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

    Summary
    EudraCT number
    		 2015-003034-27
    Trial protocol
    		 ES   SE   GB   LT   HU   PT   CZ   FI   BE   DK   AT   SI   PL   DE   BG   HR   FR   IT  
    Global end of trial date
    31 May 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    05 Aug 2020
    First version publication date
    08 Jun 2020
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    BN29552
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02670083
    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
    31 May 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 May 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the safety and efficacy of Crenezumab
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Mar 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 13 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 16
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Bulgaria: 6
    Country: Number of subjects enrolled
    Canada: 45
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    Costa Rica: 7
    Country: Number of subjects enrolled
    Czech Republic: 3
    Country: Number of subjects enrolled
    Germany: 39
    Country: Number of subjects enrolled
    Denmark: 12
    Country: Number of subjects enrolled
    Spain: 108
    Country: Number of subjects enrolled
    Finland: 7
    Country: Number of subjects enrolled
    France: 21
    Country: Number of subjects enrolled
    United Kingdom: 28
    Country: Number of subjects enrolled
    Hong Kong: 7
    Country: Number of subjects enrolled
    Croatia: 11
    Country: Number of subjects enrolled
    Hungary: 7
    Country: Number of subjects enrolled
    Italy: 50
    Country: Number of subjects enrolled
    Japan: 20
    Country: Number of subjects enrolled
    Korea, Republic of: 24
    Country: Number of subjects enrolled
    Lithuania: 10
    Country: Number of subjects enrolled
    Mexico: 32
    Country: Number of subjects enrolled
    Poland: 14
    Country: Number of subjects enrolled
    Portugal: 6
    Country: Number of subjects enrolled
    Russian Federation: 38
    Country: Number of subjects enrolled
    Slovenia: 1
    Country: Number of subjects enrolled
    Sweden: 16
    Country: Number of subjects enrolled
    Turkey: 16
    Country: Number of subjects enrolled
    Ukraine: 8
    Country: Number of subjects enrolled
    United States: 254
    Worldwide total number of subjects
    813
    EEA total number of subjects
    344
    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)
    182
    From 65 to 84 years
    625
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 249 centers in 30 countries.

    Pre-assignment
    Screening details
    		 A total of 813 subjects were enrolled at 249 centers. 4 subjects did not receive any study treatment meaning that the modified intent-to-treat and safety populations consisted of 809 subjects.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo was administered by intravenous (IV) infusion every 4 weeks (Q4W) at a matching dosage to Crenezumab of 60mg/kg.

    Arm title
    		 Crenezumab
    Arm description
    		 Subjects received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Crenezumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Crenezumab was administered by intravenous (IV) infusion every 4 weeks (Q4W) at a dose of 60mg/kg.

    Number of subjects in period 1
    		Placebo Crenezumab
    Started
    409
    404
    Completed
    88
    85
    Not completed
    321
    319
         Adverse event, serious fatal
    4
    6
         Consent withdrawn by subject
    32
    31
         Physician decision
    -
    2
         Adverse event, non-fatal
    16
    13
         Study Terminated By Sponsor
    257
    254
         Multiple Reasons
    9
    9
         Non-Compliance With Study Drug
    1
    -
         Symptomatic Deterioration
    -
    2
         Lost to follow-up
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks.

    Reporting group title
    Crenezumab
    Reporting group description
    		 Subjects received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.

    Reporting group values
    		 Placebo Crenezumab Total
    Number of subjects
    		 409 404 813
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 99 83 182
        From 65-84 years
    		 306 319 625
        85 years and over
    		 4 2 6
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 70.3 ± 8.4 71.0 ± 7.9 -
    Sex: Female, Male
    Units:
        Female
    		 247 236 483
        Male
    		 162 168 330
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    		 39 32 71
        Not Hispanic or Latino
    		 361 369 730
        Not Stated
    		 7 2 9
        Unknown
    		 2 1 3
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 5 10 15
        Asian
    		 28 28 56
        Black or African American
    		 3 5 8
        Multiple
    		 0 1 1
        Unknown
    		 13 8 21
        White
    		 360 352 712

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks.

