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

    Summary
    EudraCT number
    2013-004277-27
    Trial protocol
    LV   LT   HR   BG   GR   HU   CZ  
    Global end of trial date
    25 May 2020

    Results information
    Results version number
    v1
    This version publication date
    27 Feb 2021
    First version publication date
    27 Feb 2021
    Other versions
    v2

    Trial information

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    Trial identification
    Sponsor protocol code
    GA28949
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02171429
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche, Ltd.
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche, Ltd., F. Hoffmann-La Roche, Ltd., 41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche, Ltd., F. Hoffmann-La Roche, Ltd., 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
    25 May 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Mar 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    25 May 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    -To evaluate the efficacy of etrolizumab (105 mg SC every 4 weeks [Q4W]) compared with placebo for the induction of remission in TNF-naive patients with ulcerative colitis as determined by the Mayo Clinic Score at Week 10
    Protection of trial subjects
    This study was conducted in full conformance with the ICH E6 guideline for Good Clinical Practice and the principles of the Declaration of Helsinki or the laws and regulations of the country in which the research is conducted, whichever afforded the greater protection to the individual. All subjects signed an informed consent form before participating in the study.
    Background therapy
    During the induction phase (Day 1 to Week 10), continuation of stable baseline doses of the following non-investigational medicinal products were permitted: oral 5-aminosalicylic acid (5-ASA); azathioprine; 6-mercaptopurine; methotrexate; corticosteroids up to 30 milligrams per day (mg/day) of prednisone (or equivalent); and budesonide up to 9 mg/day. From Week 10 to Week 14, subjects who achieved clinical remission at Week 10 were to continue immunosuppressants (AZA, 6-MP, MTX) at a stable dose unless dose reduction or discontinuation was required due to immunosuppressant-related toxicity. For subjects who stayed in the study, corticosteroids were to be tapered starting from Week 10 in those who achieved clinical remission. Throughout the study, probiotics and oral 5-ASA may have been continued at a stable dose. Occasional use of NSAIDs and acetaminophen (e.g., for headache, arthritis, myalgias, menstrual cramps) and aspirin up to 325 mg daily were permitted throughout the study. Antidiarrheals (e.g., loperamide, diphenoxylate with atropine) for control of chronic diarrhea were permitted throughout the study.
    Evidence for comparator
    -
    Actual start date of recruitment
    14 Nov 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 1
    Country: Number of subjects enrolled
    Australia: 10
    Country: Number of subjects enrolled
    Bulgaria: 24
    Country: Number of subjects enrolled
    Brazil: 23
    Country: Number of subjects enrolled
    Colombia: 4
    Country: Number of subjects enrolled
    Czechia: 13
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    Croatia: 4
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Lithuania: 16
    Country: Number of subjects enrolled
    Latvia: 9
    Country: Number of subjects enrolled
    Malaysia: 7
    Country: Number of subjects enrolled
    New Zealand: 21
    Country: Number of subjects enrolled
    Poland: 57
    Country: Number of subjects enrolled
    Russian Federation: 68
    Country: Number of subjects enrolled
    Turkey: 9
    Country: Number of subjects enrolled
    Ukraine: 76
    Country: Number of subjects enrolled
    United States: 14
    Worldwide total number of subjects
    358
    EEA total number of subjects
    125
    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)
    344
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Subjects on concomitant background therapy were allowed to continue receiving stable baseline doses of the following non-investigational medicinal products during the study: oral 5-ASA; azathioprine; 6-mercaptopurine; methotrexate; corticosteroids up to 30 mg/day of prednisone (or equivalent); and/or budesonide up to 9 mg/day.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive placebo matching to etrolizumab subcutaneously (SC) once every 4 weeks (Q4W) up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC once every 2 weeks (Q2W) up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8).
    Arm type
    Placebo

    Investigational medicinal product name
    Etrolizumab Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The placebo matching to etrolizumab was supplied in a pre-filled syringe and was administered as an SC injection once every 4 weeks up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]).

    Investigational medicinal product name
    Adalimumab Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The placebo matching to adalimumab was supplied in a pre-filled syringe and was administered as an SC injection once every 2 weeks (Q2W) up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8).

    Arm title
    Adalimumab
    Arm description
    The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive adalimumab subcutaneously (SC) Q2W up to Week 8 (160 mg at Week 0 [Day 1], 80 mg at Week 2, 40 mg at Weeks 4, 6, and 8) and placebo matching to etrolizumab SC Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]).
    Arm type
    Active comparator

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    Humira
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Adalimumab was supplied in a pre-filled syringe and was administered as an SC injection once every 2 weeks (Q2W) up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8). Adalimumab was to be administered at a dose of 160 milligrams (mg) at Week 0 (Day 1; 4 injections), 80 mg at Week 2 (2 injections), and 40 mg (1 injection) at Weeks 4, 6, and 8.

    Investigational medicinal product name
    Etrolizumab Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The placebo matching to etrolizumab was supplied in a pre-filled syringe and was administered as an SC injection once every 4 weeks up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]).

    Arm title
    Etrolizumab
    Arm description
    The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8).
    Arm type
    Experimental

    Investigational medicinal product name
    Etrolizumab
    Investigational medicinal product code
    RO5490261
    Other name
    PRO145223
    Pharmaceutical forms
    Solution for injection in pre-filled pen, Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Etrolizumab was supplied in a pre-filled syringe and was administered as an SC injection at a dose of 105 mg once every 4 weeks up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]).

    Investigational medicinal product name
    Adalimumab Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The placebo matching to adalimumab was supplied in a pre-filled syringe and was administered as an SC injection once every 2 weeks (Q2W) up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8).

    Number of subjects in period 1
    Placebo Adalimumab Etrolizumab
    Started
    72
    143
    143
    Completed Week 10 Visit
    70 [1]
    141
    141
    Completed
    71
    140
    138
    Not completed
    1
    3
    5
         Physician decision
    -
    -
    1
         Adverse event, serious fatal
    -
    -
    1
         Non-Compliance
    -
    -
    1
         Consent withdrawn by subject
    1
    1
    1
         Lost to follow-up
    -
    1
    -
         Not Specified
    -
    1
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Participants who did not complete the Week 10 visit could have subsequently completed the study if they either rolled into the open-label extension study or completed the 12 weeks of safety follow-up after early treatment discontinuation.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive placebo matching to etrolizumab subcutaneously (SC) once every 4 weeks (Q4W) up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC once every 2 weeks (Q2W) up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8).

    Reporting group title
    Adalimumab
    Reporting group description
    The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive adalimumab subcutaneously (SC) Q2W up to Week 8 (160 mg at Week 0 [Day 1], 80 mg at Week 2, 40 mg at Weeks 4, 6, and 8) and placebo matching to etrolizumab SC Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]).

    Reporting group title
    Etrolizumab
    Reporting group description
    The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8).

