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    Clinical Trial Results:
    A Double-Blind, Randomized, Multicenter Study of Higher Versus Standard Adalimumab Dosing Regimens for Induction and Maintenance Therapy in Subjects With Moderately to Severely Active Ulcerative Colitis

    Summary
    EudraCT number
    2013-001682-16
    Trial protocol
    DE   HU   BE   IT   SK   NL   ES   DK   AT   CZ   PL  
    Global end of trial date
    11 Nov 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Nov 2020
    First version publication date
    13 Nov 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    M14-033
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02065622
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AbbVie
    Sponsor organisation address
    AbbVie House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, United Kingdom, SL6 4UB
    Public contact
    Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com
    Scientific contact
    Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    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
    11 Nov 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Nov 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate safety and efficacy of two adalimumab dosing regimens for induction and maintenance (standard and higher dosing) in achieving clinical remission in subjects with moderately to severely active ulcerative colitis.
    Protection of trial subjects
    Subject and/or legal guardian read and understood the information provided about the study and gave written permission.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Mar 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Slovakia: 4
    Country: Number of subjects enrolled
    Spain: 20
    Country: Number of subjects enrolled
    Switzerland: 5
    Country: Number of subjects enrolled
    Ukraine: 75
    Country: Number of subjects enrolled
    United Kingdom: 33
    Country: Number of subjects enrolled
    United States: 178
    Country: Number of subjects enrolled
    Austria: 30
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    Canada: 71
    Country: Number of subjects enrolled
    Czech Republic: 3
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    France: 42
    Country: Number of subjects enrolled
    Germany: 21
    Country: Number of subjects enrolled
    Hungary: 12
    Country: Number of subjects enrolled
    Israel: 23
    Country: Number of subjects enrolled
    Italy: 67
    Country: Number of subjects enrolled
    Japan: 100
    Country: Number of subjects enrolled
    Netherlands: 15
    Country: Number of subjects enrolled
    Poland: 236
    Country: Number of subjects enrolled
    Romania: 5
    Worldwide total number of subjects
    952
    EEA total number of subjects
    500
    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)
    914
    From 65 to 84 years
    38
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study included a Main Study (120 sites in 19 countries) and a Japan Sub-Study (22 sites in Japan). After a 3-week screening period, participants were randomized 3:2 to an 8-week double-blind (DB) Induction Period with 2 adalimumab dosing regimens (Induction Standard Dose [I-SD] or Induction Higher Dose [I-HD]).

    Pre-assignment
    Screening details
    At Week 8, participants in Main Study were re-randomized (2:2:1) into 44-week DB Maintenance Period with 3 adalimumab dosing regimens (M-SD, M-HD, or an exploratory Therapeutic Drug Monitoring [TDM] Regimen). Participants in Japan Sub-study were re-randomized (1:1) into 44-week DB Maintenance Period with 2 adalimumab dosing regimens (M-SD, M-HD).

    Period 1
    Period 1 title
    Induction Study
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor
    Blinding implementation details
    All AbbVie personnel with direct oversight of the conduct and management of the trial (with the exception of the AbbVie Drug Supply Management Team) the Investigator, study site personnel and the subject will remain blinded to each subject's treatment throughout the blinded period of the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Induction (Main Study + Japan Substudy): I-SD
    Arm description
    Induction Standard Dose (I-SD): Double-blind adalimumab regimen of 160 mg at Week 0 followed by 80 mg at Week 2, 40 mg at Week 4, and 40 mg at Week 6.
    Arm type
    Experimental

    Investigational medicinal product name
    adalimumab
    Investigational medicinal product code
    Other name
    Humira
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Double-blind adalimumab regimen of 160 mg at Week 0 followed by 80 mg at Week 2, 40 mg at Week 4, and 40 mg at Week 6.

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    In order to retain blinding, all subjects in the Standard Induction Dose Regimen will receive matching placebo injections in addition to the adalimumab injection at Weeks 1, 2 and 3.

    Arm title
    Induction (Main Study + Japan Substudy): I-HD
    Arm description
    Induction Higher Dose (I-HD): Double-blind adalimumab regimen of 160 mg at Weeks 0, 1, 2, and 3 followed by 40 mg at Week 4 and 40 mg at Week 6.
    Arm type
    Experimental

    Investigational medicinal product name
    adalimumab
    Investigational medicinal product code
    Other name
    Humira
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Double-blind adalimumab regimen of 160 mg at Weeks 0, 1, 2, and 3 followed by 40 mg at Week 4 and 40 mg at Week 6.

    Number of subjects in period 1
    Induction (Main Study + Japan Substudy): I-SD Induction (Main Study + Japan Substudy): I-HD
    Started
    379
    573
    Enrolled in Main Study
    340
    512 [1]
    Enrolled in Japan Sub-Study
    39 [2]
    61 [3]
    Completed
    332
    514
    Not completed
    47
    59
         Adverse event
    13
    19
         Lack of efficacy
    22
    27
         Other, Not Specified
    3
    2
         Subject Noncompliance
    1
    1
         Withdrawal by subject
    3
    5
         Requires Alternative/ Prohibited Therapy
    4
    5
         Lost to follow-up
    1
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Enrolled in Main Study
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Enrolled in Japan Sub-Study
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Enrolled in Japan Sub-Study
    Period 2
    Period 2 title
    Maintenance Study
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor
    Blinding implementation details
    All AbbVie personally with direct oversight of the conduct and management of the trial (with the exception of the AbbVie Drug Supply Management Team) the Investigator, study site personnel and the subject remained blinded to each subject's treatment throughout the blinded period of the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Maintenance (Main Study + Japan Sub-study): M-SD
    Arm description
    Maintenance Standard Dose (M-SD): Double-blind adalimumab 40 mg every other week (eow), for 44 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    adalimumab
    Investigational medicinal product code
    Other name
    Humira
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Double-blind adalimumab 40 mg every other week (eow), for 44 weeks.

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Matching Placebo was administered every other week, starting at Week 9 until Week 51.

    Arm title
    Maintenance (Main Study + Japan Sub-study): M-HD
    Arm description
    Maintenance Higher Dose (M-HD): Double-blind adalimumab 40 mg every week (ew) for 44 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    adalimumab
    Investigational medicinal product code
    Other name
    Humira
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Double-blind adalimumab 40 mg every week (ew) for 44 weeks.

    Arm title
    Maintenance (Main Study): TDM Regimen
    Arm description
    Exploratory Therapeutic Drug Monitoring (TDM) Regimen: Double-blind adalimumab 40 mg eow at Week 8 and Week 10, with possible dose adjustments at Weeks 12, 24, and 37 based on criteria assessing blinded adalimumab serum concentration and rectal bleeding subscore assessments. Per protocol, the TDM Regimen arm was used to analyze exploratory outcome measures only.
    Arm type
    Experimental

    Investigational medicinal product name
    adalimumab
    Investigational medicinal product code
    Other name
    Humira
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Double-blind adalimumab 40 mg eow at Week 8 and Week 10, with possible dose adjustments at Weeks 12, 24, and 37 based on criteria assessing blinded adalimumab serum concentration and rectal bleeding subscore assessments.

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    In order to retain blinding, all subjects in the TDM Regimen will receive matching placebo injections in addition to the adalimumab injection at Weeks 9 and 11.

    Number of subjects in period 2
    Maintenance (Main Study + Japan Sub-study): M-SD Maintenance (Main Study + Japan Sub-study): M-HD Maintenance (Main Study): TDM Regimen
    Started
    345
    350
    151
    Completed
    221
    246
    105
    Not completed
    124
    104
    46
         Adverse event
    25
    22
    11
         Unknown Reason
    -
    1
    -
         Lack of efficacy
    70
    55
    19
         Other, Not Specified
    6
    14
    2
         Withdrawal by subject
    11
    5
    7
         Subject Non-Compliance
    1
    3
    2
         Requires Alternative/ Prohibited Therapy
    7
    3
    4
         Lost to follow-up
    4
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Induction (Main Study + Japan Substudy): I-SD
    Reporting group description
    Induction Standard Dose (I-SD): Double-blind adalimumab regimen of 160 mg at Week 0 followed by 80 mg at Week 2, 40 mg at Week 4, and 40 mg at Week 6.

    Reporting group title
    Induction (Main Study + Japan Substudy): I-HD
    Reporting group description
    Induction Higher Dose (I-HD): Double-blind adalimumab regimen of 160 mg at Weeks 0, 1, 2, and 3 followed by 40 mg at Week 4 and 40 mg at Week 6.

