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    Clinical Trial Results:
    A Phase I, Open–Label, Randomized, Pharmacokinetic, Pharmacodynamic, And Safety Study Of Etrolizumab Followed By Open–Label Extension And Safety Monitoring In Pediatric Patients From 4 Years To Less Than 18 Years Of Age With Moderate To Severe Ulcerative Colitis Or Moderate To Severe Crohn’s Disease

    Summary
    EudraCT number
    		 2017-003649-10
    Trial protocol
    		 ES   GB   PL   DE   BE  
    Global end of trial date
    27 Sep 2023

    Results information
    Results version number
    		 v3(current)
    This version publication date
    05 Apr 2024
    First version publication date
    04 Jun 2020
    Other versions
    		 v1 , v2
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    CA40192
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03478956
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche, Ltd.
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche, Ltd., F. Hoffmann-La Roche, Ltd., +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche, Ltd., F. Hoffmann-La Roche, Ltd., +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001434-PIP01-13
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 Sep 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Sep 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the pharmacokinetics and pharmacodynamics of etrolizumab in a pediatric inflammatory bowel disease patient population.
    Protection of trial subjects
    This study was conducted in full conformance with the ICH E6 guideline for Good Clinical Practice and the principles of the Declaration of Helsinki, or the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. The Informed Consent Forms and Child's Informed Assent Forms were signed and dated by the patient or the patient’s legally authorized representative before his or her participation in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Mar 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Poland: 20
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    United Kingdom: 1
    Worldwide total number of subjects
    24
    EEA total number of subjects
    23
    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)
    8
    Adolescents (12-17 years)
    16
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 30 patients were screened and 6 failed screenings, 2 due to administrative reasons and 4 due to failure to meet exclusion criteria; a total of 24 subjects were enrolled in the study.

    Period 1
    Period 1 title
    Randomized Treatment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Etrolizumab Q4W
    Arm description
    		 Etrolizumab 1.5 milligrams per kilogram of body weight (mg/kg) was administered by subcutaneous (SC) injection once every 4 weeks (Q4W) for a total of 4 doses over the course of the 24-week randomized treatment phase (16-week treatment period plus 8-week safety follow-up). Participants were then given the option to participate in the 312-week open-label extension (OLE) treatment phase with etrolizumab 1.5 mg/kg SC Q4W followed by the 104-week safety surveillance phase (no etrolizumab treatment) to monitor for progressive multifocal leukoencephalopathy (PML). All participants who chose not to enter the OLE phase after the 24-week randomized treatment phase entered the 104-week PML monitoring phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Etrolizumab
    Investigational medicinal product code
    RO5490261/F02-01
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    All participants randomized to this arm received 150 milligrams per millilitre (mg/mL) etrolizumab by subcutaneous injection of 0.01 mL per kilogram (kg) of body weight (1.5 mg/kg) once every 4 weeks (Q4W) during the 24-week randomized treatment phase. Following the completion of this phase, participants who chose to enter the open-label extension phase received 150 mg/mL etrolizumab by subcutaneous injection of 0.01 mL per kg of body weight (1.5 mg/kg) Q4W for up to 312 weeks.

    Arm title
    		 Etrolizumab Q8W
    Arm description
    		 Etrolizumab 3.0 mg/kg was administered by subcutaneous (SC) injection once every 8 weeks (Q8W) for a total of 2 doses over the course of the 24-week randomized treatment phase (16-week treatment period plus 8-week safety follow-up). Participants were then given the option to participate in the 312-week open-label extension (OLE) treatment phase with etrolizumab 1.5 mg/kg SC Q4W followed by the 104-week safety surveillance phase (no etrolizumab treatment) to monitor for progressive multifocal leukoencephalopathy (PML). All participants who chose not to enter the OLE phase after the 24-week randomized treatment phase entered the 104-week PML monitoring phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Etrolizumab
    Investigational medicinal product code
    RO5490261/F02-01
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    All participants randomized to this arm received 150 milligrams per millilitre (mg/mL) etrolizumab by subcutaneous injection of 0.02 mL per kg of body weight (3 mg/kg) once every 8 weeks (Q8W) during the 24-week randomized treatment phase. Following the completion of this phase, participants who chose to enter the open-label extension phase received 150 mg/mL etrolizumab by subcutaneous injection of 0.01 mL per kg of body weight (1.5 mg/kg) Q4W for up to 312 weeks.

    Number of subjects in period 1
    		Etrolizumab Q4W Etrolizumab Q8W
    Started
    12
    12
    Received at Least One Dose of Study Drug
    12
    12
    Completed Treatment
    11
    10 [1]
    Completed
    11
    11
    Not completed
    1
    1
         Consent withdrawn by subject
    -
    1
         Adverse event
    1
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Number reflects the number of subjects who completed treatment.
    Period 2
    Period 2 title
    Open Label Extension (OLE) and PML
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Etrolizumab Q4W
    Arm description
    		 Etrolizumab 1.5 milligrams per kilogram of body weight (mg/kg) was administered by subcutaneous (SC) injection once every 4 weeks (Q4W) for a total of 4 doses over the course of the 24-week randomized treatment phase (16-week treatment period plus 8-week safety follow-up). Participants were then given the option to participate in the 312-week open-label extension (OLE) treatment phase with etrolizumab 1.5 mg/kg SC Q4W followed by the 104-week safety surveillance phase (no etrolizumab treatment) to monitor for progressive multifocal leukoencephalopathy (PML). All participants who chose not to enter the OLE phase after the 24-week randomized treatment phase entered the 104-week PML monitoring phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Etrolizumab
    Investigational medicinal product code
    RO5490261/F02-01
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    All participants randomized to this arm received 150 milligrams per millilitre (mg/mL) etrolizumab by subcutaneous injection of 0.01 mL per kilogram (kg) of body weight (1.5 mg/kg) once every 4 weeks (Q4W) during the 24-week randomized treatment phase. Following the completion of this phase, participants who chose to enter the open-label extension phase received 150 mg/mL etrolizumab by subcutaneous injection of 0.01 mL per kg of body weight (1.5 mg/kg) Q4W for up to 312 weeks.

