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    Clinical Trial Results:
    An Open-Label, Multicenter, Rollover Study to Evaluate the Safety, Tolerability, and Efficacy of Long-Term Gantenerumab Administration in Participants with Alzheimer’s Disease

    Summary
    EudraCT number
    2020-000766-42
    Trial protocol
    GB   DK   PT   PL   HU   DE   FR   IT   LT   NL   BE   FI   HR  
    Global end of trial date
    06 Mar 2023

    Results information
    Results version number
    v1(current)
    This version publication date
    20 Mar 2024
    First version publication date
    20 Mar 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    WN42171
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04374253
    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
    06 Mar 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Mar 2023
    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 safety and tolerability of long-term gantenerumab administered by subcutaneous (SC) injection.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form (ICF).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    26 Jan 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 38
    Country: Number of subjects enrolled
    Australia: 48
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Brazil: 15
    Country: Number of subjects enrolled
    Canada: 36
    Country: Number of subjects enrolled
    Chile: 37
    Country: Number of subjects enrolled
    China: 2
    Country: Number of subjects enrolled
    Germany: 73
    Country: Number of subjects enrolled
    Denmark: 16
    Country: Number of subjects enrolled
    Spain: 239
    Country: Number of subjects enrolled
    Finland: 17
    Country: Number of subjects enrolled
    France: 33
    Country: Number of subjects enrolled
    United Kingdom: 34
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Italy: 58
    Country: Number of subjects enrolled
    Japan: 115
    Country: Number of subjects enrolled
    Korea, Republic of: 45
    Country: Number of subjects enrolled
    Lithuania: 11
    Country: Number of subjects enrolled
    Mexico: 37
    Country: Number of subjects enrolled
    Netherlands: 7
    Country: Number of subjects enrolled
    Peru: 28
    Country: Number of subjects enrolled
    Poland: 89
    Country: Number of subjects enrolled
    Portugal: 27
    Country: Number of subjects enrolled
    Russian Federation: 57
    Country: Number of subjects enrolled
    Sweden: 17
    Country: Number of subjects enrolled
    Türkiye: 1
    Country: Number of subjects enrolled
    Taiwan: 24
    Country: Number of subjects enrolled
    United States: 266
    Worldwide total number of subjects
    1381
    EEA total number of subjects
    598
    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)
    186
    From 65 to 84 years
    1116
    85 years and over
    79

    Subject disposition

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    Recruitment
    Recruitment details
    Participants took part at 258 investigative centers across 28 countries from 26 January 2021 to 06 March 2023. A total of 1381 participants who completed either double-blind (DB) part or open-label extension (OLE) part in GRADUATE parent studies WN29922 (NCT03444870) or WN39658 (NCT03443973) were enrolled to receive open-label gantenerumab.

    Pre-assignment
    Screening details
    Participants who completed DB and OLE part received gantenerumab approximately 2 weeks after OLE Week 34 visit or final OLE dose visit in the parent study. Participants who completed DB part and did not enter the OLE part received gantenerumab approximately 2 weeks after the Week 116 visit of the parent study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo: Participated in Graduate OLE
    Arm description
    Participants treated with placebo in the DB part and who completed the DB and OLE up titration in study WN29922 (GRADUATE I) or WN39658 (GRADUATE II), continued receiving open-label gantenerumab, 510 milligrams (mg), SC, every two weeks (Q2W).
    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 at a dose of 510 mg, Q2W.

    Arm title
    Placebo: No Participation in Graduate OLE
    Arm description
    Participants treated with placebo in the DB part and who did not enter the OLE part of study WN29922 (GRADUATE I) or WN39658 (GRADUATE II) received gantenerumab SC injections with gradual up titration starting at a dose of 120 mg, every four weeks (Q4W) for 3 doses, followed by 255 mg, Q4W for 3 doses, and then at a dose of 510 mg, Q4W for 3 doses before receiving open-label gantenerumab, 510 mg SC injections, Q2W. 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 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 then at a dose of 510 mg, Q4W up 3 doses before receiving open label gantenerumab, 510 mg SC injections, Q2W. To maintain the blind to previous treatment assignment, participants received Q2W, SC injections, with alternate doses containing gantenerumab matching placebo.

    Arm title
    Gantenerumab: Participated in Graduate OLE
    Arm description
    Participants treated with gantenerumab in the DB part and who completed the DB and OLE part of study WN29922 (GRADUATE I) or WN39658 (GRADUATE II) continued receiving open-label gantenerumab, 510 mg, SC, Q2W.
    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 at a dose of 510 mg, Q2W.

    Arm title
    Gantenerumab: No Participation in Graduate OLE
    Arm description
    Participants treated with gantenerumab in the DB part and who did not enter the OLE part of study WN29922 (GRADUATE I) or WN39658 (GRADUATE II) continued receiving open-label gantenerumab 510 mg SC, Q2W.
    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 at a dose of 510 mg, Q2W.

    Number of subjects in period 1
    Placebo: Participated in Graduate OLE Placebo: No Participation in Graduate OLE Gantenerumab: Participated in Graduate OLE Gantenerumab: No Participation in Graduate OLE
    Started
    15
    696
    28
    642
    Completed
    0
    0
    0
    0
    Not completed
    15
    696
    28
    642
         Adverse event, serious fatal
    -
    3
    1
    1
         Physician decision
    1
    10
    1
    10
         Consent withdrawn by subject
    -
    55
    3
    40
         Adverse event, non-fatal
    -
    26
    2
    12
         Reason Not Specified
    -
    8
    -
    8
         Study terminated by sponsor
    13
    593
    21
    566
         Lost to follow-up
    1
    1
    -
    2
         Protocol deviation
    -
    -
    -
    2
         Lack of efficacy
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo: Participated in Graduate OLE
    Reporting group description
    Participants treated with placebo in the DB part and who completed the DB and OLE up titration in study WN29922 (GRADUATE I) or WN39658 (GRADUATE II), continued receiving open-label gantenerumab, 510 milligrams (mg), SC, every two weeks (Q2W).

    Reporting group title
    Placebo: No Participation in Graduate OLE
    Reporting group description
    Participants treated with placebo in the DB part and who did not enter the OLE part of study WN29922 (GRADUATE I) or WN39658 (GRADUATE II) received gantenerumab SC injections with gradual up titration starting at a dose of 120 mg, every four weeks (Q4W) for 3 doses, followed by 255 mg, Q4W for 3 doses, and then at a dose of 510 mg, Q4W for 3 doses before receiving open-label gantenerumab, 510 mg SC injections, Q2W. To maintain the blind to previous treatment assignment, participants received Q2W, SC injections, with alternate doses containing gantenerumab matching placebo.

    Reporting group title
    Gantenerumab: Participated in Graduate OLE
    Reporting group description
    Participants treated with gantenerumab in the DB part and who completed the DB and OLE part of study WN29922 (GRADUATE I) or WN39658 (GRADUATE II) continued receiving open-label gantenerumab, 510 mg, SC, Q2W.

    Reporting group title
    Gantenerumab: No Participation in Graduate OLE
    Reporting group description
    Participants treated with gantenerumab in the DB part and who did not enter the OLE part of study WN29922 (GRADUATE I) or WN39658 (GRADUATE II) continued receiving open-label gantenerumab 510 mg SC, Q2W.

