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    Clinical Trial Results:
    Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Two Year Study to Evaluate the Effect of Subcutaneous RO4909832 on Cognition and Function in Prodromal Alzheimer's Disease with Option for up to an Additional Two Years of Treatment and an Open-Label Extension with Active Study Treatment

    Summary
    EudraCT number
    		 2010-019895-66
    Trial protocol
    		 GB   SE   DE   IT   ES   FI   NL   DK   CZ   BE   PT  
    Global end of trial date
    10 Sep 2020

    Results information
    Results version number
    		 v3(current)
    This version publication date
    11 Jan 2022
    First version publication date
    15 Jul 2016
    Other versions
    		 v1 , v2
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    WN25203
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01224106
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Sep 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Sep 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of Subcutaneous RO4909832 on Cognition and Function in Prodromal Alzheimer's Disease
    Protection of trial subjects
    All study subjects were required to sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Nov 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 36
    Country: Number of subjects enrolled
    Australia: 49
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Brazil: 13
    Country: Number of subjects enrolled
    Canada: 58
    Country: Number of subjects enrolled
    Switzerland: 4
    Country: Number of subjects enrolled
    Chile: 6
    Country: Number of subjects enrolled
    Czechia: 8
    Country: Number of subjects enrolled
    Germany: 55
    Country: Number of subjects enrolled
    Denmark: 9
    Country: Number of subjects enrolled
    Spain: 101
    Country: Number of subjects enrolled
    Finland: 5
    Country: Number of subjects enrolled
    France: 51
    Country: Number of subjects enrolled
    United Kingdom: 57
    Country: Number of subjects enrolled
    Italy: 55
    Country: Number of subjects enrolled
    Korea, Republic of: 17
    Country: Number of subjects enrolled
    Mexico: 47
    Country: Number of subjects enrolled
    Netherlands: 33
    Country: Number of subjects enrolled
    Poland: 22
    Country: Number of subjects enrolled
    Portugal: 7
    Country: Number of subjects enrolled
    Russian Federation: 17
    Country: Number of subjects enrolled
    Sweden: 13
    Country: Number of subjects enrolled
    Turkey: 20
    Country: Number of subjects enrolled
    United States: 112
    Worldwide total number of subjects
    797
    EEA total number of subjects
    361
    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)
    156
    From 65 to 84 years
    630
    85 years and over
    11

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 128 centers in 24 countries.

    Pre-assignment
    Screening details
    		 A total of 799 subjects were randomised in this study. Of these, 797 subjects were enrolled and received at least one dose of any study drug (represented the Safety population) during the Double-Blind Treatment (DBT) Phase of the study. From the DBT Phase, a total of 154 subjects (at 53 sites) enrolled into Open-Label Extension Phase of the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo (Parts 1 and 2)
    Arm description
    		 Subjects with Alzheimer's disease received Placebo by SC injection every 4 weeks (Q4W) for 104 weeks or approximately 2 years during Part 1 of the study. Subjects who completed the Week 104 visit were given an option to continue the treatment received during Part 1, for 2 additional years in Part 2.
    Arm type
    		 Placebo

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

    Arm title
    		 Gantenerumab 105 mg (Parts 1 and 2)
    Arm description
    		 Subjects with Alzheimer's disease received Gantenerumab 105 mg by SC injection every 4 weeks (Q4W) for 104 weeks or approximately 2 years during Part 1 of the study. Subjects who completed the Week 104 visit were given an option to continue the treatment received during Part 1, for 2 additional years in Part 2.
    Arm type
    		 Experimental

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

    Arm title
    		 Gantenerumab 225 mg (Parts 1 and 2)
    Arm description
    		 Subjects with Alzheimer's disease received Gantenerumab 225 mg by SC injection every 4 weeks (Q4W) for 104 weeks or approximately 2 years during Part 1 of the study. Subjects who completed the Week 104 visit were given an option to continue the treatment received during Part 1, for 2 additional years in Part 2.
    Arm type
    		 Experimental

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

    Number of subjects in period 1
    		Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2)
    Started
    266
    271
    260
    Completed
    187
    185
    180
    Not completed
    79
    86
    80
         Adverse event, serious fatal
    3
    -
    -
         Physician decision
    6
    5
    4
         Participant/legal guardian decision
    7
    8
    8
         Adverse event, non-fatal
    -
    5
    3
         Parts 1 and 2 Termination by Sponsor
    62
    68
    63
         Unspecified
    -
    -
    1
         Lost to follow-up
    1
    -
    1
    Period 2
    Period 2 title
    Open-Label Extension (OLE) Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Plac (Parts 1 + 2) switched to Gant Up to 1200mg (Part 3 OLE)
    Arm description
    		 Subjects with Alzheimer's disease who had received Placebo by SC injection in Part 1 or Part 2, now received Gantenerumab at doses up to 1200 mg by SC injection every 4 weeks (Q4W) for up to 5 additional years.
    Arm type
    		 Placebo

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

    Arm title
    		 Gant Up to 1200 mg (Part 3 OLE)
    Arm description
    		 Subjects with Alzheimer's disease who had received Gantenerumab by SC injection in Part 1 or Part 2, now received Gantenerumab at doses up to 1200 mg by SC injection every 4 weeks (Q4W) for up to 5 additional years.
    Arm type
    		 Experimental

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

    Number of subjects in period 2 [1]
    		Plac (Parts 1 + 2) switched to Gant Up to 1200mg (Part 3 OLE) Gant Up to 1200 mg (Part 3 OLE)
    Started
    49
    105
    Completed
    33
    71
    Not completed
    16
    34
         Adverse event, serious fatal
    1
    3
         Physician decision
    2
    7
         Consent withdrawn by subject
    6
    15
         Adverse event, non-fatal
    2
    6
         Unspecified
    5
    3
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Out of the 797 subjects that enrolled into the Double-Blind Treatment phase of this study and entire study, a subset (154) subjects moved into the OLE phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo (Parts 1 and 2)
    Reporting group description
    		 Subjects with Alzheimer's disease received Placebo by SC injection every 4 weeks (Q4W) for 104 weeks or approximately 2 years during Part 1 of the study. Subjects who completed the Week 104 visit were given an option to continue the treatment received during Part 1, for 2 additional years in Part 2.

    Reporting group title
    Gantenerumab 105 mg (Parts 1 and 2)
    Reporting group description
    		 Subjects with Alzheimer's disease received Gantenerumab 105 mg by SC injection every 4 weeks (Q4W) for 104 weeks or approximately 2 years during Part 1 of the study. Subjects who completed the Week 104 visit were given an option to continue the treatment received during Part 1, for 2 additional years in Part 2.

    Reporting group title
    Gantenerumab 225 mg (Parts 1 and 2)
    Reporting group description
    		 Subjects with Alzheimer's disease received Gantenerumab 225 mg by SC injection every 4 weeks (Q4W) for 104 weeks or approximately 2 years during Part 1 of the study. Subjects who completed the Week 104 visit were given an option to continue the treatment received during Part 1, for 2 additional years in Part 2.

    Reporting group values
    		 Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2) Total
    Number of subjects
    		 266 271 260 797
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 59 57 40 156
        From 65-84 years
    		 202 210 218 630
        85 years and over
    		 5 4 2 11
    Age Continuous
    Parts 1, 2 and 3 of the study
    Units: years
        arithmetic mean (standard deviation)
    		 69.5 ± 7.5 70.3 ± 7.0 71.3 ± 7.1 -
    Sex: Female, Male
    Parts 1, 2 and 3 of the study.
    Units: Participants
        Female
    		 149 152 152 453
        Male
    		 117 119 108 344
    Race/Ethnicity, Customized
    Parts 1, 2 and 3 of the study (Race).
    Units: Subjects
        American Indian or Alaska native
    		 1 6 5 12
        Asian
    		 9 4 7 20
        Black
    		 1 2 2 5
        White
    		 239 252 239 730
        Not Available
    		 16 7 7 30
    Race/Ethnicity, Customized
    Parts 1, 2 and 3 of the study (Ethnicity).
    Units: Subjects
        Non-Hispanic
    		 217 221 210 648
        Hispanic
    		 41 39 47 127
        Unknown
    		 8 11 3 22
    Subject analysis sets

    Subject analysis set title
    Plac (Parts 1 + 2) switched to Gant Up to 1200mg (Part 3 OLE)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects with Alzheimer's disease who had received Placebo by SC injection in Part 1 or Part 2, now received Gantenerumab at doses up to 1200 mg by SC injection every 4 weeks (Q4W) for 5 additional years.