    Arm title
    		 Etrolizumab Q8W
    Arm description
    		 Etrolizumab 3.0 mg/kg was administered by subcutaneous (SC) injection once every 8 weeks (Q8W) for a total of 2 doses over the course of the 24-week randomized treatment phase (16-week treatment period plus 8-week safety follow-up). Participants were then given the option to participate in the 312-week open-label extension (OLE) treatment phase with etrolizumab 1.5 mg/kg SC Q4W followed by the 104-week safety surveillance phase (no etrolizumab treatment) to monitor for progressive multifocal leukoencephalopathy (PML). All participants who chose not to enter the OLE phase after the 24-week randomized treatment phase entered the 104-week PML monitoring phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Etrolizumab
    Investigational medicinal product code
    RO5490261/F02-01
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    All participants randomized to this arm received 150 milligrams per millilitre (mg/mL) etrolizumab by subcutaneous injection of 0.02 mL per kg of body weight (3 mg/kg) once every 8 weeks (Q8W) during the 24-week randomized treatment phase. Following the completion of this phase, participants who chose to enter the open-label extension phase received 150 mg/mL etrolizumab by subcutaneous injection of 0.01 mL per kg of body weight (1.5 mg/kg) Q4W for up to 312 weeks.

    Arm title
    		 PML Safety Monitoring
    Arm description
    		 After the randomized treatment period (if participants did not enter the OLE period) or after the OLE period participants were monitored during the 104-week safety surveillance phase (no etrolizumab treatment) for progressive multifocal leukoencephalopathy (PML).
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Etrolizumab Q4W Etrolizumab Q8W PML Safety Monitoring
    Started
    11
    10
    13
    Completed
    0
    0
    4
    Not completed
    11
    10
    9
         Consent withdrawn by subject
    -
    2
    -
         Study terminated by sponsor
    4
    2
    9
         Adverse event
    3
    1
    -
         Lack of efficacy
    3
    5
    -
         Reason not provided
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Etrolizumab Q4W
    Reporting group description
    		 Etrolizumab 1.5 milligrams per kilogram of body weight (mg/kg) was administered by subcutaneous (SC) injection once every 4 weeks (Q4W) for a total of 4 doses over the course of the 24-week randomized treatment phase (16-week treatment period plus 8-week safety follow-up). Participants were then given the option to participate in the 312-week open-label extension (OLE) treatment phase with etrolizumab 1.5 mg/kg SC Q4W followed by the 104-week safety surveillance phase (no etrolizumab treatment) to monitor for progressive multifocal leukoencephalopathy (PML). All participants who chose not to enter the OLE phase after the 24-week randomized treatment phase entered the 104-week PML monitoring phase.

    Reporting group title
    Etrolizumab Q8W
    Reporting group description
    		 Etrolizumab 3.0 mg/kg was administered by subcutaneous (SC) injection once every 8 weeks (Q8W) for a total of 2 doses over the course of the 24-week randomized treatment phase (16-week treatment period plus 8-week safety follow-up). Participants were then given the option to participate in the 312-week open-label extension (OLE) treatment phase with etrolizumab 1.5 mg/kg SC Q4W followed by the 104-week safety surveillance phase (no etrolizumab treatment) to monitor for progressive multifocal leukoencephalopathy (PML). All participants who chose not to enter the OLE phase after the 24-week randomized treatment phase entered the 104-week PML monitoring phase.

    Reporting group values
    		 Etrolizumab Q4W Etrolizumab Q8W Total
    Number of subjects
    		 12 12 24
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 4 4 8
        Adolescents (12-17 years)
    		 8 8 16
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 12.25 ( 3.62 ) 13.42 ( 4.46 ) -
    Sex: Female, Male
    Units: Participants
        Male
    		 8 5 13
        Female
    		 4 7 11
    Race
    Units: Subjects
        White
    		 12 12 24
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 1 1
        Not Hispanic or Latino
    		 12 11 23
    Disease Indication: Crohn's Disease or Ulcerative Colitis
    Units: Subjects
        Crohn's Disease
    		 5 5 10
        Ulcerative Colitis
    		 7 7 14
    Randomization Stratification Factor: Body Weight <40 kg or ≥40 kg
    Units: Subjects
        <40 kg
    		 5 4 9
        ≥40 kg
    		 7 8 15

    End points

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    End points reporting groups
    Reporting group title
    Etrolizumab Q4W
    Reporting group description
    		 Etrolizumab 1.5 milligrams per kilogram of body weight (mg/kg) was administered by subcutaneous (SC) injection once every 4 weeks (Q4W) for a total of 4 doses over the course of the 24-week randomized treatment phase (16-week treatment period plus 8-week safety follow-up). Participants were then given the option to participate in the 312-week open-label extension (OLE) treatment phase with etrolizumab 1.5 mg/kg SC Q4W followed by the 104-week safety surveillance phase (no etrolizumab treatment) to monitor for progressive multifocal leukoencephalopathy (PML). All participants who chose not to enter the OLE phase after the 24-week randomized treatment phase entered the 104-week PML monitoring phase.

    Reporting group title
    Etrolizumab Q8W
    Reporting group description
    		 Etrolizumab 3.0 mg/kg was administered by subcutaneous (SC) injection once every 8 weeks (Q8W) for a total of 2 doses over the course of the 24-week randomized treatment phase (16-week treatment period plus 8-week safety follow-up). Participants were then given the option to participate in the 312-week open-label extension (OLE) treatment phase with etrolizumab 1.5 mg/kg SC Q4W followed by the 104-week safety surveillance phase (no etrolizumab treatment) to monitor for progressive multifocal leukoencephalopathy (PML). All participants who chose not to enter the OLE phase after the 24-week randomized treatment phase entered the 104-week PML monitoring phase.
    Reporting group title
    Etrolizumab Q4W
    Reporting group description
    		 Etrolizumab 1.5 milligrams per kilogram of body weight (mg/kg) was administered by subcutaneous (SC) injection once every 4 weeks (Q4W) for a total of 4 doses over the course of the 24-week randomized treatment phase (16-week treatment period plus 8-week safety follow-up). Participants were then given the option to participate in the 312-week open-label extension (OLE) treatment phase with etrolizumab 1.5 mg/kg SC Q4W followed by the 104-week safety surveillance phase (no etrolizumab treatment) to monitor for progressive multifocal leukoencephalopathy (PML). All participants who chose not to enter the OLE phase after the 24-week randomized treatment phase entered the 104-week PML monitoring phase.