    Reporting group values
    Placebo Adalimumab Etrolizumab Total
    Number of subjects
    72 143 143 358
    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)
    70 139 135 344
        From 65-84 years
    2 4 8 14
        85 years and over
    0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    40.3 ± 12.5 39.7 ± 12.6 41.1 ± 14.4 -
    Sex: Female, Male
    Units: Participants
        Female
    34 62 59 155
        Male
    38 81 84 203
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    4 4 4 12
        Black or African American
    1 4 1 6
        White
    65 131 133 329
        Other
    2 4 5 11
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    5 11 12 28
        Not Hispanic or Latino
    67 130 128 325
        Unknown or Not Reported
    0 2 3 5
    Disease Location
    Units: Subjects
        Left-Sided Colitis
    48 86 86 220
        Extensive Colitis
    7 13 11 31
        Pancolitis
    17 44 46 107
    Mayo Clinic Score (MCS) ≤9 or ≥10 at Baseline
    Participants were stratified by concomitant treatment with corticosteroids (yes/no) at randomization, concomitant treatment with immunosuppressants (yes/no) at randomization, and disease activity measured during screening (MCS ≤9/MCS ≥10). The MCS ranges from 0 to 12 and is a composite of the four following assessments of disease activity: stool frequency subscore, rectal bleeding subscore, endoscopy subscore, and physician's global assessment (PGA) subscore. Each of the four assessments was rated with a score from 0 to 3, with higher scores indicating more severe disease.
    Units: Subjects
        MCS ≤9
    46 96 96 238
        MCS ≥10
    26 47 47 120
    Baseline Treatment: None, Corticosteroids (CS) or Immunosuppressants (IS) Alone, or Both CS and IS
    Participants were stratified by concomitant treatment with corticosteroids (yes/no) at randomization, concomitant treatment with immunosuppressants (yes/no) at randomization, and disease activity measured during screening (MCS ≤9/MCS ≥10).
    Units: Subjects
        None
    27 53 55 135
        Corticosteroids (CS) Alone
    23 42 40 105
        Immunosuppressants (IS) Alone
    14 28 28 70
        Both CS and IS
    8 20 20 48
    Nancy Histological Index (NHI) Score of ≤1 or >1, or Missing, at Baseline
    Histologic disease activity was measured using the Nancy Histological Index (NHI) score, ranging from 0 to 4, with the following definitions for each grade: 0 is no histologically significant disease; 1 is chronic inflammatory infiltrate with no acute inflammatory infiltrate; and 2, 3, and 4 are mildly, moderately, and severely active disease, respectively.
    Units: Subjects
        NHI Score ≤1
    9 23 21 53
        NHI Score >1
    62 114 108 284
        Missing
    1 6 14 21

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive placebo matching to etrolizumab subcutaneously (SC) once every 4 weeks (Q4W) up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC once every 2 weeks (Q2W) up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8).

    Reporting group title
    Adalimumab
    Reporting group description
    The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive adalimumab subcutaneously (SC) Q2W up to Week 8 (160 mg at Week 0 [Day 1], 80 mg at Week 2, 40 mg at Weeks 4, 6, and 8) and placebo matching to etrolizumab SC Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]).

    Reporting group title
    Etrolizumab
    Reporting group description
    The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8).

    Primary: Percentage of Participants in Remission With Etrolizumab Compared With Placebo at Week 10, as Determined by the Mayo Clinic Score (MCS)

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    End point title
    Percentage of Participants in Remission With Etrolizumab Compared With Placebo at Week 10, 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 the four following assessments of disease activity: stool frequency subscore, rectal bleeding subscore, endoscopy subscore, and physician's global assessment (PGA) subscore. Each of the four assessments was rated with a score from 0 to 3, with higher scores indicating more severe disease. Remission was defined as MCS less than or equal to (≤)2 with individual subscores ≤1 and a rectal bleeding subscore of 0. Participants were also classified as non-remitters if Week 10 assessments were missing or if they had received permitted/prohibited rescue therapy prior to assessment. Participants were stratified by concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening (MCS ≤9/MCS ≥10); the Cochran-Mantel-Haenszel test adjusted the difference in remission rates and associated 95% confidence interval for the stratification factors.
    End point type
    Primary
    End point timeframe
    Week 10
    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: The primary outcome measure only compared remission rates between the etrolizumab and placebo arms.
    End point values
    Placebo Etrolizumab
    Number of subjects analysed
    72
    143
    Units: Percentage of participants
        number (confidence interval 95%)
    11.1 (5.74 to 20.42)
    18.2 (12.72 to 25.31)
    Statistical analysis title
    Etrolizumab vs. Placebo: Remission at Week 10
    Statistical analysis description
    The null hypothesis (H0): the percentage of participants achieving remission at Week 10 was the same in both the placebo and etrolizumab arms. The alternative hypothesis (H1): the percentage of participants achieving remission at Week 10 was not the same in the placebo and etrolizumab arms.
    Comparison groups
    Placebo v Etrolizumab
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1729 [2]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in Remission Rates
    Point estimate
    7.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.83
         upper limit
    16.12
    Notes
    [2] - The threshold for statistical significance was a p-value <0.05.

    Secondary: Percentage of Participants in Remission With Etrolizumab Compared With Adalimumab at Week 10, as Determined by the MCS

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    End point title
    Percentage of Participants in Remission With Etrolizumab Compared With Adalimumab at Week 10, as Determined by the MCS [3]
    End point description
    The Mayo Clinic Score (MCS) ranges from 0 to 12 and is a composite of the four following assessments of disease activity: stool frequency subscore, rectal bleeding subscore, endoscopy subscore, and physician's global assessment (PGA) subscore. Each of the four assessments was rated with a score from 0 to 3, with higher scores indicating more severe disease. Remission was defined as MCS less than or equal to (≤)2 with individual subscores ≤1 and a rectal bleeding subscore of 0. Participants were also classified as non-remitters if Week 10 assessments were missing or if they had received permitted/prohibited rescue therapy prior to assessment. Participants were stratified by concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening (MCS ≤9/MCS ≥10). The Cochran-Mantel-Haenszel test adjusted the difference in remission rates and associated 95% confidence interval for the stratification factors.
    End point type
    Secondary
    End point timeframe
    Week 10
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This secondary outcome measure only compared remission rates between the etrolizumab and adalimumab arms.
    End point values
    Adalimumab Etrolizumab
    Number of subjects analysed
    143
    143
    Units: Percentage of participants
        number (confidence interval 95%)
    24.5 (18.16 to 32.13)
    18.2 (12.72 to 25.31)
    Statistical analysis title
    Etrolizumab vs. Adalimumab: Remission at Week 10
    Statistical analysis description
    Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details. Individual study results are shown, however, this endpoint was formally tested using pooled study data from this study and an identically designed study (GA28948); those pooled results cannot be provided on the registry due to its limitations.
    Comparison groups
    Adalimumab v Etrolizumab
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1458 [4]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in Remission Rates
    Point estimate
    -6.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16.26
         upper limit
    2.73
    Notes
    [4] - Nominal p-value; it has not been adjusted for multiplicity.

    Secondary: Percentage of Participants in Clinical Remission at Week 10, as Determined by the MCS

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    End point title
    Percentage of Participants in Clinical Remission at Week 10, as Determined by the MCS
    End point description
    The Mayo Clinic Score (MCS) ranges from 0 to 12 and is a composite of the four following assessments of disease activity: stool frequency subscore, rectal bleeding subscore, endoscopy subscore, and physician's global assessment (PGA) subscore. Each of the four assessments was rated with a score from 0 to 3, with higher scores indicating more severe disease. Clinical remission was defined as MCS less than or equal to (≤)2 with individual subscores ≤1. Participants were also classified as non-remitters if Week 10 assessments were missing or if they had received permitted/prohibited rescue therapy prior to assessment. Participants were stratified by concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening (MCS ≤9/MCS ≥10). The Cochran-Mantel-Haenszel test adjusted the differences in remission rates and associated 95% confidence intervals for the stratification factors.
    End point type
    Secondary
    End point timeframe
    Week 10
    End point values
    Placebo Adalimumab Etrolizumab
    Number of subjects analysed
    72
    143
    143
    Units: Percentage of participants
        number (confidence interval 95%)
    11.1 (5.74 to 20.42)
    25.9 (19.39 to 33.62)
    18.9 (13.31 to 26.08)
    Statistical analysis title
    Etro vs. Placebo: Clinical Remission at Week 10
    Statistical analysis description
    Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details.
    Comparison groups
    Placebo v Etrolizumab
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1382 [5]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in Remission Rates
    Point estimate
    7.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.19
         upper limit
    16.87
    Notes
    [5] - Nominal p-value; it has not been adjusted for multiplicity.
    Statistical analysis title
    Etro vs. Adalimumab: Clinical Remission at Week 10
    Statistical analysis description
    Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details.
    Comparison groups
    Adalimumab v Etrolizumab
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1163 [6]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in Remission Rates
    Point estimate
    -7.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -17.1
         upper limit
    2.22
    Notes
    [6] - Nominal p-value; it has not been adjusted for multiplicity.