    Subject analysis set title
    Gant Up to 1200 mg (Part 3 OLE)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects with Alzheimer's disease who had received Gantenerumab by SC injection in Part 1 or Part 2, now received Gantenerumab at doses up to 1200 mg by SC injection every 4 weeks (Q4W) for 5 additional years.

    Subject analysis set title
    Placebo Match Gantenerumab 225 mg (Parts 1 and 2)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with Alzheimer's disease received matching Placebo to Gantenerumab 225 mg by SC injection Q4W for 104 weeks or approximately 2 years during Part 1 of the study. Subjects who completed the Week 104 visit were given an option to continue the treatment received during Part 1, for 2 additional years in Part 2.

    Subject analysis set title
    Gant 1200 mg (Part 3 OLE)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with Alzheimer's disease who had received Gantenerumab by SC injection in Part 1 or Part 2, now received Gantenerumab at a dose of 1200 mg by SC injection every 4 weeks (Q4W) for 5 additional years.

    Subject analysis sets values
    		 Plac (Parts 1 + 2) switched to Gant Up to 1200mg (Part 3 OLE) Gant Up to 1200 mg (Part 3 OLE) Placebo Match Gantenerumab 225 mg (Parts 1 and 2) Gant 1200 mg (Part 3 OLE)
    Number of subjects
    49
    105
    107
    99
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    0
    9
        From 65-84 years
    46
    92
        85 years and over
    3
    4
    Age Continuous
    Parts 1, 2 and 3 of the study
    Units: years
        arithmetic mean (standard deviation)
    75.5 ± 5.8
    73.7 ± 7.3
    ±
    ±
    Sex: Female, Male
    Parts 1, 2 and 3 of the study.
    Units: Participants
        Female
    27
    64
        Male
    22
    41
    Race/Ethnicity, Customized
    Parts 1, 2 and 3 of the study (Race).
    Units: Subjects
        American Indian or Alaska native
    0
    3
        Asian
    2
    0
        Black
    0
    0
        White
    42
    101
        Not Available
    5
    1
    Race/Ethnicity, Customized
    Parts 1, 2 and 3 of the study (Ethnicity).
    Units: Subjects
        Non-Hispanic
    39
    88
        Hispanic
    10
    17
        Unknown
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    Placebo (Parts 1 and 2)
    Reporting group description
    		 Subjects with Alzheimer's disease received Placebo by SC injection every 4 weeks (Q4W) for 104 weeks or approximately 2 years during Part 1 of the study. Subjects who completed the Week 104 visit were given an option to continue the treatment received during Part 1, for 2 additional years in Part 2.

    Reporting group title
    Gantenerumab 105 mg (Parts 1 and 2)
    Reporting group description
    		 Subjects with Alzheimer's disease received Gantenerumab 105 mg by SC injection every 4 weeks (Q4W) for 104 weeks or approximately 2 years during Part 1 of the study. Subjects who completed the Week 104 visit were given an option to continue the treatment received during Part 1, for 2 additional years in Part 2.

    Reporting group title
    Gantenerumab 225 mg (Parts 1 and 2)
    Reporting group description
    		 Subjects with Alzheimer's disease received Gantenerumab 225 mg by SC injection every 4 weeks (Q4W) for 104 weeks or approximately 2 years during Part 1 of the study. Subjects who completed the Week 104 visit were given an option to continue the treatment received during Part 1, for 2 additional years in Part 2.
    Reporting group title
    Plac (Parts 1 + 2) switched to Gant Up to 1200mg (Part 3 OLE)
    Reporting group description
    		 Subjects with Alzheimer's disease who had received Placebo by SC injection in Part 1 or Part 2, now received Gantenerumab at doses up to 1200 mg by SC injection every 4 weeks (Q4W) for up to 5 additional years.

    Reporting group title
    Gant Up to 1200 mg (Part 3 OLE)
    Reporting group description
    		 Subjects with Alzheimer's disease who had received Gantenerumab by SC injection in Part 1 or Part 2, now received Gantenerumab at doses up to 1200 mg by SC injection every 4 weeks (Q4W) for up to 5 additional years.

    Subject analysis set title
    Plac (Parts 1 + 2) switched to Gant Up to 1200mg (Part 3 OLE)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects with Alzheimer's disease who had received Placebo by SC injection in Part 1 or Part 2, now received Gantenerumab at doses up to 1200 mg by SC injection every 4 weeks (Q4W) for 5 additional years.

    Subject analysis set title
    Gant Up to 1200 mg (Part 3 OLE)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects with Alzheimer's disease who had received Gantenerumab by SC injection in Part 1 or Part 2, now received Gantenerumab at doses up to 1200 mg by SC injection every 4 weeks (Q4W) for 5 additional years.

    Subject analysis set title
    Placebo Match Gantenerumab 225 mg (Parts 1 and 2)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with Alzheimer's disease received matching Placebo to Gantenerumab 225 mg by SC injection Q4W for 104 weeks or approximately 2 years during Part 1 of the study. Subjects who completed the Week 104 visit were given an option to continue the treatment received during Part 1, for 2 additional years in Part 2.

    Subject analysis set title
    Gant 1200 mg (Part 3 OLE)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with Alzheimer's disease who had received Gantenerumab by SC injection in Part 1 or Part 2, now received Gantenerumab at a dose of 1200 mg by SC injection every 4 weeks (Q4W) for 5 additional years.

    Primary: Mean Change From Baseline in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) Total Score at Week 104 (Double-Blind Treatment Phase)

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    End point title
    		 Mean Change From Baseline in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) Total Score at Week 104 (Double-Blind Treatment Phase)
    End point description
    The CDR (Clinical Dementia Rating) is obtained through semi-structured interviews of participants and informants, and cognitive functioning is rated in six domains of functioning: memory, orientation, judgement and problem solving, community affairs, home and hobbies, and personal care. Each domain is rated on a five-point scale of functioning as follows: 0, no impairment; 0.5, questionable impairment; 1, mild impairment; 2, moderate impairment; and 3, severe impairment. The CDR-SOB (Clinical Dementia Rating-Sum of Boxes) is based on summing each of the domain box scores with total scores ranging from 0-18, where lower total scores represent better outcomes and higher total scores represent worse outcomes.
    End point type
    Primary
    End point timeframe
    Baseline, Week 104
    End point values
    		 Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects analysed
    104
    105
    100
    Units: Scores on a Scale
    arithmetic mean (standard deviation)
        Week 104
    1.19 ± 1.68
    1.41 ± 2.02
    1.47 ± 1.89
    Statistical analysis title
    		 Statistical Analysis I
    Comparison groups
    Placebo (Parts 1 and 2) v Gantenerumab 105 mg (Parts 1 and 2)
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6744
    Method
    		 Mixed models analysis
    Parameter type
    		 Effect Size
    Point estimate
    -0.044
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.248
         upper limit
    		 0.161
    Statistical analysis title
    		 Statistical Analysis II
    Comparison groups
    Placebo (Parts 1 and 2) v Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4494
    Method
    		 Mixed models analysis
    Parameter type
    		 Effect Size
    Point estimate
    -0.085
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.304
         upper limit
    		 0.135

    Primary: Number of Subjects with Adverse Events (AEs) or Serious Adverse Events (SAEs) (OLE Phase)

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    End point title
    		 Number of Subjects with Adverse Events (AEs) or Serious Adverse Events (SAEs) (OLE Phase) [1]
    End point description
    An Adverse Event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
    End point type
    Primary
    End point timeframe
    Baseline up until a maximum of 5 years
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were performed, as the OLE phase in reality only had 1 arm with all subjects receiving Gantenerumab (up to 1200mg).
    End point values
    		 Plac (Parts 1 + 2) switched to Gant Up to 1200mg (Part 3 OLE) Gant Up to 1200 mg (Part 3 OLE)
    Number of subjects analysed
    49
    105
    Units: Subjects
    number (not applicable)
        AEs
    46
    100
        SAEs
    18
    28
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in Alzheimer Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog-11) Scores at Week 104 (Double-Blind Treatment Phase)