    Reporting group values
    Placebo: Participated in Graduate OLE Placebo: No Participation in Graduate OLE Gantenerumab: Participated in Graduate OLE Gantenerumab: No Participation in Graduate OLE Total
    Number of subjects
    15 696 28 642 1381
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    76.7 ± 7.8 73.6 ± 7.4 74.1 ± 8.0 73.0 ± 7.7 -
    Sex: Female, Male
    Units: participants
        Female
    11 387 14 382 794
        Male
    4 309 14 260 587
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 25 4 18 47
        Asian
    1 104 1 87 193
        Native Hawaiian or Other Pacific Islander
    0 0 0 0 0
        Black or African American
    0 6 0 4 10
        White
    14 549 22 518 1103
        More than one race
    0 0 0 0 0
        Unknown or Not Reported
    0 12 1 15 28
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    6 116 14 89 225
        Not Hispanic or Latino
    9 576 14 548 1147
        Unknown or Not Reported
    0 4 0 5 9

    End points

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    End points reporting groups
    Reporting group title
    Placebo: Participated in Graduate OLE
    Reporting group description
    Participants treated with placebo in the DB part and who completed the DB and OLE up titration in study WN29922 (GRADUATE I) or WN39658 (GRADUATE II), continued receiving open-label gantenerumab, 510 milligrams (mg), SC, every two weeks (Q2W).

    Reporting group title
    Placebo: No Participation in Graduate OLE
    Reporting group description
    Participants treated with placebo in the DB part and who did not enter the OLE part of study WN29922 (GRADUATE I) or WN39658 (GRADUATE II) received gantenerumab SC injections with gradual up titration starting at a dose of 120 mg, every four weeks (Q4W) for 3 doses, followed by 255 mg, Q4W for 3 doses, and then at a dose of 510 mg, Q4W for 3 doses before receiving open-label gantenerumab, 510 mg SC injections, Q2W. To maintain the blind to previous treatment assignment, participants received Q2W, SC injections, with alternate doses containing gantenerumab matching placebo.

    Reporting group title
    Gantenerumab: Participated in Graduate OLE
    Reporting group description
    Participants treated with gantenerumab in the DB part and who completed the DB and OLE part of study WN29922 (GRADUATE I) or WN39658 (GRADUATE II) continued receiving open-label gantenerumab, 510 mg, SC, Q2W.

    Reporting group title
    Gantenerumab: No Participation in Graduate OLE
    Reporting group description
    Participants treated with gantenerumab in the DB part and who did not enter the OLE part of study WN29922 (GRADUATE I) or WN39658 (GRADUATE II) continued receiving open-label gantenerumab 510 mg SC, Q2W.

    Subject analysis set title
    Gantenerumab: Participated in Graduate OLE
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants treated with gantenerumab in the DB part and who completed the DB and OLE part of study WN29922 (GRADUATE I) or WN39658 (GRADUATE II) continued receiving open-label gantenerumab, 510 mg, SC, Q2W.

    Subject analysis set title
    Gantenerumab: No Participation in Graduate OLE
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants treated with gantenerumab in the DB part and who did not enter the OLE part of Study WN29922 (GRADUATE I) or WN39658 (GRADUATE II), continued receiving open-label gantenerumab 510 mg SC, Q2W.

    Primary: Number of Participants With at Least One Adverse Event (AE) and Serious Adverse Event (SAE)

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    End point title
    Number of Participants With at Least One Adverse Event (AE) and Serious Adverse Event (SAE) [1] [2]
    End point description
    AE is any untoward medical occurrence in clinical investigation participant administered a pharmaceutical product, regardless of casual attribution. SAE is any fatal AE, life threatening, requires or prolongs inpatient hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study drug or a significant medical event in investigator’s judgment. Safety evaluable (SE) analysis set included all participants enrolled who received at least one dose of study drug in this study or in OLE part of parent studies (GRADUATE I or GRADUATE II). 6 participants randomized to placebo arm during double-blind treatment in parent studies received at least one dose of gantenerumab and were considered in gantenerumab arm for safety evaluable set. First dosing visit in OLE (first dosing in current study or first dosing in OLE period of parent GRADUATE studies) was considered as baseline (OLE Day 1).
    End point type
    Primary
    End point timeframe
    From Baseline (OLE Day 1) up to 14 weeks after the last dose (up to 134 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: Only descriptive statistics was planned for this endpoint.
    [2] - 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: Data for all arms of the study is reported. Due to difference in overall number analyzed, arms: 'Gantenerumab: Participated in Graduate OLE' and 'Gantenerumab: No Participation in Graduate OLE' are added as subject analysis set.
    End point values
    Placebo: Participated in Graduate OLE Placebo: No Participation in Graduate OLE Gantenerumab: Participated in Graduate OLE Gantenerumab: No Participation in Graduate OLE
    Number of subjects analysed
    14
    691
    29
    647
    Units: participants
        AEs
    13
    510
    25
    487
        SAEs
    2
    72
    4
    54
    No statistical analyses for this end point

    Primary: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using Columbia–Suicide Severity Rating Scale (C-SSRS) Score

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    End point title
    Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using Columbia–Suicide Severity Rating Scale (C-SSRS) Score [3] [4]
    End point description
    C-SSRS assesses lifetime suicidality of participant (baseline) & any new instances of suicidality (since last visit). Structured interview prompts recollection of suicidal ideation (intensity of ideation, behavior, & attempts with actual/potential lethality). Categories have yes/no responses, include Wish to be Dead; Non-specific Active Suicidal Thoughts; Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act; Active Suicidal Ideation with Some Intent to Act, without Specific Plan; Active Suicidal Ideation with Specific Plan and Intent, Preparatory Acts and Behavior; Aborted/Interrupted Attempt; Actual Attempt (non-fatal); Completed Suicide.Suicidal ideation/behavior=“yes” to any of listed categories. Score 0= no suicide risk. Score 1 or higher=suicidal ideation or behavior. Categories with non-zero values are only reported here. First dosing visit in OLE (first dosing in current study or OLE period of parent GRADUATE studies)=baseline (OLE Day 1).SE analysis set.
    End point type
    Primary
    End point timeframe
    From Baseline (OLE Day 1) up to 14 weeks after the last dose (up to 134 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: Only descriptive statistics was planned for this endpoint.
    [4] - 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: Data for all arms of the study is reported. Due to difference in overall number analyzed, arms: 'Gantenerumab: Participated in Graduate OLE' is added as subject analysis set.
    End point values
    Placebo: Participated in Graduate OLE Placebo: No Participation in Graduate OLE Gantenerumab: No Participation in Graduate OLE Gantenerumab: Participated in Graduate OLE
    Number of subjects analysed
    14
    631
    588
    29
    Units: participants
        Suicidal Ideation (SI): Passive
    1
    11
    11
    1
        SI: Active-Nonspecific (No Intent, or Plan)
    0
    3
    2
    0
        SI: Active-Method, but No Intent or Plan
    1
    0
    0
    1
        Suicidal Ideation: No event
    12
    617
    575
    27
        Suicidal Behavior: Aborted Attempt
    0
    1
    0
    0
        Suicidal Behavior: Preparatory Actions
    0
    1
    0
    0
        Suicidal Behavior: No event
    14
    629
    586
    29
        Self-Injurious Behavior - No Suicidal Intent
    0
    2
    0
    0
        Self-Injurious Behavior Without Intent: No event
    14
    629
    588
    29
        Suicidal Behaviour: Completed Suicide
    0
    0
    2
    0
    No statistical analyses for this end point

