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

    Summary
    EudraCT number
    		 2013-004280-31
    Trial protocol
    		 CZ   DK   DE   HU   SK   PL  
    Global end of trial date
    06 Apr 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    12 Aug 2021
    First version publication date
    15 Apr 2021
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GA29102
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02165215
    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
    04 Nov 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Apr 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of etrolizumab compared with placebo for remission of Ulcerative Colitis (UC) at Week 62 among patients with a clinical response at Week 10
    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
    12 Aug 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
    Brazil: 43
    Country: Number of subjects enrolled
    Canada: 20
    Country: Number of subjects enrolled
    Czechia: 15
    Country: Number of subjects enrolled
    Germany: 18
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    Hungary: 21
    Country: Number of subjects enrolled
    India: 53
    Country: Number of subjects enrolled
    Israel: 14
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Mexico: 7
    Country: Number of subjects enrolled
    Poland: 9
    Country: Number of subjects enrolled
    Slovakia: 4
    Country: Number of subjects enrolled
    Ukraine: 25
    Country: Number of subjects enrolled
    United States: 106
    Country: Number of subjects enrolled
    South Africa: 15
    Worldwide total number of subjects
    359
    EEA total number of subjects
    76
    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)
    343
    From 65 to 84 years
    16
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 359 patients entered the Induction phase of the study. For the double-blind maintenance phase, 102 patients were randomized and dosed to the Placebo arm and 108 to the Etrolizumab arm.

    Period 1
    Period 1 title
    Induction Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Open-Label Induction Phase: Etrolizumab
    Arm description
    		 All participants will receive treatment with open-label etrolizumab 105 milligrams (mg) subcutaneous (SC) injection once every 4 weeks (Q4W) up to Week 10.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Etrolizumab
    Investigational medicinal product code
    Other name
    RG7413, RO5490261, PRO145223, rhuMAb Beta7
    Pharmaceutical forms
    Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    105 mg once every 4 weeks (Q4W)

    Number of subjects in period 1
    		Open-Label Induction Phase: Etrolizumab
    Started
    359
    Dosed
    358
    Completed
    336
    Not completed
    23
         Consent withdrawn by subject
    10
         Physician decision
    1
         Non-Compliance
    2
         Adverse event, non-fatal
    1
         Lost to follow-up
    6
         Protocol deviation
    1
         Lack of efficacy
    2
    Period 2
    Period 2 title
    Maintenance Phase
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Double-Blind Maintenance Phase: Etrolizumab
    Arm description
    		 Participants who achieved a clinical response at Week 10 during the induction phase and randomized to this arm for the double-blind maintenance phase will receive etrolizumab 105 mg SC injection Q4W from Week 12 up to Week 62.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Etrolizumab
    Investigational medicinal product code
    Other name
    RG7413, RO5490261, PRO145223, rhuMAb Beta7
    Pharmaceutical forms
    Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    105 mg once every 4 weeks (Q4W)

    Arm title
    		 Double-Blind Maintenance Phase: Placebo
    Arm description
    		 Participants who achieved a clinical response at Week 10 during the induction phase and randomized to this arm for the double-blind maintenance phase will receive placebo (matched to etrolizumab) SC injection Q4W from Week 12 up to Week 62.
    Arm type
    		 Placebo

    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
    Matched to etrolizumab

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 was an induction phase of the study and all participants received the same treatment. The Maintenance phase (during which the test product was compared to placebo) has been reported as the baseline period to provide more relevant comparative data.
    Number of subjects in period 2 [2] [3]
    		Double-Blind Maintenance Phase: Etrolizumab Double-Blind Maintenance Phase: Placebo
    Started
    108
    106
    Dosed
    108
    102
    Completed
    96
    101
    Not completed
    12
    5
         Consent withdrawn by subject
    7
    3
         Adverse event, non-fatal
    1
    1
         Lost to follow-up
    2
    -
         Multiple reasons
    2
    1
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 210 participants were enrolled and dosed in the Maintenance phase. The worldwide number includes all participants in the Induction phase (n=359).
    [3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Out of the participants that completed the Induction phase, only 210 met all criteria for dosing in the Maintenance phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Double-Blind Maintenance Phase: Etrolizumab
    Reporting group description
    		 Participants who achieved a clinical response at Week 10 during the induction phase and randomized to this arm for the double-blind maintenance phase will receive etrolizumab 105 mg SC injection Q4W from Week 12 up to Week 62.