    Secondary: Percentage of Participants With Clinical Response at Week 10, as Determined by the MCS

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    End point title
    Percentage of Participants With Clinical Response at Week 10, as Determined by the MCS
    End point description
    The Mayo Clinic Score (MCS) ranges from 0 to 12 and is a composite of the four following assessments of disease activity: stool frequency subscore, rectal bleeding subscore, endoscopy subscore, and physician's global assessment subscore. Each of the four assessments was rated with a score from 0 to 3, with higher scores indicating more severe disease. Clinical Response was defined as: MCS ≥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. Non-responders also included participants with missing Week 10 assessments or those who had received permitted/prohibited rescue therapy prior to assessment. Participants were stratified by concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening (MCS ≤9 or ≥10); the CMH test adjusted the differences in response rates and associated 95% CIs for the stratification factors.
    End point type
    Secondary
    End point timeframe
    Week 10
    End point values
    Placebo Adalimumab Etrolizumab
    Number of subjects analysed
    72
    143
    143
    Units: Percentage of participants
        number (confidence interval 95%)
    38.9 (28.47 to 50.44)
    54.5 (46.37 to 62.48)
    52.4 (44.31 to 60.46)
    Statistical analysis title
    Etro vs. Placebo: Clinical Response at Week 10
    Statistical analysis description
    Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details.
    Comparison groups
    Placebo v Etrolizumab
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1729 [7]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in Response Rates
    Point estimate
    14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.12
         upper limit
    27.19
    Notes
    [7] - p-value has been adjusted for multiplicity.
    Statistical analysis title
    Etro vs. Adalimumab: Clinical Response at Week 10
    Statistical analysis description
    Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details. Individual study results are shown, however, this endpoint was formally tested using pooled study data from this study and an identically designed study (GA28948); those pooled results cannot be provided on the registry due to its limitations.
    Comparison groups
    Adalimumab v Etrolizumab
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6726 [8]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in Response Rates
    Point estimate
    -2.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -13.83
         upper limit
    9.01
    Notes
    [8] - Nominal p-value; it has not been adjusted for multiplicity.

    Secondary: Percentage of Participants With Improvement in Endoscopic Appearance of the Mucosa at Week 10, as Determined by the Mayo Endoscopy Subscore

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    End point title
    Percentage of Participants With Improvement in Endoscopic Appearance of the Mucosa at Week 10, as Determined by the Mayo Endoscopy Subscore
    End point description
    Improvement in endoscopic appearance of the mucosa was defined as a Mayo Clinic Score (MCS) endoscopy subscore ≤1. Blinded gastroenterologists experienced in inflammatory bowel disease performed central reading of endoscopies at an independent review facility. The rectum, sigmoid, and descending colon segments were assessed and each segment was assigned a score of 0 to 3, with higher scores indicating more severe disease. At baseline all segments were reviewed and the worst score from the three segments was recorded as the endoscopy subscore. Post-baseline the endoscopy score was the worst score of all segments that had been assessed at baseline, if the baseline endoscopy score had a sigmoid colon score ≤1. If at baseline the sigmoid colon score was ≥2, the post-baseline endoscopy score was the sigmoid colon score value. Non-responders also included participants with missing Week 10 assessments or those who had received permitted/prohibited rescue therapy prior to assessment.
    End point type
    Secondary
    End point timeframe
    Week 10
    End point values
    Placebo Adalimumab Etrolizumab
    Number of subjects analysed
    72
    143
    143
    Units: Percentage of participants
        number (confidence interval 95%)
    30.6 (21.13 to 41.95)
    42.7 (34.85 to 50.85)
    39.9 (32.20 to 48.05)
    Statistical analysis title
    Etro vs. Placebo: Endoscopic Appearance at Week 10
    Statistical analysis description
    Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details.
    Comparison groups
    Placebo v Etrolizumab
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2372 [9]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in Response Rates
    Point estimate
    9.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.31
         upper limit
    21.95
    Notes
    [9] - p-value has been adjusted for multiplicity.
    Statistical analysis title
    Etro vs. Ada.: Endoscopic Appearance at Week 10
    Statistical analysis description
    Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details. Individual study results are shown, however, this endpoint was formally tested using pooled study data from this study and an identically designed study (GA28948); those pooled results cannot be provided on the registry due to its limitations.
    Comparison groups
    Adalimumab v Etrolizumab
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5341 [10]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in Response Rates
    Point estimate
    -3.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14.76
         upper limit
    7.82
    Notes
    [10] - Nominal p-value; it has not been adjusted for multiplicity.

    Secondary: Percentage of Participants in Endoscopic Remission at Week 10, as Determined by the MCS Endoscopy Subscore

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    End point title
    Percentage of Participants in Endoscopic Remission at Week 10, as Determined by the MCS Endoscopy Subscore
    End point description
    Endoscopic remission was defined as a Mayo Clinic Score (MCS) endoscopy subscore of 0. Blinded gastroenterologists experienced in inflammatory bowel disease performed central reading of endoscopies at an independent review facility. The rectum, sigmoid, and descending colon segments were assessed and each segment was assigned a score of 0 to 3, with higher scores indicating more severe disease. At baseline all segments were reviewed and the worst score from the three segments was recorded as the endoscopy subscore. Post-baseline the endoscopy score was the worst score of all segments that had been assessed at baseline, if the baseline endoscopy score had a sigmoid colon score ≤1. If at baseline the sigmoid colon score was ≥2, the post-baseline endoscopy score was the sigmoid colon score value. Non-responders also included participants with missing Week 10 assessments or those who had received permitted/prohibited rescue therapy prior to assessment.
    End point type
    Secondary
    End point timeframe
    Week 10
    End point values
    Placebo Adalimumab Etrolizumab
    Number of subjects analysed
    72
    143
    143
    Units: Percentage of participants
        number (confidence interval 95%)
    8.3 (3.88 to 17.01)
    26.6 (20.02 to 34.36)
    19.6 (13.91 to 26.84)
    Statistical analysis title
    Etro vs. Placebo: Endoscopic Remission at Week 10
    Statistical analysis description
    Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details.
    Comparison groups
    Placebo v Etrolizumab
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2372 [11]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in Remission Rates
    Point estimate
    11.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.59
         upper limit
    19.76
    Notes
    [11] - p-value has been adjusted for multiplicity.
    Statistical analysis title
    Etro vs. Ada.: Endoscopic Remission at Week 10
    Statistical analysis description
    Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details. Individual study results are shown, however, this endpoint was formally tested using pooled study data from this study and an identically designed study (GA28948); those pooled results cannot be provided on the registry due to its limitations.
    Comparison groups
    Adalimumab v Etrolizumab
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1192 [12]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in Remission Rates
    Point estimate
    -7.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -17.2
         upper limit
    2.33
    Notes
    [12] - Nominal p-value; it has not been adjusted for multiplicity.

