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    Clinical Trial Results:
    A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy, and Safety Study of Gantenerumab in Patients With Early (Prodromal to Mild) Alzheimer's Disease

    Summary
    EudraCT number
    		 2017-001365-24
    Trial protocol
    		 ES   GB   DK   BE   PT   PL   NL   SE   FI   HR  
    Global end of trial date
    28 Nov 2022

    Results information
    Results version number
    		 v2(current)
    This version publication date
    13 Apr 2024
    First version publication date
    08 Oct 2023
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Update in OM description.

    Trial information

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    Trial identification
    Sponsor protocol code
    WN39658
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03444870
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    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
    28 Nov 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Nov 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of this study was to evaluate the efficacy and safety of gantenerumab administered by subcutaneous (SC) injection compared with placebo.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form (ICF).
    Background therapy
    		 Participants were allowed to take standard of care symptomatic treatment throughout the study i.e., cholinesterase inhibitors and/or memantine.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Aug 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 62
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Chile: 46
    Country: Number of subjects enrolled
    Denmark: 18
    Country: Number of subjects enrolled
    Spain: 155
    Country: Number of subjects enrolled
    Finland: 23
    Country: Number of subjects enrolled
    United Kingdom: 54
    Country: Number of subjects enrolled
    Croatia: 1
    Country: Number of subjects enrolled
    Japan: 64
    Country: Number of subjects enrolled
    Korea, Republic of: 54
    Country: Number of subjects enrolled
    Mexico: 50
    Country: Number of subjects enrolled
    Netherlands: 8
    Country: Number of subjects enrolled
    Poland: 127
    Country: Number of subjects enrolled
    Portugal: 32
    Country: Number of subjects enrolled
    Singapore: 10
    Country: Number of subjects enrolled
    Sweden: 24
    Country: Number of subjects enrolled
    Turkey: 3
    Country: Number of subjects enrolled
    United States: 234
    Worldwide total number of subjects
    975
    EEA total number of subjects
    398
    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)
    167
    From 65 to 84 years
    771
    85 years and over
    37

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled in the study across 151 investigative sites in 18 countries from 22 August 2018 to 28 November 2022.

    Pre-assignment
    Screening details
    		 A total of 975 participants with early (prodromal to mild) Alzheimer’s Disease (AD) were randomized to either the gantenerumab (n=498) or placebo arm (n=477) to enter the double-blind treatment (DBT) period.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo: DBT
    Arm description
    		 Participants received, gantenerumab matching placebo, subcutaneous (SC) injections, every four weeks (Q4W) up to Week 36 and then every two weeks (Q2W) up to Week 114 of the DBT period.
    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
    Gantenerumab matching placebo administered as SC injections, Q4W up to Week 36 and then Q2W up to Week 114 of the DBT period.

    Arm title
    		 Gantenerumab: DBT
    Arm description
    		 Participants received gantenerumab, SC injections with gradual up-titration starting at a dose of 120 milligrams (mg), Q4W for 3 doses, followed by 255 mg, Q4W for 3 doses, and 510 mg, Q4W for 3 doses. Following this, from Week 36 onwards, participants received gantenerumab, SC injections, at a dose of 510 mg, Q2W up to Week 114 of the DBT period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gantenerumab
    Investigational medicinal product code
    RO4909832
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Gantenerumab administered as SC injections with gradual up titration starting at a dose of 120 mg, Q4W for 3 doses, followed by 255 mg, Q4W for 3 doses, and 510 mg, Q4W for 3 doses. After Week 36, gantenerumab, SC injections, at a dose of 510 mg, Q2W up to Week 114 of the DBT period.

    Number of subjects in period 1
    		Placebo: DBT Gantenerumab: DBT
    Started
    477
    498
    Completed
    397
    372
    Not completed
    80
    126
         Adverse event, serious fatal
    5
    7
         Consent withdrawn by subject
    54
    79
         Physician decision
    5
    6
         Adverse event, non-fatal
    5
    19
         Protocol Deviation
    1
    2
         Reason Not Specified
    9
    11
         Lost to follow-up
    -
    1
         Lack of efficacy
    1
    1
    Period 2
    Period 2 title
    Open-label Extension Period
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Participants were blinded to previous treatment assignments through a blinded titration period.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo (DBT) to Gantenerumab: Open-label Extension (OLE)
    Arm description
    		 Participants who received gantenerumab matching placebo in the DBT period received gantenerumab SC injections with gradual up titration starting at a dose of 120 mg, Q4W for 3 doses, followed by 255 mg, Q4W for 3 doses, and then at a dose of 510 mg, Q4W up to Week 34 of the OLE period. To maintain the blind to previous treatment assignment, participants received Q2W, SC injections, with alternate doses containing gantenerumab matching placebo.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gantenerumab
    Investigational medicinal product code
    RO4909832
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Gantenerumab SC injections with gradual up titration starting at a dose of 120 mg, Q4W for 3 doses, followed by 255 mg, Q4W for 3 doses, and then at a dose of 510 mg, Q4W up to Week 34 of the OLE period. To maintain the blind to previous treatment assignment, participants received Q2W, SC injections, with alternate doses containing gantenerumab matching placebo.

    Arm title
    		 Gantenerumab (DBT) to Gantenerumab: OLE
    Arm description
    		 Participants who received gantenerumab in the DBT period continued receiving gantenerumab, SC injections, 510 mg, Q2W up to Week 34 of the OLE period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gantenerumab
    Investigational medicinal product code
    RO4909832
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Gantenerumab, SC injections, 510 mg, Q2W up to Week 34 of the OLE period.

    Number of subjects in period 2 [1]
    		Placebo (DBT) to Gantenerumab: Open-label Extension (OLE) Gantenerumab (DBT) to Gantenerumab: OLE
    Started
    13
    14
    Completed
    8
    13
    Not completed
    5
    1
         Consent withdrawn by subject
    2
    1
         Reason Not Specified
    3
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Participants who completed the DBT Period enrolled into the OLE Period or choose to enter the safety follow up or rolled over to PostGraduate OLE (WN42171) study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo: DBT
    Reporting group description
    		 Participants received, gantenerumab matching placebo, subcutaneous (SC) injections, every four weeks (Q4W) up to Week 36 and then every two weeks (Q2W) up to Week 114 of the DBT period.

    Reporting group title
    Gantenerumab: DBT
    Reporting group description
    		 Participants received gantenerumab, SC injections with gradual up-titration starting at a dose of 120 milligrams (mg), Q4W for 3 doses, followed by 255 mg, Q4W for 3 doses, and 510 mg, Q4W for 3 doses. Following this, from Week 36 onwards, participants received gantenerumab, SC injections, at a dose of 510 mg, Q2W up to Week 114 of the DBT period.

    Reporting group values
    		 Placebo: DBT Gantenerumab: DBT Total
    Number of subjects
    		 477 498 975
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 71.8 ± 7.4 71.6 ± 7.8 -
    Sex: Female, Male
    Units: participants
        Female
    		 285 288 573
        Male
    		 192 210 402
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 13 13 26
        Asian
    		 75 56 131
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 4 5 9
        White
    		 385 424 809
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 119 112 231
        Not Hispanic or Latino
    		 358 386 744
        Unknown or Not Reported
    		 0 0 0
    Clinical Dementia Rating-Sum of Boxes (CDR-SB)
    CDR was derived by semi-structured interview with participant & informant & rated impairment across 6 domains: memory,orientation,judgment & problem solving,community affairs,home & hobbies & personal care on 5-point scale for which 0=no impairment, 0.5=questionable impairment & 1, 2 & 3=mild,moderate,severe impairment respectively. CDR-SB is based on summing each domain box scores with total score ranging 0-18 with higher scores=greater cognitive & functional impairment. ITT analysis set included all participants randomised during global phase who received at least 1 dose of study drug.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 3.52 ± 1.54 3.67 ± 1.61 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo: DBT
    Reporting group description
    		 Participants received, gantenerumab matching placebo, subcutaneous (SC) injections, every four weeks (Q4W) up to Week 36 and then every two weeks (Q2W) up to Week 114 of the DBT period.

