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    Clinical Trial Results:
    Phase III, Randomized, Multicenter Double-Blind, Double Dummy Study to Evaluate the Efficacy and Safety of Etrolizumab Compared With Infliximab in Patients With Moderate to Severe Active Ulcerative Colitis Who Are Naive to TNF Inhibitors

    Summary
    EudraCT number
    		 2013-004282-14
    Trial protocol
    		 GB   DE   CZ   AT   PT   NL   NO   ES   BE   IT   HU   FR  
    Global end of trial date
    23 Jun 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Jul 2021
    First version publication date
    04 Jul 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GA29103
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02136069
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F.Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F.Hoffmann-La Roche AG, F.Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F.Hoffmann-La Roche AG, F.Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Jun 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jun 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of etrolizumab subcutaneously [SC] every 4 weeks (Q4W) compared with infliximab in achieving both clinical response at Week 10 and clinical remission at Week 54 in patients with ulcerative colitis (UC).
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Dec 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
    Austria: 2
    Country: Number of subjects enrolled
    Belgium: 21
    Country: Number of subjects enrolled
    Canada: 22
    Country: Number of subjects enrolled
    Switzerland: 8
    Country: Number of subjects enrolled
    Czechia: 70
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    France: 18
    Country: Number of subjects enrolled
    United Kingdom: 34
    Country: Number of subjects enrolled
    Hungary: 39
    Country: Number of subjects enrolled
    Israel: 12
    Country: Number of subjects enrolled
    Italy: 57
    Country: Number of subjects enrolled
    Korea, Republic of: 58
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    Norway: 1
    Country: Number of subjects enrolled
    Portugal: 5
    Country: Number of subjects enrolled
    Romania: 14
    Country: Number of subjects enrolled
    Singapore: 2
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    South Africa: 5
    Worldwide total number of subjects
    397
    EEA total number of subjects
    256
    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)
    370
    From 65 to 84 years
    27
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 397 patients were randomized in a 1:1 ratio into the study and received treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Etrolizumab + Placebo (IV)
    Arm description
    		 Participants will receive ertolizumab (SC) Q4W until Week 52 along with placebo matched to infliximab as IV infusion until Week 46.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Etrolizumab
    Investigational medicinal product code
    Other name
    PRO145223, RO5490261 and RG7413
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    105 mg administered by subcutaneous (SC) injection once every 4 weeks (Q4W)

    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
    Etrolizumab matching placebo

    Arm title
    		 Infliximab + Placebo (Injection)
    Arm description
    		 Participants will receive IV infusion of infliximab at Weeks 0,2, and 6, then every 8 weeks until Week 46 partnered with placebo matched to etrolizumab by SC injection Q4W until Week 52.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Infliximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/kg administered by intravenous (IV) infusion

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Infliximab matching placebo

    Number of subjects in period 1
    		Etrolizumab + Placebo (IV) Infliximab + Placebo (Injection)
    Started
    199
    198
    Completed
    165
    170
    Not completed
    34
    28
         Adverse event, serious fatal
    -
    1
         Non-Compliance
    1
    -
         Physician decision
    5
    4
         Consent withdrawn by subject
    10
    11
         Adverse event, non-fatal
    6
    8
         UC flare-up
    1
    -
         Lost to follow-up
    1
    -
         Lack of efficacy
    10
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Etrolizumab + Placebo (IV)
    Reporting group description
    		 Participants will receive ertolizumab (SC) Q4W until Week 52 along with placebo matched to infliximab as IV infusion until Week 46.

    Reporting group title
    Infliximab + Placebo (Injection)
    Reporting group description
    		 Participants will receive IV infusion of infliximab at Weeks 0,2, and 6, then every 8 weeks until Week 46 partnered with placebo matched to etrolizumab by SC injection Q4W until Week 52.