    Reporting group values
    Induction (Main Study + Japan Substudy): I-SD Induction (Main Study + Japan Substudy): I-HD Total
    Number of subjects
    379 573 952
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    40.2 ± 13.14 40.5 ± 12.89 -
    Gender categorical
    Units: Subjects
        Female
    166 239 405
        Male
    213 334 547
    Race
    Units: Subjects
        White
    326 484 810
        Black or African American
    8 16 24
        Asian
    44 70 114
        Native Hawaiian/ Other Pacific Islander
    0 1 1
        Multiracial
    1 1 2
        Missing
    0 1 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    19 28 47
        Japanese
    39 61 100
        Other, Not Specified
    321 484 805
    Region
    Units: Subjects
        United States
    65 113 178
        Non-United States
    314 460 774
    Full Mayo Score (FMS)
    The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy, and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). Measure Analysis Population Description: participants with an assessment (n=379, 570)
    Units: units on a scale
        arithmetic mean (standard deviation)
    8.69 ± 1.509 8.87 ± 1.571 -
    FMS: Rectal Bleeding Subscore
    The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy, and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). Measure Analysis Population Description: participants with an assessment (n=379, 570).
    Units: units on a scale
        arithmetic mean (standard deviation)
    1.68 ± 0.955 1.75 ± 0.967 -

    End points

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    End points reporting groups
    Reporting group title
    Induction (Main Study + Japan Substudy): I-SD
    Reporting group description
    Induction Standard Dose (I-SD): Double-blind adalimumab regimen of 160 mg at Week 0 followed by 80 mg at Week 2, 40 mg at Week 4, and 40 mg at Week 6.

    Reporting group title
    Induction (Main Study + Japan Substudy): I-HD
    Reporting group description
    Induction Higher Dose (I-HD): Double-blind adalimumab regimen of 160 mg at Weeks 0, 1, 2, and 3 followed by 40 mg at Week 4 and 40 mg at Week 6.
    Reporting group title
    Maintenance (Main Study + Japan Sub-study): M-SD
    Reporting group description
    Maintenance Standard Dose (M-SD): Double-blind adalimumab 40 mg every other week (eow), for 44 weeks.

    Reporting group title
    Maintenance (Main Study + Japan Sub-study): M-HD
    Reporting group description
    Maintenance Higher Dose (M-HD): Double-blind adalimumab 40 mg every week (ew) for 44 weeks.

    Reporting group title
    Maintenance (Main Study): TDM Regimen
    Reporting group description
    Exploratory Therapeutic Drug Monitoring (TDM) Regimen: Double-blind adalimumab 40 mg eow at Week 8 and Week 10, with possible dose adjustments at Weeks 12, 24, and 37 based on criteria assessing blinded adalimumab serum concentration and rectal bleeding subscore assessments. Per protocol, the TDM Regimen arm was used to analyze exploratory outcome measures only.

    Subject analysis set title
    Induction (Main Study): I-SD
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Induction Standard Dose: Double-blind adalimumab regimen of 160 mg at Week 0 followed by 80 mg at Week 2, 40 mg at Week 4, and 40 mg at Week 6.

    Subject analysis set title
    Induction (Main Study): I-HD
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Induction Higher Dose: Double-blind adalimumab regimen of 160 mg at Weeks 0, 1, 2, and 3 followed by 40 mg at Week 4 and 40 mg at Week 6.

    Subject analysis set title
    Induction (Main Study + Japan Substudy): I-SD
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Induction Standard Dose: Double-blind adalimumab regimen of 160 mg at Week 0 followed by 80 mg at Week 2, 40 mg at Week 4, and 40 mg at Week 6.

    Subject analysis set title
    Induction (Main Study + Japan Substudy): I-HD
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Induction Higher Dose: Double-blind adalimumab regimen of 160 mg at Weeks 0, 1, 2, and 3 followed by 40 mg at Week 4 and 40 mg at Week 6.

    Subject analysis set title
    Maintenance (Main Study): M-SD
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Maintenance Standard Dose: Double-blind adalimumab 40 mg every other week (eow), for 44 weeks.

    Subject analysis set title
    Maintenance (Main Study): M-HD
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Maintenance Higher Dose: Double-blind adalimumab 40 mg every week (ew) for 44 weeks.

    Subject analysis set title
    Maintenance (Main Study + Japan Sub-study): M-SD
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Maintenance Standard Dose: Double-blind adalimumab 40 mg every other week (eow), for 44 weeks.

    Subject analysis set title
    Maintenance (Main Study + Japan Sub-study): M-HD
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Maintenance Higher Dose: Double-blind adalimumab 40 mg every week (ew) for 44 weeks.

    Primary: Induction Period Primary Endpoint: Percentage of Participants With Clinical Remission Per Full Mayo Score (FMS) at Week 8

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    End point title
    Induction Period Primary Endpoint: Percentage of Participants With Clinical Remission Per Full Mayo Score (FMS) at Week 8
    End point description
    The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy [confirmed by a central reader], and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). Negative changes indicate improvement. Clinical remission per FMS is defined as Mayo Score ≤ 2 and no individual subscore > 1. Induction Study Intent-to-Treat (ITT) set: all participants who were randomized at Baseline. Non-responder imputation.
    End point type
    Primary
    End point timeframe
    Week 8
    End point values
    Induction (Main Study): I-SD Induction (Main Study): I-HD Induction (Main Study + Japan Substudy): I-SD Induction (Main Study + Japan Substudy): I-HD
    Number of subjects analysed
    340
    512
    379
    573
    Units: percentage of participants
        number (not applicable)
    10.9
    13.3
    11.6
    13.8
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel test adjusted for previous infliximab use and baseline corticosteroid use.
    Comparison groups
    Induction (Main Study): I-SD v Induction (Main Study): I-HD
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.269
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    2.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2
         upper limit
    7
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Induction (Main Study): I-SD v Induction (Main Study): I-HD
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.447 [1]
    Method
    Breslow-Day test
    Confidence interval
    Notes
    [1] - Breslow-Day test of homogeneity across strata.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel test adjusted for previous infliximab use and baseline corticosteroid use.
    Comparison groups
    Induction (Main Study + Japan Substudy): I-HD v Induction (Main Study + Japan Substudy): I-SD
    Number of subjects included in analysis
    952
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.301
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    2.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2
         upper limit
    6.6
    Statistical analysis title
    Statistical Analysis 4
    Comparison groups
    Induction (Main Study + Japan Substudy): I-SD v Induction (Main Study + Japan Substudy): I-HD
    Number of subjects included in analysis
    952
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.502 [2]
    Method
    Breslow-Day test
    Confidence interval
    Notes
    [2] - Breslow-Day test of homogeneity across strata.

    Primary: Maintenance Period Primary Endpoint: Percentage of Week 8 Responders (Per FMS) With Clinical Remission (Per FMS) at Week 52

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    End point title
    Maintenance Period Primary Endpoint: Percentage of Week 8 Responders (Per FMS) With Clinical Remission (Per FMS) at Week 52
    End point description
    The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy [confirmed by a central reader], and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). Negative changes indicate improvement. Week 8 responders (per FMS) are defined as participants with a decrease in Full Mayo score of ≥ 3 points and ≥ 30% from Baseline plus a decrease from baseline in the rectal bleeding subscore (RBS) ≥ 1 or an absolute RBS ≤ 1. Clinical remission per FMS is defined as Mayo Score ≤ 2 and no individual subscore > 1. ITT-Responder population (I-ITT-RP): all participants in the Induction ITT population who achieve Week 8 response based on the FMS utilizing the endoscopy subscore provided by the central reader. Non-responder imputation.
    End point type
    Primary
    End point timeframe
    Week 52
    End point values
    Maintenance (Main Study): M-SD Maintenance (Main Study): M-HD Maintenance (Main Study + Japan Sub-study): M-SD Maintenance (Main Study + Japan Sub-study): M-HD
    Number of subjects analysed
    145
    152
    163
    175
    Units: percentage of participants
        number (not applicable)
    29.0
    39.5
    30.1
    41.1
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for induction treatment regimen and week 8 remission status.
    Comparison groups
    Maintenance (Main Study): M-SD v Maintenance (Main Study): M-HD
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.069
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    9.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.8
         upper limit
    20.6
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Maintenance (Main Study): M-SD v Maintenance (Main Study): M-HD
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.085 [3]
    Method
    Breslow-Day test
    Confidence interval
    Notes
    [3] - Breslow-Day test of homogeneity across strata.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for induction treatment regimen and week 8 remission status.
    Comparison groups
    Maintenance (Main Study + Japan Sub-study): M-HD v Maintenance (Main Study + Japan Sub-study): M-SD
    Number of subjects included in analysis
    338
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.045
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    10.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.2
         upper limit
    20.4
    Statistical analysis title
    Statistical Analysis 4
    Comparison groups
    Maintenance (Main Study + Japan Sub-study): M-SD v Maintenance (Main Study + Japan Sub-study): M-HD
    Number of subjects included in analysis
    338
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.106 [4]
    Method
    Breslow-Day test
    Confidence interval
    Notes
    [4] - Breslow-Day test of homogeneity across strata.