    Primary: Number of Participants with at Least One Amyloid-Related Imaging Abnormalities-Edema (ARIA-E) Confirmed by MRI

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    End point title
    Number of Participants with at Least One Amyloid-Related Imaging Abnormalities-Edema (ARIA-E) Confirmed by MRI [5] [6]
    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. The first dosing visit in the OLE (first dosing in current study or first dosing in the OLE period of the parent GRADUATE studies) was considered as baseline (OLE Day 1). M-SE analysis set included all participants in the SE analysis set who had at least one post-baseline safety MRI scan.
    End point type
    Primary
    End point timeframe
    From Baseline (OLE Day 1) up to 14 weeks after the last dose (up to 134 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: Only descriptive statistics was planned for this endpoint.
    [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: Data for all arms of the study is reported. Due to difference in overall number analyzed, arms: 'Gantenerumab: Participated in Graduate OLE' and 'Gantenerumab: No Participation in Graduate OLE' are added as subject analysis set.
    End point values
    Placebo: Participated in Graduate OLE Placebo: No Participation in Graduate OLE Gantenerumab: No Participation in Graduate OLE Gantenerumab: Participated in Graduate OLE
    Number of subjects analysed
    14
    671
    627
    29
    Units: participants
    6
    104
    27
    5
    No statistical analyses for this end point

    Primary: Number of Participants with at Least One Amyloid-Related Imaging Abnormalities-Haemosiderin Deposition (ARIA-H) Confirmed by MRI

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    End point title
    Number of Participants with at Least One Amyloid-Related Imaging Abnormalities-Haemosiderin Deposition (ARIA-H) Confirmed by MRI [7] [8]
    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. The first dosing visit in the OLE (first dosing in current study or first dosing in the OLE period of the parent GRADUATE studies) was considered as baseline (OLE Day 1). M-SE analysis set included all participants in the SE analysis set who had at least one post-baseline safety MRI scan.
    End point type
    Primary
    End point timeframe
    From Baseline (OLE Day 1) up to 14 weeks after the last dose (up to 134 weeks)
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics was planned for this endpoint.
    [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: Data for all arms of the study is reported. Due to difference in overall number analyzed, arms: 'Gantenerumab: Participated in Graduate OLE' and 'Gantenerumab: No Participation in Graduate OLE' are added as subject analysis set.
    End point values
    Placebo: Participated in Graduate OLE Placebo: No Participation in Graduate OLE Gantenerumab: No Participation in Graduate OLE Gantenerumab: Participated in Graduate OLE
    Number of subjects analysed
    14
    671
    627
    29
    Units: participants
    3
    85
    40
    4
    No statistical analyses for this end point

    Primary: Number of Participants with Injection-Site Reactions (ISRs)

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    End point title
    Number of Participants with Injection-Site Reactions (ISRs) [9] [10]
    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. SE analysis set included all participants enrolled who received at least one dose of study drug in this study or in the OLE part of the parent studies (GRADUATE I or GRADUATE II). Six participants randomized to placebo arm during the double-blind treatment in the parent studies received at least one dose of gantenerumab and were considered in the gantenerumab arm for safety evaluable set. The first dosing visit in the OLE (first dosing in current study or first dosing in the OLE period of the parent GRADUATE studies) was considered as baseline (OLE Day 1).
    End point type
    Primary
    End point timeframe
    From Baseline (OLE Day 1) up to 14 weeks after the last dose (up to 134 weeks)
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics was planned for this endpoint.
    [10] - 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: Data for all arms of the study is reported. Due to difference in overall number analyzed, arms: 'Gantenerumab: Participated in Graduate OLE' and 'Gantenerumab: No Participation in Graduate OLE' are added as subject analysis set.
    End point values
    Placebo: Participated in Graduate OLE Placebo: No Participation in Graduate OLE Gantenerumab: Participated in Graduate OLE Gantenerumab: No Participation in Graduate OLE
    Number of subjects analysed
    14
    691
    29
    647
    Units: participants
    3
    63
    1
    80
    No statistical analyses for this end point

    Primary: Number of Participants With at Least One Adverse Event of Special Interest (AESI)

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    End point title
    Number of Participants With at Least One Adverse Event of Special Interest (AESI) [11] [12]
    End point description
    An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of casual attribution. AEs that were considered to be of special interest for this study included cases of potential drug-induced liver injury that include an elevated ALT or AST in combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law and suspected transmission of an infectious agent by the study drug. Participants in SE analysis set were analysed. Six participants randomized to placebo arm during the double-blind treatment in the parent studies received at least one dose of gantenerumab and were considered in the gantenerumab arm for safety evaluable set. The first dosing visit in the OLE (first dosing in current study or first dosing in the OLE period of the parent GRADUATE studies) was considered as baseline (OLE Day 1).
    End point type
    Primary
    End point timeframe
    From Baseline (OLE Day 1) up to 14 weeks after the last dose (up to 134 weeks)
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics was planned for this endpoint.
    [12] - 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: Data for all arms of the study is reported. Due to difference in overall number analyzed, arms: 'Gantenerumab: Participated in Graduate OLE' and 'Gantenerumab: No Participation in Graduate OLE' are added as subject analysis set.
    End point values
    Placebo: Participated in Graduate OLE Placebo: No Participation in Graduate OLE Gantenerumab: Participated in Graduate OLE Gantenerumab: No Participation in Graduate OLE
    Number of subjects analysed
    14
    691
    29
    647
    Units: participants
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Participants Who Discontinued the Study Due an AE

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    End point title
    Number of Participants Who Discontinued the Study Due an AE [13] [14]
    End point description
    An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of casual attribution. SE analysis set included all participants enrolled who received at least one dose of study drug in this study or in the OLE part of the parent studies (GRADUATE I or GRADUATE II). Six participants randomized to placebo arm during the double-blind treatment in the parent studies received at least one dose of gantenerumab and were considered in the gantenerumab arm for safety evaluable set. The first dosing visit in the OLE (first dosing in current study or first dosing in the OLE period of the parent GRADUATE studies) was considered as baseline (OLE Day 1).
    End point type
    Primary
    End point timeframe
    From Baseline (OLE Day 1) up to 14 weeks after the last dose (up to 134 weeks)
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics was planned for this endpoint.
    [14] - 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: Data for all arms of the study is reported. Due to difference in overall number analyzed, arms: 'Gantenerumab: Participated in Graduate OLE' and 'Gantenerumab: No Participation in Graduate OLE' are added as subject analysis set.
    End point values
    Placebo: Participated in Graduate OLE Placebo: No Participation in Graduate OLE Gantenerumab: Participated in Graduate OLE Gantenerumab: No Participation in Graduate OLE
    Number of subjects analysed
    14
    691
    29
    647
    Units: participants
    0
    9
    1
    7
    No statistical analyses for this end point

    Secondary: Change From Baseline Over Time in Clinical Dementia Rating – Global Score (CDR-GS)

