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    Clinical Trial Results:
    A Phase II, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy, and Safety Study of MTAU9937A in Patients With Prodromal to Mild Alzheimer's Disease

    Summary
    EudraCT number
    2017-001800-31
    Trial protocol
    SE   GB   DK   FI   DE   PL   BE   NL   ES   FR   IT  
    Global end of trial date
    15 Jan 2021

    Results information
    Results version number
    v2(current)
    This version publication date
    08 Apr 2022
    First version publication date
    21 Jan 2022
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Correction to SI3/No Event data cell for Change From Baseline on the C-SSRS Endpoint.

    Trial information

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    Trial identification
    Sponsor protocol code
    GN39763
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03289143
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland,
    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
    15 Jan 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Jan 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of this study were to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of MTAU9937A in participants with prodromal AD (pAD) or mild AD (mAD), ages 50-80, who are amyloid positive by CSF or amyloid PET.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    04 Oct 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    3 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Belgium: 7
    Country: Number of subjects enrolled
    Canada: 27
    Country: Number of subjects enrolled
    Germany: 19
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    Spain: 43
    Country: Number of subjects enrolled
    France: 25
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    Italy: 23
    Country: Number of subjects enrolled
    Netherlands: 20
    Country: Number of subjects enrolled
    Poland: 55
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    United States: 222
    Worldwide total number of subjects
    457
    EEA total number of subjects
    196
    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)
    110
    From 65 to 84 years
    347
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    The study consisted of a double-blind treatment period and an optional open-label extension (OLE) period. OLE period was available to participants who completed the double-blind treatment period and who, in the judgment of the investigator, would potentially benefit from open-label semorinemab treatment.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Matching placebo dose of Semorinemab was administered intravenously in the double-blind treatment period. Optional Open Label Extension was available to participants who completed the double-blind treatment period and who, in the judgment of the investigator, would potentially benefit from open-label extension.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Matching placebo doses of Semorinemab was given intravenously (IV).

    Arm title
    Dose 1 Semorinemab
    Arm description
    Semorinemab was administered intravenously at dose 1 in the double-blind treatment period. Optional Open Label Extension was available to participants who completed the double-blind treatment period and who, in the judgment of the investigator, would potentially benefit from open-label extension.
    Arm type
    Experimental

    Investigational medicinal product name
    Semorinemab
    Investigational medicinal product code
    Other name
    RG6100, MTAU9937A, RO7105705
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Semorinemab dose 1 was administered intravenously (IV).

    Investigational medicinal product name
    [18F]GTP1
    Investigational medicinal product code
    Other name
    RO6880276
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    [18F]GTP1 was administered as a solution for intravenous (IV) use.

    Arm title
    Dose 2 Semorinemab
    Arm description
    Semorinemab was administered intravenously at dose 2 in the double-blind treatment period. Optional Open Label Extension was available to participants who completed the double-blind treatment period and who, in the judgment of the investigator, would potentially benefit from open-label extension.
    Arm type
    Experimental

    Investigational medicinal product name
    [18F]GTP1
    Investigational medicinal product code
    Other name
    RO6880276
    Pharmaceutical forms
    Infusion, Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    [18F]GTP1 was administered as a solution for intravenous (IV) use.

    Investigational medicinal product name
    Semorinemab
    Investigational medicinal product code
    Other name
    RG6100, MTAU9937A, RO7105705
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Semorinemab dose 2 was administered intravenously (IV).

    Arm title
    Dose 3 Semorinemab
    Arm description
    Semorinemab was administered intravenously at dose 3 in the double-blind treatment period. Optional Open Label Extension was available to participants who completed the double-blind treatment period and who, in the judgment of the investigator, would potentially benefit from open-label extension.
    Arm type
    Experimental

    Investigational medicinal product name
    Semorinemab
    Investigational medicinal product code
    Other name
    RG6100, MTAU9937A, RO7105705
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Semorinemab dose 3 was administered intravenously (IV).

    Investigational medicinal product name
    [18F]GTP1
    Investigational medicinal product code
    Other name
    RO6880276
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    [18F]GTP1 was administered as a solution for intravenous (IV) use.

    Number of subjects in period 1
    Placebo Dose 1 Semorinemab Dose 2 Semorinemab Dose 3 Semorinemab
    Started
    135
    94
    136
    92
    Completed
    1
    0
    2
    0
    Not completed
    134
    94
    134
    92
         Medical Monitor Decision
    1
    -
    -
    -
         Caregiver and Participant Withdrew Consent
    -
    -
    1
    -
         Physician decision
    -
    2
    2
    2
         Withdrawal by Participant
    14
    6
    14
    12
         Adverse Event
    10
    7
    6
    5
         Protocol Deviation
    2
    1
    3
    1
         Drug Interrupted for Too Long
    -
    -
    1
    -
         Caregiver Passed Away & Family Moved Out of State
    -
    -
    1
    -
         Withdrawal by Caregiver
    -
    1
    -
    -
         Absence of Consistent and Reliable Caregiver
    -
    -
    -
    1
         Research Department Closure
    -
    -
    1
    -
         Participant Non Compliance With Concomitant Meds
    -
    -
    1
    -
         Participant Non-Compliance
    -
    -
    1
    -
         Caregiver Unavailability
    1
    1
    -
    -
         Study Terminated By Sponsor
    101
    75
    100
    69
         Death
    2
    -
    2
    1
         Caregiver Passed Away
    1
    -
    -
    -
         Lost to follow-up
    2
    1
    1
    -
         Participant No Longer Has Study Partner
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Matching placebo dose of Semorinemab was administered intravenously in the double-blind treatment period. Optional Open Label Extension was available to participants who completed the double-blind treatment period and who, in the judgment of the investigator, would potentially benefit from open-label extension.

    Reporting group title
    Dose 1 Semorinemab
    Reporting group description
    Semorinemab was administered intravenously at dose 1 in the double-blind treatment period. Optional Open Label Extension was available to participants who completed the double-blind treatment period and who, in the judgment of the investigator, would potentially benefit from open-label extension.