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    End point title
    		 Mean Change From Baseline in Alzheimer Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog-11) Scores at Week 104 (Double-Blind Treatment Phase)
    End point description
    The ADAS-Cog-11 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 score range for ADAS-Cog-11 is from 0 to 70 with higher scores representing severe dysfunction.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    		 Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects analysed
    105
    104
    100
    Units: Scores on a Scale
    arithmetic mean (standard deviation)
        Week 104
    3.68 ± 6.64
    3.52 ± 6.28
    3.97 ± 6.89
    Statistical analysis title
    		 Statistical Analysis I
    Comparison groups
    Placebo (Parts 1 and 2) v Gantenerumab 105 mg (Parts 1 and 2)
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7458
    Method
    		 Mixed models analysis
    Parameter type
    		 Effect Size
    Point estimate
    0.035
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.179
         upper limit
    		 0.25
    Statistical analysis title
    		 Statistical Analysis II
    Comparison groups
    Placebo (Parts 1 and 2) v Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.723
    Method
    		 Mixed models analysis
    Parameter type
    		 Effect Size
    Point estimate
    0.042
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.191
         upper limit
    		 0.275

    Secondary: Time to Onset of Dementia at Week 104 (Double-Blind Treatment Phase)

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    End point title
    		 Time to Onset of Dementia at Week 104 (Double-Blind Treatment Phase)
    End point description
    Time to Onset of Dementia was defined as the time interval between the first treatment date and the date that subject is assessed as having Alzheimer-type dementia by investigators.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    		 Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects analysed
    91
    95
    91
    Units: Days
        median (confidence interval 95%)
    63.64 (56.63 to 69.82)
    62.98 (56.00 to 69.16)
    70.64 (63.34 to 76.75)
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in Cambridge Neuropsychological Test Automated Battery (CANTAB) Composite Score at Week 104 (Double-Blind Treatment Phase)

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    End point title
    		 Mean Change From Baseline in Cambridge Neuropsychological Test Automated Battery (CANTAB) Composite Score at Week 104 (Double-Blind Treatment Phase)
    End point description
    The Cambridge Neuropsychological Test Automated Battery (CANTAB) ® is a cognitive test battery that incorporates a variety of executive and memory tasks in order to assess neuropsychological function. The end outcome as reported below, is a Z-Composite Score. The score range of the Z-Composite Score is from (-) infinity to (+) infinity with a score of zero representing the population mean, lower (negative) scores representing poorer cognitive outcomes and higher (positive) scores representing better cognitive outcomes.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    		 Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2) Placebo Match Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects analysed
    90
    87
    80
    73
    Units: Z-Score
    arithmetic mean (standard deviation)
        Week 104
    -1.72 ± 2.99
    -1.37 ± 2.74
    -1.4 ± 3.11
    -1.93 ± 3.08
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline in Free and Cued Selective Reminding Test (FCSRT) Score at Week 104 (Double-Blind Treatment Phase)

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    End point title
    		 Mean Change from Baseline in Free and Cued Selective Reminding Test (FCSRT) Score at Week 104 (Double-Blind Treatment Phase)
    End point description
    FCSRT assesses verbal episodic memory. Performances in free recalls, cued recalls and in a recognition task were analyzed, as the process of encoding is controlled. Subjects were asked to remember a list of 16 words. Three tasks of free and cued recalls, as well as 1 recognition task and one delayed recall give the scores. Total recall was obtained by the addition of cued recalls to free recalls. Maximum score is 48 for immediate: 16 words multiplied by (*) 3 corresponding to immediate free recall + immediate cued recall + immediate recognition test. Maximum score is 64 (better score) when delayed recall: 16 words*4. The minimum score is 0 (worse).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    		 Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2) Placebo Match Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects analysed
    100
    102
    97
    79
    Units: Scores on a Scale
    arithmetic mean (standard deviation)
        Week 104
    -4.05 ± 8.73
    -4.11 ± 8.57
    -6.42 ± 8.45
    -4.05 ± 8.68
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in Functional Activities Questionnaire (FAQ) Score at Week 104 (Double-Blind Treatment Phase)

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    End point title
    		 Mean Change From Baseline in Functional Activities Questionnaire (FAQ) Score at Week 104 (Double-Blind Treatment Phase)
    End point description
    Subjects completed the FAQ for physical function. Overall scores ranged from 0 (independent) to 30 (dependent) where lower scores represented an improvement in physical function.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    		 Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2) Placebo Match Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects analysed
    105
    104
    99
    84
    Units: Scores on a Scale
    arithmetic mean (standard deviation)
        Week 104
    3.59 ± 4.93
    4.89 ± 6.2
    4.03 ± 5.75
    3.6 ± 4.93
    Statistical analysis title
    		 Statistical Analysis II
    Comparison groups
    Placebo (Parts 1 and 2) v Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7171
    Method
    		 Mixed models analysis
    Parameter type
    		 Effect Size
    Point estimate
    0.043
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.19
         upper limit
    		 0.276
    Statistical analysis title
    		 Statistical Analysis I
    Comparison groups
    Placebo (Parts 1 and 2) v Gantenerumab 105 mg (Parts 1 and 2)
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0825
    Method
    		 Mixed models analysis
    Parameter type
    		 Effect Size
    Point estimate
    -0.191
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.407
         upper limit
    		 0.025

    Secondary: Mean Change From Baseline in CDR-Global Score at Week 104 (Double-Blind Treatment Phase)

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    End point title
    		 Mean Change From Baseline in CDR-Global Score at Week 104 (Double-Blind Treatment Phase)
    End point description
    The CDR-GS represents a semi-structured interview which 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 CDR 0 = no dementia and CDR 0.5, 1, 2 or 3 = questionable, mild, moderate or severe dementia respectively. The range in scores for the CDR-GS is from 0 to 3 and a high score on the CDR-GS would indicate a high disease severity.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    		 Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2) Placebo Match Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects analysed
    104
    105
    100
    83
    Units: Scores on a Scale
    arithmetic mean (standard deviation)
        Week 104
    0.1 ± 0.29
    0.18 ± 0.36
    0.14 ± 0.33
    0.1 ± 0.31
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline in Neuropsychiatric Inventory (NPI) Questionnaire Score at Week 104 (Double-Blind Treatment Phase)

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    End point title
    		 Mean Change from Baseline in Neuropsychiatric Inventory (NPI) Questionnaire Score at Week 104 (Double-Blind Treatment Phase)
    End point description
    The NPI is a retrospective (to 1 month) caregiver-informant interview assessing frequency and severity of 12 neuropsychiatric symptom domains. The NPI score is based on the sum of the severity ratings (0=absent, 1=mild, 3=severe). The 12 symptom domains include delusions, hallucinations, agitation/aggression, dysphoria/depression, anxiety, euphoria/elation, apathy/indifference, disinhibition, irritability/lability, aberrant motor behaviors, nighttime behavioral disturbances, and appetite/eating abnormalities. The NPI severity score is based on severity ratings (0=absent, 1=mild to 3=severe).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    		 Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2) Placebo Match Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects analysed
    103
    105
    99
    82
    Units: Scores on a Scale
        arithmetic mean (standard deviation)
    0.6 ± 3.22
    0.39 ± 2.57
    0.34 ± 2.84
    0.72 ± 3.35
    No statistical analyses for this end point

    Secondary: Percentage Change from Baseline in Cerebrospinal Fluid Biomarkers (Phosphorylated-tau [p-tau], Amyloid Beta 1-42 [Abeta 1-42], Total tau [t-tau]) at Week 104 (Double-Blind Treatment Phase)