    Reporting group title
    Double-Blind Maintenance Phase: Placebo
    Reporting group description
    		 Participants who achieved a clinical response at Week 10 during the induction phase and randomized to this arm for the double-blind maintenance phase will receive placebo (matched to etrolizumab) SC injection Q4W from Week 12 up to Week 62.

    Reporting group values
    		 Double-Blind Maintenance Phase: Etrolizumab Double-Blind Maintenance Phase: Placebo Total
    Number of subjects
    		 108 106 214
    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)
    		 104 104 208
        From 65-84 years
    		 4 2 6
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 38.3 ( 13.7 ) 39.2 ( 13.5 ) -
    Sex: Female, Male
    Maintenance Phase
    Units:
        Female
    		 48 54 102
        Male
    		 60 52 112
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 2 2 4
        Asian
    		 21 13 34
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 2 6 8
        White
    		 79 78 157
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 4 7 11

    End points

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    End points reporting groups
    Reporting group title
    Open-Label Induction Phase: Etrolizumab
    Reporting group description
    		 All participants will receive treatment with open-label etrolizumab 105 milligrams (mg) subcutaneous (SC) injection once every 4 weeks (Q4W) up to Week 10.
    Reporting group title
    Double-Blind Maintenance Phase: Etrolizumab
    Reporting group description
    		 Participants who achieved a clinical response at Week 10 during the induction phase and randomized to this arm for the double-blind maintenance phase will receive etrolizumab 105 mg SC injection Q4W from Week 12 up to Week 62.

    Reporting group title
    Double-Blind Maintenance Phase: Placebo
    Reporting group description
    		 Participants who achieved a clinical response at Week 10 during the induction phase and randomized to this arm for the double-blind maintenance phase will receive placebo (matched to etrolizumab) SC injection Q4W from Week 12 up to Week 62.

    Primary: Maintenance Phase: Percentage of Participants in Remission at Week 62 Among Randomized Participants with a Clinical Response at Week 10, as Determined by the Mayo Clinic Score (MCS)

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    End point title
    		 Maintenance Phase: Percentage of Participants in Remission at Week 62 Among Randomized Participants with a Clinical Response at Week 10, as Determined by the Mayo Clinic Score (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. 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. Remission is MCS ≤2 with individual subscores ≤1 and a rectal bleeding subscore of 0.
    End point type
    Primary
    End point timeframe
    Week 62
    End point values
    		 Double-Blind Maintenance Phase: Etrolizumab Double-Blind Maintenance Phase: Placebo
    Number of subjects analysed
    108
    102
    Units: percentage of participants
        number (not applicable)
    29.6
    20.6
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Double-Blind Maintenance Phase: Etrolizumab v Double-Blind Maintenance Phase: Placebo
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1942
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted difference in response rates
    Point estimate
    7.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.2
         upper limit
    		 19.2

    Secondary: Maintenance Phase: Percentage of Participants Who Maintained Clinical Remission at Week 62 Among Randomized Participants in Clinical Remission at Week 10, as Determined by the MCS

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    End point title
    		 Maintenance Phase: Percentage of Participants Who Maintained Clinical Remission at Week 62 Among Randomized Participants in Clinical Remission 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. Clinical Remission is MCS ≤2 with individual subscores ≤1.
    End point type
    Secondary
    End point timeframe
    Week 62
    End point values
    		 Double-Blind Maintenance Phase: Etrolizumab Double-Blind Maintenance Phase: Placebo
    Number of subjects analysed
    45
    44
    Units: percentage of participants
        number (not applicable)
    44.4
    27.3
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Double-Blind Maintenance Phase: Etrolizumab v Double-Blind Maintenance Phase: Placebo
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1524 [1]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted difference in remission rates
    Point estimate
    14.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.55
         upper limit
    		 33.15
    Notes
    [1] - p-value has not been adjusted for multiplicity

