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    Clinical Trial Results:
    A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Vedolizumab Subcutaneous as Maintenance Therapy in Subjects With Moderately to Severely Active Crohn’s Disease Who Achieved Clinical Response Following Open-Label Vedolizumab Intravenous Therapy

    Summary
    EudraCT number
    		 2015-000481-58
    Trial protocol
    		 SK   CZ   NL   BG   GB   DE   BE   SE   DK   LT   HU   ES   IT  
    Global end of trial date
    06 Aug 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 May 2020
    First version publication date
    23 May 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MLN0002SC-3031
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02611817
    WHO universal trial number (UTN)
    		 U1111-1168-0845
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    40 Landsdowne Street, Cambridge, MA, United States, 02139
    Public contact
    Medical Director, Clinical Science, Takeda, +1 877-825-3327, trialdisclosure@takeda.com
    Scientific contact
    Medical Director, Clinical Science, Takeda, +1 877-825-3327, trialdisclosure@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
    06 Aug 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Aug 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to assess the effect of vedolizumab subcutaneous (SC) as maintenance treatment in subjects with moderately to severely active Crohn's disease (CD) who achieved clinical response following administration of vedolizumab intravenous (IV) induction therapy.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Jan 2016
    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?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 13
    Country: Number of subjects enrolled
    South Africa: 5
    Country: Number of subjects enrolled
    Czech Republic: 32
    Country: Number of subjects enrolled
    Hungary: 24
    Country: Number of subjects enrolled
    Poland: 122
    Country: Number of subjects enrolled
    Romania: 15
    Country: Number of subjects enrolled
    Serbia: 14
    Country: Number of subjects enrolled
    Slovakia: 10
    Country: Number of subjects enrolled
    Japan: 21
    Country: Number of subjects enrolled
    Korea, Republic of: 18
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 1
    Country: Number of subjects enrolled
    Bulgaria: 2
    Country: Number of subjects enrolled
    Estonia: 2
    Country: Number of subjects enrolled
    Israel: 33
    Country: Number of subjects enrolled
    Russian Federation: 49
    Country: Number of subjects enrolled
    Turkey: 6
    Country: Number of subjects enrolled
    Ukraine: 38
    Country: Number of subjects enrolled
    Canada: 37
    Country: Number of subjects enrolled
    United States: 133
    Country: Number of subjects enrolled
    Brazil: 10
    Country: Number of subjects enrolled
    Mexico: 1
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Italy: 15
    Country: Number of subjects enrolled
    Lithuania: 5
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    United Kingdom: 7
    Worldwide total number of subjects
    644
    EEA total number of subjects
    265
    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)
    621
    From 65 to 84 years
    23
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects with moderate to severe CD took part in the study at 169 investigative sites in North America, South America, Western/Northern Europe, Central Europe, Eastern Europe, East Asia, and Africa/Australia from 04 Jan 2016 to 06 Aug 2019.

    Pre-assignment
    Screening details
    		 Subjects were enrolled in open-label (OL) induction phase to receive vedolizumab IV. Subjects with CR at Week 6 were randomized into double-blind maintenance phase to receive vedolizumab subcutaneous/placebo, and who did not achieve CR at Week 6 received 3rd infusion of OL vedolizumab IV and completed Week 14 visit.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Open-label Induction Phase: Vedolizumab 300 mg IV
    Arm description
    		 Vedolizumab 300 milligram (mg), infusion, intravenously, once at Weeks 0, 2 in the open-label induction phase. Subjects who did not achieve clinical response at Week 6 received third infusion of vedolizumab 300 mg IV on Week 6.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vedolizumab 300 mg IV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vedolizumab 300 mg, infusion, intravenously, once at Weeks 0, 2 in the open-label induction phase. Subjects who did not achieve clinical response at Week 6 received third infusion of vedolizumab 300 mg IV on Week 6.

