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    Clinical Trial Results:
    A Randomized, Double-Blind, Double-Dummy, Multicenter, Active-Controlled Study to Evaluate the Efficacy and Safety of Vedolizumab IV Compared to Adalimumab SC in Subjects with Ulcerative Colitis

    Summary
    EudraCT number
    2015-000939-33
    Trial protocol
    CZ   SK   NL   BG   GB   DE   HU   BE   ES   LV   EE   LT   PL   DK   PT   HR  
    Global end of trial date
    18 Jan 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Oct 2019
    First version publication date
    04 Oct 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MLN0002-3026
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02497469
    WHO universal trial number (UTN)
    U1111-1168-6713
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    40 Landsdowne Street, Cambridge, MA, United States, 02139
    Public contact
    Medical Director, Takeda, +1877 8253327, trialdisclosures@takeda.com
    Scientific contact
    Medical Director, Takeda, +1877 8253327, trialdisclosures@takeda.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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Jan 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to evaluate the efficacy and safety of vedolizumab intravenous (IV) treatment compared to adalimumab subcutaneous (SC) treatment over a 52-week treatment period.
    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
    29 Jun 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    6 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 8
    Country: Number of subjects enrolled
    Hong Kong: 5
    Country: Number of subjects enrolled
    Korea, Republic of: 35
    Country: Number of subjects enrolled
    Taiwan: 5
    Country: Number of subjects enrolled
    Czech Republic: 21
    Country: Number of subjects enrolled
    Hungary: 32
    Country: Number of subjects enrolled
    Poland: 163
    Country: Number of subjects enrolled
    Serbia: 29
    Country: Number of subjects enrolled
    Slovakia: 13
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 3
    Country: Number of subjects enrolled
    Bulgaria: 16
    Country: Number of subjects enrolled
    Croatia: 16
    Country: Number of subjects enrolled
    Israel: 22
    Country: Number of subjects enrolled
    Romania: 12
    Country: Number of subjects enrolled
    Russian Federation: 85
    Country: Number of subjects enrolled
    Turkey: 14
    Country: Number of subjects enrolled
    Ukraine: 65
    Country: Number of subjects enrolled
    Canada: 38
    Country: Number of subjects enrolled
    United States: 71
    Country: Number of subjects enrolled
    Argentina: 4
    Country: Number of subjects enrolled
    Colombia: 4
    Country: Number of subjects enrolled
    Mexico: 12
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Italy: 20
    Country: Number of subjects enrolled
    Latvia: 13
    Country: Number of subjects enrolled
    Lithuania: 14
    Country: Number of subjects enrolled
    Portugal: 13
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Denmark: 11
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Spain: 1
    Worldwide total number of subjects
    771
    EEA total number of subjects
    371
    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)
    737
    From 65 to 84 years
    34
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants took part in the study at 205 investigative sites worldwide from 29 June 2015 up to 18 January 2019.

    Pre-assignment
    Screening details
    Participants with a diagnosis of moderately to severely active ulcerative colitis (UC) were enrolled in a 1:1 ratio to receive vedolizumab or adalimumab or matching placebo.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Adalimumab SC, 160/80/40 mg
    Arm description
    Adalimumab 160 mg, injection, subcutaneously on Day 1, adalimumab 80 mg, injection, subcutaneously at Week 2, then adalimumab 40 mg, injection, subcutaneously every 2 weeks thereafter up to Week 50. Vedolizumab placebo-matching infusion, intravenously on Day 1 and Weeks 2, 6, 14, 22, 30, 38, and 46.
    Arm type
    Experimental

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    HUMIRA
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Adalimumab 160 mg, injection, subcutaneously on Day 1, adalimumab 80 mg, injection, subcutaneously at Week 2, then adalimumab 40 mg, injection, subcutaneously every 2 weeks thereafter up to Week 50. Vedolizumab placebo-matching infusion, intravenously on Day 1 and Weeks 2, 6, 14, 22, 30, 38, and 46.

    Arm title
    Vedolizumab IV 300 mg
    Arm description
    Vedolizumab 300 mg, infusion, intravenously over 30 minutes on Day 1 and Weeks 2, 6, 14, 22, 30, 38, and 46. Adalimumab placebo-matching injection, subcutaneously on Day 1, Week 2, and every 2 weeks thereafter up to Week 50.
    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 300 mg, infusion, intravenously over 30 minutes on Day 1 and Weeks 2, 6, 14, 22, 30, 38, and 46. Adalimumab placebo-matching injection, subcutaneously on Day 1, Week 2, and every 2 weeks thereafter up to Week 50.

