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    Clinical Trial Results:
    An Open-Label Extension and Safety Monitoring Study of Patients With Moderately to Severely Active Crohn's Disease Previously Enrolled in the Etrolizumab Phase III Protocol GA29144

    Summary
    EudraCT number
    		 2014-003855-76
    Trial protocol
    		 SE   EE   LT   LV   HU   DE   ES   NL   SK   CZ   BE   AT   FR   HR   IT  
    Global end of trial date
    09 Oct 2023

    Results information
    Results version number
    		 v1
    This version publication date
    24 Oct 2024
    First version publication date
    24 Oct 2024
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    GA29145
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02403323
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4058
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    09 Oct 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Oct 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The aim of the study is to evaluate the efficacy and safety of etrolizumab in participants with Crohn's disease (CD).
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Jun 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Russian Federation: 61
    Country: Number of subjects enrolled
    United States: 171
    Country: Number of subjects enrolled
    Poland: 51
    Country: Number of subjects enrolled
    Canada: 46
    Country: Number of subjects enrolled
    Czechia: 47
    Country: Number of subjects enrolled
    France: 36
    Country: Number of subjects enrolled
    Australia: 36
    Country: Number of subjects enrolled
    Brazil: 33
    Country: Number of subjects enrolled
    Hungary: 35
    Country: Number of subjects enrolled
    Ukraine: 27
    Country: Number of subjects enrolled
    Spain: 27
    Country: Number of subjects enrolled
    Korea, Republic of: 23
    Country: Number of subjects enrolled
    New Zealand: 20
    Country: Number of subjects enrolled
    Germany: 20
    Country: Number of subjects enrolled
    Italy: 17
    Country: Number of subjects enrolled
    United Kingdom: 23
    Country: Number of subjects enrolled
    Israel: 15
    Country: Number of subjects enrolled
    Slovakia: 11
    Country: Number of subjects enrolled
    Netherlands: 13
    Country: Number of subjects enrolled
    Serbia: 10
    Country: Number of subjects enrolled
    Austria: 9
    Country: Number of subjects enrolled
    Switzerland: 9
    Country: Number of subjects enrolled
    Belgium: 7
    Country: Number of subjects enrolled
    Türkiye: 7
    Country: Number of subjects enrolled
    Bulgaria: 5
    Country: Number of subjects enrolled
    Romania: 5
    Country: Number of subjects enrolled
    Latvia: 4
    Country: Number of subjects enrolled
    Lithuania: 6
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    South Africa: 4
    Country: Number of subjects enrolled
    Croatia: 4
    Country: Number of subjects enrolled
    Estonia: 3
    Country: Number of subjects enrolled
    Argentina: 1
    Worldwide total number of subjects
    790
    EEA total number of subjects
    300
    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)
    761
    From 65 to 84 years
    29
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled in this study in 33 countries. All participants who enrolled into this study previously took part in study GA29144 (NCT02394028).

    Pre-assignment
    Screening details
    		 This study consists of 2 parts, Part 1: Open-label extension (OLE) period; Part 2: Progressive multifocal leukoencephalopathy (PML) safety monitoring (SM) period. 790 participants were enrolled in the study, 751 participants in Part 1 & 359 participants in Part 2. Of the 359, 39 participants directly entered Part 2 from study GA29144.

    Period 1
    Period 1 title
    Part 1: Open Label Extension Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 1 (OLE): Etrolizumab Only
    Arm description
    		 Participants received etrolizumab 105 milligrams (mg), subcutaneously (SC), once every 4 weeks (Q4W) for a maximum of 320 weeks followed by a 12-week safety follow-up.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Etrolizumab
    Investigational medicinal product code
    RO5490261
    Other name
    RG7413, PRO145223, rhuMAb Beta7
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Etrolizumab 105 mg,administered SC, Q4W for maximum of 320 weeks.

    Arm title
    		 Part 1 (OLE) to Part 2 (PML SM)
    Arm description
    		 Participants received etrolizumab 105 mg, SC, Q4W for maximum of 320 weeks, followed by a 12-week safety follow-up in the OLE period. After the OLE period, participants were given the option to enter Part 2 (PML SM). Participants who chose to enter the PML SM period were monitored for PML for a maximum of 92-weeks, during which no etrolizumab treatment was administered.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Etrolizumab
    Investigational medicinal product code
    RO5490261
    Other name
    RG7413, PRO145223, rhuMAb Beta7
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Etrolizumab 105 mg, administered SC, Q4W for maximum of 320 weeks in Part 1 (OLE) only. No treatment was administered in Part 2 (PML SM).