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    End point title
    Change From Baseline Over Time in Clinical Dementia Rating – Global Score (CDR-GS)
    End point description
    CDR was derived through semi-structured interview with participant and an appropriate informant, and it rated impairment across 6 domains: memory, orientation, judgment, and problem solving, community affairs, home and hobbies, and personal care on a 5-point scale for which 0=normal, 0.5=very mild dementia, 1=mild dementia, 2=moderate dementia, and 3= severe dementia. Score range for CDR-GS is from 0 to 3 and a high score on the CDR-GS would indicate a high disease severity. A negative change from baseline indicates improvement. Participants in ITT analysis set were analysed. Overall number analyzed is number of participants with data available for analyses. Number of participants analyzed indicates number of participants with data available for analyses at specified timepoint. First dosing visit in OLE (first dosing in current study or first dosing in OLE period of parent GRADUATE studies) was considered as baseline (OLE Day 1).
    End point type
    Secondary
    End point timeframe
    Baseline (OLE Day 1), Weeks 24, 36, 52, 76 and 104
    End point values
    Placebo: Participated in Graduate OLE Placebo: No Participation in Graduate OLE Gantenerumab: Participated in Graduate OLE Gantenerumab: No Participation in Graduate OLE
    Number of subjects analysed
    15
    693
    25
    641
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change from Baseline at Week 24 (n=15,611,25,561)
    0.4 ± 0.50
    0.1 ± 0.43
    0.1 ± 0.53
    0.1 ± 0.41
        Change from Baseline at Week 36 (n=5,107,9,89)
    0.4 ± 0.55
    0.3 ± 0.55
    0.1 ± 0.42
    0.2 ± 0.47
        Change from Baseline at Week 52 (n=14,336,20,327)
    0.3 ± 0.46
    0.2 ± 0.44
    -0.1 ± 0.43
    0.2 ± 0.46
        Change from Baseline at Week 76 (n=11,169,19,161)
    0.5 ± 0.69
    0.3 ± 0.47
    0.2 ± 0.75
    0.3 ± 0.44
        Change from Baseline at Week 104 (n=5,19,13,20)
    0.6 ± 0.89
    0.6 ± 0.52
    0.2 ± 0.43
    0.3 ± 0.50
    No statistical analyses for this end point

    Secondary: Change From Baseline Over Time in Clinical Dementia Rating (CDR) – Sum of Boxes (SB)

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    End point title
    Change From Baseline Over Time in Clinical Dementia Rating (CDR) – Sum of Boxes (SB)
    End point description
    CDR rated impairment across 6 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. CDR-SB is based on summing each of 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. Overall number analyzed is the number of participants with data available for analyses. The number of participants analyzed indicates the number of participants with data available for analyses at the specified timepoint. The first dosing visit in the OLE (first dosing in current study or first dosing in the OLE period of the parent GRADUATE studies) was considered as baseline (OLE Day 1).
    End point type
    Secondary
    End point timeframe
    Baseline (OLE Day 1), Weeks 24, 36, 52, 76 and 104
    End point values
    Placebo: Participated in Graduate OLE Placebo: No Participation in Graduate OLE Gantenerumab: Participated in Graduate OLE Gantenerumab: No Participation in Graduate OLE
    Number of subjects analysed
    15
    693
    28
    641
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change from Baseline at Week 24 (n=15,611,25,561)
    2.10 ± 2.473
    0.83 ± 1.787
    1.00 ± 2.529
    0.70 ± 1.754
        Change from Baseline at Week 36 (n=5,107,9,89)
    2.90 ± 2.608
    1.39 ± 2.397
    0.72 ± 2.265
    1.11 ± 2.161
        Change from Baseline at Week 52 (n=14,336,20,327)
    2.57 ± 2.286
    1.60 ± 1.906
    0.80 ± 1.351
    1.50 ± 2.051
        Change from Baseline at Week 76 (n=11,169,19,161)
    2.68 ± 3.133
    2.20 ± 1.994
    1.95 ± 3.218
    1.97 ± 2.249
        Change from Baseline at Week 104 (n=5,19,13,20)
    3.80 ± 3.213
    3.26 ± 2.751
    1.15 ± 2.470
    1.80 ± 1.949
    No statistical analyses for this end point

    Secondary: Change From Baseline Over Time in Mini-Mental State Examination (MMSE) Score

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    End point title
    Change From Baseline Over Time in Mini-Mental State Examination (MMSE) 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. Overall number analyzed is the number of participants with data available for analyses. The number of participants analyzed indicates the number of participants with data available for analyses at the specified timepoint. The first dosing visit in the OLE (first dosing in current study or first dosing in the OLE period of the parent GRADUATE studies) was considered as baseline (OLE Day 1).
    End point type
    Secondary
    End point timeframe
    Baseline (OLE Day 1), Weeks 24, 36, 52, 76 and 104
    End point values
    Placebo: Participated in Graduate OLE Placebo: No Participation in Graduate OLE Gantenerumab: Participated in Graduate OLE Gantenerumab: No Participation in Graduate OLE
    Number of subjects analysed
    15
    694
    28
    641
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change from Baseline at Week 24 (n=15,622,27,571)
    -0.3 ± 2.41
    -1.2 ± 2.87
    -0.9 ± 2.39
    -1.1 ± 2.69
        Change from Baseline at Week 36 (n=5,111,9,93)
    -1.8 ± 3.35
    -1.6 ± 2.83
    -0.3 ± 1.66
    -1.7 ± 3.18
        Change from Baseline at Week 52 (n=15,346,21,337)
    -1.9 ± 2.94
    -2.3 ± 3.15
    -2.0 ± 3.49
    -2.1 ± 3.14
        Change from Baseline at Week 76 (n=12,173,20,165)
    -2.9 ± 3.20
    -3.2 ± 3.39
    -2.9 ± 3.97
    -3.0 ± 3.56
        Change from Baseline at Week 104 (n=5,19,14,21)
    -3.6 ± 5.13
    -4.3 ± 3.93
    -2.9 ± 3.92
    -3.0 ± 4.12
    No statistical analyses for this end point

    Secondary: Change From Baseline Over Time in Alzheimer Disease Assessment Scale-Cognition, Subscale 11 (ADAS-Cog11) Score

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    End point title
    Change From Baseline Over Time 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 Alzheimer's Disease (AD) and consisted of 11 tasks. The test included 7 performance items and 4 clinician-rated items. The total score was the sum of all 11 individual items, ranging from 0 (no impairment) to 70 (severe impairment). ITT analysis set included all enrolled participants, who received at least one dose of study drug. Participants will be analyzed by the treatment they were randomized to in the parent studies (GRADUATE I or GRADUATE II). Overall number analyzed is the number of participants with data available for analyses. The number of participants analyzed indicates the number of participants with data available for analyses at the specified timepoint. The first dosing visit in the OLE (first dosing in current study or first dosing in the OLE period of the parent GRADUATE studies) was considered as baseline (OLE Day 1).
    End point type
    Secondary
    End point timeframe
    Baseline (OLE Day 1), Weeks 24, 36, 52, 76 and 104
    End point values
    Placebo: Participated in Graduate OLE Placebo: No Participation in Graduate OLE Gantenerumab: Participated in Graduate OLE Gantenerumab: No Participation in Graduate OLE
    Number of subjects analysed
    14
    688
    28
    630
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change from Baseline at Week 24 (n=14,611,27,549)
    2.4 ± 5.56
    2.4 ± 5.47
    1.6 ± 5.29
    2.8 ± 5.22
        Change from Baseline at Week 36 (n=5,107,9,86)
    12.0 ± 10.00
    3.9 ± 6.80
    -3.7 ± 5.50
    4.0 ± 5.46
        Change from Baseline at Week 52 (n=14,332,20,326)
    5.6 ± 9.55
    3.7 ± 6.13
    1.9 ± 5.89
    4.7 ± 6.61
        Change from Baseline at Week 76 (n=11,170,20,162)
    6.6 ± 10.90
    5.9 ± 7.52
    7.0 ± 9.50
    6.1 ± 7.80
        Change from Baseline at Week 104 (n=5,19,13,22)
    8.4 ± 14.12
    7.8 ± 7.65
    3.8 ± 6.67
    8.2 ± 10.26
    No statistical analyses for this end point