    Reporting group title
    Etrolizumab Q8W
    Reporting group description
    		 Etrolizumab 3.0 mg/kg was administered by subcutaneous (SC) injection once every 8 weeks (Q8W) for a total of 2 doses over the course of the 24-week randomized treatment phase (16-week treatment period plus 8-week safety follow-up). Participants were then given the option to participate in the 312-week open-label extension (OLE) treatment phase with etrolizumab 1.5 mg/kg SC Q4W followed by the 104-week safety surveillance phase (no etrolizumab treatment) to monitor for progressive multifocal leukoencephalopathy (PML). All participants who chose not to enter the OLE phase after the 24-week randomized treatment phase entered the 104-week PML monitoring phase.

    Reporting group title
    PML Safety Monitoring
    Reporting group description
    		 After the randomized treatment period (if participants did not enter the OLE period) or after the OLE period participants were monitored during the 104-week safety surveillance phase (no etrolizumab treatment) for progressive multifocal leukoencephalopathy (PML).

    Primary: Maximum Serum Concentration (Cmax) of Etrolizumab After First and Last Dose During the Randomized Treatment Phase

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    End point title
    		 Maximum Serum Concentration (Cmax) of Etrolizumab After First and Last Dose During the Randomized Treatment Phase [1]
    End point description
    Etrolizumab concentrations in all pharmacokinetics (PK) samples were measured using a validated assay method. Non-compartmental analysis methods were employed to calculate PK parameters. The PK Evaluable Population included all participants who received at least one dose of study drug and had evaluable PK data. This analysis included data from participants who had received their first dose (Day 1 for both arms) and last dose (on Day 56 for Q8W arm and Day 84 for Q4W arm) of study drug.
    End point type
    Primary
    End point timeframe
    Arm Etro Q4W: Day 1, 84 and Arm Etro Q8W: Day 1, 56
    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 hypothesis testing was planned for this study. All analyses were summarized by descriptive statistics.
    End point values
    		 Etrolizumab Q4W Etrolizumab Q8W
    Number of subjects analysed
    11
    12
    Units: micrograms per millilitre (μg/mL)
    arithmetic mean (standard deviation)
        After First Dose (n = 10, 12)
    7.73 ( 2.18 )
    19.0 ( 8.21 )
        After Last Dose (n = 11, 11)
    9.80 ( 4.86 )
    18.1 ( 6.25 )
    No statistical analyses for this end point

    Primary: Time to Maximum Serum Concentration (Tmax) of Etrolizumab After First and Last Dose During the Randomized Treatment Phase

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    End point title
    		 Time to Maximum Serum Concentration (Tmax) of Etrolizumab After First and Last Dose During the Randomized Treatment Phase [2]
    End point description
    Etrolizumab concentrations in all pharmacokinetics (PK) samples were measured using a validated assay method. Non-compartmental analysis methods were employed to calculate PK parameters. The PK Evaluable Population included all participants who received at least one dose of study drug and had evaluable PK data. This analysis included data from participants who had received their first dose (Day 1 for both arms) and last dose (on Day 56 for Q8W arm and Day 84 for Q4W arm) of study drug.
    End point type
    Primary
    End point timeframe
    Arm Etro Q4W: Day 1, 84 and Arm Etro Q8W: Day 1, 56
    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 hypothesis testing was planned for this study. All analyses were summarized by descriptive statistics.
    End point values
    		 Etrolizumab Q4W Etrolizumab Q8W
    Number of subjects analysed
    11
    12
    Units: Day
    arithmetic mean (standard deviation)
        After First Dose (n = 10, 12)
    4.65 ( 1.43 )
    4.00 ( 1.48 )
        After Last Dose (n = 11, 11)
    5.04 ( 2.92 )
    4.94 ( 3.28 )
    No statistical analyses for this end point

    Primary: Area Under the Concentration-Time Curve Within the Last Dosing Interval (AUC-tau) of Etrolizumab During the Randomized Treatment Phase

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    End point title
    		 Area Under the Concentration-Time Curve Within the Last Dosing Interval (AUC-tau) of Etrolizumab During the Randomized Treatment Phase [3]
    End point description
    Etrolizumab concentrations in all pharmacokinetics (PK) samples were measured using a validated assay method. Non-compartmental analysis methods were employed to calculate PK parameters. The PK Evaluable Population included all participants who received at least one dose of study drug and had evaluable PK data. This analysis included data from participants who had received their last dose of study drug (on Day 56 for Q8W arm and Day 84 for Q4W arm). The value '999999' indicates that the mean and standard deviation were not reported because 0 participants were assessed at that timepoint.
    End point type
    Primary
    End point timeframe
    Arm Etro Q4W: Days 56, 84, 88, 98, 112 and Arm Etro Q8W: Day 56, 60, 70, 84, 88, 98, 112
    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 hypothesis testing was planned for this study. All analyses were summarized by descriptive statistics.
    End point values
    		 Etrolizumab Q4W Etrolizumab Q8W
    Number of subjects analysed
    11
    10
    Units: Day*μg/mL
    arithmetic mean (standard deviation)
        AUC56-112 (n = 0, 10)
    999999 ( 999999 )
    521 ( 306 )
        AUC84-112 (n = 11, 0)
    167 ( 86.9 )
    999999 ( 999999 )
    No statistical analyses for this end point

    Primary: Elimination Half-Life (t1/2) of Etrolizumab After Last Dose During the Randomized Treatment Phase