    Arm title
    		 Part 2: PML SM Only
    Arm description
    		 Participants from study GA29144 who completed the 12-week safety follow-up period and were not eligible/did not wish to enroll in the Part 1 (OLE), enrolled directly in Part 2 (PML SM). Participant were monitored for PML for a maximum of 92-weeks, during which no etrolizumab treatment was administered.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Part 1 (OLE): Etrolizumab Only Part 1 (OLE) to Part 2 (PML SM) Part 2: PML SM Only
    Started
    431
    320
    39
    Completed
    5
    320
    39
    Not completed
    426
    0
    0
         Physician decision
    61
    -
    -
         Adverse Event
    26
    -
    -
         Study Terminated By Sponsor
    19
    -
    -
         Death
    3
    -
    -
         Reason Not Specified
    59
    -
    -
         Unknown
    1
    -
    -
         Withdrawal by Subject
    232
    -
    -
         Non- compliance
    2
    -
    -
         Lost to follow-up
    23
    -
    -
    Period 2
    Period 2 title
    Part 2: PML Safety Monitoring Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 1 (OLE) to Part 2 (PML-SM)
    Arm description
    		 After the OLE period, participants were given the option to enter the Part 2 (PML SM). Participants who chose to enter the PML SM period were monitored for PML for a maximum of 92 weeks, during which no etrolizumab treatment was administered.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Part 2: PML-SM Only
    Arm description
    		 Participants from study GA29144 who completed the 12-week safety follow-up period and were not eligible/did not wish to enroll in the Part 1 (OLE), enrolled directly in Part 2 (PML SM). Participants were monitored for PML for a maximum of 92-weeks, during which no etrolizumab treatment was administered.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2 [1]
    		Part 1 (OLE) to Part 2 (PML-SM) Part 2: PML-SM Only
    Started
    320
    39
    Completed
    112
    33
    Not completed
    208
    6
         Physician decision
    7
    -
         Adverse Event
    4
    -
         Study Terminated By Sponsor
    167
    -
         Death
    1
    -
         Reason Not Specified
    6
    1
         Unknown
    1
    -
         Withdrawal by Subject
    12
    2
         Non- compliance
    1
    -
         Lost to follow-up
    9
    3
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Participants who discontinued Part1: OLE also had an option to enter the Part 2: PML SM phase. Hence, the number of participants who started Part 2: PML SM period is more than the participants who completed the Part1: OLE period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1 (OLE): Etrolizumab Only
    Reporting group description
    		 Participants received etrolizumab 105 milligrams (mg), subcutaneously (SC), once every 4 weeks (Q4W) for a maximum of 320 weeks followed by a 12-week safety follow-up.

    Reporting group title
    Part 1 (OLE) to Part 2 (PML SM)
    Reporting group description
    		 Participants received etrolizumab 105 mg, SC, Q4W for maximum of 320 weeks, followed by a 12-week safety follow-up in the OLE period. After the OLE period, participants were given the option to enter Part 2 (PML SM). Participants who chose to enter the PML SM period were monitored for PML for a maximum of 92-weeks, during which no etrolizumab treatment was administered.

    Reporting group title
    Part 2: PML SM Only
    Reporting group description
    		 Participants from study GA29144 who completed the 12-week safety follow-up period and were not eligible/did not wish to enroll in the Part 1 (OLE), enrolled directly in Part 2 (PML SM). Participant were monitored for PML for a maximum of 92-weeks, during which no etrolizumab treatment was administered.

    Reporting group values
    		 Part 1 (OLE): Etrolizumab Only Part 1 (OLE) to Part 2 (PML SM) Part 2: PML SM Only Total
    Number of subjects
    		 431 320 39 431
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 37.8 ( 13.0 ) 39.7 ( 13.6 ) 36.8 ( 13.0 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 199 158 19 376
        Male
    		 232 162 20 414
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 4 0 4
        Asian
    		 25 8 2 35
        Black or African American
    		 15 10 2 27
        White
    		 358 277 33 668
        Multiple
    		 2 1 0 3
        Unknown
    		 21 14 1 36
        Other
    		 10 6 1 17
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 24 24 3 51
        Not Hispanic or Latino
    		 385 280 35 700
        Unknown or Not Reported
    		 22 16 1 39

    End points

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    End points reporting groups
    Reporting group title
    Part 1 (OLE): Etrolizumab Only
    Reporting group description
    		 Participants received etrolizumab 105 milligrams (mg), subcutaneously (SC), once every 4 weeks (Q4W) for a maximum of 320 weeks followed by a 12-week safety follow-up.

