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    Clinical Trial Results:
    Phase III, Multicenter, Randomized, Double-blinded, Placebo-controlled, Parallel-group Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Intravenous MLN0002 (300 mg) Infusion in Induction and Maintenance Therapy in Japanese Subjects with Moderate or Severe Crohn's Disease

    Summary
    EudraCT number
    2019-001199-12
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    21 May 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    18 Dec 2019
    First version publication date
    18 Dec 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MLN0002/CCT-001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02038920
    WHO universal trial number (UTN)
    U1111-1150-2688
    Other trial identifiers
    Japan Ministry of Health, Labour and Welfare: JapicCTI-142402
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    Takeda Pharmaceutical Company Limited, 1-1, Doshomachi 4-chome, Chuo-ku, Osaka-shi, Osaka, Japan,
    Public contact
    Medical Director, Clinical Science, Takeda, +1 877-825-3327, clinicaltrialregistry@tpna.com
    Scientific contact
    Medical Director, Clinical Science, Takeda, +1 877-825-3327, clinicaltrialregistry@tpna.com
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 May 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 May 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study is a phase 3, multicenter, randomised, double-blinded, placebo-controlled, parallel-group study to examine the efficacy, safety, and pharmacokinetics of vedolizumab (MLN0002) in induction and maintenance therapy in Japanese participants with moderately or severely active Crohn's disease.
    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
    28 Jan 2014
    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
    Japan: 157
    Worldwide total number of subjects
    157
    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)
    0
    Adolescents (12-17 years)
    6
    Adults (18-64 years)
    149
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants took part in the study at 77 investigative sites in Japan from 28 Jan 2014 to 21 May 2019.

    Pre-assignment
    Screening details
    Participants with moderate to severe Crohn’s disease were enrolled. 157 participants enrolled in induction phase, 41 participants entered maintenance phase and 134 participants entered open-label cohort and received placebo or vedolizumab 300 mg. Open-label cohort occurred between Week 10 and 154 through study with maximum of 94 weeks of treatment.

    Period 1
    Period 1 title
    Induction Phase (Week 0 to 14)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Carer, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Induction Phase: Vedolizumab, 300 mg
    Arm description
    Vedolizumab 300 mg, intravenous (IV) infusion, once at Weeks 0, 2 and 6 in the induction phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Vedolizumab
    Investigational medicinal product code
    Other name
    MLN0002
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vedolizumab IV injection

    Arm title
    Induction Phase: Placebo
    Arm description
    Vedolizumab placebo-matching IV infusion once at Weeks 0, 2 and 6 in the induction phase.
    Arm type
    Placebo

    Investigational medicinal product name
    Vedolizumab placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vedolizumab placebo-matching IV infusion

    Number of subjects in period 1
    Induction Phase: Vedolizumab, 300 mg Induction Phase: Placebo
    Started
    79
    78
    Completed
    73
    66
    Not completed
    6
    12
         Voluntary Withdrawal
    2
    -
         Lack of efficacy
    1
    1
         Pretreatment Event/Adverse Event
    3
    11
    Period 2
    Period 2 title
    Maintenance Phase (Week 14 to 60)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Carer, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Maintenance Phase: Vedolizumab 300 mg
    Arm description
    Vedolizumab placebo-matching, IV infusion, once at Weeks 14, 22, 30, 38, 46 and 54 in maintenance phase. Participants received vedolizumab in induction phase and achieved Crohn's Disease Activity Index (CDAI)-70 response at Week 10 and were randomized to receive vedolizumab in maintenance phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Vedolizumab
    Investigational medicinal product code
    Other name
    MLN0002
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vedolizumab IV injection

    Arm title
    Maintenance Phase: Placebo
    Arm description
    Vedolizumab placebo-matching, IV infusion, once at Weeks 14, 22, 30, 38, 46 and 54 in maintenance phase. Participants received vedolizumab in induction phase and achieved CDAI-70 response at Week 10 and were randomized to receive placebo in maintenance phase.
    Arm type
    Placebo

    Investigational medicinal product name
    Vedolizumab placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vedolizumab placebo-matching IV infusion

    Arm title
    Maintenance Phase: Placebo Continuation
    Arm description
    Vedolizumab placebo-matching, IV infusion, once at Weeks 14, 22, 30, 38, 46 and 54 in maintenance phase. Participants received vedolizumab placebo-matching in induction phase and achieved CDAI-70 response at Week 10 received placebo in maintenance phase without randomization.
    Arm type
    Placebo

    Investigational medicinal product name
    Vedolizumab placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vedolizumab placebo-matching IV infusion

    Number of subjects in period 2 [1]
    Maintenance Phase: Vedolizumab 300 mg Maintenance Phase: Placebo Maintenance Phase: Placebo Continuation
    Started
    12
    12
    17
    Completed
    7
    4
    5
    Not completed
    5
    8
    12
         Lack of efficacy
    2
    4
    10
         Lost to follow-up
    1
    -
    -
         Pretreatment Event/Adverse Event
    2
    4
    2
    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: Not all participants from the Induction Phase entered the Maintenance Phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Induction Phase: Vedolizumab, 300 mg
    Reporting group description
    Vedolizumab 300 mg, intravenous (IV) infusion, once at Weeks 0, 2 and 6 in the induction phase.