    Reporting group title
    Gantenerumab: DBT
    Reporting group description
    		 Participants received gantenerumab, SC injections with gradual up-titration starting at a dose of 120 milligrams (mg), Q4W for 3 doses, followed by 255 mg, Q4W for 3 doses, and 510 mg, Q4W for 3 doses. Following this, from Week 36 onwards, participants received gantenerumab, SC injections, at a dose of 510 mg, Q2W up to Week 114 of the DBT period.
    Reporting group title
    Placebo (DBT) to Gantenerumab: Open-label Extension (OLE)
    Reporting group description
    		 Participants who received gantenerumab matching placebo in the DBT period received gantenerumab SC injections with gradual up titration starting at a dose of 120 mg, Q4W for 3 doses, followed by 255 mg, Q4W for 3 doses, and then at a dose of 510 mg, Q4W up to Week 34 of the OLE period. To maintain the blind to previous treatment assignment, participants received Q2W, SC injections, with alternate doses containing gantenerumab matching placebo.

    Reporting group title
    Gantenerumab (DBT) to Gantenerumab: OLE
    Reporting group description
    		 Participants who received gantenerumab in the DBT period continued receiving gantenerumab, SC injections, 510 mg, Q2W up to Week 34 of the OLE period.

    Subject analysis set title
    Gantenerumab: DBT
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received gantenerumab, SC injections with gradual up-titration starting at a dose of 120 mg, Q4W for 3 doses, followed by 255 mg, Q4W for 3 doses, and 510 mg, Q4W for 3 doses. Following this, from Week 36 onwards, participants received gantenerumab, SC injections, at a dose of 510 mg, Q2W up to Week 114 of the DBT period.

    Primary: DBT Period: Change From Baseline to Week 116 in Global Outcome, as Measured by CDR-SB

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    End point title
    		 DBT Period: Change From Baseline to Week 116 in Global Outcome, as Measured by CDR-SB
    End point description
    CDR was derived through semi-structured interview with the participant and an appropriate informant, and it rated impairment across six domains: memory, orientation, judgment, and problem solving, community affairs, home and hobbies, and personal care on a 5-point scale for which 0=no impairment, 0.5=questionable impairment, and 1, 2, and 3=mild, moderate, and severe impairment, respectively. The CDR-SB is based on summing each of the domain box scores with total score ranging from 0-18 with higher scores reflecting greater cognitive and functional impairment. A negative change from baseline indicates improvement. ITT analysis set included all participants randomised during the global phase, who received at least one dose of study drug. Overall number analysed is the number of participants with data available for analysis.
    End point type
    Primary
    End point timeframe
    Baseline, Week 116
    End point values
    		 Placebo: DBT Gantenerumab: DBT
    Number of subjects analysed
    477
    497
    Units: score on a scale
        arithmetic mean (standard error)
    3.01 ± 0.15
    2.82 ± 0.14
    Statistical analysis title
    		 Placebo: DBT, Gantenerumab: DBT
    Statistical analysis description
    Change from Baseline was calculated based on ANCOVA analysis model which included the following covariates and stratification factors =Treatment + Baseline (BL) + Geographic Region + Disease Stage + AD Medication at BL + Apolipoprotein E, Allele e4 (APOE e4) + Baseline ADAS COG13 + Baseline Alzheimer Disease Cooperative Study Group-Activities of Daily Living (ADCS-ADL).
    Comparison groups
    Placebo: DBT v Gantenerumab: DBT
    Number of subjects included in analysis
    974
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2998
    Method
    		 ANCOVA
    Parameter type
    		 Difference in Adjusted mean
    Point estimate
    -0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.55
         upper limit
    		 0.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.18

    Primary: OLE Period: Number of Participants with Adverse Events (AEs)

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    End point title
    		 OLE Period: Number of Participants with Adverse Events (AEs) [1]
    End point description
    An adverse event is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. OLE safety-evaluable set included all participants randomized during the global enrollment phase who received at least one dose of study drug and who entered the OLE period.
    End point type
    Primary
    End point timeframe
    From day of first dose in OLE period up to 14 weeks after the last OLE dose (up to 48 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 comparison was planned.
    End point values
    		 Placebo (DBT) to Gantenerumab: Open-label Extension (OLE) Gantenerumab (DBT) to Gantenerumab: OLE
    Number of subjects analysed
    13
    14
    Units: participants
    8
    6
    No statistical analyses for this end point

    Primary: OLE Period: Number of Participants With Change from Baseline in Columbia-Suicide Severity Rating Scale (C-SSRS) Score

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    End point title
    		 OLE Period: Number of Participants With Change from Baseline in Columbia-Suicide Severity Rating Scale (C-SSRS) Score [2]
    End point description
    C-SSRS=assessment tool used to assess lifetime suicidality of participant and any new instances of suicidality. Structured interview prompts recollection of suicidal ideation, including intensity of ideation, behavior& attempts with actual/potential lethality. Responses to categories: yes/no[Wish to be Dead;Non-specific Active Suicidal Thoughts; Active Suicidal Ideation with Any Methods without Intent to Act;Active Suicidal Ideation with Some Intent to Act, without Specific Plan;Active Suicidal Ideation with Specific Plan &Intent, Preparatory Acts &Behavior; Aborted Attempt; Interrupted Attempt; Actual Attempt (non-fatal)]; Completed Suicide. Suicidal ideation/behavior is indicated by a "yes" answer to any of the listed categories. Score=0, if no suicide risk is present. Score=1/higher indicates suicidal ideation/behavior. OLE safety-evaluable set=all participants randomized during global enrollment phase who received at least one dose of study drug & who entered OLE period.
    End point type
    Primary
    End point timeframe
    From day of first dose in OLE period up to 14 weeks after the last OLE dose (up to 48 weeks)
    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 comparison was planned.
    End point values
    		 Placebo (DBT) to Gantenerumab: Open-label Extension (OLE) Gantenerumab (DBT) to Gantenerumab: OLE
    Number of subjects analysed
    12
    13
    Units: participants
        Suicidal Ideation: Passive
    1
    0
        Suicidal Ideation: Active-Method, No Intent/Plan
    1
    0
        Suicidal Ideation: No Event
    10
    13
        Suicidal Behavior: No Event
    12
    13
        Self-injurious Behavior Without Intent: No Event
    12
    13
    No statistical analyses for this end point

    Primary: OLE Period : Number of Participants with Amyloid-Related Imaging Abnormalities-Haemosiderin deposition (ARIA-H) Confirmed by MRI