    Reporting group title
    Dose 2 Semorinemab
    Reporting group description
    Semorinemab was administered intravenously at dose 2 in the double-blind treatment period. Optional Open Label Extension was available to participants who completed the double-blind treatment period and who, in the judgment of the investigator, would potentially benefit from open-label extension.

    Reporting group title
    Dose 3 Semorinemab
    Reporting group description
    Semorinemab was administered intravenously at dose 3 in the double-blind treatment period. Optional Open Label Extension was available to participants who completed the double-blind treatment period and who, in the judgment of the investigator, would potentially benefit from open-label extension.

    Reporting group values
    Placebo Dose 1 Semorinemab Dose 2 Semorinemab Dose 3 Semorinemab Total
    Number of subjects
    135 94 136 92 457
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0
        Adults (18-64 years)
    29 17 39 25 110
        From 65-84 years
    106 77 97 67 347
        85 years and over
    0 0 0 0 0
    Age Continuous
    Units: Year
        arithmetic mean (standard deviation)
    69.7 ( 7.3 ) 70.2 ( 6.7 ) 69.3 ( 7.1 ) 69.6 ( 6.7 ) -
    Sex: Female, Male
    Units: Participants
        Female
    75 51 79 48 253
        Male
    60 43 57 44 204
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 1 0 0 1
        Asian
    0 1 2 0 3
        Native Hawaiian or Other Pacific Islander
    1 0 0 0 1
        Black or African American
    0 2 1 1 4
        White
    129 83 128 82 422
        More than one race
    1 1 0 0 2
        Unknown or Not Reported
    4 6 5 9 24
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    1 4 5 3 13
        Not Hispanic or Latino
    126 80 125 79 410
        Unknown or Not Reported
    8 10 6 10 34

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Matching placebo dose of Semorinemab was administered intravenously in the double-blind treatment period. Optional Open Label Extension was available to participants who completed the double-blind treatment period and who, in the judgment of the investigator, would potentially benefit from open-label extension.

    Reporting group title
    Dose 1 Semorinemab
    Reporting group description
    Semorinemab was administered intravenously at dose 1 in the double-blind treatment period. Optional Open Label Extension was available to participants who completed the double-blind treatment period and who, in the judgment of the investigator, would potentially benefit from open-label extension.

    Reporting group title
    Dose 2 Semorinemab
    Reporting group description
    Semorinemab was administered intravenously at dose 2 in the double-blind treatment period. Optional Open Label Extension was available to participants who completed the double-blind treatment period and who, in the judgment of the investigator, would potentially benefit from open-label extension.

    Reporting group title
    Dose 3 Semorinemab
    Reporting group description
    Semorinemab was administered intravenously at dose 3 in the double-blind treatment period. Optional Open Label Extension was available to participants who completed the double-blind treatment period and who, in the judgment of the investigator, would potentially benefit from open-label extension.

    Subject analysis set title
    Placebo Double Blind
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Matching placebo dose of Semorinemab was administered intravenously in the double-blind treatment period.

    Subject analysis set title
    Dose 1 Semorinemab Double Blind
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Semorinemab was administered intravenously at dose 1 in the double-blind treatment period.

    Subject analysis set title
    Dose 2 Semorinemab Double Blind
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Semorinemab was administered intravenously at dose 2 in the double-blind treatment period.

    Subject analysis set title
    Dose 3 Semorinemab Double Blind
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Semorinemab was administered intravenously at dose 3 in the double-blind treatment period.

    Subject analysis set title
    Dose 2 Semorinemab Open Label Extension Period
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Semorinemab was administered intravenously at dose 2 in the open-label extension period.

    Primary: Change From Baseline on the CDR-SB

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    End point title
    Change From Baseline on the CDR-SB
    End point description
    The Clinical Dementia Rating-Sum of Boxes (CDR-SB) rates impairment in 6 categories (memory, orientation, judgement and problem solving, community affairs, home and hobbies and personal care) on a 5-point scale in which no impairment = 0, questionable impairment = 0.5 and mild, moderate and severe impairment = 1, 2 and 3 respectively. The score range is from 0 to 18 with a high score indicating a high disease severity. The difference in mean change from Baseline to Week 73 between Semorinemab doses and Placebo treated participants was estimated.
    End point type
    Primary
    End point timeframe
    Baseline and 73 Weeks
    End point values
    Placebo Double Blind Dose 1 Semorinemab Double Blind Dose 2 Semorinemab Double Blind Dose 3 Semorinemab Double Blind
    Number of subjects analysed
    105
    77
    113
    74
    Units: Units on a scale
        arithmetic mean (standard error)
    2.19 ( 0.226 )
    2.36 ( 0.268 )
    2.36 ( 0.222 )
    2.41 ( 0.27 )
    Statistical analysis title
    Placebo DB (Double Blind), Dose 1 Semorinemab DB
    Comparison groups
    Placebo Double Blind v Dose 1 Semorinemab Double Blind
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6147 [1]
    Method
    Mixed-effect Model Repeated Measures
    Confidence interval
    Notes
    [1] - Unadjusted
    Statistical analysis title
    Placebo DB, Dose 3 Semorinemab DB
    Comparison groups
    Placebo Double Blind v Dose 3 Semorinemab Double Blind
    Number of subjects included in analysis
    179
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5136 [2]
    Method
    Mixed-effect Model Repeated Measures
    Confidence interval
    Notes
    [2] - Unadjusted
    Statistical analysis title
    Placebo DB, Dose 2 Semorinemab DB
    Comparison groups
    Placebo Double Blind v Dose 2 Semorinemab Double Blind
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5778 [3]
    Method
    Mixed-effect Model Repeated Measures
    Confidence interval
    Notes
    [3] - Unadjusted