    Secondary: Induction Period Ranked Secondary Endpoint 1: Percentage of Participants With Endoscopic Improvement at Week 8

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    End point title
    Induction Period Ranked Secondary Endpoint 1: Percentage of Participants With Endoscopic Improvement at Week 8
    End point description
    The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy [confirmed by a central reader], and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). Negative changes indicate improvement. Endoscopic improvement is defined as an endoscopy subscore of 0 or 1. Induction Study Intent-to-Treat (ITT) set: all participants who were randomized at Baseline. Non-responder imputation.
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    Induction (Main Study): I-SD Induction (Main Study): I-HD Induction (Main Study + Japan Substudy): I-SD Induction (Main Study + Japan Substudy): I-HD
    Number of subjects analysed
    340
    512
    379
    573
    Units: percentage of participants
        number (not applicable)
    27.1
    31.1
    26.9
    30.5
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel test adjusted for previous infliximab use and baseline corticosteroid use.
    Comparison groups
    Induction (Main Study): I-SD v Induction (Main Study): I-HD
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.181
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    4.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2
         upper limit
    10.5
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel test adjusted for previous infliximab use and baseline corticosteroid use.
    Comparison groups
    Induction (Main Study + Japan Substudy): I-SD v Induction (Main Study + Japan Substudy): I-HD
    Number of subjects included in analysis
    952
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    3.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2
         upper limit
    9.7

    Secondary: Induction Period Ranked Secondary Endpoint 2: Percentage of Participants With Fecal Calprotectin < 150 mg/kg at Week 8

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    End point title
    Induction Period Ranked Secondary Endpoint 2: Percentage of Participants With Fecal Calprotectin < 150 mg/kg at Week 8
    End point description
    Induction Study Intent-to-Treat (ITT) set: all participants who were randomized at Baseline. Non-responder imputation.
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    Induction (Main Study): I-SD Induction (Main Study): I-HD Induction (Main Study + Japan Substudy): I-SD Induction (Main Study + Japan Substudy): I-HD
    Number of subjects analysed
    340
    512
    379
    573
    Units: percentage of participants
        number (not applicable)
    27.1
    31.1
    26.9
    30.5
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel test adjusted for previous infliximab use and baseline corticosteroid use.
    Comparison groups
    Induction (Main Study): I-SD v Induction (Main Study): I-HD
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.6
         upper limit
    8.6
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel test adjusted for previous infliximab use and baseline corticosteroid use.
    Comparison groups
    Induction (Main Study + Japan Substudy): I-SD v Induction (Main Study + Japan Substudy): I-HD
    Number of subjects included in analysis
    952
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.254
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    3.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.2
         upper limit
    8.4

    Secondary: Induction Period Ranked Secondary Endpoint 3: Percentage of Participants With Inflammatory Bowel Disease Questionnaire (IBDQ) Response (Increase of IBDQ ≥ 16 From Baseline) at Week 8

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    End point title
    Induction Period Ranked Secondary Endpoint 3: Percentage of Participants With Inflammatory Bowel Disease Questionnaire (IBDQ) Response (Increase of IBDQ ≥ 16 From Baseline) at Week 8
    End point description
    The IBDQ is a self-administered 32-item questionnaire to evaluate quality of life across 4 dimensional scores: bowel, systemic, social and emotional. Responses to each question range from 1 (severe problem) to 7 (normal health). Total IBDQ score is the sum of the responses to the individual IBDQ questions, and ranges from 32 to 224 with higher scores indicating a better quality of life. Induction Study Intent-to-Treat (ITT) set: all participants who were randomized at Baseline. Non-responder imputation.
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    Induction (Main Study): I-SD Induction (Main Study): I-HD Induction (Main Study + Japan Substudy): I-SD Induction (Main Study + Japan Substudy): I-HD
    Number of subjects analysed
    340
    512
    379
    573
    Units: percentage of participants
        number (not applicable)
    60.9
    67.2
    60.7
    65.3
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel test adjusted for previous infliximab use and baseline corticosteroid use.
    Comparison groups
    Induction (Main Study): I-SD v Induction (Main Study): I-HD
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.05
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    6.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    13.1
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel test adjusted for previous infliximab use and baseline corticosteroid use.
    Comparison groups
    Induction (Main Study + Japan Substudy): I-SD v Induction (Main Study + Japan Substudy): I-HD
    Number of subjects included in analysis
    952
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.131
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    4.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.4
         upper limit
    11

    Secondary: Induction Period Ranked Secondary Endpoint 4: Percentage of Participants With Clinical Response Per FMS at Week 8

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    End point title
    Induction Period Ranked Secondary Endpoint 4: Percentage of Participants With Clinical Response Per FMS at Week 8
    End point description
    The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy [confirmed by a central reader], and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). Negative changes indicate improvement. Clinical response is defined as a decrease in FMS of ≥ 3 points and ≥ 30% from baseline, plus a decrease in the rectal bleeding subscore (RBS) ≥ 1 or an absolute RBS ≤ 1. Induction Study Intent-to-Treat (ITT) set: all participants who were randomized at Baseline. Non-responder imputation.
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    Induction (Main Study): I-SD Induction (Main Study): I-HD Induction (Main Study + Japan Substudy): I-SD Induction (Main Study + Japan Substudy): I-HD
    Number of subjects analysed
    340
    512
    379
    573
    Units: percentage of participants
        number (not applicable)
    40.0
    47.1
    38.8
    47.3
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel test adjusted for previous infliximab use and baseline corticosteroid use.
    Comparison groups
    Induction (Main Study): I-SD v Induction (Main Study): I-HD
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.035
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    7.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5
         upper limit
    14.1
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel test adjusted for previous infliximab use and baseline corticosteroid use.
    Comparison groups
    Induction (Main Study + Japan Substudy): I-SD v Induction (Main Study + Japan Substudy): I-HD
    Number of subjects included in analysis
    952
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.008
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    8.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.3
         upper limit
    15.1

    Secondary: Induction Period Ranked Secondary Endpoint 5: Percentage of Participants With Endoscopic Remission at Week 8

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    End point title
    Induction Period Ranked Secondary Endpoint 5: Percentage of Participants With Endoscopic Remission at Week 8
    End point description
    The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy [confirmed by a central reader], and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). Negative changes indicate improvement. Endoscopic remission is defined as an endoscopy subscore of 0. Induction Study Intent-to-Treat (ITT) set: all participants who were randomized at Baseline. Non-responder imputation.
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    Induction (Main Study): I-SD Induction (Main Study): I-HD Induction (Main Study + Japan Substudy): I-SD Induction (Main Study + Japan Substudy): I-HD
    Number of subjects analysed
    340
    512
    379
    573
    Units: percentage of participants
        number (not applicable)
    10.0
    13.1
    10.0
    12.9
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel test adjusted for previous infliximab use and baseline corticosteroid use.
    Comparison groups
    Induction (Main Study): I-HD v Induction (Main Study): I-SD
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.16
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    3.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.3
         upper limit
    7.6
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel test adjusted for previous infliximab use and baseline corticosteroid use.
    Comparison groups
    Induction (Main Study + Japan Substudy): I-SD v Induction (Main Study + Japan Substudy): I-HD
    Number of subjects included in analysis
    952
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.166
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    2.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.2
         upper limit
    7.1

    Secondary: Induction Period Ranked Secondary Endpoint 6: Percentage of Participants Achieving Response in IBDQ Bowel Symptom Domain at Week 8

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    End point title
    Induction Period Ranked Secondary Endpoint 6: Percentage of Participants Achieving Response in IBDQ Bowel Symptom Domain at Week 8
    End point description
    The IBDQ is a self-administered 32-item questionnaire to evaluate quality of life across 4 dimensional scores: bowel, systemic, social and emotional. Responses to each question range from 1 (severe problem) to 7 (normal health). The range for Bowel Symptom domain score is 10 (severe problem) to 70 (normal health). Response in IBDQ Bowel Symptom domain is defined as an increase of IBDQ Bowel Symptom domain score ≥ 6. Induction Study Intent-to-Treat (ITT) set: all participants who were randomized at Baseline. Non-responder imputation.
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    Induction (Main Study): I-SD Induction (Main Study): I-HD Induction (Main Study + Japan Substudy): I-SD Induction (Main Study + Japan Substudy): I-HD
    Number of subjects analysed
    340
    512
    379
    573
    Units: percentage of participants
        number (not applicable)
    63.2
    71.3
    63.1
    69.8
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel test adjusted for previous infliximab use and baseline corticosteroid use.
    Comparison groups
    Induction (Main Study): I-SD v Induction (Main Study): I-HD
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.011
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    8.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.9
         upper limit
    14.7
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel test adjusted for previous infliximab use and baseline corticosteroid use.
    Comparison groups
    Induction (Main Study + Japan Substudy): I-SD v Induction (Main Study + Japan Substudy): I-HD
    Number of subjects included in analysis
    952
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.025
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9
         upper limit
    13

    Secondary: Induction Period Ranked Secondary Endpoint 7: Percentage of Participants Achieving Response in IBDQ Fatigue Item at Week 8