    Reporting group title
    Crenezumab
    Reporting group description
    		 Subjects received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.

    Subject analysis set title
    Placebo (Modified ITT)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Subjects received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks. The Modified Intent-To-Treat population (Placebo (n = 407); Cren (n = 402)) was defined as all randomized subjects who received at least 1 dose of study drug, with subjects grouped according to the treatment assigned at randomization.

    Subject analysis set title
    Crenezumab (Modified ITT)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Subjects received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks. The Modified Intent-To-Treat population (Placebo (n = 407); Cren (n = 402)) was defined as all randomized subjects who received at least 1 dose of study drug, with subjects grouped according to the treatment assigned at randomization.

    Subject analysis set title
    Placebo (Safety)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks. The Safety analysis population included all randomized subjects who received at least 1 dose of study drug with subjects grouped according to actual treatment received. If a subject received at least 2 vials of crenezumab, then they were placed in the crenezumab arm.

    Subject analysis set title
    Crenezumab (Safety)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks. The Safety analysis population included all randomized subjects who received at least 1 dose of study drug with subjects grouped according to actual treatment received. If a subject received at least 2 vials of crenezumab, then they were placed in the crenezumab arm.

    Primary: Change from Baseline to Week 105 in Clinical Dementia Rating-Sum of Boxes (CDR-SB) Score

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    End point title
    		 Change from Baseline to Week 105 in Clinical Dementia Rating-Sum of Boxes (CDR-SB) Score
    End point description
    The CDR-SB rates impairment in 6 categories (memory, orientation, judgement and problem solving, community affairs, home and hobbies and personal care) on a 5-point scale in which no impairment = 0, questionable impairment = 0.5 and mild, moderate and severe impairment = 1, 2 and 3 respectively. The score range is from 0 to 18 with a high score indicating a high disease severity. The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated subjects was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline for this primary endpoint. Data after 29 January 2019 are censored for the primary and secondary efficacy analyses to avoid potential biases due to investigators, subjects, raters, etc. being potentially influenced by early closure of the study due to lack of efficacy.
    End point type
    Primary
    End point timeframe
    Baseline, Week 105
    End point values
    		 Placebo (Modified ITT) Crenezumab (Modified ITT)
    Number of subjects analysed
    88 [1]
    86 [2]
    Units: Units on a Scale
    least squares mean (standard error)
        Week 105
    3.42 ± 0.263
    3.59 ± 0.264
    Notes
    [1] - Data presented is only for subjects that were included in the actual analysis.
    [2] - Data presented is only for subjects that were included in the actual analysis.
    Statistical analysis title
    		 Crenezumab versus Placebo
    Comparison groups
    Placebo (Modified ITT) v Crenezumab (Modified ITT)
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.86
         upper limit
    		 0.53
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.354

    Secondary: Change from Baseline to Week 105 on Cognition, as assessed by Alzheimer's Disease Assessment Scale-Cognition (ADAS-Cog) (subscale) 13 (ADAS-Cog-13)

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    End point title
    		 Change from Baseline to Week 105 on Cognition, as assessed by Alzheimer's Disease Assessment Scale-Cognition (ADAS-Cog) (subscale) 13 (ADAS-Cog-13)
    End point description
    The ADAS-Cog-13 assesses multiple cognitive domains including memory, comprehension, praxis, orientation, and spontaneous speech. Most of these are assessed by tests although some are rated by the clinician on a 5-point scale. The ADAS-Cog-13 is the ADAS-Cog-11 with 2 further items: delayed word recall and total digit cancellation. The score range for ADAS-Cog-13 is from 0 to 85 with high scores representing severe dysfunction. The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated subjects was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline. Data presented below is only for subjects that were included in the actual analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 105
    End point values
    		 Placebo (Modified ITT) Crenezumab (Modified ITT)
    Number of subjects analysed
    86
    80
    Units: Units on a Scale
    least squares mean (standard error)
        Week 105
    9.55 ± 0.824
    9.82 ± 0.841
    Statistical analysis title
    		 Crenezumab versus Placebo
    Comparison groups
    Placebo (Modified ITT) v Crenezumab (Modified ITT)
    Number of subjects included in analysis
    166
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.39
         upper limit
    		 1.87
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.083