    Reporting group values
    		 Etrolizumab + Placebo (IV) Infliximab + Placebo (Injection) Total
    Number of subjects
    		 199 198 397
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 181 189 370
        From 65-84 years
    		 18 9 27
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 40.0 ( 15.2 ) 39.5 ( 13.4 ) -
    Sex: Female, Male
    Units:
        Female
    		 81 66 147
        Male
    		 118 132 250
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 39 30 69
        Black or African American
    		 1 0 1
        White
    		 150 158 308
        Other
    		 9 10 19
    Mayo Clinic Score (MCS) ≤9 or ≥10 at Baseline
    Measure Description: Participants were stratified by concomitant treatment with corticosteroids (yes/no) at randomization, concomitant treatment with immunosuppressants (yes/no) at randomization, and disease activity measured during screening (MCS ≤9/MCS ≥10). The MCS ranges from 0 to 12 and is a composite of the four following assessments of disease activity: stool frequency subscore, rectal bleeding subscore, endoscopy subscore, and physician's global assessment (PGA) subscore. Each of the four assessments was rated with a score from 0 to 3, with higher scores indicating more severe disease.
    Units: Subjects
        MCS ≤9
    		 139 147 286
        MCS ≥10
    		 60 50 110
        Unknown
    		 0 1 1
    Baseline Treatment: None, Corticosteroids (CS) or Immunosuppressants (IS) Alone, or Both CS and IS
    Participants were stratified by concomitant treatment with corticosteroids (yes/no) at randomization, concomitant treatment with immunosuppressants (yes/no) at randomization, and disease activity measured during screening (MCS ≤9/MCS ≥10).
    Units: Subjects
        Corticosteroids (CS) Alone
    		 59 56 115
        Immunosuppressants (IS) Alone
    		 40 36 76
        Both CS and IS
    		 25 30 55
        None
    		 75 76 151

    End points

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    End points reporting groups
    Reporting group title
    Etrolizumab + Placebo (IV)
    Reporting group description
    		 Participants will receive ertolizumab (SC) Q4W until Week 52 along with placebo matched to infliximab as IV infusion until Week 46.

    Reporting group title
    Infliximab + Placebo (Injection)
    Reporting group description
    		 Participants will receive IV infusion of infliximab at Weeks 0,2, and 6, then every 8 weeks until Week 46 partnered with placebo matched to etrolizumab by SC injection Q4W until Week 52.

    Primary: Percentage of Participants with Both Clinical Response at Week 10 and Clinical Remission at Week 54, as determined by the Mayo Clinic Score (MCS)

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    End point title
    		 Percentage of Participants with Both Clinical Response at Week 10 and Clinical Remission at Week 54, as determined by the Mayo Clinic Score (MCS)
    End point description
    Mayo Clinic Score (MCS) is a composite of 4 assessments, each rated from 0-3: stool frequency, rectal bleeding, endoscopy, and physician’s global assessment. Higher scores indicate more severe disease. Clinical Response is MCS with ≥3-point decrease and 30% reduction from baseline as well as ≥1-point decrease in rectal bleeding subscore or an absolute rectal bleeding score of 0 or 1. Clinical Remission is MCS ≤2 with individual subscores ≤1.
    End point type
    Primary
    End point timeframe
    Week 10, Week 54
    End point values
    		 Etrolizumab + Placebo (IV) Infliximab + Placebo (Injection)
    Number of subjects analysed
    199
    198
    Units: percentage of participants
        number (not applicable)
    18.6
    19.7
    Statistical analysis title
    		 Etrolizumab vs. Infliximab
    Comparison groups
    Etrolizumab + Placebo (IV) v Infliximab + Placebo (Injection)
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.8114
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference in Remission Rates
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.7
         upper limit
    		 6.83

    Secondary: Percentage of Participants Achieving Clinical Remission at Week 10, Defined as MCS ≤2 with Individual Subscores ≤1

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    End point title
    		 Percentage of Participants Achieving Clinical Remission at Week 10, Defined as MCS ≤2 with Individual Subscores ≤1
    End point description
    MCS is a composite of 4 assessments, each rated from 0-3: stool frequency, rectal bleeding, endoscopy, and physician’s global assessment. Higher scores indicate more severe disease.
    End point type
    Secondary
    End point timeframe
    Week 10
    End point values
    		 Etrolizumab + Placebo (IV) Infliximab + Placebo (Injection)
    Number of subjects analysed
    199
    198
    Units: percentage of participants
        number (not applicable)
    20.6
    32.8
    Statistical analysis title
    		 Etrolizumab vs. Infliximab
    Comparison groups
    Etrolizumab + Placebo (IV) v Infliximab + Placebo (Injection)
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 = 0.1293 [2]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference in Remission Rates
    Point estimate
    -12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.5
         upper limit
    		 -3.26
    Notes
    [1] - with margin -12.5%
    [2] - p-values are not multiplicity adjusted