    Reporting group title
    Induction Phase: Placebo
    Reporting group description
    Vedolizumab placebo-matching IV infusion once at Weeks 0, 2 and 6 in the induction phase.

    Reporting group values
    Induction Phase: Vedolizumab, 300 mg Induction Phase: Placebo Total
    Number of subjects
    79 78
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    33.9 ± 12.25 32.6 ± 10.93 -
    Sex: Female, Male
    Units: Subjects
        Female
    28 26 54
        Male
    51 52 103
    Disease Localization
    Units: Subjects
        Small Intestine Type
    13 9 22
        Large Intestine Type
    11 19 30
        Small/large Intestine Type
    55 50 105
    Smoking Classification
    Units: Subjects
        Never Smoked
    46 42 88
        Current Smoker
    13 11 24
        Ex-smoker
    20 25 45
    Extraintestinal Manifestations (Based on CDAI subscore)
    CDAI is scoring system for the Assessment of Crohn's Disease Activity. The total CDAI score ranges from 0 to approximately 600, where higher scores indicate more severe disease. Index values of 150 and below are associated with quiescent disease; values above that indicate active disease.
    Units: Subjects
        Had No Extraintestinal Manifestations
    24 22 46
        Had Extraintestinal Manifestations
    55 56 111
    Extraintestinal Manifestations (Based on Case Report Form)
    Units: Subjects
        Had No Extraintestinal Manifestations
    42 52 94
        Had Extraintestinal Manifestations
    37 26 63
    History of Prior Surgery for Crohn's Disease (CD)
    Units: Subjects
        Had No Surgical History
    55 48 103
        Had Surgical History
    24 30 54
    Current Medical Condition Related to Fistula
    Units: Subjects
        Had No Current Medical Condition
    72 66 138
        Had Current Medical Condition
    7 12 19
    Region of Enrollment
    Units: Subjects
        Japan
    79 78 157
    Height
    Units: cm
        arithmetic mean (standard deviation)
    166.3 ± 8.73 166.4 ± 7.97 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    58.53 ± 14.095 55.03 ± 8.928 -
    Body Mass Index (BMI)
    Body Mass Index = weight(kg)/[height(m)^2]
    Units: kg/m^2
        arithmetic mean (standard deviation)
    21.15 ± 4.942 19.81 ± 2.567 -
    Duration of Crohn's Disease
    Duration between the first diagnosis of Crohn's disease and the start of the study was reported.
    Units: years
        median (full range (min-max))
    7.20 (0.3 to 27.8) 8.35 (0.3 to 32.0) -
    C-Reactive Protein (CRP)
    Units: mg/dL
        arithmetic mean (standard deviation)
    2.234 ± 2.1763 2.848 ± 3.2303 -
    CDAI Score at Week 0
    CDAI is scoring system for the Assessment of Crohn's Disease Activity. The total CDAI score ranges from 0 to approximately 600 , where higher scores indicate more severe disease. Index values of 150 and below are associated with quiescent disease; values above that indicate active disease.
    Units: score on a scale
        arithmetic mean (standard deviation)
    303.9 ± 63.19 295.0 ± 64.81 -

    End points

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    End points reporting groups
    Reporting group title
    Induction Phase: Vedolizumab, 300 mg
    Reporting group description
    Vedolizumab 300 mg, intravenous (IV) infusion, once at Weeks 0, 2 and 6 in the induction phase.

    Reporting group title
    Induction Phase: Placebo
    Reporting group description
    Vedolizumab placebo-matching IV infusion once at Weeks 0, 2 and 6 in the induction phase.
    Reporting group title
    Maintenance Phase: Vedolizumab 300 mg
    Reporting group description
    Vedolizumab placebo-matching, IV infusion, once at Weeks 14, 22, 30, 38, 46 and 54 in maintenance phase. Participants received vedolizumab in induction phase and achieved Crohn's Disease Activity Index (CDAI)-70 response at Week 10 and were randomized to receive vedolizumab in maintenance phase.

    Reporting group title
    Maintenance Phase: Placebo
    Reporting group description
    Vedolizumab placebo-matching, IV infusion, once at Weeks 14, 22, 30, 38, 46 and 54 in maintenance phase. Participants received vedolizumab in induction phase and achieved CDAI-70 response at Week 10 and were randomized to receive placebo in maintenance phase.

    Reporting group title
    Maintenance Phase: Placebo Continuation
    Reporting group description
    Vedolizumab placebo-matching, IV infusion, once at Weeks 14, 22, 30, 38, 46 and 54 in maintenance phase. Participants received vedolizumab placebo-matching in induction phase and achieved CDAI-70 response at Week 10 received placebo in maintenance phase without randomization.

    Subject analysis set title
    Open-Label: Vedolizumab 300 mg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Vedolizumab 300 mg, IV infusion, once at Weeks 0, 2 and 6 and then every 8 weeks thereafter up to Week 94 as a maximum duration in open-label phase.