    Arm title
    		 Maintenance Phase: Induction IV + Placebo
    Arm description
    		 Vedolizumab placebo-matching injection, subcutaneously, once every 2 weeks from Week 6 up to Week 50. Subjects who received vedolizumab 300 mg IV infusion in open-label induction phase and achieved clinical response at Week 6 were randomized to receive placebo in maintenance phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Vedolizumab placebo-matching injection, subcutaneously, once every 2 weeks from Week 6 up to Week 50. Subjects who received vedolizumab 300 mg IV infusion in open-label induction phase and achieved clinical response at Week 6 were randomized to receive placebo in maintenance phase.

    Arm title
    		 Maintenance Phase: Induction IV + Vedolizumab 108 mg SC
    Arm description
    		 Vedolizumab 108 mg, injection, subcutaneously, once every 2 weeks from Week 6 up to Week 50. Subjects who received vedolizumab 300 mg IV infusion in open-label induction phase and achieved clinical response at Week 6 were randomized to receive vedolizumab injection subcutaneously in maintenance phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vedolizumab 108 mg SC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Vedolizumab 108 mg, injection, subcutaneously, once every 2 weeks from Week 6 up to Week 50. Subjects who received vedolizumab 300 mg IV infusion in open-label induction phase and achieved clinical response at Week 6 were randomized to receive vedolizumab injection subcutaneously in maintenance phase.

    Number of subjects in period 1
    		Open-label Induction Phase: Vedolizumab 300 mg IV Maintenance Phase: Induction IV + Placebo Maintenance Phase: Induction IV + Vedolizumab 108 mg SC
    Started
    235
    134
    275
    Completed
    235
    72
    168
    Not completed
    0
    62
    107
         Consent withdrawn by subject
    -
    5
    14
         Adverse event, non-fatal
    -
    12
    11
         Other
    -
    1
    2
         Pregnancy
    -
    -
    1
         Randomized but not Treated
    -
    1
    -
         Lost to follow-up
    -
    -
    1
         Lack of efficacy
    -
    43
    78

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Open-label Induction Phase: Vedolizumab 300 mg IV
    Reporting group description
    		 Vedolizumab 300 milligram (mg), infusion, intravenously, once at Weeks 0, 2 in the open-label induction phase. Subjects who did not achieve clinical response at Week 6 received third infusion of vedolizumab 300 mg IV on Week 6.

    Reporting group title
    Maintenance Phase: Induction IV + Placebo
    Reporting group description
    		 Vedolizumab placebo-matching injection, subcutaneously, once every 2 weeks from Week 6 up to Week 50. Subjects who received vedolizumab 300 mg IV infusion in open-label induction phase and achieved clinical response at Week 6 were randomized to receive placebo in maintenance phase.

    Reporting group title
    Maintenance Phase: Induction IV + Vedolizumab 108 mg SC
    Reporting group description
    		 Vedolizumab 108 mg, injection, subcutaneously, once every 2 weeks from Week 6 up to Week 50. Subjects who received vedolizumab 300 mg IV infusion in open-label induction phase and achieved clinical response at Week 6 were randomized to receive vedolizumab injection subcutaneously in maintenance phase.

    Reporting group values
    		 Open-label Induction Phase: Vedolizumab 300 mg IV Maintenance Phase: Induction IV + Placebo Maintenance Phase: Induction IV + Vedolizumab 108 mg SC Total
    Number of subjects
    		 235 134 275 644
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 228 131 262 621
        From 65-84 years
    		 7 3 13 23
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 37.4 ( 12.79 ) 36.1 ( 12.93 ) 38.2 ( 13.85 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 119 68 118 305
        Male
    		 116 66 157 339
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 1 2 3
        Not Hispanic or Latino
    		 50 20 60 130
        Unknown or Not Reported
    		 185 113 213 511
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 2 0 2
        Asian
    		 23 6 17 46
        Native Hawaiian or Other Pacific Islander
    		 2 1 0 3
        Black or African American
    		 3 1 7 11
        White
    		 207 124 250 581
        More than one race
    		 0 0 1 1
        Unknown or Not Reported
    		 0 0 0 0
    Smoking Classification
    Units: Subjects
        Never smoked
    		 140 85 148 373
        Current smoker
    		 49 26 54 129
        Ex-smoker
    		 46 23 73 142
    Weight
    Units: kilogram (kg)
        arithmetic mean (standard deviation)
    		 69.94 ( 18.403 ) 69.79 ( 18.103 ) 74.08 ( 18.994 ) -
    Body Mass Index
    Units: kilogram per square meter (kg/m^2)
        arithmetic mean (standard deviation)
    		 24.20 ( 6.073 ) 23.93 ( 5.541 ) 25.06 ( 5.915 ) -