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    End point title
    		 Elimination Half-Life (t1/2) of Etrolizumab After Last Dose During the Randomized Treatment Phase [4]
    End point description
    Etrolizumab concentrations in all pharmacokinetics (PK) samples were measured using a validated assay method. Non-compartmental analysis methods were employed to calculate PK parameters. The PK Evaluable Population included all participants who received at least one dose of study drug and had evaluable PK data. This analysis included data from participants who had received their last dose of study drug (on Day 56 for Q8W arm and Day 84 for Q4W arm).
    End point type
    Primary
    End point timeframe
    Arm Etro Q4W: Days 84, 88, 98, 112, 126, 140, 168 and Arm Etro Q8W: Days 56, 60, 70, 84, 88, 98, 112, 126, 140, 168
    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 hypothesis testing was planned for this study. All analyses were summarized by descriptive statistics.
    End point values
    		 Etrolizumab Q4W Etrolizumab Q8W
    Number of subjects analysed
    11
    10
    Units: Day
    arithmetic mean (standard deviation)
        After Last Dose
    7.31 ( 1.76 )
    8.65 ( 3.74 )
    No statistical analyses for this end point

    Primary: Serum Trough Concentration (Ctrough) of Etrolizumab at the End of Each Dosing Interval During the Randomized Treatment Phase

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    End point title
    		 Serum Trough Concentration (Ctrough) of Etrolizumab at the End of Each Dosing Interval During the Randomized Treatment Phase [5]
    End point description
    Etrolizumab concentrations in all pharmacokinetics (PK) samples were measured using a validated assay method. The PK Evaluable Population included all participants who received at least one dose of study drug and had evaluable PK data. This analysis included data from participants at the end of each dosing interval (on Days 28, 56, 84, and 112 for Q4W arm and Days 56 and 112 for Q8W arm). The value '999999' indicates that the mean and standard deviation were not reported because 0 participants were assessed at that timepoint.
    End point type
    Primary
    End point timeframe
    Arm Etro Q4W: Predose on Days 28, 56, 84, 112 and Arm Etro Q8W: Predose on Days 56, 112
    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 hypothesis testing was planned for this study. All analyses were summarized by descriptive statistics.
    End point values
    		 Etrolizumab Q4W Etrolizumab Q8W
    Number of subjects analysed
    11
    12
    Units: micrograms per millilitre (μg/mL)
    arithmetic mean (standard deviation)
        Day 28 (n = 11, 0)
    1.87 ( 1.32 )
    999999 ( 999999 )
        Day 56 (n = 11, 11)
    3.22 ( 2.24 )
    1.82 ( 1.99 )
        Day 84 (n = 11, 0)
    3.00 ( 2.38 )
    999999 ( 999999 )
        Day 112 (n = 11, 10)
    2.79 ( 2.01 )
    3.70 ( 4.64 )
    No statistical analyses for this end point

    Primary: Percentage of Baseline Absolute Numbers of Beta7 Receptor-Expressing Gut Homing CD3, CD4, and CD8 T Cells and CD19 B Cells with Unoccupied Beta7 Receptors in Peripheral Blood, Assessed by Flow Cytometry, During the Randomized Treatment Phase

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    End point title
    		 Percentage of Baseline Absolute Numbers of Beta7 Receptor-Expressing Gut Homing CD3, CD4, and CD8 T Cells and CD19 B Cells with Unoccupied Beta7 Receptors in Peripheral Blood, Assessed by Flow Cytometry, During the Randomized Treatment Phase [6]
    End point description
    Target engagement of etrolizumab was assessed via measurement of Beta7 receptor occupancy on Beta7 receptor expressing gut homing lymphocyte subsets in peripheral blood, including CD3, CD4, and CD8 T cells and CD19 B cells, using qualified flow cytometry methods. A decrease to 0% of baseline (BL) in median absolute cell counts of Beta7 receptor-expressing T and B cell subsets with unoccupied Beta7 receptors following etrolizumab treatment indicated maximal receptor occupancy by etrolizumab. The Pharmacodynamics (PD) Evaluable Population included all participants who received at least one dose of study treatment and had evaluable PD data.
    End point type
    Primary
    End point timeframe
    Predose at Baseline (Day 1) and on Days 4, 56, 84, 98, and 112 (Treatment Period), and Days 126, 140, and 168 (Follow-Up Period)
    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 hypothesis testing was planned for this study. All analyses were summarized by descriptive statistics.
    End point values
    		 Etrolizumab Q4W Etrolizumab Q8W
    Number of subjects analysed
    12
    12
    Units: Percentage of BL Unoccupied Beta7 Cells
    median (standard deviation)
        CD3 T Cells: Baseline (n = 11, 10)
    100 ( 0.0 )
    100 ( 0.0 )
        CD3 T Cells: Day 4 (n = 8, 10)
    0.18 ( 0.2 )
    0.40 ( 0.4 )
        CD3 T Cells: Day 56 (n = 9, 10)
    1.92 ( 1.9 )
    13.74 ( 13.5 )
        CD3 T Cells: Day 84 (n = 9, 9)
    7.43 ( 6.0 )
    1.06 ( 1.1 )
        CD3 T Cells: Day 98 (n = 10, 9)
    0.36 ( 0.4 )
    1.06 ( 1.1 )
        CD3 T Cells: Day 112 (n = 10, 9)
    4.06 ( 2.6 )
    6.01 ( 5.6 )
        CD3 T Cells: Day 126 (n = 9, 8)
    12.00 ( 12.0 )
    27.24 ( 24.6 )
        CD3 T Cells: Day 140 (n = 9, 9)
    47.47 ( 21.9 )
    56.82 ( 22.2 )
        CD3 T Cells: Day 168 (n = 10, 9)
    71.64 ( 22.4 )
    51.79 ( 23.1 )
        CD4 T Cells: Baseline (n = 11, 10)
    100 ( 0.0 )
    100 ( 0.0 )
        CD4 T Cells: Day 4 (n = 8, 10)
    0.17 ( 0.2 )
    0.00 ( 0.0 )
        CD4 T Cells: Day 56 (n = 9, 10)
    3.33 ( 3.3 )
    16.56 ( 16.1 )
        CD4 T Cells: Day 84 (n = 9, 9)
    7.14 ( 7.1 )
    1.28 ( 1.0 )
        CD4 T Cells: Day 98 (n = 10, 9)
    0.24 ( 0.2 )
    1.28 ( 1.3 )
        CD4 T Cells: Day 112 (n = 10, 9)
    3.60 ( 3.1 )
    6.74 ( 6.4 )
        CD4 T Cells: Day 126 (n = 9, 8)
    13.33 ( 13.3 )
    37.03 ( 33.7 )
        CD4 T Cells: Day 140 (n = 9, 9)
    55.34 ( 23.9 )
    62.01 ( 20.3 )
        CD4 T Cells: Day 168 (n = 10, 9)
    74.49 ( 26.1 )
    50.00 ( 16.3 )
        CD8 T Cells: Baseline (n = 11, 10)
    100 ( 0.0 )
    100 ( 0.0 )
        CD8 T Cells: Day 4 (n = 8, 10)
    0.00 ( 0.0 )
    0.00 ( 0.0 )
        CD8 T Cells: Day 56 (n = 9, 10)
    1.56 ( 1.6 )
    8.41 ( 8.4 )
        CD8 T Cells: Day 84 (n = 9, 9)
    2.72 ( 2.7 )
    0.00 ( 0.0 )
        CD8 T Cells: Day 98 (n = 10, 9)
    1.10 ( 1.1 )
    2.33 ( 2.3 )
        CD8 T Cells: Day 112 (n = 10, 9)
    0.97 ( 1.0 )
    2.46 ( 2.5 )
        CD8 T Cells: Day 126 (n = 9, 8)
    20.00 ( 20.0 )
    14.51 ( 14.5 )
        CD8 T Cells: Day 140 (n = 9, 9)
    54.17 ( 18.8 )
    40.98 ( 24.7 )
        CD8 T Cells: Day 168 (n = 10, 9)
    63.34 ( 40.1 )
    55.56 ( 21.1 )
        CD19 B Cells: Baseline (n = 11, 10)
    100 ( 0.0 )
    100 ( 0.0 )
        CD19 B Cells: Day 4 (n = 8, 10)
    0.00 ( 0.0 )
    0.00 ( 0.0 )
        CD19 B Cells: Day 56 (n = 9, 10)
    3.57 ( 3.6 )
    19.14 ( 17.1 )
        CD19 B Cells: Day 84 (n = 9, 9)
    10.71 ( 10.7 )
    0.00 ( 0.0 )
        CD19 B Cells: Day 98 (n = 10, 9)
    0.00 ( 0.0 )
    0.00 ( 0.0 )
        CD19 B Cells: Day 112 (n = 9, 9)
    7.14 ( 7.1 )
    7.14 ( 7.1 )
        CD19 B Cells: Day 126 (n = 9, 8)
    42.86 ( 21.4 )
    33.93 ( 32.3 )
        CD19 B Cells: Day 140 (n = 9, 9)
    68.00 ( 30.5 )
    77.78 ( 32.6 )
        CD19 B Cells: Day 168 (n = 10, 9)
    73.21 ( 17.7 )
    40.00 ( 13.2 )
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events by Highest Severity Grade, Assessed According to National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI-CTCAE v4.0), During the Randomized Treatment Phase