    Primary: Percentage of Participants with Adverse Events

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    End point title
    Percentage of Participants with Adverse Events [4]
    End point description
    Percentage of participants with at least one adverse event.
    End point type
    Primary
    End point timeframe
    Up to the data cutoff date 15 January 2021 (up to approximately 39 months)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis for this endpoint.
    End point values
    Placebo Dose 1 Semorinemab Dose 2 Semorinemab Dose 3 Semorinemab Dose 2 Semorinemab Open Label Extension Period
    Number of subjects analysed
    130
    89
    132
    90
    360
    Units: Percentage of participants
        number (not applicable)
    93.1
    88.8
    94.7
    92.2
    47.5
    No statistical analyses for this end point

    Primary: Change From Baseline on the C-SSRS

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    End point title
    Change From Baseline on the C-SSRS [5]
    End point description
    Categories are as defined in the Classification Algorithm for Suicide Assessment (CASA) based on the Columbia Suicide Severity Rating Scale (C-SSRS) questionnaire. SI1: Passive category is "Wish to be dead", SI2: Active-Nonspecific (no method, intent or plan), SI3: Active-Method, but no intent or Plan, SI4: Active-Method and intent, but no plan in C-SSRS. The worst post-baseline suicidal ideation is the highest across post-baseline visits, with highest as SI5 and lowest as SI1. Percentages are based on the total number of subjects in a treatment group. Baseline is the last observation prior to initiation of study drug.
    End point type
    Primary
    End point timeframe
    Baseline to data cutoff date 15 January 2021 (up to approximately 39 months)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis for this endpoint.
    End point values
    Placebo Dose 1 Semorinemab Dose 2 Semorinemab Dose 3 Semorinemab Dose 2 Semorinemab Open Label Extension Period
    Number of subjects analysed
    130
    89
    132
    90
    360
    Units: Percentage of participants
    number (not applicable)
        Missing/No Event
    0.8
    0
    0
    0
    0.8
        Missing/SI1
    0
    0
    0
    0
    0
        Missing/SI2
    0
    0
    0
    0
    0
        Missing/SI3
    0
    0
    0
    0
    0
        Missing/SI4
    0
    0
    0
    0
    0
        Missing/Missing
    0
    0
    0
    0
    0
        No Event/No Event
    91.5
    89.9
    93.2
    92.2
    93.3
        No Event/SI1
    2.3
    3.4
    0.8
    4.4
    1.4
        No Event/ SI2
    0
    1.1
    0
    0
    0.3
        No Event/SI3
    0
    0
    0
    0
    0
        No Event/ SI4
    0
    0
    0
    0
    0
        No Event/ Missing
    0.8
    0
    0
    1.1
    0.3
        SI1/No Event
    2.3
    3.4
    0.8
    1.1
    2.2
        SI1/SI1
    0
    0
    0
    0
    0.3
        SI1/SI2
    0.8
    0
    0
    0
    0
        SI1/SI3
    0
    0
    0
    0
    0
        SI1/SI4
    0.8
    0
    0
    0
    0
        SI1/Missing
    0
    0
    0
    0
    0
        SI2/No Event
    0
    1.1
    1.5
    0
    0.3
        SI2/SI1
    0
    0
    0.8
    0
    0.6
        SI2/SI2
    0
    0
    0
    1.1
    0
        SI2/SI3
    0
    0
    0
    0
    0
        SI2/SI4
    0
    0
    0
    0
    0
        SI2/Missing
    0
    0
    0
    0
    0
        SI3/No Event
    0.8
    0
    0
    0
    0.3
        SI3/SI1
    0
    0
    4.4
    0
    0
        SI3/SI2
    0
    0
    0
    0
    0
        SI3/SI3
    0
    0
    0
    0
    0
        SI3/SI4
    0
    0
    0
    0
    0
        SI3/Missing
    0
    0
    1.1
    0
    0
        SI4/No Event
    0
    0
    0
    0
    0
        SI4/SI1
    0
    0
    0
    0
    0
        SI4/SI2
    0
    0
    0
    0
    0
        SI4/SI3
    0
    0
    0
    0
    0.3
        SI4/Missing
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Other Abnormal MRI Findings