    Primary: Induction phase: Percentage of Participants with Crohn's Disease Activity Index (CDAI)-100 Response

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    End point title
    Induction phase: Percentage of Participants with Crohn's Disease Activity Index (CDAI)-100 Response
    End point description
    A response to therapy is considered a decrease from baseline of at least 100 points in the CDAI score at Week 10. CDAI is scoring system for the assessment of Crohn's disease activity. The total CDAI score ranges from 0 to approximately 600, where higher scores indicate more severe disease. Index values of 150 and below are associated with quiescent disease; values above that indicate active disease. Full analysis set (FAS) in the induction phase included participants who were randomised and received at least one dose of the study drug in induction phase.
    End point type
    Primary
    End point timeframe
    Week 10
    End point values
    Induction Phase: Vedolizumab, 300 mg Induction Phase: Placebo
    Number of subjects analysed
    79
    78
    Units: percentage of participants
        number (confidence interval 95%)
    26.6 (17.268 to 37.720)
    16.7 (9.184 to 26.813)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    MLN0002 group/placebo group. Cochran-Mantel-Haenszel (CMH) test was used for analysis. Prior tumor necrosis factor alpha (TNFα) antagonist use (yes/no) was used as stratification factor.
    Comparison groups
    Induction Phase: Vedolizumab, 300 mg v Induction Phase: Placebo
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1448
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.816
         upper limit
    3.958

    Primary: Maintenance Phase: Percentage of Participants with Clinical Remission

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    End point title
    Maintenance Phase: Percentage of Participants with Clinical Remission
    End point description
    Clinical remission is defined as the CDAI score ≤150. CDAI is scoring system for the assessment of Crohn's disease activity. Index values of 150 and below are associated with quiescent disease; values above that indicate active disease. FAS in the maintenance phase included participants who were randomised and received at least one dose of the study drug in the maintenance phase. The FAS in the maintenance phase does not include participants who received placebo in the induction phase and were enrolled into the maintenance phase.
    End point type
    Primary
    End point timeframe
    Week 60
    End point values
    Maintenance Phase: Vedolizumab 300 mg Maintenance Phase: Placebo
    Number of subjects analysed
    12
    12
    Units: percentage of participants
        number (confidence interval 95%)
    41.7 (15.165 to 72.333)
    16.7 (2.086 to 48.414)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    MLN0002 group/placebo group
    Comparison groups
    Maintenance Phase: Vedolizumab 300 mg v Maintenance Phase: Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1779
    Method
    Pearson's Chi-square Test
    Parameter type
    Odds ratio (OR)
    Point estimate
    3.57
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.532
         upper limit
    23.953

    Primary: Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Events (TEAEs) [1]
    End point description
    An Adverse event (AE) is defined as any untoward medical occurrence in a study participant who received a drug (including a study drug); it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug whether or not it is considered related to the drug. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. Safety analysis set included participants who received at least one dose of the study drug in either the induction phase, the maintenance phase or the open-label cohort.
    End point type
    Primary
    End point timeframe
    From Baseline up to 16 weeks after the last dose of study drug (Up to approximately 170 weeks)
    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 end point.
    End point values
    Induction Phase: Vedolizumab, 300 mg Maintenance Phase: Vedolizumab 300 mg Induction Phase: Placebo Maintenance Phase: Placebo Maintenance Phase: Placebo Continuation Open-Label: Vedolizumab 300 mg
    Number of subjects analysed
    79
    12
    78
    12
    17
    134
    Units: participants
    49
    9
    42
    10
    12
    130
    No statistical analyses for this end point

    Primary: Number of Participants with TEAE Related to Body Weight (Weight Decreased)

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    End point title
    Number of Participants with TEAE Related to Body Weight (Weight Decreased) [2]
    End point description
    Reported events on this outcome measure were “Weight Decreased”. Safety analysis set included participants who received at least one dose of the study drug in either the induction phase, the maintenance phase or the open-label cohort.
    End point type
    Primary
    End point timeframe
    From Baseline up to 16 weeks after the last dose of study drug (Up to approximately 170 weeks)
    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 end point.
    End point values
    Induction Phase: Vedolizumab, 300 mg Maintenance Phase: Vedolizumab 300 mg Induction Phase: Placebo Maintenance Phase: Placebo Maintenance Phase: Placebo Continuation Open-Label: Vedolizumab 300 mg
    Number of subjects analysed
    79
    12
    78
    12
    17
    134
    Units: participants
    0
    0
    0
    0
    0
    2
    No statistical analyses for this end point

    Primary: Number of Participants with TEAE Related to Vital Signs

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    End point title
    Number of Participants with TEAE Related to Vital Signs [3]
    End point description
    Vital signs included body temperature (axilla), sitting blood pressure (after the participant has rested for at least 5 minutes), and pulse (bpm). Reported events on this outcome measure were “Pyrexia”, “Body temperature increased”, “Hypertension”, and “Orthostatic hypotension”. Safety analysis set included participants who received at least one dose of the study drug in either the induction phase, the maintenance phase or the open-label cohort.
    End point type
    Primary
    End point timeframe
    From Baseline up to 16 weeks after the last dose of study drug (Up to approximately 170 weeks)
    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 end point.
    End point values
    Induction Phase: Vedolizumab, 300 mg Maintenance Phase: Vedolizumab 300 mg Induction Phase: Placebo Maintenance Phase: Placebo Maintenance Phase: Placebo Continuation Open-Label: Vedolizumab 300 mg
    Number of subjects analysed
    79
    12
    78
    12
    17
    134
    Units: participants
        Pyrexia
    3
    0
    1
    1
    1
    19
        Body Temperature Increased
    1
    0
    0
    0
    0
    0
        Hypertension
    0
    1
    0
    0
    0
    1
        Orthostatic Hypotension
    0
    0
    0
    0
    0
    1
    No statistical analyses for this end point

