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    Clinical Trial Results:
    A Phase III, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter, Efficacy and Safety Study of Gantenerumab in Patients With Mild Alzheimer's Disease; Part II: Open-Label Extension For Participating Patients

    Summary
    EudraCT number
    2013-003390-95
    Trial protocol
    GB   DE   SE   ES   PT   IT   NL   BE   HU   FI   BG   DK   FR  
    Global end of trial date
    16 Apr 2021

    Results information
    Results version number
    v2(current)
    This version publication date
    22 Jul 2022
    First version publication date
    25 Apr 2022
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Updated pre-assignment details, updated overall number of participants analysed, timeframe, and unit of measure in the endpoint.

    Trial information

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    Trial identification
    Sponsor protocol code
    WN28745
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02051608
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Apr 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Apr 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of subcutaneous Gantenerumab on cognition and function in mild Alzheimer’s disease.
    Protection of trial subjects
    All study subjects were required to sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Mar 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    1 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Denmark: 14
    Country: Number of subjects enrolled
    Finland: 4
    Country: Number of subjects enrolled
    France: 15
    Country: Number of subjects enrolled
    Germany: 16
    Country: Number of subjects enrolled
    Hungary: 5
    Country: Number of subjects enrolled
    Italy: 19
    Country: Number of subjects enrolled
    Portugal: 6
    Country: Number of subjects enrolled
    Sweden: 14
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    Argentina: 7
    Country: Number of subjects enrolled
    Australia: 9
    Country: Number of subjects enrolled
    Canada: 34
    Country: Number of subjects enrolled
    Japan: 21
    Country: Number of subjects enrolled
    Korea, Republic of: 22
    Country: Number of subjects enrolled
    Russian Federation: 28
    Country: Number of subjects enrolled
    Turkey: 13
    Country: Number of subjects enrolled
    United States: 95
    Country: Number of subjects enrolled
    Netherlands: 8
    Country: Number of subjects enrolled
    Spain: 31
    Country: Number of subjects enrolled
    Switzerland: 4
    Worldwide total number of subjects
    387
    EEA total number of subjects
    136
    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)
    105
    From 65 to 84 years
    273
    85 years and over
    9

    Subject disposition

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    Recruitment
    Recruitment details
    Part 1 of the study was conducted at 116 centers in 21 countries and part 2 was conducted at 75 centers in 17 countries.

    Pre-assignment
    Screening details
    A total of 389 participants were enrolled out of which 387 randomised and treated (192=gantenerumab and 195=placebo) in part 1 of study. Of these, a total of 230 participants enrolled in Part 2 of study:225 participants received at least one dose of study drug. Participants who discontinued from Part 1 of study were not allowed to enroll in Part 2.

    Period 1
    Period 1 title
    Part 1: Double Blind Treatment
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Part 1: Placebo
    Arm description
    Participants received matching placebo by SC injection Q4W up to 100 weeks during Part 1 of the study.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received gantenerumab matching placebo SC injection Q4W.

    Arm title
    Part 1: Gantenerumab
    Arm description
    Participants received 105 mg Gantenerumab by SC injection Q4W for 24 weeks and if eligible 225 mg SC injection Q4W from weeks 28-100 during Part 1 of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Gantenerumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received gantenerumab SC injection Q4W.

    Number of subjects in period 1
    Part 1: Placebo Part 1: Gantenerumab
    Started
    195
    192
    Completed
    134
    136
    Not completed
    61
    56
         Part 1 Terminated by Sponsor
    3
    2
         Protocol deviation
    -
    1
         Death
    3
    3
         Physician decision
    2
    4
         Adverse event
    2
    8
         Withdrawal by subject
    42
    29
         Not specified
    6
    3
         Non-Compliance
    2
    4
         Lost to follow-up
    1
    2
    Period 2
    Period 2 title
    Part 2: Open-label Extension
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Part 2 (OLE treatment): Placebo switched to Gant to 1200 mg
    Arm description
    Participants who had received Placebo in Part 1, received Gantenerumab at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.
    Arm type
    Experimental

    Investigational medicinal product name
    Gantenerumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received gantenerumab SC injection Q4W

    Arm title
    Part 2 (OLE treatment): Gantenerumab up to 1200 mg
    Arm description
    Participants who had received Gantenerumab in Part 1, received treatment at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.
    Arm type
    Experimental

    Investigational medicinal product name
    Gantenerumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received gantenerumab SC injection Q4W

    Number of subjects in period 2 [1]
    Part 2 (OLE treatment): Placebo switched to Gant to 1200 mg Part 2 (OLE treatment): Gantenerumab up to 1200 mg
    Started
    119
    111
    Completed
    49
    50
    Not completed
    70
    61
         Death
    7
    4
         Physician decision
    8
    5
         Adverse event
    6
    8
         Not specified
    9
    9
         Non-Compliance
    1
    1
         Study Terminated By Sponsor
    -
    1
         Withdrawal by subjects
    39
    32
         Lost to follow-up
    -
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: A total of 230 participants were enrolled in OLE. Of these, 225 were treated in OLE phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1: Placebo
    Reporting group description
    Participants received matching placebo by SC injection Q4W up to 100 weeks during Part 1 of the study.

    Reporting group title
    Part 1: Gantenerumab
    Reporting group description
    Participants received 105 mg Gantenerumab by SC injection Q4W for 24 weeks and if eligible 225 mg SC injection Q4W from weeks 28-100 during Part 1 of the study.

    Reporting group values
    Part 1: Placebo Part 1: Gantenerumab Total
    Number of subjects
    195 192 387
    Age categorical
    Units: Participants
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    70.1 ± 8.6 69.7 ± 8.9 -
    Sex: Female, Male
    Units: Participants
        Female
    113 98 211
        Male
    82 94 176
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    11 12 23
        Not Hispanic or Latino
    178 176 354
        Unknown or Not Reported
    6 4 10
    Race
    Units: Subjects
        Asian
    23 21 44
        Black or African American
    2 2 4
        Native Hawaiian or other Pacific Islander
    0 1 1
        White
    164 166 330
        More than one race
    1 0 1
        Unknown or Not Reported
    5 2 7
        American Indian or Alaska Native
    0 0 0
    Subject analysis sets

    Subject analysis set title
    Part 2 (OLE): Placebo switched to Gantenerumab up to 1200 mg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants who had received Placebo in Part 1, received Gantenerumab at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.

    Subject analysis set title
    Part 2 (OLE): Gantenerumab up to 1200 mg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants who had received Gantenerumab in Part 1, received treatment at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.