    Secondary: Maintenance Phase: Percentage of Participants in Clinical Remission at Week 62, as Determined by the MCS

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    End point title
    		 Maintenance Phase: Percentage of Participants in Clinical Remission at Week 62, 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. Clinical Remission is MCS ≤2 with individual subscores ≤1.
    End point type
    Secondary
    End point timeframe
    Week 62
    End point values
    		 Double-Blind Maintenance Phase: Etrolizumab Double-Blind Maintenance Phase: Placebo
    Number of subjects analysed
    108
    102
    Units: percentage of participants
        number (not applicable)
    30.6
    20.6
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Double-Blind Maintenance Phase: Etrolizumab v Double-Blind Maintenance Phase: Placebo
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1466 [2]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted difference in remission rates
    Point estimate
    8.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.26
         upper limit
    		 20.21
    Notes
    [2] - p-value has not been adjusted for multiplicity

    Secondary: Maintenance Phase: Percentage of Participants in Remission at Week 62 Among Randomized Participants in Remission at Week 10, as Determined by the MCS

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    End point title
    		 Maintenance Phase: Percentage of Participants in Remission at Week 62 Among Randomized Participants in Remission 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. Remission is MCS ≤2 with individual subscores ≤1 and a rectal bleeding subscore of 0.
    End point type
    Secondary
    End point timeframe
    Week 62
    End point values
    		 Double-Blind Maintenance Phase: Etrolizumab Double-Blind Maintenance Phase: Placebo
    Number of subjects analysed
    40
    41
    Units: percentage of participants
        number (not applicable)
    40.0
    26.8
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Double-Blind Maintenance Phase: Etrolizumab v Double-Blind Maintenance Phase: Placebo
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3083 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted difference in remission rates
    Point estimate
    10.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.72
         upper limit
    		 30.49
    Notes
    [3] - p-value has not been adjusted for multiplicity

    Secondary: Maintenance Phase: Percentage of Participants with Improvement from Baseline in Endoscopic Appearance of the Mucosa at Week 62, as Determined by the MCS Endoscopic Subscore

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    End point title
    		 Maintenance Phase: Percentage of Participants with Improvement from Baseline in Endoscopic Appearance of the Mucosa at Week 62, as Determined by the MCS Endoscopic Subscore
    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. Improvement in endoscopic appearance of the mucosa is Endoscopy subscore ≤1.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 62
    End point values
    		 Double-Blind Maintenance Phase: Etrolizumab Double-Blind Maintenance Phase: Placebo
    Number of subjects analysed
    108
    102
    Units: percentage of participants
        number (not applicable)
    38.0
    22.5
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Double-Blind Maintenance Phase: Etrolizumab v Double-Blind Maintenance Phase: Placebo
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0235 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted difference in response rates
    Point estimate
    14.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.84
         upper limit
    		 26.28
    Notes
    [4] - p-value has not been adjusted for multiplicity

    Secondary: Maintenance Phase: Percentage of Participants with Endoscopic Remission at Week 62, as Determined by the MCS Endoscopic Subscore

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    End point title
    		 Maintenance Phase: Percentage of Participants with Endoscopic Remission at Week 62, as Determined by the MCS Endoscopic Subscore
    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. Endoscopic Remission is Endoscopy subscore = 0.
    End point type
    Secondary
    End point timeframe
    Week 62
    End point values
    		 Double-Blind Maintenance Phase: Etrolizumab Double-Blind Maintenance Phase: Placebo
    Number of subjects analysed
    108
    102
    Units: percentage of participants
        number (not applicable)
    30.6
    16.7
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Double-Blind Maintenance Phase: Etrolizumab v Double-Blind Maintenance Phase: Placebo
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0293 [5]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted difference in remission rates
    Point estimate
    12.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.13
         upper limit
    		 23.89
    Notes
    [5] - p-value has not been adjusted for multiplicity