    End points

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    End points reporting groups
    Reporting group title
    Open-label Induction Phase: Vedolizumab 300 mg IV
    Reporting group description
    		 Vedolizumab 300 milligram (mg), infusion, intravenously, once at Weeks 0, 2 in the open-label induction phase. Subjects who did not achieve clinical response at Week 6 received third infusion of vedolizumab 300 mg IV on Week 6.

    Reporting group title
    Maintenance Phase: Induction IV + Placebo
    Reporting group description
    		 Vedolizumab placebo-matching injection, subcutaneously, once every 2 weeks from Week 6 up to Week 50. Subjects who received vedolizumab 300 mg IV infusion in open-label induction phase and achieved clinical response at Week 6 were randomized to receive placebo in maintenance phase.

    Reporting group title
    Maintenance Phase: Induction IV + Vedolizumab 108 mg SC
    Reporting group description
    		 Vedolizumab 108 mg, injection, subcutaneously, once every 2 weeks from Week 6 up to Week 50. Subjects who received vedolizumab 300 mg IV infusion in open-label induction phase and achieved clinical response at Week 6 were randomized to receive vedolizumab injection subcutaneously in maintenance phase.

    Subject analysis set title
    Maintenance Phase: Induction IV + Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Vedolizumab placebo-matching injection, subcutaneously, once every 2 weeks from Week 6 up to Week 50. Subjects who received vedolizumab 300 mg IV infusion in open-label induction phase and achieved clinical response at Week 6 were randomized to receive placebo in maintenance phase.

    Subject analysis set title
    Maintenance Phase: Induction IV + Vedolizumab 108 mg SC
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Vedolizumab 108 mg, injection, subcutaneously, once every 2 weeks from Week 6 up to Week 50. Subjects who received vedolizumab 300 mg IV infusion in open-label induction phase and achieved clinical response at Week 6 were randomized to receive vedolizumab injection subcutaneously in maintenance phase.

    Primary: Percentage of Subjects Achieving Clinical Remission at Week 52

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    End point title
    		 Percentage of Subjects Achieving Clinical Remission at Week 52 [1]
    End point description
    Clinical remission:Crohn's Disease Activity Index (CDAI) score less than or equal to(<=)150 at Week52.CDAI is a multi-item instrument which measures severity of active Crohn's Disease monitored over 7 days includes subject reported symptoms,physician-assessed signs/laboratory markers. CDAI score is equal to (=) sum of weighted scores for subjective items (number of liquid/soft stools,degree of abdominal pain,general well-being); objective items (use of anti-diarrhoeal medication, abdominal mass, haematocrit, presence of extraintestinal manifestations, body weight). CDAI scores range approx. from 0 to 600, higher scores indicating greater disease activity. Full analysis set(FAS):All randomized subjects who received at least 1 dose of study SC drug (placebo/VDZ).Subjects who only received induction IV therapy and not randomized into the maintenance phase were not included in FAS.Subjects in this set were analyzed according to treatment they were randomized to receive.
    End point type
    Primary
    End point timeframe
    Week 52
    Notes
    [1] - 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: Descriptive data was planned to be analyzed for the reported arms.
    End point values
    		 Maintenance Phase: Induction IV + Placebo Maintenance Phase: Induction IV + Vedolizumab 108 mg SC
    Number of subjects analysed
    134
    275
    Units: percentage of subjects
        number (confidence interval 95%)
    34.3 (26.3 to 43.0)
    48.0 (42.0 to 54.1)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    P-value was calculated by Cochran-Mantel-Haenszel (CMH) test stratified by electronic data capture (EDC) stratum according to concomitant use of corticosteroids, clinical remission status at Week 6, and previous TNF-alpha antagonist failure/exposed or concomitant immunomodulator use.
    Comparison groups
    Maintenance Phase: Induction IV + Placebo v Maintenance Phase: Induction IV + Vedolizumab 108 mg SC
    Number of subjects included in analysis
    409
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.008
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Clopper-Pearson method
    Point estimate
    13.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.8
         upper limit
    		 23.7

