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    Clinical Trial Results:
    A Phase III, Double-Blind, Placebo-Controlled, Multicenter Study of the Efficacy and Safety of Etrolizumab During Induction and Maintenance in Patients With Moderate to Severe Active Ulcerative Colitis who are Refractory to or Intolerant of TNF Inhibitors.

    Summary
    EudraCT number
    		 2013-004278-88
    Trial protocol
    		 LT   GR   DE   CZ   DK   BE   HU   AT   ES   NL   IT   FR   PL  
    Global end of trial date
    16 Apr 2020

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GA28950
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02100696
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH4070
    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
    16 Apr 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Apr 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy and safety of Etrolizumab
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 All subjects were on immunosuppressants and/or corticosteroids.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 May 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 3 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 2
    Country: Number of subjects enrolled
    Australia: 22
    Country: Number of subjects enrolled
    Austria: 16
    Country: Number of subjects enrolled
    Belgium: 29
    Country: Number of subjects enrolled
    Brazil: 24
    Country: Number of subjects enrolled
    Canada: 41
    Country: Number of subjects enrolled
    Switzerland: 9
    Country: Number of subjects enrolled
    Czechia: 39
    Country: Number of subjects enrolled
    Germany: 38
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    Spain: 18
    Country: Number of subjects enrolled
    France: 71
    Country: Number of subjects enrolled
    United Kingdom: 26
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    Hungary: 43
    Country: Number of subjects enrolled
    Israel: 9
    Country: Number of subjects enrolled
    Italy: 36
    Country: Number of subjects enrolled
    Korea, Republic of: 22
    Country: Number of subjects enrolled
    Lithuania: 6
    Country: Number of subjects enrolled
    Mexico: 3
    Country: Number of subjects enrolled
    Netherlands: 16
    Country: Number of subjects enrolled
    Poland: 27
    Country: Number of subjects enrolled
    Romania: 1
    Country: Number of subjects enrolled
    United States: 107
    Worldwide total number of subjects
    609
    EEA total number of subjects
    344
    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)
    580
    From 65 to 84 years
    29
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 184 centers in 24 countries.

    Pre-assignment
    Screening details
    		 A total of 609 subjects were enrolled into the Induction phase of this study and the entire study. A subset (259) of these subjects moved into the Maintenance phase of this study.

    Period 1
    Period 1 title
    Induction Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1: Etrolizumab (Open-Label Induction (OLI) Phase)
    Arm description
    		 Participants assigned to this arm will receive treatment with open-label etrolizumab 105 milligrams (mg) subcutaneous (SC) injection once every 4 weeks (Q4W) for 14 weeks during the induction phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Etrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    105mg once every 4 weeks

    Arm title
    		 Cohort 2: Placebo (Double-Blind Induction Phase)
    Arm description
    		 Participants randomized to this arm will receive treatment with double-blind placebo SC injection Q4W for 14 weeks during the induction phase.
    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

    Arm title
    		 Cohort 2: Etrolizumab (Double-Blind Induction Phase)
    Arm description
    		 Participants randomized to this arm will receive treatment with double-blind etrolizumab 105 mg SC injection Q4W for 14 weeks during the induction phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Etrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    105mg once every 4 weeks

    Number of subjects in period 1
    		Cohort 1: Etrolizumab (Open-Label Induction (OLI) Phase) Cohort 2: Placebo (Double-Blind Induction Phase) Cohort 2: Etrolizumab (Double-Blind Induction Phase)
    Started
    130
    95
    384
    Completed
    115
    90
    358
    Not completed
    15
    5
    26
         Consent withdrawn by subject
    8
    2
    13
         Physician decision
    1
    -
    2
         Adverse event, non-fatal
    -
    -
    1
         Multiple Reasons
    5
    2
    8
         Lost to follow-up
    1
    -
    1
         Protocol deviation
    -
    1
    1
    Period 2
    Period 2 title
    Maintenance Phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo Responders: Placebo (Maintenance Phase)
    Arm description
    		 Participants who received placebo during the induction phase, Cohort 2: Placebo (Double-Blind Induction Phase), and achieve a clinical response with placebo at Week 14 will continue to receive blinded placebo from Week 16 up to Week 66 during the maintenance phase.
    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

    Arm title
    		 Etrolizumab Responders: Placebo (Maintenance Phase)
    Arm description
    		 Participants who received etrolizumab during the induction phase, Cohort 1: Etrolizumab (Open-Label Induction Phase) and Cohort 2: Etrolizumab (Double-Blind Induction Phase), and achieved a clinical response at Week 14 will be re-randomized by Week 16 for the double-blind maintenance phase. Clinical responders re-randomized to this arm will receive placebo SC injection Q4W from Week 16 up to Week 66.
    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

    Arm title
    		 Etrolizumab Responders: Etrolizumab (Maintenance Phase)
    Arm description
    		 Participants who received etrolizumab during the induction phase, Cohort 1: Etrolizumab (Open-Label Induction Phase) and Cohort 2: Etrolizumab (Double-Blind Induction Phase), and achieved a clinical response at Week 14 will be re-randomized by Week 16 for the double-blind maintenance phase. Clinical responders re-randomized to this arm will receive etrolizumab 105 mg SC injection Q4W from Week 16 up to Week 66.
    Arm type
    		 Experimental

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

    Number of subjects in period 2 [1]
    		Placebo Responders: Placebo (Maintenance Phase) Etrolizumab Responders: Placebo (Maintenance Phase) Etrolizumab Responders: Etrolizumab (Maintenance Phase)
    Started
    27
    115
    117
    Completed
    26
    106
    112
    Not completed
    1
    9
    5
         Consent withdrawn by subject
    1
    4
    2
         Physician decision
    -
    1
    -
         Adverse event, non-fatal
    -
    -
    2
         Multiple Reasons
    -
    2
    1
         Lost to follow-up
    -
    1
    -
         Protocol deviation
    -
    1
    -
    Notes
    [1] - 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 609 subjects that enrolled into the Induction phase of this study and entire study, a subset (259) subjects moved into the Maintenance phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: Etrolizumab (Open-Label Induction (OLI) Phase)
    Reporting group description
    		 Participants assigned to this arm will receive treatment with open-label etrolizumab 105 milligrams (mg) subcutaneous (SC) injection once every 4 weeks (Q4W) for 14 weeks during the induction phase.

    Reporting group title
    Cohort 2: Placebo (Double-Blind Induction Phase)
    Reporting group description
    		 Participants randomized to this arm will receive treatment with double-blind placebo SC injection Q4W for 14 weeks during the induction phase.

    Reporting group title
    Cohort 2: Etrolizumab (Double-Blind Induction Phase)
    Reporting group description
    		 Participants randomized to this arm will receive treatment with double-blind etrolizumab 105 mg SC injection Q4W for 14 weeks during the induction phase.

    Reporting group values
    		 Cohort 1: Etrolizumab (Open-Label Induction (OLI) Phase) Cohort 2: Placebo (Double-Blind Induction Phase) Cohort 2: Etrolizumab (Double-Blind Induction Phase) Total
    Number of subjects
    		 130 95 384 609
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 123 90 367 580
        From 65-84 years
    		 7 5 17 29
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 39.5 ( 13.5 ) 38.8 ( 13.9 ) 40.7 ( 13.3 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 52 41 160 253
        Male
    		 78 54 224 356
    Race/Ethnicity, Customized
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 4 5 30 39
        Not Hispanic or Latino
    		 118 76 321 515
        Not Reported or Unknown
    		 8 14 33 55
    Race/Ethnicity, Customized
    Race
    Units: Subjects
        Asian
    		 6 5 26 37
        Black or African American
    		 3 1 6 10
        White
    		 109 73 304 486
        Other
    		 12 15 48 75
        American Indian or Alaska Native
    		 0 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: Etrolizumab (Open-Label Induction (OLI) Phase)
    Reporting group description
    		 Participants assigned to this arm will receive treatment with open-label etrolizumab 105 milligrams (mg) subcutaneous (SC) injection once every 4 weeks (Q4W) for 14 weeks during the induction phase.

    Reporting group title
    Cohort 2: Placebo (Double-Blind Induction Phase)
    Reporting group description
    		 Participants randomized to this arm will receive treatment with double-blind placebo SC injection Q4W for 14 weeks during the induction phase.