    Secondary: Percentage of Participants in Remission at Week 10 and Week 14, as Determined by the MCS

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    End point title
    Percentage of Participants in Remission at Week 10 and Week 14, as Determined by the MCS
    End point description
    The Mayo Clinic Score (MCS) ranges from 0 to 12 and is a composite of the four following assessments of disease activity: stool frequency subscore, rectal bleeding subscore, endoscopy subscore, and physician's global assessment (PGA) subscore. Each of the four assessments was rated with a score from 0 to 3, with higher scores indicating more severe disease. Remission was defined as MCS less than or equal to (≤)2 with individual subscores ≤1 and a rectal bleeding subscore of 0. Participants were also classified as non-remitters if Week 10 or 14 assessments were missing or the participant received permitted/prohibited rescue therapy prior to assessment. Participants were stratified by concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening (MCS ≤9/MCS ≥10). The Cochran-Mantel-Haenszel test adjusted the differences in remission rates and associated 95% confidence intervals for the stratification factors.
    End point type
    Secondary
    End point timeframe
    Week 10 and 14
    End point values
    Placebo Adalimumab Etrolizumab
    Number of subjects analysed
    72
    143
    143
    Units: Percentage of participants
        number (confidence interval 95%)
    6.9 (3.00 to 15.25)
    14.7 (9.81 to 21.41)
    9.8 (5.92 to 15.76)
    Statistical analysis title
    Etro vs. Placebo: Remission at Weeks 10 and 14
    Statistical analysis description
    Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details.
    Comparison groups
    Placebo v Etrolizumab
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4772 [13]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in Remission Rates
    Point estimate
    2.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.47
         upper limit
    10.14
    Notes
    [13] - Nominal p-value; it has not been adjusted for multiplicity.
    Statistical analysis title
    Etro vs. Ada.: Remission at Weeks 10 and 14
    Statistical analysis description
    Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details.
    Comparison groups
    Adalimumab v Etrolizumab
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1801 [14]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in Remission Rates
    Point estimate
    -5.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.95
         upper limit
    2.63
    Notes
    [14] - Nominal p-value; it has not been adjusted for multiplicity.

    Secondary: Percentage of Participants With Histologic Remission at Week 10, as Determined by the Nancy Histological Index

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    End point title
    Percentage of Participants With Histologic Remission at Week 10, as Determined by the Nancy Histological Index
    End point description
    Histologic remission is defined by the resolution of neutrophilic inflammation (e.g., absence of neutrophils in the crypts and lamina propria), defined by a Nancy Histological Index (NHI) score of ≤1. The NHI score ranges from 0 to 4, with the following definitions for each grade: 0 is no histologically significant disease; 1 is chronic inflammatory infiltrate with no acute inflammatory infiltrate; and 2, 3, and 4 are mildly, moderately, and severely active disease, respectively. A small pool of central readers who were blinded to both treatment arm and timepoint performed the histologic scoring. The same reader scored all slides for a given participant based on biopsies from the most inflamed region of the sigmoid colon. Participants were also classified as non-remitters if Week 10 assessments were missing or if they had received rescue therapy prior to assessment. The Cochran-Mantel-Haenszel test adjusted the difference in remission rates and 95% CI for the stratification factors.
    End point type
    Secondary
    End point timeframe
    Week 10
    End point values
    Placebo Adalimumab Etrolizumab
    Number of subjects analysed
    62 [15]
    114 [16]
    108 [17]
    Units: Percentage of participants
        number (confidence interval 95%)
    21.0 (12.68 to 32.64)
    43.9 (35.10 to 53.02)
    30.6 (22.66 to 39.79)
    Notes
    [15] - Subjects analyzed only includes those with NHI score >1 at baseline.
    [16] - Subjects analyzed only includes those with NHI score >1 at baseline.
    [17] - Subjects analyzed only includes those with NHI score >1 at baseline.
    Statistical analysis title
    Etro vs. Placebo: Histologic Remission at Week 10
    Statistical analysis description
    Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details.
    Comparison groups
    Placebo v Etrolizumab
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2729 [18]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in Remission Rates
    Point estimate
    9.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.71
         upper limit
    22.02
    Notes
    [18] - p-value has been adjusted for multiplicity.
    Statistical analysis title
    Etro vs. Ada.: Histologic Remission at Week 10
    Statistical analysis description
    Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details. Individual study results are shown, however, this endpoint was formally tested using pooled study data from this study and an identically designed study (GA28948); those pooled results cannot be provided on the registry due to its limitations.
    Comparison groups
    Adalimumab v Etrolizumab
    Number of subjects included in analysis
    222
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0215 [19]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in Remission Rates
    Point estimate
    -14.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -26.97
         upper limit
    -2.04
    Notes
    [19] - Nominal p-value; it has not been adjusted for multiplicity.

    Secondary: Change From Baseline in MCS Rectal Bleeding Subscore at Week 6

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    End point title
    Change From Baseline in MCS Rectal Bleeding Subscore at Week 6
    End point description
    Rectal bleeding data were collected via the participant’s diaries and each day a participant 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). Participants 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, Week 6
    End point values
    Placebo Adalimumab Etrolizumab
    Number of subjects analysed
    72
    143
    143
    Units: Score on a scale
        median (inter-quartile range (Q1-Q3))
    0.0 (-1.0 to 0.0)
    -1.0 (-2.0 to 0.0)
    -1.0 (-2.0 to 0.0)
    Statistical analysis title
    Etro vs. Placebo: MCS Rectal Bleeding at Week 6
    Statistical analysis description
    Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details.
    Comparison groups
    Placebo v Etrolizumab
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1729 [20]
    Method
    Rank ANCOVA
    Confidence interval
    Notes
    [20] - p-value has been adjusted for multiplicity.
    Statistical analysis title
    Etro vs. Ada.: MCS Rectal Bleeding at Week 6
    Statistical analysis description
    Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details. Individual study results are shown, however, this endpoint was formally tested using pooled study data from this study and an identically designed study (GA28948); those pooled results cannot be provided on the registry due to its limitations.
    Comparison groups
    Adalimumab v Etrolizumab
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2864 [21]
    Method
    Rank ANCOVA
    Confidence interval
    Notes
    [21] - Nominal p-value; it has not been adjusted for multiplicity.

    Secondary: Change From Baseline in MCS Stool Frequency Subscore at Week 6

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    End point title
    Change From Baseline in MCS Stool Frequency Subscore at Week 6
    End point description
    Stool frequency data were collected via the participant’s diaries and each day a participant 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). Participants 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, Week 6
    End point values
    Placebo Adalimumab Etrolizumab
    Number of subjects analysed
    72
    143
    143
    Units: Score on a scale
        median (inter-quartile range (Q1-Q3))
    0.0 (-1.0 to 0.0)
    -1.0 (-1.0 to 0.0)
    -1.0 (-1.0 to 0.0)
    Statistical analysis title
    Etro vs. Placebo: MCS Stool Frequency at Week 6
    Statistical analysis description
    Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details.
    Comparison groups
    Placebo v Etrolizumab
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1729 [22]
    Method
    Rank ANCOVA
    Confidence interval
    Notes
    [22] - p-value has been adjusted for multiplicity.
    Statistical analysis title
    Etro vs. Ada.: MCS Stool Frequency at Week 6
    Statistical analysis description
    Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details. Individual study results are shown, however, this endpoint was formally tested using pooled study data from this study and an identically designed study (GA28948); those pooled results cannot be provided on the registry due to its limitations.
    Comparison groups
    Adalimumab v Etrolizumab
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4174 [23]
    Method
    Rank ANCOVA
    Confidence interval
    Notes
    [23] - Nominal p-value; it has not been adjusted for multiplicity.