    Secondary: Change From Baseline Over Time in Alzheimer Disease Assessment Scale-Cognition, Subscale 13 (ADAS-Cog13) Score

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    End point title
    Change From Baseline Over Time 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. Overall number analyzed is the number of participants with data available for analyses. The number of participants analyzed indicates the number of participants with data available for analyses at the specified timepoint. The first dosing visit in the OLE (first dosing in current study or first dosing in the OLE period of the parent GRADUATE studies) was considered as baseline (OLE Day 1).
    End point type
    Secondary
    End point timeframe
    Baseline (OLE Day 1), Weeks 24, 36, 52, 76 and 104
    End point values
    Placebo: Participated in Graduate OLE Placebo: No Participation in Graduate OLE Gantenerumab: Participated in Graduate OLE Gantenerumab: No Participation in Graduate OLE
    Number of subjects analysed
    14
    677
    28
    623
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change from Baseline at Week 24 (n=14,597,27,542)
    2.9 ± 6.29
    3.0 ± 5.73
    2.0 ± 5.53
    3.3 ± 5.45
        Change from Baseline at Week 36 (n=5,104,9,84)
    13.2 ± 11.52
    4.7 ± 7.05
    -3.4 ± 5.39
    4.7 ± 5.85
        Change from Baseline at Week 52 (n=14,325,20,319)
    6.7 ± 10.13
    4.3 ± 6.45
    2.7 ± 6.01
    5.3 ± 6.94
        Change from Baseline at Week 76 (n=11,164,20,161)
    7.9 ± 11.89
    6.8 ± 7.85
    7.7 ± 9.76
    6.7 ± 8.22
        Change from Baseline at Week 104 (n=5,19,13,22)
    10.4 ± 14.98
    8.7 ± 8.13
    4.8 ± 6.74
    8.8 ± 10.22
    No statistical analyses for this end point

    Secondary: Change From Baseline Over Time in Verbal Fluency Task Score

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    End point title
    Change From Baseline Over Time in Verbal Fluency Task 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 enrolled participants, who received at least one dose of study drug. Participants will be analyzed by the treatment they were randomized to in the parent studies (GRADUATE I or GRADUATE II). Overall number analyzed is the number of participants with data available for analyses. The number of participants analyzed indicates the number of participants with data available for analyses at the specified timepoint. The first dosing visit in the OLE (first dosing in current study or first dosing in the OLE period of the parent GRADUATE studies) was considered as baseline (OLE Day 1).
    End point type
    Secondary
    End point timeframe
    Baseline (OLE Day 1), Weeks 24, 36, 52, 76 and 104
    End point values
    Placebo: Participated in Graduate OLE Placebo: No Participation in Graduate OLE Gantenerumab: Participated in Graduate OLE Gantenerumab: No Participation in Graduate OLE
    Number of subjects analysed
    15
    693
    28
    641
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change from Baseline at Week 24 (n=15,622,27,567)
    0.2 ± 2.73
    -0.9 ± 3.15
    -1.0 ± 2.83
    -0.6 ± 4.73
        Change from Baseline at Week 36 (n=5,108,9,90)
    -2.2 ± 3.42
    -1.2 ± 3.07
    -0.6 ± 2.70
    -1.4 ± 3.45
        Change from Baseline at Week 52 (n=15,346,20,337)
    -1.5 ± 3.02
    -1.5 ± 3.60
    -0.4 ± 2.39
    -1.5 ± 5.77
        Change from Baseline at Week 76 (n=12,176,19,164)
    -1.3 ± 2.83
    -2.1 ± 3.66
    -1.3 ± 4.36
    -2.8 ± 7.54
        Change from Baseline at Week 104 (n=5,19,13,21)
    -0.6 ± 4.22
    -3.8 ± 3.79
    -0.8 ± 4.09
    -3.3 ± 2.50
    No statistical analyses for this end point

    Secondary: Change From Baseline Over Time in Coding (Digit Symbol Substitution Test [DSST]) Subset

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    End point title
    Change From Baseline Over Time in Coding (Digit Symbol Substitution Test [DSST]) Subset
    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 enrolled participants, who received at least one dose of study drug. Participants will be analyzed by the treatment they were randomized to in the parent studies (GRADUATE I or GRADUATE II). Overall number analyzed is the number of participants with data available for analyses. The number of participants analyzed indicates the number of participants with data available for analyses at the specified timepoint. The first dosing visit in the OLE (first dosing in current study or first dosing in the OLE period of the parent GRADUATE studies) was considered as baseline (OLE Day 1).
    End point type
    Secondary
    End point timeframe
    Baseline (OLE Day 1), Weeks 24, 36, 52, 76 and 104
    End point values
    Placebo: Participated in Graduate OLE Placebo: No Participation in Graduate OLE Gantenerumab: Participated in Graduate OLE Gantenerumab: No Participation in Graduate OLE
    Number of subjects analysed
    15
    693
    28
    640
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change from Baseline at Week 24 (n=14,617,27,563)
    -0.5 ± 6.31
    -2.8 ± 7.84
    -0.3 ± 9.02
    -2.3 ± 8.04
        Change from Baseline at Week 36 (n=5,107,9,89)
    -8.0 ± 10.00
    -4.8 ± 8.09
    6.2 ± 13.96
    -3.0 ± 9.66
        Change from Baseline at Week 52 (n=15,343,20,333)
    -3.1 ± 7.61
    -5.0 ± 8.60
    -2.8 ± 14.00
    -4.7 ± 8.79
        Change from Baseline at Week 76 (n=11,171,19,164)
    -3.4 ± 8.49
    -7.2 ± 10.12
    -7.1 ± 8.99
    -6.0 ± 9.71
        Change from Baseline at Week 104 (n=5,19,13,21)
    0.4 ± 9.94
    -4.5 ± 13.25
    -5.2 ± 11.95
    -7.0 ± 11.04
    No statistical analyses for this end point