    Primary: Number of Participants with TEAE Related to Electrocardiogram (ECG) [Bundle Branch Block Right]

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    End point title
    Number of Participants with TEAE Related to Electrocardiogram (ECG) [Bundle Branch Block Right] [4]
    End point description
    Reported events on this outcome measure were “Bundle Branch Block Right”. Safety analysis set included participants who received at least one dose of the study drug in either the induction phase, the maintenance phase or the open-label cohort.
    End point type
    Primary
    End point timeframe
    From Baseline up to 16 weeks after the last dose of study drug (Up to approximately 170 weeks)
    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 end point.
    End point values
    Induction Phase: Vedolizumab, 300 mg Maintenance Phase: Vedolizumab 300 mg Induction Phase: Placebo Maintenance Phase: Placebo Maintenance Phase: Placebo Continuation Open-Label: Vedolizumab 300 mg
    Number of subjects analysed
    79
    12
    78
    12
    17
    134
    Units: participants
    0
    0
    0
    0
    0
    1
    No statistical analyses for this end point

    Primary: Number of Participants with Markedly Abnormal Values of Laboratory Parameters Values

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    End point title
    Number of Participants with Markedly Abnormal Values of Laboratory Parameters Values [5]
    End point description
    The laboratory values outside the range (Hemoglobin <=7 g/dL, Lymphocytes <500 /microL, White Blood Cell (WBC) <2000 /microL, Platelets <7.5 10^4/microL, Neutrophils <1000 /microL, Alanine Aminotransferase (ALT) (Glutamic Pyruvic Transaminase; GPT) >3.0 U/L x upper limit of normal (ULN), Aspartate Aminotransferase (AST) (Glutamic Oxaloacetic Transaminase; GOT) >3.0 U/L x ULN, Total Bilirubin >2.0 mg/dL x ULN, Amylase >2.0 (U/L) x ULN are considered markedly abnormal. Safety analysis set included participants who received at least one dose of the study drug in either the induction phase, the maintenance phase or the open-label cohort.
    End point type
    Primary
    End point timeframe
    From Baseline up to 16 weeks after the last dose of study drug (Up to approximately 170 weeks)
    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 end point.
    End point values
    Induction Phase: Vedolizumab, 300 mg Maintenance Phase: Vedolizumab 300 mg Induction Phase: Placebo Maintenance Phase: Placebo Maintenance Phase: Placebo Continuation Open-Label: Vedolizumab 300 mg
    Number of subjects analysed
    79
    11
    78
    12
    17
    134
    Units: participants
        Hemoglobin (g/dL) <=7
    0
    0
    1
    0
    0
    4
        Lymphocytes (/uL) <500
    7
    1
    6
    2
    1
    18
        WBC (/uL) <2000
    0
    0
    0
    0
    0
    1
        Platelets (10^4/uL) <7.5
    0
    0
    0
    0
    0
    1
        Neutrophils (/uL) <1000
    0
    0
    0
    0
    0
    1
        ALT (GPT) (U/L) >3.0 x ULN
    1
    0
    1
    0
    0
    1
        AST (GOT) (U/L) >3.0 x ULN
    1
    0
    0
    0
    0
    1
        Total Bilirubin (mg/dL) >2.0 x ULN
    0
    0
    0
    0
    0
    4
        Amylase (U/L) >2.0 x ULN
    1
    0
    0
    0
    0
    8
    No statistical analyses for this end point

    Secondary: Induction phase: Percentage of Participants with Clinical Remission

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    End point title
    Induction phase: Percentage of Participants with Clinical Remission
    End point description
    Clinical remission is defined as the CDAI score ≤150. CDAI is scoring system for the assessment of Crohn's disease activity. Index values of 150 and below are associated with quiescent disease; values above that indicate active disease. FAS in the induction phase included participants who were randomised and received at least one dose of the study drug in induction phase.
    End point type
    Secondary
    End point timeframe
    Week 10
    End point values
    Induction Phase: Vedolizumab, 300 mg Induction Phase: Placebo
    Number of subjects analysed
    79
    78
    Units: percentage of participants
        number (confidence interval 95%)
    17.7 (10.041 to 27.942)
    10.3 (4.533 to 19.213)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    MLN0002 group/placebo group. Cochran-Mantel-Haenszel (CMH) test was used for analysis. Prior tumor necrosis factor alpha (TNFα) antagonist use (yes/no) was used as stratification factor.
    Comparison groups
    Induction Phase: Vedolizumab, 300 mg v Induction Phase: Placebo
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1963
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.72
         upper limit
    4.673