    Secondary: Percentage of Participants Achieving Clinical Remission at Week 54, as determined by the MCS

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    End point title
    		 Percentage of Participants Achieving Clinical Remission at Week 54, as determined by the MCS
    End point description
    Mayo Clinic Score (MCS) is a composite of 4 assessments, each rated from 0-3: stool frequency, rectal bleeding, endoscopy, and physician’s global assessment. Higher scores indicate more severe disease. Clinical Remission is MCS ≤2 with individual subscores ≤1.
    End point type
    Secondary
    End point timeframe
    Week 54
    End point values
    		 Etrolizumab + Placebo (IV) Infliximab + Placebo (Injection)
    Number of subjects analysed
    199
    198
    Units: percentage of participants
        number (not applicable)
    20.1
    23.7
    Statistical analysis title
    		 Etrolizumab vs. Infliximab
    Comparison groups
    Etrolizumab + Placebo (IV) v Infliximab + Placebo (Injection)
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4056 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference in Remission Rates
    Point estimate
    -3.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.53
         upper limit
    		 4.74
    Notes
    [3] - p-values are not multiplicity adjusted

    Secondary: Percentage of Participants Achieving Clinical Remission at Both Week 10 and Week 54, as determined by the MCS

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    End point title
    		 Percentage of Participants Achieving Clinical Remission at Both Week 10 and Week 54, as determined by the MCS
    End point description
    MCS is a composite of 4 assessments, each rated from 0-3: stool frequency, rectal bleeding, endoscopy, and physician’s global assessment. Higher scores indicate more severe disease. Clinical Remission is MCS ≤2 with individual subscores ≤1.
    End point type
    Secondary
    End point timeframe
    Week 10 and Week 54
    End point values
    		 Etrolizumab + Placebo (IV) Infliximab + Placebo (Injection)
    Number of subjects analysed
    199
    198
    Units: percentage of participants
        number (not applicable)
    10.6
    13.1
    Statistical analysis title
    		 Etrolizumab vs. Infliximab
    Comparison groups
    Etrolizumab + Placebo (IV) v Infliximab + Placebo (Injection)
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4591 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference in Remission Rates
    Point estimate
    -2.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.88
         upper limit
    		 4.14
    Notes
    [4] - p-value has not been adjusted for multiplicity

    Secondary: Percentage of Participants Achieving Clinical Remission at Week 54 Among Those with a Clinical Response at Week 10, as determined by the MCS

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    End point title
    		 Percentage of Participants Achieving Clinical Remission at Week 54 Among Those with a Clinical Response at Week 10, as determined by the MCS
    End point description
    MCS is a composite of 4 assessments, each rated from 0-3: stool frequency, rectal bleeding, endoscopy, and physician’s global assessment. Higher scores indicate more severe disease. Clinical Remission is MCS ≤2 with individual subscores ≤1. Clinical Response is MCS with ≥3-point decrease and 30% reduction from baseline as well as ≥1-point decrease in rectal bleeding subscore or an absolute rectal bleeding score of 0 or 1.
    End point type
    Secondary
    End point timeframe
    Week 10 and Week 54
    End point values
    		 Etrolizumab + Placebo (IV) Infliximab + Placebo (Injection)
    Number of subjects analysed
    199
    198
    Units: percentage of participants
        number (not applicable)
    37.8
    33.3
    Statistical analysis title
    		 Etrolizumab vs. Infliximab
    Comparison groups
    Etrolizumab + Placebo (IV) v Infliximab + Placebo (Injection)
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4196 [5]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference in Remission Rates
    Point estimate
    5.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.54
         upper limit
    		 18.13
    Notes
    [5] - p-value has not been adjusted for multiplicity

    Secondary: Percentage of Participants with Endoscopic Remission at Week 54, as determined by the MCS

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    End point title
    		 Percentage of Participants with Endoscopic Remission at Week 54, as determined by the MCS
    End point description
    MCS is a composite of 4 assessments, each rated from 0-3: stool frequency, rectal bleeding, endoscopy, and physician’s global assessment. Higher scores indicate more severe disease. Endoscopic Remission is Endoscopy subscore = 0.
    End point type
    Secondary
    End point timeframe
    Week 54
    End point values
    		 Etrolizumab + Placebo (IV) Infliximab + Placebo (Injection)
    Number of subjects analysed
    199
    198
    Units: percentage of participants
        number (not applicable)
    17.6
    22.7
    Statistical analysis title
    		 Etrolizumab vs. Infliximab
    Comparison groups
    Etrolizumab + Placebo (IV) v Infliximab + Placebo (Injection)
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2168 [6]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference in Remission Rates
    Point estimate
    -5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.84
         upper limit
    		 2.94
    Notes
    [6] - p-value has not been adjusted for multiplicity