    Subject analysis set title
    Part 2 (OLE): Gantenerumab 1200 mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants who had received placebo or gantenerumab in Part 1, received gantenerumab at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.

    Subject analysis sets values
    Part 2 (OLE): Placebo switched to Gantenerumab up to 1200 mg Part 2 (OLE): Gantenerumab up to 1200 mg Part 2 (OLE): Gantenerumab 1200 mg
    Number of subjects
    117
    108
    223
    Age categorical
    Units: Participants
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    71.82 ± 8.09
    71.01 ± 9.31
    ±
    Sex: Female, Male
    Units: Participants
        Female
    69
    61
        Male
    48
    47
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    9
    10
        Not Hispanic or Latino
    108
    96
        Unknown or Not Reported
    0
    2
    Race
    Units: Subjects
        Asian
    19
    19
        Black or African American
    2
    2
        Native Hawaiian or other Pacific Islander
    0
    1
        White
    94
    85
        More than one race
    0
    0
        Unknown or Not Reported
    2
    1
        American Indian or Alaska Native
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    Part 1: Placebo
    Reporting group description
    Participants received matching placebo by SC injection Q4W up to 100 weeks during Part 1 of the study.

    Reporting group title
    Part 1: Gantenerumab
    Reporting group description
    Participants received 105 mg Gantenerumab by SC injection Q4W for 24 weeks and if eligible 225 mg SC injection Q4W from weeks 28-100 during Part 1 of the study.
    Reporting group title
    Part 2 (OLE treatment): Placebo switched to Gant to 1200 mg
    Reporting group description
    Participants who had received Placebo in Part 1, received Gantenerumab at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.

    Reporting group title
    Part 2 (OLE treatment): Gantenerumab up to 1200 mg
    Reporting group description
    Participants who had received Gantenerumab in Part 1, received treatment at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.

    Subject analysis set title
    Part 2 (OLE): Placebo switched to Gantenerumab up to 1200 mg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants who had received Placebo in Part 1, received Gantenerumab at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.

    Subject analysis set title
    Part 2 (OLE): Gantenerumab up to 1200 mg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants who had received Gantenerumab in Part 1, received treatment at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.

    Subject analysis set title
    Part 2 (OLE): Gantenerumab 1200 mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants who had received placebo or gantenerumab in Part 1, received gantenerumab at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.

    Primary: Part 2: Percentage of Participants with Adverse Events (AEs) or Serious Adverse Events (SAEs)

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    End point title
    Part 2: Percentage of Participants with Adverse Events (AEs) or Serious Adverse Events (SAEs) [1]
    End point description
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. SAE is any adverse event that is fatal or which requires or prolongs inpatient hospitalization or results in persistent or significant disability/incapacity or causes congenital anomaly/birth defect or results in a significant medical event in the investigator's judgment.
    End point type
    Primary
    End point timeframe
    First dose up to 4 weeks after the last dose of study drug (up to 249 weeks)
    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 statistical analyses were performed
    End point values
    Part 2 (OLE treatment): Placebo switched to Gant to 1200 mg Part 2 (OLE treatment): Gantenerumab up to 1200 mg
    Number of subjects analysed
    117
    108
    Units: Percentage of Participants
    number (not applicable)
        AEs
    91.5
    95.4
        SAEs
    24.8
    38.0
    No statistical analyses for this end point

    Primary: Part 2: Percentage of Participants with Treatment Emergent Anti-Drug Antibodies (ADAs)

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    End point title
    Part 2: Percentage of Participants with Treatment Emergent Anti-Drug Antibodies (ADAs) [2]
    End point description
    Participants were considered positive or negative for ADA based on their baseline and post-baseline sample results. The number and percentage of participants with confirmed positive ADA levels were determined for participants previously (in part 1) on Gantenerumab and Placebo. The prevalence of ADA at baseline was calculated as the percentage of participants with confirmed positive ADA levels at baseline relative to the total number of participants with a sample available at baseline. The incidence of treatment-emergent ADAs was determined as the percentage of participants with confirmed post-baseline positive ADAs relative to the total number of participants that had at least one post-baseline sample available for ADA analysis.
    End point type
    Primary
    End point timeframe
    First dose up to last dose (Baseline up to until maximum 5 years)
    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 statistical analyses were performed
    End point values
    Part 2 (OLE treatment): Placebo switched to Gant to 1200 mg Part 2 (OLE treatment): Gantenerumab up to 1200 mg
    Number of subjects analysed
    115 [3]
    106 [4]
    Units: Percentage of Participants
        number (not applicable)
    2.6
    2.8
    Notes
    [3] - The number of participants analysed indicates the number of participants evaluated for the endpoint.
    [4] - The number of participants analysed indicates the number of participants evaluated for the endpoint.
    No statistical analyses for this end point

    Primary: Part 2: Percentage of Participants With Adverse Events Leading to Discontinuation of Treatment

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    End point title
    Part 2: Percentage of Participants With Adverse Events Leading to Discontinuation of Treatment [5]
    End point description
    Percentage of participants with adverse events leading to discontinuation from treatment were reported. The safety population consisted of all participants who had received at least one dose of study drug, regardless of whether the participants withdrew prematurely or not.
    End point type
    Primary
    End point timeframe
    First dose up to 4 weeks after the last dose in OLE (Up to approximately 249 weeks)
    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 statistical analyses were performed
    End point values
    Part 2 (OLE treatment): Placebo switched to Gant to 1200 mg Part 2 (OLE treatment): Gantenerumab up to 1200 mg
    Number of subjects analysed
    117
    108
    Units: Percentage of Participants
        number (not applicable)
    12.0
    15.7
    No statistical analyses for this end point

    Secondary: Part 1: Percentage of Participants With AEs, SAEs

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    End point title
    Part 1: Percentage of Participants With AEs, SAEs
    End point description
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. SAE is any adverse event that is fatal or which requires or prolongs inpatient hospitalization or results in persistent or significant disability/incapacity or causes congenital anomaly/birth defect or results in a significant medical event in the investigator's judgment.
    End point type
    Secondary
    End point timeframe
    First dose up to last dose (Up to approximately 152 weeks)
    End point values
    Part 1: Placebo Part 1: Gantenerumab
    Number of subjects analysed
    195
    192
    Units: Percentage of Participants
    number (not applicable)
        AEs
    80.5
    82.8
        SAEs
    12.3
    12.0
    No statistical analyses for this end point