    Secondary: Percentage of Subjects Achieving Enhanced Clinical Response at Week 52

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    End point title
    		 Percentage of Subjects Achieving Enhanced Clinical Response at Week 52 [2]
    End point description
    Enhanced clinical response: A decrease from Baseline of greater than or equal to(>=)100 points in the CDAI score at Week 52.CDAI is a multi-item instrument which measures severity of active CD monitored over 7 days includes subject reported symptoms, physician-assessed signs, and laboratory markers.CDAI score = Sum of weighted scores for subjective items (number of liquid/soft stools, degree of abdominal pain, general well-being); and objective items (use of anti-diarrhoeal medication, abdominal mass, haematocrit, presence of extraintestinal manifestations, body weight). CDAI scores range approx from 0 to 600, higher scores indicating greater disease activity. FAS included all randomized subjects who received at least 1 dose of study SC drug (placebo/VDZ). Subjects who only received induction IV therapy and not randomized into the maintenance phase were not included in FAS. Subjects in this set were analyzed according to the treatment they were randomized to receive.
    End point type
    Secondary
    End point timeframe
    Week 52
    Notes
    [2] - 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: Descriptive data was planned to be analyzed for the reported arms.
    End point values
    		 Maintenance Phase: Induction IV + Placebo Maintenance Phase: Induction IV + Vedolizumab 108 mg SC
    Number of subjects analysed
    134
    275
    Units: percentage of subjects
        number (confidence interval 95%)
    44.8 (36.2 to 53.6)
    52.0 (45.9 to 58.0)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    P-value was calculated by CMH test stratified by EDC stratum according to concomitant use of corticosteroids, clinical remission status at Week 6, and previous TNF-alpha antagonist failure/exposed or concomitant immunomodulator use.
    Comparison groups
    Maintenance Phase: Induction IV + Placebo v Maintenance Phase: Induction IV + Vedolizumab 108 mg SC
    Number of subjects included in analysis
    409
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.167
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Clopper-Pearson method
    Point estimate
    7.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3
         upper limit
    		 17.5

    Secondary: Percentage of Subjects Achieving Corticosteroid-free Remission at Week 52

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    End point title
    		 Percentage of Subjects Achieving Corticosteroid-free Remission at Week 52 [3]
    End point description
    Corticosteroid-free remission is defined as subjects using oral corticosteroids at Baseline (Week 0) who have discontinued oral corticosteroids and are in clinical remission at Week 52. Clinical remission is defined as a CDAI score <=150 at Week 52. CDAI score = Sum of weighted scores for subjective items (number of liquid/soft stools, degree of abdominal pain, general well-being); and objective items (use of anti-diarrhoeal medication, abdominal mass, haematocrit, presence of extraintestinal manifestations, body weight). CDAI scores range approximately from 0 to 600, higher scores indicating greater disease activity. Subjects from FAS, who used concomitant oral corticosteroid at Baseline. FAS had all subjects who received at least 1 dose of SC drug. Subjects who only received induction IV therapy and were not randomized into maintenance phase were not included in FAS. Subjects were analyzed according to randomized treatment assignment.
    End point type
    Secondary
    End point timeframe
    Week 52
    Notes
    [3] - 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: Descriptive data was planned to be analyzed for the reported arms.
    End point values
    		 Maintenance Phase: Induction IV + Placebo Maintenance Phase: Induction IV + Vedolizumab 108 mg SC
    Number of subjects analysed
    44
    95
    Units: percentage of subjects
        number (confidence interval 95%)
    18.2 (8.2 to 32.7)
    45.3 (35.0 to 55.8)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    P-value was calculated by CMH test stratified by EDC stratum according to concomitant use of corticosteroids, clinical remission status at Week 6, and previous TNF-alpha antagonist failure/exposed or concomitant immunomodulator use.
    Comparison groups
    Maintenance Phase: Induction IV + Placebo v Maintenance Phase: Induction IV + Vedolizumab 108 mg SC
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Clopper-Pearson method
    Point estimate
    27.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 11.9
         upper limit
    		 42.3