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    End point title
    		 Number of Participants with Adverse Events by Highest Severity Grade, Assessed According to National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI-CTCAE v4.0), During the Randomized Treatment Phase
    End point description
    All adverse events (AEs) were graded for severity using the NCI-CTCAE v4.0. Any AE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. Not all grades are appropriate for all AEs; some AEs have fewer than 5 options. The terms "severe" and "serious" are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade.
    End point type
    Secondary
    End point timeframe
    From Baseline until 12 weeks (Q4W arm only) or 16 weeks (Q8W arm only) after the last dose of study drug during the randomized treatment phase (up to 24 weeks)
    End point values
    		 Etrolizumab Q4W Etrolizumab Q8W
    Number of subjects analysed
    12
    12
    Units: Participants
        Any Adverse Event - Any Grade
    9
    10
        Any Adverse Event - Grade 1
    2
    2
        Any Adverse Event - Grade 2
    4
    5
        Any Adverse Event - Grade 3
    3
    3
        Any Adverse Event - Grade 4
    0
    0
        Any Adverse Event - Grade 5
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Serious Infection-Related Adverse Events by Highest Severity Grade, Assessed According to NCI-CTCAE v4.0, During the Randomized Treatment Phase

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    End point title
    		 Number of Participants with Serious Infection-Related Adverse Events by Highest Severity Grade, Assessed According to NCI-CTCAE v4.0, During the Randomized Treatment Phase
    End point description
    Serious infection-related AEs were graded for severity per the NCI-CTCAE v4.0. Any AE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. Not all grades are appropriate for all AEs; some AEs have fewer than 5 options. The terms "severe" and "serious" are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade.
    End point type
    Secondary
    End point timeframe
    From Baseline until 12 weeks (Q4W arm only) or 16 weeks (Q8W arm only) after the last dose of study drug during the randomized treatment phase (up to 24 weeks)
    End point values
    		 Etrolizumab Q4W Etrolizumab Q8W
    Number of subjects analysed
    12
    12
    Units: Participants
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Hypersensitivity Reactions by Highest Severity Grade, Assessed According to NCI-CTCAE v4.0, During the Randomized Treatment Phase

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    End point title
    		 Number of Participants with Hypersensitivity Reactions by Highest Severity Grade, Assessed According to NCI-CTCAE v4.0, During the Randomized Treatment Phase
    End point description
    Hypersensitivity reactions were graded for severity using the NCI-CTCAE v4.0. Any AE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. Not all grades are appropriate for all AEs; some AEs have fewer than 5 options. The terms "severe" and "serious" are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade.
    End point type
    Secondary
    End point timeframe
    From Baseline until 12 weeks (Q4W arm only) or 16 weeks (Q8W arm only) after the last dose of study drug during the randomized treatment phase (up to 24 weeks)
    End point values
    		 Etrolizumab Q4W Etrolizumab Q8W
    Number of subjects analysed
    12
    12
    Units: Participants
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Malignancies by Highest Severity Grade, Assessed According to NCI-CTCAE v4.0, During the Randomized Treatment Phase