    Reporting group title
    Part 1 (OLE) to Part 2 (PML SM)
    Reporting group description
    		 Participants received etrolizumab 105 mg, SC, Q4W for maximum of 320 weeks, followed by a 12-week safety follow-up in the OLE period. After the OLE period, participants were given the option to enter Part 2 (PML SM). Participants who chose to enter the PML SM period were monitored for PML for a maximum of 92-weeks, during which no etrolizumab treatment was administered.

    Reporting group title
    Part 2: PML SM Only
    Reporting group description
    		 Participants from study GA29144 who completed the 12-week safety follow-up period and were not eligible/did not wish to enroll in the Part 1 (OLE), enrolled directly in Part 2 (PML SM). Participant were monitored for PML for a maximum of 92-weeks, during which no etrolizumab treatment was administered.
    Reporting group title
    Part 1 (OLE) to Part 2 (PML-SM)
    Reporting group description
    		 After the OLE period, participants were given the option to enter the Part 2 (PML SM). Participants who chose to enter the PML SM period were monitored for PML for a maximum of 92 weeks, during which no etrolizumab treatment was administered.

    Reporting group title
    Part 2: PML-SM Only
    Reporting group description
    		 Participants from study GA29144 who completed the 12-week safety follow-up period and were not eligible/did not wish to enroll in the Part 1 (OLE), enrolled directly in Part 2 (PML SM). Participants were monitored for PML for a maximum of 92-weeks, during which no etrolizumab treatment was administered.

    Subject analysis set title
    Part 1 (OLE): Etrolizumab
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received etrolizumab 105 mg, SC, Q4W for a maximum of 320 weeks followed by a 12-week safety follow-up.

    Subject analysis set title
    Part 2: PML SM
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants from Part 1 (OLE) and from the study GA29144 who were not eligible/did not wish to enroll in Part 1 (OLE) and had completed the 12-week safety follow-up period were enrolled in Part 2 (PML SM). Participants were monitored for PML for a maximum of 92-weeks, during which no etrolizumab treatment was administered.

    Primary: Part 1: Number of Participants with Crohn's Disease Activity Index (CDAI) Remission at 12-week Intervals

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    End point title
    		 Part 1: Number of Participants with Crohn's Disease Activity Index (CDAI) Remission at 12-week Intervals [1]
    End point description
    CDAI is a score obtained from composite of eight assessments: number of liquid or soft stools, abdominal pain, general well-being, presence of complications, taking lomotil (diphenoxylate/atropine) or other opiates for diarrhea, presence of an abdominal mass, hematocrit, and percentage deviation from standard weight. A decrease in CDAI over time indicates improvement in disease activity. CDAI scores range from 0 to 600. A higher score indicates worse outcome. A total score of less than 150 corresponds to remission. OLE population included all participants who received at least one dose of study drug in Study GA29145 Part 1 (OLE). "n"= number of participants with data available for analysis at the specified timepoint.
    End point type
    Primary
    End point timeframe
    Day 1 and Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240 and 252 of OLE
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analysis was planned for this endpoint.
    End point values
    		 Part 1 (OLE): Etrolizumab
    Number of subjects analysed
    751
    Units: participants
        Day 1 (n=751)
    230
        Week 12 (n=354)
    166
        Week 24 (n=285)
    165
        Week 36 (n=250)
    161
        Week 48 (n=163)
    113
        Week 60 (n=198)
    137
        Week 72 (n=180)
    124
        Week 84 (n=160)
    119
        Week 96 (n=119)
    88
        Week 108 (n=123)
    96
        Week 120 (n=109)
    85
        Week 132 (n=97)
    73
        Week 144 (n=87)
    62
        Week 156 (n=80)
    58
        Week 168 (n=81)
    57
        Week 180 (n=73)
    53
        Week 192 (n=50)
    39
        Week 204 (n=46)
    29
        Week 216 (n=44)
    32
        Week 228 (n=33)
    18
        Week 240 (n=24)
    13
        Week 252 (n=21)
    12
    No statistical analyses for this end point

    Primary: Part 1: Number of Participants with Clinical Remission (CR) at 12-week Intervals