    Secondary: Percentage of Participants Achieving Clinical Response at Week 10, as determined by the MCS

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    End point title
    		 Percentage of Participants Achieving Clinical Response at Week 10, as determined by the MCS
    End point description
    MCS is a composite of 4 assessments, each rated from 0-3: stool frequency, rectal bleeding, endoscopy, and physician’s global assessment. Higher scores indicate more severe disease. Clinical Response is MCS with ≥3-point decrease and 30% reduction from baseline as well as ≥1-point decrease in rectal bleeding subscore or an absolute rectal bleeding score of 0 or 1.
    End point type
    Secondary
    End point timeframe
    Week 10
    End point values
    		 Etrolizumab + Placebo (IV) Infliximab + Placebo (Injection)
    Number of subjects analysed
    199
    198
    Units: percentage of participants
        number (not applicable)
    49.2
    59.1
    Statistical analysis title
    		 Etrolizumab vs. Infliximab
    Comparison groups
    Etrolizumab + Placebo (IV) v Infliximab + Placebo (Injection)
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0564 [7]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference in Response Rates
    Point estimate
    -9.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.06
         upper limit
    		 0.29
    Notes
    [7] - p-value has not been adjusted for multiplicity

    Secondary: Percentage of Participants Achieving Clinical Response at Both Weeks 10 and 54, as determined by the MCS

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    End point title
    		 Percentage of Participants Achieving Clinical Response at Both Weeks 10 and 54, as determined by the MCS
    End point description
    MCS is a composite of 4 assessments, each rated from 0-3: stool frequency, rectal bleeding, endoscopy, and physician’s global assessment. Higher scores indicate more severe disease. Clinical Response is MCS with ≥3-point decrease and 30% reduction from baseline as well as ≥1-point decrease in rectal bleeding subscore or an absolute rectal bleeding score of 0 or 1.
    End point type
    Secondary
    End point timeframe
    Week 10, Week 54
    End point values
    		 Etrolizumab + Placebo (IV) Infliximab + Placebo (Injection)
    Number of subjects analysed
    199
    198
    Units: percentage of participants
        number (not applicable)
    23.1
    29.3
    Statistical analysis title
    		 Etrolizumab vs. Infliximab
    Comparison groups
    Etrolizumab + Placebo (IV) v Infliximab + Placebo (Injection)
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1729 [8]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference in Response Rates
    Point estimate
    -6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.51
         upper limit
    		 2.7
    Notes
    [8] - p-value has not been adjusted for multiplicity

    Secondary: Percentage of Participants that Achieve Clinical Remission Corticosteroid-Free at Week 54 (off Corticosteroid for at Least 24 Weeks Prior to Week 54) Among Those Who Were Receiving Corticosteroids at Baseline, as determined by the MCS

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    End point title
    		 Percentage of Participants that Achieve Clinical Remission Corticosteroid-Free at Week 54 (off Corticosteroid for at Least 24 Weeks Prior to Week 54) Among Those Who Were Receiving Corticosteroids at Baseline, as determined by the MCS
    End point description
    MCS is a composite of 4 assessments, each rated from 0-3: stool frequency, rectal bleeding, endoscopy, and physician’s global assessment. Higher scores indicate more severe disease. Clinical Remission is MCS ≤2 with individual subscores ≤1.
    End point type
    Secondary
    End point timeframe
    Week 54
    End point values
    		 Etrolizumab + Placebo (IV) Infliximab + Placebo (Injection)
    Number of subjects analysed
    84
    86
    Units: percentage of participants
        number (not applicable)
    15.5
    17.4
    Statistical analysis title
    		 Etrolizumab vs. Infliximab
    Comparison groups
    Etrolizumab + Placebo (IV) v Infliximab + Placebo (Injection)
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.8941 [9]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference in Remission Rates
    Point estimate
    -0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.01
         upper limit
    		 10.68
    Notes
    [9] - p-value has not been adjusted for multiplicity