    Secondary: Part 1: Percentage of Participants with Treatment-emergent ADAs

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    End point title
    Part 1: Percentage of Participants with Treatment-emergent ADAs
    End point description
    Participants were considered positive or negative for ADA based on their baseline and post-baseline sample results. The number and percentage of participants with confirmed positive ADA levels were determined for Gantenerumab and Placebo groups. The prevalence of ADA at baseline was calculated as the percentage of participants with confirmed positive ADA levels at baseline relative to the total number of participants with a sample available at baseline. The incidence of treatment-emergent ADAs was determined as the percentage of participants with confirmed post-baseline positive ADAs relative to the total number of participants that had at least one post-baseline sample available for ADA analysis.
    End point type
    Secondary
    End point timeframe
    First dose up to last dose (Up to approximately 152 weeks)
    End point values
    Part 1: Placebo Part 1: Gantenerumab
    Number of subjects analysed
    194 [6]
    191 [7]
    Units: Percentage of Participants
        number (not applicable)
    3.6
    11.5
    Notes
    [6] - The number of participants analysed indicates the number of participants evaluated for the endpoint.
    [7] - The number of participants analysed indicates the number of participants evaluated for the endpoint.
    No statistical analyses for this end point

    Secondary: Part 1: Gantenerumab Plasma Concentration at Multiple Timepoints

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    End point title
    Part 1: Gantenerumab Plasma Concentration at Multiple Timepoints [8]
    End point description
    The pharmacokinetic (PK) evaluable population consisted of all participants that were treated with gantenerumab and provided at least 1 post-baseline PK sample. “n” = number analysed is the number of participants with data available for analyses at the given time-point.
    End point type
    Secondary
    End point timeframe
    Pre-dose: Weeks 4, 8, 12, 24, 48, 72 and Post dose: Day 4
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analyses were performed
    End point values
    Part 1: Gantenerumab
    Number of subjects analysed
    192
    Units: μg/mL
    arithmetic mean (standard deviation)
        Day 4 (n=183)
    4.11 ± 2.59
        Week 4 (n=190)
    2.06 ± 0.89
        Week 8 (n=188)
    3.11 ± 1.41
        Week 12 (n=184)
    3.35 ± 1.63
        Week 24 (n=177)
    3.71 ± 2.13
        Week 48 (n=137)
    7.61 ± 3.88
        Week 72 (n=79)
    7.66 ± 4.44
    No statistical analyses for this end point

    Secondary: Part 1: Percentage of Participants with Adverse Events Leading to Discontinuation of Treatment

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    End point title
    Part 1: Percentage of Participants with Adverse Events Leading to Discontinuation of Treatment
    End point description
    Percentage of participants with adverse events leading to discontinuation from treatment were reported. The safety population consisted of all participants who received at least one dose of study drug, regardless of whether the participants withdrew prematurely or not.
    End point type
    Secondary
    End point timeframe
    First dose up to last dose (Up to approximately 152 weeks)
    End point values
    Part 1: Placebo Part 1: Gantenerumab
    Number of subjects analysed
    195
    192
    Units: Percentage of Participants
        number (not applicable)
    2.6
    6.8
    No statistical analyses for this end point

    Secondary: Part 2: Percent Change From Baseline in Hippocampal Volume at Week 104

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    End point title
    Part 2: Percent Change From Baseline in Hippocampal Volume at Week 104
    End point description
    Change from baseline in hippocampal right volume (HRV) and hippocampal left volume (HLV) were analysed at Week 104 using magnetic resonance imaging. The safety population consisted of all participants who received at least one dose of gantenerumab during the OLE and also had at least one post baseline MRI. Number analyzed is the number of participants with data available for analyses at the given time-point.
    End point type
    Secondary
    End point timeframe
    Baseline (Part 1 screening), Week 104
    End point values
    Part 2 (OLE treatment): Placebo switched to Gant to 1200 mg Part 2 (OLE treatment): Gantenerumab up to 1200 mg
    Number of subjects analysed
    52 [9]
    44 [10]
    Units: Percent Change
    arithmetic mean (standard deviation)
        HLV- Percent Change at Week 104 (n=50, n=43)
    -11.24 ± 4.04
    -12.10 ± 4.45
        HRV- Percent Change at Week 104 (n=52, n=44)
    -12.49 ± 4.03
    -11.34 ± 4.41
    Notes
    [9] - The number of participants analysed indicates the number of participants evaluated for the endpoint.
    [10] - The number of participants analysed indicates the number of participants evaluated for the endpoint.
    No statistical analyses for this end point

    Secondary: Part 2: Percent Change From Baseline in Whole Brain Volume at Week 104

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    End point title
    Part 2: Percent Change From Baseline in Whole Brain Volume at Week 104
    End point description
    Change from baseline brain volume were analysed at Week 104 using magnetic resonance imaging. The safety population consisted of all participants who received at least one dose of gantenerumab during the OLE and also had at least one post baseline MRI.
    End point type
    Secondary
    End point timeframe
    Baseline (Part 1 screening), Week 104
    End point values
    Part 2 (OLE treatment): Placebo switched to Gant to 1200 mg Part 2 (OLE treatment): Gantenerumab up to 1200 mg
    Number of subjects analysed
    54 [11]
    44 [12]
    Units: Percent Change
        arithmetic mean (standard deviation)
    -4.89 ± 1.90
    -4.91 ± 1.58
    Notes
    [11] - The number of participants analysed indicates the number of participants evaluated for the endpoint.
    [12] - The number of participants analysed indicates the number of participants evaluated for the endpoint.
    No statistical analyses for this end point

    Secondary: Part 2: Percent Change From Baseline in Cortical Thickness at Week 104

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    End point title
    Part 2: Percent Change From Baseline in Cortical Thickness at Week 104
    End point description
    Change from baseline in cortical thickness were analysed at Week 104 using magnetic resonance imaging. The safety population consisted of all participants who received at least one dose of gantenerumab during the OLE and also had at least one post baseline MRI.
    End point type
    Secondary
    End point timeframe
    Baseline (Part 1 screening), Week 104
    End point values
    Part 2 (OLE treatment): Placebo switched to Gant to 1200 mg Part 2 (OLE treatment): Gantenerumab up to 1200 mg
    Number of subjects analysed
    54 [13]
    44 [14]
    Units: Percent Change
        arithmetic mean (standard deviation)
    -5.84 ± 2.33
    -5.58 ± 1.87
    Notes
    [13] - The number of participants analysed indicates the number of participants evaluated for the endpoint.
    [14] - The number of participants analysed indicates the number of participants evaluated for the endpoint.
    No statistical analyses for this end point