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    End point title
    Other Abnormal MRI Findings [6]
    End point description
    Other abnormal MRI findings by visit. For the Double Blind Period, baseline is defined as last results prior to initiation of study drug. For the Open Label Extension Period, baseline is defined as last results prior to entering the open label period. (Note: SD=Study Treatment; 777777=Not reportable because no participants were analyzed.)
    End point type
    Primary
    End point timeframe
    Baseline, Week 9, Week 49, and Week 73, Study Treatment Discontinuation, and Week 89
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis for this endpoint.
    End point values
    Placebo Dose 1 Semorinemab Dose 2 Semorinemab Dose 3 Semorinemab Dose 2 Semorinemab Open Label Extension Period
    Number of subjects analysed
    135
    94
    136
    92
    360
    Units: Number of participants
        Cerebrovascular Pathology, Baseline
    3
    0
    2
    1
    5
        CNS Trauma, Baseline
    0
    0
    0
    1
    1
        Intracranial Tumor, Baseline
    0
    0
    3
    2
    4
        Lacunar Infarct, Baseline
    13
    3
    11
    6
    23
        Superficial Hemosiderosis, Baseline
    3
    0
    2
    0
    7
        Territorial Infarct, Baseline
    3
    1
    0
    0
    4
        Vasogenic Edema/Sulcal Effusion, Baseline
    0
    0
    0
    0
    0
        Cerebrovascular Pathology, Week 9
    0
    1
    0
    0
    777777
        CNS Trauma, Week 9
    0
    0
    0
    0
    777777
        Intracranial Tumor, Week 9
    0
    0
    0
    0
    777777
        Lacunar Infarct, Week 9
    0
    1
    0
    0
    777777
        Superficial Hemosiderosis, Week 9
    3
    0
    0
    1
    777777
        Territorial Infarct, Week 9
    0
    0
    0
    0
    777777
        Vasogenic Edema/Sulcal Effusion, Week 9
    0
    0
    1
    0
    777777
        Cerebrovascular Pathology, Week 49
    0
    0
    0
    0
    777777
        CNS Trauma, Week 49
    0
    0
    0
    0
    777777
        Intracranial Tumor, Week 49
    0
    0
    0
    0
    777777
        Lacunar Infarct, Week 49
    0
    0
    0
    0
    777777
        Superficial Hemosiderosis, Week 49
    1
    1
    1
    0
    777777
        Territorial Infarct, Week 49
    0
    0
    0
    0
    777777
        Vasogenic Edema/Sulcal Effusion, Week 49
    0
    0
    0
    0
    777777
        Cerebrovascular Pathology, Week 73
    0
    0
    0
    0
    777777
        CNS Trauma, Week 73
    0
    0
    0
    0
    777777
        Intracranial Tumor, Week 73
    1
    0
    0
    0
    777777
        Lacunar Infarct, Week 73
    0
    1
    0
    0
    777777
        Superficial Hemosiderosis, Week 73
    0
    1
    0
    1
    777777
        Territorial Infarct, Week 73
    0
    0
    0
    0
    777777
        Vasogenic Edema/Sulcal Effusion, Week 73
    1
    0
    0
    0
    777777
        Cerebrovascular Pathology, Study Tx ED
    0
    0
    0
    0
    777777
        CSN Trauma, Study Tx ED
    0
    0
    0
    0
    777777
        Intracranial Tumor, Study Tx ED
    0
    0
    0
    0
    777777
        Lucunar Infarct, Study Tx ED
    1
    0
    0
    0
    777777
        Superficial Hemosiderosis, Study Tx ED
    1
    0
    0
    0
    777777
        Territorial Infarct, Study Tx ED
    0
    0
    0
    0
    777777
        Vasogenic Edema/Sulcal Effusion, Study Tx ED
    0
    0
    0
    0
    777777
        Cerebrovascular Pathology, Week 89 OLE
    777777
    777777
    777777
    777777
    0
        CNS Trauma, Week 89 OLE
    777777
    777777
    777777
    777777
    0
        Intracranial Tumor, Week 89 OLE
    777777
    777777
    777777
    777777
    1
        Lacunar Infarct, Week 89 OLE
    777777
    777777
    777777
    777777
    0
        Superficial Hemosiderosis, Week 89 OLE
    777777
    777777
    777777
    777777
    0
        Territorial Infarct, Week 89 OLE
    777777
    777777
    777777
    777777
    0
        Vasogenic Edema/Sulcal Effusion, Week 89 OLE
    777777
    777777
    777777
    777777
    1
    No statistical analyses for this end point

    Secondary: Change From Baseline on the Repeatable Battery for Assessment of Neuropsychological Status (RBANS)

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    End point title
    Change From Baseline on the Repeatable Battery for Assessment of Neuropsychological Status (RBANS)
    End point description
    The RBANS is a validated neuropsychological assessment has been shown to be a useful tool in both clinical and research settings. The RBANS consists of ten subtests that are combined to provide five indices, one for each of the five domains tested (immediate memory, visuospatial/constructional, language, attention, and delayed memory). Scores range from 40 to 160 and a higher score indicates better cognitive functioning. A decrease in the outcome measure from baseline corresponds to disease worsening. The difference in mean change from Baseline to Week 73 between Semorinemab doses and Placebo treated participants was estimated.
    End point type
    Secondary
    End point timeframe
    Baseline and 73 weeks
    End point values
    Placebo Double Blind Dose 1 Semorinemab Double Blind Dose 2 Semorinemab Double Blind Dose 3 Semorinemab Double Blind
    Number of subjects analysed
    87
    62
    93
    63
    Units: Score on a scale
        arithmetic mean (standard error)
    -5.53 ( 0.787 )
    -5.25 ( 0.93 )
    -4.62 ( 0.765 )
    -6.15 ( 0.926 )
    Statistical analysis title
    Placebo DB, Dose 1 Semorinemab DB
    Comparison groups
    Placebo Double Blind v Dose 1 Semorinemab Double Blind
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8198 [7]
    Method
    Mixed-effect Model Repeated Measures
    Confidence interval
    Notes
    [7] - Unadjusted
    Statistical analysis title
    Placebo DB, Dose 3 Semorinemab DB
    Comparison groups
    Placebo Double Blind v Dose 3 Semorinemab Double Blind
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6043 [8]
    Method
    Mixed-effect Model Repeated Measures
    Confidence interval
    Notes
    [8] - Unadjusted
    Statistical analysis title
    Placebo DB, Dose 2 Semorinemab DB
    Comparison groups
    Placebo Double Blind v Dose 2 Semorinemab Double Blind
    Number of subjects included in analysis
    180
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3961 [9]
    Method
    Mixed-effect Model Repeated Measures
    Confidence interval
    Notes
    [9] - Unadjusted

    Secondary: Change from Baseline on the Alzheimer’s Disease Assessment Scale−Cognitive Subscale 13 (ADAS-Cog-13) Subscale Score

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    End point title
    Change from Baseline on the Alzheimer’s Disease Assessment Scale−Cognitive Subscale 13 (ADAS-Cog-13) Subscale Score
    End point description
    The ADAS-Cog-13 assesses multiple cognitive domains including memory, comprehension, praxis, orientation, and spontaneous speech. Most of these are assessed by tests although some are rated by the clinician on a 5-point scale. The ADAS-Cog-13 is the ADAS-Cog-11 with 2 further items: delayed word recall and total digit cancellation. The score range for ADAS-Cog-13 is from 0 to 85 with high scores representing severe dysfunction. The difference in mean change from Baseline to Week 73 between Semorinemab doses and Placebo treated participants was estimated.
    End point type
    Secondary
    End point timeframe
    Baseline and 73 weeks
    End point values
    Placebo Double Blind Dose 1 Semorinemab Double Blind Dose 2 Semorinemab Double Blind Dose 3 Semorinemab Double Blind
    Number of subjects analysed
    94
    67
    97
    66
    Units: Score on a scale
        arithmetic mean (standard error)
    6.56 ( 0.777 )
    8.68 ( 0.937 )
    6 ( 0.769 )
    7.58 ( 0.932 )
    Statistical analysis title
    Placebo DB, Dose 1 Semorinemab DB
    Comparison groups
    Placebo Double Blind v Dose 1 Semorinemab Double Blind
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0783 [10]
    Method
    Mixed-effect Model Repeated Measures
    Confidence interval
    Notes
    [10] - Unadjusted
    Statistical analysis title
    Placebo DB, Dose 2 Semorinemab DB
    Comparison groups
    Placebo Double Blind v Dose 2 Semorinemab Double Blind
    Number of subjects included in analysis
    191
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.601 [11]
    Method
    Mixed-effect Model Repeated Measures
    Confidence interval
    Notes
    [11] - Unadjusted
    Statistical analysis title
    Placebo DB, Dose 3 Semorinemab DB
    Comparison groups
    Placebo Double Blind v Dose 3 Semorinemab Double Blind
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3961 [12]
    Method
    Mixed-effect Model Repeated Measures
    Confidence interval
    Notes
    [12] - Unadjusted