    Reporting group title
    Cohort 2: Etrolizumab (Double-Blind Induction Phase)
    Reporting group description
    		 Participants randomized to this arm will receive treatment with double-blind etrolizumab 105 mg SC injection Q4W for 14 weeks during the induction phase.
    Reporting group title
    Placebo Responders: Placebo (Maintenance Phase)
    Reporting group description
    		 Participants who received placebo during the induction phase, Cohort 2: Placebo (Double-Blind Induction Phase), and achieve a clinical response with placebo at Week 14 will continue to receive blinded placebo from Week 16 up to Week 66 during the maintenance phase.

    Reporting group title
    Etrolizumab Responders: Placebo (Maintenance Phase)
    Reporting group description
    		 Participants who received etrolizumab during the induction phase, Cohort 1: Etrolizumab (Open-Label Induction Phase) and Cohort 2: Etrolizumab (Double-Blind Induction Phase), and achieved a clinical response at Week 14 will be re-randomized by Week 16 for the double-blind maintenance phase. Clinical responders re-randomized to this arm will receive placebo SC injection Q4W from Week 16 up to Week 66.

    Reporting group title
    Etrolizumab Responders: Etrolizumab (Maintenance Phase)
    Reporting group description
    		 Participants who received etrolizumab during the induction phase, Cohort 1: Etrolizumab (Open-Label Induction Phase) and Cohort 2: Etrolizumab (Double-Blind Induction Phase), and achieved a clinical response at Week 14 will be re-randomized by Week 16 for the double-blind maintenance phase. Clinical responders re-randomized to this arm will receive etrolizumab 105 mg SC injection Q4W from Week 16 up to Week 66.

    Subject analysis set title
    Cohort 1: Etro (OLI Phase) + Cohort 2: Etro (DB Ind Phase)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Cohort 1: Participants assigned to this arm will receive treatment with open-label etrolizumab 105 milligrams (mg) subcutaneous (SC) injection once every 4 weeks (Q4W) for 14 weeks during the induction phase. Cohort 2: Participants randomized to this arm will receive treatment with double-blind etrolizumab 105 mg SC injection Q4W for 14 weeks during the induction phase. Subjects in this arm did not enter into the Maintenance phase of the study.

    Subject analysis set title
    Etrolizumab Responders: Placebo (Maintenance Phase) (mITT)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Participants who received etrolizumab during the induction phase, Cohort 1: Etrolizumab (Open-Label Induction Phase) and Cohort 2: Etrolizumab (Double-Blind Induction Phase), and achieved a clinical response at Week 14 will be re-randomized by Week 16 for the double-blind maintenance phase. Clinical responders re-randomized to this arm will receive placebo SC injection Q4W from Week 16 up to Week 66.

    Subject analysis set title
    Etrolizumab Responders: Etrolizumab (Maintenance Phase) (mITT)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Participants who received etrolizumab during the induction phase, Cohort 1: Etrolizumab (Open-Label Induction Phase) and Cohort 2: Etrolizumab (Double-Blind Induction Phase), and achieved a clinical response at Week 14 will be re-randomized by Week 16 for the double-blind maintenance phase. Clinical responders re-randomized to this arm will receive etrolizumab SC injection Q4W from Week 16 up to Week 66.

    Primary: Induction Phase: Percentage of Subjects with Remission at Week 14, as Determined by the Mayo Clinic Score (MCS)

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    End point title
    		 Induction Phase: Percentage of Subjects with Remission at Week 14, as Determined by the Mayo Clinic Score (MCS) [1]
    End point description
    The Mayo Clinic Score (MCS) ranges from 0 to 12 and is a composite of 4 assessments (each rated from 0-3): stool frequency, rectal bleeding, endoscopy, and physician’s global assessment. Higher scores represent greater disease severity. Remission was defined as MCS less than or equal to (≤)2 with individual subscores ≤1 and a rectal bleeding subscore of 0.
    End point type
    Primary
    End point timeframe
    Week 14
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This analysis was only performed on the 'Induction phase' arms and hence why not all arms are presented.
    End point values
    		 Cohort 2: Placebo (Double-Blind Induction Phase) Cohort 2: Etrolizumab (Double-Blind Induction Phase)
    Number of subjects analysed
    95
    384
    Units: Percentage of Subjects
        number (not applicable)
    6.3
    18.5
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Cohort 2: Placebo (Double-Blind Induction Phase) v Cohort 2: Etrolizumab (Double-Blind Induction Phase)
    Number of subjects included in analysis
    479
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0033
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted difference in response rates
    Point estimate
    12.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.95
         upper limit
    		 17.67

    Primary: Maintenance Phase: Percentage of Subjects with Remission at Week 66 Among Subjects Who Had Achieved a Clinical Response at Week 14, as Determined by the MCS

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    End point title
    		 Maintenance Phase: Percentage of Subjects with Remission at Week 66 Among Subjects Who Had Achieved a Clinical Response at Week 14, as Determined by the MCS
    End point description
    The MCS ranges from 0 to 12 and is a composite of 4 assessments (each rated from 0-3): stool frequency, rectal bleeding, endoscopy, and physician’s global assessment. Higher scores represent greater disease severity. Remission was defined as MCS less than or equal to (≤)2 with individual subscores ≤1 and a rectal bleeding subscore of 0. 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
    Primary
    End point timeframe
    Week 66
    End point values
    		 Etrolizumab Responders: Placebo (Maintenance Phase) (mITT) Etrolizumab Responders: Etrolizumab (Maintenance Phase) (mITT)
    Number of subjects analysed
    114
    112
    Units: Percentage of Subjects
        number (not applicable)
    20.2
    24.1
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Etrolizumab Responders: Placebo (Maintenance Phase) (mITT) v Etrolizumab Responders: Etrolizumab (Maintenance Phase) (mITT)
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4956
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    3.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.13
         upper limit
    		 14.56

    Secondary: Induction Phase: Percentage of Subjects with Clinical Remission at Week 14, as Determined by the MCS

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    End point title
    		 Induction Phase: Percentage of Subjects with Clinical Remission at Week 14, as Determined by the MCS [2]
    End point description
    The MCS ranges from 0 to 12 and is a composite of 4 assessments (each rated from 0-3): stool frequency, rectal bleeding, endoscopy, and physician’s global assessment. Higher scores represent greater disease severity. Clinical Remission is MCS ≤2 with individual subscores ≤1.
    End point type
    Secondary
    End point timeframe
    Week 14
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This analysis was only performed on the 'Induction phase' arms and hence why not all arms are presented.
    End point values
    		 Cohort 2: Placebo (Double-Blind Induction Phase) Cohort 2: Etrolizumab (Double-Blind Induction Phase)
    Number of subjects analysed
    95
    384
    Units: Percentage of Subjects
        number (not applicable)
    6.3
    18.8
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Cohort 2: Placebo (Double-Blind Induction Phase) v Cohort 2: Etrolizumab (Double-Blind Induction Phase)
    Number of subjects included in analysis
    479
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0028 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference in Remission Rates
    Point estimate
    12.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.19
         upper limit
    		 17.94
    Notes
    [3] - Nominal P-value reported (not adjusted for multiplicity)

    Secondary: Induction Phase: Percentage of Subjects with Clinical Response at Week 14, as Determined by the MCS

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    End point title
    		 Induction Phase: Percentage of Subjects with Clinical Response at Week 14, as Determined by the MCS [4]
    End point description
    The MCS ranges from 0 to 12 and is a composite of 4 assessments (each rated from 0-3): stool frequency, rectal bleeding, endoscopy, and physician’s global assessment. Higher scores represent greater disease severity. Remission was defined as MCS less than or equal to (≤)2 with individual subscores ≤1 and a rectal bleeding subscore of 0. 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 14
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This analysis was only performed on the 'Induction phase' arms and hence why not all arms are presented.
    End point values
    		 Cohort 2: Placebo (Double-Blind Induction Phase) Cohort 2: Etrolizumab (Double-Blind Induction Phase)
    Number of subjects analysed
    95
    384
    Units: Percentage of Subjects
        number (not applicable)
    31.6
    45.8
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Cohort 2: Placebo (Double-Blind Induction Phase) v Cohort 2: Etrolizumab (Double-Blind Induction Phase)
    Number of subjects included in analysis
    479
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0241 [5]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference in Response Rates
    Point estimate
    14.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.21
         upper limit
    		 24.14
    Notes
    [5] - Multiplicity P-value reported (adjusted for multiplicity)

