantification
    median (confidence interval 95%)
        week 0
    0.0027 (0.0014 to 0.004)
    0.0023 (0.0013 to 0.0034)
    0.0024 (0.0016 to 0.0032)
    0.0019 (0.001 to 0.0028)
        week 7
    0.0016 (0.00045 to 0.0028)
    0.0011 (0.0003 to 0.0019)
    0.0016 (0.00083 to 0.0024)
    0.0023 (0.00041 to 0.0042)
    Notes
    [24] - w7=7
    [25] - w7=16
    [26] - w7=5
    No statistical analyses for this end point

    Secondary: CAMP expression

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    End point title
    		 CAMP expression
    End point description
    End point type
    Secondary
    End point timeframe
    mRNA expression of CAMP week 0 and 7
    End point values
    		 Infliximab+vitamin D Infliximab+placebo vitamin D Placebo infliximab+Vitamin D PLacebo infliximab+placebo vitamin D
    Number of subjects analysed
    7
    8 [27]
    14 [28]
    8 [29]
    Units: relative quantification
    median (confidence interval 95%)
        week 0
    0.00059 (0.000086 to 0.0011)
    0.00053 (0.000095 to 0.00097)
    0.0007 (0.00028 to 0.0011)
    0.00059 (0.00011 to 0.0011)
        week 7
    0.00023 (-0.00001 to 0.00047)
    0.00026 (-0.000013 to 0.00053)
    0.00073 (0.00021 to 0.0013)
    0.00075 (-0.00013 to 0.0016)
    Notes
    [27] - w7=7
    [28] - w7=16
    [29] - w7=5
    No statistical analyses for this end point

    Secondary: CDEIS score

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    End point title
    		 CDEIS score
    End point description
    End point type
    Secondary
    End point timeframe
    CDEIS score are given week 0 and week 7
    End point values
    		 Infliximab+vitamin D Infliximab+placebo vitamin D Placebo infliximab+Vitamin D PLacebo infliximab+placebo vitamin D
    Number of subjects analysed
    8 [30]
    8
    16
    8
    Units: score
    median (confidence interval 95%)
        week 0
    17.49 (11.4 to 23.58)
    18.30 (11.92 to 24.68)
    14 (10.55 to 17.45)
    17.39 (11.33 to 23.44)
        week 7
    2.37 (0.57 to 4.17)
    4.31 (1.18 to 7.45)
    10.49 (5.1 to 15.89)
    12.11 (3.3 to 20.92)
    Notes
    [30] - w7=7
    No statistical analyses for this end point

    Secondary: Calprotectin

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    End point title
    		 Calprotectin
    End point description
    End point type
    Secondary
    End point timeframe
    calprotectin measurements during intervention (week 0 to 7) and during follow up.
    End point values
    		 Infliximab+vitamin D Infliximab+placebo vitamin D Placebo infliximab+Vitamin D PLacebo infliximab+placebo vitamin D
    Number of subjects analysed
    8
    8
    16
    8
    Units: mg/kg
    median (confidence interval 95%)
        week 0
    644 (180 to 1109)
    712 (199 to 1226)
    639 (305 to 972)
    782 (218 to 1346)
        week 2
    116 (22 to 210)
    254 (70 to 437)
    575 (274 to 877)
    1150 (288 to 2011)
        week 6
    61 (11 to 110)
    151 (41 to 260)
    395 (187 to 602)
    678 (187 to 1169)
        follow up week 15
    32 (0 to 69)
    205 (0 to 431)
    87 (22 to 152)
    328 (0 to 747)
        follow up week 23
    81 (0 to 198)
    321 (0 to 731)
    64 (10 to 118)
    166 (0 to 429)
        follow up week 31
    74 (0 to 178)
    132 (0 to 302)
    62 (0 to 129)
    132 (0 to 302)
        follow up week 52
    62 (0 to 129)
    67 (0 to 149)
    65 (22 to 107)
    113 (0 to 253)
    No statistical analyses for this end point