    Secondary: Change from baseline on the Amsterdam Instrumental Activity of Daily Living (iADL) questionnaire

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    End point title
    Change from baseline on the Amsterdam Instrumental Activity of Daily Living (iADL) questionnaire
    End point description
    The Amsterdam iADL questionnaire is an informant-based instrument for measuring iADL problems in participants with dementia. This instrument consists of 70 items, scored on a 5-point scale, that uses item response theory for scoring. Items presented to the informant are tailored to responses to earlier items; thus each administration of the Amsterdam iADL may consist of less than the total of 70 items. The resulting score ranges from 20 to 80 with lower scores indicating poorer performance. A decrease in the outcome measure from baseline corresponds to disease worsening. The difference in mean change from Baseline to Week 73 between Semorinemab doses and Placebo treated participants was estimated.
    End point type
    Secondary
    End point timeframe
    Baseline and 73 weeks
    End point values
    Placebo Double Blind Dose 1 Semorinemab Double Blind Dose 2 Semorinemab Double Blind Dose 3 Semorinemab Double Blind
    Number of subjects analysed
    95
    70
    109
    67
    Units: Score on a scale
        arithmetic mean (standard error)
    -6.59 ( 0.856 )
    -6.55 ( 0.999 )
    -6.92 ( 0.824 )
    -7.31 ( 1.013 )
    Statistical analysis title
    Placebo DB, Dose 1 Semorinemab DB
    Comparison groups
    Placebo Double Blind v Dose 1 Semorinemab Double Blind
    Number of subjects included in analysis
    165
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9749 [13]
    Method
    Mixed-effect Model Repeated Measures
    Confidence interval
    Notes
    [13] - Unadjusted
    Statistical analysis title
    Placebo DB, Dose 3 Semorinemab DB
    Comparison groups
    Placebo Double Blind v Dose 3 Semorinemab Double Blind
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5789
    Method
    Mixed-effect Model Repeated Measures
    Confidence interval
    Statistical analysis title
    Placebo DB, Dose 2 Semorinemab DB
    Comparison groups
    Placebo Double Blind v Dose 2 Semorinemab Double Blind
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7718 [14]
    Method
    Mixed-effect Model Repeated Measures
    Confidence interval
    Notes
    [14] - Unadjusted

    Secondary: Change from baseline on the Alzheimer’s Disease Cooperative Study Group−Activities of Daily Living Inventory

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    End point title
    Change from baseline on the Alzheimer’s Disease Cooperative Study Group−Activities of Daily Living Inventory
    End point description
    The ADCS-ADL (Alzheimer's Disease Cooperative Study-Activities of Daily Living) is the scale most widely used to assess functional outcomes in participants with AD. The ADCS-ADL covers both basic ADL (e.g., eating and toileting) and more complex 'instrumental' ADL or iADL (e.g., using the telephone, managing finances and preparing a meal). The ADCS-ADL consists of 23 questions with a score range of 0 to 78 where a higher score represents better function. The difference in mean change from Baseline to Week 73 between Semorinemab doses and Placebo treated participants was estimated.
    End point type
    Secondary
    End point timeframe
    Baseline and 73 weeks
    End point values
    Placebo Double Blind Dose 1 Semorinemab Double Blind Dose 2 Semorinemab Double Blind Dose 3 Semorinemab Double Blind
    Number of subjects analysed
    104
    76
    112
    74
    Units: Score on a scale
        arithmetic mean (standard error)
    -8.55 ( 0.996 )
    -9.52 ( 1.179 )
    -7.75 ( 0.986 )
    -7.99 ( 1.183 )
    Statistical analysis title
    Placebo DB, Dose 1 Semorinemab DB
    Comparison groups
    Placebo Double Blind v Dose 1 Semorinemab Double Blind
    Number of subjects included in analysis
    180
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5235 [15]
    Method
    Mixed-effect Model Repeated Measures
    Confidence interval
    Notes
    [15] - Unadjusted
    Statistical analysis title
    Placebo DB, Dose 3 Semorinemab DB
    Comparison groups
    Placebo Double Blind v Dose 3 Semorinemab Double Blind
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.713 [16]
    Method
    Mixed-effect Model Repeated Measures
    Confidence interval
    Notes
    [16] - Unadjusted
    Statistical analysis title
    Placebo DB, Dose 2 Semorinemab DB
    Comparison groups
    Placebo Double Blind v Dose 2 Semorinemab Double Blind
    Number of subjects included in analysis
    216
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5612 [17]
    Method
    Mixed-effect Model Repeated Measures
    Confidence interval
    Notes
    [17] - Unadjusted