    Secondary: Number of Participants with Adverse Events, Severity Determined According to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0)

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    End point title
    		 Number of Participants with Adverse Events, Severity Determined According to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0)
    End point description
    All adverse events (AEs) were graded for severity using the NCI-CTCAE v4.0. Any AE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. Not all grades are appropriate for all AEs; some AEs have fewer than 5 options. The terms "severe" and "serious" are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade.
    End point type
    Secondary
    End point timeframe
    Baseline until the end of study (up to 66 weeks)
    End point values
    		 Etrolizumab + Placebo (IV) Infliximab + Placebo (Injection)
    Number of subjects analysed
    199
    198
    Units: participants
        Grade 1
    42
    48
        Grade 2
    72
    74
        Grade 3
    35
    23
        Grade 4
    5
    5
        Grade 5
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events Leading to Study Drug Discontinuation

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    End point title
    		 Number of Participants with Adverse Events Leading to Study Drug Discontinuation
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline until the end of study (up to 66 weeks)
    End point values
    		 Etrolizumab + Placebo (IV) Infliximab + Placebo (Injection)
    Number of subjects analysed
    199
    198
    Units: participants
    29
    25
    No statistical analyses for this end point

    Secondary: Number of Participants with Infection-Related Adverse Events, Severity Determined According to the NCI CTCAE v4.0

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    End point title
    		 Number of Participants with Infection-Related Adverse Events, Severity Determined According to the NCI CTCAE v4.0
    End point description
    All AEs were graded for severity using the NCI-CTCAE v4.0. Any AE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. Not all grades are appropriate for all AEs; some AEs have fewer than 5 options. The terms "severe" and "serious" are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade.
    End point type
    Secondary
    End point timeframe
    Baseline until the end of study (up to 66 weeks)
    End point values
    		 Etrolizumab + Placebo (IV) Infliximab + Placebo (Injection)
    Number of subjects analysed
    199
    198
    Units: participants
        Grade 1
    28
    27
        Grade 2
    31
    29
        Grade 3
    8
    4
        Grade 4
    2
    1
        Grade 5
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Serious Infection-Related Adverse Events

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    End point title
    		 Number of Participants with Serious Infection-Related Adverse Events
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline until the end of study (up to 66 weeks)
    End point values
    		 Etrolizumab + Placebo (IV) Infliximab + Placebo (Injection)
    Number of subjects analysed
    199
    198
    Units: participants
    11
    3
    No statistical analyses for this end point

    Secondary: Number of Participants with Malignancies

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    End point title
    		 Number of Participants with Malignancies
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline until the end of study (up to 66 weeks)
    End point values
    		 Etrolizumab + Placebo (IV) Infliximab + Placebo (Injection)
    Number of subjects analysed
    199
    198
    Units: participants
    3
    1
    No statistical analyses for this end point

    Secondary: Number of Participants with Injection-Site Reactions, Severity Determined According to the NCI CTCAE v4.0

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    End point title
    		 Number of Participants with Injection-Site Reactions, Severity Determined According to the NCI CTCAE v4.0
    End point description
    All adverse events (AEs) were graded for severity using the NCI-CTCAE v4.0. Any AE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. Not all grades are appropriate for all AEs; some AEs have fewer than 5 options. The terms "severe" and "serious" are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade.
    End point type
    Secondary
    End point timeframe
    Baseline until the end of study (up to 66 weeks)
    End point values
    		 Etrolizumab + Placebo (IV) Infliximab + Placebo (Injection)
    Number of subjects analysed
    199
    198
    Units: participants
        Grade 1
    7
    5
        Grade 2
    0
    2
        Grade 3
    0
    0
        Grade 4
    0
    0
        Grade 5
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Hypersensitivity Reaction Events, Severity Determined According to the NCI CTCAE v4.0

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    End point title
    		 Number of Participants with Hypersensitivity Reaction Events, Severity Determined According to the NCI CTCAE v4.0
    End point description
    All adverse events (AEs) were graded for severity using the NCI-CTCAE v4.0. Any AE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. Not all grades are appropriate for all AEs; some AEs have fewer than 5 options. The terms "severe" and "serious" are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade.
    End point type
    Secondary
    End point timeframe
    Baseline until the end of study (up to 66 weeks)
    End point values
    		 Etrolizumab + Placebo (IV) Infliximab + Placebo (Injection)
    Number of subjects analysed
    199
    198
    Units: participants
        Grade 1
    0
    2
        Grade 2
    0
    7
        Grade 3
    0
    1
        Grade 4
    0
    2
        Grade 5
    0
    0
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Etrolizumab Serum Concentration