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    End point title
    		 Percentage Change from Baseline in Cerebrospinal Fluid Biomarkers (Phosphorylated-tau [p-tau], Amyloid Beta 1-42 [Abeta 1-42], Total tau [t-tau]) at Week 104 (Double-Blind Treatment Phase)
    End point description
    CSF biomarker phospho-tau (p-tau) is an indicator of neuronal injury and neurodegeneration. An elevation in levels of tau, as well as specific p-tau species, is thought to be a marker for progressive cellular degeneration in AD.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    		 Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2) Placebo Match Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects analysed
    72
    71
    66
    56
    Units: Percentage Change
    arithmetic mean (standard deviation)
        p-tau (Week 104)
    2.77 ± 20.69
    -4.78 ± 11.9
    -7.34 ± 10.09
    2.84 ± 23.19
        t-tau (Week 104)
    3.43 ± 19.95
    -1.36 ± 12.89
    -2.12 ± 11.01
    3.46 ± 22.32
        Abeta (Week 104)
    4.87 ± 36.14
    2.45 ± 24.57
    15.2 ± 45.24
    4.3 ± 39.31
    Statistical analysis title
    		 Statistical Analysis I
    Statistical analysis description
    Statistical analysis of the Abeta 1-42 CSF biomarker between "Placebo (Parts 1 and 2)" and "Gantenerumab 105 mg (Parts 1 and 2)" treatment arms at Week 104.
    Comparison groups
    Placebo (Parts 1 and 2) v Gantenerumab 105 mg (Parts 1 and 2)
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.9734
    Method
    		 Mixed models analysis
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis II
    Statistical analysis description
    Statistical analysis of the Abeta 1-42 CSF biomarker between "Placebo (Parts 1 and 2)" and "Gantenerumab 225 mg (Parts 1 and 2)" treatment arms at Week 104.
    Comparison groups
    Placebo (Parts 1 and 2) v Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0629
    Method
    		 Mixed models analysis
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis III
    Statistical analysis description
    Statistical analysis of the p-tau CSF biomarker between "Placebo (Parts 1 and 2)" and "Gantenerumab 105 mg (Parts 1 and 2)" treatment arms at Week 104.
    Comparison groups
    Placebo (Parts 1 and 2) v Gantenerumab 105 mg (Parts 1 and 2)
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0084
    Method
    		 Mixed models analysis
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis IV
    Statistical analysis description
    Statistical analysis of the p-tau CSF biomarker between "Placebo (Parts 1 and 2)" and "Gantenerumab 225 mg (Parts 1 and 2)" treatment arms at Week 104.
    Comparison groups
    Placebo (Parts 1 and 2) v Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0003
    Method
    		 Mixed models analysis
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis V
    Statistical analysis description
    Statistical analysis of the t-tau CSF biomarker between "Placebo (Parts 1 and 2)" and "Gantenerumab 105 mg (Parts 1 and 2)" treatment arms at Week 104.
    Comparison groups
    Placebo (Parts 1 and 2) v Gantenerumab 105 mg (Parts 1 and 2)
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0903
    Method
    		 Mixed models analysis
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis VI
    Statistical analysis description
    Statistical analysis of the t-tau CSF biomarker between "Placebo (Parts 1 and 2)" and "Gantenerumab 225 mg (Parts 1 and 2)" treatment arms at Week 104.
    Comparison groups
    Placebo (Parts 1 and 2) v Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0434
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Percentage Change from Baseline in Hippocampal Volume at Week 104 (Double-Blind Treatment Phase)

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    End point title
    		 Percentage Change from Baseline in Hippocampal Volume at Week 104 (Double-Blind Treatment Phase)
    End point description
    Change from baseline in hippocampal right volume (HRV) and hippocampal left volume (HLV) were analysed at Week 104 using magnetic resonance imaging.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    		 Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2) Placebo Match Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects analysed
    131
    124
    119
    107
    Units: Percentage Change
    arithmetic mean (standard deviation)
        HRV (Week 104)
    -7.61 ± 4.03
    -7.52 ± 3.96
    -7.34 ± 3.84
    -7.7 ± 4.01
        HLV (Week 104)
    -7.8 ± 4.28
    -7.76 ± 3.74
    -7.27 ± 3.78
    -8.12 ± 4.19
    No statistical analyses for this end point

    Secondary: Percentage Change From Baseline in Cortical Composite Sustained Uptake Volume Ratio (SUVr) in Different Brain Regions at Week 156 (Double-Blind Treatment Phase)

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    End point title
    		 Percentage Change From Baseline in Cortical Composite Sustained Uptake Volume Ratio (SUVr) in Different Brain Regions at Week 156 (Double-Blind Treatment Phase)
    End point description
    The different regions of the brain that were analyzed included cerebellum gray, whole cerebellum, composite white matter, subcortical white matter, pons and composite reference.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 156
    End point values
    		 Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2) Placebo Match Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects analysed
    6
    4
    10
    4
    Units: Percentage Change
    arithmetic mean (standard deviation)
        Cerebellum gray (Week 156)
    6.26 ± 9.1
    2.7 ± 10.59
    -8.36 ± 9.11
    5.95 ± 11.13
        Whole Cerebellum (Week 156)
    5.41 ± 7.13
    2.07 ± 8.65
    -8.44 ± 8.06
    5.17 ± 8.66
        Composite White Matter (Week 156)
    2.75 ± 3.18
    -0.87 ± 2.95
    -4.86 ± 6.35
    3.07 ± 2.07
        Subcortical White Matter (Week 156)
    4.83 ± 4.95
    1.69 ± 4.45
    -0.42 ± 8.26
    4.59 ± 0.55
        Pons (Week 156)
    1.72 ± 2.51
    -2.83 ± 3.39
    -6.99 ± 5.65
    2.1 ± 2.73
        Composite Reference (Week 156)
    4.5 ± 3.48
    1.19 ± 5.63
    -6.75 ± 6.1
    4.46 ± 4.49
    No statistical analyses for this end point

    Secondary: Gantenerumab Plasma Concentrations at Different Time Points (Double-Blind Treatment Phase)

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    End point title
    		 Gantenerumab Plasma Concentrations at Different Time Points (Double-Blind Treatment Phase) [2]
    End point description
    The PK analyses includes tabulation of plasma concentration data and summarisation of plasma concentrations by visits with subjects grouped according to treatment received. Descriptive summary statistics for the Arithmetic Mean and Standard Deviation are presented below. (n=X; n=X) indicates the number of subjects analysed at each timepoint.
    End point type
    Secondary
    End point timeframe
    Pre-Dose: Weeks 8, 20, 44, 68 and 100; Post-Dose: Weeks 1, 53 and 101
    Notes
    [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: This analysis was only performed on the 'Double-Blind Treatment Phase' arms and hence why not all arms are presented.
    End point values
    		 Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects analysed
    239
    227
    Units: µg/ml (micrograms per milliliter)
    arithmetic mean (standard deviation)
        Week 1 (Post-Dose) (n=239; n=227)
    3.56 ± 2.36
    7.4 ± 4.28
        Week 8 (Pre-Dose) (n=237; n=225)
    2.87 ± 1.84
    5.92 ± 3.16
        Week 20 (Pre-Dose) (n=228; n=220)
    3.7 ± 2.15
    7.66 ± 4.14
        Week 44 (Pre-Dose) (n=212; n=199)
    4.08 ± 2.44
    8.22 ± 4.51
        Week 53 (Post-Dose) (n=195; n=185)
    6.77 ± 3.94
    15 ± 9.34
        Week 68 (Pre-Dose) (n=165; n=155)
    3.95 ± 2.35
    8.91 ± 4.86
        Week 100 (Pre-Dose) (n=98; n=86)
    4.35 ± 2.34
    9.4 ± 4.69
        Week 101 (Post-Dose) (n=95; n=77)
    7.32 ± 3.53
    16.63 ± 7.96
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in Mini Mental State Exam (MMSE) Score at Week 104 (Double-Blind Treatment Phase)

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    End point title
    		 Mean Change From Baseline in Mini Mental State Exam (MMSE) Score at Week 104 (Double-Blind Treatment Phase)
    End point description
    The MMSE is a brief, practical screening test for cognitive dysfunction. The test consists of five sections (orientation, registration, attention-calculation, recall, and language); the total score can range from 0 to 30, with a higher score indicating better function. A positive change score indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    		 Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects analysed
    104
    105
    99
    Units: Scores on a Scale
    arithmetic mean (standard deviation)
        Week 104
    -2.31 ± 3.23
    -2.46 ± 3.68
    -2.25 ± 3.31
    No statistical analyses for this end point

    Secondary: Number of Subjects with Adverse Events (AEs) or Serious Adverse Events (SAEs) (Double-Blind Treatment Phase)

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    End point title
    		 Number of Subjects with Adverse Events (AEs) or Serious Adverse Events (SAEs) (Double-Blind Treatment Phase)
    End point description
    An Adverse Event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
    End point type
    Secondary
    End point timeframe
    Baseline up until a maximum of 4.5 years
    End point values
    		 Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects analysed
    266
    271
    260
    Units: Subjects
    number (not applicable)
        AEs
    250
    241
    240
        SAEs
    55
    48
    46
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Anti-Drug Antibodies (ADAs) (Double-Blind Treatment Phase)

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    End point title
    		 Percentage of Subjects with Anti-Drug Antibodies (ADAs) (Double-Blind Treatment Phase)
    End point description
    Subjects were considered positive or negative for ADA based on their baseline and post-baseline sample results. The number and percentage of subjects with confirmed positive ADA levels were determined for Gantenerumab and Placebo groups. The prevalence of ADA at baseline was calculated as the proportion of subjects with confirmed positive ADA levels at baseline relative to the total number of subjects with a sample available at baseline. The incidence of treatment-emergent ADAs was determined as the proportion of subjects with confirmed post-baseline positive ADAs relative to the total number of subjects that had at least one post-baseline sample available for ADA analysis. (n=X; n=X; n=X) indicates the number of subjects analysed at each timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline up until a maximum of 4.5 years
    End point values
    		 Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects analysed
    259
    266
    256
    Units: Percentage of Subjects
    number (not applicable)
        Baseline ADAs (n=259; n=266; n=256)
    5.8
    7.5
    5.5
        Treatment Emergent ADAs (n=259; n=258; n=250)
    5.0
    7.0
    6.4
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in Alzheimer Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog-11) Scores at Week 156 (OLE Phase)