    Secondary: Part 2: Ventricular Volume as Measured by MRI at Week 104

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    End point title
    Part 2: Ventricular Volume as Measured by MRI at Week 104
    End point description
    Ventricular volume were analysed at Week 104 using magnetic resonance imaging. The safety population consisted of all participants who received at least one dose of gantenerumab during the OLE and also had at least one post baseline MRI.
    End point type
    Secondary
    End point timeframe
    Part 2: Week 104
    End point values
    Part 2 (OLE treatment): Placebo switched to Gant to 1200 mg Part 2 (OLE treatment): Gantenerumab up to 1200 mg
    Number of subjects analysed
    63 [15]
    52 [16]
    Units: mL
        arithmetic mean (standard deviation)
    86.70 ± 38.37
    86.21 ± 30.49
    Notes
    [15] - The number of participants analysed indicates the number of participants evaluated for the endpoint.
    [16] - The number of participants analysed indicates the number of participants evaluated for the endpoint.
    No statistical analyses for this end point

    Secondary: Part 2: Gantenerumab Plasma Concentration at Multiple Timepoints

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    End point title
    Part 2: Gantenerumab Plasma Concentration at Multiple Timepoints
    End point description
    Of the 225 participants in the OLE safety evaluable population, evaluable PK information was available from 223 participants. The PK evaluable population consisted of all participants that were treated with gantenerumab and provided at least 1 post-baseline PK sample. “n” = number analysed is the number of participants with data available for analyses at the given time-point.
    End point type
    Secondary
    End point timeframe
    Pre-dose: Weeks 104, 116, 156, 208; Post-dose: Weeks 53, 101
    End point values
    Part 2 (OLE): Gantenerumab 1200 mg
    Number of subjects analysed
    223 [17]
    Units: μg/mL
    arithmetic mean (standard deviation)
        Week 53 (n=128)
    80.6 ± 38.4
        Week 101 (n=111)
    89.1 ± 33.6
        Week 104 (n=141)
    43.5 ± 22.4
        Week 116 (n=15)
    3.66 ± 2.29
        Week 156 (n=80)
    45.2 ± 22.5
        Week 208 (n=48)
    55.8 ± 37.9
    Notes
    [17] - The number of participants analysed indicated the number of participants evaluated for the endpoint.
    No statistical analyses for this end point

    Secondary: Part 2: Change from Baseline in Brain Amyloid Load at Week 156 in a Subset of Participants

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    End point title
    Part 2: Change from Baseline in Brain Amyloid Load at Week 156 in a Subset of Participants
    End point description
    Brain amyloid load over time was assessed using a Florbetapir [F18] injection, a positron emission tomography (PET) radioligand selective to amyloid. Analysis was conducted in a subset of participants who signed consent to participate in the PET substudy. Amyloid PET burden was measured in a composite region of interest (ROI) by using standardized uptake value ratio (SUVR) mapped to the centiloid scale. The composite region was composed of the following six bilateral regions: frontal lobe, parietal lobe, temporal lobe, posterior cingulate cortex, anterior cingulate cortex. The reference region used to normalize the composite region was the cerebellar cortex. SUVR is ratio of tracer uptake in each of cingulate, frontal, parietal and temporal cortexes relative to cerebellum. The centiloid scale anchor points are 0 and 100, where 0 represents a high-certainty amyloid negative scan and 100 represents the amount of global amyloid deposition found in a typical AD scans. Safety population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 156
    End point values
    Part 2 (OLE treatment): Placebo switched to Gant to 1200 mg Part 2 (OLE treatment): Gantenerumab up to 1200 mg
    Number of subjects analysed
    13 [18]
    8 [19]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -81.01 ± 47.08
    -84.93 ± 28.38
    Notes
    [18] - Participants who had discontinued from Part 1 of the study were not allowed to enroll in Part 2.
    [19] - Participants who had discontinued from Part 1 of the study were not allowed to enroll in Part 2.
    No statistical analyses for this end point

    Other pre-specified: Part 1: Mean Change from Baseline in Alzheimer's Disease Activity Scale-Cognitive Subscale 13 (ADAS-Cog13) Scores at Week 104

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    End point title
    Part 1: Mean Change from Baseline in Alzheimer's Disease Activity Scale-Cognitive Subscale 13 (ADAS-Cog13) Scores at Week 104
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 104
    End point values
    Part 1: Placebo Part 1: Gantenerumab
    Number of subjects analysed
    0 [20]
    0 [21]
    Units: Units on the scale
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [20] - For part 1, the efficacy endpoints became exploratory in nature.
    [21] - For part 1, the efficacy endpoints became exploratory in nature.
    No statistical analyses for this end point

    Other pre-specified: Part 1: Mean Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scores at week 104

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    End point title
    Part 1: Mean Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scores at week 104
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 104
    End point values
    Part 1: Placebo Part 1: Gantenerumab
    Number of subjects analysed
    0 [22]
    0 [23]
    Units: Units on the scale
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [22] - For part 1, the efficacy endpoints became exploratory in nature.
    [23] - For part 1, the efficacy endpoints became exploratory in nature.
    No statistical analyses for this end point

    Other pre-specified: Part 1: Percentage Change From Baseline in Total Tau (t-tau) in CSF at Week 104

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    End point title
    Part 1: Percentage Change From Baseline in Total Tau (t-tau) in CSF at Week 104
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 104
    End point values
    Part 1: Placebo Part 1: Gantenerumab
    Number of subjects analysed
    0 [24]
    0 [25]
    Units: Percent Change
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [24] - For part 1, the efficacy endpoints became exploratory in nature.
    [25] - For part 1, the efficacy endpoints became exploratory in nature.
    No statistical analyses for this end point

    Other pre-specified: Part 1: Percentage Change From Baseline in Abeta 1-42 levels in CSF at Week 104

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    End point title
    Part 1: Percentage Change From Baseline in Abeta 1-42 levels in CSF at Week 104
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 104
    End point values
    Part 1: Placebo Part 1: Gantenerumab
    Number of subjects analysed
    0 [26]
    0 [27]
    Units: Percent Change
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [26] - For part 1, the efficacy endpoints became exploratory in nature.
    [27] - For part 1, the efficacy endpoints became exploratory in nature.
    No statistical analyses for this end point

    Other pre-specified: Part 1: Percentage Change From Baseline in phosphorylated tau [p-tau] in CSF at Week 104

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    End point title
    Part 1: Percentage Change From Baseline in phosphorylated tau [p-tau] in CSF at Week 104
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 104
    End point values
    Part 1: Placebo Part 1: Gantenerumab
    Number of subjects analysed
    0 [28]
    0 [29]
    Units: Percent Change
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [28] - For part 1, the efficacy endpoints became exploratory in nature.
    [29] - For part 1, the efficacy endpoints became exploratory in nature.
    No statistical analyses for this end point