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    End point title
    		 Part 1: Number of Participants with Clinical Remission (CR) at 12-week Intervals [2]
    End point description
    Clinical remission was defined as a liquid/soft stool frequency (SF) mean daily score ≤3 and an abdominal pain (AP) mean daily score ≤1 with no worsening in either subscore compared to baseline, where the average was taken over 7 days prior to visit. Abdominal pain severity was assessed using the abdominal pain questionnaire which is an 11-point numeric rating scale with score ranging from 0 (no pain) to 10 (worse pain). Liquid/soft stool frequency was reported using the bristol stool form scale which classifies stools into seven groups based on its consistency. OLE population included all participants who received at least one dose of study drug in Study GA29145 Part 1 (OLE). "n"=number of participants with data available for analysis at the specified timepoint.
    End point type
    Primary
    End point timeframe
    Day 1 and Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240 and 252 of OLE
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analysis was planned for this endpoint.
    End point values
    		 Part 1 (OLE): Etrolizumab
    Number of subjects analysed
    751
    Units: participants
        Day 1 (n=751)
    200
        Week 12 (n=397)
    161
        Week 24 (n=346)
    168
        Week 36 (n=302)
    162
        Week 48 (n=244)
    135
        Week 60 (n=231)
    131
        Week 72 (n=221)
    132
        Week 84 (n=193)
    119
        Week 96 (n=171)
    103
        Week 108 (n=141)
    89
        Week 120 (n=128)
    87
        Week 132 (n=116)
    71
        Week 144 (n=106)
    71
        Week 156 (n=102)
    64
        Week 168 (n=97)
    62
        Week 180 (n=88)
    57
        Week 192 (n=67)
    41
        Week 204 (n=53)
    34
        Week 216 (n=53)
    32
        Week 228 (n=45)
    20
        Week 240 (n=29)
    13
        Week 252 (n=23)
    10
    No statistical analyses for this end point

    Primary: Part 1: Number of Participants with Adverse Event (AE) and Severity of AEs as Assessed Using National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI-CTCAE v4.0)

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    End point title
    		 Part 1: Number of Participants with Adverse Event (AE) and Severity of AEs as Assessed Using National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI-CTCAE v4.0) [3]
    End point description
    An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. AEs were graded as per NCI CTCAE v4.0. Grade 1=Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated; Grade 2=Moderate; minimal, local or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living; Grade 3=Severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4=Life threatening consequences, urgent intervention indicated; Grade 5=Death related to AE. OLE population included all participants who received at least one dose of study drug in study GA29145 Part 1 (OLE).
    End point type
    Primary
    End point timeframe
    From Day 1 up to end of 12-week safety follow-up in OLE (approximately 6.3 years)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analysis was planned for this endpoint.
    End point values
    		 Part 1 (OLE): Etrolizumab
    Number of subjects analysed
    751
    Units: participants
        AEs, Any Grade
    624
        Grade 1 AEs
    120
        Grade 2 AEs
    259
        Grade 3 AEs
    214
        Grade 4 AEs
    27
        Grade 5 AEs
    3
    No statistical analyses for this end point

    Primary: Part 1: Number of Participants With Improvement in Simple Endoscopic Score for Crohn's Disease (SES-CD) Score at Week 108

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    End point title
    		 Part 1: Number of Participants With Improvement in Simple Endoscopic Score for Crohn's Disease (SES-CD) Score at Week 108 [4]
    End point description
    SES-CD is an endoscopic score composite of 4 variables (ulcers size, percentage of ulcerated surface, inflamed surface, and presence of narrowing) in up to 5 ileocolonic segments (ileum right, colon, transverse colon, left colon, rectum) and scored on a scale of 0-3, with total score from 0-60. Higher score indicates higher ulcer surface/size in the 4 variables. Endoscopic improvement was defined as ≥50% reduction in SES-CD score compared to baseline. OLE population included all participants who received at least one dose of study drug in Study GA29145 Part 1 (OLE). Number analyzed is the number of participants with data available for analysis.
    End point type
    Primary
    End point timeframe
    At OLE Week 108
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analysis was planned for this endpoint.
    End point values
    		 Part 1 (OLE): Etrolizumab
    Number of subjects analysed
    242
    Units: participants
    147
    No statistical analyses for this end point

    Primary: Part 1: Number of Participants with Serious Adverse Events (SAEs)

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    End point title
    		 Part 1: Number of Participants with Serious Adverse Events (SAEs) [5]
    End point description
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and regardless of causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of an investigation, whether or not considered related to the medicinal (investigational) product. A SAE is any significant hazard, contraindication, side effect that is fatal or life-threatening, requires hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability/ incapacity, is a congenital anomaly/ birth defect, is medically significant or requires intervention to prevent one or other of the outcomes listed above. OLE popuation included all participants who received at least one dose of study drug in study GA29145 Part 1 (OLE).
    End point type
    Primary
    End point timeframe
    From Day 1 up to end of 12-week safety follow up in OLE (approximately 6.3 years)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analysis was planned for this endpoint.
    End point values
    		 Part 1 (OLE): Etrolizumab
    Number of subjects analysed
    751
    Units: participants
    206
    No statistical analyses for this end point

    Primary: Part 1: Number of Participants With Infection Related AEs and Severity of Infection-Related AEs Assessed Using NCI CTCAE v4.0