    Secondary: Maintenance Phase: Percentage of Participants with Histologic Remission at Week 62, as Determined by the Nancy Histological Index

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    End point title
    		 Maintenance Phase: Percentage of Participants with Histologic Remission at Week 62, as Determined by the Nancy Histological Index
    End point description
    Nancy Histological Index (NHI) is a 5-level classification ranging from grade 0 (No histologically significant disease) to grade 4 (severely active disease). Histologic remission is defined as a Nancy histological index of 0 or 1.
    End point type
    Secondary
    End point timeframe
    Week 62
    End point values
    		 Double-Blind Maintenance Phase: Etrolizumab Double-Blind Maintenance Phase: Placebo
    Number of subjects analysed
    85
    78
    Units: percentage of participants
        number (not applicable)
    42.4
    21.8
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Double-Blind Maintenance Phase: Etrolizumab v Double-Blind Maintenance Phase: Placebo
    Number of subjects included in analysis
    163
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0075 [6]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted difference in remission rates
    Point estimate
    19.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.16
         upper limit
    		 33.11
    Notes
    [6] - p-value has not been adjusted for multiplicity

    Secondary: Maintenance Phase: Percentage of Participants with Corticosteroid-Free Clinical Remission at Week 62 Among Participants Who Were Receiving Corticosteroids at Baseline, as Determined by the MCS

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    End point title
    		 Maintenance Phase: Percentage of Participants with Corticosteroid-Free Clinical Remission at Week 62 Among Participants 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. Clinical Remission is MCS ≤2 with individual subscores ≤1.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 62
    End point values
    		 Double-Blind Maintenance Phase: Etrolizumab Double-Blind Maintenance Phase: Placebo
    Number of subjects analysed
    55
    50
    Units: percentage of participants
        number (not applicable)
    18.2
    8.0
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Double-Blind Maintenance Phase: Etrolizumab v Double-Blind Maintenance Phase: Placebo
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1415 [7]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted difference in remission rates
    Point estimate
    9.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.47
         upper limit
    		 23.13
    Notes
    [7] - p-value has not been adjusted for multiplicity

    Secondary: Maintenance Phase: Percentage of Participants with Corticosteroid-Free Remission at Week 62 Among Participants Who Were Receiving Corticosteroids at Baseline, as Determined by the MCS

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    End point title
    		 Maintenance Phase: Percentage of Participants with Corticosteroid-Free Remission at Week 62 Among Participants 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. Remission is MCS ≤2 with individual subscores ≤1 and a rectal bleeding subscore of 0.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 62
    End point values
    		 Double-Blind Maintenance Phase: Etrolizumab Double-Blind Maintenance Phase: Placebo
    Number of subjects analysed
    55
    50
    Units: percentage of participants
        number (not applicable)
    18.2
    8.0
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Double-Blind Maintenance Phase: Etrolizumab v Double-Blind Maintenance Phase: Placebo
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1415 [8]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted difference in remission rates
    Point estimate
    9.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.47
         upper limit
    		 23.13
    Notes
    [8] - p-value has not been adjusted for multiplicity

    Secondary: Maintenance Phase: Change from Baseline to Week 62 in UC Bowel Movement Signs and Symptoms, as Assessed by the Ulcerative Colitis Patient-Reported Outcome Signs and Symptoms (UC-PRO/SS) Questionnaire