    Secondary: Change from Baseline to Week 105 on Cognition, as assessed by Alzheimer's Disease Assessment Scale-Cognition (ADAS-Cog) (subscale) 11 (ADAS-Cog-11)

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    End point title
    		 Change from Baseline to Week 105 on Cognition, as assessed by Alzheimer's Disease Assessment Scale-Cognition (ADAS-Cog) (subscale) 11 (ADAS-Cog-11)
    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 high scores representing severe dysfunction. The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated subjects was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline. Data presented below is only for subjects that were included in the actual analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 105
    End point values
    		 Placebo (Modified ITT) Crenezumab (Modified ITT)
    Number of subjects analysed
    86
    80
    Units: Units on a Scale
    least squares mean (standard error)
        Week 105
    8.43 ± 0.758
    8.53 ± 0.773
    Statistical analysis title
    		 Crenezumab versus Placebo
    Comparison groups
    Placebo (Modified ITT) v Crenezumab (Modified ITT)
    Number of subjects included in analysis
    166
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.08
         upper limit
    		 1.88
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.006

    Secondary: Change from Baseline to Week 105 on Severity of Dementia, Assessed Using the CDR-Global Score (CDR-GS)

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    End point title
    		 Change from Baseline to Week 105 on Severity of Dementia, Assessed Using the CDR-Global Score (CDR-GS)
    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. The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated subjects was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline. Data presented below is only for subjects that were included in the actual analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 105
    End point values
    		 Placebo (Modified ITT) Crenezumab (Modified ITT)
    Number of subjects analysed
    88
    86
    Units: Units on a Scale
    least squares mean (standard error)
        Week 105
    0.55 ± 0.056
    0.50 ± 0.056
    Statistical analysis title
    		 Crenezumab versus Placebo
    Comparison groups
    Placebo (Modified ITT) v Crenezumab (Modified ITT)
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.076

    Secondary: Change from Baseline to Week 105 on Severity of Dementia, Assessed Using the Mini Mental State Evaluation (MMSE)

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    End point title
    		 Change from Baseline to Week 105 on Severity of Dementia, Assessed Using the Mini Mental State Evaluation (MMSE)
    End point description
    The MMSE is a set of standardized questions used to evaluate possible cognitive impairment and help stage the severity level of this impairment. The questions target 6 areas: orientation, registration, attention, short-term recall, language and constructional praxis/visuospatial abilities. The scores on the MMSE range from 0 to 30, with higher scores indicating better function. The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated subjects was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline. Data presented below is only for subjects that were included in the actual analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 105
    End point values
    		 Placebo (Modified ITT) Crenezumab (Modified ITT)
    Number of subjects analysed
    90
    87
    Units: Units on a Scale
    least squares mean (standard error)
        Week 105
    -4.63 ± 0.377
    -4.96 ± 0.383
    Statistical analysis title
    		 Crenezumab versus Placebo
    Comparison groups
    Placebo (Modified ITT) v Crenezumab (Modified ITT)
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.62
         upper limit
    		 1.29
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.486

    Secondary: Change from Baseline to Week 105 on function as assessed by the ADCS-ADL total score

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    End point title
    		 Change from Baseline to Week 105 on function as assessed by the ADCS-ADL total score
    End point description
    The ADCS-ADL (Alzheimer's Disease Cooperative Study-Activities of Daily Living) is the scale most widely used to assess functional outcomes in subjects with AD. The ADCS-ADL covers both basic ADL (e.g., eating and toileting) and more complex 'instrumental' ADL or iADL (e.g., using the telephone, managing finances and preparing a meal). The ADCS-ADL consists of 23 questions with a score range of 0 to 78 where a higher score represents better function. The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated subjects was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline. Data presented below is only for subjects that were included in the actual analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 105
    End point values
    		 Placebo (Modified ITT) Crenezumab (Modified ITT)
    Number of subjects analysed
    90
    88
    Units: Units on a Scale
    least squares mean (standard error)
        Week 105
    -11.51 ± 1.226
    -13.39 ± 1.242
    Statistical analysis title
    		 Crenezumab versus Placebo
    Comparison groups
    Placebo (Modified ITT) v Crenezumab (Modified ITT)
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    1.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.43
         upper limit
    		 5.18
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.679