    Secondary: Induction Phase: Percentage of Subjects with Improvement from Baseline in Endoscopic Appearance of the Mucosa at Week 14, as Determined by the MCS Endoscopic Subscore

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    End point title
    		 Induction Phase: Percentage of Subjects with Improvement from Baseline in Endoscopic Appearance of the Mucosa at Week 14, as Determined by the MCS Endoscopic Subscore [6]
    End point description
    The MCS ranges from 0 to 12 and is a composite of 4 assessments (each rated from 0-3): stool frequency, rectal bleeding, endoscopy, and physician’s global assessment. Higher scores represent greater disease severity. Improvement in endoscopic appearance of the mucosa is Endoscopy subscore ≤1.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 14
    Notes
    [6] - 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: This analysis was only performed on the 'Induction phase' arms and hence why not all arms are presented.
    End point values
    		 Cohort 2: Placebo (Double-Blind Induction Phase) Cohort 2: Etrolizumab (Double-Blind Induction Phase)
    Number of subjects analysed
    95
    384
    Units: Percentage of Subjects
        number (not applicable)
    25.3
    33.3
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Cohort 2: Placebo (Double-Blind Induction Phase) v Cohort 2: Etrolizumab (Double-Blind Induction Phase)
    Number of subjects included in analysis
    479
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1605 [7]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference in Response Rates
    Point estimate
    8.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.54
         upper limit
    		 17.22
    Notes
    [7] - Multiplicity P-value reported (adjusted for multiplicity)

    Secondary: Induction Phase: Percentage of Subjects with Endoscopic Remission at Week 14, as Determined by the MCS Endoscopic Subscore

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    End point title
    		 Induction Phase: Percentage of Subjects with Endoscopic Remission at Week 14, as Determined by the MCS Endoscopic Subscore [8]
    End point description
    The MCS ranges from 0 to 12 and is a composite of 4 assessments (each rated from 0-3): stool frequency, rectal bleeding, endoscopy, and physician’s global assessment. Higher scores represent greater disease severity. Endoscopic Remission is Endoscopy subscore = 0.
    End point type
    Secondary
    End point timeframe
    Week 14
    Notes
    [8] - 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: This analysis was only performed on the 'Induction phase' arms and hence why not all arms are presented.
    End point values
    		 Cohort 2: Placebo (Double-Blind Induction Phase) Cohort 2: Etrolizumab (Double-Blind Induction Phase)
    Number of subjects analysed
    95
    384
    Units: Percentage of Subjects
        number (not applicable)
    9.5
    17.2
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Cohort 2: Placebo (Double-Blind Induction Phase) v Cohort 2: Etrolizumab (Double-Blind Induction Phase)
    Number of subjects included in analysis
    479
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3881 [9]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference in Remission Rates
    Point estimate
    7.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.22
         upper limit
    		 13.66
    Notes
    [9] - Multiplicity P-value reported (adjusted for multiplicity)

    Secondary: Induction Phase: Percentage of Subjects with Histologic Remission at Week 14, as Determined by the Nancy Histological Index

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    End point title
    		 Induction Phase: Percentage of Subjects with Histologic Remission at Week 14, as Determined by the Nancy Histological Index [10]
    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 14
    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: This analysis was only performed on the 'Induction phase' arms and hence why not all arms are presented.
    End point values
    		 Cohort 2: Placebo (Double-Blind Induction Phase) Cohort 2: Etrolizumab (Double-Blind Induction Phase)
    Number of subjects analysed
    80
    310
    Units: Percentage of Subjects
        number (not applicable)
    25.0
    29.7
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Cohort 2: Placebo (Double-Blind Induction Phase) v Cohort 2: Etrolizumab (Double-Blind Induction Phase)
    Number of subjects included in analysis
    390
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5879 [11]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference in Remission Rates
    Point estimate
    4.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.78
         upper limit
    		 14.69
    Notes
    [11] - Multiplicity P-value reported (adjusted for multiplicity)

    Secondary: Induction Phase: Change from Baseline to Week 6 in MCS Rectal Bleed Subscore

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    End point title
    		 Induction Phase: Change from Baseline to Week 6 in MCS Rectal Bleed Subscore [12]
    End point description
    Rectal bleeding data were collected via the subject's diaries and each day a subject provided a score from 0 to 3 according to the following definitions: 0 = no blood in the stool; 1 = streaks of blood with stool less than half the time; 2 = obvious blood with stool most of the time; 3 = blood alone passed. The Mayo Clinic Score (MCS) rectal bleeding subscore was calculated as the worst value of three days of daily diary scores closest to anchor dates at baseline and post-baseline. The data was considered non-parametric and was reported using RANK analysis of covariance (ANCOVA). Subjects were stratified by concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening (MCS ≤9/MCS ≥10); the model adjusted for these stratification factors along with the baseline rectal bleeding (RB) subscore.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 6
    Notes
    [12] - 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: This analysis was only performed on the 'Induction phase' arms and hence why not all arms are presented.
    End point values
    		 Cohort 2: Placebo (Double-Blind Induction Phase) Cohort 2: Etrolizumab (Double-Blind Induction Phase)
    Number of subjects analysed
    94
    383
    Units: Score on a Scale
        arithmetic mean (standard deviation)
    -0.4 ( 0.8 )
    -0.7 ( 0.9 )
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Cohort 2: Placebo (Double-Blind Induction Phase) v Cohort 2: Etrolizumab (Double-Blind Induction Phase)
    Number of subjects included in analysis
    477
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0351 [13]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in Unadjusted Means
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 0
    Notes
    [13] - Multiplicity P-value reported (adjusted for multiplicity)

    Secondary: Induction Phase: Change from Baseline to Week 6 in MCS Stool Frequency Subscore

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    End point title
    		 Induction Phase: Change from Baseline to Week 6 in MCS Stool Frequency Subscore [14]
    End point description
    Stool frequency data were collected via the subject's diaries and each day a subject provided a score from 0 to 3 according to the following definitions: 0 = normal number of stools; 1 = 1 to 2 more stools than normal; 2 = 3 to 4 more stools than normal; 3 = 5 or more stools than normal. The Mayo Clinic Score (MCS) stool frequency subscore was calculated as the average of three days daily diary scores closest to anchor dates at baseline and post-baseline. The data was considered non-parametric and was reported using RANK analysis of covariance (ANCOVA). Subjects were stratified by concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening (MCS ≤9/MCS ≥10); the model adjusted for these stratification factors along with the baseline stool frequency (SF) subscore.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 6
    Notes
    [14] - 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: This analysis was only performed on the 'Induction phase' arms and hence why not all arms are presented.
    End point values
    		 Cohort 2: Placebo (Double-Blind Induction Phase) Cohort 2: Etrolizumab (Double-Blind Induction Phase)
    Number of subjects analysed
    94
    383
    Units: Score on a Scale
        arithmetic mean (standard deviation)
    -0.5 ( 0.9 )
    -0.6 ( 1.0 )
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Cohort 2: Placebo (Double-Blind Induction Phase) v Cohort 2: Etrolizumab (Double-Blind Induction Phase)
    Number of subjects included in analysis
    477
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2698 [15]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in Unadjusted Means
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 0.1
    Notes
    [15] - Multiplicity P-value reported (adjusted for multiplicity)

    Secondary: Induction Phase: Change from Baseline to Week 14 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
    		 Induction Phase: Change from Baseline to Week 14 in UC Bowel Movement Signs and Symptoms, as Assessed by the Ulcerative Colitis Patient-Reported Outcome Signs and Symptoms (UC-PRO/SS) Questionnaire [16]
    End point description
    The UC-PRO questionnaire is collected in the e-diary and completed by subjects 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 and Week 14
    Notes
    [16] - 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: This analysis was only performed on the 'Induction phase' arms and hence why not all arms are presented.
    End point values
    		 Cohort 2: Placebo (Double-Blind Induction Phase) Cohort 2: Etrolizumab (Double-Blind Induction Phase)
    Number of subjects analysed
    80
    272
    Units: Score on a Scale
        least squares mean (standard error)
    -3.6 ( 0.6 )
    -5.2 ( 0.3 )
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Cohort 2: Placebo (Double-Blind Induction Phase) v Cohort 2: Etrolizumab (Double-Blind Induction Phase)
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2698 [17]
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in Least Square Means
    Point estimate
    -1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.9
         upper limit
    		 -0.3
    Notes
    [17] - Multiplicity P-value reported (adjusted for multiplicity)