    Secondary: Serum Concentrations of Semorinemab at Specified Timepoints

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    End point title
    Serum Concentrations of Semorinemab at Specified Timepoints [18]
    End point description
    Serum concentrations of Semorinemab at specified timepoints. Note: 999999=Not reportable. Below the level of detection. 888888=Data not reported because SD was non-estimable since only 1 participant was evaluated for this category. 777777=Not reportable. No participants were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 109 weeks
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis for this endpoint.
    End point values
    Dose 1 Semorinemab Dose 2 Semorinemab Dose 3 Semorinemab
    Number of subjects analysed
    89
    132
    90
    Units: ug/mL
    arithmetic mean (standard deviation)
        Week 1, 0-4 Hours Predose (n=87, n=132, n=90)
    999999 ( 999999 )
    999999 ( 999999 )
    999999 ( 999999 )
        Week 1, 1 Hour Postdose (n=87, n=132,n=90)
    472 ( 131 )
    1580 ( 496 )
    2690 ( 689 )
        Week 1, 2 Hours Postdose (n=86, n=130, n=90)
    476 ( 123 )
    1510 ( 419 )
    2600 ( 707 )
        Week 1, 4 Hours postdose (n=86, n=128, n=89)
    463 ( 135 )
    1370 ( 405 )
    2570 ( 785 )
        Week 3, 0-4 hours Predose (n=89, n=131, n=89)
    184 ( 52.7 )
    601 ( 211 )
    1100 ( 449 )
        Week 3, 30 min Post dose (n=88, n=130, n=88)
    718 ( 198 )
    2320 ( 581 )
    4190 ( 1010 )
        Week 5, 0-4 Hours Predose (n=88, n=131, n=87)
    318 ( 81.5 )
    955 ( 256 )
    1920 ( 614 )
        Week 5, 30 min Postdose (n=86, n=130, n=85)
    908 ( 508 )
    2780 ( 695 )
    4860 ( 1250 )
        Week 9, 0-4 hours Predose (n=88, n=130, n=83)
    344 ( 128 )
    961 ( 288 )
    1840 ( 513 )
        Week 9, 30 Minutes Postdose (n=89, n=129, n=85)
    889 ( 321 )
    2790 ( 757 )
    4960 ( 1270 )
        Week 13, 0-4 Hours Predose (n=87, n=128, n=86)
    360 ( 105 )
    1060 ( 333 )
    1910 ( 545 )
        Week 13, 30 Minutes Postdose (n=86, n=127, n=86)
    998 ( 896 )
    2900 ( 668 )
    4880 ( 1250 )
        Week 17 (n=0, n=0, n=1)
    7777777 ( 777777 )
    777777 ( 777777 )
    1750 ( 888888 )
        Week 17, 0-4 Hours Predose (n=84, n=127,n=83)
    386 ( 116 )
    1040 ( 316 )
    1890 ( 522 )
        Week 17, 30 Minutes Postdose (n=84, n=126, n=86)
    819 ( 242 )
    2930 ( 902 )
    4770 ( 1270 )
        Week 33, 0-4 Hours Predose (n=83, n=126, n=83)
    404 ( 134 )
    960 ( 277 )
    2050 ( 648 )
        Week 33, 30 Minutes Postdose (n=82, n=126, n=80)
    801 ( 260 )
    2540 ( 853 )
    4800 ( 1200 )
        Week 49, 0-4 Hours Predose (n=78, n=119, n=79)
    377 ( 105 )
    1060 ( 332 )
    2160 ( 605 )
        Week 49, 30 Minutes Postdose (n=77, n=117, n=80)
    871 ( 260 )
    2810 ( 967 )
    4960 ( 1030 )
        Week 65 (n=0, n=0, n=1)
    777777 ( 777777 )
    777777 ( 777777 )
    2100 ( 888888 )
        Week 65, 0-4 Hours Predose (n=67, n=101, n=66)
    405 ( 127 )
    1170 ( 276 )
    2020 ( 681 )
        Week 65, 30 Minutes Postdose (n=67, n=100, n=67)
    963 ( 401 )
    2930 ( 830 )
    4710 ( 1450 )
        Week 73, n=71, n=104, n=69)
    327 ( 154 )
    1030 ( 451 )
    1830 ( 752 )
        Week 73, 0-4 Hours Predose (n=0, n=1, n=0)
    777777 ( 777777 )
    382 ( 888888 )
    777777 ( 777777 )
        Week 73, 1 Hour Postdose (n=0, n=1, n=0)
    777777 ( 777777 )
    1910 ( 888888 )
    777777 ( 777777 )
        Week 73, 2 Hours Postdose (n=0, n=1, n=0)
    777777 ( 777777 )
    1740 ( 888888 )
    777777 ( 777777 )
        Week 73, 4 Hours Postdose (n=0, n=1, n=0)
    777777 ( 777777 )
    1710 ( 888888 )
    777777 ( 777777 )
        Week 77 OLE, 0-4 Hours Predose (n=13, n=20, n=13)
    180 ( 71.0 )
    724 ( 167 )
    1030 ( 345 )
        Week 77 OLE, 1 hour Postdose (n=12, n=20, n=12)
    1700 ( 523 )
    2460 ( 868 )
    2670 ( 707 )
        Week 77 OLE, 2 hours Postdose (n=13, n=20, n=13)
    1830 ( 552 )
    2270 ( 442 )
    2510 ( 579 )
        Week 77 OLE, 4 hours Postdose (n=11, n=20, n=12)
    1850 ( 516 )
    2270 ( 480 )
    2790 ( 558 )
        Week 93 OLE, 0-4 Hours Pre-dose (n=2, n=2, n=4)
    632 ( 37.5 )
    1040 ( 113 )
    1290 ( 3007 )
        Week 93 OLE, 30 Minutes Postdose (n=2, n=2, n=4)
    1920 ( 431 )
    2570 ( 91.9 )
    2880 ( 492 )
        Week 109 OLE, 0-4 Hours Predose (n=0, n=1, n=0)
    777777 ( 777777 )
    1270 ( 888888 )
    777777 ( 777777 )
        Week 109 OLE, 30 Minutes Postdose (n=0, n=1, n=0)
    777777 ( 777777 )
    3330 ( 888888 )
    777777 ( 777777 )
    No statistical analyses for this end point

    Secondary: Presence of anti-drug antibodies during the study relative to their presence at baseline