    Secondary: HBI score

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    End point title
    		 HBI score
    End point description
    End point type
    Secondary
    End point timeframe
    HBI score week 0, 2 and 6 during intervention and in follow up week 15, 23, 31 and 52. The given medians are from log transformed data which are back-transformed to reflect the mixed model data.
    End point values
    		 Infliximab+vitamin D Infliximab+placebo vitamin D Placebo infliximab+Vitamin D PLacebo infliximab+placebo vitamin D
    Number of subjects analysed
    8
    8
    16
    8
    Units: score
    median (confidence interval 95%)
        week 0
    8 (6.3 to 9.7)
    7.5 (5.8 to 9.2)
    6.9 (5.6 to 8.1)
    6.8 (5 to 8.5)
        week 2
    4.1 (1.7 to 6.6)
    4.5 (2.1 to 6.9)
    5.1 (3.4 to 6.9)
    5.8 (3.3 to 8.2)
        week 6
    3.5 (1 to 6)
    3.8 (1.2 to 6.2)
    6 (4.2 to 7.8)
    5.9 (3.4 to 8.4)
        follow up week 15
    2.1 (1 to 3.3)
    4.8 (2.3 to 7.4)
    3.7 (2.3 to 5)
    2.7 (1.3 to 4.2)
        follow up week 23
    3.9 (1.1 to 6.7)
    3.7 (1 to 6.4)
    3.3 (1.8 to 4.8)
    2.3 (1 to 3.9)
        follow up week 31
    2.9 (1 to 4.7)
    4.2 (1 to 7.3)
    3.2 (2 to 4.5)
    3.1 (1.2 to 4.9)
        follow up week 52
    4.3 (1.6 to 7.1)
    3.7 (1.6 to 5.9)
    3.2 (1.9 to 4.4)
    1.9 (1 to 3.3)
    No statistical analyses for this end point

    Secondary: CRP

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    End point title
    		 CRP
    End point description
    End point type
    Secondary
    End point timeframe
    CRP week 0, 2 and 6 and 15, 23, 31 and 52.The given medians are from log transformed data which are back-transformed to reflect the mixed model data.
    End point values
    		 Infliximab+vitamin D Infliximab+placebo vitamin D Placebo infliximab+Vitamin D PLacebo infliximab+placebo vitamin D
    Number of subjects analysed
    8
    8
    16
    8
    Units: mg/l
    median (confidence interval 95%)
        week 0
    3.9 (0.2 to 7.7)
    10.7 (0.5 to 20.9)
    5.1 (1.7 to 8.5)
    7.5 (0.4 to 14.6)
        week 2
    1.7 (0.2 to 3.3)
    3.1 (0.3 to 5.8)
    4.2 (1.5 to 6.9)
    8.1 (0.8 to 15.5)
        week 6
    1.4 (0.2 to 2.5)
    3.3 (0.5 to 6)
    5.1 (2 to 8.1)
    6.4 (1.1 to 11.7)
        follow up week 15
    1 (0.2 to 1.9)
    3.3 (0.7 to 5.8)
    1.6 (0.8 to 2.4)
    2.4 (0.4 to 4.5)
        follow up week 23
    1.3 (0 to 2.6)
    3.3 (0.2 to 6.3)
    1.2 (0.5 to 2)
    2.5 (0 to 5.1)
        follow up week 31
    1.2 (0.1 to 2.3)
    2.9 (0.4 to 5.5)
    1.1 (0.5 to 1.8)
    2.8 (0.3 to 5.3)
        follow up week 52
    1 (0 to 2)
    4.1 (0.4 to 7.8)
    1.6 (0.7 to 2.6)
    2.1 (0.1 to 4.2)
    No statistical analyses for this end point

    Secondary: Short health score

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    End point title
    		 Short health score
    End point description
    End point type
    Secondary
    End point timeframe
    Short health during intervention
    End point values
    		 Infliximab+vitamin D Infliximab+placebo vitamin D Placebo infliximab+Vitamin D PLacebo infliximab+placebo vitamin D
    Number of subjects analysed
    8
    8
    16
    8
    Units: score
    median (confidence interval 95%)
        week 0
    19.3 (10.9 to 27.6)
    16.1 (9.1 to 23.1)
    14.2 (9.9 to 18.6)
    16.2 (9.2 to 23.2)
        week 2
    16.3 (6.5 to 26.1)
    9.4 (3.8 to 15)
    12.6 (7.3 to 17.9)
    10.7 (4.4 to 17.1)
        week 6
    11.4 (3.7 to 19.2)
    9.6 (3.4 to 15.8)
    10.9 (5.9 to 15.9)
    10.9 (3.9 to 17.9)
    No statistical analyses for this end point