    Secondary: Induction Phase: Change from Baseline to Week 14 in UC Functional Symptoms, as Assessed by the UC-PRO/SS Questionnaire

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    End point title
    		 Induction Phase: Change from Baseline to Week 14 in UC Functional Symptoms, as Assessed by the UC-PRO/SS Questionnaire [18]
    End point description
    The UC-PRO questionnaire is collected in the e-diary and completed by subjects 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 (abdominal symptoms) domain score ranges from 0-12, with a higher score indicating a worse disease state.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 14
    Notes
    [18] - 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: This analysis was only performed on the 'Induction phase' arms and hence why not all arms are presented.
    End point values
    		 Cohort 2: Placebo (Double-Blind Induction Phase) Cohort 2: Etrolizumab (Double-Blind Induction Phase)
    Number of subjects analysed
    80
    272
    Units: Score on a Scale
        least squares mean (standard error)
    -1.1 ( 0.2 )
    -1.5 ( 0.1 )
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Cohort 2: Placebo (Double-Blind Induction Phase) v Cohort 2: Etrolizumab (Double-Blind Induction Phase)
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3881 [19]
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in Least Square Means
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 0
    Notes
    [19] - Multiplicity P-value reported (adjusted for multiplicity)

    Secondary: Induction Phase: Change from Baseline to Week 14 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
    		 Induction Phase: Change from Baseline to Week 14 in Health-Related Quality of Life, as Assessed by the Overall Score of the Inflammatory Bowel Disease Questionnaire (IBDQ) [20]
    End point description
    The IBDQ score is a Total Score summed up from across all 32 questions on the questionnaire. The Total Score range is from 32 to 224 with higher scores representing a better quality of life.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 14
    Notes
    [20] - 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: This analysis was only performed on the 'Induction phase' arms and hence why not all arms are presented.
    End point values
    		 Cohort 2: Placebo (Double-Blind Induction Phase) Cohort 2: Etrolizumab (Double-Blind Induction Phase)
    Number of subjects analysed
    74
    293
    Units: Scores on a Scale
        least squares mean (standard error)
    28.4 ( 4.12 )
    37.4 ( 2.17 )
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Cohort 2: Placebo (Double-Blind Induction Phase) v Cohort 2: Etrolizumab (Double-Blind Induction Phase)
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0445 [21]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in Adjusted Means
    Point estimate
    9.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 17.9
    Notes
    [21] - Nominal P-value reported (not adjusted for multiplicity)

    Secondary: Maintenance Phase: Percentage of Subjects with Clinical Remission at Week 66 Among Subjects Who Had Achieved Clinical Remission at Week 14, as Determined by the MCS

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    End point title
    		 Maintenance Phase: Percentage of Subjects with Clinical Remission at Week 66 Among Subjects Who Had Achieved Clinical Remission at Week 14, as Determined by the MCS
    End point description
    The MCS ranges from 0 to 12 and is a composite of 4 assessments (each rated from 0-3): stool frequency, rectal bleeding, endoscopy, and physician’s global assessment. Higher scores represent greater disease severity. Remission was defined as MCS less than or equal to (≤)2 with individual subscores ≤1 and a rectal bleeding subscore of 0. Clinical Remission is MCS ≤2 with individual subscores ≤1.
    End point type
    Secondary
    End point timeframe
    Week 66
    End point values
    		 Etrolizumab Responders: Placebo (Maintenance Phase) (mITT) Etrolizumab Responders: Etrolizumab (Maintenance Phase) (mITT)
    Number of subjects analysed
    44
    42
    Units: Percentage of Subjects
        number (not applicable)
    36.4
    38.1
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Etrolizumab Responders: Placebo (Maintenance Phase) (mITT) v Etrolizumab Responders: Etrolizumab (Maintenance Phase) (mITT)
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.9959 [22]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference in Remission Rates
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.67
         upper limit
    		 19.88
    Notes
    [22] - Nominal P-value reported (not adjusted for multiplicity)

    Secondary: Maintenance Phase: Percentage of Subjects with Clinical Remission at Week 66, as Determined by the MCS

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    End point title
    		 Maintenance Phase: Percentage of Subjects with Clinical Remission at Week 66, as Determined by the MCS
    End point description
    The MCS ranges from 0 to 12 and is a composite of 4 assessments (each rated from 0-3): stool frequency, rectal bleeding, endoscopy, and physician’s global assessment. Higher scores represent greater disease severity. Remission was defined as MCS less than or equal to (≤)2 with individual subscores ≤1 and a rectal bleeding subscore of 0. Clinical Remission is MCS ≤2 with individual subscores ≤1.
    End point type
    Secondary
    End point timeframe
    Week 66
    End point values
    		 Etrolizumab Responders: Placebo (Maintenance Phase) (mITT) Etrolizumab Responders: Etrolizumab (Maintenance Phase) (mITT)
    Number of subjects analysed
    114
    112
    Units: Percentage of Subjects
        number (not applicable)
    21.1
    25.0
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Etrolizumab Responders: Placebo (Maintenance Phase) (mITT) v Etrolizumab Responders: Etrolizumab (Maintenance Phase) (mITT)
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5014 [23]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference in Remission Rates
    Point estimate
    3.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.26
         upper limit
    		 14.7
    Notes
    [23] - Nominal P-value reported (not adjusted for multiplicity)

    Secondary: Maintenance Phase: Percentage of Subjects with Remission at Week 66 Among Subjects Who Had Achieved Remission at Week 14, as Determined by the MCS

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    End point title
    		 Maintenance Phase: Percentage of Subjects with Remission at Week 66 Among Subjects Who Had Achieved Remission at Week 14, as Determined by the MCS
    End point description
    The MCS ranges from 0 to 12 and is a composite of 4 assessments (each rated from 0-3): stool frequency, rectal bleeding, endoscopy, and physician’s global assessment. Higher scores represent greater disease severity. Remission was defined as MCS less than or equal to (≤)2 with individual subscores ≤1 and a rectal bleeding subscore of 0.
    End point type
    Secondary
    End point timeframe
    Week 66
    End point values
    		 Etrolizumab Responders: Placebo (Maintenance Phase) (mITT) Etrolizumab Responders: Etrolizumab (Maintenance Phase) (mITT)
    Number of subjects analysed
    44
    41
    Units: Percentage of Subjects
        number (not applicable)
    34.1
    36.6
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Etrolizumab Responders: Placebo (Maintenance Phase) (mITT) v Etrolizumab Responders: Etrolizumab (Maintenance Phase) (mITT)
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.9538 [24]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference in Remission Rates
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.08
         upper limit
    		 20.35
    Notes
    [24] - Nominal P-value reported (not adjusted for multiplicity)

    Secondary: Maintenance Phase: Percentage of Subjects with Improvement From Baseline in Endoscopic Appearance of the Mucosa at Week 66, as Determined by the MCS Endoscopic Subscore

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    End point title
    		 Maintenance Phase: Percentage of Subjects with Improvement From Baseline in Endoscopic Appearance of the Mucosa at Week 66, as Determined by the MCS Endoscopic Subscore
    End point description
    The MCS ranges from 0 to 12 and is a composite of 4 assessments (each rated from 0-3): stool frequency, rectal bleeding, endoscopy, and physician’s global assessment. Higher scores represent greater disease severity. Improvement in endoscopic appearance of the mucosa is Endoscopy subscore ≤1.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 66
    End point values
    		 Etrolizumab Responders: Placebo (Maintenance Phase) (mITT) Etrolizumab Responders: Etrolizumab (Maintenance Phase) (mITT)
    Number of subjects analysed
    114
    112
    Units: Percentage of Subjects
        number (not applicable)
    21.1
    35.7
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Etrolizumab Responders: Placebo (Maintenance Phase) (mITT) v Etrolizumab Responders: Etrolizumab (Maintenance Phase) (mITT)
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0153 [25]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference in Response Rates
    Point estimate
    14.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.66
         upper limit
    		 25.78
    Notes
    [25] - Nominal P-value reported (not adjusted for multiplicity)

    Secondary: Maintenance Phase: Percentage of Subjects with Histologic Remission at Week 66, as Determined by the Nancy Histological Index