    Secondary: Change From Baseline in Ulcerative Colitis (UC) Bowel Movement Signs and Symptoms at Week 10, as Assessed by UC Patient-Reported Outcome Signs and Symptoms (UC-PRO/SS)

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    End point title
    Change From Baseline in Ulcerative Colitis (UC) Bowel Movement Signs and Symptoms at Week 10, as Assessed by UC Patient-Reported Outcome Signs and Symptoms (UC-PRO/SS)
    End point description
    The UC-PRO/SS questionnaire was collected in the e-diary and completed by participants for at least 9 to 12 consecutive days prior to a study visit. The bowel movement domain score ranges from 0 to 27, with a higher score indicating a worse disease state. The most recent 7 daily scores available (not including the visit) were selected for the calculation of the visit score. For each item in the questionnaire, a score was calculated for a visit by taking the average of the selected daily scores. The domain score for a visit was calculated as the sum of the averaged items for each question. A Mixed Model for Repeated Measures (MMRM) analysis of the data included the fixed categorical effects of treatment, visit, study stratification factors, and treatment-by-visit interaction, and the continuous covariates of the baseline UC-PRO/SS domain and baseline UC-PRO/SS domain-by-visit interaction. An unstructured covariance matrix was used to model the within-patient errors within the MMRM.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 10
    End point values
    Placebo Adalimumab Etrolizumab
    Number of subjects analysed
    59 [24]
    111 [25]
    108 [26]
    Units: Score on a scale
        least squares mean (standard error)
    -4.7 ± 0.7
    -5.9 ± 0.5
    -5.8 ± 0.5
    Notes
    [24] - Only subjects with baseline and at least 1 post-baseline result were included.
    [25] - Only subjects with baseline and at least 1 post-baseline result were included.
    [26] - Only subjects with baseline and at least 1 post-baseline result were included.
    Statistical analysis title
    Etro vs. Placebo: UC Bowel Movement SS at Week 10
    Statistical analysis description
    Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details. Individual study results are shown, however, this endpoint was formally tested using pooled study data from this study and an identically designed study (GA28948); those pooled results cannot be provided on the registry due to its limitations.
    Comparison groups
    Placebo v Etrolizumab
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1659 [27]
    Method
    Mixed Model for Repeated Measures
    Parameter type
    Mean difference (net)
    Point estimate
    -1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.8
         upper limit
    0.5
    Notes
    [27] - Nominal p-value; it has not been adjusted for multiplicity.
    Statistical analysis title
    Etro vs. Ada.: UC Bowel Movement SS at Week 10
    Statistical analysis description
    Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details. Individual study results are shown, however, this endpoint was formally tested using pooled study data from this study and an identically designed study (GA28948); those pooled results cannot be provided on the registry due to its limitations.
    Comparison groups
    Adalimumab v Etrolizumab
    Number of subjects included in analysis
    219
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9182 [28]
    Method
    Mixed Model for Repeated Measures
    Parameter type
    Mean difference (net)
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.3
         upper limit
    1.4
    Notes
    [28] - Nominal p-value; it has not been adjusted for multiplicity.

    Secondary: Change From Baseline in UC Functional Symptoms at Week 10, as Assessed by UC-PRO/SS

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    End point title
    Change From Baseline in UC Functional Symptoms at Week 10, as Assessed by UC-PRO/SS
    End point description
    The UC-PRO/SS questionnaire was collected in the e-diary and completed by participants for at least 9 to 12 consecutive days prior to a study visit. The functional symptoms domain score ranges from 0 to 12, with a higher score indicating a worse disease state. The most recent 7 daily scores available (not including the visit) were selected for the calculation of the visit score. For each item in the questionnaire, a score was calculated for a visit by taking the average of the selected daily scores. The domain score for a visit was calculated as the sum of the averaged items for each question. A Mixed Model for Repeated Measures (MMRM) analysis of the data included the fixed categorical effects of treatment, visit, study stratification factors, and treatment-by-visit interaction, and the continuous covariates of the baseline UC-PRO/SS domain and baseline UC-PRO/SS domain-by-visit interaction. An unstructured covariance matrix was used to model the within-patient errors in the MMRM.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 10
    End point values
    Placebo Adalimumab Etrolizumab
    Number of subjects analysed
    59 [29]
    111 [30]
    108 [31]
    Units: Score on a scale
        least squares mean (standard error)
    -1.0 ± 0.3
    -1.8 ± 0.2
    -2.0 ± 0.2
    Notes
    [29] - Only subjects with baseline and at least 1 post-baseline result were included.
    [30] - Only subjects with baseline and at least 1 post-baseline result were included.
    [31] - Only subjects with baseline and at least 1 post-baseline result were included.
    Statistical analysis title
    Etro vs. Placebo: UC Functional SS at Week 10
    Statistical analysis description
    Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details. Individual study results are shown, however, this endpoint was formally tested using pooled study data from this study and an identically designed study (GA28948); those pooled results cannot be provided on the registry due to its limitations.
    Comparison groups
    Placebo v Etrolizumab
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0116 [32]
    Method
    Mixed Model for Repeated Measures
    Parameter type
    Mean difference (net)
    Point estimate
    -1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.7
         upper limit
    -0.2
    Notes
    [32] - Nominal p-value; it has not been adjusted for multiplicity.
    Statistical analysis title
    Etro vs. Ada.: UC Functional SS at Week 10
    Statistical analysis description
    Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details. Individual study results are shown, however, this endpoint was formally tested using pooled study data from this study and an identically designed study (GA28948); those pooled results cannot be provided on the registry due to its limitations.
    Comparison groups
    Adalimumab v Etrolizumab
    Number of subjects included in analysis
    219
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6771 [33]
    Method
    Mixed Model for Repeated Measures
    Parameter type
    Mean difference (net)
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.8
         upper limit
    0.5
    Notes
    [33] - Nominal p-value; it has not been adjusted for multiplicity.

    Secondary: Change From Baseline in Health-Related Quality of Life at Week 10, as Assessed by the Total Inflammatory Bowel Disease Questionnaire (IBDQ) Score

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    End point title
    Change From Baseline in Health-Related Quality of Life at Week 10, as Assessed by the Total Inflammatory Bowel Disease Questionnaire (IBDQ) Score
    End point description
    The IBDQ is a 32-item questionnaire containing four domains: bowel symptoms (10 items), systemic symptoms (5 items), emotional function (12 items), and social function (5 items). An overall total IBDQ score was computed by summing the individual 32-item scores. The range for the IBDQ total score is 32 to 224, with higher scores denoting better health-related quality of life. The unadjusted mean and standard deviation for each study arm are reported. The change from baseline in the IBDQ score was analyzed using an ANCOVA model taking the stratification factors used at randomization into account (concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening [MCS ≤9/MCS ≥10]), and the baseline IBDQ score used as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 10
    End point values
    Placebo Adalimumab Etrolizumab
    Number of subjects analysed
    62 [34]
    125 [35]
    125 [36]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    31.2 ± 39.5
    34.8 ± 36.5
    36.2 ± 43.4
    Notes
    [34] - Only subjects with baseline and at least 1 post-baseline result were included.
    [35] - Only subjects with baseline and at least 1 post-baseline result were included.
    [36] - Only subjects with baseline and at least 1 post-baseline result were included.
    Statistical analysis title
    Etro vs. Placebo: IBDQ Change at Week 10
    Statistical analysis description
    Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details.
    Comparison groups
    Placebo v Etrolizumab
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4833 [37]
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.2
         upper limit
    15.2
    Notes
    [37] - Nominal p-value; it has not been adjusted for multiplicity.
    Statistical analysis title
    Etro vs. Ada.: IBDQ Change at Week 10
    Statistical analysis description
    Primary and secondary outcome measures were evaluated for statistical significance in a hierarchical manner with a component-wise multistage gatekeeping procedure. Please refer to the statistical analysis plan for details.
    Comparison groups
    Adalimumab v Etrolizumab
    Number of subjects included in analysis
    250
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9931 [38]
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.2
         upper limit
    9.1
    Notes
    [38] - Nominal p-value; it has not been adjusted for multiplicity.