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    End point title
    		 OLE Period : Number of Participants with Amyloid-Related Imaging Abnormalities-Haemosiderin deposition (ARIA-H) Confirmed by MRI [3]
    End point description
    ARIA are an identified risk with anti-amyloid antibodies, including gantenerumab. These changes can be identified on brain MRI. ARIA-H (H for hemosiderosis) are small foci of signal loss observed on MRI sequences sensitive for paramagnetic tissue properties and comprise cerebral microbleeds (small foci of bleeding in the brain parenchyma) and leptomeningeal hemosiderosis (small foci of bleeding on the surface of the brain). These changes also occur sporadically in AD. MRI Safety-evaluable analysis set included all participants in the Safety-evaluable analysis set who had at least one post-baseline safety MRI scan.
    End point type
    Primary
    End point timeframe
    From day of first dose in OLE period up to 14 weeks after the last OLE dose (up to 48 weeks)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical comparison was planned.
    End point values
    		 Placebo (DBT) to Gantenerumab: Open-label Extension (OLE) Gantenerumab (DBT) to Gantenerumab: OLE
    Number of subjects analysed
    13
    14
    Units: participants
    2
    1
    No statistical analyses for this end point

    Primary: OLE Period: Number of Participants with Amyloid-Related Imaging Abnormalities-Edema (ARIA-E) Confirmed by Magnetic Resonance Imaging (MRI)

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    End point title
    		 OLE Period: Number of Participants with Amyloid-Related Imaging Abnormalities-Edema (ARIA-E) Confirmed by Magnetic Resonance Imaging (MRI) [4]
    End point description
    ARIA are an identified risk with anti-amyloid antibodies, including gantenerumab. These changes can be identified on brain MRI. In ARIA-E, (E for oedema or effusion), oedema can be seen in different areas of the brain on MRI, representing fluid leakage into the brain parenchyma or sulcal spaces. MRI Safety-evaluable analysis set included all participants in the Safety-evaluable analysis set who had at least one post-baseline safety MRI scan.
    End point type
    Primary
    End point timeframe
    From day of first dose in OLE period up to 14 weeks after the last OLE dose (up to 48 weeks)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical comparison was planned.
    End point values
    		 Placebo (DBT) to Gantenerumab: Open-label Extension (OLE) Gantenerumab (DBT) to Gantenerumab: OLE
    Number of subjects analysed
    13
    14
    Units: participants
    0
    1
    No statistical analyses for this end point

    Primary: OLE Period: Number of Participants with Injection-Site Reactions

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    End point title
    		 OLE Period: Number of Participants with Injection-Site Reactions [5]
    End point description
    An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product or other protocol-imposed intervention, regardless of attribution. Local injection reactions (or injection site reactions) are defined as AEs related to the injection site that occur during or within 24 hours after study drug administration that are judged to be related to the study drug injection. OLE safety-evaluable set included all participants randomized during the global enrollment phase who received at least one dose of study drug and who entered the OLE period.
    End point type
    Primary
    End point timeframe
    From day of first dose in OLE period up to 14 weeks after the last OLE dose (up to 48 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 comparison was planned.
    End point values
    		 Placebo (DBT) to Gantenerumab: Open-label Extension (OLE) Gantenerumab (DBT) to Gantenerumab: OLE
    Number of subjects analysed
    13
    14
    Units: participants
    0
    1
    No statistical analyses for this end point

    Secondary: DBT Period: Change from Baseline to Week 116 in Alzheimer Disease Assessment Scale-Cognition Subscale 13 (ADAS-Cog13) Score

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    End point title
    		 DBT Period: Change from Baseline to Week 116 in Alzheimer Disease Assessment Scale-Cognition Subscale 13 (ADAS-Cog13) Score
    End point description
    The ADAS-Cog13 total score includes all of the items in the ADAS-Cog11 in addition to delayed word recall and the number cancellation. For the ADAS-cog 13 the range is 0-85 (score range for Delayed Word Recall [DWR] score is 0-10 and for Number Cancellation [NC] is 0-5, thus the score is ADAS-cog 11[0-70] plus the scores for DWR and NC). A higher score indicates worse performance. A negative change from baseline indicates improvement in cognitive function. ITT analysis set included all participants randomised during the global phase, who received at least one dose of study drug. Overall number analysed is the number of participants with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 116
    End point values
    		 Placebo: DBT Gantenerumab: DBT
    Number of subjects analysed
    475
    491
    Units: score on a scale
        arithmetic mean (standard error)
    7.94 ± 0.49
    6.66 ± 0.42
    Statistical analysis title
    		 Placebo: DBT, Gantenerumab: DBT
    Statistical analysis description
    Change from BL was calculated based on ANCOVA analysis model which included the following covariates and stratification factors = Treatment + Baseline + Geographical Region + Disease Stage + AD Medication at BL + APOE e4
    Comparison groups
    Placebo: DBT v Gantenerumab: DBT
    Number of subjects included in analysis
    966
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0273
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted mean
    Point estimate
    -1.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.41
         upper limit
    		 -0.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.58

    Secondary: DBT Period: Change From Baseline to Week 116 in Alzheimer's Disease Cooperative Study- Activities of Daily Living (ADCS-ADL) Total Score

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    End point title
    		 DBT Period: Change From Baseline to Week 116 in Alzheimer's Disease Cooperative Study- Activities of Daily Living (ADCS-ADL) Total Score
    End point description
    ADCS-ADL is a 23-item rater-administered, observer-reported outcome (ObsRO) that captures a participant’s ability to perform basic activities of daily living (e.g., eating and toileting) and more complex ADL or instrumental activities of daily living (iADL, e.g., using the telephone, managing finances, preparing a meal). Total score ranges from 0-78, with higher scores reflecting better functioning. A positive change from baseline indicates improvement. ITT analysis set included all participants randomised during the global phase, who received at least one dose of study drug. Overall number analysed is the number of participants with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 116
    End point values
    		 Placebo: DBT Gantenerumab: DBT
    Number of subjects analysed
    475
    496
    Units: score on a scale
        arithmetic mean (standard error)
    -9.26 ± 0.62
    -8.44 ± 0.58
    Statistical analysis title
    		 Placebo: DBT, Gantenerumab: DBT
    Statistical analysis description
    Change from BL was calculated based on ANCOVA analysis model which included the following covariates and stratification factors = Treatment + Baseline + Region + Disease Stage + AD Medication at BL + APOE e4
    Comparison groups
    Placebo: DBT v Gantenerumab: DBT
    Number of subjects included in analysis
    971
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2918
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted mean
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 2.34
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.78

    Secondary: DBT Period: Change From Baseline to Week 116 in Functional Activities Questionnaire (FAQ) Score

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    End point title
    		 DBT Period: Change From Baseline to Week 116 in Functional Activities Questionnaire (FAQ) Score
    End point description
    FAQ is a rater-administered ObsRO (informant-based measure) that measures a participant’s functional ability to perform complex higher-order activities. The observer provides performance ratings of the target person on ten complex higher-order activities. Total score that ranges from 0-30, with higher scores reflecting greater functional impairment. A negative change from baseline indicates improvement. ITT analysis set included all participants randomised during the global phase, who received at least one dose of study drug. Overall number analysed is the number of participants with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 116
    End point values
    		 Placebo: DBT Gantenerumab: DBT
    Number of subjects analysed
    476
    496
    Units: score on a scale
        arithmetic mean (standard error)
    6.72 ± 0.33
    5.86 ± 0.31
    Statistical analysis title
    		 Placebo: DBT, Gantenerumab: DBT
    Statistical analysis description
    Change from BL was calculated based on ANCOVA analysis model which included the following covariates and stratification factors = Treatment + Baseline + Geographical Region + Disease Stage + AD Medication at BL + APOE e4.
    Comparison groups
    Placebo: DBT v Gantenerumab: DBT
    Number of subjects included in analysis
    972
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0438
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted mean
    Point estimate
    -0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.7
         upper limit
    		 -0.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.43

    Secondary: DBT Period: Change From Baseline to Week 116 in Mini-Mental State Examination (MMSE) Total Score