    Other pre-specified: 25-hydroxyvitamin D

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    End point title
    		 25-hydroxyvitamin D
    End point description
    End point type
    Other pre-specified
    End point timeframe
    25 hydroxyvitamin D measurement for safety
    End point values
    		 Infliximab+vitamin D Infliximab+placebo vitamin D Placebo infliximab+Vitamin D PLacebo infliximab+placebo vitamin D
    Number of subjects analysed
    8
    8
    16
    8
    Units: nmol/l
    median (confidence interval 95%)
        week 0
    42 (29 to 55)
    61 (42 to 80)
    64 (50 to 78)
    62 (43 to 81)
        week 2
    167 (134 to 201)
    49 (39 to 58)
    172 (148 to 196)
    57 (46 to 69)
        week 6
    192 (152 to 233)
    47 (38 to 57)
    219 (187 to 251)
    57 (45 to 68)
        follow up week 15
    109 (81 to 138)
    41 (30 to 51)
    148 (122 to 173)
    59 (45 to 68)
        follow up week 23
    84 (57 to 111)
    55 (40 to 71)
    115 (92 to 139)
    65 (45 to 84)
        follow up week 31
    87 (66 to 107)
    71 (55 to 86)
    98 (84 to 112)
    64 (50 to 79)
        follow up week 52
    64 (50 to 79)
    64 (48 to 81)
    83 (70 to 96)
    57 (43 to 71)
    No statistical analyses for this end point

    Other pre-specified: calcium ion

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    End point title
    		 calcium ion
    End point description
    End point type
    Other pre-specified
    End point timeframe
    calcium ion measured for safety during intervention and follow up
    End point values
    		 Infliximab+vitamin D Infliximab+placebo vitamin D Placebo infliximab+Vitamin D PLacebo infliximab+placebo vitamin D
    Number of subjects analysed
    8
    8
    16
    8
    Units: mmol/l
    median (confidence interval 95%)
        week 0
    1.27 (1.25 to 1.3)
    1.25 (1.23 to 1.27)
    1.25 (1.24 to 1.27)
    1.26 (1.24 to 1.28)
        week 2
    1.27 (1.25 to 1.29)
    1.25 (1.23 to 1.27)
    1.28 (1.26 to 1.29)
    1.24 (1.22 to 1.26)
        week 6
    1.27 (1.24 to 1.29)
    1.25 (1.23 to 1.27)
    1.27 (1.25 to 1.28)
    1.25 (1.23 to 1.27)
        follow up week 15
    1.27 (1.25 to 1.29)
    1.24 (1.23 to 1.26)
    1.27 (1.26 to 1.28)
    1.25 (1.23 to 1.26)
        follow up week 23
    1.25 (1.23 to 1.27)
    1.24 (1.22 to 1.26)
    1.26 (1.25 to 1.27)
    1.23 (1.22 to 1.25)
        follow up week 31
    1.26 (1.23 to 1.28)
    1.25 (1.23 to 1.27)
    1.26 (1.24 to 1.28)
    1.25 (1.22 to 1.27)
        follow up week 52
    1.25 (1.22 to 1.27)
    1.25 (1.22 to 1.27)
    1.27 (1.25 to 1.29)
    1.25 (1.22 to 1.28)
    No statistical analyses for this end point

    Post-hoc: CYP27B1 expression

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    End point title
    		 CYP27B1 expression
    End point description
    End point type
    Post-hoc
    End point timeframe
    mRNA expression in CYP27B1 week 0 and 7
    End point values
    		 Infliximab+vitamin D Infliximab+placebo vitamin D Placebo infliximab+Vitamin D PLacebo infliximab+placebo vitamin D
    Number of subjects analysed
    7 [31]
    8 [32]
    14 [33]
    8 [34]
    Units: relative quantification
    median (confidence interval 95%)
        week 0
    0.0019 (0 to 0.0053)
    0.0024 (0 to 0.0064)
    0.0022 (0 to 0.0049)
    0.0009 (0 to 0.0024)
        week 7
    0.00005 (0 to 0.00014)
    0.00012 (0 to 0.00031)
    0.0012 (0 to 0.0024)
    0.001 (0 to 0.0028)
    Notes
    [31] - w7=4
    [32] - w7=6
    [33] - w7=15
    [34] - w7=5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    adverse event are reported separately during week 0 to 7 the intervention and separately from follow up week 8 to 52.
    Adverse event reporting additional description
    patients were questioned if they have had adverse events every time they went for control visits
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10
    Reporting groups
    Reporting group title
    Infliximab+vitamin D - intervention
    Reporting group description
    		 from week 0 to 7