    Secondary: Induction phase: Change from Baseline in C-reactive Protein (CRP) Values

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    End point title
    Induction phase: Change from Baseline in C-reactive Protein (CRP) Values
    End point description
    Participants from 'FAS in the induction phase' with CRP value exceeding 0.30 mg/dL at Baseline were analysed at given time point. Number analysed is the number of participants with evaluable data at the given time-point.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 10
    End point values
    Induction Phase: Vedolizumab, 300 mg Induction Phase: Placebo
    Number of subjects analysed
    79
    78
    Units: mg/dL
    arithmetic mean (standard deviation)
        Change from Baseline at Week 2 (n=64, 70)
    0.022 ± 2.1421
    -0.125 ± 2.8417
        Change from Baseline at Week 6 (n=61, 65)
    -0.089 ± 2.0266
    0.130 ± 2.1674
        Change from Baseline at Week 10 (n=60, 59)
    -0.164 ± 2.2729
    0.077 ± 2.8690
    No statistical analyses for this end point

    Secondary: Maintenance Phase: Percentage of Participants with Crohn's Disease Activity Index (CDAI)-100 Response

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    End point title
    Maintenance Phase: Percentage of Participants with Crohn's Disease Activity Index (CDAI)-100 Response
    End point description
    A response to therapy is considered a decrease from baseline of at least 100 points in the CDAI score at Week 10. CDAI is scoring system for the assessment of Crohn's disease activity. The total CDAI score ranges from 0 to approximately 600, where higher scores indicate more severe disease. Index values of 150 and below are associated with quiescent disease; values above that indicate active disease. FAS in the maintenance phase included participants who were randomised and received at least one dose of the study drug in the maintenance phase. The FAS in the maintenance phase does not include participants who received placebo in the induction phase and were enrolled into the maintenance phase.
    End point type
    Secondary
    End point timeframe
    Week 60
    End point values
    Maintenance Phase: Vedolizumab 300 mg Maintenance Phase: Placebo
    Number of subjects analysed
    12
    12
    Units: percentage of participants
        number (confidence interval 95%)
    58.3 (27.667 to 84.835)
    8.3 (0.211 to 38.480)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Maintenance Phase: Vedolizumab 300 mg v Maintenance Phase: Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0094
    Method
    Pearson's Chi-square Test
    Parameter type
    Odds ratio (OR)
    Point estimate
    15.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.473
         upper limit
    160.972

    Secondary: Maintenance Phase: Percentage of Participants with Durable Clinical Remission

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    End point title
    Maintenance Phase: Percentage of Participants with Durable Clinical Remission
    End point description
    Durable clinical remission is defined as participants with CDAI score ≤ 150 at both Weeks 14 and 60. CDAI is scoring system for the assessment of Crohn's disease activity. The total CDAI score ranges from 0 to approximately 600, where higher scores indicate more severe disease. Index values of 150 and below are associated with quiescent disease; values above that indicate active disease. FAS in the maintenance phase included participants who were randomised and received at least one dose of the study drug in the maintenance phase. The FAS in the maintenance phase does not include participants who received placebo in the induction phase and were enrolled into the maintenance phase.
    End point type
    Secondary
    End point timeframe
    From Week 14 and Week 60
    End point values
    Maintenance Phase: Vedolizumab 300 mg Maintenance Phase: Placebo
    Number of subjects analysed
    12
    12
    Units: percentage of participants
        number (confidence interval 95%)
    33.3 (9.925 to 65.112)
    25.0 (5.486 to 57.186)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    MLN0002 group/placebo group
    Comparison groups
    Maintenance Phase: Vedolizumab 300 mg v Maintenance Phase: Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6534
    Method
    Pearson's Chi-square Test
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.254
         upper limit
    8.844

    Secondary: Maintenance Phase: Percentage of Participants with Corticosteroid-free Clinical Remission

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    End point title
    Maintenance Phase: Percentage of Participants with Corticosteroid-free Clinical Remission
    End point description
    Corticosteroid-free clinical remission is defined as participants using oral corticosteroids at baseline (Week 0) who discontinued corticosteroids and were in clinical remission (CDAI score ≤ 150) at Week 60. CDAI is scoring system for the assessment of Crohn's disease activity. The total CDAI score ranges from 0 to approximately 600, where higher scores indicate more severe disease. Index values of 150 and below are associated with quiescent disease; values above that indicate active disease. Participants from FAS in maintenance phase included participants who were randomised and received at least one dose of the study drug in the maintenance phase and administered oral corticosteroids concomitantly at Week 0, were analsed at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Week 60
    End point values
    Maintenance Phase: Vedolizumab 300 mg Maintenance Phase: Placebo
    Number of subjects analysed
    5
    3
    Units: percentage of participants
        number (confidence interval 95%)
    40.0 (5.274 to 85.337)
    0.0 (0.000 to 70.760)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Maintenance Phase: Vedolizumab 300 mg v Maintenance Phase: Placebo
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2059
    Method
    Pearson's Chi-square Test
    Confidence interval