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    End point title
    		 Part 1: Number of Participants With Infection Related AEs and Severity of Infection-Related AEs Assessed Using NCI CTCAE v4.0 [6]
    End point description
    AE=untoward medical occurrence in participant administered a pharmaceutical product & regardless of causal relationship with this treatment.AE can be any unfavorable & unintended sign (including abnormal laboratory finding), symptom/disease temporally associated with use of investigational product, whether/not considered related to it. AEs were graded as per NCI CTCAE v4.0.Grade 1=Mild; asymptomatic/mild symptoms; clinical/diagnostic observations only; intervention not indicated; Grade 2=Moderate; minimal, local/ non-invasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL);Grade 3=Severe/medically significant, but not immediately life-threatening; hospitalization/prolongation of hospitalization indicated; disabling; limiting self-care ADL; Grade 4=Life-threatening consequences/urgent intervention indicated; Grade 5=Death related to AE. OLE population=all participants who received at least one dose of study drug in GA29145 Part 1 (OLE).
    End point type
    Primary
    End point timeframe
    From Day 1 up to end of 12-week safety follow up in OLE (approximately 6.3 years)
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analysis was planned for this endpoint.
    End point values
    		 Part 1 (OLE): Etrolizumab
    Number of subjects analysed
    751
    Units: participants
        Infection Related AEs, Any Grade
    366
        Grade 1 Infection Related AEs
    239
        Grade 2 Infection Related AEs
    194
        Grade 3 Infection Related AEs
    56
        Grade 4 Infection Related AEs
    5
        Grade 5 Infection Related AEs
    1
    No statistical analyses for this end point

    Primary: Part 1: Number of Participants with Adverse Events Leading to Etrolizumab Discontinuation

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    End point title
    		 Part 1: Number of Participants with Adverse Events Leading to Etrolizumab Discontinuation [7]
    End point description
    An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product. Number of participants who discontinued etrolizumab treatment during the OLE period have been reported here. OLE population included all participants who received at least one dose of study drug in study GA29145 Part 1 (OLE).
    End point type
    Primary
    End point timeframe
    From Day 1 up to end of 12-week safety follow up in OLE (approximately 6.3 years)
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analysis was planned for this endpoint.
    End point values
    		 Part 1 (OLE): Etrolizumab
    Number of subjects analysed
    751
    Units: participants
    112
    No statistical analyses for this end point

    Primary: Part 1: Number of Participants With Serious Infection Related AES

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    End point title
    		 Part 1: Number of Participants With Serious Infection Related AES [8]
    End point description
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and regardless of causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of an investigation, whether or not considered related to the medicinal (investigational) product. A SAE is any significant hazard, contraindication, side effect that is fatal or life-threatening, requires hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability/ incapacity, is a congenital anomaly/ birth defect, is medically significant or requires intervention to prevent one or other of the outcomes listed above. OLE population included all participants who received at least one dose of study drug in study GA29145 Part 1 (OLE).
    End point type
    Primary
    End point timeframe
    From Day 1 up to end of 12-week safety follow up in OLE (approximately 6.3 years)
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analysis was planned for this endpoint.
    End point values
    		 Part 1 (OLE): Etrolizumab
    Number of subjects analysed
    751
    Units: participants
    58
    No statistical analyses for this end point

    Primary: Part 1: Incidence Rate of Infection-related Adverse Event

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    End point title
    		 Part 1: Incidence Rate of Infection-related Adverse Event [9]
    End point description
    AE=any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product & that does not necessarily have a causal relationship with this treatment. AE can therefore be any unfavorable & unintended sign (including abnormal laboratory finding), symptom/disease temporally associated with use of investigational product, whether/not considered related to the it. AE rate (per 100 participant years) = [Total number of AEs (in OLE only) / Total number of participant years at risk (in OLE only)]*100. Total participant-years at risk is the sum over all participants of the time intervals (in years) from first dose of study treatment in Part 1 (OLE) until participant completes/withdraws from study (including 12-week safety follow-up, if applicable). OLE population=all participants who received at least one dose of study drug in study GA29145 Part 1 (OLE).
    End point type
    Primary
    End point timeframe
    From Day 1 up to end of 12-week safety follow up in OLE (approximately 6.3 years)
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analysis was planned for this endpoint.
    End point values
    		 Part 1 (OLE): Etrolizumab
    Number of subjects analysed
    751
    Units: event per 100 participant-years
        number (confidence interval 95%)
    62.74 (58.74 to 66.94)
    No statistical analyses for this end point

    Primary: Part 1: Number of Participants With Injection Site Reactions and Severity of Injection Site Reactions Assessed Using NCI CTCAE v4.0