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    End point title
    		 Pharmacokinetics: Etrolizumab Serum Concentration [10]
    End point description
    End point type
    Secondary
    End point timeframe
    Weeks 2, 10, 12, 30, and 54
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Etrolizumab concentrations are provided only for the arm that received treatment with etrolizumab.
    End point values
    		 Etrolizumab + Placebo (IV)
    Number of subjects analysed
    153
    Units: microgram/milliliter
    arithmetic mean (standard deviation)
        Week 2
    7.64 ( 2.75 )
        Week 10
    12.0 ( 4.63 )
        Week 12
    6.92 ( 3.18 )
        Week 32
    13.9 ( 5.96 )
        Week 54
    13.2 ( 5.68 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Overall Score at Weeks 10, 30, and 54

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    End point title
    		 Change from Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Overall Score at Weeks 10, 30, and 54
    End point description
    The IBDQ is used to assess participant's health-related quality of life (QOL). The 32-item questionnaire contains four domains: bowel symptoms (10 items), systemic symptoms (5 items), emotional function (12 items), and social function (5 items). The items are scored on a 7-point Likert scale with a higher score indicating better health-related QOL.
    End point type
    Secondary
    End point timeframe
    Weeks 10, 30, and 54
    End point values
    		 Etrolizumab + Placebo (IV) Infliximab + Placebo (Injection)
    Number of subjects analysed
    165
    156
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Week 10
    43.2 ( 36.6 )
    45.1 ( 39.4 )
        Week 30
    53.5 ( 40.8 )
    59.6 ( 34.4 )
        Week 54
    58.2 ( 32.9 )
    63.2 ( 38.5 )
    Statistical analysis title
    		 Etrolizumab vs. Infliximab
    Comparison groups
    Etrolizumab + Placebo (IV) v Infliximab + Placebo (Injection)
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    		 [11]
    P-value
    		 = 0.4106 [12]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in Adjusted Means
    Point estimate
    -3.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.6
         upper limit
    		 4.3
    Notes
    [11] - Week 10
    [12] - p-value has not been adjusted for multiplicity
    Statistical analysis title
    		 Etrolizumab vs. Infliximab
    Comparison groups
    Etrolizumab + Placebo (IV) v Infliximab + Placebo (Injection)
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    		 [13]
    P-value
    		 = 0.1434 [14]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in Adjusted Means
    Point estimate
    -5.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.3
         upper limit
    		 1.9
    Notes
    [13] - Week 30
    [14] - p-value has not been adjusted for multiplicity
    Statistical analysis title
    		 Etrolizumab vs. Infliximab
    Comparison groups
    Etrolizumab + Placebo (IV) v Infliximab + Placebo (Injection)
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    		 [15]
    P-value
    		 = 0.1103 [16]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in Adjusted Means
    Point estimate
    -6.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.6
         upper limit
    		 1.4
    Notes
    [15] - Week 54
    [16] - p-value has not been adjusted for multiplicity

    Secondary: Number of Participants with Anti-Therapeutic Antibodies (ATAs) to Etrolizumab

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    End point title
    		 Number of Participants with Anti-Therapeutic Antibodies (ATAs) to Etrolizumab [17]
    End point description
    End point type
    Secondary
    End point timeframe
    Weeks 0, 4, 10, 12, 30, and 54
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: ATAs to Etrolizumab were provided only for the arm that received treatment with etrolizumab.
    End point values
    		 Etrolizumab + Placebo (IV)
    Number of subjects analysed
    196
    Units: participants
    69
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Improvement in Endoscopic Appearance of the Mucosa at Week 10, determined by the MCS