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    End point title
    		 Maintenance Phase: Percentage of Subjects with Histologic Remission at Week 66, 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 66
    End point values
    		 Etrolizumab Responders: Placebo (Maintenance Phase) (mITT) Etrolizumab Responders: Etrolizumab (Maintenance Phase) (mITT)
    Number of subjects analysed
    92
    91
    Units: Percentage of Subjects
        number (not applicable)
    14.1
    30.8
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Etrolizumab Responders: Placebo (Maintenance Phase) (mITT) v Etrolizumab Responders: Etrolizumab (Maintenance Phase) (mITT)
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0073 [26]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference in Remission Rates
    Point estimate
    16.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.44
         upper limit
    		 28.41
    Notes
    [26] - Nominal P-value reported (not adjusted for multiplicity)

    Secondary: Maintenance Phase: Percentage of Subjects with Endoscopic Remission at Week 66, as Determined by the MCS Endoscopic Subscore

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    End point title
    		 Maintenance Phase: Percentage of Subjects with Endoscopic Remission at Week 66, as Determined by the MCS Endoscopic Subscore
    End point description
    The MCS ranges from 0 to 12 and is a composite of 4 assessments (each rated from 0-3): stool frequency, rectal bleeding, endoscopy, and physician’s global assessment. Higher scores represent greater disease severity. Endoscopic Remission is Endoscopy subscore = 0.
    End point type
    Secondary
    End point timeframe
    Week 66
    End point values
    		 Etrolizumab Responders: Placebo (Maintenance Phase) (mITT) Etrolizumab Responders: Etrolizumab (Maintenance Phase) (mITT)
    Number of subjects analysed
    114
    112
    Units: Percentage of Subjects
        number (not applicable)
    11.4
    23.2
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Etrolizumab Responders: Placebo (Maintenance Phase) (mITT) v Etrolizumab Responders: Etrolizumab (Maintenance Phase) (mITT)
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0174 [27]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference in Remission Rates
    Point estimate
    11.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.87
         upper limit
    		 21.71
    Notes
    [27] - Nominal P-value reported (not adjusted for multiplicity)

    Secondary: Maintenance Phase: Percentage of Subjects with Corticosteroid-Free Clinical Remission at Week 66 Among Subjects Who Were Receiving Corticosteroids at Baseline, as Determined by the MCS

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    End point title
    		 Maintenance Phase: Percentage of Subjects with Corticosteroid-Free Clinical Remission at Week 66 Among Subjects Who Were Receiving Corticosteroids at Baseline, as Determined by the MCS
    End point description
    The MCS ranges from 0 to 12 and is a composite of 4 assessments (each rated from 0-3): stool frequency, rectal bleeding, endoscopy, and physician’s global assessment. Higher scores represent greater disease severity. Corticosteroid-Free analysis was conducted only on a subgroup of participants who were randomized into the maintenance phase and receiving Corticosteroids (CS) at baseline. Subjects were defined as being off CS if they had no record of taking CS on the date that was 24 weeks prior to Week 66.
    End point type
    Secondary
    End point timeframe
    Week 66
    End point values
    		 Etrolizumab Responders: Placebo (Maintenance Phase) (mITT) Etrolizumab Responders: Etrolizumab (Maintenance Phase) (mITT)
    Number of subjects analysed
    55
    54
    Units: Percentage of Subjects
        number (not applicable)
    12.7
    20.4
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Etrolizumab Responders: Placebo (Maintenance Phase) (mITT) v Etrolizumab Responders: Etrolizumab (Maintenance Phase) (mITT)
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3015 [28]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference in Remission Rates
    Point estimate
    7.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.83
         upper limit
    		 21.6
    Notes
    [28] - Nominal P-value reported (not adjusted for multiplicity)

    Secondary: Maintenance Phase: Percentage of Subjects with Corticosteroid-Free Remission at Week 66 Among Subjects Who Were Receiving Corticosteroids at Baseline, as Determined by the MCS

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    End point title
    		 Maintenance Phase: Percentage of Subjects with Corticosteroid-Free Remission at Week 66 Among Subjects Who Were Receiving Corticosteroids at Baseline, as Determined by the MCS
    End point description
    The MCS ranges from 0 to 12 and is a composite of 4 assessments (each rated from 0-3): stool frequency, rectal bleeding, endoscopy, and physician’s global assessment. Higher scores represent greater disease severity. Corticosteroid-Free analysis was conducted only on a subgroup of subjects who were randomized into the maintenance phase and receiving Corticosteroids (CS) at baseline. Subjects were defined as being off CS if they had no record of taking CS on the date that was 24 weeks prior to Week 66.
    End point type
    Secondary
    End point timeframe
    Week 66
    End point values
    		 Etrolizumab Responders: Placebo (Maintenance Phase) (mITT) Etrolizumab Responders: Etrolizumab (Maintenance Phase) (mITT)
    Number of subjects analysed
    55
    54
    Units: Percentage of Subjects
        number (not applicable)
    10.9
    18.5
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Etrolizumab Responders: Placebo (Maintenance Phase) (mITT) v Etrolizumab Responders: Etrolizumab (Maintenance Phase) (mITT)
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2787 [29]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference in Remission Rates
    Point estimate
    7.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.23
         upper limit
    		 21.17
    Notes
    [29] - Nominal P-value reported (not adjusted for multiplicity)

    Secondary: Maintenance Phase: Change From Baseline to Week 66 in UC Bowel Movement Signs and Symptoms, as Assessed by the UC-PRO/SS Questionnaire

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    End point title
    		 Maintenance Phase: Change From Baseline to Week 66 in UC Bowel Movement Signs and 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 subjects 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 and Week 66
    End point values
    		 Etrolizumab Responders: Placebo (Maintenance Phase) (mITT) Etrolizumab Responders: Etrolizumab (Maintenance Phase) (mITT)
    Number of subjects analysed
    83
    83
    Units: Score on a Scale
        least squares mean (standard error)
    -6.3 ( 0.6 )
    -7.8 ( 0.6 )
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Etrolizumab Responders: Placebo (Maintenance Phase) (mITT) v Etrolizumab Responders: Etrolizumab (Maintenance Phase) (mITT)
    Number of subjects included in analysis
    166
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0763 [30]
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in Least Square Means
    Point estimate
    -1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.1
         upper limit
    		 0.2
    Notes
    [30] - Nominal P-value reported (not adjusted for multiplicity)

    Secondary: Maintenance Phase: Change From Baseline to Week 66 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 66 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 subjects 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 (abdominal symptoms) domain score ranges from 0-12, with a higher score indicating a worse disease state.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 66
    End point values
    		 Etrolizumab Responders: Placebo (Maintenance Phase) (mITT) Etrolizumab Responders: Etrolizumab (Maintenance Phase) (mITT)
    Number of subjects analysed
    83
    83
    Units: Score on a Scale
        least squares mean (standard error)
    -1.8 ( 0.3 )
    -2.0 ( 0.3 )
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Etrolizumab Responders: Placebo (Maintenance Phase) (mITT) v Etrolizumab Responders: Etrolizumab (Maintenance Phase) (mITT)
    Number of subjects included in analysis
    166
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5329 [31]
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in Least Square Means
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 0.5
    Notes
    [31] - Nominal P-value reported (not adjusted for multiplicity)

    Secondary: Maintenance Phase: Change From Baseline to Week 66 in Health-Related Quality of Life, as Assessed by the Overall Score of the IBDQ

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    End point title
    		 Maintenance Phase: Change From Baseline to Week 66 in Health-Related Quality of Life, as Assessed by the Overall Score of the IBDQ
    End point description
    The IBDQ is used to assess participant's health-related quality of life (QOL). The IBDQ score is a Total Score summed up from across all 32 questions on the questionnaire. The Total Score range is from 32 to 224 with higher scores representing a better quality of life.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 66
    End point values
    		 Etrolizumab Responders: Placebo (Maintenance Phase) (mITT) Etrolizumab Responders: Etrolizumab (Maintenance Phase) (mITT)
    Number of subjects analysed
    99
    99
    Units: Scores on a Scale
        least squares mean (standard error)
    57.2 ( 3.1 )
    52.3 ( 3.1 )
    Statistical analysis title
    		 Etrolizumab vs. Placebo
    Comparison groups
    Etrolizumab Responders: Placebo (Maintenance Phase) (mITT) v Etrolizumab Responders: Etrolizumab (Maintenance Phase) (mITT)
    Number of subjects included in analysis
    198
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2228 [32]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in Adjusted Means
    Point estimate
    -4.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.7
         upper limit
    		 3
    Notes
    [32] - Nominal P-value reported (not adjusted for multiplicity)