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    End point title
    		 Maintenance Phase: Change from Baseline to Week 62 in UC Bowel Movement Signs and Symptoms, as Assessed by the Ulcerative Colitis Patient-Reported Outcome Signs and Symptoms (UC-PRO/SS) Questionnaire
    End point description
    The UC-PRO questionnaire is collected in the e-diary and completed by participants for at least 9-12 consecutive days prior to a study visit. The UC-PRO is being reported in three domains; two domains are key endpoints and reported as UC-PRO Signs and Symptoms (UC-PRO/SS). The bowel domain score ranges from 0-27, with a higher score indicating a worse disease state.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 62
    End point values
    		 Double-Blind Maintenance Phase: Etrolizumab Double-Blind Maintenance Phase: Placebo
    Number of subjects analysed
    68
    73
    Units: score on a scale
        least squares mean (standard error)
    -9.6 ( 0.8 )
    -6.7 ( 0.9 )
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Double-Blind Maintenance Phase: Etrolizumab v Double-Blind Maintenance Phase: Placebo
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0266 [9]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Least Square Means
    Point estimate
    -2.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.3
         upper limit
    		 -0.4
    Notes
    [9] - p-value has not been adjusted for multiplicity

    Secondary: Maintenance Phase: Change from Baseline to Week 62 in UC Functional Symptoms, as Assessed by the UC-PRO/SS Questionnaire

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    End point title
    		 Maintenance Phase: Change from Baseline to Week 62 in UC Functional Symptoms, as Assessed by the UC-PRO/SS Questionnaire
    End point description
    The UC-PRO questionnaire is collected in the e-diary and completed by participants for at least 9-12 consecutive days prior to a study visit. The UC-PRO is being reported in three domains; two domains are key endpoints and reported as UC-PRO Signs and Symptoms (UC-PRO/SS). The functional domain score ranges from 0-12, with a higher score indicating a worse disease state.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 62
    End point values
    		 Double-Blind Maintenance Phase: Etrolizumab Double-Blind Maintenance Phase: Placebo
    Number of subjects analysed
    68
    73
    Units: score on a scale
        least squares mean (standard error)
    -3.0 ( 0.3 )
    -1.8 ( 0.4 )
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Double-Blind Maintenance Phase: Etrolizumab v Double-Blind Maintenance Phase: Placebo
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0175 [10]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Least Square Means
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.2
         upper limit
    		 -0.2
    Notes
    [10] - p-value has not been adjusted for multiplicity

    Secondary: Maintenance Phase: Change from Baseline to Week 62 in Health-Related Quality of Life, as Assessed by the Overall Score of the Inflammatory Bowel Disease Questionnaire (IBDQ)

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    End point title
    		 Maintenance Phase: Change from Baseline to Week 62 in Health-Related Quality of Life, as Assessed by the Overall Score of the Inflammatory Bowel Disease Questionnaire (IBDQ)
    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. IBDQ score is a total score summed up from across all 32 questions on the questionnaire. The score can range from 32-224 and the higher score indicates a better quality of life.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 62
    End point values
    		 Double-Blind Maintenance Phase: Etrolizumab Double-Blind Maintenance Phase: Placebo
    Number of subjects analysed
    108
    102
    Units: scores on a scale
        least squares mean (standard error)
    66.9 ( 3.39 )
    64.8 ( 3.45 )
    Statistical analysis title
    		 Etro vs. Placebo
    Comparison groups
    Double-Blind Maintenance Phase: Etrolizumab v Double-Blind Maintenance Phase: Placebo
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6331 [11]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in Adjusted Mean
    Point estimate
    2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.6
         upper limit
    		 10.8
    Notes
    [11] - p-value has not been adjusted for multiplicity

    Secondary: Number of Participants with at Least One Adverse Event by Severity, According to 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 at Least One Adverse Event by Severity, According to 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
    From Baseline up to Week 74
    End point values
    		 Open-Label Induction Phase: Etrolizumab Double-Blind Maintenance Phase: Etrolizumab Double-Blind Maintenance Phase: Placebo
    Number of subjects analysed
    358
    108
    102
    Units: participants
        Grade 1
    95
    24
    23
        Grade 2
    58
    30
    44
        Grade 3
    24
    14
    15
        Grade 4
    3
    2
    0
        Grade 5
    0
    0
    0
    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
    From Baseline up to Week 74
    End point values
    		 Open-Label Induction Phase: Etrolizumab Double-Blind Maintenance Phase: Etrolizumab Double-Blind Maintenance Phase: Placebo
    Number of subjects analysed
    358
    108
    102
    Units: participants
    9
    5
    9
    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
    From Baseline up to Week 74
    End point values
    		 Open-Label Induction Phase: Etrolizumab Double-Blind Maintenance Phase: Etrolizumab Double-Blind Maintenance Phase: Placebo
    Number of subjects analysed
    358
    108
    102
    Units: participants
    6
    2
    2
    No statistical analyses for this end point