    Other pre-specified: Part 1: Percent Change From Baseline in Hippocampal Volume at Week 104

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    End point title
    Part 1: Percent Change From Baseline in Hippocampal Volume at Week 104
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 104
    End point values
    Part 1: Placebo Part 1: Gantenerumab
    Number of subjects analysed
    0 [30]
    0 [31]
    Units: Percent Change
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [30] - For part 1, the efficacy endpoints became exploratory in nature.
    [31] - For part 1, the efficacy endpoints became exploratory in nature.
    No statistical analyses for this end point

    Other pre-specified: Part 1: Percent Change From Baseline in Whole Brain Volume at Week 104

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    End point title
    Part 1: Percent Change From Baseline in Whole Brain Volume at Week 104
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 104
    End point values
    Part 1: Placebo Part 1: Gantenerumab
    Number of subjects analysed
    0 [32]
    0 [33]
    Units: Percent Change
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [32] - For part 1, the efficacy endpoints became exploratory in nature.
    [33] - For part 1, the efficacy endpoints became exploratory in nature.
    No statistical analyses for this end point

    Other pre-specified: Part 1: Percent Change From Baseline in Cortical Thickness at Week 104

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    End point title
    Part 1: Percent Change From Baseline in Cortical Thickness at Week 104
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 104
    End point values
    Part 1: Placebo Part 1: Gantenerumab
    Number of subjects analysed
    0 [34]
    0 [35]
    Units: Percent Change
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [34] - For part 1, the efficacy endpoints became exploratory in nature.
    [35] - For part 1, the efficacy endpoints became exploratory in nature.
    No statistical analyses for this end point

    Other pre-specified: Part 1: Ventricular Volume as Measured by MRI at Week 104

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    End point title
    Part 1: Ventricular Volume as Measured by MRI at Week 104
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 104
    End point values
    Part 1: Placebo Part 1: Gantenerumab
    Number of subjects analysed
    0 [36]
    0 [37]
    Units: ml
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [36] - For part 1, the efficacy endpoints became exploratory in nature.
    [37] - For part 1, the efficacy endpoints became exploratory in nature.
    No statistical analyses for this end point

    Other pre-specified: Part 1: Change From Baseline in Clinical Dementia Rating Global Score (CDR-GS) at Week 104

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    End point title
    Part 1: Change From Baseline in Clinical Dementia Rating Global Score (CDR-GS) at Week 104
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 104
    End point values
    Part 1: Placebo Part 1: Gantenerumab
    Number of subjects analysed
    0 [38]
    0 [39]
    Units: Units on the scale
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [38] - For part 1, the efficacy endpoints became exploratory in nature.
    [39] - For part 1, the efficacy endpoints became exploratory in nature.
    No statistical analyses for this end point

    Other pre-specified: Part 1: Change From Baseline in CDR Sum of Boxes (SB) at Week 104

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    End point title
    Part 1: Change From Baseline in CDR Sum of Boxes (SB) at Week 104
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 104
    End point values
    Part 1: Placebo Part 1: Gantenerumab
    Number of subjects analysed
    0 [40]
    0 [41]
    Units: Units on the scale
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [40] - For part 1, the efficacy endpoints became exploratory in nature.
    [41] - For part 1, the efficacy endpoints became exploratory in nature.
    No statistical analyses for this end point

    Other pre-specified: Part 1: Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at Week 104

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    End point title
    Part 1: Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at Week 104
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 104
    End point values
    Part 1: Placebo Part 1: Gantenerumab
    Number of subjects analysed
    0 [42]
    0 [43]
    Units: Units on the scale
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [42] - For part 1, the efficacy endpoints became exploratory in nature.
    [43] - For part 1, the efficacy endpoints became exploratory in nature.
    No statistical analyses for this end point

    Other pre-specified: Part 1: Change From Baseline in NPI Domain Score at Week 104

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    End point title
    Part 1: Change From Baseline in NPI Domain Score at Week 104
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 104
    End point values
    Part 1: Placebo Part 1: Gantenerumab
    Number of subjects analysed
    0 [44]
    0 [45]
    Units: Units on the scale
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [44] - For part 1, the efficacy endpoints became exploratory in nature.
    [45] - For part 1, the efficacy endpoints became exploratory in nature.
    No statistical analyses for this end point

    Other pre-specified: Part 1: Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Week 104

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    End point title
    Part 1: Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Week 104
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 104
    End point values
    Part 1: Placebo Part 1: Gantenerumab
    Number of subjects analysed
    0 [46]
    0 [47]
    Units: Units on the Scale
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [46] - For part 1, the efficacy endpoints became exploratory in nature.
    [47] - For part 1, the efficacy endpoints became exploratory in nature.
    No statistical analyses for this end point

    Other pre-specified: Part 1: Change From Baseline in Alzheimer's Dementia (QoL-AD) Global Score at Week 104

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    End point title
    Part 1: Change From Baseline in Alzheimer's Dementia (QoL-AD) Global Score at Week 104
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 104
    End point values
    Part 1: Placebo Part 1: Gantenerumab
    Number of subjects analysed
    0 [48]
    0 [49]
    Units: Units on the scale
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [48] - For part 1, the efficacy endpoints became exploratory in nature.
    [49] - For part 1, the efficacy endpoints became exploratory in nature.
    No statistical analyses for this end point

    Other pre-specified: Part 1: Change From Baseline in Symptom Guide Facilitated (GAS) at Week 104

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    End point title
    Part 1: Change From Baseline in Symptom Guide Facilitated (GAS) at Week 104
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 104
    End point values
    Part 1: Placebo Part 1: Gantenerumab
    Number of subjects analysed
    0 [50]
    0 [51]
    Units: Units on the scale
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [50] - For part 1, the efficacy endpoints became exploratory in nature.
    [51] - For part 1, the efficacy endpoints became exploratory in nature.
    No statistical analyses for this end point

    Other pre-specified: Part 1: Change from Baseline in Dependence Scale (DS) at Week 104

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    End point title
    Part 1: Change from Baseline in Dependence Scale (DS) at Week 104
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 104
    End point values
    Part 1: Placebo Part 1: Gantenerumab
    Number of subjects analysed
    0 [52]
    0 [53]
    Units: Units on the scale
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [52] - For part 1, the efficacy endpoints became exploratory in nature.
    [53] - For part 1, the efficacy endpoints became exploratory in nature.
    No statistical analyses for this end point