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    End point title
    		 Mean Change From Baseline in Alzheimer Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog-11) Scores at Week 156 (OLE Phase)
    End point description
    The ADAS-Cog-11 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 score range for ADAS-Cog-11 is from 0 to 70 with higher scores representing severe dysfunction.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 156
    End point values
    		 Plac (Parts 1 + 2) switched to Gant Up to 1200mg (Part 3 OLE) Gant Up to 1200 mg (Part 3 OLE)
    Number of subjects analysed
    21
    51
    Units: Scores on a Scale
    arithmetic mean (standard deviation)
        Week 156
    5.8 ± 7.3
    8.9 ± 9.7
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) Total Score at Week 156 (OLE Phase)

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    End point title
    		 Mean Change From Baseline in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) Total Score at Week 156 (OLE Phase)
    End point description
    The CDR (Clinical Dementia Rating) is obtained through semi-structured interviews of participants and informants, and cognitive functioning is rated in six domains of functioning: memory, orientation, judgement and problem solving, community affairs, home and hobbies, and personal care. Each domain is rated on a five-point scale of functioning as follows: 0, no impairment; 0.5, questionable impairment; 1, mild impairment; 2, moderate impairment; and 3, severe impairment. The CDR-SOB (Clinical Dementia Rating-Sum of Boxes) is based on summing each of the domain box scores with total scores ranging from 0-18, where lower total scores represent better outcomes and higher total scores represent worse outcomes.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 156
    End point values
    		 Plac (Parts 1 + 2) switched to Gant Up to 1200mg (Part 3 OLE) Gant Up to 1200 mg (Part 3 OLE)
    Number of subjects analysed
    21
    52
    Units: Scores on a Scale
    arithmetic mean (standard deviation)
        Week 156
    3.3 ± 2.4
    2.8 ± 3.0
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in Alzheimer Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog-13) Scores at Week 156 (OLE Phase)

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    End point title
    		 Mean Change From Baseline in Alzheimer Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog-13) Scores at Week 156 (OLE Phase)
    End point description
    The ADAS-Cog-13 assesses multiple cognitive domains including memory, comprehension, praxis, orientation, and spontaneous speech. The score range for ADAS-Cog-13 is from 0 to 85 with higher scores representing severe dysfunction.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 156
    End point values
    		 Plac (Parts 1 + 2) switched to Gant Up to 1200mg (Part 3 OLE) Gant Up to 1200 mg (Part 3 OLE)
    Number of subjects analysed
    21
    51
    Units: Scores on a Scale
    arithmetic mean (standard deviation)
        Week 156
    8.0 ± 8.2
    10.4 ± 10.6
    No statistical analyses for this end point

    Secondary: Time to Onset of Dementia at Week 156 (OLE Phase)

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    End point title
    		 Time to Onset of Dementia at Week 156 (OLE Phase)
    End point description
    Time to Onset of Dementia was defined as the time interval between the first treatment date and the date that subject is assessed as having Alzheimer-type dementia by investigators.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 156
    End point values
    		 Plac (Parts 1 + 2) switched to Gant Up to 1200mg (Part 3 OLE) Gant Up to 1200 mg (Part 3 OLE)
    Number of subjects analysed
    3
    14
    Units: Days
        median (confidence interval 95%)
    38.18 (9.90 to 66.97)
    50.82 (32.04 to 66.87)
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline in Free and Cued Selective Reminding Test (FCSRT) Score at Week 156 (OLE Phase)

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    End point title
    		 Mean Change from Baseline in Free and Cued Selective Reminding Test (FCSRT) Score at Week 156 (OLE Phase)
    End point description
    FCSRT assesses verbal episodic memory. Performances in free recalls, cued recalls and in a recognition task were analyzed, as the process of encoding is controlled. Subjects were asked to remember a list of 16 words. Three tasks of free and cued recalls, as well as 1 recognition task and one delayed recall give the scores. Total recall was obtained by the addition of cued recalls to free recalls. Maximum score is 48 for immediate: 16 words multiplied by (*) 3 corresponding to immediate free recall + immediate cued recall + immediate recognition test. Maximum score is 64 (better score) when delayed recall: 16 words*4. The minimum score is 0 (worse).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 156
    End point values
    		 Plac (Parts 1 + 2) switched to Gant Up to 1200mg (Part 3 OLE) Gant Up to 1200 mg (Part 3 OLE)
    Number of subjects analysed
    22
    51
    Units: Scores on a Scale
    arithmetic mean (standard deviation)
        Week 156
    -7.7 ± 9.3
    -4.1 ± 8.3
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in Functional Activities Questionnaire (FAQ) Score at Week 156 (OLE Phase)

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    End point title
    		 Mean Change From Baseline in Functional Activities Questionnaire (FAQ) Score at Week 156 (OLE Phase)
    End point description
    Subjects completed the FAQ for physical function. Overall scores ranged from 0 (independent) to 30 (dependent) where lower scores represented an improvement in physical function.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 156
    End point values
    		 Plac (Parts 1 + 2) switched to Gant Up to 1200mg (Part 3 OLE) Gant Up to 1200 mg (Part 3 OLE)
    Number of subjects analysed
    22
    52
    Units: Scores on a Scale
    arithmetic mean (standard deviation)
        Week 156
    8.1 ± 5.3
    6.8 ± 6.8
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in CDR-Global Score at Week 156 (OLE Phase)

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    End point title
    		 Mean Change From Baseline in CDR-Global Score at Week 156 (OLE Phase)
    End point description
    The CDR-GS represents a semi-structured interview which 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 CDR 0 = no dementia and CDR 0.5, 1, 2 or 3 = questionable, mild, moderate or severe dementia respectively. The range in scores for the CDR-GS is from 0 to 3 and a high score on the CDR-GS would indicate a high disease severity.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 156
    End point values
    		 Plac (Parts 1 + 2) switched to Gant Up to 1200mg (Part 3 OLE) Gant Up to 1200 mg (Part 3 OLE)
    Number of subjects analysed
    21
    52
    Units: Scores on a Scale
    arithmetic mean (standard deviation)
        Week 156
    0.6 ± 0.6
    0.5 ± 0.6
    No statistical analyses for this end point

    Secondary: Percentage Change from Baseline in Hippocampal Volume at Week 152 (OLE Phase)

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    End point title
    		 Percentage Change from Baseline in Hippocampal Volume at Week 152 (OLE Phase)
    End point description
    Change from baseline in hippocampal right volume (HRV) and hippocampal left volume (HLV) were analysed at Week 152 using magnetic resonance imaging.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 152
    End point values
    		 Plac (Parts 1 + 2) switched to Gant Up to 1200mg (Part 3 OLE) Gant Up to 1200 mg (Part 3 OLE)
    Number of subjects analysed
    18
    51
    Units: Percentage Change
    arithmetic mean (standard deviation)
        HRV (Week 152)
    16.7 ± 8.4
    16.1 ± 8.2
        HLV (Week 152)
    16.2 ± 13.0
    18.0 ± 8.9
    No statistical analyses for this end point

    Secondary: Percentage Change From Baseline in Cortical Composite Sustained Uptake Volume Ratio (SUVr) in Different Brain Regions at Week 156 (OLE Phase)

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    End point title
    		 Percentage Change From Baseline in Cortical Composite Sustained Uptake Volume Ratio (SUVr) in Different Brain Regions at Week 156 (OLE Phase)
    End point description
    The different regions of the brain that were analyzed included cerebellum gray, whole cerebellum, composite white matter, subcortical white matter, pons and composite reference.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 156
    End point values
    		 Gant Up to 1200 mg (Part 3 OLE)
    Number of subjects analysed
    2
    Units: Percentage Change
    arithmetic mean (standard deviation)
        Cerebellum gray (Week 156)
    -0.2 ± 0.2
        Composite Reference (Week 156)
    -41.4 ± 29.9
    No statistical analyses for this end point

    Secondary: Gantenerumab Plasma Concentrations at Different Time Points (OLE Phase)