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    End point title
    		 DBT Period: Change From Baseline to Week 116 in Mini-Mental State Examination (MMSE) Total Score
    End point description
    MMSE is a rater-administered performance-based outcome (PerfO) that includes a set of standardized questions used to evaluate possible cognitive impairment and help stage the severity level of this impairment. The questions target six areas: orientation, registration, attention, short-term recall, language, and constructional praxis/visuospatial abilities. Total score ranges from 0-30, with lower scores indicating greater impairment. A positive change from baseline indicates improvement. ITT analysis set included all participants randomised during the global phase, who received at least one dose of study drug. Overall number analysed is the number of participants with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 116
    End point values
    		 Placebo: DBT Gantenerumab: DBT
    Number of subjects analysed
    477
    497
    Units: score on a scale
        arithmetic mean (standard error)
    -4.53 ± 0.22
    -4.00 ± 0.20
    Statistical analysis title
    		 Placebo: DBT, Gantenerumab: DBT
    Statistical analysis description
    Change from Baseline was calculated based on ANCOVA analysis model which included the following covariates and stratification factors =Treatment + Baseline + Geographic Region + Disease Stage + AD Medication at BL + APOE e4.
    Comparison groups
    Placebo: DBT v Gantenerumab: DBT
    Number of subjects included in analysis
    974
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0566
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted mean
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.01
         upper limit
    		 1.06
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.27

    Secondary: DBT Period: Change From Baseline to Week 116 in Alzheimer Disease Assessment Scale-Cognition Subscale 11 (ADAS-Cog11) Score

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    End point title
    		 DBT Period: Change From Baseline to Week 116 in Alzheimer Disease Assessment Scale-Cognition Subscale 11 (ADAS-Cog11) Score
    End point description
    The ADAS-Cog11 was designed to measure cognitive symptom change in participants with AD, consisted of 11 tasks. Standard 11 items (& score range) were: word recall (0-10), commands (0-5), constructional praxis (0-5), naming objects & fingers (0-5), ideational praxis (0-5), orientation (0-8), word recognition (0-12), spoken language ability (0-5), comprehension of spoken language (0-5), word-finding difficulty (0-5) & remembering test instructions (0-5). Test included 7 performance items & 4 clinician-rated items. ADAS-Cog11 total score=sum of all 11 individual items, with a total score ranging from 0 (no impairment)-70 (severe impairment). Higher scores indicated more severe cognitive impairment. A negative change from baseline indicates improvement. ITT analysis set was used. Overall number analyzed is number of participants with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 116
    End point values
    		 Placebo: DBT Gantenerumab: DBT
    Number of subjects analysed
    475
    491
    Units: score on a scale
        arithmetic mean (standard error)
    6.97 ± 0.46
    5.77 ± 0.38
    Statistical analysis title
    		 Placebo: DBT, Gantenerumab: DBT
    Statistical analysis description
    Change from BL was calculated based on ANCOVA analysis model which included the following covariates and stratification factors = Treatment + Baseline + Geographical Region + Disease Stage + AD Medication at BL + APOE e4.
    Comparison groups
    Placebo: DBT v Gantenerumab: DBT
    Number of subjects included in analysis
    966
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.026
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted mean
    Point estimate
    -1.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.24
         upper limit
    		 -0.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.53

    Secondary: DBT Period: Change From Baseline to Week 116 in Verbal Fluency Task (VFT) Score

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    End point title
    		 DBT Period: Change From Baseline to Week 116 in Verbal Fluency Task (VFT) Score
    End point description
    VFT is a rater administered PerfO that measures speed and flexibility of verbal thought with a total score that ranges from 0-99 (lower scores indicating lower performance). A positive change from baseline indicates improvement. ITT analysis set included all participants randomised during the global phase, who received at least one dose of study drug. Overall number analysed is the number of participants with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 116
    End point values
    		 Placebo: DBT Gantenerumab: DBT
    Number of subjects analysed
    477
    497
    Units: score on a scale
        arithmetic mean (standard error)
    -2.68 ± 0.22
    -2.71 ± 0.21
    Statistical analysis title
    		 Placebo: DBT, Gantenerumab: DBT
    Statistical analysis description
    Change from BL was calculated based on ANCOVA analysis model which included the following covariates and stratification factors = Treatment + Baseline + Geographical Region + Disease Stage + AD Medication at BL + APOE e4.
    Comparison groups
    Placebo: DBT v Gantenerumab: DBT
    Number of subjects included in analysis
    974
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9086
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted mean
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.59
         upper limit
    		 0.52
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.28

    Secondary: DBT Period: Change from Baseline to Week 116 in the Coding (Digit Symbol Substitution Test [DSST]) Subtest

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    End point title
    		 DBT Period: Change from Baseline to Week 116 in the Coding (Digit Symbol Substitution Test [DSST]) Subtest
    End point description
    Coding, also called DSST is a rater administered PerfO that measures speed of processing and associative memory with a total score that ranges from 0-135 (lower scores indicating lower performance). The DSST was adapted from the Wechsler Adult Intelligence Scale. The 120-second version of the test was used in this study. Positive change from baseline indicates improvement. ITT analysis set included all participants randomised during the global phase, who received at least one dose of study drug. Overall number analysed is the number of participants with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 116
    End point values
    		 Placebo: DBT Gantenerumab: DBT
    Number of subjects analysed
    475
    497
    Units: score on a scale
        arithmetic mean (standard error)
    -6.90 ± 0.59
    -5.49 ± 0.55
    Statistical analysis title
    		 Placebo: DBT, Gantenerumab: DBT
    Statistical analysis description
    Change from BL was calculated based on ANCOVA analysis model which included the following covariates and stratification factors = Treatment + Baseline + Geographical Region + Disease Stage + AD Medication at BL + APOE e4.
    Comparison groups
    Placebo: DBT v Gantenerumab: DBT
    Number of subjects included in analysis
    972
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0629
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted mean
    Point estimate
    1.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.08
         upper limit
    		 2.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.76

    Secondary: DBT Period: Change From Baseline to Week 116 in Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL) Instrumental Score

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    End point title
    		 DBT Period: Change From Baseline to Week 116 in Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL) Instrumental Score
    End point description
    The ADCS-iADL measures activities such as using the telephone, shopping and preparing a meal. The ADCS-iADL consists of 16 questions with a score range of 0 to 56 where a higher score represents better function. Positive change from baseline indicates improvement. ITT analysis set included all participants randomised during the global phase, who received at least one dose of study drug. Overall number analysed is the number of participants with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 116
    End point values
    		 Placebo: DBT Gantenerumab: DBT
    Number of subjects analysed
    475
    496
    Units: score on a scale
        arithmetic mean (standard error)
    -8.22 ± 0.53
    -7.43 ± 0.49
    Statistical analysis title
    		 Placebo: DBT, Gantenerumab: DBT
    Statistical analysis description
    Change from BL was calculated based on ANCOVA analysis model which included the following covariates and stratification factors = Treatment + Baseline + Geographical Region + Disease Stage + AD Medication at BL + APOE e4.
    Comparison groups
    Placebo: DBT v Gantenerumab: DBT
    Number of subjects included in analysis
    971
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2348
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted mean
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.51
         upper limit
    		 2.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.66

    Secondary: DBT Period: Number of Participants With Change from Baseline in C-SSRS Score