    Secondary: Change from Baseline to Week 105 on function as assessed by the ADCS-instrumental (ADCS-iADL) subscore

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    End point title
    		 Change from Baseline to Week 105 on function as assessed by the ADCS-instrumental (ADCS-iADL) subscore
    End point description
    The ADCS-iADL (Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living) measures activities such as using the telephone, managing finances and preparing a meal. The ADCS-iADL consists of 16 questions with a score range of 0 to 56 where a higher score represents better function. The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated subjects was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline. Data presented below is only for subjects that were included in the actual analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 105
    End point values
    		 Placebo (Modified ITT) Crenezumab (Modified ITT)
    Number of subjects analysed
    90
    88
    Units: Units on a Scale
    least squares mean (standard error)
        Week 105
    -9.22 ± 0.967
    -10.44 ± 0.979
    Statistical analysis title
    		 Crenezumab versus Placebo
    Comparison groups
    Placebo (Modified ITT) v Crenezumab (Modified ITT)
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    1.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.35
         upper limit
    		 3.79
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.306

    Secondary: Change from Baseline to Week 105 on a measure of dependence derived from the ADCS-ADL score

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    End point title
    		 Change from Baseline to Week 105 on a measure of dependence derived from the ADCS-ADL score
    End point description
    Please note that for this Outcome Measure, no subjects were evaluated at all as the derivation of this endpoint was not pre-specified before the Sponsor terminated the study and therefore it was not reported.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 105
    End point values
    		 Placebo (Modified ITT) Crenezumab (Modified ITT)
    Number of subjects analysed
    0 [3]
    0 [4]
    Units: Units on a Scale
        least squares mean (standard error)
    ±
    ±
    Notes
    [3] - No Subjects were evaluated at all as described above.
    [4] - No Subjects were evaluated at all as described above.
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 105 assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q)

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    End point title
    		 Change from Baseline to Week 105 assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q)
    End point description
    The NPI-Q is an informant-based instrument that evaluates 12 neuropsychiatric disturbances common in dementia: delusions, hallucinations, agitation, dysphoria, anxiety, apathy, irritability, euphoria, disinhibition, aberrant motor behavior, night-time behavioral disturbances and appetite and eating abnormalities. The severity of each neuropsychiatric symptom is rated on a 3-point scale (mild, moderate and marked). The total severity score range is from 0 to 36 with higher scores representing higher severity. The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated subjects was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 105
    End point values
    		 Placebo (Modified ITT) Crenezumab (Modified ITT)
    Number of subjects analysed
    84 [5]
    87 [6]
    Units: Units on a Scale
    least squares mean (standard error)
        Week 105
    1.02 ± 0.562
    1.55 ± 0.556
    Notes
    [5] - Data presented is only for subjects that were included in the actual analysis.
    [6] - Data presented is only for subjects that were included in the actual analysis.
    Statistical analysis title
    		 Crenezumab versus Placebo
    Comparison groups
    Placebo (Modified ITT) v Crenezumab (Modified ITT)
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.95
         upper limit
    		 0.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.723

    Secondary: Quality of Life-Alzheimer's Disease (QoL-AD) Scale Score

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    End point title
    		 Quality of Life-Alzheimer's Disease (QoL-AD) Scale Score
    End point description
    The QoL-AD (Quality of Life - Alzheimer's Disease) scale assesses QoL in subjects who have dementia. The QoL-AD consists of 13 items covering aspects of subjects’ relationships with friends and family, physical condition, mood, concerns about finances and overall assessment of QoL. Items are rated on 4-point Likert-type scales ranging from 1 [poor] to 4 [excellent]. The score range is from 13 to 52, with higher scores indicating a better QoL. The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated subjects was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline. Data presented below is only for subjects that were included in the actual analysis.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 105
    End point values
    		 Placebo (Modified ITT) Crenezumab (Modified ITT)
    Number of subjects analysed
    90
    86
    Units: Units on a Scale
    least squares mean (standard error)
        Week 105
    -1.69 ± 0.501
    -2.08 ± 0.513
    Statistical analysis title
    		 Crenezumab versus Placebo
    Comparison groups
    Placebo (Modified ITT) v Crenezumab (Modified ITT)
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.81
         upper limit
    		 1.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.609