    Secondary: Percentage of TNF-alpha Antagonist Naive Subjects Achieving Clinical Remission at Week 52

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    End point title
    		 Percentage of TNF-alpha Antagonist Naive Subjects Achieving Clinical Remission at Week 52 [4]
    End point description
    Clinical remission is defined as CDAI score <=150 at Week 52. CDAI score = Sum of weighted scores for subjective items (number of liquid/soft stools, degree of abdominal pain, general well-being); and objective items (use of anti-diarrhoeal medication, abdominal mass, haematocrit, presence of extraintestinal manifestation, body weight). CDAI scores range approximately from 0 to 600, higher scores indicating greater disease activity. Subjects from FAS, who were TNF-alpha antagonist naïve and had clinical remission. FAS had all subjects who received at least 1 dose of SC drug. Subjects who only received induction IV therapy and were not randomized in maintenance phase were not included in FAS. Subjects were analyzed according to randomized treatment assignment.
    End point type
    Secondary
    End point timeframe
    Week 52
    Notes
    [4] - 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: Descriptive data was planned to be analyzed for the reported arms.
    End point values
    		 Maintenance Phase: Induction IV + Placebo Maintenance Phase: Induction IV + Vedolizumab 108 mg SC
    Number of subjects analysed
    63
    107
    Units: percentage of subjects
        number (confidence interval 95%)
    42.9 (30.5 to 56.0)
    48.6 (38.8 to 58.5)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    P-value was calculated by CMH test stratified by EDC stratum according to concomitant use of corticosteroids, clinical remission status at Week 6, and previous TNF-alpha antagonist failure/exposed or concomitant immunomodulator use.
    Comparison groups
    Maintenance Phase: Induction IV + Placebo v Maintenance Phase: Induction IV + Vedolizumab 108 mg SC
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.591
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Clopper-Pearson method
    Point estimate
    4.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.6
         upper limit
    		 20.3

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events are adverse events that started after the first dose of study drug up to 18 weeks after the last dose of study drug (up to Week 68)
    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 subject 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
    22.0
    Reporting groups
    Reporting group title
    Induction Phase Only: Vedolizumab 300 mg IV
    Reporting group description
    		 Vedolizumab 300 mg, infusion, intravenously, once at Weeks 0, 2 in the open-label induction phase. Subjects who did not achieve clinical response at Week 6 received third infusion of vedolizumab 300 mg IV on Week 6.

    Reporting group title
    Maintenance Phase: Induction IV + Vedolizumab 108 mg SC
    Reporting group description
    		 Vedolizumab 108 mg, injection, subcutaneously, once every 2 weeks from Week 6 up to Week 50. Subjects who received vedolizumab 300 mg IV infusion in open-label induction phase and achieved clinical response at Week 6 were randomized to receive vedolizumab injection subcutaneously in maintenance phase.

    Reporting group title
    Maintenance Phase: Induction IV + Placebo
    Reporting group description
    		 Vedolizumab placebo-matching injection, subcutaneously, once every 2 weeks from Week 6 up to Week 50. Subjects who received vedolizumab 300 mg IV infusion in open-label induction phase and achieved clinical response at Week 6 were randomized to receive placebo in maintenance phase.