    Secondary: Serum Vedolizumab Concentration in Induction Phase

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    End point title
    Serum Vedolizumab Concentration in Induction Phase [6]
    End point description
    Participants from 'FAS in Induction Phase', who were randomised and received at least one dose of the study drug in the induction phase and for whom samples were available for pharmacokinetic (PK) analysis. Number analysed is the number of participants with evaluable data at the given time-point.
    End point type
    Secondary
    End point timeframe
    Weeks 2, 6, 10 and 14
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all participants from the Baseline Period are applicable for this endpoint.
    End point values
    Induction Phase: Vedolizumab, 300 mg
    Number of subjects analysed
    79
    Units: ug/mL
    arithmetic mean (standard deviation)
        Week 2 (n=57)
    28.23 ± 11.018
        Week 6 (n=50)
    21.01 ± 14.076
        Week 10 (n=60)
    22.31 ± 14.049
        Week 14 (n=17)
    12.24 ± 10.350
    No statistical analyses for this end point

    Secondary: Serum Vedolizumab Concentration in Maintenance Phase

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    End point title
    Serum Vedolizumab Concentration in Maintenance Phase
    End point description
    Participants from 'FAS in Maintenance Phase', who were randomised and received at least one dose of the study drug in the maintenance phase and for whom samples were available for PK analysis. Number analysed is the number of participants with evaluable data at the given time-point.
    End point type
    Secondary
    End point timeframe
    Weeks 2, 6, 10, 14, 22, 30 and 60
    End point values
    Maintenance Phase: Vedolizumab 300 mg Maintenance Phase: Placebo
    Number of subjects analysed
    12
    12
    Units: ug/mL
    arithmetic mean (standard deviation)
        Week 2 (n=10, 9)
    29.32 ± 13.880
    30.54 ± 9.7495
        Week 6 (n=10, 9)
    25.19 ± 17.054
    24.90 ± 14.490
        Week 10 (n=11, 9)
    26.24 ± 15.464
    26.60 ± 15.642
        Week 14 (n=10, 7)
    11.20 ± 8.5793
    13.72 ± 13.072
        Week 22 (n=9, 7)
    9.102 ± 6.1809
    1.502 ± 2.8285
        Week 30 (n=8, 4)
    9.013 ± 6.8774
    0.000 ± 0.0000
        Week 60 (n=6, 3)
    13.68 ± 4.2659
    0.000 ± 0.0000
    No statistical analyses for this end point

    Secondary: Number of Participants with Anti-vedolizumab Antibodies (AVA) in Induction Phase

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    End point title
    Number of Participants with Anti-vedolizumab Antibodies (AVA) in Induction Phase [7]
    End point description
    Participants who underwent proper AVA test out of 'the FAS in the induction phase' were analysed in this outcome measure. Number analysed is the number of participants with evaluable data at the given time-point.
    End point type
    Secondary
    End point timeframe
    Weeks 0, 10 and 16 weeks after the last dose of study drug in induction phase
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all participants from the Baseline Period are applicable for this endpoint.
    End point values
    Induction Phase: Vedolizumab, 300 mg
    Number of subjects analysed
    79
    Units: participants
        Week 0 (n=63)
    1
        Week 10 (n=63)
    1
        16 Weeks After Last Administration (n=4)
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Anti-vedolizumab Antibodies (AVA) in Maintenance Phase

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    End point title
    Number of Participants with Anti-vedolizumab Antibodies (AVA) in Maintenance Phase
    End point description
    Participants who underwent proper AVA test out of the 'FAS in Maintenance Phase', the participants who received at least one dose of study drug in the maintenance phase were analysed in this outcome measure. Number analysed is the number of participants with evaluable data at the given time-point.
    End point type
    Secondary
    End point timeframe
    Weeks 0, 10, 30, 60 and 16 weeks after the last dose of study drug in maintenance phase
    End point values
    Maintenance Phase: Vedolizumab 300 mg Maintenance Phase: Placebo
    Number of subjects analysed
    12
    12
    Units: participants
        Week 0 (n=11, 9)
    0
    0
        Week 10 (n=11, 9)
    0
    0
        Week 30 (n=10, 9)
    0
    2
        Week 60 (n=9, 4)
    0
    1
        16 Weeks After Last Administration (n=1, 1)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Anti-vedolizumab Antibodies (AVA) in Open Label Cohort

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    End point title
    Number of Participants with Anti-vedolizumab Antibodies (AVA) in Open Label Cohort
    End point description
    Participants who underwent proper AVA test out of the 'FAS in Open Label Cohort', the participants who received at least one dose of study drug in the open label cohort were analysed in this outcome measure. Number analysed is the number of participants with evaluable data at the given time-point.
    End point type
    Secondary
    End point timeframe
    Weeks 0, 10, 30, 62, 94 and 16 weeks after the last dose of study drug in open-label cohort
    End point values
    Open-Label: Vedolizumab 300 mg
    Number of subjects analysed
    134
    Units: participants
        Week 0 (n=57)
    2
        Week 10 (n=108)
    2
        Week 30 (n=94)
    2
        Week 62 (n=66)
    0
        Week 94 (n=49)
    0
        16 Weeks After Last Administration (n=98)
    2
    No statistical analyses for this end point