    Secondary: Zarit Caregiver Interview for Alzheimer's Disease (ZCI-AD) Scale Score

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    End point title
    		 Zarit Caregiver Interview for Alzheimer's Disease (ZCI-AD) Scale Score
    End point description
    The ZCI-AD is a modified version of the Zarit Burden Interview, which was originally designed to reflect the stresses experienced by caregivers of people with dementia. This modified version includes slight modifications in item and title wording (e.g., removal of “your relative” to refer directly to the patient, removal of “burden” from title) and the use of 11-point numerical rating scales. The ZCI-AD scale consists of a total of 30 items. Total scores will be calculated with a total score range from 0 to 300 (higher scores indicate a higher burden on the caregiver). The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated subjects was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 105
    End point values
    		 Placebo (Modified ITT) Crenezumab (Modified ITT)
    Number of subjects analysed
    86
    87
    Units: Units on a Scale
    least squares mean (standard error)
        Week 105
    22.72 ± 5.135
    24.11 ± 5.106
    Statistical analysis title
    		 Crenezumab versus Placebo
    Comparison groups
    Placebo (Modified ITT) v Crenezumab (Modified ITT)
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -1.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.64
         upper limit
    		 10.86
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.214

    Secondary: EQ-5D Questionnaire Domain Score for Subjects

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    End point title
    		 EQ-5D Questionnaire Domain Score for Subjects
    End point description
    The EQ-5D is a standardized measure of health status designed to provide a simple generic measure of health for clinical and economic appraisal. It is broadly applicable across a wide range of health conditions and treatment. The EQ-5D assesses five domains to provide a health state index. These are anxiety/depression, pain/discomfort, usual activities, mobility, and self-care. The scores on the EQ-5D ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated subjects was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline. Data presented below is only for subjects that were included in the actual analysis.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 105
    End point values
    		 Placebo (Modified ITT) Crenezumab (Modified ITT)
    Number of subjects analysed
    89
    87
    Units: Units on a Scale
    least squares mean (standard error)
        Week 105
    -4.54 ± 1.732
    -6.35 ± 1.761
    Statistical analysis title
    		 Crenezumab versus Placebo
    Comparison groups
    Placebo (Modified ITT) v Crenezumab (Modified ITT)
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    1.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.64
         upper limit
    		 6.27
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.26

    Secondary: EQ-5D Questionnaire Domain Score for Caregivers

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    End point title
    		 EQ-5D Questionnaire Domain Score for Caregivers
    End point description
    The EQ-5D is a standardized measure of health status designed to provide a simple generic measure of health for clinical and economic appraisal. It is broadly applicable across a wide range of health conditions and treatment. The EQ-5D assesses five domains to provide a health state index. These are anxiety/depression, pain/discomfort, usual activities, mobility, and self-care. The scores on the EQ-5D ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated subjects was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline. Data presented below is only for subjects that were included in the actual analysis.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 105
    End point values
    		 Placebo (Modified ITT) Crenezumab (Modified ITT)
    Number of subjects analysed
    89
    88
    Units: Units on a Scale
    least squares mean (standard error)
        Week 105
    -3.16 ± 1.713
    -4.09 ± 1.721
    Statistical analysis title
    		 Crenezumab versus Placebo
    Comparison groups
    Placebo (Modified ITT) v Crenezumab (Modified ITT)
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.45
         upper limit
    		 5.32
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.222

    Secondary: Percentage of Subjects with Adverse Event (AEs) and Serious Adverse Event (SAEs)

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    End point title
    		 Percentage of Subjects with Adverse Event (AEs) and Serious Adverse Event (SAEs)
    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 16 weeks after the last dose of study drug (up to 117 weeks).
    End point values
    		 Placebo (Safety) Crenezumab (Safety)
    Number of subjects analysed
    405
    404
    Units: Percentage
    number (not applicable)
        AEs
    83.2
    85.9
        SAEs
    15.6
    16.6
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Anti-Crenezumab Antibodies