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    End point title
    Induction Period Ranked Secondary Endpoint 7: Percentage of Participants Achieving Response in IBDQ Fatigue Item at Week 8
    End point description
    The IBDQ is a self-administered 32-item questionnaire to evaluate quality of life across 4 dimensional scores: bowel, systemic, social and emotional. Responses to each question range from 1 (severe problem) to 7 (normal health). The IBDQ Fatigue item score range is from 1 (severe problem) to 7 (normal health). Response is defined as an increase of IBDQ Fatigue item score ≥ 1. Induction Study Intent-to-Treat (ITT) set: all participants who were randomized at Baseline. Non-responder imputation.
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    Induction (Main Study): I-SD Induction (Main Study): I-HD Induction (Main Study + Japan Substudy): I-SD Induction (Main Study + Japan Substudy): I-HD
    Number of subjects analysed
    340
    512
    379
    573
    Units: percentage of participants
        number (not applicable)
    57.1
    61.1
    57.5
    59.9
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel test adjusted for previous infliximab use and baseline corticosteroid use.
    Comparison groups
    Induction (Main Study): I-SD v Induction (Main Study): I-HD
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.218
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    4.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.5
         upper limit
    10.9
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel test adjusted for previous infliximab use and baseline corticosteroid use.
    Comparison groups
    Induction (Main Study + Japan Substudy): I-SD v Induction (Main Study + Japan Substudy): I-HD
    Number of subjects included in analysis
    952
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.456
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    2.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4
         upper limit
    8.8

    Secondary: Maintenance Period Ranked Secondary Endpoint 1: Percentage of Week 8 Responders (Per FMS) With Endoscopic Improvement at Week 52

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    End point title
    Maintenance Period Ranked Secondary Endpoint 1: Percentage of Week 8 Responders (Per FMS) With Endoscopic Improvement at Week 52
    End point description
    The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy [confirmed by a central reader], and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). Negative changes indicate improvement. Week 8 responders are defined as participants with a decrease in FMS of ≥ 3 points and ≥ 30% from Baseline plus a decrease in the rectal bleeding subscore (RBS) ≥ 1 or an absolute RBS ≤ 1. Endoscopic improvement is defined as an endoscopy subscore of 0 or 1. ITT-Responder population (I-ITT-RP): all participants in the Induction ITT population who achieve Week 8 response based on the FMS utilizing the endoscopy subscore provided by the central reader. Non-responder imputation.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Maintenance (Main Study): M-SD Maintenance (Main Study): M-HD Maintenance (Main Study + Japan Sub-study): M-SD Maintenance (Main Study + Japan Sub-study): M-HD
    Number of subjects analysed
    145
    152
    163
    175
    Units: percentage of participants
        number (not applicable)
    41.4
    51.3
    41.7
    52.0
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for induction treatment regimen and week 8 remission status.
    Comparison groups
    Maintenance (Main Study): M-SD v Maintenance (Main Study): M-HD
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.098
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    9.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.7
         upper limit
    20.8
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for induction treatment regimen and week 8 remission status.
    Comparison groups
    Maintenance (Main Study + Japan Sub-study): M-SD v Maintenance (Main Study + Japan Sub-study): M-HD
    Number of subjects included in analysis
    338
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.066
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    9.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.7
         upper limit
    20.5

    Secondary: Maintenance Period Ranked Secondary Endpoint 2: Percentage of Week 8 Responders With Steroid Usage at Baseline and Steroid Free at Least 90 Days at Week 52

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    End point title
    Maintenance Period Ranked Secondary Endpoint 2: Percentage of Week 8 Responders With Steroid Usage at Baseline and Steroid Free at Least 90 Days at Week 52
    End point description
    The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy [confirmed by a central reader], and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). Negative changes indicate improvement. Week 8 responders, per FMS, are defined as participants with a decrease in FMS of ≥ 3 points and ≥ 30% from Baseline plus a decrease in the rectal bleeding subscore (RBS) ≥ 1 or an absolute RBS ≤ 1. I-ITT-RP: participants in the Induction ITT population who achieve Week 8 response based on the FMS utilizing the endoscopy subscore provided by the central reader. Participants with steroid use at Baseline. Non-responder imputation.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Maintenance (Main Study): M-SD Maintenance (Main Study): M-HD Maintenance (Main Study + Japan Sub-study): M-SD Maintenance (Main Study + Japan Sub-study): M-HD
    Number of subjects analysed
    92
    95
    103
    108
    Units: percentage of participants
        number (not applicable)
    53.3
    74.7
    54.4
    74.1
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for induction treatment regimen and week 8 remission status.
    Comparison groups
    Maintenance (Main Study): M-SD v Maintenance (Main Study): M-HD
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.002
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    21.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    7.6
         upper limit
    35.4
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for induction treatment regimen and week 8 remission status.
    Comparison groups
    Maintenance (Main Study + Japan Sub-study): M-SD v Maintenance (Main Study + Japan Sub-study): M-HD
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.003
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    19.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.6
         upper limit
    32.7

    Secondary: Maintenance Period Ranked Secondary Endpoint 3: Percentage of Week 8 Responders With Steroid Usage at Baseline and Steroid Free at Least 90 Days and With Clinical Remission at Week 52

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    End point title
    Maintenance Period Ranked Secondary Endpoint 3: Percentage of Week 8 Responders With Steroid Usage at Baseline and Steroid Free at Least 90 Days and With Clinical Remission at Week 52
    End point description
    The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy [confirmed by a central reader], and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). Negative changes indicate improvement. Week 8 responders, per FMS, are defined as participants with a decrease in FMS of ≥ 3 points and ≥ 30% from Baseline plus a decrease in the rectal bleeding subscore (RBS) ≥ 1 or an absolute RBS ≤ 1. Clinical remission is defined as FMS ≤ 2 with no subscore > 1. I-ITT-RP: participants in the Induction ITT population who achieve Week 8 response based on the FMS utilizing the endoscopy subscore provided by the central reader. Participants with steroid use at Baseline. Non-responder imputation.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Maintenance (Main Study): M-SD Maintenance (Main Study): M-HD Maintenance (Main Study + Japan Sub-study): M-SD Maintenance (Main Study + Japan Sub-study): M-HD
    Number of subjects analysed
    92
    95
    103
    108
    Units: percentage of participants
        number (not applicable)
    27.2
    38.9
    28.2
    39.8
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for induction treatment regimen and week 8 remission status.
    Comparison groups
    Maintenance (Main Study): M-SD v Maintenance (Main Study): M-HD
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.093
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    11.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.9
         upper limit
    25
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for induction treatment regimen and week 8 remission status.
    Comparison groups
    Maintenance (Main Study + Japan Sub-study): M-SD v Maintenance (Main Study + Japan Sub-study): M-HD
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.088
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    11.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.7
         upper limit
    23.8

    Secondary: Maintenance Period Ranked Secondary Endpoint 4: Percentage of Week 8 Remitters (Per FMS) With Clinical Remission (Per FMS) at Week 52

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    End point title
    Maintenance Period Ranked Secondary Endpoint 4: Percentage of Week 8 Remitters (Per FMS) With Clinical Remission (Per FMS) at Week 52
    End point description
    The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy [confirmed by a central reader], and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). Negative changes indicate improvement. Week 8 remitters are defined as participants with clinical remission (per FMS) at Week 8. Clinical remission is defined as a FMS ≤ 2 with no subscore > 1. Endoscopy subscore provided by the central reader. ITT-Remitter (ITT-RM) Population included all participants in the ITT population who achieved Week 8 remission based on the FMS utilizing the endoscopy subscore provided by the central reader. Non-responder imputation.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Maintenance (Main Study): M-SD Maintenance (Main Study): M-HD Maintenance (Main Study + Japan Sub-study): M-SD Maintenance (Main Study + Japan Sub-study): M-HD
    Number of subjects analysed
    37
    42
    45
    52
    Units: percentage of participants
        number (not applicable)
    40.5
    57.1
    44.4
    55.8
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for induction treatment regimen and week 8 remission status.
    Comparison groups
    Maintenance (Main Study): M-SD v Maintenance (Main Study): M-HD
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.161
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    15.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.3
         upper limit
    38.2
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for induction treatment regimen and week 8 remission status.
    Comparison groups
    Maintenance (Main Study + Japan Sub-study): M-SD v Maintenance (Main Study + Japan Sub-study): M-HD
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.312
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    10.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.8
         upper limit
    30.6

    Secondary: Maintenance Period Ranked Secondary Endpoint 5: Percentage of Week 8 Remitters (Per FMS) With Endoscopic Improvement at Week 52

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    End point title
    Maintenance Period Ranked Secondary Endpoint 5: Percentage of Week 8 Remitters (Per FMS) With Endoscopic Improvement at Week 52
    End point description
    The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy [confirmed by a central reader], and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). Negative changes indicate improvement. Week 8 remitters are defined as participants with clinical remission (per FMS) at Week 8. Clinical remission is defined as a FMS ≤ 2 with no subscore > 1. Endoscopic improvement is defined as an endoscopy subscore of 0 or 1. Endoscopy subscore provided by the central reader. ITT-Remitter (ITT-RM) Population included all participants in the ITT population who achieved Week 8 remission based on the FMS utilizing the endoscopy subscore provided by the central reader. Non-responder imputation.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Maintenance (Main Study): M-SD Maintenance (Main Study): M-HD Maintenance (Main Study + Japan Sub-study): M-SD Maintenance (Main Study + Japan Sub-study): M-HD
    Number of subjects analysed
    37
    42
    45
    52
    Units: percentage of participants
        number (not applicable)
    51.4
    64.3
    55.6
    61.5
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for induction treatment regimen and week 8 remission status.
    Comparison groups
    Maintenance (Main Study): M-HD v Maintenance (Main Study): M-SD
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.272
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    12.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.7
         upper limit
    34.4
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for induction treatment regimen and week 8 remission status.
    Comparison groups
    Maintenance (Main Study + Japan Sub-study): M-SD v Maintenance (Main Study + Japan Sub-study): M-HD
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    5.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14.6
         upper limit
    25.2