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    End point title
    		 Number of Participants with Malignancies by Highest Severity Grade, Assessed According to NCI-CTCAE v4.0, During the Randomized Treatment Phase
    End point description
    Malignancies were graded for severity using the NCI-CTCAE v4.0. Any AE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. Not all grades are appropriate for all AEs; some AEs have fewer than 5 options. The terms "severe" and "serious" are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade.
    End point type
    Secondary
    End point timeframe
    From Baseline until 12 weeks (Q4W arm only) or 16 weeks (Q8W arm only) after the last dose of study drug during the randomized treatment phase (up to 24 weeks)
    End point values
    		 Etrolizumab Q4W Etrolizumab Q8W
    Number of subjects analysed
    12
    12
    Units: Participants
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Anti-Drug Antibodies (ADAs) to Etrolizumab at Baseline and Post-Baseline During the Randomized Treatment Phase

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    End point title
    		 Number of Participants with Anti-Drug Antibodies (ADAs) to Etrolizumab at Baseline and Post-Baseline During the Randomized Treatment Phase
    End point description
    Participants were considered to be etrolizumab anti-drug antibody (ADA) positive if they were ADA negative or had missing data at Baseline (BL) but developed an ADA response following study drug exposure (i.e., treatment-induced ADA positive), or if they were ADA positive at baseline and the titer of one or more postbaseline samples was at least 0.60 titer unit greater than the titer of the baseline sample (i.e., treatment-enhanced ADA positive); these ADA positive responses are summarized together (induced + enhanced) in the 'treatment-emergent ADA positive' category. Participants were considered to be ADA negative if they were ADA negative or had missing data at Baseline (BL) and all postbaseline samples were negative (i.e., treatment-emergent ADA negative), or if they were ADA positive at baseline but did not have any postbaseline samples with a titer that was at least 0.60 titer unit greater than the titer of the baseline sample (i.e., treatment unaffected).
    End point type
    Secondary
    End point timeframe
    Predose (dosing days only) on Days 1, 28, 84, 112, and 168 (up to the end of the randomized treatment phase at Week 24)
    End point values
    		 Etrolizumab Q4W Etrolizumab Q8W
    Number of subjects analysed
    12
    12
    Units: Participants
        Baseline (BL): ADA Positive
    1
    0
        BL: ADA Negative
    11
    12
        Post-BL: Treatment-Emergent ADA Positive
    4
    2
        Post-BL: Treatment-Induced ADA Positive
    4
    2
        Post-BL: Treatment-Enhanced ADA Positive
    0
    0
        Post-BL: Treatment-Emergent ADA Negative
    7
    10
        Post-BL: Treatment Unaffected
    1
    0
    No statistical analyses for this end point

    Secondary: Long-Term Safety of Etrolizumab: Number of Participants with Adverse Events by Highest Severity Grade, Assessed According to NCI-CTCAE v4.0

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    End point title
    		 Long-Term Safety of Etrolizumab: Number of Participants with Adverse Events by Highest Severity Grade, Assessed According to NCI-CTCAE v4.0
    End point description
    All adverse events (AEs) were graded for severity using the NCI-CTCAE v4.0. Any AE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. Not all grades are appropriate for all AEs; some AEs have fewer than 5 options. The terms "severe" and "serious" are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade.
    End point type
    Secondary
    End point timeframe
    From the start of 312-week OLE and the 104-week PML safety surveillance phase until the participant withdrew from the study (from Week 24 up to approximately 5.5 years)
    End point values
    		 Etrolizumab Q4W Etrolizumab Q8W PML Safety Monitoring
    Number of subjects analysed
    11
    10
    1 [7]
    Units: Participants
        OLE: Any AE - Any Grade (n=11, 10, 0)
    11
    9
    0
        OLE: Any AE - Grade 1 (n=11, 10, 0)
    0
    0
    0
        OLE: Any AE - Grade 2 (n=11, 10, 0)
    8
    4
    0
        OLE: Any AE - Grade 3 (n=11, 10, 0)
    3
    5
    0
        OLE: Any AE - Grade 4 (n=11, 10, 0)
    0
    0
    0
        OLE: Any AE - Grade 5 (n=11, 10, 0)
    0
    0
    0
        PML: Any AE - Any Grade (n=6, 6, 1)
    2
    2
    0
        PML: Any AE - Grade 1 (n=6, 6, 1)
    1
    1
    0
        PML: Any AE - Grade 2 (n=6, 6, 1)
    1
    1
    0
        PML: Any AE - Grade 3 (n=6, 6, 1)
    0
    0
    0
        PML: Any AE - Grade 4 (n=6, 6, 1)
    0
    0
    0
        PML: Any AE - Grade 5 (n=6, 6, 1)
    0
    0
    0
    Notes
    [7] - n=12 (6 each) captured under PML data for Etro Q4W and Q8W
    No statistical analyses for this end point

    Secondary: Long-Term Safety of Etrolizumab: Number of Participants with Serious Infection-Related Adverse Events

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    End point title
    		 Long-Term Safety of Etrolizumab: Number of Participants with Serious Infection-Related Adverse Events
    End point description
    Serious infection-related AEs were assessed using NCI-CTCAE v4.0. Safety Population: all participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    From the start of 312-week OLE and the 104-week PML safety surveillance phase until the participant withdrew from the study (from Week 24 up to approximately 5.5 years)
    End point values
    		 Etrolizumab Q4W Etrolizumab Q8W PML Safety Monitoring
    Number of subjects analysed
    11
    10
    1 [8]
    Units: Participants
        OLE phase (n=11, 10, 0)
    1
    0
    0
        PML phase (n=6, 6, 1)
    0
    0
    0
    Notes
    [8] - n=12 (6 each) captured under PML data for Etro Q4W and Q8W
    No statistical analyses for this end point

    Secondary: Long-Term Safety of Etrolizumab: Number of Participants with Hypersensitivity Reactions

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    End point title
    		 Long-Term Safety of Etrolizumab: Number of Participants with Hypersensitivity Reactions
    End point description
    Hypersensitivity reactions were assessed using NCI-CTCAE v4.0. Safety Population: all participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    From the start of 312-week OLE and the 104-week PML safety surveillance phase until the participant withdrew from the study (from Week 24 up to approximately 5.5 years)
    End point values
    		 Etrolizumab Q4W Etrolizumab Q8W PML Safety Monitoring
    Number of subjects analysed
    11
    10
    1 [9]
    Units: Participants
        OLE phase (n=11, 10, 0)
    2
    2
    0
        PML phase (n=6, 6, 1)
    0
    1
    0
    Notes
    [9] - n=12 (6 each) captured under PML data for Etro Q4W and Q8W
    No statistical analyses for this end point