    Secondary: Pharmacokinetics of Etrolizumab: Serum Concentration

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    End point title
    Pharmacokinetics of Etrolizumab: Serum Concentration [39]
    End point description
    Serum concentrations of etrolizumab were evaluated at the primary endpoint visit (Week 10) and the secondary endpoint visit (Week 14). Both time points were two weeks after the most recent dose.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hour) at Weeks 10 and 14
    Notes
    [39] - 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: The PK outcome measure of etrolizumab serum concentration was only assessed for those who had received etrolizumab.
    End point values
    Etrolizumab
    Number of subjects analysed
    139
    Units: micrograms per millilitre (μg/mL)
    arithmetic mean (standard deviation)
        Week 10 (n = 137)
    12.4 ± 5.51
        Week 14 (n = 21)
    15.5 ± 6.49
    No statistical analyses for this end point

    Secondary: Number of Participants With at Least One Adverse Event by Severity, According to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE v4.0)

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    End point title
    Number of Participants With at Least One Adverse Event by Severity, According to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE v4.0)
    End point description
    An adverse event (AE) is any untoward medical occurrence in a clinical investigation in which a patient is administered a pharmaceutical product, regardless of causal attribution. The investigator independently assessed the severity and seriousness of each recorded AE. The AE severity grading scale for the NCI CTCAE v4.0 was used for assessing severity; any AE not specifically listed was rated according to the following grading scale from 1 to 5: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = death. AEs of special interest (AESIs) included: elevated AST/ALT in combination with either elevated bilirubin or clinical jaundice; suspected transmission of infectious agent by the study drug; anaphylactic, anaphylactoid and systemic hypersensitivity reactions; and neurological signs, symptoms, and AEs that may suggest possible progressive multifocal leukoencephalopathy (PML).
    End point type
    Secondary
    End point timeframe
    From Baseline until the end of study (up to 26 weeks)
    End point values
    Placebo Adalimumab Etrolizumab
    Number of subjects analysed
    72
    143
    143
    Units: Participants
        Any Adverse Event (AE)
    33
    62
    63
        AE with Fatal Outcome
    0
    0
    1
        Serious AE
    5
    3
    7
        AE Leading to Study Treatment Discontinuation
    1
    2
    4
        AE Leading to Dose Interruption
    0
    2
    1
        Related AE
    9
    15
    12
        AE by Worst Severity, Grade 1
    14
    29
    30
        AE by Worst Severity, Grade 2
    13
    25
    24
        AE by Worst Severity, Grade 3
    6
    8
    8
        AE by Worst Severity, Grade 4
    0
    0
    0
        AE by Worst Severity, Grade 5
    0
    0
    1
        Any AESIs, Except for Hypersensitivity Reactions
    0
    0
    0
        AESIs: Anaphylactic and Hypersensitivity Reactions
    0
    1
    0
        Confirmed PML
    0
    0
    0
        Infections
    13
    18
    23
        Serious Infections
    0
    1
    2
        Gastrointestinal Infections
    1
    0
    3
        Opportunistic Infections
    0
    0
    0
        Malignancies
    0
    2
    0
        Injection Site Reactions
    2
    3
    2
    No statistical analyses for this end point

    Secondary: Number of Participants by Marked Laboratory Abnormality Status for Hematology Parameters as a Shift Table from Baseline to Week 10

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    End point title
    Number of Participants by Marked Laboratory Abnormality Status for Hematology Parameters as a Shift Table from Baseline to Week 10
    End point description
    Laboratory tests for hematology parameters were performed and values were compared with the Roche marked reference range. A marked abnormality was defined as a test result that was outside of the Roche marked reference range (labelled as 'High' or 'Low') and represented a clinically significant change from baseline. Not every laboratory abnormality qualified as an adverse event. A laboratory test result must have been reported as an adverse event if it met any of the following criteria: was accompanied by clinical symptoms; resulted in a change in study treatment or a medical intervention; or was clinically significant in the investigator's judgment. The results are presented as a shift from the baseline status to the post-baseline (Week 10) status. Baseline was defined as the last available assessment prior to first receipt of study drug. The 'missing' status included participants with missing baseline or post-baseline values. Abs = absolute count; Ery. = erythrocyte
    End point type
    Secondary
    End point timeframe
    From Baseline up to Week 10
    End point values
    Placebo Adalimumab Etrolizumab
    Number of subjects analysed
    72
    143
    143
    Units: Participants
        Eosinophils Abs - Normal to Normal
    63
    133
    124
        Eosinophils Abs - Normal to High
    0
    0
    2
        Eosinophils Abs - Normal to Missing
    7
    9
    15
        Eosinophils Abs - High to Normal
    2
    1
    0
        Eosinophils Abs - High to High
    0
    0
    1
        Eosinophils Abs - Missing to Normal
    0
    0
    1
        Hematocrit - Low to Low
    0
    1
    1
        Hematocrit - Low to Normal
    3
    2
    5
        Hematocrit - Low to Missing
    0
    0
    1
        Hematocrit - Normal to Low
    0
    1
    2
        Hematocrit - Normal to Normal
    62
    128
    119
        Hematocrit - Normal to Missing
    7
    10
    14
        Hematocrit - Missing to Normal
    0
    1
    1
        Hemoglobin - Low to Low
    3
    10
    13
        Hemoglobin - Low to Normal
    2
    7
    9
        Hemoglobin - Low to Missing
    2
    3
    4
        Hemoglobin - Normal to Low
    4
    4
    7
        Hemoglobin - Normal to Normal
    56
    113
    99
        Hemoglobin - Normal to Missing
    5
    6
    10
        Hemoglobin - Missing to Normal
    0
    0
    1
        Lymphocytes Abs - Low to Low
    2
    2
    2
        Lymphocytes Abs - Low to Normal
    2
    9
    4
        Lymphocytes Abs - Low to Missing
    0
    0
    1
        Lymphocytes Abs - Normal to Low
    1
    2
    2
        Lymphocytes Abs - Normal to Normal
    60
    121
    119
        Lymphocytes Abs - Normal to Missing
    7
    9
    14
        Lymphocytes Abs - Missing to Normal
    0
    0
    1
        Ery. Mean Corpuscular Volume - Normal to Low
    0
    1
    1
        Ery. Mean Corpuscular Volume - Normal to Normal
    65
    130
    126
        Ery. Mean Corpuscular Volume - Normal to Missing
    7
    9
    15
        Ery. Mean Corpuscular Volume - High to High
    0
    1
    0
        Ery. Mean Corpuscular Volume - High to Missing
    0
    1
    0
        Ery. Mean Corpuscular Volume - Missing to Normal
    0
    1
    1
        Neutrophils, Total, Abs - Low to Low
    1
    1
    0
        Neutrophils, Total, Abs - Low to Normal
    0
    3
    4
        Neutrophils, Total, Abs - Low to Missing
    0
    1
    0
        Neutrophils, Total, Abs - Normal to Low
    0
    7
    4
        Neutrophils, Total, Abs - Normal to Normal
    55
    105
    105
        Neutrophils, Total, Abs - Normal to High
    1
    1
    2
        Neutrophils, Total, Abs - Normal to Missing
    8
    7
    15
        Neutrophils, Total, Abs - High to Normal
    3
    15
    7
        Neutrophils, Total, Abs - High to High
    4
    1
    5
        Neutrophils, Total, Abs - High to Missing
    0
    2
    0
        Neutrophils, Total, Abs - Missing to Normal
    0
    0
    1
        Platelets - Normal to Normal
    59
    128
    116
        Platelets - Normal to High
    1
    0
    3
        Platelets - Normal to Missing
    9
    9
    15
        Platelets - High to Normal
    2
    2
    4
        Platelets - High to High
    1
    2
    2
        Platelets - High to Missing
    0
    1
    2
        Platelets - Missing to Normal
    0
    1
    1
        White Blood Cell Count - Low to Low
    1
    1
    0
        White Blood Cell Count - Low to Normal
    0
    4
    2
        White Blood Cell Count - Low to Missing
    0
    1
    0
        White Blood Cell Count - Normal to Low
    0
    3
    2
        White Blood Cell Count - Normal to Normal
    64
    123
    124
        White Blood Cell Count - Normal to High
    0
    1
    0
        White Blood Cell Count - Normal to Missing
    7
    8
    14
        White Blood Cell Count - High to Normal
    0
    2
    0
        White Blood Cell Count - Missing to Normal
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Participants by Marked Laboratory Abnormality Status for Chemistry Parameters as a Shift Table from Baseline to Week 10