    Secondary: Number of Participants with Neutralizing Anti-vedolizumab Antibodies (AVA) in Induction Phase

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    End point title
    Number of Participants with Neutralizing Anti-vedolizumab Antibodies (AVA) in Induction Phase [8]
    End point description
    Participants who underwent proper AVA test out of 'the FAS in the induction phase' were analysed in this outcome measure. Number analysed is the number of participants with evaluable data at the given time-point.
    End point type
    Secondary
    End point timeframe
    Weeks 0, 10 and 16 weeks after the last dose of study drug in induction phase
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all participants from the Baseline Period are applicable for this endpoint.
    End point values
    Induction Phase: Vedolizumab, 300 mg
    Number of subjects analysed
    79
    Units: participants
        Week 0 (n=63)
    0
        Week 10 (n=63)
    1
        16 Weeks After Last Administration (n=4)
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Neutralizing Anti-vedolizumab Antibodies (AVA) in Maintenance Phase

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    End point title
    Number of Participants with Neutralizing Anti-vedolizumab Antibodies (AVA) in Maintenance Phase
    End point description
    Participants who underwent proper AVA test out of the 'FAS in Maintenance Phase', the participants who received at least one dose of study drug in the maintenance phase were analysed in this outcome measure. Number analysed is the number of participants with evaluable data at the given time-point.
    End point type
    Secondary
    End point timeframe
    Weeks 0, 10, 30, 60 and 16 weeks after the last dose of study drug in maintenance phase
    End point values
    Maintenance Phase: Vedolizumab 300 mg Maintenance Phase: Placebo
    Number of subjects analysed
    12
    12
    Units: participants
        Week 0 (n=11, 9)
    0
    0
        Week 10 (n=11, 9)
    0
    0
        Week 30 (n=10, 9)
    0
    2
        Week 60 (n=9, 4)
    0
    1
        16 Weeks After Last Administration (n=1, 1)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Neutralizing Anti-vedolizumab Antibodies (AVA) in Open Label Cohort

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    End point title
    Number of Participants with Neutralizing Anti-vedolizumab Antibodies (AVA) in Open Label Cohort
    End point description
    Participants who underwent proper AVA test out of the 'FAS in Open Label Cohort', the participants who received at least one dose of study drug in the open label cohort were analysed in this outcome measure. Number analysed is the number of participants with evaluable data at the given time-point.
    End point type
    Secondary
    End point timeframe
    Weeks 0, 10, 30, 62, 94 and 16 weeks after the last dose of study drug in open-label cohort
    End point values
    Open-Label: Vedolizumab 300 mg
    Number of subjects analysed
    134
    Units: participants
        Week 0 (n=57)
    2
        Week 10 (n=108)
    2
        Week 30 (n=94)
    1
        Week 62 (n=66)
    0
        Week 94 (n=49)
    0
        16 Weeks After Last Administration (n=98)
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline up to 16 weeks after the last dose of study drug (Up to approximately 170 weeks)
    Adverse event reporting additional description
    At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Induction Phase: Vedolizumab, 300 mg
    Reporting group description
    Vedolizumab 300 mg, IV infusion, once at Weeks 0, 2 and 6 in the induction phase.

    Reporting group title
    Induction Phase: Placebo
    Reporting group description
    Vedolizumab placebo-matching IV infusion once at Weeks 0, 2 and 6 in the induction phase.

    Reporting group title
    Maintenance Phase: Vedolizumab 300 mg
    Reporting group description
    Vedolizumab placebo-matching, IV infusion, once at Weeks 14, 22, 30, 38, 46 and 54 in maintenance phase. Participants received vedolizumab in induction phase and achieved CDAI -70 response at Week 10 and were randomized to receive vedolizumab in maintenance phase.

    Reporting group title
    Maintenance Phase: Placebo
    Reporting group description
    Vedolizumab placebo-matching, IV infusion, once at Weeks 14, 22, 30, 38, 46 and 54 in maintenance phase. Participants received vedolizumab in induction phase and achieved CDAI-70 response at Week 10 and were randomized to receive placebo in maintenance phase.

    Reporting group title
    Maintenance Phase: Placebo Continuation
    Reporting group description
    Vedolizumab placebo-matching, IV infusion, once at Weeks 14, 22, 30, 38, 46 and 54 in maintenance phase. Participants received vedolizumab placebo-matching in induction phase and achieved CDAI-70 response at Week 10 received placebo in maintenance phase without randomization.

    Reporting group title
    Open-Label: Vedolizumab 300 mg
    Reporting group description
    Vedolizumab 300 mg, IV infusion, once at Weeks 0, 2 and 6 and then every 8 weeks thereafter up to Week 94 as a maximum duration in open-label phase.