    Reporting group title
    Infliximab+placebo vitamin D - intervention
    Reporting group description
    		 week 0 to 7

    Reporting group title
    Placebo infliximab+Vitamin D - intervention
    Reporting group description
    		 week 0 to 7

    Reporting group title
    Placebo infliximab+placebo vitamin D - intervention
    Reporting group description
    		 week 0 to 7

    Reporting group title
    Infliximab+vitamin D - follow up
    Reporting group description
    		 -

    Reporting group title
    Infliximab+placebo vitamin D - follow up
    Reporting group description
    		 week 8 to 52

    Reporting group title
    Placebo infliximab+Vitamin D - follow up
    Reporting group description
    		 week 8 to 52

    Reporting group title
    PLacebo infliximab+placebo vitamin D - follow up
    Reporting group description
    		 -

    Serious adverse events
    		 Infliximab+vitamin D - intervention Infliximab+placebo vitamin D - intervention Placebo infliximab+Vitamin D - intervention Placebo infliximab+placebo vitamin D - intervention Infliximab+vitamin D - follow up Infliximab+placebo vitamin D - follow up Placebo infliximab+Vitamin D - follow up PLacebo infliximab+placebo vitamin D - follow up
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    Investigations
    Abdominal pain
    Additional description: sever abdominal pain after colonoscoscopy, patient was in hospitalised and examined and observed for perforation. no perforation was found.
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Stenosis
    Additional description: fibrostenosis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Allergic respiratory symptom
    Additional description: infusion reaction with second infusion treatment, this was infliximab (patient were unblinded after the reaction)
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Throat irritation
    Additional description: patient experienced throat irritation and other unspecified symptoms. she was in hospitalised to observation for drug induced reaction. this was not the case. The unspecified symptoms were unrelated to the study drug
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Infliximab+vitamin D - intervention Infliximab+placebo vitamin D - intervention Placebo infliximab+Vitamin D - intervention Placebo infliximab+placebo vitamin D - intervention Infliximab+vitamin D - follow up Infliximab+placebo vitamin D - follow up Placebo infliximab+Vitamin D - follow up PLacebo infliximab+placebo vitamin D - follow up
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 8 (50.00%)
    5 / 8 (62.50%)
    7 / 16 (43.75%)
    4 / 8 (50.00%)
    4 / 6 (66.67%)
    7 / 7 (100.00%)
    10 / 16 (62.50%)
    5 / 6 (83.33%)
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    0
    Insomnia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Iron deficiency
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 16 (12.50%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    2
    1
    Hypophosphataemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    2
    Gastroenteritis
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 8 (25.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    0
    1
    2
    1
    0
    Abdominal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    3 / 16 (18.75%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    3 / 16 (18.75%)
    2 / 6 (33.33%)
         occurrences all number
    0
    1
    3
    1
    0
    1
    3
    2
    Overgrowth bacterial
    Additional description: In the small bowel
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 16 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    2
    0
    Constipation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    Parasitic test positive
    Additional description: threadworm seen at endoscopy
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Gastric hypomotility
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Fistula
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Stenosis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Hepatobiliary disorders
    Transaminases increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    1
    Dermatitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    3 / 6 (50.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    3
    0
    1
    0
    Hidradenitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Acne
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Dermatitis allergic
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Urticaria
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Endocrine disorders
    Weight increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    Infections and infestations
    Pharyngitis
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 8 (37.50%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    2 / 6 (33.33%)
    3 / 7 (42.86%)
    2 / 16 (12.50%)
    2 / 6 (33.33%)
         occurrences all number
    0
    3
    1
    0
    2
    4
    2
    2
    Candida infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0
    Influenza
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Cystitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0

    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.
    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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