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    End point title
    		 Part 1: Number of Participants With Injection Site Reactions and Severity of Injection Site Reactions Assessed Using NCI CTCAE v4.0 [10]
    End point description
    AE=untoward medical occurrence in participant administered a pharmaceutical product & regardless of causal relationship with this treatment.AE can be any unfavorable & unintended sign(including abnormal laboratory finding),symptom/disease temporally associated with use of investigational product,whether/not considered related to it. Injection-site reaction=any local reaction occurring at the site of injection following study drug administration. Signs (e.g., erythema, induration/swelling) and symptoms (e.g., pain, pruritus). Injection site reactions were graded per NCI CTCAE v4.0.Grade 1=Tenderness with /without symptoms (e.g., warmth, erythema, itching);Grade 2=Pain; lipodystrophy; edema; phlebitis;Grade 3=Ulceration/necrosis; severe tissue damage;operative intervention indicated;Grade 4=life-threatening consequences/urgent intervention indicated;Grade=5 death related to AE. OLE population=participants who received at least 1 dose of study drug in study GA29145 Part 1(OLE).
    End point type
    Primary
    End point timeframe
    From Day 1 up to end of safety 12-week follow-up in OLE (approximately 6.3 years)
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analysis was planned for this endpoint.
    End point values
    		 Part 1 (OLE): Etrolizumab
    Number of subjects analysed
    751
    Units: participants
        Injection Site Reaction, Any Grade
    15
        Injection Site Reaction, Grade 1
    14
        Injection Site Reaction, Grade 2
    1
        Injection Site Reaction, Grade 3
    0
        Injection Site Reaction, Grade 4
    0
        Injection Site Reaction, Grade 5
    0
    No statistical analyses for this end point

    Primary: Part 2: Number of Participants with Confirmed or Suspected Progressive Multifocal Leukoencephalopathy (PML)

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    End point title
    		 Part 2: Number of Participants with Confirmed or Suspected Progressive Multifocal Leukoencephalopathy (PML) [11]
    End point description
    PML was assessed by the PML Subjective Checklist (symptom assessment) and the PML Objective Checklist (neurologic evaluation). PML SM population included all participants who entered the PML SM phase. No treatment was administered in PML SM period, and hence participants entering from Part 1 (OLE) and the parent study have been reported together.
    End point type
    Primary
    End point timeframe
    From end of safety follow-up in Part 1 or study GA29144 up to maximum of 92 weeks
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analysis was planned for this endpoint.
    End point values
    		 Part 2: PML SM
    Number of subjects analysed
    359
    Units: participants
    0
    No statistical analyses for this end point

    Primary: Part 1: Number of Participants with Malignancies

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    End point title
    		 Part 1: Number of Participants with Malignancies [12]
    End point description
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and regardless of causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product. Number of participants who developed malignancies during the OLE period have been reported here. OLE population included all participants who received at least one dose of study drug in study GA29145 Part 1 (OLE).
    End point type
    Primary
    End point timeframe
    From Day 1 up to end of 12-week safety follow up in OLE (approximately 6.3 years)
    Notes
    [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analysis was planned for this endpoint.
    End point values
    		 Part 1 (OLE): Etrolizumab
    Number of subjects analysed
    751
    Units: participants
    18
    No statistical analyses for this end point

    Primary: Part 1: Incidence Rate of Malignancies

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    End point title
    		 Part 1: Incidence Rate of Malignancies [13]
    End point description
    Malignancy rate (per 100 participant years) = [Total number of malignancies (in OLE only) / Total number of participant years at risk (in OLE only)]*100. Total participant-years at risk is the sum over all participants of the time intervals (in years) from the first dose of study treatment in Part 1 (OLE) until the participant completes/withdraws from the study (including the 12-week safety follow-up, if applicable). OLE population included all participants who received at least one dose of study drug in study GA29145 Part 1 (OLE).
    End point type
    Primary
    End point timeframe
    From Day 1 up to end of 12-week safety follow up in OLE (approximately 6.3 years)
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analysis was planned for this endpoint.
    End point values
    		 Part 1 (OLE): Etrolizumab
    Number of subjects analysed
    751
    Units: events per 100-participant-years
        number (confidence interval 95%)
    1.85 (1.22 to 2.70)
    No statistical analyses for this end point

    Primary: Part 1: Number of Participants with Hypersensitivity Reactions and Severity of Hypersensitivity Assessed Using NCI-CTCAE v4.0