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    End point title
    		 Gantenerumab Plasma Concentrations at Different Time Points (OLE Phase)
    End point description
    The PK analyses includes tabulation of plasma concentration data and summarisation of plasma concentrations by visits with subjects grouped according to treatment received. Descriptive summary statistics for the Arithmetic Mean and Standard Deviation are presented below. (n=X) indicates the number of subjects analysed at each timepoint.
    End point type
    Secondary
    End point timeframe
    Pre-Dose: Weeks 64, 100, 104, 136, 156 and 208; Post-Dose: Week 101
    End point values
    		 Gant 1200 mg (Part 3 OLE)
    Number of subjects analysed
    99
    Units: µg/ml (micrograms per milliliter)
    arithmetic mean (standard deviation)
        Week 64 (Pre-Dose) (n=99)
    33.0 ± 21.7
        Week 100 (Pre-Dose) (n=89)
    39.2 ± 22.7
        Week 101 (Post-Dose) (n=88)
    80.5 ± 37.8
        Week 104 (Pre-Dose) (n=91)
    40.5 ± 22.5
        Week 136 (Pre-Dose) (n=83)
    45.2 ± 22.4
        Week 156 (Pre-Dose) (n=93)
    39.6 ± 28.2
        Week 208 (Pre-Dose) (n=26)
    37.1 ± 29.2
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in Mini Mental State Exam (MMSE) Score at Week 156 (OLE Phase)

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    End point title
    		 Mean Change From Baseline in Mini Mental State Exam (MMSE) Score at Week 156 (OLE Phase)
    End point description
    The MMSE is a brief, practical screening test for cognitive dysfunction. The test consists of five sections (orientation, registration, attention-calculation, recall, and language); the total score can range from 0 to 30, with a higher score indicating better function. A positive change score indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 156
    End point values
    		 Plac (Parts 1 + 2) switched to Gant Up to 1200mg (Part 3 OLE) Gant Up to 1200 mg (Part 3 OLE)
    Number of subjects analysed
    22
    53
    Units: Scores on a Scale
    arithmetic mean (standard deviation)
        Week 156
    -4.3 ± 4.3
    -4.7 ± 4.6
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Anti-Drug Antibodies (ADAs) (OLE Phase)

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    End point title
    		 Percentage of Subjects with Anti-Drug Antibodies (ADAs) (OLE Phase)
    End point description
    Subjects were considered positive or negative for ADA based on their baseline and post-baseline sample results. The number and percentage of subjects with confirmed positive ADA levels were determined. The prevalence of ADA at baseline was calculated as the proportion of subjects with confirmed positive ADA levels at baseline relative to the total number of subjects with a sample available at baseline. The incidence of treatment-emergent ADAs was determined as the proportion of subjects with confirmed post-baseline positive ADAs relative to the total number of subjects that had at least one post-baseline sample available for ADA analysis. (n=X; n=X) indicates the number of subjects analysed at each timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline up until a maximum of 5 years
    End point values
    		 Plac (Parts 1 + 2) switched to Gant Up to 1200mg (Part 3 OLE) Gant Up to 1200 mg (Part 3 OLE)
    Number of subjects analysed
    49
    104
    Units: Percentage of Subjects
    number (not applicable)
        Baseline ADAs (n=49; n=104)
    2.0
    5.8
        Treatment Emergent ADAs (n=46; n=102)
    2.2
    2.9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up until a maximum of 9.5 years
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Placebo (Parts 1 and 2)
    Reporting group description
    		 Subjects with Alzheimer's disease received Placebo by SC injection every 4 weeks (Q4W) for 104 weeks or approximately 2 years during Part 1 of the study. Subjects who completed the Week 104 visit were given an option to continue the treatment received during Part 1, for 2 additional years in Part 2.

    Reporting group title
    Gantenerumab 105 mg (Parts 1 and 2)
    Reporting group description
    		 Subjects with Alzheimer's disease received Gantenerumab 105 mg by SC injection every 4 weeks (Q4W) for 104 weeks or approximately 2 years during Part 1 of the study. Subjects who completed the Week 104 visit were given an option to continue the treatment received during Part 1, for 2 additional years in Part 2.

    Reporting group title
    Gantenerumab 225 mg (Parts 1 and 2)
    Reporting group description
    		 Subjects with Alzheimer's disease received Gantenerumab 225 mg by SC injection every 4 weeks (Q4W) for 104 weeks or approximately 2 years during Part 1 of the study. Subjects who completed the Week 104 visit were given an option to continue the treatment received during Part 1, for 2 additional years in Part 2.

    Reporting group title
    Plac (Parts 1 + 2) switched to Gant Up to 1200mg (Part 3 OLE)
    Reporting group description
    		 Subjects with Alzheimer's disease who had received Placebo by SC injection in Part 1 or Part 2, now received Gantenerumab at doses up to 1200 mg by SC injection every 4 weeks (Q4W) for up to 5 additional years.

    Reporting group title
    Gant Up to 1200 mg (Part 3 OLE)
    Reporting group description
    		 Subjects with Alzheimer's disease who had received Gantenerumab by SC injection in Part 1 or Part 2, now received Gantenerumab at doses up to 1200 mg by SC injection every 4 weeks (Q4W) for up to 5 additional years.