    Secondary: Number of Subjects 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 Subjects 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 subject at the highest (worst) grade.
    End point type
    Secondary
    End point timeframe
    From Baseline up to Week 78
    End point values
    		 Cohort 1: Etrolizumab (Open-Label Induction (OLI) Phase) Placebo Responders: Placebo (Maintenance Phase) Cohort 2: Placebo (Double-Blind Induction Phase) Etrolizumab Responders: Placebo (Maintenance Phase) Cohort 2: Etrolizumab (Double-Blind Induction Phase) Etrolizumab Responders: Etrolizumab (Maintenance Phase)
    Number of subjects analysed
    130
    27
    95
    114
    384
    112
    Units: Subjects
        Grade 1
    39
    8
    31
    19
    117
    33
        Grade 2
    38
    14
    26
    64
    97
    45
        Grade 3
    15
    1
    5
    14
    37
    19
        Grade 4
    0
    0
    1
    0
    2
    1
        Grade 5
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

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

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    End point title
    		 Number of Subjects with Adverse Events Leading to Study Drug Discontinuation
    End point description
    End point type
    Secondary
    End point timeframe
    From Baseline up to Week 78
    End point values
    		 Cohort 1: Etrolizumab (Open-Label Induction (OLI) Phase) Placebo Responders: Placebo (Maintenance Phase) Cohort 2: Placebo (Double-Blind Induction Phase) Etrolizumab Responders: Placebo (Maintenance Phase) Cohort 2: Etrolizumab (Double-Blind Induction Phase) Etrolizumab Responders: Etrolizumab (Maintenance Phase)
    Number of subjects analysed
    130
    27
    95
    114
    384
    112
    Units: Subjects
    2
    4
    1
    9
    12
    10
    No statistical analyses for this end point

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

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    End point title
    		 Number of Subjects with Serious Infection-Related Adverse Events
    End point description
    End point type
    Secondary
    End point timeframe
    From Baseline up to Week 78
    End point values
    		 Cohort 1: Etrolizumab (Open-Label Induction (OLI) Phase) Placebo Responders: Placebo (Maintenance Phase) Cohort 2: Placebo (Double-Blind Induction Phase) Etrolizumab Responders: Placebo (Maintenance Phase) Cohort 2: Etrolizumab (Double-Blind Induction Phase) Etrolizumab Responders: Etrolizumab (Maintenance Phase)
    Number of subjects analysed
    130
    27
    95
    114
    384
    112
    Units: Subjects
    2
    0
    1
    3
    5
    3
    No statistical analyses for this end point

    Secondary: Number of Subjects with Infection-Related Adverse Events

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    End point title
    		 Number of Subjects with Infection-Related Adverse Events
    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. 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 subject at the highest (worst) grade.
    End point type
    Secondary
    End point timeframe
    From Baseline up to Week 78
    End point values
    		 Cohort 1: Etrolizumab (Open-Label Induction (OLI) Phase) Placebo Responders: Placebo (Maintenance Phase) Cohort 2: Placebo (Double-Blind Induction Phase) Etrolizumab Responders: Placebo (Maintenance Phase) Cohort 2: Etrolizumab (Double-Blind Induction Phase) Etrolizumab Responders: Etrolizumab (Maintenance Phase)
    Number of subjects analysed
    130
    27
    95
    114
    384
    112
    Units: Subjects
    38
    13
    29
    44
    100
    58
    No statistical analyses for this end point

    Secondary: Number of Subjects with Injection-Site Reaction-Related Adverse Events

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    End point title
    		 Number of Subjects with Injection-Site Reaction-Related Adverse Events
    End point description
    End point type
    Secondary
    End point timeframe
    From Baseline up to Week 78
    End point values
    		 Cohort 1: Etrolizumab (Open-Label Induction (OLI) Phase) Placebo Responders: Placebo (Maintenance Phase) Cohort 2: Placebo (Double-Blind Induction Phase) Etrolizumab Responders: Placebo (Maintenance Phase) Cohort 2: Etrolizumab (Double-Blind Induction Phase) Etrolizumab Responders: Etrolizumab (Maintenance Phase)
    Number of subjects analysed
    130
    27
    95
    114
    384
    112
    Units: Subjects
    7
    2
    5
    2
    4
    8
    No statistical analyses for this end point

    Secondary: Number of Subjects with Hypersensitivity Reaction-Related Adverse Events

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    End point title
    		 Number of Subjects with Hypersensitivity Reaction-Related Adverse Events
    End point description
    End point type
    Secondary
    End point timeframe
    From Baseline up to Week 78
    End point values
    		 Cohort 1: Etrolizumab (Open-Label Induction (OLI) Phase) Placebo Responders: Placebo (Maintenance Phase) Cohort 2: Placebo (Double-Blind Induction Phase) Etrolizumab Responders: Placebo (Maintenance Phase) Cohort 2: Etrolizumab (Double-Blind Induction Phase) Etrolizumab Responders: Etrolizumab (Maintenance Phase)
    Number of subjects analysed
    130
    27
    95
    114
    384
    112
    Units: Subjects
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects with Malignancies

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    End point title
    		 Number of Subjects with Malignancies
    End point description
    End point type
    Secondary
    End point timeframe
    From Baseline up to Week 78
    End point values
    		 Cohort 1: Etrolizumab (Open-Label Induction (OLI) Phase) Placebo Responders: Placebo (Maintenance Phase) Cohort 2: Placebo (Double-Blind Induction Phase) Etrolizumab Responders: Placebo (Maintenance Phase) Cohort 2: Etrolizumab (Double-Blind Induction Phase) Etrolizumab Responders: Etrolizumab (Maintenance Phase)
    Number of subjects analysed
    130
    27
    95
    114
    384
    112
    Units: Subjects
    0
    0
    0
    0
    2
    2
    No statistical analyses for this end point

    Secondary: Number of Subjects with Anti-Therapeutic Antibodies to Etrolizumab at Baseline and During the Study

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    End point title
    		 Number of Subjects with Anti-Therapeutic Antibodies to Etrolizumab at Baseline and During the Study
    End point description
    A tiered strategy was used to detect and characterize etrolizumab antibodies within this clinical study. When determining post baseline incidence, subjects were considered to be ADA positive if they were ADA negative or had missing data at baseline but developed an ADA response following etrolizumab drug exposure (treatment-induced ADA response), or if they were ADA positive at baseline and the titer of one or more post baseline samples was at least 0.60 titer unit greater than the titer of the baseline sample (treatment-enhanced ADA response). Subjects were considered to be ADA negative if they were ADA negative or had missing data at baseline and all post baseline samples were negative, or if they were ADA positive at baseline but did not have any post baseline samples with a titer that was at least 0.60 titer unit greater than the titer of the baseline sample (treatment unaffected). (n=X; n=X; n=X) refers to Number of Subjects analysed at each timepoint.
    End point type
    Secondary
    End point timeframe
    Pre-dose at Baseline, Weeks 4, 14, 24, 44, and 66, and Early Termination/End of Safety Follow-Up (up to Week 78)
    End point values
    		 Cohort 1: Etro (OLI Phase) + Cohort 2: Etro (DB Ind Phase) Etrolizumab Responders: Placebo (Maintenance Phase) (mITT) Etrolizumab Responders: Etrolizumab (Maintenance Phase) (mITT)
    Number of subjects analysed
    286
    114
    112
    Units: Subjects
        Baseline (n=286; n=114; n=110)
    9
    2
    6
        Post-Baseline (n=284; n=114; n=112)
    68
    35
    28
    No statistical analyses for this end point

    Secondary: Etrolizumab Serum Trough Concentration (for Arms/Timepoints above LLOQ)

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    End point title
    		 Etrolizumab Serum Trough Concentration (for Arms/Timepoints above LLOQ)
    End point description
    As per Protocol, the timepoints for each arm where more than a third of the samples were above the lower limit of quantification (LLOQ), full summary statistics (Mean and Standard Deviation) were reported. For timepoints below the LLOQ, only the Median and Max were reported as a separate outcome measure below. (n=X; n=X; n=X) refers to Number of Subjects analysed at each timepoint.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hour) at Baseline and Weeks 14, 24, 44 and 66
    End point values
    		 Cohort 1: Etro (OLI Phase) + Cohort 2: Etro (DB Ind Phase) Etrolizumab Responders: Placebo (Maintenance Phase) (mITT) Etrolizumab Responders: Etrolizumab (Maintenance Phase) (mITT)
    Number of subjects analysed
    251
    113
    110
    Units: micrograms per millilitre (μg/mL)
    arithmetic mean (standard deviation)
        Week 14 (n=251; n=113; n=110)
    11.0 ( 4.66 )
    12.7 ( 5.50 )
    14.0 ( 6.12 )
        Week 24 (n=0; n=93; n=92)
    0 ( 0 )
    0.474 ( 0.742 )
    9.55 ( 5.24 )
        Week 44 (n=0; n=0; n=71)
    0 ( 0 )
    0 ( 0 )
    10.7 ( 5.72 )
        Week 66 (n=0; n=0; n=59)
    0 ( 0 )
    0 ( 0 )
    16.2 ( 7.75 )
    No statistical analyses for this end point