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    End point title
    		 Percentage of Subjects with Anti-Crenezumab Antibodies
    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 Crenezumab 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. Data below is only for subjects included in the actual analysis. (Pla = X; Cre = X) represents number of subjects analysed at each timepoint for both arms.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 105
    End point values
    		 Placebo (Safety) Crenezumab (Safety)
    Number of subjects analysed
    385
    404
    Units: Percentage
    number (not applicable)
        Baseline ADAs (Pla = 385; Cre = 404)
    0.3
    0.2
        Treatment Emergent ADAs (Pla = 382; Cre = 397)
    0.5
    0.5
    No statistical analyses for this end point

    Secondary: Serum Concentration of Crenezumab

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    End point title
    		 Serum Concentration of Crenezumab [7]
    End point description
    Serum concentration data for Crenezumab will be tabulated and summarized. Descriptive summary statistics will include the arithmetic mean and SD. Since a sparse PK sampling design is being used, population (non-linear mixed-effects) modeling will be used to analyze the dose concentration-time data of crenezumab. Information from other clinical studies may be incorporated to establish the PK model. The PK Analysis population was defined as all subjects who have received at least one dose of crenezumab and with at least one evaluable post-dose PK sample. Please note that Post-dose samples were not collected at Weeks 37 and 105. Data presented below is only for subjects that were included in the actual analysis. 999 = Not Estimable. (n = X) refers to Number of Subjects analysed at each timepoint.
    End point type
    Secondary
    End point timeframe
    Pre-infusion (0 hour), 60-90 minutes post-infusion on Day 1 Week 1 and on Week 25; Weeks 13, 37 (Pre-dose), 53, 77 and 105 (infusion length = as per the Pharmacy Manual)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: PK Analysis was only conducted on the Crenezumab treatment group and so data for Placebo was not reported.
    End point values
    		 Crenezumab
    Number of subjects analysed
    392
    Units: ug/mL
    arithmetic mean (standard deviation)
        Week 1 Day 1 Predose (n = 392)
    999 ± 999
        Week 1 Day 1 Postdose (n = 74)
    1350 ± 319
        Week 13 Predose (n = 388)
    345 ± 146
        Week 13 Postdose (n = 384)
    1580 ± 487
        Week 25 Predose (n = 378)
    369 ± 130
        Week 25 Postdose (n = 54)
    1700 ± 443
        Week 37 Predose (n = 366)
    368 ± 152
        Week 53 Predose (n = 363)
    393 ± 164
        Week 53 Postdose (n = 60)
    1800 ± 420
        Week 77 Predose (n = 263)
    410 ± 261
        Week 77 Postdose (n = 50)
    1790 ± 496
        Week 105 (n = 89)
    408 ± 186
    No statistical analyses for this end point

    Secondary: Plasma Amyloid Beta (Abeta) 40 Concentrations

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    End point title
    		 Plasma Amyloid Beta (Abeta) 40 Concentrations [8]
    End point description
    Plasma Abeta 40 concentrations will be measured over time and descriptive summary statistics will include the arithmetic mean and SD. The PD Analysis population was defined as all subjects who have received at least one dose of crenezumab and with at least one evaluable post-dose PK sample. Data presented below is only for subjects that were included in the actual analysis. Please note that a Post-dose sample was only collected at Week 13. (n = X) refers to Number of Subjects analysed at each timepoint.
    End point type
    Secondary
    End point timeframe
    Week 1 Day 1; Weeks 13, 25, 53, 77 and 105
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: PD Analysis was only conducted on the Crenezumab treatment group and so data for Placebo was not reported.
    End point values
    		 Crenezumab
    Number of subjects analysed
    101
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 1 Day 1 Predose (n = 101)
    0.377 ± 0.136
        Week 13 Predose (n = 20)
    44.6 ± 10.0
        Week 13 Postdose (n = 21)
    44.3 ± 9.5
        Week 25 Predose (n = 46)
    46.4 ± 10.1
        Week 53 Predose (n = 94)
    48.8 ± 10.7
        Week 77 (n = 40)
    47.5 ± 12.2
        Week 105 Predose (n = 38)
    48.6 ± 14.0
    No statistical analyses for this end point