    Secondary: Maintenance Period Ranked Secondary Endpoint 6: Percentage of Week 8 Remitters (Per FMS) With Steroid Usage at Baseline and Steroid Free at Least 90 Days at Week 52

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    End point title
    Maintenance Period Ranked Secondary Endpoint 6: Percentage of Week 8 Remitters (Per FMS) With Steroid Usage at Baseline and Steroid Free at Least 90 Days at Week 52
    End point description
    The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy [confirmed by a central reader], and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). Negative changes indicate improvement. Week 8 remitters are defined as participants with clinical remission (per FMS) at Week 8. Clinical remission is defined as a FMS ≤ 2 with no subscore > 1. ITT-RM Population: participants in ITT population who achieved Week 8 remission based on the FMS utilizing the endoscopy subscore provided by the central reader. Participants with steroid use at Baseline. Non-responder imputation.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Maintenance (Main Study): M-SD Maintenance (Main Study): M-HD Maintenance (Main Study + Japan Sub-study): M-SD Maintenance (Main Study + Japan Sub-study): M-HD
    Number of subjects analysed
    26
    27
    32
    35
    Units: percentage of participants
        number (not applicable)
    53.8
    77.8
    56.3
    71.4
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for induction treatment regimen and week 8 remission status.
    Comparison groups
    Maintenance (Main Study): M-SD v Maintenance (Main Study): M-HD
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.074
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    23.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.3
         upper limit
    49.9
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for induction treatment regimen and week 8 remission status.
    Comparison groups
    Maintenance (Main Study + Japan Sub-study): M-SD v Maintenance (Main Study + Japan Sub-study): M-HD
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.21
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.5
         upper limit
    38.4

    Secondary: Maintenance Period Ranked Secondary Endpoint 7: Percentage of Week 8 Remitters (Per FMS) With Steroid Usage at Baseline and Steroid Free at Least 90 Days and With Clinical Remission (Per FMS) at Week 52

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    End point title
    Maintenance Period Ranked Secondary Endpoint 7: Percentage of Week 8 Remitters (Per FMS) With Steroid Usage at Baseline and Steroid Free at Least 90 Days and With Clinical Remission (Per FMS) at Week 52
    End point description
    The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy [confirmed by a central reader], and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). Negative changes indicate improvement. Week 8 remitters are defined as participants with clinical remission (per FMS) at Week 8. Clinical remission is defined as a FMS ≤ 2 with no subscore > 1. ITT-RM Population: all participants in the ITT population who achieved Week 8 remission based on the FMS utilizing the endoscopy subscore provided by the central reader. Participants with steroid usage. Non-responder imputation.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Maintenance (Main Study): M-SD Maintenance (Main Study): M-HD Maintenance (Main Study + Japan Sub-study): M-SD Maintenance (Main Study + Japan Sub-study): M-HD
    Number of subjects analysed
    26
    27
    32
    35
    Units: percentage of participants
        number (not applicable)
    34.6
    55.6
    37.5
    51.4
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for induction treatment regimen and week 8 remission status.
    Comparison groups
    Maintenance (Main Study): M-SD v Maintenance (Main Study): M-HD
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.151
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    20
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.3
         upper limit
    47.3
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for induction treatment regimen and week 8 remission status.
    Comparison groups
    Maintenance (Main Study + Japan Sub-study): M-SD v Maintenance (Main Study + Japan Sub-study): M-HD
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.299
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    12.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11.3
         upper limit
    36.8

    Secondary: Maintenance Period Ranked Secondary Endpoint 8: Percentage of Week 8 Responders (Per FMS) With IBDQ Response (Increase of IBDQ ≥ 16 From Baseline) at Week 52

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    End point title
    Maintenance Period Ranked Secondary Endpoint 8: Percentage of Week 8 Responders (Per FMS) With IBDQ Response (Increase of IBDQ ≥ 16 From Baseline) at Week 52
    End point description
    The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy [confirmed by a central reader], and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). Negative changes indicate improvement. Week 8 responders are defined as participants with a decrease in FMS of ≥ 3 points and ≥ 30% from Baseline plus a decrease in the rectal bleeding subscore (RBS) ≥ 1 or an absolute RBS ≤ 1. The IBDQ is a self-administered 32-item questionnaire to evaluate quality of life across 4 dimensional scores: bowel, systemic, social and emotional. Responses to each question range from 1 (severe problem) to 7 (normal health). Total IBDQ score is the sum of responses to the individual IBDQ questions, and ranges from 32 to 224 with higher scores indicating a better quality of life.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Maintenance (Main Study): M-SD Maintenance (Main Study): M-HD Maintenance (Main Study + Japan Sub-study): M-SD Maintenance (Main Study + Japan Sub-study): M-HD
    Number of subjects analysed
    145 [5]
    152 [6]
    163 [7]
    175 [8]
    Units: percentage of participants
        number (not applicable)
    62.1
    66.4
    62.6
    65.7
    Notes
    [5] - ITT-Responder population (ITT-RP). Non-responder imputation.
    [6] - ITT-Responder population (ITT-RP). Non-responder imputation.
    [7] - ITT-Responder population (ITT-RP). Non-responder imputation.
    [8] - ITT-Responder population (ITT-RP). Non-responder imputation.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for induction treatment regimen and week 8 remission status.
    Comparison groups
    Maintenance (Main Study): M-SD v Maintenance (Main Study): M-HD
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.422
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    4.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.4
         upper limit
    15.3
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for induction treatment regimen and week 8 remission status.
    Comparison groups
    Maintenance (Main Study + Japan Sub-study): M-SD v Maintenance (Main Study + Japan Sub-study): M-HD
    Number of subjects included in analysis
    338
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.513
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    3.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.8
         upper limit
    13.6

    Secondary: Maintenance Period Ranked Secondary Endpoint 9: Percentage of Week 8 Non-Responders With Clinical Remission (Per FMS) at Week 52

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    End point title
    Maintenance Period Ranked Secondary Endpoint 9: Percentage of Week 8 Non-Responders With Clinical Remission (Per FMS) at Week 52
    End point description
    The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy [confirmed by a central reader], and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). Negative changes indicate improvement. Week 8 non-responders are defined as participants not meeting the criteria of response (defined as a decrease in FMS of ≥ 3 points and ≥ 30% from baseline, plus a decrease in the rectal bleeding subscore [RBS] ≥ 1 or an absolute RBS ≤ 1) at Week 8. Clinical remission is defined as a FMS ≤ 2 with no subscore > 1. ITT-Non-Responder (ITT-NRP) Population: all participants in ITT who did not achieve Week 8 response based on the Full Mayo Score utilizing the endoscopy subscore provided by the central reader. Non-responder imputation.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Maintenance (Main Study): M-SD Maintenance (Main Study): M-HD Maintenance (Main Study + Japan Sub-study): M-SD Maintenance (Main Study + Japan Sub-study): M-HD
    Number of subjects analysed
    157
    152
    182
    175
    Units: percentage of participants
        number (not applicable)
    12.1
    15.8
    12.1
    16.0
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for induction treatment regimen and week 8 remission status.
    Comparison groups
    Maintenance (Main Study): M-SD v Maintenance (Main Study): M-HD
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.351
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    3.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.1
         upper limit
    11.4
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for induction treatment regimen and week 8 remission status.
    Comparison groups
    Maintenance (Main Study + Japan Sub-study): M-SD v Maintenance (Main Study + Japan Sub-study): M-HD
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.292
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    3.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.3
         upper limit
    11.1

    Secondary: Maintenance Period Ranked Secondary Endpoint 10: Percentage of Week 8 Non-Remitters With Clinical Remission (Per FMS) at Week 52