    Serious adverse events
    Induction Phase: Vedolizumab, 300 mg Induction Phase: Placebo Maintenance Phase: Vedolizumab 300 mg Maintenance Phase: Placebo Maintenance Phase: Placebo Continuation Open-Label: Vedolizumab 300 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 79 (10.13%)
    10 / 78 (12.82%)
    2 / 12 (16.67%)
    4 / 12 (33.33%)
    2 / 17 (11.76%)
    70 / 134 (52.24%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Intestinal anastomosis complication
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post lumbar puncture syndrome
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Thyroid adenoma
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    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
    Respiratory, thoracic and mediastinal disorders
    Pleurisy
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactoid reaction
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 78 (1.28%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyslalia
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial hypotension
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Inflammation
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Crohn's disease
         subjects affected / exposed
    2 / 79 (2.53%)
    10 / 78 (12.82%)
    1 / 12 (8.33%)
    2 / 12 (16.67%)
    1 / 17 (5.88%)
    35 / 134 (26.12%)
         occurrences causally related to treatment / all
    0 / 2
    3 / 10
    0 / 1
    0 / 2
    0 / 1
    3 / 39
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 78 (1.28%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Intestinal obstruction
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    4 / 134 (2.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal adhesions
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    3 / 134 (2.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal stenosis
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    3 / 134 (2.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterovesical fistula
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileal stenosis
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestinal stenosis
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Ureterolithiasis
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 78 (1.28%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema nodosum
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 17 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    4 / 134 (2.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Cellulitis
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 17 (5.88%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal abscess
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis infectious
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mesenteric abscess
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mycotic endophthalmitis
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periumbilical abscess
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mediastinitis
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Induction Phase: Vedolizumab, 300 mg Induction Phase: Placebo Maintenance Phase: Vedolizumab 300 mg Maintenance Phase: Placebo Maintenance Phase: Placebo Continuation Open-Label: Vedolizumab 300 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 79 (21.52%)
    19 / 78 (24.36%)
    9 / 12 (75.00%)
    7 / 12 (58.33%)
    12 / 17 (70.59%)
    113 / 134 (84.33%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Ocular neoplasm
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Skin papilloma
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 17 (5.88%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Immune system disorders
    Allergy to metals
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Seasonal allergy
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 17 (5.88%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    1 / 17 (5.88%)
    19 / 134 (14.18%)
         occurrences all number
    0
    0
    0
    1
    1
    30
    Chest pain
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 17 (5.88%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Swelling
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    9 / 134 (6.72%)
         occurrences all number
    0
    0
    0
    0
    0
    13
    Injury, poisoning and procedural complications
    Bone contusion
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Heat illness
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Investigations
    Blood urine present
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 17 (5.88%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Glucose urine present
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 17 (5.88%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Anaemia
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    13 / 134 (9.70%)
         occurrences all number
    0
    0
    0
    0
    0
    16
    Respiratory, thoracic and mediastinal disorders
    Upper respiratory tract inflammation
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    1 / 17 (5.88%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 79 (1.27%)
    4 / 78 (5.13%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    9 / 134 (6.72%)
         occurrences all number
    1
    4
    0
    0
    0
    9
    Hypoaesthesia
         subjects affected / exposed
    4 / 79 (5.06%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    4
    0
    0
    0
    0
    0
    Cervicobrachial syndrome
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Gastrointestinal disorders
    Crohn's disease
         subjects affected / exposed
    0 / 79 (0.00%)
    5 / 78 (6.41%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    2 / 17 (11.76%)
    27 / 134 (20.15%)
         occurrences all number
    0
    5
    0
    0
    2
    28
    Diarrhoea
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    1 / 17 (5.88%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Abdominal pain
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 17 (5.88%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 17 (0.00%)
    9 / 134 (6.72%)
         occurrences all number
    0
    0
    0
    1
    0
    10
    Constipation
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 17 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Dental caries
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 17 (5.88%)
    15 / 134 (11.19%)
         occurrences all number
    0
    0
    0
    0
    2
    17
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    11 / 134 (8.21%)
         occurrences all number
    0
    0
    1
    0
    0
    11
    Stomatitis
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 17 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    10 / 134 (7.46%)
         occurrences all number
    0
    0
    0
    0
    0
    11
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 17 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Dermatitis
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 17 (5.88%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Dry skin
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Eczema
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 17 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Ingrowing nail
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    8 / 134 (5.97%)
         occurrences all number
    0
    0
    0
    0
    0
    9
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    11 / 79 (13.92%)
    11 / 78 (14.10%)
    4 / 12 (33.33%)
    4 / 12 (33.33%)
    4 / 17 (23.53%)
    55 / 134 (41.04%)
         occurrences all number
    12
    13
    6
    6
    6
    90
    Enteritis infectious
         subjects affected / exposed
    4 / 79 (5.06%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    4
    0
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
    1 / 17 (5.88%)
    10 / 134 (7.46%)
         occurrences all number
    0
    0
    1
    1
    1
    19
    Anal abscess
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
    0 / 17 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    2 / 17 (11.76%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Dermatophytosis of nail
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 17 (5.88%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Pharyngotonsillitis
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 17 (5.88%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Tonsillitis
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 17 (5.88%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Influenza
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    16 / 134 (11.94%)
         occurrences all number
    0
    0
    0
    0
    0
    18
    Gastroenteritis
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    8 / 134 (5.97%)
         occurrences all number
    0
    0
    0
    0
    0
    9
    Pharyngitis
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 17 (0.00%)
    7 / 134 (5.22%)
         occurrences all number
    0
    0
    0
    0
    0
    8

    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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