    Other pre-specified: Part 1: Change From Baseline in Resource Utilization Dementia-Lite (RUD - Lite) Scale at Week 104

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    End point title
    Part 1: Change From Baseline in Resource Utilization Dementia-Lite (RUD - Lite) Scale at Week 104
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 104
    End point values
    Part 1: Placebo Part 1: Gantenerumab
    Number of subjects analysed
    0 [54]
    0 [55]
    Units: Units on the scale
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [54] - For part 1, the efficacy endpoints became exploratory in nature.
    [55] - For part 1, the efficacy endpoints became exploratory in nature.
    No statistical analyses for this end point

    Other pre-specified: Part 1: Change From Baseline in Zarit Caregiver Interview for Alzheimer's Disease (ZCI-AD) at Week 104

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    End point title
    Part 1: Change From Baseline in Zarit Caregiver Interview for Alzheimer's Disease (ZCI-AD) at Week 104
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 104
    End point values
    Part 1: Placebo Part 1: Gantenerumab
    Number of subjects analysed
    0 [56]
    0 [57]
    Units: Units on the scale
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [56] - For part 1, the efficacy endpoints became exploratory in nature.
    [57] - For part 1, the efficacy endpoints became exploratory in nature.
    No statistical analyses for this end point

    Other pre-specified: Part 1: Time to Clinical Decline

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    End point title
    Part 1: Time to Clinical Decline
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to Week 104
    End point values
    Part 1: Placebo Part 1: Gantenerumab
    Number of subjects analysed
    0 [58]
    0 [59]
    Units: Weeks
        median (full range (min-max))
    ( to )
    ( to )
    Notes
    [58] - For part 1, the efficacy endpoints became exploratory in nature.
    [59] - For part 1, the efficacy endpoints became exploratory in nature.
    No statistical analyses for this end point

    Other pre-specified: Part 1: Change from Baseline in Clinical Composite Score (Prespecified Items From The ADAS-Cog, MMSE, and CDR) at Week 104

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    End point title
    Part 1: Change from Baseline in Clinical Composite Score (Prespecified Items From The ADAS-Cog, MMSE, and CDR) at Week 104
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 104
    End point values
    Part 1: Placebo Part 1: Gantenerumab
    Number of subjects analysed
    0 [60]
    0 [61]
    Units: Units on the scale
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [60] - For part 1, the efficacy endpoints became exploratory in nature.
    [61] - For part 1, the efficacy endpoints became exploratory in nature.
    No statistical analyses for this end point

    Other pre-specified: Part 1: Percentage of participants with ADAS-Cog Response

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    End point title
    Part 1: Percentage of participants with ADAS-Cog Response
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to Week 152
    End point values
    Part 1: Placebo Part 1: Gantenerumab
    Number of subjects analysed
    0 [62]
    0 [63]
    Units: Units on the scale
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [62] - For part 1, the efficacy endpoints became exploratory in nature.
    [63] - For part 1, the efficacy endpoints became exploratory in nature.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 52 weeks after the last dose of study drug (up to 7 years)
    Adverse event reporting additional description
    The safety-evaluable population consisted of all participants who had received at least one dose of study drug, regardless of whether the participants withdrew prematurely or not.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Part 1: Placebo
    Reporting group description
    Participants received matching placebo by SC injection Q4W up to 100 weeks during Part 1 of the study.

    Reporting group title
    Part 1: Gantenerumab
    Reporting group description
    Participants received 105 mg Gantenerumab by SC injection Q4W for 24 weeks and if eligible 225 mg SC injection Q4W from weeks 28-100 during Part 1 of the study.

    Reporting group title
    Part 2 (OLE treatment): Placebo switched to Gant to 1200 mg
    Reporting group description
    Participants who had received Placebo in Part 1, received Gantenerumab at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.

    Reporting group title
    Part 2 (OLE treatment): Gantenerumab up to 1200 mg
    Reporting group description
    Participants who had received Gantenerumab in Part 1, received treatment at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.