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    End point title
    		 Percentage of Participants with Improvement in Endoscopic Appearance of the Mucosa at Week 10, determined by the MCS
    End point description
    MCS is a composite of 4 assessments, each rated from 0-3: stool frequency, rectal bleeding, endoscopy, and physician’s global assessment. Higher scores indicate more severe disease. Improvement in endoscopic appearance of the mucosa is Endoscopy subscore ≤1.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 10
    End point values
    		 Etrolizumab + Placebo (IV) Infliximab + Placebo (Injection)
    Number of subjects analysed
    199
    198
    Units: percentage of participants
        number (not applicable)
    36.7
    49.5
    Statistical analysis title
    		 Etrolizumab vs. Infliximab
    Comparison groups
    Etrolizumab + Placebo (IV) v Infliximab + Placebo (Injection)
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0118 [18]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference in Response Rates
    Point estimate
    -12.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.84
         upper limit
    		 -2.66
    Notes
    [18] - p-value has not been adjusted for multiplicity

    Secondary: Percentage of Participants with Improvement in Endoscopic Appearance of the Mucosa at Week 54, as determined by the MCS

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    End point title
    		 Percentage of Participants with Improvement in Endoscopic Appearance of the Mucosa at Week 54, as determined by the MCS
    End point description
    MCS is a composite of 4 assessments, each rated from 0-3: stool frequency, rectal bleeding, endoscopy, and physician’s global assessment. Higher scores indicate more severe disease. Improvement in endoscopic appearance of the mucosa is Endoscopy subscore ≤1.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 54
    End point values
    		 Etrolizumab + Placebo (IV) Infliximab + Placebo (Injection)
    Number of subjects analysed
    199
    198
    Units: percentage of participants
        number (not applicable)
    27.1
    32.3
    Statistical analysis title
    		 Etrolizumab vs. Infliximab
    Comparison groups
    Etrolizumab + Placebo (IV) v Infliximab + Placebo (Injection)
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2845 [19]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference in Response Rates
    Point estimate
    -4.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.76
         upper limit
    		 4.12
    Notes
    [19] - p-value has not been adjusted for multiplicity

    Secondary: Percentage of Participants with Improvement in Endoscopic Appearance of the Mucosa at Both Week 10 and Week 54, as determined by the MCS

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    End point title
    		 Percentage of Participants with Improvement in Endoscopic Appearance of the Mucosa at Both Week 10 and Week 54, as determined by the MCS
    End point description
    MCS is a composite of 4 assessments, each rated from 0-3: stool frequency, rectal bleeding, endoscopy, and physician’s global assessment. Higher scores indicate more severe disease. Improvement in endoscopic appearance of the mucosa is Endoscopy subscore ≤1.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 10, Week 54
    End point values
    		 Etrolizumab + Placebo (IV) Infliximab + Placebo (Injection)
    Number of subjects analysed
    199
    198
    Units: percentage of participants
        number (not applicable)
    18.1
    24.7
    Statistical analysis title
    		 Etrolizumab vs. Infliximab
    Comparison groups
    Etrolizumab + Placebo (IV) v Infliximab + Placebo (Injection)
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1234 [20]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference in Response Rates
    Point estimate
    -6.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.3
         upper limit
    		 1.84
    Notes
    [20] - p-value has not been adjusted for multiplicity

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline until the end of study (up to 66 weeks)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    Etrolizumab + Placebo (IV)
    Reporting group description
    		 Participants will receive ertolizumab (SC) Q4W until Week 52 along with placebo matched to infliximab as IV infusion until Week 46.

    Reporting group title
    Infliximab + Placebo (Injection)
    Reporting group description
    		 Participants will receive IV infusion of infliximab at Weeks 0,2, and 6, then every 8 weeks until Week 46 partnered with placebo matched to etrolizumab by SC injection Q4W until Week 52.