    Secondary: Long-Term Safety of Etrolizumab: Number of Participants with Malignancies

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    End point title
    		 Long-Term Safety of Etrolizumab: Number of Participants with Malignancies
    End point description
    Malignancies were assessed using NCI-CTCAE v4.0. Safety Population: all participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    From the start of 312-week OLE and the 104-week PML safety surveillance phase until the participant withdrew from the study (from Week 24 up to approximately 5.5 years)
    End point values
    		 Etrolizumab Q4W Etrolizumab Q8W PML Safety Monitoring
    Number of subjects analysed
    11
    10
    1 [10]
    Units: Participants
        OLE phase (n=11, 10, 0)
    0
    0
    0
        PML phase (n=6, 6, 1)
    0
    0
    0
    Notes
    [10] - n=12 (6 each) captured under PML data for Etro Q4W and Q8W
    No statistical analyses for this end point

    Secondary: Long-Term Safety of Etrolizumab: Number of Participants with Anti-Drug Antibodies (ADAs) to Etrolizumab at Baseline and Post-Baseline

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    End point title
    		 Long-Term Safety of Etrolizumab: Number of Participants with Anti-Drug Antibodies (ADAs) to Etrolizumab at Baseline and Post-Baseline
    End point description
    Participants were ADA positive if they were ADA negative or had missing data at Baseline (BL) but developed an ADA response following study drug exposure (treatment-induced ADA positive), or if they were ADA positive at baseline and the titer of one or more postbaseline samples was at least 0.60 titer unit greater than that of the baseline sample (treatment-enhanced ADA positive); ADA induced + enhanced are combined in the 'treatment-emergent ADA positive' category. Participants were ADA negative if they were ADA negative or had missing data at Baseline (BL) and all postbaseline samples were negative (treatment-emergent ADA negative), or if they were ADA positive at baseline but did not have any postbaseline samples with a titer that was at least 0.60 titer unit greater than the titer of the baseline sample (treatment unaffected). All participants, who received at least one dose of study treatment and had at least one baseline or post-baseline ADA result, were evaluated.
    End point type
    Secondary
    End point timeframe
    Predose (dosing days only) at Baseline (Day 1), Days 28, 84, and 112, Weeks 24, 36, 72, and 120, and every 12 weeks thereafter for up to 4.25 years
    End point values
    		 Etrolizumab Q4W Etrolizumab Q8W
    Number of subjects analysed
    12
    12
    Units: Participants
        Baseline (BL): ADA Positive
    1
    0
        BL: ADA Negative
    11
    12
        Post-BL: Treatment-Emergent ADA Positive
    4
    3
        Post-BL: Treatment-Induced ADA Positive
    4
    3
        Post-BL: Treatment-Enhanced ADA Positive
    0
    0
        Post-BL: Treatment-Emergent ADA Negative
    7
    9
        Post-BL: Treatment Unaffected
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Confirmed Progressive Multifocal Leukoencephalopathy (PML) During the 104-Week Post-Treatment PML Monitoring Phase

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    End point title
    		 Number of Participants with Confirmed Progressive Multifocal Leukoencephalopathy (PML) During the 104-Week Post-Treatment PML Monitoring Phase
    End point description
    The 104-week safety surveillance PML-monitoring phase (no etrolizumab treatment) consisted of telephone calls approximately every 6 months with administration of the protocol's PML Subjective Checklist. If there were any signs or symptoms suggestive of PML identified on this subjective checklist during the telephone call, the participant was asked to come into the clinic for a neurologic examination. The protocol's PML Algorithm was followed for any suspected case of PML, and any confirmed case of PML would be reported as a serious adverse event. Safety Population: all participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Approximately every 6 months from last dose of study drug until the end of the PML monitoring phase (up to 104 weeks)
    End point values
    		 PML Safety Monitoring
    Number of subjects analysed
    13
    Units: Participants
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 5.5 years
    Adverse event reporting additional description
    After informed consent but prior to initiation of study drug, only serious AEs caused by protocol-mandated intervention were reported. After initiation of study drug, all AEs were reported until the last study visit or 12 weeks after the last dose of study drug. After this period, only serious AEs related to prior study drug were reported.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Etrolizumab Q4W
    Reporting group description
    		 Etrolizumab Q4W Etrolizumab 1.5 milligrams per kilogram of body weight (mg/kg) was administered by subcutaneous (SC) injection once every 4 weeks (Q4W) for a total of 4 doses over the course of the 24-week randomized treatment phase (16-week treatment period plus 8-week safety follow-up).

    Reporting group title
    PML Safety Monitoring
    Reporting group description
    		 After the randomized treatment period (if participants did not enter the OLE period) or after the OLE period participants were monitored during the 104-week safety surveillance phase (no etrolizumab treatment) for progressive multifocal leukoencephalopathy (PML).

    Reporting group title
    Open Label Extension (OLE)
    Reporting group description
    		 After the randomized treatment phase, participants were given the option to participate in the 312-week open-label extension (OLE) treatment phase. Participants were administered etrolizumab 1.5 mg/kg SC Q4W.

    Reporting group title
    Etrolizumab Q8W
    Reporting group description
    		 Etrolizumab Q8W Etrolizumab 3.0 mg/kg was administered by subcutaneous (SC) injection once every 8 weeks (Q8W) for a total of 2 doses over the course of the 24-week randomized treatment phase (16-week treatment period plus 8-week safety follow-up).