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    End point title
    		 DBT Period: Number of Participants With Change from Baseline in C-SSRS Score [6]
    End point description
    C-SSRS=assessment tool used to assess lifetime suicidality of a participant &any new instances of suicidality. Categories have binary responses (yes/no) &include Wish to be Dead; Non-specific Active Suicidal Thoughts; Active Suicidal Ideation with Any Methods without Intent to Act; Active Suicidal Ideation with Some Intent to Act, without Specific Plan; Active Suicidal Ideation with Specific Plan & Intent, Preparatory Acts &Behavior; Aborted Attempt; Interrupted Attempt; Actual Attempt (non-fatal); Completed Suicide. Suicidal ideation/behavior indicated by a "yes" answer to any listed categories. 0= no suicide risk is present. Score of 1/higher= suicidal ideation/behavior. Safety-evaluable set=all participants randomised during global phase who received at least one dose of study drug. 3 participants randomized to placebo received at least one dose of gantenerumab & were considered in gantenerumab arm for safety evaluable set. Categories with non-zero values are only reported.
    End point type
    Secondary
    End point timeframe
    From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 128 weeks)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint represents data for DBT period only.
    End point values
    		 Placebo: DBT Gantenerumab: DBT
    Number of subjects analysed
    464
    483
    Units: participants
        Suicidal Ideation: Passive
    20
    12
        Suicidal Ideation: Active-Nonspecific
    4
    2
        Suicidal Ideation: Active-Method, No Intent/Plan
    2
    2
        Suicidal Ideation: Active-Method &Intent;No Plan
    1
    1
        Suicidal Ideation: Active-Method, Intent & Plan
    0
    2
        Suicidal Ideation: No Event
    437
    464
        Suicidal Behavior: No Event
    464
    483
        Self-injurious Behavior, No Suicidal Intent
    0
    2
        Self-injurious Behavior Without Intent: No Event
    464
    481
    No statistical analyses for this end point

    Secondary: DBT Period: Number of Participants with AEs

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    End point title
    		 DBT Period: Number of Participants with AEs [7]
    End point description
    An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. Safety-evaluable set included all participants randomised during the global phase who received at least one dose of study drug. In the DBT period, three participants randomized to placebo arm received at least one dose of gantenerumab and were considered in the gantenerumab arm for safety evaluable set.
    End point type
    Secondary
    End point timeframe
    From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 128 weeks)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint represents data for DBT period only.
    End point values
    		 Placebo: DBT Gantenerumab: DBT
    Number of subjects analysed
    474
    501
    Units: participants
    409
    451
    No statistical analyses for this end point

    Secondary: DBT Period: Number of Participants with ARIA-E Confirmed by MRI

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    End point title
    		 DBT Period: Number of Participants with ARIA-E Confirmed by MRI
    End point description
    ARIA are an identified risk with anti-amyloid antibodies, including gantenerumab. These changes can be identified on brain MRI. In ARIA-E, (E for oedema or effusion), oedema can be seen in different areas of the brain on MRI, representing fluid leakage into the brain parenchyma or sulcal spaces. MRI Safety-evaluable analysis set included all participants in the Safety-evaluable analysis set who had at least one post-baseline safety MRI scan.
    End point type
    Secondary
    End point timeframe
    From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 128 weeks)
    End point values
    		 Placebo: DBT Gantenerumab: DBT
    Number of subjects analysed
    470
    496
    Units: participants
    18
    128
    No statistical analyses for this end point

    Secondary: DBT Period : Number of Participants with ARIA-H Confirmed by MRI

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    End point title
    		 DBT Period : Number of Participants with ARIA-H Confirmed by MRI
    End point description
    ARIA are an identified risk with anti-amyloid antibodies, including gantenerumab. These changes can be identified on brain MRI. ARIA-H (H for hemosiderosis) are small foci of signal loss observed on MRI sequences sensitive for paramagnetic tissue properties and comprise cerebral microbleeds (small foci of bleeding in the brain parenchyma) and leptomeningeal hemosiderosis (small foci of bleeding on the surface of the brain). These changes also occur sporadically in AD. MRI Safety-evaluable analysis set included all participants in the Safety-evaluable analysis set who had at least one post-baseline safety MRI scan.
    End point type
    Secondary
    End point timeframe
    From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 128 weeks)
    End point values
    		 Placebo: DBT Gantenerumab: DBT
    Number of subjects analysed
    470
    496
    Units: participants
    57
    109
    No statistical analyses for this end point

    Secondary: DBT Period: Number of Participants With Anti-Drug Antibodies (ADA) to Gantenerumab

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    End point title
    		 DBT Period: Number of Participants With Anti-Drug Antibodies (ADA) to Gantenerumab
    End point description
    Number of participants with positive results for ADA against gantenerumab at any post-baseline (PB) assessment time-points were reported. Participant with ADA assay result from at least 1 post-baseline sample = PB evaluable participant. Treatment Emergent ADA = participant with negative/missing baseline ADA result(s) & at least 1 positive PB ADA result. ADA-evaluable analysis set included participants who received at least one dose of study drug and who provided at least one post-baseline ADA sample. In the DBT period, three participants randomized to placebo arm received at least one dose of gantenerumab and were considered in the gantenerumab arm. As pre-specified in the protocol, ADA data for studies WN29922 and WN39658 from the OLE period will be reported when the results for study WN42171 will be posted.
    End point type
    Secondary
    End point timeframe
    From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 128 weeks)
    End point values
    		 Gantenerumab: DBT
    Number of subjects analysed
    501
    Units: participants
        Number of Participants with Treatment-emergent ADA
    12
    No statistical analyses for this end point

    Secondary: Change from Baseline in Brain Amyloid Load as Measured by Amyloid Positron Emission Tomography (PET) Scan in a Subset of Participants

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    End point title
    		 Change from Baseline in Brain Amyloid Load as Measured by Amyloid Positron Emission Tomography (PET) Scan in a Subset of Participants
    End point description
    Brain amyloid load over time was assessed using [18F] florbetaben or [18F] flutemetamol tracers. These are PET radioligand selective to amyloid. Amyloid PET burden was measured in composite region of interest by using standardized uptake value ratio (SUVR) mapped to centiloid scale. Centiloid scale anchor points are 0 & 100, where 0=high-certainty amyloid negative scan & 100=amount of global amyloid deposition found in typical AD scan. Amyloid-PET-modified-ITT (mITT) included all participants in ITT analysis set who participated in the Amyloid PET sub-study and who had at least 1 Amyloid PET scan with valid quantitative measurement performed with either florbetaben or flutemetamol who did not withdraw from the Amyloid PET substudy before randomisation. Overall number analysed is number of participants with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 116
    End point values
    		 Placebo: DBT Gantenerumab: DBT
    Number of subjects analysed
    44
    40
    Units: score on a scale
        arithmetic mean (standard error)
    8.46 ± 2.768
    -48.00 ± 2.845
    Statistical analysis title
    		 Placebo: DBT, Gantenerumab: DBT
    Statistical analysis description
    Change from BL was calculated based on mixed-effect model of repeated measure which included the following covariates and stratification factors = Baseline + APOE e4 status + Type of Tracer + Analysis Visit + Treatment + Treatment*Analysis Visit + Analysis Visit*Baseline.
    Comparison groups
    Placebo: DBT v Gantenerumab: DBT
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed Model for Repeated Measures
    Parameter type
    		 Difference in adjusted means
    Point estimate
    -56.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -64.36
         upper limit
    		 -48.56
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.976