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

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    End point title
    		 Number of Participants with Infection-Related Adverse Events by Severity, According to 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
    From Baseline up to Week 74
    End point values
    		 Open-Label Induction Phase: Etrolizumab Double-Blind Maintenance Phase: Etrolizumab Double-Blind Maintenance Phase: Placebo
    Number of subjects analysed
    358
    108
    102
    Units: participants
        Grade 1
    39
    18
    22
        Grade 2
    21
    17
    10
        Grade 3
    6
    1
    1
        Grade 4
    0
    1
    0
        Grade 5
    0
    0
    0
    No statistical analyses for this end point

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

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    End point title
    		 Number of Participants with Injection-Site Reactions by Severity, According to 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
    From Baseline up to Week 74
    End point values
    		 Open-Label Induction Phase: Etrolizumab Double-Blind Maintenance Phase: Etrolizumab Double-Blind Maintenance Phase: Placebo
    Number of subjects analysed
    358
    108
    102
    Units: participants
        Grade 1
    8
    4
    3
        Grade 2
    0
    0
    0
        Grade 3
    0
    0
    0
        Grade 4
    0
    0
    0
        Grade 5
    0
    0
    0
    No statistical analyses for this end point

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

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    End point title
    		 Number of Participants with Hypersensitivity Reaction Events by Severity, According to 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
    From Baseline up to Week 74
    End point values
    		 Open-Label Induction Phase: Etrolizumab Double-Blind Maintenance Phase: Etrolizumab Double-Blind Maintenance Phase: Placebo
    Number of subjects analysed
    358
    108
    102
    Units: participants
        Grade 1
    0
    0
    0
        Grade 2
    1
    0
    0
        Grade 3
    0
    0
    0
        Grade 4
    0
    0
    0
        Grade 5
    0
    0
    0
    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
    From Baseline up to Week 74
    End point values
    		 Open-Label Induction Phase: Etrolizumab Double-Blind Maintenance Phase: Etrolizumab Double-Blind Maintenance Phase: Placebo
    Number of subjects analysed
    358
    108
    102
    Units: participants
    0
    2
    1
    No statistical analyses for this end point

    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
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 12, 24, 44, and 62, and and Early Termination/End of Safety Follow-Up (up to Week 74)
    End point values
    		 Open-Label Induction Phase: Etrolizumab Double-Blind Maintenance Phase: Etrolizumab Double-Blind Maintenance Phase: Placebo
    Number of subjects analysed
    337
    108
    102
    Units: participants
    62
    35
    33
    No statistical analyses for this end point

    Secondary: Maintenance Phase: Etrolizumab Serum Trough Concentration

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    End point title
    		 Maintenance Phase: Etrolizumab Serum Trough Concentration
    End point description
    Here 99999 represents data that were not analyzed as more than a third of the samples were below the lower limit of quantitation (LLOQ)
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hour) at Baseline and Weeks 12, 24, 44, and 62
    End point values
    		 Double-Blind Maintenance Phase: Etrolizumab Double-Blind Maintenance Phase: Placebo
    Number of subjects analysed
    105
    100
    Units: micrograms per millilitre (μg/mL)
    arithmetic mean (standard deviation)
        Week 12
    7.66 ( 4.21 )
    7.63 ( 3.67 )
        Week 24
    10 ( 4.86 )
    99999 ( 99999 )
        Week 44
    10 ( 4.88 )
    99999 ( 99999 )
        Week 62
    15.4 ( 7.46 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline up to Week 74
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Open-Label Induction Phase: Etrolizumab
    Reporting group description
    		 All participants will receive treatment with open-label etrolizumab 105 milligrams (mg) subcutaneous (SC) injection once every 4 weeks (Q4W) up to Week 10.