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    End point title
    		 Part 1: Number of Participants with Hypersensitivity Reactions and Severity of Hypersensitivity Assessed Using NCI-CTCAE v4.0 [14]
    End point description
    Hypersensitivity was reported using the MedDRA anaphylactic reaction standard MedDRA query (SMQ) & Sampson’s criteria. Hypersensitivity was assessed as per NCI CTCAE v4.0. Grade 1 = Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated; Grade 2 = Moderate; minimal, local or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living; Grade 3 = Severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. OLE population included all participants who received at least one dose of study drug in study GA29145 Part 1 (OLE).
    End point type
    Primary
    End point timeframe
    From Day 1 up to end of 12-week safety follow up in OLE (approximately 6.3 years)
    Notes
    [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analysis was planned for this endpoint.
    End point values
    		 Part 1 (OLE): Etrolizumab
    Number of subjects analysed
    751
    Units: participants
        Hypersensitivity Reactions, Any Grade
    3
        Hypersensitivity Reactions, Grade 1
    2
        Hypersensitivity Reactions, Grade 2
    0
        Hypersensitivity Reactions, Grade 3
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Part 1 (OLE): From Day 1 up to end of 12-week safety follow up in OLE (approximately 6.3 years); Part 2 (PML SM): From end of safety follow-up in Part 1 or in study GA29144 up to a maximum of 92-weeks
    Adverse event reporting additional description
    OLE population included all participants who received at least one dose of open label etrolizumab in Part 1 of the study. PML SM population included all participants who entered the PML SM period. Part 2: PML SM arm includes all participants who entered Part 2 (PML SM) from Part 1 (OLE) or from the parent study GA29144.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Part 2 (PML SM)
    Reporting group description
    		 Participants from Part 1 (OLE) and from the study GA29144 who were not eligible/did not wish to enroll in Part 1 (OLE) and had completed the 12-week safety follow-up period were enrolled in Part 2 (PML SM). Participants were monitored for PML for a maximum of 92-weeks, during which no etrolizumab treatment was administered.

    Reporting group title
    Part 1 (OLE): Etrolizumab
    Reporting group description
    		 Participants received etrolizumab 105 mg, SC, Q4W for a maximum of 320 weeks followed by a 12-week safety follow-up.