    Serious adverse events
    Part 1: Placebo Part 1: Gantenerumab Part 2 (OLE treatment): Placebo switched to Gant to 1200 mg Part 2 (OLE treatment): Gantenerumab up to 1200 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    53 / 195 (27.18%)
    61 / 192 (31.77%)
    29 / 117 (24.79%)
    41 / 108 (37.96%)
         number of deaths (all causes)
    11
    8
    8
    5
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Vascular disorders
    Aortic aneurysm rupture
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    1 / 117 (0.85%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 195 (0.51%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Giant cell arteritis
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder transitional cell carcinoma
         subjects affected / exposed
    1 / 195 (0.51%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebellar tumour
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    1 / 117 (0.85%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Colon cancer
         subjects affected / exposed
    2 / 195 (1.03%)
    0 / 192 (0.00%)
    2 / 117 (1.71%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Invasive lobular breast carcinoma
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    1 / 117 (0.85%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Ovarian epithelial cancer
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of pharynx
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (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
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (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
    Cyst
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (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
    Pain
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Affective disorder
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (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
    Aggression
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    1 / 117 (0.85%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    1 / 195 (0.51%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (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
    Psychotic symptom
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide threat
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (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
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 195 (0.51%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest injury
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (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
    Comminuted fracture
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    1 / 117 (0.85%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    3 / 195 (1.54%)
    5 / 192 (2.60%)
    0 / 117 (0.00%)
    3 / 108 (2.78%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 195 (0.51%)
    2 / 192 (1.04%)
    1 / 117 (0.85%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 195 (0.51%)
    1 / 192 (0.52%)
    1 / 117 (0.85%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaw fracture
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (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
    Meniscus injury
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Optic nerve injury
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    1 / 117 (0.85%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    2 / 195 (1.03%)
    0 / 192 (0.00%)
    1 / 117 (0.85%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 195 (0.00%)
    2 / 192 (1.04%)
    0 / 117 (0.00%)
    2 / 108 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    2 / 195 (1.03%)
    2 / 192 (1.04%)
    1 / 117 (0.85%)
    2 / 108 (1.85%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 195 (0.51%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Electrocardiogram abnormal
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    1 / 117 (0.85%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (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
    Angina unstable
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    1 / 117 (0.85%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 195 (0.00%)
    3 / 192 (1.56%)
    0 / 117 (0.00%)
    2 / 108 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 195 (0.51%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 195 (0.51%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 195 (0.51%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    2 / 195 (1.03%)
    1 / 192 (0.52%)
    1 / 117 (0.85%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Bronchitis chronic
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (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
    Epistaxis
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (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
    Tonsillar hypertrophy
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (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
    Nervous system disorders
    ARIA-E
         subjects affected / exposed
    2 / 195 (1.03%)
    2 / 192 (1.04%)
    2 / 117 (1.71%)
    2 / 108 (1.85%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ARIA-H
         subjects affected / exposed
    0 / 195 (0.00%)
    2 / 192 (1.04%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain stem infarction
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haematoma
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (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
    Cerebral infarction
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral venous sinus thrombosis
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Dementia Alzheimer's type
         subjects affected / exposed
    2 / 195 (1.03%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Dementia of the Alzheimer's type, with delusions
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (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
    Encephalopathy
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 195 (0.51%)
    2 / 192 (1.04%)
    1 / 117 (0.85%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (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
    Hemiplegia
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    1 / 117 (0.85%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukoencephalopathy
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (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
    Neurotoxicity
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychomotor hyperactivity
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (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
    Syncope
         subjects affected / exposed
    2 / 195 (1.03%)
    2 / 192 (1.04%)
    1 / 117 (0.85%)
    2 / 108 (1.85%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 195 (1.03%)
    0 / 192 (0.00%)
    2 / 117 (1.71%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertebral artery dissection
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertebrobasilar stroke
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (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
    Eye disorders
    Ocular hypertension
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    1 / 117 (0.85%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Enteritis
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    1 / 117 (0.85%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Faeces discoloured
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (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
    Gastric ulcer
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    1 / 117 (0.85%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (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
    Ileus
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 195 (0.00%)
    2 / 192 (1.04%)
    0 / 117 (0.00%)
    2 / 108 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    1 / 117 (0.85%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (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
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (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
    Urinary retention
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (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
    Urinary tract obstruction
         subjects affected / exposed
    0 / 195 (0.00%)
    2 / 192 (1.04%)
    0 / 117 (0.00%)
    2 / 108 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (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
    Hypercalcaemia
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (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
    Hypoglycaemia
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 195 (0.00%)
    2 / 192 (1.04%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendiceal abscess
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    1 / 117 (0.85%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    1 / 117 (0.85%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 195 (0.00%)
    2 / 192 (1.04%)
    0 / 117 (0.00%)
    2 / 108 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colonic abscess
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (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
    Erysipelas
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (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
    Periodontitis
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    1 / 117 (0.85%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 195 (1.54%)
    1 / 192 (0.52%)
    2 / 117 (1.71%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    3 / 195 (1.54%)
    0 / 192 (0.00%)
    3 / 117 (2.56%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (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
    Septic shock
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 117 (0.00%)
    0 / 108 (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
    Shunt infection
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis bacterial
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 117 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 195 (1.54%)
    3 / 192 (1.56%)
    3 / 117 (2.56%)
    2 / 108 (1.85%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 3
    0 / 2
         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
    Part 1: Placebo Part 1: Gantenerumab Part 2 (OLE treatment): Placebo switched to Gant to 1200 mg Part 2 (OLE treatment): Gantenerumab up to 1200 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    147 / 195 (75.38%)
    159 / 192 (82.81%)
    94 / 117 (80.34%)
    91 / 108 (84.26%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    13 / 195 (6.67%)
    13 / 192 (6.77%)
    4 / 117 (3.42%)
    5 / 108 (4.63%)
         occurrences all number
    13
    15
    4
    5
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    12 / 195 (6.15%)
    16 / 192 (8.33%)
    5 / 117 (4.27%)
    8 / 108 (7.41%)
         occurrences all number
    15
    21
    7
    9
    Fall
         subjects affected / exposed
    28 / 195 (14.36%)
    35 / 192 (18.23%)
    16 / 117 (13.68%)
    22 / 108 (20.37%)
         occurrences all number
    44
    69
    25
    41
    Skin abrasion
         subjects affected / exposed
    6 / 195 (3.08%)
    12 / 192 (6.25%)
    3 / 117 (2.56%)
    5 / 108 (4.63%)
         occurrences all number
    7
    17
    3
    10
    Nervous system disorders
    ARIA-E
         subjects affected / exposed
    32 / 195 (16.41%)
    42 / 192 (21.88%)
    29 / 117 (24.79%)
    30 / 108 (27.78%)
         occurrences all number
    42
    70
    35
    51
    ARIA-H
         subjects affected / exposed
    30 / 195 (15.38%)
    36 / 192 (18.75%)
    19 / 117 (16.24%)
    23 / 108 (21.30%)
         occurrences all number
    39
    42
    23
    27
    Dizziness
         subjects affected / exposed
    18 / 195 (9.23%)
    17 / 192 (8.85%)
    13 / 117 (11.11%)
    6 / 108 (5.56%)
         occurrences all number
    24
    26
    13
    6
    Headache
         subjects affected / exposed
    29 / 195 (14.87%)
    22 / 192 (11.46%)
    15 / 117 (12.82%)
    12 / 108 (11.11%)
         occurrences all number
    38
    44
    18
    24
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    49 / 195 (25.13%)
    52 / 192 (27.08%)
    48 / 117 (41.03%)
    44 / 108 (40.74%)
         occurrences all number
    284
    322
    281
    280
    Oedema peripheral
         subjects affected / exposed
    2 / 195 (1.03%)
    10 / 192 (5.21%)
    1 / 117 (0.85%)
    8 / 108 (7.41%)
         occurrences all number
    2
    11
    1
    9
    Pyrexia
         subjects affected / exposed
    4 / 195 (2.05%)
    7 / 192 (3.65%)
    2 / 117 (1.71%)
    6 / 108 (5.56%)
         occurrences all number
    4
    9
    2
    8
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    13 / 195 (6.67%)
    18 / 192 (9.38%)
    9 / 117 (7.69%)
    8 / 108 (7.41%)
         occurrences all number
    16
    21
    10
    9
    Anxiety
         subjects affected / exposed
    13 / 195 (6.67%)
    13 / 192 (6.77%)
    5 / 117 (4.27%)
    6 / 108 (5.56%)
         occurrences all number
    13
    14
    5
    6
    Depression
         subjects affected / exposed
    17 / 195 (8.72%)
    13 / 192 (6.77%)
    8 / 117 (6.84%)
    2 / 108 (1.85%)
         occurrences all number
    17
    14
    8
    2
    Insomnia
         subjects affected / exposed
    12 / 195 (6.15%)
    15 / 192 (7.81%)
    7 / 117 (5.98%)
    5 / 108 (4.63%)
         occurrences all number
    15
    16
    8
    5
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    14 / 195 (7.18%)
    16 / 192 (8.33%)
    6 / 117 (5.13%)
    0 / 108 (0.00%)
         occurrences all number
    15
    20
    7
    15
    Diarrhoea
         subjects affected / exposed
    23 / 195 (11.79%)
    11 / 192 (5.73%)
    11 / 117 (9.40%)
    8 / 108 (7.41%)
         occurrences all number
    27
    18
    14
    13
    Nausea
         subjects affected / exposed
    15 / 195 (7.69%)
    10 / 192 (5.21%)
    3 / 117 (2.56%)
    4 / 108 (3.70%)
         occurrences all number
    24
    11
    9
    4
    Vomiting
         subjects affected / exposed
    11 / 195 (5.64%)
    14 / 192 (7.29%)
    6 / 117 (5.13%)
    6 / 108 (5.56%)
         occurrences all number
    16
    18
    11
    7
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    9 / 195 (4.62%)
    12 / 192 (6.25%)
    4 / 117 (3.42%)
    5 / 108 (4.63%)
         occurrences all number
    9
    12
    4
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    14 / 195 (7.18%)
    13 / 192 (6.77%)
    8 / 117 (6.84%)
    7 / 108 (6.48%)
         occurrences all number
    15
    23
    8
    10
    Back pain
         subjects affected / exposed
    20 / 195 (10.26%)
    17 / 192 (8.85%)
    8 / 117 (6.84%)
    5 / 108 (4.63%)
         occurrences all number
    21
    19
    9
    5
    Neck pain
         subjects affected / exposed
    6 / 195 (3.08%)
    2 / 192 (1.04%)
    6 / 117 (5.13%)
    1 / 108 (0.93%)
         occurrences all number
    6
    2
    6
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    10 / 195 (5.13%)
    10 / 192 (5.21%)
    6 / 117 (5.13%)
    5 / 108 (4.63%)
         occurrences all number
    13
    11
    9
    6
    Influenza
         subjects affected / exposed
    8 / 195 (4.10%)
    14 / 192 (7.29%)
    4 / 117 (3.42%)
    10 / 108 (9.26%)
         occurrences all number
    10
    19
    4
    12
    Nasopharyngitis
         subjects affected / exposed
    27 / 195 (13.85%)
    23 / 192 (11.98%)
    13 / 117 (11.11%)
    11 / 108 (10.19%)
         occurrences all number
    35
    31
    14
    15
    Upper respiratory tract infection
         subjects affected / exposed
    20 / 195 (10.26%)
    7 / 192 (3.65%)
    10 / 117 (8.55%)
    3 / 108 (2.78%)
         occurrences all number
    30
    12
    13
    5
    Urinary tract infection
         subjects affected / exposed
    17 / 195 (8.72%)
    18 / 192 (9.38%)
    11 / 117 (9.40%)
    7 / 108 (6.48%)
         occurrences all number
    20
    28
    13
    14