    Secondary: Change in Functional Activities Questionnaire (FAQ) Score

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    End point title
    Change in Functional Activities Questionnaire (FAQ) Score
    End point description
    FAQ is a rater-administered observer-reported outcomes (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. Overall number analyzed is the number of participants with data available for analyses. The number of participants analyzed indicates the number of participants with data available for analyses at the specified timepoint. The first dosing visit in the OLE (first dosing in current study or first dosing in the OLE period of the parent GRADUATE studies) was considered as baseline (OLE Day 1).
    End point type
    Secondary
    End point timeframe
    Baseline (OLE Day 1), Weeks 24, 36, 52, 76 and 104
    End point values
    Placebo: Participated in Graduate OLE Placebo: No Participation in Graduate OLE Gantenerumab: Participated in Graduate OLE Gantenerumab: No Participation in Graduate OLE
    Number of subjects analysed
    15
    694
    27
    637
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change from Baseline at Week 24 (n=15,618,25,568)
    1.2 ± 4.04
    1.6 ± 4.36
    0.1 ± 3.15
    1.5 ± 4.09
        Change from Baseline at Week 36 (n=5,111,9,96)
    -1.0 ± 1.87
    2.7 ± 5.07
    1.3 ± 6.18
    1.7 ± 4.92
        Change from Baseline at Week 52 (n=14,346,19,333)
    2.1 ± 3.80
    2.6 ± 4.39
    2.7 ± 3.73
    2.6 ± 4.81
        Change from Baseline at Week 76 (n=13,172,20,162)
    2.3 ± 3.66
    4.0 ± 4.55
    3.3 ± 3.95
    3.5 ± 5.12
        Change from Baseline at Week 104 (n=5,17,13,21)
    3.2 ± 4.92
    4.5 ± 4.09
    4.1 ± 4.91
    1.7 ± 5.07
    No statistical analyses for this end point

    Secondary: Change in Alzheimer Disease Cooperative Study Group-Activities of Daily Living (ADCS-ADL) Score

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    End point title
    Change in Alzheimer Disease Cooperative Study Group-Activities of Daily Living (ADCS-ADL) Score
    End point description
    ADCS-ADL is a 23-item rater-administered, 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. Overall number analyzed is the number of participants with data available for analyses. The number of participants analyzed indicates the number of participants with data available for analyses at the specified timepoint. The first dosing visit in the OLE (first dosing in current study or first dosing in the OLE period of the parent GRADUATE studies) was considered as baseline (OLE Day 1).
    End point type
    Secondary
    End point timeframe
    Baseline (OLE Day 1), Weeks 24, 36, 52, 76 and 104
    End point values
    Placebo: Participated in Graduate OLE Placebo: No Participation in Graduate OLE Gantenerumab: Participated in Graduate OLE Gantenerumab: No Participation in Graduate OLE
    Number of subjects analysed
    15
    694
    27
    639
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change from Baseline at Week 24 (n=15,618,25,569)
    -4.7 ± 5.15
    -2.9 ± 7.07
    -2.0 ± 7.10
    -3.2 ± 6.69
        Change from Baseline at Week 36 (n=4,111,9,96)
    -12.5 ± 12.40
    -5.6 ± 9.55
    -2.1 ± 6.23
    -4.9 ± 8.53
        Change from Baseline at Week 52 (n=14,344,19,334)
    -9.4 ± 7.49
    -5.9 ± 8.97
    -4.4 ± 8.09
    -6.2 ± 8.38
        Change from Baseline at Week 76 (n=13,172,20,162)
    -10.8 ± 11.19
    -7.8 ± 9.87
    -8.3 ± 11.22
    -6.9 ± 9.62
        Change from Baseline at Week 104 (n=5,17,13,21)
    -11.6 ± 17.99
    -6.6 ± 10.20
    -6.3 ± 13.52
    -9.9 ± 12.21
    No statistical analyses for this end point

    Secondary: Number of Participants with Anti-drug Antibody (ADA) to Gantenerumab

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    End point title
    Number of Participants with Anti-drug Antibody (ADA) to Gantenerumab [15]
    End point description
    The number of participants with positive results for ADA against gantenerumab at any of the post-baseline assessment time-points were reported. Evaluable participant during OLE was participant with an ADA assay result from at least one sample during OLE. Treatment Emergent ADA = A participant with a negative or missing baseline ADA result(s) and at least one positive post-baseline ADA result. SE analysis set included all participants enrolled who received at least one dose of study drug in this study or in the OLE part of the parent studies (GRADUATE I or GRADUATE II). Six participants randomized to placebo arm during the double-blind treatment in the parent studies received at least one dose of gantenerumab and were considered in the gantenerumab arm for safety evaluable set. The first dosing visit in the OLE (first dosing in current study or first dosing in the OLE period of the parent GRADUATE studies) was considered as baseline (OLE Day 1).
    End point type
    Secondary
    End point timeframe
    Baseline (OLE Day 1) up to 14 weeks after the last dose (up to 134 weeks)
    Notes
    [15] - 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: Data for all arms of the study is reported. Due to difference in overall number analyzed, arms: 'Gantenerumab: Participated in Graduate OLE' and 'Gantenerumab: No Participation in Graduate OLE' are added as subject analysis set.
    End point values
    Placebo: Participated in Graduate OLE Placebo: No Participation in Graduate OLE Gantenerumab: Participated in Graduate OLE Gantenerumab: No Participation in Graduate OLE
    Number of subjects analysed
    14
    656
    29
    617
    Units: participants
    1
    17
    1
    14
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline (OLE Day 1) up to 14 weeks after the last dose (up to 110 weeks)
    Adverse event reporting additional description
    SE analysis set. 6 participants randomized to placebo arm during double-blind treatment in parent studies received at least 1 dose of gantenerumab and were considered in gantenerumab arm for SE set. 1st dosing visit in OLE (1st dosing in current study or first dosing in OLE period of parent GRADUATE studies) was considered as baseline (OLE Day 1).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Placebo: Participated in Graduate OLE
    Reporting group description
    Participants treated with placebo in the DB part and who completed the DB and OLE up titration part of WN29922 or WN39658, were enrolled in this arm and continued receiving open-label gantenerumab, 510 mg, SC, Q2W.

    Reporting group title
    Gantenerumab: Participated in Graduate OLE
    Reporting group description
    Participants treated with gantenerumab in the DB part and who completed the DB and OLE part of Study WN29922 or WN39658, were enrolled in this arm and continued receiving open-label gantenerumab, 510 mg, SC, Q2W.

    Reporting group title
    Gantenerumab: No Participation in Graduate OLE
    Reporting group description
    Participants treated with gantenerumab in the DB part and who did not enter the OLE part of Study WN29922 or WN39658, were enrolled in this arm and continued receiving open-label gantenerumab 510 mg SC, Q2W.

    Reporting group title
    Placebo: No Participation in Graduate OLE
    Reporting group description
    Participants treated with placebo in the DB part and who did not enter the OLE part of Study WN29922 or WN39658, were enrolled in this arm to receive 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, 510 mg Q4W for 3 doses before receiving open-label gantenerumab, 510 mg SC injections, Q2W. To maintain the blind to previous treatment assignment, participants received Q2W, SC injections, with alternate doses containing gantenerumab matching placebo.