    Secondary: DBT Period: Number of Participants with Injection-Site Reactions

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    End point title
    		 DBT Period: Number of Participants with Injection-Site Reactions [8]
    End point description
    An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product or other protocol-imposed intervention, regardless of attribution. Local injection reactions (or injection site reactions) are defined as AEs related to the injection site that occur during or within 24 hours after study drug administration that are judged to be related to the study drug injection. Safety-evaluable set included all participants randomised during the global phase who received at least one dose of study drug. In the DBT period, three participants randomized to placebo arm received at least one dose of gantenerumab and were considered in the gantenerumab arm for safety evaluable set.
    End point type
    Secondary
    End point timeframe
    From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 128 weeks)
    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: The endpoint represents data for DBT period only.
    End point values
    		 Placebo: DBT Gantenerumab: DBT
    Number of subjects analysed
    474
    501
    Units: participants
    31
    75
    No statistical analyses for this end point

    Secondary: Change From Baseline in Brain Tau Load, as Measured by Tau PET Scan in a Subset of Participants

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    End point title
    		 Change From Baseline in Brain Tau Load, as Measured by Tau PET Scan in a Subset of Participants
    End point description
    Change in tau load represents amount of neurofibrillary tau pathology present in brain assessed using PET Scan. [18F] GTP1 (RO6880276) = tau PET radioligand. Tau load was measured using SUVR in four composite target ROIs(both left & right): Temporal composite target region included; Medial temporal composite region not including hippocampus; Frontal lobe; Parietal lobe. Inferior cerebellar grey matter = reference region for calculating SUVRs for all four target regionsAs pre-specified in protocol/SAP single tau PET substudy analyzed participants from 2 studies i.e. WN29922 & WN39658, hence data for Tau PET was analyzed at pooled level of WN29922 &WN39658. These studies had identical study design &enrolled an Early AD population. Tau-PET-mITT analysis set= all participants in ITT set who participated in Tau PET sub-study & who had at least one Tau PET scan with valid quantitative measurement & who did not withdraw from Tau PET substudy before randomization.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 116
    End point values
    		 Placebo: DBT Gantenerumab: DBT
    Number of subjects analysed
    29
    48
    Units: SUVR
    arithmetic mean (standard error)
        ROI: Temporal Composite Region
    0.12 ± 0.018
    0.13 ± 0.014
        ROI: Medial Temporal Composite Region
    0.08 ± 0.014
    0.09 ± 0.011
        ROI: Frontal Lobe
    0.08 ± 0.012
    0.08 ± 0.009
        ROI: Parietal Lobe
    0.09 ± 0.020
    0.09 ± 0.016
    Statistical analysis title
    		 Placebo: DBT, Gantenerumab: DBT
    Statistical analysis description
    Temporal Composite Region: Change from BL was calculated based on mixed-effect model of repeated measure which included the following covariates and stratification factors = Baseline + APOE e4 status + Study + Analysis Visit + Treatment + Treatment*Analysis Visit + Analysis Visit*Baseline.
    Comparison groups
    Placebo: DBT v Gantenerumab: DBT
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7816
    Method
    		 Mixed Model for Repeated Measures
    Parameter type
    		 Difference in adjusted mean
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.023
    Statistical analysis title
    		 Placebo: DBT, Gantenerumab: DBT
    Statistical analysis description
    Parietal Lobe: Change from BL was calculated based on mixed-effect model of repeated measure which included the following covariates and stratification factors = Baseline + APOE e4 status + Study + Analysis Visit + Treatment + Treatment*Analysis Visit + Analysis Visit*Baseline.
    Comparison groups
    Placebo: DBT v Gantenerumab: DBT
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9022
    Method
    		 Mixed Model for Repeated Measures
    Parameter type
    		 Difference in adjusted means
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    		 Frontal Lobe: Placebo: DBT, Gantenerumab: DBT
    Statistical analysis description
    Frontal Lobe: Change from BL was calculated based on mixed-effect model of repeated measure which included the following covariates and stratification factors = Baseline + APOE e4 status + Study + Analysis Visit + Treatment + Treatment*Analysis Visit + Analysis Visit*Baseline.
    Comparison groups
    Placebo: DBT v Gantenerumab: DBT
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7754
    Method
    		 Mixed Model for Repeated Measures
    Parameter type
    		 Difference in adjusted means
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03
         upper limit
    		 0.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.015
    Statistical analysis title
    		 Placebo: DBT, Gantenerumab: DBT
    Statistical analysis description
    Medial Temporal Composite Region: Change from BL was calculated based on mixed-effect model of repeated measure which included the following covariates and stratification factors = Baseline + APOE e4 status + Study + Analysis Visit + Treatment + Treatment*Analysis Visit + Analysis Visit*Baseline.
    Comparison groups
    Placebo: DBT v Gantenerumab: DBT
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6203
    Method
    		 Mixed Model for Repeated Measures
    Parameter type
    		 Difference in adjusted means
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03
         upper limit
    		 0.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.018

    Secondary: DBT Period: Percent Change From Baseline in Cerebrospinal Fluid (CSF) Marker of Disease in a Subset of Participants - Neurofilament Light Chain (NFL)

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    End point title
    		 DBT Period: Percent Change From Baseline in Cerebrospinal Fluid (CSF) Marker of Disease in a Subset of Participants - Neurofilament Light Chain (NFL)
    End point description
    NFL is a neuronal cytoplasmic protein highly expressed in large, myelinated axons. Its levels increase in CSF and blood proportionally to the degree of axonal damage in a variety of neurological disorders, including AD. CSF modified ITT analysis set included all participants in the ITT analysis set who had at least one valid quantitative CSF measurement. Overall number analyzed is the number of participants with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 116
    End point values
    		 Placebo: DBT Gantenerumab: DBT
    Number of subjects analysed
    72
    74
    Units: percent change in NFL
        geometric mean (confidence interval 95%)
    25.5 (15.83 to 35.97)
    8.9 (0.60 to 17.83)
    Statistical analysis title
    		 Placebo: DBT vs Gantenerumab: DBT
    Comparison groups
    Placebo: DBT v Gantenerumab: DBT
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.014
    Method
    		 ANCOVA
    Parameter type
    		 Percent Difference in Geometric Mean
    Point estimate
    -13.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.51
         upper limit
    		 -2.87

    Secondary: DBT Period: Percent Change From Baseline in CSF Marker of Disease in a Subset of Participants - Neurogranin

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    End point title
    		 DBT Period: Percent Change From Baseline in CSF Marker of Disease in a Subset of Participants - Neurogranin
    End point description
    CSF modified ITT analysis set included all participants in the ITT analysis set who had at least one valid quantitative CSF measurement. Overall number analyzed is the number of participants with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 116
    End point values
    		 Placebo: DBT Gantenerumab: DBT
    Number of subjects analysed
    72
    72
    Units: percent change in neurograinin
        geometric mean (confidence interval 95%)
    -6.1 (-11.99 to 0.12)
    -19.6 (-24.66 to -14.30)
    Statistical analysis title
    		 Placebo: DBT vs Gantenerumab: DBT
    Comparison groups
    Placebo: DBT v Gantenerumab: DBT
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Percent Difference in Geometric Mean
    Point estimate
    -6.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.88
         upper limit
    		 -2.87

    Secondary: DBT Period: Percent Change From Baseline in CSF Marker of Disease in a Subset of Participants - Total Tau (tTau)

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    End point title
    		 DBT Period: Percent Change From Baseline in CSF Marker of Disease in a Subset of Participants - Total Tau (tTau)
    End point description
    CSF biomarker tTau has been considered as a general marker of neurodegeneration. CSF phospho-tau is an indicator of neuronal injury and neurodegeneration. CSF modified ITT analysis set included all participants in the ITT analysis set who had at least one valid quantitative CSF measurement. Overall number analysed is the number of participants with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 116
    End point values
    		 Placebo: DBT Gantenerumab: DBT
    Number of subjects analysed
    72
    71
    Units: percent change in tTau
        geometric mean (confidence interval 95%)
    1.8 (-4.46 to 8.45)
    -16.4 (-21.55 to -10.87)
    Statistical analysis title
    		 Placebo: DBT, Gantenerumab: DBT
    Comparison groups
    Placebo: DBT v Gantenerumab: DBT
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Confidence interval