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    End point title
    Number of Participants by Marked Laboratory Abnormality Status for Chemistry Parameters as a Shift Table from Baseline to Week 10
    End point description
    Laboratory tests for chemistry parameters were performed and values were compared with the Roche marked reference range. A marked abnormality was defined as a test result that was outside of the Roche marked reference range (labelled as 'High' or 'Low') and represented a clinically significant change from baseline. Not every laboratory abnormality qualified as an adverse event. A laboratory test result must have been reported as an adverse event if it met any of the following criteria: was accompanied by clinical symptoms; resulted in a change in study treatment or a medical intervention; or was clinically significant in the investigator's judgment. The results are presented as a shift from the baseline status to the post-baseline (Week 10) status. Baseline was defined as the last available assessment prior to first receipt of study drug. The 'missing' status included participants with missing baseline or post-baseline values.
    End point type
    Secondary
    End point timeframe
    From Baseline up to Week 10
    End point values
    Placebo Adalimumab Etrolizumab
    Number of subjects analysed
    72
    143
    143
    Units: Participants
        Albumin - Low to Normal
    2
    3
    2
        Albumin - Low to Missing
    0
    0
    2
        Albumin - Normal to Low
    0
    1
    0
        Albumin - Normal to Normal
    65
    134
    137
        Albumin - Normal to Missing
    5
    5
    2
        Alkaline Phosphatase - Normal to Normal
    67
    138
    137
        Alkaline Phosphatase - Normal to Missing
    5
    5
    5
        Alkaline Phosphatase - High to Normal
    0
    0
    1
        Alanine Aminotransferase - Normal to Normal
    65
    134
    134
        Alanine Aminotransferase - Normal to High
    0
    1
    0
        Alanine Aminotransferase - Normal to Missing
    6
    7
    5
        Alanine Aminotransferase - High to Normal
    1
    1
    2
        Alanine Aminotransferase - High to High
    0
    0
    2
        Aspartate Aminotransferase - Normal to Normal
    65
    135
    135
        Aspartate Aminotransferase - Normal to High
    0
    0
    2
        Aspartate Aminotransferase - Normal to Missing
    6
    8
    5
        Aspartate Aminotransferase - High to Normal
    1
    0
    1
        Bicarbonate (CO2) - Low to Low
    1
    0
    0
        Bicarbonate (CO2) - Low to Normal
    1
    3
    0
        Bicarbonate (CO2) - Normal to Low
    6
    9
    10
        Bicarbonate (CO2) - Normal to Normal
    55
    121
    116
        Bicarbonate (CO2) - Normal to High
    0
    0
    1
        Bicarbonate (CO2) - Normal to Missing
    5
    7
    3
        Bicarbonate (CO2) - High to Normal
    4
    1
    10
        Bicarbonate (CO2) - High to High
    0
    2
    1
        Bicarbonate (CO2) - High to Missing
    0
    0
    2
        Blood Urea Nitrogen - Normal to Normal
    67
    138
    139
        Blood Urea Nitrogen - Normal to Missing
    5
    5
    4
        Calcium - Normal to Normal
    67
    138
    139
        Calcium - Normal to Missing
    5
    5
    4
        Chloride - Low to Low
    0
    1
    0
        Chloride - Low to Missing
    0
    1
    0
        Chloride - Normal to Low
    1
    1
    3
        Chloride - Normal to Normal
    66
    135
    136
        Chloride - Normal to Missing
    5
    5
    4
        Creatinine - Normal to Normal
    67
    138
    139
        Creatinine - Normal to Missing
    5
    5
    4
        Direct Bilirubin - Normal to Normal
    66
    132
    137
        Direct Bilirubin - Normal to Missing
    6
    10
    6
        Direct Bilirubin - Missing to Normal
    0
    1
    0
        Potassium - Normal to Low
    0
    1
    0
        Potassium - Normal to Normal
    66
    135
    137
        Potassium - Normal to Missing
    6
    7
    6
        Sodium - Normal to Normal
    67
    137
    139
        Sodium - Normal to Missing
    5
    6
    4
        Total Bilirubin - Normal to Normal
    66
    135
    136
        Total Bilirubin - Normal to High
    1
    3
    3
        Total Bilirubin - Normal to Missing
    5
    5
    4
        Protein, Total - Low to Normal
    1
    0
    1
        Protein, Total - Normal to Low
    0
    1
    0
        Protein, Total - Normal to Normal
    64
    132
    135
        Protein, Total - Normal to High
    1
    5
    0
        Protein, Total - Normal to Missing
    5
    5
    5
        Protein, Total - High to Normal
    1
    0
    1
        Protein, Total - High to High
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Participants With Anti-Drug Antibodies (ADAs) to Etrolizumab at Baseline and Anytime Post-Baseline

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    End point title
    Number of Participants With Anti-Drug Antibodies (ADAs) to Etrolizumab at Baseline and Anytime Post-Baseline [40]
    End point description
    Anti-drug antibody (ADA) serum samples were collected from participants and analyzed using validated assays. Participants were considered to be ADA positive post-baseline 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 units greater than the titer of the baseline sample (treatment-enhanced ADA response). Participants 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).
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hour) on Day 1 and Week 4, Week 10, Week 14, and early termination/end of safety follow-up (up to 26 weeks)
    Notes
    [40] - 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: The immunogenicity outcome measure of ADAs to etrolizumab at baseline and post-baseline was only assessed for those who had received etrolizumab.
    End point values
    Etrolizumab
    Number of subjects analysed
    141
    Units: Participants
        Positive for ADAs at Baseline (BL)
    7
        Negative for ADAs at BL
    134
        Post-BL: Positive for Treatment Emergent ADAs
    26
        Post-BL ADA Positive: Treatment-Induced ADAs
    26
        Post-BL ADA Positive: Treatment-Enhanced ADAs
    0
        Post-BL: Negative for Treatment Emergent ADAs
    115
        Post-BL ADA Negative: Treatment Unaffected
    7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline until the end of study (up to 26 weeks)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive placebo matching to etrolizumab subcutaneously (SC) once every 4 weeks (Q4W) up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC once every 2 weeks (Q2W) up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8).

    Reporting group title
    Adalimumab
    Reporting group description
    The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive adalimumab subcutaneously (SC) Q2W up to Week 8 (160 mg at Week 0 [Day 1], 80 mg at Week 2, 40 mg at Weeks 4, 6, and 8) and placebo matching to etrolizumab SC Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]).