    Serious adverse events
    Placebo: Participated in Graduate OLE Gantenerumab: Participated in Graduate OLE Gantenerumab: No Participation in Graduate OLE Placebo: No Participation in Graduate OLE
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 14 (14.29%)
    4 / 29 (13.79%)
    54 / 647 (8.35%)
    72 / 691 (10.42%)
         number of deaths (all causes)
    0
    1
    4
    5
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Basal cell carcinoma
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Gastric leiomyoma
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Lung neoplasm
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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 / 1
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    2 / 691 (0.29%)
         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
    Colon cancer
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    1 / 691 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary neoplasm
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Bladder cancer
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Melanoma recurrent
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Invasive breast carcinoma
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Glioblastoma
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Malignant melanoma
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Prostate cancer
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Gastric cancer
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Chronic myeloid leukaemia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    3 / 691 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery aneurysm
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Hypertension
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Aortic dissection
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Pain
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Chest pain
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Pyrexia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Generalised oedema
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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 / 1
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Prostatitis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    1 / 691 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vaginal prolapse
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    0 / 691 (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
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    5 / 691 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Acute respiratory failure
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    1 / 691 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Confusional state
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    2 / 691 (0.29%)
         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 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Delusion
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Investigations
    Troponin increased
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Injury, poisoning and procedural complications
    Toxicity to various agents
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Contusion
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Accidental overdose
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Wound
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Subdural haemorrhage
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Radius fracture
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Fracture displacement
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Spinal compression fracture
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 29 (3.45%)
    1 / 647 (0.15%)
    0 / 691 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post-traumatic pain
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Head injury
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Concussion
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Hip fracture
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    3 / 691 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    1 / 691 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 29 (3.45%)
    0 / 647 (0.00%)
    0 / 691 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Fall
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 29 (3.45%)
    4 / 647 (0.62%)
    4 / 691 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    2 / 691 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    1 / 691 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrioventricular block complete
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Myocardial infarction
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Bradycardia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Tachycardia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Cor pulmonale acute
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Atrial fibrillation
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    1 / 691 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    2 / 691 (0.29%)
         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 / 2
    Cardiac arrest
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Acute myocardial infarction
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    2 / 647 (0.31%)
    2 / 691 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Nervous system disorders
    Upper motor neurone lesion
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Loss of consciousness
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    2 / 647 (0.31%)
    0 / 691 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    2 / 647 (0.31%)
    1 / 691 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vasogenic cerebral oedema
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Cerebral ischaemia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Presyncope
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Headache
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    1 / 691 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epileptic encephalopathy
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Cerebral infarction
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Hydrocephalus
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Seizure
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 29 (3.45%)
    0 / 647 (0.00%)
    0 / 691 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Syncope
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    3 / 691 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Amyloid related imaging abnormality-oedema/effusion
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    2 / 691 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Thalamus haemorrhage
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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 hygroma
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Motor dysfunction
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Dysstasia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Ear and labyrinth disorders
    Meniere's disease
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Small intestinal obstruction
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Anal ulcer
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Inguinal hernia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    1 / 691 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Diarrhoea
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Intestinal obstruction
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    1 / 691 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Anal fistula
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Rash
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Decubitus ulcer
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Calculus bladder
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    1 / 691 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Infections and infestations
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Urinary tract infection
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    2 / 691 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Pneumonia
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 29 (3.45%)
    1 / 647 (0.15%)
    3 / 691 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    COVID-19
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    3 / 647 (0.46%)
    3 / 691 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    2 / 647 (0.31%)
    1 / 691 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    2 / 647 (0.31%)
    0 / 691 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Respiratory tract infection
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         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
    Sepsis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    2 / 647 (0.31%)
    1 / 691 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Pyelonephritis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Hyponatraemia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (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
    Malnutrition
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo: Participated in Graduate OLE Gantenerumab: Participated in Graduate OLE Gantenerumab: No Participation in Graduate OLE Placebo: No Participation in Graduate OLE
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 14 (92.86%)
    21 / 29 (72.41%)
    358 / 647 (55.33%)
    395 / 691 (57.16%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 29 (0.00%)
    11 / 647 (1.70%)
    10 / 691 (1.45%)
         occurrences all number
    2
    0
    11
    10
    Hypertensive crisis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         occurrences all number
    1
    0
    0
    1
    Arteriosclerosis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    4 / 691 (0.58%)
         occurrences all number
    1
    0
    1
    4
    Hypertension
         subjects affected / exposed
    3 / 14 (21.43%)
    2 / 29 (6.90%)
    19 / 647 (2.94%)
    14 / 691 (2.03%)
         occurrences all number
    3
    2
    22
    15
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    3 / 14 (21.43%)
    1 / 29 (3.45%)
    80 / 647 (12.36%)
    63 / 691 (9.12%)
         occurrences all number
    5
    10
    266
    157
    Fatigue
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 29 (6.90%)
    10 / 647 (1.55%)
    17 / 691 (2.46%)
         occurrences all number
    0
    2
    10
    20
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 29 (3.45%)
    1 / 647 (0.15%)
    3 / 691 (0.43%)
         occurrences all number
    2
    1
    2
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 29 (3.45%)
    16 / 647 (2.47%)
    16 / 691 (2.32%)
         occurrences all number
    1
    1
    16
    17
    Hallucination
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    4 / 691 (0.58%)
         occurrences all number
    1
    0
    1
    4
    Aggression
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 29 (3.45%)
    3 / 647 (0.46%)
    8 / 691 (1.16%)
         occurrences all number
    2
    1
    3
    8
    Confusional state
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    9 / 647 (1.39%)
    11 / 691 (1.59%)
         occurrences all number
    1
    0
    13
    12
    Irritability
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 29 (6.90%)
    4 / 647 (0.62%)
    5 / 691 (0.72%)
         occurrences all number
    0
    2
    4
    5
    Anxiety
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 29 (3.45%)
    14 / 647 (2.16%)
    11 / 691 (1.59%)
         occurrences all number
    1
    1
    14
    11
    Depression
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 29 (6.90%)
    5 / 647 (0.77%)
    12 / 691 (1.74%)
         occurrences all number
    0
    2
    5
    12
    Delusion
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 29 (6.90%)
    4 / 647 (0.62%)
    2 / 691 (0.29%)
         occurrences all number
    0
    2
    4
    2
    Investigations
    Vitamin B12 decreased
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 29 (6.90%)
    5 / 647 (0.77%)
    11 / 691 (1.59%)
         occurrences all number
    0
    2
    5
    12
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 29 (3.45%)
    4 / 647 (0.62%)
    5 / 691 (0.72%)
         occurrences all number
    1
    1
    4
    5
    Contusion
         subjects affected / exposed
    3 / 14 (21.43%)
    2 / 29 (6.90%)
    13 / 647 (2.01%)
    20 / 691 (2.89%)
         occurrences all number
    4
    2
    35
    21
    Wrist fracture
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         occurrences all number
    1
    0
    0
    1
    Procedural pain
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    2 / 691 (0.29%)
         occurrences all number
    2
    0
    0
    4
    Fall
         subjects affected / exposed
    4 / 14 (28.57%)
    6 / 29 (20.69%)
    59 / 647 (9.12%)
    50 / 691 (7.24%)
         occurrences all number
    7
    10
    92
    67
    Spinal compression fracture
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 29 (6.90%)
    2 / 647 (0.31%)
    0 / 691 (0.00%)
         occurrences all number
    0
    2
    3
    0
    Congenital, familial and genetic disorders
    Hydrocele
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         occurrences all number
    1
    0
    0
    1
    Cardiac disorders
    Cardiac failure chronic
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    0 / 691 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    0 / 691 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Arrhythmia
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 29 (6.90%)
    0 / 647 (0.00%)
    0 / 691 (0.00%)
         occurrences all number
    1
    3
    0
    0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    3 / 691 (0.43%)
         occurrences all number
    2
    0
    1
    3
    Dysarthria
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    0 / 691 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Neuralgia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    1 / 691 (0.14%)
         occurrences all number
    1
    0
    1
    1
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    2 / 691 (0.29%)
         occurrences all number
    1
    0
    0
    2
    Amyloid related imaging abnormality-microhaemorrhages and haemosiderin deposits
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    7 / 647 (1.08%)
    21 / 691 (3.04%)
         occurrences all number
    1
    0
    7
    22
    Migraine
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    3 / 691 (0.43%)
         occurrences all number
    1
    0
    1
    3
    Amyloid related imaging abnormality-oedema/effusion
         subjects affected / exposed
    5 / 14 (35.71%)
    3 / 29 (10.34%)
    16 / 647 (2.47%)
    67 / 691 (9.70%)
         occurrences all number
    5
    4
    17
    76
    Dizziness
         subjects affected / exposed
    0 / 14 (0.00%)
    4 / 29 (13.79%)
    22 / 647 (3.40%)
    23 / 691 (3.33%)
         occurrences all number
    0
    5
    23
    27
    Headache
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 29 (3.45%)
    24 / 647 (3.71%)
    33 / 691 (4.78%)
         occurrences all number
    1
    1
    46
    41
    Somnolence
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 29 (6.90%)
    3 / 647 (0.46%)
    8 / 691 (1.16%)
         occurrences all number
    1
    2
    3
    10
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    2 / 647 (0.31%)
    4 / 691 (0.58%)
         occurrences all number
    1
    0
    2
    4
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    2 / 647 (0.31%)
    3 / 691 (0.43%)
         occurrences all number
    1
    0
    2
    3
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    23 / 647 (3.55%)
    10 / 691 (1.45%)
         occurrences all number
    1
    0
    29
    15
    Anal incontinence
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    6 / 647 (0.93%)
    5 / 691 (0.72%)
         occurrences all number
    1
    0
    7
    5
    Diarrhoea
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    17 / 647 (2.63%)
    13 / 691 (1.88%)
         occurrences all number
    1
    0
    20
    15
    Umbilical hernia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    0 / 691 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dysphagia
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 29 (3.45%)
    1 / 647 (0.15%)
    2 / 691 (0.29%)
         occurrences all number
    1
    1
    1
    2
    Colitis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         occurrences all number
    1
    0
    0
    1
    Constipation
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    13 / 647 (2.01%)
    14 / 691 (2.03%)
         occurrences all number
    1
    0
    13
    14
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 29 (6.90%)
    9 / 647 (1.39%)
    11 / 691 (1.59%)
         occurrences all number
    1
    2
    12
    12
    Alopecia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    1 / 691 (0.14%)
         occurrences all number
    1
    0
    1
    1
    Dermatosis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    0 / 691 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Erythema
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    8 / 647 (1.24%)
    4 / 691 (0.58%)
         occurrences all number
    1
    0
    8
    4
    Renal and urinary disorders
    Bladder irritation
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    0 / 691 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Stress urinary incontinence
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    0 / 691 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Incontinence
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    0 / 691 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Urinary incontinence
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    4 / 647 (0.62%)
    6 / 691 (0.87%)
         occurrences all number
    1
    0
    4
    6
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 29 (6.90%)
    32 / 647 (4.95%)
    15 / 691 (2.17%)
         occurrences all number
    0
    2
    36
    16
    Osteoporosis
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 29 (6.90%)
    0 / 647 (0.00%)
    1 / 691 (0.14%)
         occurrences all number
    0
    2
    0
    1
    Neck pain
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 29 (3.45%)
    5 / 647 (0.77%)
    6 / 691 (0.87%)
         occurrences all number
    1
    1
    6
    6
    Myalgia
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 29 (6.90%)
    3 / 647 (0.46%)
    3 / 691 (0.43%)
         occurrences all number
    0
    2
    3
    3
    Arthritis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Arthralgia
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 29 (3.45%)
    33 / 647 (5.10%)
    25 / 691 (3.62%)
         occurrences all number
    0
    1
    39
    26
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    3 / 14 (21.43%)
    1 / 29 (3.45%)
    37 / 647 (5.72%)
    30 / 691 (4.34%)
         occurrences all number
    9
    2
    52
    38
    Urosepsis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    0 / 691 (0.00%)
         occurrences all number
    3
    0
    0
    0
    COVID-19
         subjects affected / exposed
    3 / 14 (21.43%)
    3 / 29 (10.34%)
    90 / 647 (13.91%)
    114 / 691 (16.50%)
         occurrences all number
    3
    3
    92
    116
    Sinusitis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    4 / 691 (0.58%)
         occurrences all number
    1
    0
    0
    5
    Bacteriuria
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    1 / 647 (0.15%)
    0 / 691 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Dacryocystitis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    0 / 691 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Pharyngitis
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 29 (3.45%)
    1 / 647 (0.15%)
    4 / 691 (0.58%)
         occurrences all number
    1
    1
    1
    4
    Dermatophytosis of nail
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    3 / 691 (0.43%)
         occurrences all number
    1
    0
    0
    3
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 29 (6.90%)
    1 / 647 (0.15%)
    1 / 691 (0.14%)
         occurrences all number
    0
    2
    1
    1
    Pelvic inflammatory disease
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    0 / 647 (0.00%)
    0 / 691 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    6 / 647 (0.93%)
    4 / 691 (0.58%)
         occurrences all number
    1
    0
    7
    4
    Nasopharyngitis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 29 (0.00%)
    29 / 647 (4.48%)
    25 / 691 (3.62%)
         occurrences all number
    2
    0
    30
    28
    Metabolism and nutrition disorders
    Vitamin B12 deficiency
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 29 (6.90%)
    15 / 647 (2.32%)
    14 / 691 (2.03%)
         occurrences all number
    0
    2
    15
    14