    Secondary: DBT Period: Percent Change From Baseline in CSF Marker of Disease in a Subset of Participants - Phosphorylated Tau (pTau-181)

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    End point title
    		 DBT Period: Percent Change From Baseline in CSF Marker of Disease in a Subset of Participants - Phosphorylated Tau (pTau-181)
    End point description
    CSF phospho-tau is an indicator of neuronal injury and neurodegeneration. CSF biomarker tTau has been considered as a general marker of neurodegeneration. An elevation in levels of pTau species, is thought to be a marker for progressive cellular degeneration in AD. CSF modified ITT analysis set included all participants in the ITT analysis set who had at least one valid quantitative CSF measurement. Overall number analysed is the number of participants with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 116
    End point values
    		 Placebo: DBT Gantenerumab: DBT
    Number of subjects analysed
    71
    70
    Units: percent change in pTau-181
        geometric mean (confidence interval 95%)
    0.1 (-6.50 to 7.16)
    -20.9 (-26.17 to -15.31)
    Statistical analysis title
    		 Placebo: DBT, Gantenerumab: DBT
    Comparison groups
    Placebo: DBT v Gantenerumab: DBT
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    DBT Period: Day 1 to 14 weeks post last dose of study drug (up to 128 weeks); OLE Period: Day 1 (OLE) to 14 weeks post last OLE dose (up to 48 weeks) Deaths: DBT: Day 1 to end of study (approx. 164 weeks); OLE: OLE Day 1 to end of study (approx. 86 weeks
    Adverse event reporting additional description
    Safety-evaluable set=all participants randomized during global phase who received at least one dose of study drug.3 participants in placebo received at least one dose of gantenerumab &were represented in gantenerumab arm;OLE safety set=all participants randomized during global enrollment &who received at least one dose of drug &entered OLE period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Placebo: DBT
    Reporting group description
    		 Participants received, gantenerumab matching placebo, SC injections, Q4W up to Week 36 and then Q2W up to Week 114 of the DBT period.

    Reporting group title
    Gantenerumab (DBT) to Gantenerumab: OLE
    Reporting group description
    		 Participants who received gantenerumab in the DBT period continued receiving gantenerumab, SC injections, 510 mg, Q2W up to Week 34 of the OLE period.

    Reporting group title
    Placebo (DBT) to Gantenerumab: OLE
    Reporting group description
    		 Participants who received gantenerumab matching placebo in the DBT period received gantenerumab SC injections with gradual up titration starting at a dose of 120 mg, Q4W for 3 doses, followed by 255 mg, Q4W for 3 doses, and then at a dose of 510 mg, Q4W up to Week 34 of the OLE period. To maintain the blind to previous treatment assignment, participants received Q2W, SC injections, with alternate doses containing gantenerumab matching placebo.

    Reporting group title
    Gantenerumab: DBT
    Reporting group description
    		 Participants received gantenerumab, SC injections with gradual up-titration starting at a dose of 120 mg, Q4W for 3 doses, followed by 255 mg, Q4W for 3 doses, and 510 mg, Q4W for 3 doses. Following this, from Week 36 onwards, participants received gantenerumab, SC injections, at the a dose of 510 mg, Q2W up to Week 114 of the DBT period.