    Serious adverse events
    		 Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2) Plac (Parts 1 + 2) switched to Gant Up to 1200mg (Part 3 OLE) Gant Up to 1200 mg (Part 3 OLE)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    55 / 266 (20.68%)
    48 / 271 (17.71%)
    46 / 260 (17.69%)
    18 / 49 (36.73%)
    28 / 105 (26.67%)
         number of deaths (all causes)
    6
    0
    2
    1
    3
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Biliary cancer metastatic
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Breast cancer
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    1 / 105 (0.95%)
         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
    Colon cancer
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    1 / 260 (0.38%)
    1 / 49 (2.04%)
    0 / 105 (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
    Leukaemia
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Lung cancer metastatic
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    1 / 105 (0.95%)
         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
    Metastases to bone
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Plasmacytoma
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Prostate cancer
         subjects affected / exposed
    2 / 266 (0.75%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small cell carcinoma
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Basal cell carcinoma
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Benign ovarian tumour
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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 cancer
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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 / 266 (0.00%)
    1 / 271 (0.37%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone sarcoma
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Breast cancer stage II
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Gastrointestinal tract adenoma
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Glioma
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Intestinal adenocarcinoma
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Intraductal proliferative breast lesion
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Pharyngeal neoplasm benign
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Rectal adenocarcinoma
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Renal cell carcinoma
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Renal oncocytoma
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Tongue neoplasm malignant stage unspecified
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Laryngeal squamous cell carcinoma
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    1 / 105 (0.95%)
         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
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery aneurysm
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Hypotension
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Malignant hypertension
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Peripheral ischaemia
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    1 / 49 (2.04%)
    0 / 105 (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
    Surgical and medical procedures
    Hip arthroplasty
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Knee arthroplasty
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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 decompression
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Urethral dilation procedure
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Rotator cuff repair
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    1 / 49 (2.04%)
    0 / 105 (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
    Urethral caruncle removal
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Device dislocation
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Malaise
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Pain
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Pyrexia
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Asthenia
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    1 / 105 (0.95%)
         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
    Gait disturbance
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    1 / 49 (2.04%)
    0 / 105 (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
    Sudden death
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    1 / 105 (0.95%)
         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
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Type I hypersensitivity
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    Reproductive system and breast disorders
    Prostatomegaly
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    2 / 260 (0.77%)
    0 / 49 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Cystocele
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Ovarian cyst
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Respiratory, thoracic and mediastinal disorders
    Delirium
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Pulmonary embolism
         subjects affected / exposed
    1 / 266 (0.38%)
    1 / 271 (0.37%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    1 / 49 (2.04%)
    0 / 105 (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
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Confusional state
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    3 / 105 (2.86%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Behavioral and psychological symptoms of dementia
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Depression
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Major depression
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Suicide attempt
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Delusion
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    1 / 105 (0.95%)
         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
    Neuropsychiatric symptoms
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Suicidal behaviour
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    1 / 105 (0.95%)
         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
    Investigations
    Blood pressure increased
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Body temperature increased
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    1 / 105 (0.95%)
         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
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    2 / 49 (4.08%)
    4 / 105 (3.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    1 / 105 (0.95%)
         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
    Head injury
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    1 / 49 (2.04%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 266 (0.38%)
    1 / 271 (0.37%)
    2 / 260 (0.77%)
    1 / 49 (2.04%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 1
    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 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Post lumbar puncture syndrome
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    1 / 105 (0.95%)
         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
    Subdural haemorrhage
         subjects affected / exposed
    1 / 266 (0.38%)
    1 / 271 (0.37%)
    1 / 260 (0.38%)
    1 / 49 (2.04%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    1 / 49 (2.04%)
    0 / 105 (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
    Ankle fracture
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Femur fracture
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Humerus fracture
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Laceration
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Ligament rupture
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Lower limb fracture
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Meniscus injury
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Post procedural haematuria
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Radiation mucositis
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Radius fracture
         subjects affected / exposed
    2 / 266 (0.75%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    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 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Spinal fracture
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Tibia fracture
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Urinary retention postoperative
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Muscle strain
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    1 / 105 (0.95%)
         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
    Joint injury
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    1 / 105 (0.95%)
         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
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    1 / 49 (2.04%)
    0 / 105 (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
    Bradycardia
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    1 / 105 (0.95%)
         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
    Cardiac failure
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Mitral valve incompetence
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Myocardial infarction
         subjects affected / exposed
    2 / 266 (0.75%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    1 / 105 (0.95%)
         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
    Acute coronary syndrome
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Angina unstable
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Arteriosclerosis coronary artery
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Atrial fibrillation
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Atrial thrombosis
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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 ventricular thrombosis
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Coronary artery disease
         subjects affected / exposed
    0 / 266 (0.00%)
    2 / 271 (0.74%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial rupture
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Sinus arrest
         subjects affected / exposed
    1 / 266 (0.38%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    1 / 105 (0.95%)
         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
    Atrial flutter
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    1 / 49 (2.04%)
    0 / 105 (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
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Cerebellar infarction
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    1 / 49 (2.04%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Dementia with Lewy bodies
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Epilepsy
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    2 / 105 (1.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Retrograde amnesia
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Seizure
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thalamic infarction
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Amyotrophic lateral sclerosis
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    Dizziness
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Ischaemic stroke
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    2 / 260 (0.77%)
    0 / 49 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Monoparesis
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Presyncope
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Radial nerve palsy
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    2 / 266 (0.75%)
    1 / 271 (0.37%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient global amnesia
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Transient ischaemic attack
         subjects affected / exposed
    1 / 266 (0.38%)
    1 / 271 (0.37%)
    2 / 260 (0.77%)
    0 / 49 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ARIA-E
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    2 / 105 (1.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haematoma
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    1 / 49 (2.04%)
    0 / 105 (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
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    1 / 105 (0.95%)
         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
    Headache
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Neuropathy peripheral
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    1 / 49 (2.04%)
    0 / 105 (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
    Speech disorder
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    1 / 105 (0.95%)
         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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    1 / 105 (0.95%)
         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
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    1 / 49 (2.04%)
    0 / 105 (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
    Ear and labyrinth disorders
    Deafness unilateral
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    1 / 49 (2.04%)
    0 / 105 (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
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    0 / 266 (0.00%)
    2 / 271 (0.74%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Visual impairment
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Gastrointestinal disorders
    Gastric haemorrhage
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Gastric ulcer
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Inguinal hernia
         subjects affected / exposed
    2 / 266 (0.75%)
    1 / 271 (0.37%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Abdominal pain
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Diarrhoea
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Gastritis
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Hiatus hernia
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Pancreatic mass
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Umbilical hernia
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Constipation
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    1 / 49 (2.04%)
    0 / 105 (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
    Intestinal obstruction
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    1 / 49 (2.04%)
    0 / 105 (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
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Cholelithiasis
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Renal and urinary disorders
    Bladder obstruction
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Haematuria
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Endocrine disorders
    Diabetes insipidus
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 266 (0.38%)
    1 / 271 (0.37%)
    1 / 260 (0.38%)
    1 / 49 (2.04%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis reactive
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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 column stenosis
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Osteitis
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    1 / 105 (0.95%)