    Number of subjects in period 1
    Adalimumab SC, 160/80/40 mg Vedolizumab IV 300 mg
    Started
    386
    385
    Safety Analysis Set
    386
    383
    Completed
    217
    270
    Not completed
    169
    115
         Voluntary Withdrawal
    39
    41
         Significant Protocol Deviation
    4
    5
         Randomized but not Treated
    -
    2
         Lack of efficacy
    86
    40
         Pregnancy
    1
    1
         Leukopenia or Lymphopenia
    1
    -
         Reason not Specified
    6
    6
         Lost to follow-up
    14
    4
         Pretreatment Event/Adverse Event
    18
    16

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Adalimumab SC, 160/80/40 mg
    Reporting group description
    Adalimumab 160 mg, injection, subcutaneously on Day 1, adalimumab 80 mg, injection, subcutaneously at Week 2, then adalimumab 40 mg, injection, subcutaneously every 2 weeks thereafter up to Week 50. Vedolizumab placebo-matching infusion, intravenously on Day 1 and Weeks 2, 6, 14, 22, 30, 38, and 46.

    Reporting group title
    Vedolizumab IV 300 mg
    Reporting group description
    Vedolizumab 300 mg, infusion, intravenously over 30 minutes on Day 1 and Weeks 2, 6, 14, 22, 30, 38, and 46. Adalimumab placebo-matching injection, subcutaneously on Day 1, Week 2, and every 2 weeks thereafter up to Week 50.

    Reporting group values
    Adalimumab SC, 160/80/40 mg Vedolizumab IV 300 mg Total
    Number of subjects
    386 385 771
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    371 366 737
        From 65-85 years
    15 19 34
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    40.5 ± 13.44 40.8 ± 13.74 -
    Sex: Female, Male
    Units: Subjects
        Female
    170 151 321
        Male
    216 234 450
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    6 8 14
        Not Hispanic or Latino
    39 23 62
        Unknown or Not Reported
    341 354 695
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    11 4 15
        Asian
    30 32 62
        Native Hawaiian or Other Pacific Islander
    1 0 1
        Black or African American
    3 2 5
        White
    341 345 686
        More than one race
    0 2 2
        Unknown or Not Reported
    0 0 0
    Smoking Classification
    Units: Subjects
        Has Never Smoked
    259 280 539
        Is a Current Smoker
    23 19 42
        Is an Ex-smoker
    104 84 188
        Missing
    0 2 2
    Region of Enrollment
    Units: Subjects
        Australia
    3 5 8
        Hong Kong
    1 4 5
        Korea, Republic Of
    19 16 35
        Taiwan, Province Of China
    4 1 5
        Czech Republic
    13 8 21
        Hungary
    16 16 32
        Poland
    78 85 163
        Serbia
    11 18 29
        Slovakia
    5 8 13
        Bosnia
    2 1 3
        Bulgaria
    10 6 16
        Croatia
    11 5 16
        Israel
    9 13 22
        Romania
    6 6 12
        Russia
    41 44 85
        Turkey
    9 5 14
        Ukraine
    26 39 65
        Canada
    18 20 38
        United States
    42 29 71
        Argentina
    1 3 4
        Colombia
    2 2 4
        Mexico
    9 3 12
        France
    4 6 10
        Germany
    3 6 9
        Italy
    9 11 20
        Latvia
    6 7 13
        Lithuania
    7 7 14
        Portugal
    9 4 13
        United Kingdom
    2 3 5
        Denmark
    8 3 11
        Belgium
    0 1 1
        Netherlands
    1 0 1
        Spain
    1 0 1
    Height
    Units: cm
        arithmetic mean (standard deviation)
    170.5 ± 9.65 172.0 ± 9.90 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    73.43 ± 18.374 72.67 ± 16.952 -
    Body Mass Index (BMI)
    BMI is calculated from the weight taken prior to the first dose of study drug and height taken at Screening using formula, Body Mass Index = weight/[height]^2.
    Units: kg/m^2
        arithmetic mean (standard deviation)
    25.17 ± 5.646 24.46 ± 4.786 -

    End points

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    End points reporting groups
    Reporting group title
    Adalimumab SC, 160/80/40 mg
    Reporting group description
    Adalimumab 160 mg, injection, subcutaneously on Day 1, adalimumab 80 mg, injection, subcutaneously at Week 2, then adalimumab 40 mg, injection, subcutaneously every 2 weeks thereafter up to Week 50. Vedolizumab placebo-matching infusion, intravenously on Day 1 and Weeks 2, 6, 14, 22, 30, 38, and 46.