    Serious adverse events
    		 Placebo: DBT Gantenerumab (DBT) to Gantenerumab: OLE Placebo (DBT) to Gantenerumab: OLE Gantenerumab: DBT
    Total subjects affected by serious adverse events
         subjects affected / exposed
    63 / 474 (13.29%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    61 / 501 (12.18%)
         number of deaths (all causes)
    5
    0
    0
    7
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial adenocarcinoma
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Invasive breast carcinoma
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer metastatic
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Ureteric cancer
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Deep vein thrombosis
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Venous thrombosis limb
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    2 / 501 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    2 / 474 (0.42%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Nasal polyps
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Dyspnoea
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Haemothorax
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcoholism
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Delusion
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    2 / 501 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    SARS-CoV-2 test positive
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Femoral neck fracture
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    0 / 501 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Avulsion fracture
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Back injury
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    5 / 474 (1.05%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    3 / 501 (0.60%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acetabulum fracture
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Head injury
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Hip fracture
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    2 / 501 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Multiple injuries
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Humerus fracture
         subjects affected / exposed
    2 / 474 (0.42%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Radius fracture
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    2 / 474 (0.42%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Road traffic accident
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic fracture
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    2 / 501 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    2 / 474 (0.42%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Acute myocardial infarction
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    2 / 501 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bundle branch block left
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Myocardial infarction
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Chronic coronary syndrome
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Coronary artery disease
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus arrhythmia
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Focal dyscognitive seizures
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    2 / 501 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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 haemorrhage
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Peripheral paralysis
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Ischaemic stroke
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    2 / 501 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Normal pressure hydrocephalus
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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 haematoma
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertebrobasilar stroke
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 474 (0.42%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    3 / 474 (0.63%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    2 / 501 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Speech disorder
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Seizure
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    2 / 501 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertigo positional
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Vestibular disorder
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal vein occlusion
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Large intestine polyp
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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 haemorrhage
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Intestinal perforation
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Constipation
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Small intestinal obstruction
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Ureterolithiasis
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 474 (0.42%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Spondylitis
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Infections and infestations
    Chronic sinusitis
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Appendicitis perforated
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asymptomatic COVID-19
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    3 / 474 (0.63%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    3 / 501 (0.60%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    COVID-19 pneumonia
         subjects affected / exposed
    2 / 474 (0.42%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocarditis bacterial
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Helicobacter gastritis
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Labyrinthitis
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Sepsis
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Pneumonia
         subjects affected / exposed
    2 / 474 (0.42%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    4 / 501 (0.80%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Pyelonephritis
         subjects affected / exposed
    2 / 474 (0.42%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Suspected COVID-19
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    2 / 501 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 474 (0.63%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    4 / 501 (0.80%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Dehydration
         subjects affected / exposed
    2 / 474 (0.42%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 501 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo: DBT Gantenerumab (DBT) to Gantenerumab: OLE Placebo (DBT) to Gantenerumab: OLE Gantenerumab: DBT
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    296 / 474 (62.45%)
    6 / 14 (42.86%)
    8 / 13 (61.54%)
    358 / 501 (71.46%)
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    1 / 474 (0.21%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    4 / 501 (0.80%)
         occurrences all number
    1
    1
    0
    4
    Hypertension
         subjects affected / exposed
    35 / 474 (7.38%)
    0 / 14 (0.00%)
    2 / 13 (15.38%)
    34 / 501 (6.79%)
         occurrences all number
    40
    0
    2
    38
    Varicose vein
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    1 / 501 (0.20%)
         occurrences all number
    0
    0
    1
    1
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    31 / 474 (6.54%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    75 / 501 (14.97%)
         occurrences all number
    58
    5
    0
    319
    Fatigue
         subjects affected / exposed
    12 / 474 (2.53%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    15 / 501 (2.99%)
         occurrences all number
    15
    1
    0
    17
    Reproductive system and breast disorders
    Pruritus genital
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 501 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    4 / 474 (0.84%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    5 / 501 (1.00%)
         occurrences all number
    4
    1
    0
    6
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    2 / 474 (0.42%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    0 / 501 (0.00%)
         occurrences all number
    4
    0
    1
    0
    Anxiety
         subjects affected / exposed
    22 / 474 (4.64%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    26 / 501 (5.19%)
         occurrences all number
    23
    0
    0
    31
    Confusional state
         subjects affected / exposed
    5 / 474 (1.05%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    13 / 501 (2.59%)
         occurrences all number
    6
    0
    1
    14
    Investigations
    Blood pressure diastolic decreased
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 501 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Skin abrasion
         subjects affected / exposed
    9 / 474 (1.90%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    5 / 501 (1.00%)
         occurrences all number
    12
    0
    1
    8
    Periorbital haematoma
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    0 / 501 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Head injury
         subjects affected / exposed
    7 / 474 (1.48%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    6 / 501 (1.20%)
         occurrences all number
    7
    0
    1
    6
    Fall
         subjects affected / exposed
    47 / 474 (9.92%)
    1 / 14 (7.14%)
    2 / 13 (15.38%)
    47 / 501 (9.38%)
         occurrences all number
    58
    1
    3
    74
    Bone fissure
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences all number
    0
    1
    0
    1
    Skin laceration
         subjects affected / exposed
    9 / 474 (1.90%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    10 / 501 (2.00%)
         occurrences all number
    10
    0
    1
    15
    Spinal compression fracture
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    2 / 501 (0.40%)
         occurrences all number
    0
    1
    0
    2
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    2 / 501 (0.40%)
         occurrences all number
    1
    0
    1
    2
    Nervous system disorders
    Amyloid related imaging abnormality-microhaemorrhages and haemosiderin deposits
         subjects affected / exposed
    2 / 474 (0.42%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    33 / 501 (6.59%)
         occurrences all number
    2
    0
    0
    35
    Amyloid related imaging abnormality-oedema/effusion
         subjects affected / exposed
    12 / 474 (2.53%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    114 / 501 (22.75%)
         occurrences all number
    15
    1
    0
    162
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    4 / 501 (0.80%)
         occurrences all number
    0
    1
    0
    5
    Dizziness
         subjects affected / exposed
    29 / 474 (6.12%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    39 / 501 (7.78%)
         occurrences all number
    36
    0
    1
    54
    Headache
         subjects affected / exposed
    50 / 474 (10.55%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    64 / 501 (12.77%)
         occurrences all number
    64
    0
    0
    118
    Syncope
         subjects affected / exposed
    9 / 474 (1.90%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    14 / 501 (2.79%)
         occurrences all number
    9
    0
    1
    17
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    13 / 474 (2.74%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    22 / 501 (4.39%)
         occurrences all number
    20
    0
    1
    38
    Diarrhoea
         subjects affected / exposed
    25 / 474 (5.27%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    39 / 501 (7.78%)
         occurrences all number
    33
    1
    0
    44
    Constipation
         subjects affected / exposed
    15 / 474 (3.16%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    11 / 501 (2.20%)
         occurrences all number
    16
    0
    1
    12
    Oesophagitis
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    1 / 501 (0.20%)
         occurrences all number
    0
    1
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    3 / 474 (0.63%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    3 / 501 (0.60%)
         occurrences all number
    3
    0
    1
    3
    Arthralgia
         subjects affected / exposed
    42 / 474 (8.86%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    39 / 501 (7.78%)
         occurrences all number
    49
    0
    0
    47
    Back pain
         subjects affected / exposed
    32 / 474 (6.75%)
    1 / 14 (7.14%)
    1 / 13 (7.69%)
    29 / 501 (5.79%)
         occurrences all number
    39
    1
    1
    33
    Osteoporosis
         subjects affected / exposed
    4 / 474 (0.84%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    6 / 501 (1.20%)
         occurrences all number
    4
    1
    0
    6
    Pain in extremity
         subjects affected / exposed
    25 / 474 (5.27%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    15 / 501 (2.99%)
         occurrences all number
    27
    0
    0
    18
    Infections and infestations
    Dacryocystitis
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    1 / 501 (0.20%)
         occurrences all number
    0
    0
    2
    1
    COVID-19
         subjects affected / exposed
    30 / 474 (6.33%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    36 / 501 (7.19%)
         occurrences all number
    31
    1
    0
    36
    Oral candidiasis
         subjects affected / exposed
    2 / 474 (0.42%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    1 / 501 (0.20%)
         occurrences all number
    3
    0
    1
    1
    Groin infection
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 501 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    49 / 474 (10.34%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    45 / 501 (8.98%)
         occurrences all number
    62
    0
    2
    53
    Urinary tract infection
         subjects affected / exposed
    26 / 474 (5.49%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    32 / 501 (6.39%)
         occurrences all number
    38
    1
    0
    34
    Upper respiratory tract infection
         subjects affected / exposed
    24 / 474 (5.06%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    29 / 501 (5.79%)
         occurrences all number
    26
    0
    0
    38
    Suspected COVID-19
         subjects affected / exposed
    5 / 474 (1.05%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    8 / 501 (1.60%)
         occurrences all number
    5
    1
    0
    8
    Pharyngitis
         subjects affected / exposed
    5 / 474 (1.05%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    4 / 501 (0.80%)
         occurrences all number
    7
    0
    1
    4
    Metabolism and nutrition disorders
    Vitamin D deficiency
         subjects affected / exposed
    4 / 474 (0.84%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    2 / 501 (0.40%)
         occurrences all number
    4
    0
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Feb 2018
    The purpose of this protocol amendment was to present the results of the relative bioavailability study (WP40052) and to adjust the dosing regimen of GRADUATE II according to these results. No participants were enrolled in the study at the time of implementation of the updated protocol. In addition, the entry criteria of the study population were revised to increase the homogeneity of the study population and to better target the appropriate study population.
    21 Jan 2020
    The purpose of this protocol update was to update the sample size of the study. While protocol wording allowed an increase in total enrollment up to 1,140 participants based on factors external to the study, the Sponsor clarified that upon initial learnings from external studies, a decision was made to increase the power of the study. Thus, the sample size was increased from 760 participants to 1,016 (508 patients randomized to gantenerumab and 508 randomized to placebo). In addition, the protocol was amended to allow the first patients enrolled in the study to enroll in an OLE as planned. Details on this procedure and the OLE schedule of activities was also added.
    28 May 2020
    The purpose of this protocol amendment was to respond to the COVID-19 pandemic due to the SARS-CoV-2 virus. This amendment extended the double-blind treatment period (originally 104 weeks) by 12 weeks in order to mitigate the impact of missed administrations and preserve the scientific integrity of the study by enabling more participants to receive study drug at the initially intended exposures. The continuing impact of the COVID-19 pandemic on study procedures was closely monitored and, if there were greater than anticipated disruptions to study drug administration, the amendment also allowed the option of further extending the double blind treatment period by another 12 weeks (to 128 weeks). For the same reason, the upper limit of the sample size was increased from 1140 to 1322 participants. This further extension of the double-blind treatment period to 128 weeks was not implemented, nor was the sample size increased.
    04 Aug 2021
    The purpose of this protocol amendment was to update the list of exploratory endpoints for the double-blind treatment period of the study and introduce the estimands approachfor the primary analysis to align with the addendum to ICH E9 guidance (ICH E9). An update of the overall benefit-risk summary to address the impact of the COVID-19 pandemic was also made.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    11 Nov 2022
    Following results of a pre-planned primary analysis of the safety and efficacy of Gant in Graduate I&II (WN29922/WN39658) a decision was made to terminate development of Gantenerumab for treatment of prodromal/mild/early stage Alzheimer's disease.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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