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    End point title
    Presence of anti-drug antibodies during the study relative to their presence at baseline
    End point description
    Presence of anti-drug antibodies during the study relative to their presence at baseline.
    End point type
    Secondary
    End point timeframe
    Up to 109 weeks
    End point values
    Placebo Dose 1 Semorinemab Dose 2 Semorinemab Dose 3 Semorinemab
    Number of subjects analysed
    130
    89
    132
    90
    Units: Percentage of participants
        Baseline (n=127, n=87, n=132, n=90)
    0
    0
    0
    0
        Post-baseline (n=0, n=86, n=128, n=88)
    0
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first study drug to the data cutoff date: 15 January 2021 (up to 39 months)
    Adverse event reporting additional description
    The safety-evaluable population included all participants who were randomly allocated and received at least one dose of study drug (semorinemab or placebo) during the double-blind treatment period with treatment groups defined according to actual treatment received.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Placebo Double Blind Period
    Reporting group description
    Matching placebo dose of Semorinemab was administered intravenously in the double-blind treatment period.

    Reporting group title
    Dose 1 Semorinemab Double Blind Period
    Reporting group description
    Semorinemab was administered intravenously at dose 1 in the double-blind treatment period.

    Reporting group title
    Dose 2 Semorinemab Double Blind Period
    Reporting group description
    Semorinemab was administered intravenously at dose 2 in the double-blind treatment period.

    Reporting group title
    Dose 3 Semorinemab Double Blind Period
    Reporting group description
    Semorinemab was administered intravenously at dose 3 in the double-blind treatment period.

    Reporting group title
    Dose 2 Semorinemab Open Label
    Reporting group description
    Semorinemab was administered intravenously at dose 2 in the open-label extension period.

    Serious adverse events
    Placebo Double Blind Period Dose 1 Semorinemab Double Blind Period Dose 2 Semorinemab Double Blind Period Dose 3 Semorinemab Double Blind Period Dose 2 Semorinemab Open Label
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 130 (10.77%)
    17 / 89 (19.10%)
    17 / 132 (12.88%)
    16 / 90 (17.78%)
    17 / 360 (4.72%)
         number of deaths (all causes)
    2
    0
    1
    1
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    1 / 90 (1.11%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    1 / 90 (1.11%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colorectal cancer
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    1 / 90 (1.11%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign pancreatic neoplasm
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    1 / 132 (0.76%)
    0 / 90 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Sudden death
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 89 (1.12%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Euthanasia
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    1 / 90 (1.11%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillar cyst
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    1 / 132 (0.76%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    1 / 132 (0.76%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    1 / 132 (0.76%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 89 (1.12%)
    0 / 132 (0.00%)
    2 / 90 (2.22%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paranoia
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    1 / 132 (0.76%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aggression
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 89 (1.12%)
    0 / 132 (0.00%)
    1 / 90 (1.11%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    1 / 132 (0.76%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    1 / 132 (0.76%)
    1 / 90 (1.11%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Persecutory delusion
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    1 / 90 (1.11%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood pressure increased
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    1 / 132 (0.76%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Face injury
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    1 / 132 (0.76%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    1 / 132 (0.76%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 89 (1.12%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    1 / 132 (0.76%)
    0 / 90 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fracture displacement
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 89 (1.12%)
    2 / 132 (1.52%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 89 (1.12%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 89 (1.12%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    2 / 130 (1.54%)
    0 / 89 (0.00%)
    1 / 132 (0.76%)
    1 / 90 (1.11%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 89 (0.00%)
    1 / 132 (0.76%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin wound
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    1 / 132 (0.76%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    1 / 132 (0.76%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    1 / 132 (0.76%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congestive cardiomyopathy
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    1 / 132 (0.76%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 89 (1.12%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Coma
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxic encephalopathy
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    1 / 132 (0.76%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cluster headache
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    1 / 132 (0.76%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post-traumatic headache
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    1 / 132 (0.76%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 89 (1.12%)
    2 / 132 (1.52%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    1 / 132 (0.76%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Amnesia
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    1 / 90 (1.11%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 89 (1.12%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Inguinal hernia strangulated
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    1 / 90 (1.11%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal polyp
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 89 (1.12%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    1 / 90 (1.11%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 89 (1.12%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 89 (1.12%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 89 (1.12%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    1 / 90 (1.11%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    1 / 132 (0.76%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary bladder polyp
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 89 (1.12%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    1 / 132 (0.76%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fracture pain
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 89 (1.12%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 89 (1.12%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    1 / 132 (0.76%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    1 / 90 (1.11%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 89 (0.00%)
    1 / 132 (0.76%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    1 / 132 (0.76%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    1 / 90 (1.11%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 89 (1.12%)
    1 / 132 (0.76%)
    1 / 90 (1.11%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 130 (0.77%)
    1 / 89 (1.12%)
    1 / 132 (0.76%)
    3 / 90 (3.33%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 89 (1.12%)
    0 / 132 (0.00%)
    1 / 90 (1.11%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 89 (1.12%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    1 / 132 (0.76%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    1 / 90 (1.11%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Tooth abscess
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 89 (1.12%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 89 (1.12%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 89 (0.00%)
    0 / 132 (0.00%)
    0 / 90 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Double Blind Period Dose 1 Semorinemab Double Blind Period Dose 2 Semorinemab Double Blind Period Dose 3 Semorinemab Double Blind Period Dose 2 Semorinemab Open Label
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    76 / 130 (58.46%)
    57 / 89 (64.04%)
    88 / 132 (66.67%)
    60 / 90 (66.67%)
    76 / 360 (21.11%)
    Investigations
    Blood pressure increased
         subjects affected / exposed
    2 / 130 (1.54%)
    1 / 89 (1.12%)
    8 / 132 (6.06%)
    2 / 90 (2.22%)
    3 / 360 (0.83%)
         occurrences all number
    2
    1
    12
    3
    3
    Injury, poisoning and procedural complications
    Skin laceration
         subjects affected / exposed
    4 / 130 (3.08%)
    6 / 89 (6.74%)
    2 / 132 (1.52%)
    0 / 90 (0.00%)
    5 / 360 (1.39%)
         occurrences all number
    4
    6
    2
    0
    5
    Infusion related reaction
         subjects affected / exposed
    6 / 130 (4.62%)
    10 / 89 (11.24%)
    11 / 132 (8.33%)
    6 / 90 (6.67%)
    5 / 360 (1.39%)
         occurrences all number
    6
    16
    15
    11
    5
    Fall
         subjects affected / exposed
    22 / 130 (16.92%)
    14 / 89 (15.73%)
    22 / 132 (16.67%)
    7 / 90 (7.78%)
    18 / 360 (5.00%)
         occurrences all number
    26
    15
    33
    11
    21
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 130 (5.38%)
    4 / 89 (4.49%)
    14 / 132 (10.61%)
    5 / 90 (5.56%)
    4 / 360 (1.11%)
         occurrences all number
    7
    4
    14
    6
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 130 (7.69%)
    2 / 89 (2.25%)
    8 / 132 (6.06%)
    6 / 90 (6.67%)
    15 / 360 (4.17%)
         occurrences all number
    13
    2
    11
    9
    15
    Dizziness
         subjects affected / exposed
    12 / 130 (9.23%)
    5 / 89 (5.62%)
    6 / 132 (4.55%)
    7 / 90 (7.78%)
    4 / 360 (1.11%)
         occurrences all number
    12
    7
    7
    9
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 130 (1.54%)
    1 / 89 (1.12%)
    4 / 132 (3.03%)
    5 / 90 (5.56%)
    1 / 360 (0.28%)
         occurrences all number
    2
    1
    5
    5
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 130 (3.08%)
    5 / 89 (5.62%)
    10 / 132 (7.58%)
    4 / 90 (4.44%)
    5 / 360 (1.39%)
         occurrences all number
    4
    7
    11
    4
    6
    Nausea
         subjects affected / exposed
    0 / 130 (0.00%)
    9 / 89 (10.11%)
    8 / 132 (6.06%)
    4 / 90 (4.44%)
    3 / 360 (0.83%)
         occurrences all number
    0
    9
    9
    5
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 130 (3.08%)
    6 / 89 (6.74%)
    7 / 132 (5.30%)
    5 / 90 (5.56%)
    5 / 360 (1.39%)
         occurrences all number
    4
    6
    7
    8
    5
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 130 (2.31%)
    2 / 89 (2.25%)
    4 / 132 (3.03%)
    5 / 90 (5.56%)
    2 / 360 (0.56%)
         occurrences all number
    3
    2
    4
    5
    2
    Anxiety
         subjects affected / exposed
    3 / 130 (2.31%)
    10 / 89 (11.24%)
    6 / 132 (4.55%)
    6 / 90 (6.67%)
    1 / 360 (0.28%)
         occurrences all number
    3
    10
    7
    6
    1
    Depression
         subjects affected / exposed
    5 / 130 (3.85%)
    5 / 89 (5.62%)
    7 / 132 (5.30%)
    5 / 90 (5.56%)
    3 / 360 (0.83%)
         occurrences all number
    5
    5
    8
    6
    3
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    8 / 130 (6.15%)
    5 / 89 (5.62%)
    8 / 132 (6.06%)
    6 / 90 (6.67%)
    5 / 360 (1.39%)
         occurrences all number
    8
    5
    8
    7
    5
    Arthralgia
         subjects affected / exposed
    8 / 130 (6.15%)
    6 / 89 (6.74%)
    10 / 132 (7.58%)
    8 / 90 (8.89%)
    8 / 360 (2.22%)
         occurrences all number
    10
    7
    12
    8
    8
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    11 / 130 (8.46%)
    5 / 89 (5.62%)
    18 / 132 (13.64%)
    12 / 90 (13.33%)
    2 / 360 (0.56%)
         occurrences all number
    15
    6
    24
    14
    2
    Upper respiratory tract infection
         subjects affected / exposed
    15 / 130 (11.54%)
    6 / 89 (6.74%)
    7 / 132 (5.30%)
    5 / 90 (5.56%)
    4 / 360 (1.11%)
         occurrences all number
    21
    8
    8
    6
    4
    Urinary tract infection
         subjects affected / exposed
    10 / 130 (7.69%)
    4 / 89 (4.49%)
    10 / 132 (7.58%)
    5 / 90 (5.56%)
    10 / 360 (2.78%)
         occurrences all number
    13
    4
    11
    8
    11