    Serious adverse events
    		 Etrolizumab Q4W PML Safety Monitoring Open Label Extension (OLE) Etrolizumab Q8W
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 13 (0.00%)
    6 / 21 (28.57%)
    2 / 12 (16.67%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Nervous system disorders
    Idiopathic intracranial hypertension
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    2 / 21 (9.52%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    2 / 21 (9.52%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Intentional self-injury
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug abuse
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety disorder
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Sinusitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Etrolizumab Q4W PML Safety Monitoring Open Label Extension (OLE) Etrolizumab Q8W
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 12 (66.67%)
    4 / 13 (30.77%)
    20 / 21 (95.24%)
    9 / 12 (75.00%)
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    4 / 12 (33.33%)
    1 / 13 (7.69%)
    6 / 21 (28.57%)
    0 / 12 (0.00%)
         occurrences all number
    7
    1
    6
    0
    Peripheral swelling
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    3 / 21 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Vaccination site reaction
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    1 / 21 (4.76%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Reproductive system and breast disorders
    Amenorrhoea
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 21 (4.76%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    1
    Polymenorrhoea
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Dysmenorrhoea
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Catarrh
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Cough
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 21 (4.76%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    2
    1
    Epistaxis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    4
    0
    Nasal congestion
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    2 / 21 (9.52%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    2
    1
    Investigations
    Weight decreased
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 13 (0.00%)
    1 / 21 (4.76%)
    2 / 12 (16.67%)
         occurrences all number
    2
    0
    2
    2
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Head injury
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Ligament sprain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    1 / 21 (4.76%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Headache
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    5 / 21 (23.81%)
    3 / 12 (25.00%)
         occurrences all number
    0
    0
    8
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 12 (25.00%)
    0 / 13 (0.00%)
    4 / 21 (19.05%)
    1 / 12 (8.33%)
         occurrences all number
    3
    0
    5
    1
    Lymphopenia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 13 (0.00%)
    2 / 21 (9.52%)
    2 / 12 (16.67%)
         occurrences all number
    2
    0
    3
    2
    Crohn's disease
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 13 (0.00%)
    5 / 21 (23.81%)
    2 / 12 (16.67%)
         occurrences all number
    2
    0
    9
    2
    Abdominal pain
         subjects affected / exposed
    3 / 12 (25.00%)
    0 / 13 (0.00%)
    6 / 21 (28.57%)
    2 / 12 (16.67%)
         occurrences all number
    3
    0
    12
    4
    Abdominal pain upper
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 13 (15.38%)
    4 / 21 (19.05%)
    0 / 12 (0.00%)
         occurrences all number
    1
    2
    5
    0
    Aphthous ulcer
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    2 / 21 (9.52%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    3
    3
    Colitis ulcerative
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 13 (0.00%)
    7 / 21 (33.33%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    13
    0
    Constipation
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Toothache
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    2
    Nausea
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    3 / 21 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Haematochezia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Dyspepsia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 21 (4.76%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    1
    Odynophagia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Rash papular
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Rash
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    1 / 21 (4.76%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    1
    Erythema
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    2 / 21 (9.52%)
    1 / 12 (8.33%)
         occurrences all number
    2
    0
    2
    1
    Renal and urinary disorders
    Leukocyturia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    3 / 21 (14.29%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    3
    2
    Pain in extremity
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    2 / 21 (9.52%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    5
    3
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    1 / 21 (4.76%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    1
    Varicella
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 21 (4.76%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 13 (0.00%)
    8 / 21 (38.10%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    16
    0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    4 / 21 (19.05%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    7
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    3 / 21 (14.29%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    5
    1
    Folliculitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Herpes zoster
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    COVID-19
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    4 / 21 (19.05%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Rhinitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    4 / 21 (19.05%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Pharyngitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    5 / 21 (23.81%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    5
    0
    Oral herpes
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Iron deficiency
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 21 (4.76%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    1
    Vitamin B12 deficiency
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Aug 2018
    Protocol CA40192 Version 2 was amended to clarify the exclusion criteria and the Schedule of Assessments for the open-label extension (OLE) phase: -Exclusion criteria for patients with strictures (stenosis) of the colon have been revised to exclude patients with fixed symptomatic stenosis of the intestine; -Exclusion criteria for the use of other biologics (e.g., anti-TNF) has been clarified; -Exclusion criteria has been deleted for tube feeding, defined formula diets, or parenteral alimentation/nutrition. Based on investigator feedback, this is a standard of care for patients with Crohn's disease. Including these treatments as a exclusion criterion reduces the potential patient pool at the sites; -The option for the administration of etrolizumab outside the clinic site has been removed; -The option of patients enrolling in the adult OLE studies of GA28951 and GA29145 has been deleted. Protocols GA28951 and GA29145 do not specify that patients from this study are eligible for enrollment; -Instructions about patient withdrawal from the RBR after site closure have been modified to indicate that the investigator must inform the Sponsor of patient withdrawal by emailing the study number and patient number; -Language regarding pregnancies in partners of male patients has been modified to account for the fact that some sites may not allow follow-up on partner pregnancies; -Language has been added for consistency with Roche's current data retention policy and to accommodate more stringent local requirements (if applicable); -Appendix 1c, Schedule of Assessments, for the OLE phase has been revised to list out every 4-week, 12-week and dosing visit time point.
    22 Nov 2019
    Protocol CA40192 Version 3 was amended to increase the number of participants and to extend the duration of the open-label extension (OLE) phase: -The total number of participants enrolled in the study was increased from approximately 16 to approximately 24, in order to achieve the requirement of 4 children from 4 years to <12 years of age with evaluable pharmacokinetic profiles; -The duration of the OLE was extended from 2 years to 6 years (312 weeks) in order to ensure that participants currently in the OLE will have drug available until the start of the pediatric Phase III program; -The end of study and length of study have been updated to include the extended duration of the OLE phase; -The Schedule of Assessments for the OLE phase has been revised to include the extended duration.
    28 May 2021
    Protocol CA40192 Version 4 was amended to clarify the 12-week safety follow up period after completion or early termination of the open-label extension phase, to add results from completed Phase III ulcerative colitis studies, and to add coronavirus disease 2019 (COVID-19) vaccine-related language. In addition, guselkumab was removed from the list of prohibited therapy. Schedule of assessments during the OLE phase was updated to include visits for conducting pregnancy tests.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    27 Sep 2023
    The study was terminated due to program discontinuation, based on mixed efficacy results in the adult ulcerative colitis and Crohn's disease studies. There were no safety concerns.
    -

    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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