    Secondary: Etrolizumab Serum Trough Concentration (for Arms/Timepoints below LLOQ)

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    End point title
    		 Etrolizumab Serum Trough Concentration (for Arms/Timepoints below LLOQ)
    End point description
    As per Protocol, the timepoints for each arm where more than a third of the samples were below the LLOQ only the Median and Max were reported. 0000 = Not Estimable.
    End point type
    Secondary
    End point timeframe
    Weeks 44 and 66
    End point values
    		 Etrolizumab Responders: Placebo (Maintenance Phase)
    Number of subjects analysed
    113
    Units: micrograms per millilitre (μg/mL)
    arithmetic mean (full range (min-max))
        Week 44 (n=54)
    0.0400 (0000 to 2.73)
        Week 66 (n=40)
    0.0400 (0000 to 0.0400)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up until a maximum of 78 weeks.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Cohort 1: Etrolizumab (OLI Induction Phase)
    Reporting group description
    		 Participants assigned to this arm will receive treatment with open-label etrolizumab 105 milligrams (mg) subcutaneous (SC) injection once every 4 weeks (Q4W) for 14 weeks during the induction phase.

    Reporting group title
    Cohort 2: Placebo (Double-Blind Induction Phase)
    Reporting group description
    		 Participants randomized to this arm will receive treatment with double-blind placebo SC injection Q4W for 14 weeks during the induction phase.

    Reporting group title
    Cohort 2: Etrolizumab (Double-Blind Induction Phase)
    Reporting group description
    		 Participants randomized to this arm will receive treatment with double-blind etrolizumab 105 mg SC injection Q4W for 14 weeks during the induction phase.

    Reporting group title
    Placebo Responders: Placebo (Maintenance Phase)
    Reporting group description
    		 Participants who received placebo during the induction phase, Cohort 2: Placebo (Double-Blind Induction Phase), and achieve a clinical response with placebo at Week 14 will continue to receive blinded placebo from Week 16 up to Week 66 during the maintenance phase.

    Reporting group title
    Etrolizumab Responders: Placebo (Maintenance Phase)
    Reporting group description
    		 Participants who received etrolizumab during the induction phase, Cohort 1: Etrolizumab (Open-Label Induction Phase) and Cohort 2: Etrolizumab (Double-Blind Induction Phase), and achieved a clinical response at Week 14 will be re-randomized by Week 16 for the double-blind maintenance phase. Clinical responders re-randomized to this arm will receive placebo SC injection Q4W from Week 16 up to Week 66.

    Reporting group title
    Etrolizumab Responders: Etrolizumab (Maintenance Phase)
    Reporting group description
    		 Participants who received etrolizumab during the induction phase, Cohort 1: Etrolizumab (Open-Label Induction Phase) and Cohort 2: Etrolizumab (Double-Blind Induction Phase), and achieved a clinical response at Week 14 will be re-randomized by Week 16 for the double-blind maintenance phase. Clinical responders re-randomized to this arm will receive etrolizumab 105 mg SC injection Q4W from Week 16 up to Week 66.