    Reporting group title
    Vedolizumab IV 300 mg
    Reporting group description
    Vedolizumab 300 mg, infusion, intravenously over 30 minutes on Day 1 and Weeks 2, 6, 14, 22, 30, 38, and 46. Adalimumab placebo-matching injection, subcutaneously on Day 1, Week 2, and every 2 weeks thereafter up to Week 50.

    Primary: Percentage of Participants who Achieved Clinical Remission

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    End point title
    Percentage of Participants who Achieved Clinical Remission
    End point description
    Clinical remission was defined as a complete Mayo score of ≤2 points and no individual subscore >1 point. The Mayo score was a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consisted of 4 subscores: rectal bleeding, stool frequency, findings on endoscopy, and physician's global assessment. Each subscore was scored on a scale from 0 to 3 and the complete Mayo score ranges from 0 to 12 (higher scores indicate greater disease activity). Full Analysis Set (FAS) included all randomized participants who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Week 52
    End point values
    Adalimumab SC, 160/80/40 mg Vedolizumab IV 300 mg
    Number of subjects analysed
    386
    383
    Units: percentage of participants
        number (confidence interval 95%)
    22.5 (18.5 to 27.0)
    31.3 (26.7 to 36.2)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Adalimumab SC, 160/80/40 mg v Vedolizumab IV 300 mg
    Number of subjects included in analysis
    769
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0061 [1]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    8.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.5
         upper limit
    15
    Notes
    [1] - P-value of the adjusted difference was based on the Cochran-Mantel-Haenszel method, stratified by concomitant use of oral corticosteroids (Yes/No) and prior use of TNF-alpha antagonist (Yes/No) or the Fisher's exact method if the numerator was <=5.

    Secondary: Percentage of Participants who Achieved Mucosal Healing

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    End point title
    Percentage of Participants who Achieved Mucosal Healing
    End point description
    Mucosal healing was defined as a Mayo score endoscopic subscore of <= 1 point. The Mayo score was a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consisted of 4 subscores: rectal bleeding, stool frequency, findings on endoscopy, and physician's global assessment. Each subscore was scored on a scale from 0 to 3 and the complete Mayo score ranges from 0 to 12 (higher scores indicate greater disease activity). FAS included all randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Adalimumab SC, 160/80/40 mg Vedolizumab IV 300 mg
    Number of subjects analysed
    386
    383
    Units: percentage of participants
        number (confidence interval 95%)
    27.7 (23.3 to 32.5)
    39.7 (34.8 to 44.8)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Adalimumab SC, 160/80/40 mg v Vedolizumab IV 300 mg
    Number of subjects included in analysis
    769
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0005 [2]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    11.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    5.3
         upper limit
    18.5
    Notes
    [2] - P-value of the adjusted difference was based on the Cochran-Mantel-Haenszel method, stratified by concomitant use of oral corticosteroids (Yes/No) and prior use of TNF-alpha antagonist (Yes/No) or the Fisher's exact method if the numerator was <=5.

    Secondary: Percentage of Participants who Used Oral Corticosteroids at Baseline who Discontinued Corticosteroids and were in Clinical Remission

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    End point title
    Percentage of Participants who Used Oral Corticosteroids at Baseline who Discontinued Corticosteroids and were in Clinical Remission
    End point description
    Corticosteroid-free remission was defined as participants using oral corticosteroids at Baseline (Week 0) who had discontinued oral corticosteroids and were in clinical remission at Week 52. Clinical remission was defined as a complete Mayo score of ≤ 2 points and no individual subscore > 1 point. The Mayo score was a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consisted of 4 subscores: rectal bleeding, stool frequency, findings on endoscopy, and physician's global assessment. Each subscore was scored on a scale from 0 to 3 and the complete Mayo score ranges from 0 to 12 (higher scores indicate greater disease activity). FAS, included all randomized participants who received at least 1 dose of study drug who used who used oral corticosteroids at Baseline.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Adalimumab SC, 160/80/40 mg Vedolizumab IV 300 mg
    Number of subjects analysed
    119
    111
    Units: percentage of participants
        number (confidence interval 95%)
    21.8 (14.8 to 30.4)
    12.6 (7.1 to 20.3)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Adalimumab SC, 160/80/40 mg v Vedolizumab IV 300 mg
    Number of subjects included in analysis
    230
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0641 [3]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    -9.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -18.9
         upper limit
    0.4
    Notes
    [3] - P-value of the adjusted difference was based on the Cochran-Mantel-Haenszel method, stratified by prior use of TNF-alpha antagonist (Yes/No) or the Fisher's exact method if the numerator was <=5.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug and up to 126 days after the last dose (Up to 68 weeks)
    Adverse event reporting additional description
    At each visit investigator document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment. Safety analysis set: Participants who received at least 1 dose of study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Vedolizumab IV 300 mg
    Reporting group description
    Vedolizumab 300 mg, infusion, intravenously over 30 minutes on Day 1 and Weeks 2, 6, 14, 22, 30, 38, and 46. Adalimumab placebo-matching injection, subcutaneously on Day 1, Week 2, and every 2 weeks thereafter up to Week 50.