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Dec 2021
    The purpose of this update was primarily to include the requirement to agree not to donate blood or blood products during the study and for one year after final dose and to include the requirement for a caregiver during the study, consistent with the parent studies. In addition, an assessment of the impact of the COVID-19 pandemic on POSTGRADUATE and an assessment of concomitant administration of the COVID-19 vaccine with gantenerumab was added. Finally, this update clarified that the pharmacokinetic (PK) and biomarker objectives were exploratory. Changes to the protocol, along with a rationale for each change, are summarized in Protocol Amendment v2.
    10 May 2022
    Protocol Amendment v3 was never submitted to any Health Authorities or Institutional Review Boards (IRBs)/Ethics Committees (ECs) due to some typographical errors that occurred during editing. Although not submitted, it was decided that to maintain version control, an updated version of the document was required to ensure clarity of information.
    11 May 2022
    The purpose of this update was primarily to extend the POSTGRADUATE OLE treatment period from 2 to 4 years. Changes to the protocol, along with a rationale for each change, are summarized in Protocol Amendment v4.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    06 Mar 2023
    Decision to terminate development of Gantenerumab for treatment of prodromal/mild/early-stage Alzheimer’s disease following results of a pre-planned analysis of the safety and efficacy of Gant in Graduate I&II (WN29922/WN39658).
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    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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