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Oct 2014
    A. Protocol was amended to allow for higher doses of gantenerumab to be examined in an open-label extension and the positron emission tomography (PET) substudy protocol was amended to reflect these changes and to allow subjects participating in the PET substudy to continue their yearly PET scans according to the open label schedule. B. Overview section was updated to explain overall changes. C. Update was made in rationale of study to explain the need for up-titration. D. Study design was updated to allow for transition into open label. Also, to update the number of subjects, treatment allocation and to delete the arterial blood sampling. E. Number of subjects and inclusion criteria was updated F. Schedule of Assessment and Procedures was updated. G. Need for an additional scan was updated in preparation and administration of the radioligand. H. Warnings and precautions, sample size information and overall statistical plan was updated. I. Ongoing review of the PET data by Sponsor included in interim review of study results.
    27 Oct 2015
    A. Protocol body was updated to clarify Part 1 from Part 2. B. Protocol was amended to allow for higher doses of gantenerumab to be examined in an open-label extension and to achieve higher dosing using an APOE ε4-based titration schedule and corresponding magnetic resonance imaging monitoring. C. Screening examination and eligibility screening form were updated. D. Update was made to reflect the abbreviated rescreening visit can be combined with baseline visit as long as all procedures required at screening and Baseline are performed. E. Serology requirements for the screening and re-screening visits were specified. F. Schedule of assessments was updated. G. Roche reporting requirements were updated.
    02 Dec 2017
    A. Protocol was amended to allow subjects the option to continue receiving open-label gantenerumab until the end of 2020. B. The number of studies in which gantenerumab is investigated were updated in background on Gantenerumab. C. The period of review for independent data monitoring committee has been clarified. D. The Cardiac-PET substudy has been updated to reflect updated status. E. Update was made to reflect MMSE is the only efficacy outcome measure assessed during additional years of part 2. F. Removed the cardiac PET substudy because the substudy has been stopped. G. Pharmacokinetic sampling in case of amyloid-related imaging abnormality findings has been clarified. H. Medical monitor information has been updated to reflect the change in Medical Monitor. I. The reporting of the term “sudden death” has been updated. J. Event reporting for hospitalization has been clarified. K. The process for reviewing and handling protocol deviations has been updated. L. Appendix 2 has been updated to indicate assessments collected during the additional years of OLE.
    28 Feb 2020
    A. Protocol was amended to allow participants who complete dosing visits in study WN28745 to enroll in an OLE study (WN41874) without any unnecessary dosing gap, and to enable the use of leftover plasma samples, collected for PK and ADA analysis, for exploratory biomarker research. B. Update was made to clarify that amyloid-related imaging abnormalities (both edema/effusion and hemosiderin depositions) and injection-site reactions are identified risks for gantenerumab and to enable participants to enroll in study WN41874 (open-label rollover study) to continue to receive gantenerumab for 2 more years. Participants who enroll in study WN41874 will not undergo follow-up assessments 16 weeks after their last dose (Follow–Up 2 visit). C. Positron emission tomography tracers used in the substudies associated in this substudy are included as investigational medicinal products (IMPs) or non-IMPs. D. Update was made to enable the use of leftover plasma samples, collected for PK and ADA analysis, for exploratory biomarker research and to clarify the timing of follow-up visits for Part 1 versus Part 2. E. Medical Monitor contact information was updated. F. Documents to be used for reference safety information for the PET tracers have been specified. G. Appendix 2 has been corrected to clarify that treatment is not to be administered at the Follow-Up 1 visit. H. Appendix 2 has been updated to add an optional lumbar puncture at Week 104 for all participants.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    As the participants transitioned early to OLE, most participants did not reach the primary analysis timepoint (Week 104). Hence, the efficacy endpoints for Part 1 became exploratory in nature.
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