    Reporting group title
    Double-Blind Maintenance Phase: Etrolizumab
    Reporting group description
    		 Participants who achieved a clinical response at Week 10 during the induction phase and randomized to this arm for the double-blind maintenance phase will receive etrolizumab 105 mg SC injection Q4W from Week 12 up to Week 62.

    Reporting group title
    Double-Blind Maintenance Phase: Placebo
    Reporting group description
    		 Participants who achieved a clinical response at Week 10 during the induction phase and randomized to this arm for the double-blind maintenance phase will receive placebo (matched to etrolizumab) SC injection Q4W from Week 12 up to Week 62.

    Serious adverse events
    		 Open-Label Induction Phase: Etrolizumab Double-Blind Maintenance Phase: Etrolizumab Double-Blind Maintenance Phase: Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 358 (4.75%)
    10 / 108 (9.26%)
    8 / 102 (7.84%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Blood creatine phosphokinase increased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 108 (0.93%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer metastatic
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 108 (0.93%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gallbladder cancer
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 108 (0.93%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 108 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 108 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 108 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone marrow failure
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 108 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Iron deficiency anaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 108 (0.93%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Systemic inflammatory response syndrome
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 108 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Anal fistula
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 108 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis ulcerative
    alternative assessment type: Systematic
         subjects affected / exposed
    6 / 358 (1.68%)
    2 / 108 (1.85%)
    2 / 102 (1.96%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Crohn's disease
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 108 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea haemorrhagic
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 108 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 108 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 108 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 108 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 108 (0.93%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 108 (0.00%)
    2 / 102 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 108 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 108 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 108 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 108 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Exostosis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 108 (0.93%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 108 (0.93%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 108 (0.93%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 108 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis B
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 108 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary tuberculosis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 108 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal abscess
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 108 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 108 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 108 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 108 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Open-Label Induction Phase: Etrolizumab Double-Blind Maintenance Phase: Etrolizumab Double-Blind Maintenance Phase: Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    64 / 358 (17.88%)
    30 / 108 (27.78%)
    54 / 102 (52.94%)
    General disorders and administration site conditions
    Pyrexia
    alternative assessment type: Systematic
         subjects affected / exposed
    8 / 358 (2.23%)
    0 / 108 (0.00%)
    6 / 102 (5.88%)
         occurrences all number
    9
    0
    6
    Gastrointestinal disorders
    Abdominal pain
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 358 (0.28%)
    6 / 108 (5.56%)
    9 / 102 (8.82%)
         occurrences all number
    1
    9
    11
    Colitis ulcerative
    alternative assessment type: Systematic
         subjects affected / exposed
    24 / 358 (6.70%)
    14 / 108 (12.96%)
    34 / 102 (33.33%)
         occurrences all number
    24
    16
    35
    Diarrhoea
    alternative assessment type: Systematic
         subjects affected / exposed
    5 / 358 (1.40%)
    4 / 108 (3.70%)
    8 / 102 (7.84%)
         occurrences all number
    10
    4
    9
    Musculoskeletal and connective tissue disorders
    Arthralgia
    alternative assessment type: Systematic
         subjects affected / exposed
    9 / 358 (2.51%)
    8 / 108 (7.41%)
    11 / 102 (10.78%)
         occurrences all number
    11
    10
    11
    Infections and infestations
    Nasopharyngitis