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    End point title
    Maintenance Period Ranked Secondary Endpoint 10: Percentage of Week 8 Non-Remitters With Clinical Remission (Per FMS) at Week 52
    End point description
    The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy [confirmed by a central reader], and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). Negative changes indicate improvement. Week 8 non-remitters are defined as participants not meeting the criteria of clinical remission at Week 8. Clinical remission is defined as a FMS ≤ 2 with no subscore > 1. ITT-Non-Remitter (ITT-NRM) Population: all participants in ITT who did not achieve Week 8 remission based on the FMS utilizing the endoscopy subscore provided by the central reader. Non-responder imputation.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Maintenance (Main Study): M-SD Maintenance (Main Study): M-HD Maintenance (Main Study + Japan Sub-study): M-SD Maintenance (Main Study + Japan Sub-study): M-HD
    Number of subjects analysed
    265
    262
    300
    298
    Units: percentage of participants
        number (not applicable)
    17.4
    22.9
    17.0
    23.8
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for induction treatment regimen and week 8 remission status.
    Comparison groups
    Maintenance (Main Study): M-SD v Maintenance (Main Study): M-HD
    Number of subjects included in analysis
    527
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.121
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    5.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.4
         upper limit
    12.1
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for induction treatment regimen and week 8 remission status.
    Comparison groups
    Maintenance (Main Study + Japan Sub-study): M-SD v Maintenance (Main Study + Japan Sub-study): M-HD
    Number of subjects included in analysis
    598
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.046
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    6.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.1
         upper limit
    12.8

    Secondary: Maintenance Period Ranked Secondary Endpoint 11: Percentage of Week 8 Responders (Per FMS) With Endoscopic Subscore of 0 at Week 52

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    End point title
    Maintenance Period Ranked Secondary Endpoint 11: Percentage of Week 8 Responders (Per FMS) With Endoscopic Subscore of 0 at Week 52
    End point description
    The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy [confirmed by a central reader], and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). Negative changes indicate improvement. Week 8 responders (per Full Mayo score) are defined as participants with a decrease in Full Mayo score of ≥ 3 points and ≥ 30% from Baseline plus a decrease in the rectal bleeding subscore (RBS) ≥ 1 or an absolute RBS ≤ 1. Endoscopic remission is defined as an endoscopy subscore of 0. ITT-RP: participants in the Induction ITT population who achieve Week 8 response based on the FMS utilizing the endoscopy subscore provided by the central reader. Participants who were remitters at Week 8. Non-responder imputation.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Maintenance (Main Study): M-SD Maintenance (Main Study): M-HD Maintenance (Main Study + Japan Sub-study): M-SD Maintenance (Main Study + Japan Sub-study): M-HD
    Number of subjects analysed
    145
    152
    163
    175
    Units: percentage of participants
        number (not applicable)
    27.6
    35.5
    27.0
    35.4
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for induction treatment regimen and week 8 remission status.
    Comparison groups
    Maintenance (Main Study): M-SD v Maintenance (Main Study): M-HD
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.159
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    7.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.9
         upper limit
    17.9
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for induction treatment regimen and week 8 remission status.
    Comparison groups
    Maintenance (Main Study + Japan Sub-study): M-SD v Maintenance (Main Study + Japan Sub-study): M-HD
    Number of subjects included in analysis
    338
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.109
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.8
         upper limit
    17.9

    Secondary: Maintenance Period Ranked Secondary Endpoint 12: Percentage of Week 8 Remitters (Per FMS) With Endoscopic Subscore of 0 at Week 52

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    End point title
    Maintenance Period Ranked Secondary Endpoint 12: Percentage of Week 8 Remitters (Per FMS) With Endoscopic Subscore of 0 at Week 52
    End point description
    The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy [confirmed by a central reader], and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). Negative changes indicate improvement. Week 8 remitters are defined as participants with clinical remission (per FMS) at Week 8. Clinical remission is defined as a FMS ≤ 2 with no subscore > 1. Endoscopic remission is defined as an endoscopy subscore of 0. ITT-Remitter (ITT-RM) Population: all participants in ITT who achieved Week 8 remission based on the Full Mayo Score utilizing the endoscopy subscore provided by the central reader. Non-responder imputation.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Maintenance (Main Study): M-SD Maintenance (Main Study): M-HD Maintenance (Main Study + Japan Sub-study): M-SD Maintenance (Main Study + Japan Sub-study): M-HD
    Number of subjects analysed
    37
    42
    45
    52
    Units: percentage of participants
        number (not applicable)
    45.9
    47.6
    42.2
    44.2
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for induction treatment regimen and week 8 remission status.
    Comparison groups
    Maintenance (Main Study): M-SD v Maintenance (Main Study): M-HD
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.903
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    1.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -21
         upper limit
    23.8
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for induction treatment regimen and week 8 remission status.
    Comparison groups
    Maintenance (Main Study + Japan Sub-study): M-SD v Maintenance (Main Study + Japan Sub-study): M-HD
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.901
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -18.8
         upper limit
    21.3

    Secondary: Maintenance Period Ranked Secondary Endpoint 13: Percentage of Week 8 Responders (Per FMS) With Response in IBDQ Bowel Symptom Domain at Week 52

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    End point title
    Maintenance Period Ranked Secondary Endpoint 13: Percentage of Week 8 Responders (Per FMS) With Response in IBDQ Bowel Symptom Domain at Week 52
    End point description
    The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy [confirmed by a central reader], and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). Negative changes indicate improvement. Week 8 responders are defined as participants with a decrease in FMS of ≥ 3 points and ≥ 30% from Baseline plus a decrease in the rectal bleeding subscore [RBS] ≥ 1 or an absolute RBS ≤ 1. The IBDQ is a self-administered 32-item questionnaire to evaluate quality of life across 4 dimensional scores: bowel, systemic, social and emotional. Responses to each question range from 1 (severe problem) to 7 (normal health). Bowel Symptom domain score range is 10 (severe problem) to 70 (normal health). Response is defined as increase of Bowel Symptom domain score ≥ 6 from baseline.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Maintenance (Main Study): M-SD Maintenance (Main Study): M-HD Maintenance (Main Study + Japan Sub-study): M-SD Maintenance (Main Study + Japan Sub-study): M-HD
    Number of subjects analysed
    145 [9]
    152 [10]
    163 [11]
    175 [12]
    Units: percentage of participants
        number (not applicable)
    62.1
    69.7
    62.6
    71.4
    Notes
    [9] - ITT-Responder population (ITT-RP). Non-responder imputation.
    [10] - ITT-Responder population (ITT-RP). Non-responder imputation.
    [11] - ITT-Responder population (ITT-RP). Non-responder imputation.
    [12] - ITT-Responder population (ITT-RP). Non-responder imputation.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for induction treatment regimen and week 8 remission status.
    Comparison groups
    Maintenance (Main Study): M-SD v Maintenance (Main Study): M-HD
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.16
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    7.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3
         upper limit
    18.4
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for induction treatment regimen and week 8 remission status.
    Comparison groups
    Maintenance (Main Study + Japan Sub-study): M-SD v Maintenance (Main Study + Japan Sub-study): M-HD
    Number of subjects included in analysis
    338
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.076
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    9.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.9
         upper limit
    19.1

    Secondary: Maintenance Period Ranked Secondary Endpoint 14: Percentage of Week 8 Responders (Per FMS) With Response in IBDQ Fatigue Item at Week 52

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    End point title
    Maintenance Period Ranked Secondary Endpoint 14: Percentage of Week 8 Responders (Per FMS) With Response in IBDQ Fatigue Item at Week 52
    End point description
    The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy [confirmed by a central reader], and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). Negative changes indicate improvement. Week 8 responders are defined as participants with a decrease in FMS of ≥ 3 points and ≥ 30% from Baseline plus a decrease in the rectal bleeding subscore (RBS) ≥ 1 or an absolute RBS ≤ 1. The IBDQ is a self-administered 32-item questionnaire to evaluate quality of life across 4 dimensional scores: bowel, systemic, social and emotional. Responses to each question range from 1 (severe problem) to 7 (normal health). Response in IBDQ fatigue item (range 1 [severe problem] to 7 [normal health]) is defined as increase of IBDQ fatigue item ≥ 1 from baseline.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Maintenance (Main Study): M-SD Maintenance (Main Study): M-HD Maintenance (Main Study + Japan Sub-study): M-SD Maintenance (Main Study + Japan Sub-study): M-HD
    Number of subjects analysed
    145 [13]
    152 [14]
    163 [15]
    175 [16]
    Units: percentage of participants
        number (not applicable)
    53.8
    61.2
    55.2
    59.4
    Notes
    [13] - ITT-Responder population (ITT-RP). Non-responder imputation.
    [14] - ITT-Responder population (ITT-RP). Non-responder imputation.
    [15] - ITT-Responder population (ITT-RP). Non-responder imputation.
    [16] - ITT-Responder population (ITT-RP). Non-responder imputation.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for induction treatment regimen and week 8 remission status.
    Comparison groups
    Maintenance (Main Study): M-SD v Maintenance (Main Study): M-HD
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.207
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    7.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4
         upper limit
    18.6
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Adjusted risk difference, 95% confidence interval for the difference in the proportions between the treatment groups and P-value were calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for induction treatment regimen and week 8 remission status.
    Comparison groups
    Maintenance (Main Study + Japan Sub-study): M-SD v Maintenance (Main Study + Japan Sub-study): M-HD
    Number of subjects included in analysis
    338
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.44
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference
    Point estimate
    4.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.4
         upper limit
    14.8

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    See time frame specifics detailed for each reporting group in their respective descriptions below. Treatment-emergent adverse events (TEAEs) are presented.
    Adverse event reporting additional description
    Participants were contacted 70 days following study drug discontinuation for an assessment of any new or ongoing adverse events, except those participants who continued on adalimumab therapy after the end of study participation.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Induction (Main Study + Japan Substudy): I-SD
    Reporting group description
    Induction Standard Dose: Double-blind adalimumab regimen of 160 mg at Week 0 followed by 80 mg at Week 2, 40 mg at Week 4, and 40 mg at Week 6. TEAEs during induction period: events with an onset date on or after first dose date of study drug in induction period and up to 70 days after last dose date of the study drug in induction period and prior to first dose date of study drug in maintenance period. Mean duration of treatment was 57.5 days.