    Reporting group title
    Etrolizumab
    Reporting group description
    The double-blinded treatment period consisted of a 10-week induction period and an additional 4-week treatment period for participants who met the definition of clinical remission at Week 10. Participants with moderate-to-severe ulcerative colitis who were naive to TNF inhibitors were randomized to this arm to receive etrolizumab 105 mg subcutaneously (SC) Q4W up to Week 12 (at Weeks 0 [Day 1], 4, 8, and 12 [clinical remitters only]) and placebo matching to adalimumab SC Q2W up to Week 8 (at Weeks 0 [Day 1], 2, 4, 6, and 8).

    Serious adverse events
    Placebo Adalimumab Etrolizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 72 (6.94%)
    3 / 143 (2.10%)
    7 / 143 (4.90%)
         number of deaths (all causes)
    0
    0
    1
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 72 (2.78%)
    0 / 143 (0.00%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anaplastic oligodendroglioma
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 143 (0.70%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 143 (0.00%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Visual impairment
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 143 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Sudden cardiac death
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 143 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Colitis ulcerative
         subjects affected / exposed
    2 / 72 (2.78%)
    1 / 143 (0.70%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon dysplasia
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 143 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 143 (0.00%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 143 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 143 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Costochondritis
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 143 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Clostridium difficile infection
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 143 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulpitis dental
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 143 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 143 (0.70%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Adalimumab Etrolizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 72 (19.44%)
    23 / 143 (16.08%)
    20 / 143 (13.99%)
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 72 (6.94%)
    2 / 143 (1.40%)
    5 / 143 (3.50%)
         occurrences all number
    5
    2
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 72 (0.00%)
    9 / 143 (6.29%)
    3 / 143 (2.10%)
         occurrences all number
    0
    10
    3
    Gastrointestinal disorders
    Colitis ulcerative
         subjects affected / exposed
    8 / 72 (11.11%)
    12 / 143 (8.39%)
    11 / 143 (7.69%)
         occurrences all number
    8
    12
    11
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 72 (5.56%)
    3 / 143 (2.10%)
    4 / 143 (2.80%)
         occurrences all number
    5
    4
    4

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Jun 2014
    Protocol Version 2: The protocol was amended to reflect recommendations following assessment of Protocol GA28949 through the Voluntary Harmonisation Procedure (VHP470) as follows: -The inclusion criteria was updated to include use of spermicide and barrier (rather than barrier alone) for acceptable methods of contraception during treatment period and for at least 24 weeks after the last dose. The inclusion criteria also identified combined oral contraceptive pills, and not progestin only pills, as acceptable and highly effective methods of contraception reflecting International Conference on Harmonisation (M3) guidance. -A new exclusion criterion was added to reflect that patients with suspicion of ischemic colitis, radiation colitis, or microscopic colitis will not be enrolled in the study. -The exclusion criterion regarding the history of moderate or severe allergic or anaphylactic/anaphylactoid reactions to chimeric, human, or humanized antibodies, fusion proteins, or murine proteins was updated to include hypersensitivity to etrolizumab (active drug substance) or any of the excipients (L-histidine, L-arginine, succinic acid, Polysorbate 20).
    19 Jul 2014
    Protocol Version 3: The protocol was amended to simplify the study design and to facilitate early access to open-label etrolizumab to eligible patients as follows: -Administration of adalimumab/adalimumab placebo at Weeks 10 and 12 was removed for all arms (for earlier washout) to facilitate earlier entry into the Open-Label Extension (OLE Part 1) of the OLE-SM (Open-Label Extension-Safety Monitoring) study (Study GA28951). Table “Study Drug Administration Schema” was updated accordingly. -Only patients achieving clinical remission at Week 10 will progress to Weeks 12 and 14 of the study to confirm maintenance of induction. Patients not achieving clinical remission at Week 10 should remain in the blinded study until Week 12 (to enable adalimumab washout) at which time they may enroll in the OLE.
    18 Sep 2015
    Protocol Version 4: The protocol was amended following FDA response to a type C request as follows: -Previously, the FDA had mandated a discontinuation of immunosuppressant therapy after Week 10 because of hypothetical risk of PML, resulting in distinct instructions regarding immunosuppressant use in different countries in the protocol. However, the Sponsor received agreement from the FDA to amend the global protocol GA28948 to instruct patients to continue their stable, baseline dose of immunosuppressants to the end of study treatment with dose reduction or discontinuation if patient experiences an immunosuppressant-related toxicity. Consequently the protocol was amended to allow patients to continue with immunosuppressant use from baseline to the end of study treatment (with dose reduction or discontinuation of immunosuppressant use permitted in the event of toxicity) in United States. -Following FDA feedback, inclusion criterion for patients at U.S. sites was amended to allow patients who had had an inadequate response to either immunosuppressants and/or corticosteroids to be eligible for the study rather than the previous requirement for failure to immunosuppressants with or without failure to corticosteroids. These two changes aligned United States with the rest of world regarding immunosuppressant use during the study and eligibility requirements for prior immunosuppressant/corticosteroid usage. Contents that indicated the use of immunosuppressants in the United States had to stop at Week 10 was removed.
    18 Dec 2016
    Protocol Version 5: The protocol was amended to update and align the safety section with information regarding potential risks for etrolizumab in the current Etrolizumab Investigator’s Brochure, Version 10, and to account for a change in adalimumab formulation, as follows: -The protocol was amended to include the use of the new formulation of adalimumab as needed, when supplies of the current formulation (40 mg [0.8mL]) could no longer be procured. The new formulation consisted of 40 mg (0.4 mL) of adalimumab provided in a single-use, 1-mL, glass prefilled syringe with a fixed 29-gauge ½-inch needle. The efficacy, safety, and tolerability profile of the new formulation was comparable to that of the formulation currently in use (40 mg [0.8 mL]). -The protocol was updated and added to include potential hepatic effects to be in line with the safety profile of other anti-integrins, including vedolizumab, for which hepatic adverse events were reported. Although no clear hepatic safety signals emerged to date with etrolizumab, this potential risk was considered to be applicable across the anti-integrin class and would be evaluated in all etrolizumab studies.
    30 Aug 2017
    Protocol Version 6: The protocol was amended to enhance recruitment by reducing the complexity of the protocol, particularly at the time of screening and re-screening, as follows: -The requirement for obtaining Medical Monitor approval for extension of the screening period from 28 to 35 days was eliminated to accommodate logistic delays that might arise during the screening period and decrease site burden associated with placing approval requests. The screening window would not be extended beyond 35 days under any circumstances. -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 randomization (Day 1). Post-endoscopy subscores might be used, starting 2 days after the screening endoscopy, but only in cases where there were insufficient e-diary data to calculate these subscores prior to the bowel preparation day.
    30 Oct 2018
    Protocol Version 7: The protocol was amended primarily to reflect changes in efficacy endpoints. The changes would not impact study conduct at the site level. These changes are as follows: -To assess the onset of action of etrolizumab, secondary efficacy endpoints of change in Mayo Clinic Score (MCS) rectal bleeding and stool frequency subscores from baseline to Week 6 were added. -The secondary efficacy objective to evaluate colonic mucosal alphaE integrin concentration as a biomarker was expanded and would be evaluated as an exploratory efficacy endpoint to support additional biomarker candidate evaluations in the pivotal placebo-controlled studies within the etrolizumab Phase III Program. -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 would 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 was considered to be more reliable in assessing earlier treatment response.
    15 Mar 2019
    Protocol Version 8: The protocol was amended to provide further clarification and exploratory efficacy objectives was modified as follows: -Evaluation of response at Week 10, in subgroups by baseline expression levels of colonic tissue and/or peripheral blood biomarkers, was added to predict patient subgroups with a greater likelihood of responding to etrolizumab.

    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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