    alternative assessment type: Systematic
         subjects affected / exposed
    22 / 358 (6.15%)
    8 / 108 (7.41%)
    3 / 102 (2.94%)
         occurrences all number
    22
    10
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Apr 2014
    The definition of moderate to severe UC was updated to include stool frequency sub-score of ≥1. Further, for MCS/pMCS calculation, the worst rectal bleeding score from the most recent 3 days prior to clinical visit was to be used; Endoscopy procedures for UC disease activity assessment were modified; further, in case of any discrepancy between local versus central endoscopy readers, an adjudication read was to be added; The dosage of etrolizumab to be administered was corrected from 100 mg to 105 mg. The dose of 100 mg was not administered to patients; PML assessment was modified to include the PML Subjective Checklist (symptom assessment) and the PML Objective Checklist (neurologic evaluation). The algorithm for evaluation of PML was updated; Exclusion criteria related to hepatitis C, CMV testing, patient’s cancer history and stenosis and screening assessments related to JCV testing and the timing of endoscopy were revised; and The dosage and administration section was revised to include a 2-week window for delayed administration of study medication due to minor illness.
    08 Jul 2014
    The inclusion criterion regarding contraception use for women was amended to detail the use of spermicide and double barrier (rather than barrier alone) for acceptable methods of contraception during treatment period and for at least 24 weeks after the last dose (reflecting International Conference on Harmonisation (M3) guidance; A new exclusion criterion was added to exclude patients with suspicion of ischemic colitis, radiation colitis, or microscopic colitis; and The exclusion criterion regarding the history of moderate or severe allergic or anaphylactic/anaphylactoid reactions to chimeric, human, or humanized antibodies, fusion proteins, or murine proteins was updated to include hypersensitivity to etrolizumab (active drug substance) or any of the excipients (L-histidine, L-arginine, succinic acid, Polysorbate 20).
    22 Aug 2014
    Local amendment only (US and Canada).
    28 Aug 2015
    The protocol was amended to remove the previous requirement that immunosuppressant use stop at Week 10 in the U.S. and Canada based on HA feedback. Instead, patients were allowed to continue with immunosuppressant use from baseline throughout induction and maintenance (with dose reduction or discontinuation of immunosuppressant use permitted in the event of toxicity) in the U.S. and Canada; and Inclusion criteria were modified to allow patients with inadequate response to either immunosuppressants or corticosteroids to be eligible for the study (rather than the previous requirement for failure to immunosuppressants with or without failure to corticosteroids).
    24 Aug 2017
    The protocol was amended to update and align the safety section with information regarding potential risks for etrolizumab in the etrolizumab Investigator’s Brochure, Version 10, as follows. Guidelines for managing specific AEs were updated to include hepatic effects as a potential risk for etrolizumab, to be in line with the safety profile of other anti-integrins, including vedolizumab, for which hepatic AEs have been reported; Changes were also made to enhance recruitment by reducing the complexity of the protocol, particularly at the time of screening and re-screening, as follows: The minimum time between the diagnosis of ulcerative colitis (UC) and enrollment (Day 1) was reduced from 6 months to 3 months. This allowed patients with a more recent diagnosis of UC to be enrolled; 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 The time qualification for derivation of Mayo Clinic Score (MCS) baseline stool frequency and rectal bleeding subscores was redefined to include subscores obtained within 22 days prior to Day 1.
    27 Aug 2018
    The protocol was primarily amended to reflect changes in efficacy endpoints. The changes would not impact study conduct at site level. The primary efficacy endpoint was changed to remission at Week 62 for patients who achieved clinical response (rather than remission) at Week 10, to align with clinical practice standards whereby patients who experienced a clinical response during treatment induction continued on treatment and were assessed for remission at a later time point; Secondary and exploratory efficacy endpoints were amended to align with the revision of the primary efficacy endpoint; To assess the onset of action of etrolizumab, a secondary efficacy endpoint of change in MCS rectal bleeding and stool frequency subscores from baseline to Week 6 was added; Histologic remission, defined as a Nancy histological index of ≤1, was added as a secondary efficacy outcome measure. The definition is based on consensus guidelines recommending that histologic remission should be defined by the absence of neutrophils in the crypts and lamina propria; 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; and Histologic activity on colon biopsies would be primarily measured using the Nancy histological index instead of the Geboes scale. Language regarding local injection-site reactions was clarified.

    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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