    Serious adverse events
    		 Cohort 1: Etrolizumab (OLI Induction Phase) Cohort 2: Placebo (Double-Blind Induction Phase) Cohort 2: Etrolizumab (Double-Blind Induction Phase) Placebo Responders: Placebo (Maintenance Phase) Etrolizumab Responders: Placebo (Maintenance Phase) Etrolizumab Responders: Etrolizumab (Maintenance Phase)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 130 (8.46%)
    5 / 95 (5.26%)
    20 / 384 (5.21%)
    2 / 27 (7.41%)
    7 / 114 (6.14%)
    11 / 112 (9.82%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    0 / 384 (0.00%)
    0 / 27 (0.00%)
    0 / 114 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleomorphic adenoma
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    1 / 384 (0.26%)
    0 / 27 (0.00%)
    0 / 114 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uteric cancer
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    1 / 384 (0.26%)
    0 / 27 (0.00%)
    0 / 114 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    1 / 384 (0.26%)
    0 / 27 (0.00%)
    0 / 114 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Hypoaesthesia
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 95 (0.00%)
    0 / 384 (0.00%)
    0 / 27 (0.00%)
    0 / 114 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 95 (0.00%)
    0 / 384 (0.00%)
    0 / 27 (0.00%)
    0 / 114 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myoclonus
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    1 / 384 (0.26%)
    0 / 27 (0.00%)
    0 / 114 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 130 (0.00%)
    2 / 95 (2.11%)
    1 / 384 (0.26%)
    0 / 27 (0.00%)
    2 / 114 (1.75%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 95 (0.00%)
    0 / 384 (0.00%)
    0 / 27 (0.00%)
    1 / 114 (0.88%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Cheilitis
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    1 / 384 (0.26%)
    0 / 27 (0.00%)
    0 / 114 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    6 / 130 (4.62%)
    2 / 95 (2.11%)
    10 / 384 (2.60%)
    0 / 27 (0.00%)
    2 / 114 (1.75%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
    0 / 10
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 95 (1.05%)
    1 / 384 (0.26%)
    1 / 27 (3.70%)
    0 / 114 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal necrosis
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    1 / 384 (0.26%)
    0 / 27 (0.00%)
    0 / 114 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    1 / 384 (0.26%)
    0 / 27 (0.00%)
    0 / 114 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pouchitis
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 95 (1.05%)
    0 / 384 (0.00%)
    0 / 27 (0.00%)
    0 / 114 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    0 / 384 (0.00%)
    0 / 27 (0.00%)
    0 / 114 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eosinophilic pneumonia
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    0 / 384 (0.00%)
    0 / 27 (0.00%)
    0 / 114 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Affect liability
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    0 / 384 (0.00%)
    0 / 27 (0.00%)
    0 / 114 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    0 / 384 (0.00%)
    1 / 27 (3.70%)
    0 / 114 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 95 (0.00%)
    0 / 384 (0.00%)
    0 / 27 (0.00%)
    0 / 114 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    1 / 384 (0.26%)
    0 / 27 (0.00%)
    0 / 114 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 95 (1.05%)
    0 / 384 (0.00%)
    0 / 27 (0.00%)
    0 / 114 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    1 / 384 (0.26%)
    0 / 27 (0.00%)
    0 / 114 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    0 / 384 (0.00%)
    0 / 27 (0.00%)
    0 / 114 (0.00%)
    2 / 112 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    0 / 384 (0.00%)
    0 / 27 (0.00%)
    1 / 114 (0.88%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    1 / 384 (0.26%)
    0 / 27 (0.00%)
    1 / 114 (0.88%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    0 / 384 (0.00%)
    0 / 27 (0.00%)
    1 / 114 (0.88%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    1 / 384 (0.26%)
    0 / 27 (0.00%)
    0 / 114 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 95 (0.00%)
    0 / 384 (0.00%)
    0 / 27 (0.00%)
    0 / 114 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 95 (0.00%)
    0 / 384 (0.00%)
    0 / 27 (0.00%)
    0 / 114 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 95 (0.00%)
    0 / 384 (0.00%)
    0 / 27 (0.00%)
    0 / 114 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    0 / 384 (0.00%)
    0 / 27 (0.00%)
    1 / 114 (0.88%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    0 / 384 (0.00%)
    0 / 27 (0.00%)
    0 / 114 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    1 / 384 (0.26%)
    0 / 27 (0.00%)
    0 / 114 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    1 / 384 (0.26%)
    0 / 27 (0.00%)
    0 / 114 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    0 / 384 (0.00%)
    0 / 27 (0.00%)
    0 / 114 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1: Etrolizumab (OLI Induction Phase) Cohort 2: Placebo (Double-Blind Induction Phase) Cohort 2: Etrolizumab (Double-Blind Induction Phase) Placebo Responders: Placebo (Maintenance Phase) Etrolizumab Responders: Placebo (Maintenance Phase) Etrolizumab Responders: Etrolizumab (Maintenance Phase)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    38 / 130 (29.23%)
    31 / 95 (32.63%)
    115 / 384 (29.95%)
    20 / 27 (74.07%)
    78 / 114 (68.42%)
    78 / 112 (69.64%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    0 / 384 (0.00%)
    2 / 27 (7.41%)
    1 / 114 (0.88%)
    2 / 112 (1.79%)
         occurrences all number
    0
    0
    0
    2
    1
    2
    Headache
         subjects affected / exposed
    10 / 130 (7.69%)
    6 / 95 (6.32%)
    22 / 384 (5.73%)
    3 / 27 (11.11%)
    10 / 114 (8.77%)
    10 / 112 (8.93%)
         occurrences all number
    11
    8
    26
    3
    12
    10
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    0 / 384 (0.00%)
    2 / 27 (7.41%)
    3 / 114 (2.63%)
    5 / 112 (4.46%)
         occurrences all number
    0
    0
    0
    3
    3
    6
    Fatigue
         subjects affected / exposed
    8 / 130 (6.15%)
    1 / 95 (1.05%)
    10 / 384 (2.60%)
    1 / 27 (3.70%)
    4 / 114 (3.51%)
    12 / 112 (10.71%)
         occurrences all number
    11
    1
    13
    1
    4
    13
    Injection site erythema
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    0 / 384 (0.00%)
    2 / 27 (7.41%)
    2 / 114 (1.75%)
    5 / 112 (4.46%)
         occurrences all number
    0
    0
    0
    2
    3
    9
    Pyrexia
         subjects affected / exposed
    5 / 130 (3.85%)
    6 / 95 (6.32%)
    3 / 384 (0.78%)
    0 / 27 (0.00%)
    0 / 114 (0.00%)
    0 / 112 (0.00%)
         occurrences all number
    7
    8
    3
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    0 / 384 (0.00%)
    1 / 27 (3.70%)
    7 / 114 (6.14%)
    10 / 112 (8.93%)
         occurrences all number
    0
    0
    0
    1
    7
    11
    Colitis ulcerative
         subjects affected / exposed
    9 / 130 (6.92%)
    10 / 95 (10.53%)
    36 / 384 (9.38%)
    11 / 27 (40.74%)
    46 / 114 (40.35%)
    31 / 112 (27.68%)
         occurrences all number
    9
    10
    37
    11
    52
    32
    Diarrhoea
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    0 / 384 (0.00%)
    1 / 27 (3.70%)
    5 / 114 (4.39%)
    6 / 112 (5.36%)
         occurrences all number
    0
    0
    0
    1
    5
    6
    Nausea
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    0 / 384 (0.00%)
    2 / 27 (7.41%)
    4 / 114 (3.51%)
    7 / 112 (6.25%)
         occurrences all number
    0
    0
    0
    2
    7
    7
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    0 / 384 (0.00%)
    0 / 27 (0.00%)
    6 / 114 (5.26%)
    4 / 112 (3.57%)
         occurrences all number
    0
    0
    0
    0
    7
    4
    Rash
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    0 / 384 (0.00%)
    1 / 27 (3.70%)
    2 / 114 (1.75%)
    8 / 112 (7.14%)
         occurrences all number
    0
    0
    0
    1
    2
    12
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    0 / 384 (0.00%)
    0 / 27 (0.00%)
    2 / 114 (1.75%)
    6 / 112 (5.36%)
         occurrences all number
    0
    0
    0
    0
    2
    8
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 130 (3.85%)
    7 / 95 (7.37%)
    33 / 384 (8.59%)
    4 / 27 (14.81%)
    8 / 114 (7.02%)
    19 / 112 (16.96%)
         occurrences all number
    6
    7
    38
    6
    11
    26
    Infections and infestations
    Gastroenteritis viral
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    0 / 384 (0.00%)
    0 / 27 (0.00%)
    1 / 114 (0.88%)
    6 / 112 (5.36%)
         occurrences all number
    0
    0
    0
    0
    1
    6
    Influenza
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    0 / 384 (0.00%)
    1 / 27 (3.70%)
    9 / 114 (7.89%)
    5 / 112 (4.46%)
         occurrences all number
    0
    0
    0
    1
    9
    5
    Nasopharyngitis
         subjects affected / exposed
    12 / 130 (9.23%)
    7 / 95 (7.37%)
    33 / 384 (8.59%)
    4 / 27 (14.81%)
    17 / 114 (14.91%)
    23 / 112 (20.54%)
         occurrences all number
    12
    8
    35
    5
    22
    33
    Oral herpes
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    0 / 384 (0.00%)
    2 / 27 (7.41%)
    1 / 114 (0.88%)
    5 / 112 (4.46%)
         occurrences all number
    0
    0
    0
    2
    1
    6
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 95 (0.00%)
    0 / 384 (0.00%)
    4 / 27 (14.81%)
    5 / 114 (4.39%)
    5 / 112 (4.46%)
         occurrences all number
    0
    0
    0
    5
    8
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Jan 2014
    Following updates were made: [1] The listed dose for each etrolizumab subcutaneous (SC) administration was changed from 100 mg to 105 mg. The change was made to more accurately list the actual dose of 105 mg in each prefilled syringe, rather than the nominal dose of 100 mg and [2] The study design section was modified to clarify that any U.S. subjects receiving immunosuppressants after Week 10 were not to receive further study treatment or open-label treatment and after completion of the Week 14 visit, were to be entered into the 12-week safety follow-up phase.
    11 Mar 2014
    Following updates were made: [1] The definition of moderately to severely active Ulcerative Colitis (UC) was updated to include stool frequency sub-score of >=1. Further, for Mayo Clinic Score (MCS)/partial Mayo Clinic Score (pMCS) calculation, the worst rectal bleeding score from the most recent 3 days prior to clinical visit was to be used and [2] Progressive Multifocal Leukoencephalopathy (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.
    29 May 2014
    Following updates were made: [1] The study assessments were updated to reflect that all subjects would be queried and closely monitored for any Adverse Event (AE) at all study assessment timepoints (every 4 weeks) during both clinic visits and study assessments made over the telephone.
    27 Sep 2015
    Following updates were made: [1] The protocol was amended to reflect FDA’s agreement regarding continued use of a stable, baseline dose of immunosuppressant through the full duration of the study, with dose adjustment or discontinuation if a subject experienced related toxicity. These changes aligned instructions of immunosuppressant use in the U.S. with instructions already present for the rest of the world.
    16 Nov 2016
    Following updates were made: [1] 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.
    02 Sep 2017
    Following updates were made: [1] The inclusion criteria were revised to include subjects with previous exposure to at least one induction regimen with the following αTNF (tumor necrosis factor-alpha) therapies: infliximab, adalimumab, and/or golimumab. Subjects were categorized as TNF inhibitor refractory, TNF inhibitor intolerant, or neither refractory nor intolerant to αTNF therapies at screening; [2] 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; [3] 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 and [4] The requirement to communicate John Cunningham virus (JCV) antibody status to a subject prior to Day 1 was removed, given the high prevalence of JCV antibody positivity in the general population and risk of false-negative tests. Aside from a plasma sample collected during screening for storage, serum and plasma samples collected during the study for potential JCV testing have been removed. All subjects will be counseled on JCV prevalence and risk of progressive multifocal leukoencephalopathy.
    11 Jul 2018
    Following updates were made: [1] The primary efficacy endpoint for the maintenance phase was changed to remission at Week 66 for subjects who achieved clinical response (rather than remission) at Week 14, to align with clinical practice standards; [2] 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; [3] 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; [4] The study sample size was reduced from 800 to 605 subjects as a result of the change in the maintenance phase primary efficacy endpoint, which would be powered at >90%. The induction phase primary efficacy endpoint definition (proportion of subjects in remission at Week 14) remained unchanged, but the reduction in sample size would lead to a drop in power from >90% to 80%. For the purpose of statistical analyses and sample size calculations, the induction and maintenance phases would be treated as two independent studies, and as such, no adjustment to alpha was required and [5] 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 (Sandborn et al. 2017). 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 was 2-3. The sigmoid colon MCS endoscopic subscore is considered to be more reliable in assessing earlier treatment response.

    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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