    Serious adverse events
    		 Etrolizumab + Placebo (IV) Infliximab + Placebo (Injection)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    32 / 199 (16.08%)
    20 / 198 (10.10%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Investigations
    Haemoglobin decreased
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hodgkin's disease
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroendocrine tumour
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Incisional hernia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural intestinal perforation
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Central nervous system vasculitis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug hypersensitivity
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal vein occlusion
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 199 (1.01%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
    alternative assessment type: Systematic
         subjects affected / exposed
    12 / 199 (6.03%)
    11 / 198 (5.56%)
         occurrences causally related to treatment / all
    0 / 12
    1 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated umbilical hernia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Skin and subcutaneous tissue disorders
    Erythema
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyoderma gangrenosum
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 199 (1.01%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 199 (1.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 199 (1.01%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus colitis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 199 (0.50%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis listeria
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stitch abscess
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Etrolizumab + Placebo (IV) Infliximab + Placebo (Injection)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    94 / 199 (47.24%)
    80 / 198 (40.40%)
    Nervous system disorders
    Headache
    alternative assessment type: Systematic
         subjects affected / exposed
    22 / 199 (11.06%)
    19 / 198 (9.60%)
         occurrences all number
    30
    28
    Gastrointestinal disorders
    Abdominal pain
    alternative assessment type: Systematic
         subjects affected / exposed
    10 / 199 (5.03%)
    5 / 198 (2.53%)
         occurrences all number
    11
    6
    Colitis ulcerative
    alternative assessment type: Systematic
         subjects affected / exposed
    45 / 199 (22.61%)
    33 / 198 (16.67%)
         occurrences all number
    47
    36
    Diarrhoea
    alternative assessment type: Systematic
         subjects affected / exposed
    11 / 199 (5.53%)
    4 / 198 (2.02%)
         occurrences all number
    12
    4
    Nausea
    alternative assessment type: Systematic
         subjects affected / exposed
    10 / 199 (5.03%)
    4 / 198 (2.02%)
         occurrences all number
    10
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
    alternative assessment type: Systematic
         subjects affected / exposed
    21 / 199 (10.55%)
    15 / 198 (7.58%)
         occurrences all number
    24
    16
    Infections and infestations
    Nasopharyngitis
    alternative assessment type: Systematic
         subjects affected / exposed
    22 / 199 (11.06%)
    23 / 198 (11.62%)
         occurrences all number
    30
    30

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Mar 2014
    1) The definition of moderately to severely ulcerative colitis (UC) was updated to include stool frequency subscore of ≥1; and 2) UC Disease Activity Assessments section was modified to include that: 1) given the potential for increased rectal bleeding following endoscopic procedures, rectal bleeding Mayo Clinic Score (MCS) would be derived prior to endoscopy, 2) postbaseline endoscopy could be performed on the same day as the study visit instead of 4 days prior to the visit, 3) each segment, instead of the worst affected segment, of the colon up to the splenic flexure (rectum, sigmoid, and descending colon) would be assigned an endoscopic subscore and the score from the worst affected segment up to the splenic flexure was to be used for the MCS calculation, 4) any discrepancy between the endoscopic subscore obtained by the local versus central readers would require a third adjudication read by a different central reader.
    09 Jul 2014
    1) The primary endpoint was updated to sustained remission (including a rectal bleeding score of 0) and sustained clinical remission was changed to a secondary endpoint; and 2) Updates were made to clarify the risk mitigation strategy, including the potential risks associated with etrolizumab treatment and the risks associated with disease worsening.
    07 Dec 2015
    The protocol was amended to allow extensions of the screening and endoscopy windows when this was required to ensure enrollment of eligible patients and following approval from the Medical Monitor.
    02 Nov 2016
    The protocol was amended to update and align the safety section with information regarding potential risks for etrolizumab in the current Etrolizumab Investigator’s Brochure.
    25 Jan 2018
    1) The primary efficacy endpoint was changed from sustained remission (at Weeks 10, 30 and 54) to achievement of both clinical response at Week 10 and clinical remission at Week 54; 2) Secondary and exploratory efficacy endpoints were amended to align with the revision of the primary efficacy endpoint; 3) Derivation of the MCS endoscopic subscore at post-baseline timepoints was amended to be consistent with emerging normative standards of endoscopic assessment in clinical trials. The sigmoid colon MCS endoscopic subscore will be used (rather than the score from the worst affected segment, i.e., rectum, sigmoid colon, or descending colon) if the baseline sigmoid colon MCS endoscopic subscore is 2−3. The sigmoid colon MCS endoscopic subscore is considered to be more reliable in assessing earlier treatment response; 4) The window for performing the endoscopy prior to Day 1 was extended from 10 to 16 days. The requirement for Medical Monitor approval for endoscopies conducted during this window was eliminated; and 5) The time qualification for derivation of MCS baseline stool frequency and rectal bleeding subscores was redefined to include subscores obtained within 22 days prior to randomization (Day 1).
    22 Oct 2018
    1) The difference in treatment effect between etrolizumab and infliximab was considered to be higher than previously assumed. As a result, the estimated sample size for this study was reduced from 600 to 390 patients. Patients were continued to be randomized in the same 1:1 ratio; and 2) A secondary efficacy endpoint, to evaluate clinical remission at Week 54 among patients with a clinical response at Week 10, was added.

    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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