    Reporting group title
    Adalimumab SC, 160/80/40 mg
    Reporting group description
    Adalimumab 160 mg, injection, subcutaneously on Day 1, adalimumab 80 mg, injection, subcutaneously at Week 2, then adalimumab 40 mg, injection, subcutaneously every 2 weeks thereafter up to Week 50. Vedolizumab placebo-matching infusion, intravenously on Day 1 and Weeks 2, 6, 14, 22, 30, 38, and 46.

    Serious adverse events
    Vedolizumab IV 300 mg Adalimumab SC, 160/80/40 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    42 / 383 (10.97%)
    53 / 386 (13.73%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Hypovolaemic shock
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Therapeutic response decreased
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Major depression
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Traumatic haemothorax
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stab wound
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 383 (0.26%)
    4 / 386 (1.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain stem haemorrhage
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysgraphia
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nerve root compression
         subjects affected / exposed
    2 / 383 (0.52%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Blindness
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Large intestine polyp
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
    Additional description: One treatment-emergent death occurred during treatment with Vedolizumab IV 300 mg and was not related.
         subjects affected / exposed
    19 / 383 (4.96%)
    25 / 386 (6.48%)
         occurrences causally related to treatment / all
    3 / 20
    5 / 27
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflammatory bowel disease
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 383 (0.52%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    3 / 383 (0.78%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal haemorrhage
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated umbilical hernia
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psoriasis
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    2 / 383 (0.52%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    3 / 383 (0.78%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 386 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 383 (0.00%)
    2 / 386 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 386 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Vedolizumab IV 300 mg Adalimumab SC, 160/80/40 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    103 / 383 (26.89%)
    114 / 386 (29.53%)
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    19 / 383 (4.96%)
    23 / 386 (5.96%)
         occurrences all number
    20
    26
    Nervous system disorders
    Headache
         subjects affected / exposed
    27 / 383 (7.05%)
    21 / 386 (5.44%)
         occurrences all number
    32
    25
    Gastrointestinal disorders
    Colitis ulcerative
         subjects affected / exposed
    26 / 383 (6.79%)
    42 / 386 (10.88%)
         occurrences all number
    30
    46
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    27 / 383 (7.05%)
    30 / 386 (7.77%)
         occurrences all number
    41
    43
    Upper respiratory tract infection
         subjects affected / exposed
    20 / 383 (5.22%)
    17 / 386 (4.40%)
         occurrences all number
    22
    20

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Oct 2015
    Amendment 3: -Main changes in the protocol include inclusion of information from the adalimumab label to guide investigators as well as specific changes such as a change of period for use of contraception to align with adalimumab label - Exclusion of participants with moderate heart failure; exclusion of additional medication that could interact with adalimumab and addition of information on the risk:benefit profile of the study.
    16 Jul 2016
    Amendment 5: -Change in Takeda Signatory from Nigel Brayshaw to Jing Xu, Claudia Lopez to Vilhelm Tetens -Screening Period increased to 4-weeks to allow sufficient time to complete all assessments -Update to inclusion criteria increase the age range for eligible participants -Clarification to the main exclusion criteria - Additional objectives and endpoints added for vedolizumab concentration and immunogenicity assessment -Clarification added to Study Design -Excluded Medications for the exclusion of all live vaccines -Rescreening added to provide details on rescreening of participants -Update to Post Study Care -Information included on the Week 52 interim analysis -Updates to Appendix A for clarification purposes.
    08 Mar 2017
    Amendment 7: -Administrative change to the Responsible Medical Officer -Additional interim analysis included - Inclusion of a Data Monitoring Committee - Update to sample size determination -Update to the tumor necrosis factor-alpha naïve versus failure ratio.

    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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