    Reporting group title
    Induction (Main Study + Japan Substudy): I-HD
    Reporting group description
    Induction Higher Dose: Double-blind adalimumab regimen of 160 mg at Weeks 0, 1, 2, and 3 followed by 40 mg at Week 4 and 40 mg at Week 6. TEAEs during induction period: events with an onset date on or after first dose date of study drug in induction period and up to 70 days after last dose date of the study drug in induction period and prior to first dose date of study drug in maintenance period. Mean duration of treatment was 55.0 days.

    Reporting group title
    Maintenance (Main Study + Japan Sub-study): M-SD
    Reporting group description
    Maintenance Standard Dose: Double-blind adalimumab 40 mg every other week (eow), for 44 weeks. TEAEs during maintenance period: events with an onset date on or after first dose date of study drug in maintenance period and up to 70 days after the last dose date of the study drug in maintenance period. Mean duration of treatment was 251.5 days.

    Reporting group title
    Maintenance (Main Study + Japan Sub-study): M-HD
    Reporting group description
    Maintenance Higher Dose: Double-blind adalimumab 40 mg every week (ew) for 44 weeks. TEAEs during maintenance period: events with an onset date on or after first dose date of study drug in maintenance period and up to 70 days after the last dose date of the study drug in maintenance period. Mean duration of treatment was 263.1 days.

    Reporting group title
    Maintenance (Main Study): TDM Regimen
    Reporting group description
    Double-blind adalimumab 40 mg eow at Week 8 and Week 10, with possible dose adjustments at Weeks 12, 24, and 37 based on criteria assessing blinded adalimumab serum concentration and rectal bleeding subscore (RBS) assessments. TEAEs during maintenance period: events with an onset date on or after first dose date of study drug in maintenance period and up to 70 days after the last dose date of the study drug in maintenance period. Mean duration of treatment was 255.9 days.

    Serious adverse events
    Induction (Main Study + Japan Substudy): I-SD Induction (Main Study + Japan Substudy): I-HD Maintenance (Main Study + Japan Sub-study): M-SD Maintenance (Main Study + Japan Sub-study): M-HD Maintenance (Main Study): TDM Regimen
    Total subjects affected by serious adverse events
         subjects affected / exposed
    22 / 573 (3.84%)
    19 / 379 (5.01%)
    44 / 345 (12.75%)
    44 / 350 (12.57%)
    15 / 151 (9.93%)
         number of deaths (all causes)
    2
    0
    2
    2
    0
         number of deaths resulting from adverse events
    1
    0
    2
    2
    0
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    THROMBOPHLEBITIS
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    Surgical and medical procedures
    WOUND DRAINAGE
         subjects affected / exposed
    1 / 573 (0.17%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    BLADDER CANCER
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    FIBROMATOSIS
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MALIGNANT MELANOMA
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    MALIGNANT MELANOMA IN SITU
         subjects affected / exposed
    0 / 573 (0.00%)
    1 / 379 (0.26%)
    0 / 345 (0.00%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NON-SMALL CELL LUNG CANCER
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    OESOPHAGEAL ADENOCARCINOMA
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    SQUAMOUS CELL CARCINOMA OF THE CERVIX
         subjects affected / exposed
    0 / 573 (0.00%)
    1 / 379 (0.26%)
    0 / 345 (0.00%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UTERINE LEIOMYOMA
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    General disorders and administration site conditions
    GAIT DISTURBANCE
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    PYREXIA
         subjects affected / exposed
    1 / 573 (0.17%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    BINGE DRINKING
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    0 / 350 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    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
    BIPOLAR DISORDER
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    Reproductive system and breast disorders
    PROSTATOMEGALY
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    Injury, poisoning and procedural complications
    HUMERUS FRACTURE
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MENISCUS INJURY
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    PATELLA FRACTURE
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    POST PROCEDURAL HAEMORRHAGE
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    0 / 350 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    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
    RADIUS FRACTURE
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    RIB FRACTURE
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    UPPER LIMB FRACTURE
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    WEIGHT DECREASED
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    Cardiac disorders
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    CARDIAC ARREST
         subjects affected / exposed
    1 / 573 (0.17%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CARDIAC FAILURE CONGESTIVE
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    CORONARY ARTERY DISEASE
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    MYOCARDIAL ISCHAEMIA
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    Respiratory, thoracic and mediastinal disorders
    EMPHYSEMA
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NASAL POLYPS
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    NASAL SEPTUM DEVIATION
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    PULMONARY EMBOLISM
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    2 / 350 (0.57%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    SINUS POLYP
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    2 / 573 (0.35%)
    3 / 379 (0.79%)
    1 / 345 (0.29%)
    3 / 350 (0.86%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 2
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    IRON DEFICIENCY ANAEMIA
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    LYMPHADENOPATHY
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    THROMBOCYTOSIS
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    Nervous system disorders
    ALTERED STATE OF CONSCIOUSNESS
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHRONIC INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    0 / 350 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    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
    HYPOAESTHESIA
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ISCHAEMIC STROKE
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    0 / 350 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    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
    MONONEUROPATHY
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    EYELID PTOSIS
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OPTIC ATROPHY
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    1 / 573 (0.17%)
    1 / 379 (0.26%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ANOGENITAL DYSPLASIA
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    COLITIS
         subjects affected / exposed
    1 / 573 (0.17%)
    0 / 379 (0.00%)
    2 / 345 (0.58%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COLITIS ULCERATIVE
         subjects affected / exposed
    13 / 573 (2.27%)
    12 / 379 (3.17%)
    16 / 345 (4.64%)
    18 / 350 (5.14%)
    6 / 151 (3.97%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 17
    0 / 16
    1 / 21
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    0 / 573 (0.00%)
    1 / 379 (0.26%)
    0 / 345 (0.00%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DUODENAL ULCER PERFORATION
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    HAEMORRHOIDS
         subjects affected / exposed
    1 / 573 (0.17%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LARGE INTESTINAL STENOSIS
         subjects affected / exposed
    1 / 573 (0.17%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MALLORY-WEISS SYNDROME
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    0 / 350 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    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
    NAUSEA
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    PANCREATITIS ACUTE
         subjects affected / exposed
    1 / 573 (0.17%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RECTAL HAEMORRHAGE
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    SMALL INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    0 / 350 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    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
    UPPER GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    0 / 350 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    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
    VOMITING
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    Renal and urinary disorders
    HAEMATURIA
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    NEPHROTIC SYNDROME
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RENAL FAILURE
         subjects affected / exposed
    1 / 573 (0.17%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    URINARY RETENTION
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    0 / 350 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    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
    Hepatobiliary disorders
    BILE DUCT STONE
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    0 / 350 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    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
    HEPATITIS
         subjects affected / exposed
    1 / 573 (0.17%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PORTOSPLENOMESENTERIC VENOUS THROMBOSIS
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    0 / 350 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    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
    Skin and subcutaneous tissue disorders
    ERYTHEMA NODOSUM
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    0 / 350 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    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
    EXCESSIVE SKIN
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    LINEAR IGA DISEASE
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NIGHT SWEATS
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    PEMPHIGOID
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    0 / 350 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    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
    SUBCORNEAL PUSTULAR DERMATOSIS
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    2 / 350 (0.57%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OSTEOARTHRITIS
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    PAIN IN EXTREMITY
         subjects affected / exposed
    1 / 573 (0.17%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DIABETES MELLITUS
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    HYPONATRAEMIA
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    HYPOVOLAEMIA
         subjects affected / exposed
    1 / 573 (0.17%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    APPENDICITIS
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    BRONCHITIS
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    0 / 350 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    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
    CLOSTRIDIUM DIFFICILE INFECTION
         subjects affected / exposed
    1 / 573 (0.17%)
    0 / 379 (0.00%)
    3 / 345 (0.87%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CYTOMEGALOVIRUS COLITIS
         subjects affected / exposed
    1 / 573 (0.17%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ERYSIPELAS
         subjects affected / exposed
    0 / 573 (0.00%)
    1 / 379 (0.26%)
    0 / 345 (0.00%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    EXTERNAL EAR CELLULITIS
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROENTERITIS
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    GASTROINTESTINAL INFECTION
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    HERPES ZOSTER
         subjects affected / exposed
    0 / 573 (0.00%)
    1 / 379 (0.26%)
    0 / 345 (0.00%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INFECTION
         subjects affected / exposed
    1 / 573 (0.17%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OTITIS EXTERNA
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PELVIC INFLAMMATORY DISEASE
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    PERINEAL ABSCESS
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    PERITONSILLAR ABSCESS
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    PNEUMONIA
         subjects affected / exposed
    0 / 573 (0.00%)
    1 / 379 (0.26%)
    2 / 345 (0.58%)
    4 / 350 (1.14%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 2
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    SEPSIS
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    0 / 350 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    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
    STERNITIS
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    TUBERCULOSIS
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TUBERCULOSIS OF INTRATHORACIC LYMPH NODES
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    1 / 350 (0.29%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    VARICELLA
         subjects affected / exposed
    1 / 573 (0.17%)
    0 / 379 (0.00%)
    0 / 345 (0.00%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VIRAL INFECTION
         subjects affected / exposed
    0 / 573 (0.00%)
    0 / 379 (0.00%)
    1 / 345 (0.29%)
    0 / 350 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Induction (Main Study + Japan Substudy): I-SD Induction (Main Study + Japan Substudy): I-HD Maintenance (Main Study + Japan Sub-study): M-SD Maintenance (Main Study + Japan Sub-study): M-HD Maintenance (Main Study): TDM Regimen
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    112 / 573 (19.55%)
    74 / 379 (19.53%)
    140 / 345 (40.58%)
    141 / 350 (40.29%)
    47 / 151 (31.13%)
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    48 / 573 (8.38%)
    23 / 379 (6.07%)
    17 / 345 (4.93%)
    22 / 350 (6.29%)
    8 / 151 (5.30%)
         occurrences all number
    62
    32
    19
    36
    9
    Gastrointestinal disorders
    COLITIS ULCERATIVE
         subjects affected / exposed
    18 / 573 (3.14%)
    20 / 379 (5.28%)
    60 / 345 (17.39%)
    47 / 350 (13.43%)
    23 / 151 (15.23%)
         occurrences all number
    18
    22
    70
    58
    29
    Skin and subcutaneous tissue disorders
    RASH
         subjects affected / exposed
    10 / 573 (1.75%)
    11 / 379 (2.90%)
    11 / 345 (3.19%)
    20 / 350 (5.71%)
    4 / 151 (2.65%)
         occurrences all number
    10
    11
    13
    24
    6
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    18 / 573 (3.14%)
    11 / 379 (2.90%)
    23 / 345 (6.67%)
    23 / 350 (6.57%)
    5 / 151 (3.31%)
         occurrences all number
    19
    11
    27
    27
    5
    Infections and infestations
    NASOPHARYNGITIS
         subjects affected / exposed
    29 / 573 (5.06%)
    16 / 379 (4.22%)
    47 / 345 (13.62%)
    46 / 350 (13.14%)
    11 / 151 (7.28%)
         occurrences all number
    34
    18
    61
    57
    20
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    6 / 573 (1.05%)
    3 / 379 (0.79%)
    22 / 345 (6.38%)
    19 / 350 (5.43%)
    9 / 151 (5.96%)
         occurrences all number
    6
    3
    25
    20
    10