    Serious adverse events
    		 Induction Phase Only: Vedolizumab 300 mg IV Maintenance Phase: Induction IV + Vedolizumab 108 mg SC Maintenance Phase: Induction IV + Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    39 / 235 (16.60%)
    23 / 275 (8.36%)
    14 / 134 (10.45%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Intraductal papilloma of breast
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 275 (0.36%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 275 (0.36%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 275 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcoholism
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 275 (0.36%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 275 (0.36%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    White blood cell count increased
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 275 (0.36%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Gastrointestinal anastomotic complication
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 275 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 275 (0.36%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal anastomotic stenosis
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 275 (0.36%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 275 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 275 (0.36%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 235 (0.00%)
    2 / 275 (0.73%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 275 (0.36%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intraventricular haemorrhage
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 275 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 275 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiplegia
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 275 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemias
         subjects affected / exposed
    1 / 235 (0.43%)
    1 / 275 (0.36%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 275 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 275 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 275 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    14 / 235 (5.96%)
    6 / 275 (2.18%)
    5 / 134 (3.73%)
         occurrences causally related to treatment / all
    3 / 14
    1 / 7
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 235 (0.43%)
    1 / 275 (0.36%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileal stenosis
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 275 (0.36%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    1 / 235 (0.43%)
    1 / 275 (0.36%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterovesical fistula
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 275 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 235 (0.43%)
    2 / 275 (0.73%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 235 (0.43%)
    1 / 275 (0.36%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 235 (0.85%)
    0 / 275 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterocutaneous fistula
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 275 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jejunal perforation
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 275 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestinal ulcer
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 275 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 275 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 275 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 275 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis cholestatic
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 275 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Ureterolithiasis
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 275 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 275 (0.36%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    2 / 235 (0.85%)
    1 / 275 (0.36%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal wall abscess
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 275 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abscess intestinal
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 275 (0.36%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 275 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 275 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 275 (0.36%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 275 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 275 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 235 (0.43%)
    1 / 275 (0.36%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal abscess
         subjects affected / exposed
    4 / 235 (1.70%)
    0 / 275 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 275 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colonic abscess
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 275 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 275 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Weight gain poor
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 275 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Induction Phase Only: Vedolizumab 300 mg IV Maintenance Phase: Induction IV + Vedolizumab 108 mg SC Maintenance Phase: Induction IV + Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 235 (17.02%)
    102 / 275 (37.09%)
    54 / 134 (40.30%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 235 (4.26%)
    15 / 275 (5.45%)
    5 / 134 (3.73%)
         occurrences all number
    10
    19
    9
    Gastrointestinal disorders
    Crohn's disease
         subjects affected / exposed
    7 / 235 (2.98%)
    36 / 275 (13.09%)
    23 / 134 (17.16%)
         occurrences all number
    7
    36
    25
    Abdominal pain
         subjects affected / exposed
    9 / 235 (3.83%)
    21 / 275 (7.64%)
    11 / 134 (8.21%)
         occurrences all number
    11
    25
    14
    Nausea
         subjects affected / exposed
    9 / 235 (3.83%)
    11 / 275 (4.00%)
    7 / 134 (5.22%)
         occurrences all number
    10
    14
    7
    Vomiting
         subjects affected / exposed
    4 / 235 (1.70%)
    6 / 275 (2.18%)
    7 / 134 (5.22%)
         occurrences all number
    5
    7
    8
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    8 / 235 (3.40%)
    17 / 275 (6.18%)
    9 / 134 (6.72%)
         occurrences all number
    8
    21
    10
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 235 (2.98%)
    25 / 275 (9.09%)
    6 / 134 (4.48%)
         occurrences all number
    8
    26
    8
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 235 (0.85%)
    17 / 275 (6.18%)
    5 / 134 (3.73%)
         occurrences all number
    2
    23
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Oct 2015
    The primary purpose of this amendment was to update the protocol regarding inclusion of additional exploratory objectives and endpoints to gather alternative clinical data.
    10 Feb 2016
    The primary purpose of this amendment was to update the protocol regarding inclusion of a benefit-risk assessment.
    12 May 2016
    The primary purpose of this amendment was to update the protocol to include additional information for clarification.
    28 Jul 2016
    The primary purpose of this amendment was to clarify the inclusion/exclusion criteria and to provide additional information regarding the voluntary ileocolonoscopies.
    28 Sep 2016
    The primary purpose of this amendment was to extend the visit window for Week 6a from 3 days to 5 days to adjust for clinical practice in Japan.
    24 Aug 2017
    The primary purpose of this amendment was to include a pre-Week 14 visit and to clarify the Week 14 procedures for subjects who enroll or do not enroll into the OLE study (SC-3030).

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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