         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
    Pain in extremity
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    1 / 49 (2.04%)
    0 / 105 (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
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Atypical pneumonia
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Infection
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Sepsis
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    1 / 49 (2.04%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    1 / 49 (2.04%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Bacterial sepsis
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Cellulitis
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Cholecystitis infective
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Cystitis
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Erysipelas
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Gastroenteritis
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Gastroenteritis viral
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Lyme disease
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    Pleural infection bacterial
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Pneumonia
         subjects affected / exposed
    1 / 266 (0.38%)
    1 / 271 (0.37%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    0 / 105 (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
    Subcutaneous abscess
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
    0 / 49 (0.00%)
    0 / 105 (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
    COVID-19
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    1 / 49 (2.04%)
    0 / 105 (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
    Diverticulitis
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    1 / 105 (0.95%)
         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
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    1 / 49 (2.04%)
    0 / 105 (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
    Otitis media
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    1 / 49 (2.04%)
    0 / 105 (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
    Respiratory tract infection
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    1 / 105 (0.95%)
         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
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    1 / 105 (0.95%)
         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
    Diabetes mellitus
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    1 / 105 (0.95%)
         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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2) Plac (Parts 1 + 2) switched to Gant Up to 1200mg (Part 3 OLE) Gant Up to 1200 mg (Part 3 OLE)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    163 / 266 (61.28%)
    188 / 271 (69.37%)
    189 / 260 (72.69%)
    40 / 49 (81.63%)
    87 / 105 (82.86%)
    Investigations
    Weight decreased
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    2 / 49 (4.08%)
    6 / 105 (5.71%)
         occurrences all number
    0
    0
    0
    2
    7
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    28 / 266 (10.53%)
    23 / 271 (8.49%)
    27 / 260 (10.38%)
    13 / 49 (26.53%)
    17 / 105 (16.19%)
         occurrences all number
    42
    32
    38
    20
    29
    Contusion
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    4 / 49 (8.16%)
    5 / 105 (4.76%)
         occurrences all number
    0
    0
    0
    4
    5
    Skin laceration
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    0 / 49 (0.00%)
    7 / 105 (6.67%)
         occurrences all number
    0
    0
    0
    0
    8
    Vascular disorders
    Hypertension
         subjects affected / exposed
    18 / 266 (6.77%)
    11 / 271 (4.06%)
    20 / 260 (7.69%)
    2 / 49 (4.08%)
    8 / 105 (7.62%)
         occurrences all number
    20
    11
    23
    2
    11
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    21 / 266 (7.89%)
    21 / 271 (7.75%)
    26 / 260 (10.00%)
    4 / 49 (8.16%)
    14 / 105 (13.33%)
         occurrences all number
    21
    27
    35
    5
    18
    Headache
         subjects affected / exposed
    36 / 266 (13.53%)
    34 / 271 (12.55%)
    25 / 260 (9.62%)
    7 / 49 (14.29%)
    12 / 105 (11.43%)
         occurrences all number
    50
    47
    36
    11
    18
    ARIA-E
         subjects affected / exposed
    2 / 266 (0.75%)
    18 / 271 (6.64%)
    34 / 260 (13.08%)
    12 / 49 (24.49%)
    29 / 105 (27.62%)
         occurrences all number
    2
    20
    36
    21
    45
    ARIA-H
         subjects affected / exposed
    31 / 266 (11.65%)
    58 / 271 (21.40%)
    36 / 260 (13.85%)
    7 / 49 (14.29%)
    17 / 105 (16.19%)
         occurrences all number
    51
    92
    64
    12
    44
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    8 / 266 (3.01%)
    7 / 271 (2.58%)
    15 / 260 (5.77%)
    0 / 49 (0.00%)
    0 / 105 (0.00%)
         occurrences all number
    8
    7
    20
    0
    0
    Injection site erythema
         subjects affected / exposed
    3 / 266 (1.13%)
    29 / 271 (10.70%)
    35 / 260 (13.46%)
    17 / 49 (34.69%)
    36 / 105 (34.29%)
         occurrences all number
    3
    133
    114
    196
    359
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    4 / 49 (8.16%)
    2 / 105 (1.90%)
         occurrences all number
    0
    0
    0
    5
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    13 / 266 (4.89%)
    15 / 271 (5.54%)
    15 / 260 (5.77%)
    3 / 49 (6.12%)
    11 / 105 (10.48%)
         occurrences all number
    18
    22
    18
    3
    14
    Vomiting
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    5 / 49 (10.20%)
    6 / 105 (5.71%)
         occurrences all number
    0
    0
    0
    5
    9
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    13 / 266 (4.89%)
    11 / 271 (4.06%)
    13 / 260 (5.00%)
    5 / 49 (10.20%)
    8 / 105 (7.62%)
         occurrences all number
    14
    13
    13
    5
    12
    Productive cough
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    3 / 49 (6.12%)
    0 / 105 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    18 / 266 (6.77%)
    20 / 271 (7.38%)
    16 / 260 (6.15%)
    2 / 49 (4.08%)
    7 / 105 (6.67%)
         occurrences all number
    23
    20
    16
    2
    8
    Depression
         subjects affected / exposed
    13 / 266 (4.89%)
    23 / 271 (8.49%)
    25 / 260 (9.62%)
    0 / 49 (0.00%)
    0 / 105 (0.00%)
         occurrences all number
    14
    23
    25
    0
    0
    Agitation
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    3 / 49 (6.12%)
    8 / 105 (7.62%)
         occurrences all number
    0
    0
    0
    4
    10
    Confusional state
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    5 / 49 (10.20%)
    8 / 105 (7.62%)
         occurrences all number
    0
    0
    0
    5
    8
    Irritability
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    1 / 49 (2.04%)
    6 / 105 (5.71%)
         occurrences all number
    0
    0
    0
    1
    9
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    21 / 266 (7.89%)
    12 / 271 (4.43%)
    16 / 260 (6.15%)
    2 / 49 (4.08%)
    8 / 105 (7.62%)
         occurrences all number
    29
    14
    17
    2
    8
    Back pain
         subjects affected / exposed
    26 / 266 (9.77%)
    16 / 271 (5.90%)
    26 / 260 (10.00%)
    2 / 49 (4.08%)
    10 / 105 (9.52%)
         occurrences all number
    33
    18
    31
    2
    10
    Musculoskeletal pain
         subjects affected / exposed
    16 / 266 (6.02%)
    6 / 271 (2.21%)
    5 / 260 (1.92%)
    0 / 49 (0.00%)
    0 / 105 (0.00%)
         occurrences all number
    18
    7
    5
    0
    0
    Osteoporosis
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    3 / 49 (6.12%)
    1 / 105 (0.95%)
         occurrences all number
    0
    0
    0
    3
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    10 / 266 (3.76%)
    10 / 271 (3.69%)
    14 / 260 (5.38%)
    3 / 49 (6.12%)
    7 / 105 (6.67%)
         occurrences all number
    10
    12
    18
    3
    9
    Influenza
         subjects affected / exposed
    13 / 266 (4.89%)
    13 / 271 (4.80%)
    15 / 260 (5.77%)
    3 / 49 (6.12%)
    7 / 105 (6.67%)
         occurrences all number
    14
    18
    17
    4
    8
    Nasopharyngitis
         subjects affected / exposed
    17 / 266 (6.39%)
    30 / 271 (11.07%)
    20 / 260 (7.69%)
    7 / 49 (14.29%)
    15 / 105 (14.29%)
         occurrences all number
    34
    40
    35
    7
    23
    Upper respiratory tract infection
         subjects affected / exposed
    11 / 266 (4.14%)
    13 / 271 (4.80%)
    18 / 260 (6.92%)
    5 / 49 (10.20%)
    10 / 105 (9.52%)
         occurrences all number
    14
    15
    21
    5
    19
    Urinary tract infection
         subjects affected / exposed
    25 / 266 (9.40%)
    16 / 271 (5.90%)
    22 / 260 (8.46%)
    4 / 49 (8.16%)
    15 / 105 (14.29%)
         occurrences all number
    37
    25
    38
    6
    25
    Herpes Zoster
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
    4 / 49 (8.16%)
    1 / 105 (0.95%)
         occurrences all number
    0
    0
    0
    4
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Jun 2011
    Following updates were made: [1] An overall benefit-risk assessment subsection was added; information about the RNA sampling was added to the optional RCR sampling; age range for inclusion was changed from 50-85 to 50-80; text were added for contraception requirements for women of childbearing potential; and inclusion criteria were amended to allow for screening of subjects with abnormal memory function based on the FCSRT-IR up to one month prior to the first screening visit; [2] Experience at sites indicated that several subjects fail screening solely for right bundle branch block (RBBB). As ECG monitoring study was also used to collect data for this biological investigational drug in order to obtain regulatory waiver for a thorough QT study, the possibility to allow RBBB patients who may not be included in QTc analysis was reviewed again with the conclusion that RBBB patients can be enrolled; [3] Exclusion 35 was reformatted to more clearly quantify the amount of use permitted for some agents; information regarding the C-SSRS test was added; instructions were added to be followed in the event of a second occurrence of 2 new microbleeds on a single MRI, and explanation of the procedures to be followed if a new microbleed is seen on an MRI; [4] Analysis plan was clarified to mention that analysis may include measurement of beta amyloid pyroglutamate and CSF biomarkers; and Information regarding missed dose, and information regarding analysis and sample collection of ADA was added.
    14 Mar 2012
    Following updates were made: [1] The sample size was updated; requirements for post screening CDR global score and FCSRT-IR evaluations were added; requirements for separate interim data review committee or a separate group performing unblinded analysis were removed; [2] A negative pregnancy test requirement prior to start of treatment was extended for throughout the duration of treatment for women of child bearing potential. It was added that women of child-bearing potential must have a pregnancy test done at the site prior to each dose; [3] A paragraph requesting investigators to report increases in ALT or AST in combination with an increase in total bilirubin or jaundice as an SAE to the Sponsor due to regulatory reasons.
    15 Feb 2013
    Following updates were made: [1] Information regarding two interim analysis, an administrative interim analysis and a subsequent futility analysis, was added; text regarding sensitivity analysis and subgroup analysis were added; [2] The primary efficacy comparison of the high dose gantenerumab arm to the placebo arm was changed so that only placebo subjects with APOE 0ε4 or APOE 1ε4 were to be included in the analysis, and not the ones with APOE 2ε4; [3] Part 2 (extension) of the study was added; procedures to follow in the event of ARIA-H findings and abnormal MRI findings were updated to reflect extension of the study; [4] Information regarding the use of symptomatic treatment for AD during the study was updated; frequency for testing of the primary endpoint (CDR) as well as the ADAS-cog and MMSE was updated to every 3 months through Year 4 from every 3 months through Year 2; details regarding availability of blinded interim safety data in the IB was added; and the information on possible analysis of concentration-effect relationship using PK data was added.
    17 Jul 2014
    Following updates were made: Relevant protocol sections were updated to better align with the independent MRI Review Committee (MRI-C) Charter that was revised. Guidance was added with regard to the reset of MRI schedules after withheld and then restarted dosing due to MRI findings; [2] Requirements for a final follow-up visit for safety and limited efficacy evaluations at 52 weeks after the final dose. The reporting period for AEs was updated accordingly; [3] Cerebrospinal fluid biomarkers, Aβ1−42, T-tau, and P-tau, were changed to secondary objective from exploratory objectives. Clarification about MRI volumetric measures was also added. [4] Guidance was added for the shelf life of reconstituted IMP prepared under aseptic and non-aseptic conditions. [5] Reporting period for pregnancies was adjusted to take into account 5 half-lives of study medication, in agreement with the SOP for safety report process of the Sponsor. [6] Information regarding precautionary measures were added in the case of abnormally low neutrophils (moderate to severe neutropenia) to align WN25203 with other gantenerumab protocols.
    16 Sep 2015
    Following updates were made: [1] Based on the futility analysis findings, Part 1 and 2 of the study was terminated in December 2014. The OLE, Part 3 was added to test gantenerumab at higher doses expected to have a clinically relevant effect. Revised dosing titration schemes were imposed for the OLE to manage risks of ARIA. This amendment also provides updated safety assessments and updated formulation information.
    09 Jul 2018
    Updated to allow subjects to continue receiving open-label gantenerumab until July 2020, at which time anticipated results from other relevant monoclonal antibody treatments targeting amyloid-beta will be available. Additional updates include: [1] Gantenerumab information has been updated; [2] MRI findings were updated; [3] Clarification of OLE phase objectives; [4] Storage parameters of solution at ambient temperature have been adjusted and [5] Conditions for recording MRI observations have been adjusted.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    19 Dec 2014
    Based on the futility analysis findings, dosing in Part 1 and 2 of the study was terminated on 19 December 2014. However, due to the observed effect of gantenerumab on amyloid plaques, further higher doses than previously studied in Part 1 and 2 of are being explored in Part 3 to evaluate the potential benefit for gantenerumab to slow the progression of AD.
    16 Sep 2015

    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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    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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