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Oct 2017
    Protocol was amended to include extensions to the 8-week screening period and 15-day baseline period on a case-by-case basis. Several exclusion criteria have been modified. Amyloid positron emission tomography (PET) guidance has been clarified. The Caregiver Global Impression of Change Scales have been added to the assessments performed in both the blinded and open-label portions of the study. The requirement that participants with two consecutive Mini-Mental State Examination (MMSE) scores <10 must be discontinued from the study has been removed, as it remains uncertain whether continued efficacy might be observed in participants who progress to that level of AD severity. The primary efficacy analyses were clarified to state that they will include adjustments for baseline clinical status rather than baseline MMSE score.
    11 Jun 2019
    Protocol was amended to include modified exclusion criteria: - The exclusion criterion for biologic therapy has been clarified to indicate that any investigational biologic therapy is prohibited at screening and during the study. - The exclusion criterion for systemic immunosuppressive therapy has been revised to indicate that short courses (<=2 weeks) of high-dose corticosteroid therapy are permitted, and that chronic therapy (>2 weeks) is permitted as long as the dose is <7.5 mg/day prednisolone equivalent and the condition being treated is not expected to deteriorate significantly during the study period. The description of the recall time frame for the Caregiver Global Impression of Change Scales has been corrected to align with the time frames used for the assessment. Study visits during the protocol safety follow-up period were clarified to state that patients who discontinue from treatment early will have a treatment discontinuation visit. Adverse event reporting was clarified to include reporting of adverse events that occur after the protocol defined adverse event reporting interval following the last dose of [18F]GTP1 or study drug administration for adverse events leading to discontinuation from the study.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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