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Jun 2014
    Major changes included: updated the Study Designated Physician and contact information, clarified reference to the rectal bleeding subscore; updated biopsy language and clarified endoscopy to be colonoscopy or flexible sigmoidoscopy; added restratification details; updated inclusion criteria (IC) 4 to clarify methotrexate usage for entry into the study; updated IC 5 with additional clarification on the definition of intolerance of infliximab (IFX) for entry purposes; updated Ethics Committee (EC) 10 to add the definition of excluded medications; updated to clarify EC 16 also applied to subjects who previously received fecal microbial transplantation; updated to clarify that EC 19 also applied to subjects who previously received adalimumab; added trade name of vedolizumab; concomitant therapy updated to clarify the need for any immunosuppressants taken at Baseline to remain at stable doses throughout the study and to clarify that the taper schedule was a proposal and to clarify how changes in ulcerative colitis (UC) related medications during the study were to be handled with respect to efficacy and safety assessment; prohibited therapy updated to address marijuana use due to possible interference with subject self-assessments and align with clarification made to EC 16; updated timepoints as it is required to have the stool sample taken prior to bowel prep so this should be done during the Screening period not the Baseline visit; clarified procedures for stool collection of samples; provided further guidance around Unscheduled Visits; clarified that sites do not need to send endoscopy videos for central review if the site determines that the subject does not meet IC of an endoscopy subscore of 2 or 3 and additional information added for clarification of what sites should record in the electronic case report form (eCRF);
    02 Jun 2014
    (continued) updated to clarify collection requirements for the additional biopsy samples taken for histologic assessment, clarified that if a biopsy is taken for UC confirmation it will be processed, read locally, and added language to specify that the additional biopsies taken for histologic samples will not be read in real time by the central laboratory; updated requirements such that any positive test whether purified protein derivative (tuberculin) or interferon-γ release assays (IGRA) will be considered tuberculosis (TB) positive; added additional direction for chest x-ray (CXR) documentation; provided clarification on what were considered the baseline laboratory test values; added pH to urinalysis under clinical laboratory testing, updated to reflect that dipstick urinalyses are done and only sent on to central lab for microscopy efficacy variables will be based on the central reading endoscopy subscore and the procedure for handling missing data for continuous variables are described in the SAP; specified the endpoints for Interim Analysis are for Week 8; details added about Week 8 Mayo score will be utilizing the endoscopy subscore provided by the site; Appendix edited to allow determination of loss of response or intolerance to IFX to be based on the investigator's assessment; and added clarification that for the Japan Substudy, Unscheduled Visit procedures are only needed when subjects are coming in for assessment of their UC and removed details about immediate sending of PK samples at specific weeks because Japan Substudy does not have the TDM arm. when the dipstick is abnormal; provided the definition of "remission" and "response;" clarified that the presence of extraintestinal manifestations over time will be assessed as a nonranked secondary endpoint;
    02 Jun 2014
    (continued) efficacy variables will be based on the central reading endoscopy subscore and the procedure for handling missing data for continuous variables are described in the SAP; specified the endpoints for Interim Analysis are for Week 8; details added about Week 8 Mayo score will be utilizing the endoscopy subscore provided by the site; Appendix edited to allow determination of loss of response or intolerance to IFX to be based on the investigator's assessment; and added clarification that for the Japan Substudy, Unscheduled Visit procedures are only needed when subjects are coming in for assessment of their UC and removed details about immediate sending of PK samples at specific weeks because Japan Substudy does not have the TDM arm.
    03 Dec 2015
    Major changes included: added a secondary Sponsor/Emergency contact for sites in Japan; clarified language regarding stool collection instructions for the subject; clarified that PK testing is to remain blinded and local pharmacokinetic (PK) testing is not be performed; updated the list of approved adalimumab indications; clarified procedures for corticosteroid taper at Week 4; clarified sample collection for pharmacogenetic samples; clarified IC 4 regarding required 6 thioguanine nucleotide (TGN) level; clarified TB testing procedures at screening; clarified regarding shipment of adalimumab samples during specific weeks; updated language regarding adverse event (AE) reporting and the 24 hour AbbVie Medical Escalation Hotline; updated language regarding protocol deviations; added language regarding sample withdrawal; added language around public disclosure; and added Japan requirements for reporting AEs and Japan's Regional Medical Monitor contact information.
    16 Jun 2016
    Major changes included: updated to include updated names of statistical groups due to statistical changes in protocol; updated terminology from "arm" to "regimen," "dosing regimen" or "treatment group" as appropriate and introduce terminology Induction Study and Maintenance Study; added clarification that both Main and Substudy have an Induction Study and a Maintenance Study; updated with new study enrollment numbers; added language to clarify collection of pharmacogenetic sample; clarified corticosteroid language; added clarification to serum concentration in TDM regimen to mean adalimumab serum concentration; added clarification to the results when testing for hepatitis B surface antibody; updated to convey that 840 subjects will be enrolled at up to 125 sites in the Main Study; updates made to total number of PK samples; clarified concomitant therapy assessment rules; clarified language on how previous TB medications should be collected and added to the eCRF; primary, secondary, and additional variables explained for the Induction Study and Maintenance Study; treatments administered were updated to reflect Week 52 or Premature Discontinuation; treatment compliance clarified that instruction is for home dosing; added clarification that medications for AEs/serious adverse events (SAEs) should be collected during 70-day follow-up phone call and that all 70 day follow-up phone call data is to be entered in the eCRF and recorded in source documentation; additional information added on the SAP between the Main Study and Substudy; added language about the method and interpretation between the dosing regimens; clarified statistical analysis delineating between Induction and Maintenance Studies; updated noting that interim analysis may be performed via a database cut; updated to provide scientific justification of the increase in the number of subjects; updated power of statistical analyses;
    16 Jun 2016
    (continued) updated to collect date of last study drug administration, collect reason if 70 day follow-up call was not performed, and added additional help text; deleted Japan Substudy planned methods of statistical analysis from Appendix K; and interim analyses for the Japan Substudy was updated noting that interim analysis will be performed only if performed for the Main Study.

    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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