    Serious adverse events
    		 Part 2 (PML SM) Part 1 (OLE): Etrolizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 359 (0.28%)
    206 / 751 (27.43%)
         number of deaths (all causes)
    1
    3
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastatic malignant melanoma
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemangioma
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain neoplasm
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphangioma
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Thrombophlebitis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Peripheral revascularisation
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal resection
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernia repair
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Implantable defibrillator insertion
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parenteral nutrition
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colectomy
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileostomy closure
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurosurgery
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion induced
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Gait disturbance
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulcer haemorrhage
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Varicocele
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    0 / 359 (0.00%)
    2 / 751 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Female genital tract fistula
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    0 / 359 (0.00%)
    2 / 751 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paranasal sinus inflammation
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    0 / 359 (0.00%)
    2 / 751 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alcohol abuse
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight increased
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy test negative
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Postoperative ileus
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stoma complication
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lisfranc fracture
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stoma site haemorrhage
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Snake bite
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthropod bite
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal anastomosis complication
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 359 (0.00%)
    2 / 751 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Fall
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Memory impairment
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertebral artery stenosis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 359 (0.00%)
    6 / 751 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visual field defect
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 359 (0.00%)
    2 / 751 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal perforation
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 359 (0.00%)
    10 / 751 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    0 / 359 (0.00%)
    69 / 751 (9.19%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 84
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal stenosis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileal stenosis
         subjects affected / exposed
    0 / 359 (0.00%)
    3 / 751 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 359 (0.00%)
    5 / 751 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal prolapse
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    0 / 359 (0.00%)
    2 / 751 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal stenosis
         subjects affected / exposed
    0 / 359 (0.00%)
    2 / 751 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 359 (0.00%)
    3 / 751 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 359 (0.00%)
    2 / 751 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal stenosis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Noninfective gingivitis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    0 / 359 (0.00%)
    5 / 751 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 359 (0.00%)
    10 / 751 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterovesical fistula
         subjects affected / exposed
    0 / 359 (0.00%)
    2 / 751 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal fistula
         subjects affected / exposed
    0 / 359 (0.00%)
    2 / 751 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth disorder
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Granulomatous liver disease
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 359 (0.00%)
    2 / 751 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Henoch-Schonlein purpura
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septal panniculitis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panniculitis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 359 (0.00%)
    2 / 751 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 359 (0.00%)
    2 / 751 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fistula
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint swelling
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sacroiliitis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 359 (0.00%)
    2 / 751 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 359 (0.00%)
    3 / 751 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Perineal abscess
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 359 (0.00%)
    3 / 751 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    0 / 359 (0.00%)
    3 / 751 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter infection
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicella meningitis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal abscess
         subjects affected / exposed
    0 / 359 (0.00%)
    7 / 751 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Measles
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotavirus infection
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 359 (0.00%)
    2 / 751 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft infection
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 359 (0.28%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Latent tuberculosis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis viral
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 359 (0.00%)
    2 / 751 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin abscess
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 359 (0.00%)
    13 / 751 (1.73%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal bacterial infection
         subjects affected / exposed
    0 / 359 (0.00%)
    2 / 751 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic abscess
         subjects affected / exposed
    0 / 359 (0.00%)
    2 / 751 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal wall abscess
         subjects affected / exposed
    0 / 359 (0.00%)
    2 / 751 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus colitis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Malnutrition
         subjects affected / exposed
    0 / 359 (0.00%)
    2 / 751 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cachexia
         subjects affected / exposed
    0 / 359 (0.00%)
    2 / 751 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 751 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part 2 (PML SM) Part 1 (OLE): Etrolizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 359 (0.56%)
    453 / 751 (60.32%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 359 (0.00%)
    76 / 751 (10.12%)
         occurrences all number
    0
    96
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 359 (0.00%)
    42 / 751 (5.59%)
         occurrences all number
    0
    52
    Gastrointestinal disorders
    Crohn's disease
         subjects affected / exposed
    1 / 359 (0.28%)
    174 / 751 (23.17%)
         occurrences all number
    1
    229
    Abdominal pain
         subjects affected / exposed
    1 / 359 (0.28%)
    82 / 751 (10.92%)
         occurrences all number
    2
    109
    Vomiting
         subjects affected / exposed
    0 / 359 (0.00%)
    43 / 751 (5.73%)
         occurrences all number
    0
    52
    Nausea
         subjects affected / exposed
    0 / 359 (0.00%)
    52 / 751 (6.92%)
         occurrences all number
    0
    63
    Diarrhoea
         subjects affected / exposed
    0 / 359 (0.00%)
    53 / 751 (7.06%)
         occurrences all number
    0
    68
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 359 (0.00%)
    87 / 751 (11.58%)
         occurrences all number
    0
    119
    Back pain
         subjects affected / exposed
    0 / 359 (0.00%)
    43 / 751 (5.73%)
         occurrences all number
    0
    52
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 359 (0.00%)
    80 / 751 (10.65%)
         occurrences all number
    0
    136
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 359 (0.00%)
    58 / 751 (7.72%)
         occurrences all number
    0
    80
    Urinary tract infection
         subjects affected / exposed
    1 / 359 (0.28%)
    38 / 751 (5.06%)
         occurrences all number
    1
    46
    COVID-19
         subjects affected / exposed
    0 / 359 (0.00%)
    80 / 751 (10.65%)
         occurrences all number
    0
    81

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Dec 2014
    The Abdominal Pain Questionnaire has been added to assess the severity of patient-reported abdominal pain.
    04 Nov 2015
    Addition of ileocolonoscopy and biopsy samples at Week 108
    16 Dec 2016
    1. Addition of potential hepatic effects 2. Eligibility criteria for Part 1 (OLE) changed. 3. First dose window increased.
    14 May 2018
    1. The definition of clinical relapse was clarified. 2. Patient-Reported Outcomes-2 (PRO2) was replaced with clinical remission (unweighted stool frequency and abdominal pain) to align with outcome measure changes in the parent study, GA29144. 3. The number of participants updated to align with the parent study, GA29144. 4. The exploratory outcome measure of simple endoscopic score for crohn’s disease [SES-CD] score=0) at Week 108 replaced with the endoscopic outcome of SES-CD ≤4 (≤2 for ileal participants). 5. The definition of disease worsening updated to align with the parent study, GA29144. 6. The exclusion criteria updated to include participants who developed cytomegalovirus (CMV) colitis during Study GA29144 that led to early treatment discontinuation. 7. The directions for the biopsy pair collected at Week 108 was changed and was collected from the terminal ileum instead of the worst affected segment. 8. The requirement to assess and communicate baseline John Cunningham virus (JCV) antibody status to a participant was removed.
    29 Apr 2019
    1. The duration of Part 1 has been changed from 6.5 years to approximately 10 years. 2. Eligibility criteria have been changed to account for the closure of enrollment into the maintenance phase in parent study GA29144 after the projected sample size for this phase has been achieved. 3. Antagonists of IL-12 ±IL-23 (e.g., ustekinumab) have been added to the list of concomitant therapies prohibited. 4. Reference to participants with significant liver function test abnormalities has been removed.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    09 Oct 2023
    The study was terminated due to the Sponsor’s decision to not pursue a marketing application for etrolizumab in adult CD indication.
    -

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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