    Secondary: Plasma Amyloid Beta (Abeta) 42 Concentrations

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    End point title
    		 Plasma Amyloid Beta (Abeta) 42 Concentrations [9]
    End point description
    Plasma Abeta 42 concentrations will be measured over time and descriptive summary statistics will include the arithmetic mean and SD. The PD Analysis population was defined as all subjects who have received at least one dose of crenezumab and with at least one evaluable post-dose PK sample. Data presented below is only for subjects that were included in the actual analysis. Please note that a Post-dose sample was only collected at Week 13. (n = X) refers to Number of Subjects analysed at each timepoint.
    End point type
    Secondary
    End point timeframe
    Week 1 Day 1; Weeks 13, 25, 53, 77 and 105
    Notes
    [9] - 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: PD Analysis was only conducted on the Crenezumab treatment group and so data for Placebo was not reported.
    End point values
    		 Crenezumab
    Number of subjects analysed
    101
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 1 Day 1 Predose (n = 101)
    0.0335 ± 0.00812
        Week 13 Predose (n = 20)
    2.72 ± 0.553
        Week 13 Postdose (n = 21)
    2.71 ± 0.602
        Week 25 Predose (n = 46)
    2.73 ± 0.55
        Week 53 Predose (n = 94)
    2.87 ± 0.589
        Week 77 Predose (n = 40)
    2.79 ± 0.68
        Week 105 Predose (n = 38)
    2.87 ± 0.818
    No statistical analyses for this end point

    Secondary: Percentage Change from Baseline to Week 105 in Whole Brain Volume as Determined by Magnetic Resonance Imaging (MRI)

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    End point title
    		 Percentage Change from Baseline to Week 105 in Whole Brain Volume as Determined by Magnetic Resonance Imaging (MRI)
    End point description
    Percentage Change in Whole Brain Volume will be measured over time and descriptive summary statistics will include the arithmetic mean, median, range, SD, and coefficient of variation, as appropriate. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline. Data presented below is only for subjects that were included in the actual analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 105
    End point values
    		 Placebo (Modified ITT) Crenezumab (Modified ITT)
    Number of subjects analysed
    180
    172
    Units: Percentage
    least squares mean (standard error)
        Week 105
    -2.66 ± 0.091
    -2.65 ± 0.092
    Statistical analysis title
    		 Crenezumab versus Placebo
    Comparison groups
    Placebo (Modified ITT) v Crenezumab (Modified ITT)
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.24
         upper limit
    		 0.22
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.116

    Secondary: Percentage Change from Baseline to Week 105 in Ventricle Volume as Determined by Magnetic Resonance Imaging (MRI)

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    End point title
    		 Percentage Change from Baseline to Week 105 in Ventricle Volume as Determined by Magnetic Resonance Imaging (MRI)
    End point description
    Percentage Change in Ventricle Volume will be measured over time and descriptive summary statistics will include the arithmetic mean, median, range, SD, and coefficient of variation, as appropriate. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline. Data presented below is only for subjects that were included in the actual analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 105
    End point values
    		 Placebo (Modified ITT) Crenezumab (Modified ITT)
    Number of subjects analysed
    189
    181
    Units: Percentage
    least squares mean (standard error)
        Week 105
    22.29 ± 0.907
    23.57 ± 0.912
    Statistical analysis title
    		 Crenezumab versus Placebo
    Comparison groups
    Placebo (Modified ITT) v Crenezumab (Modified ITT)
    Number of subjects included in analysis
    370
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -1.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.72
         upper limit
    		 1.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.245

    Secondary: Percentage Change from Baseline to Week 105 in Hippocampal Volume as Determined by Magnetic Resonance Imaging (MRI)

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    End point title
    		 Percentage Change from Baseline to Week 105 in Hippocampal Volume as Determined by Magnetic Resonance Imaging (MRI)
    End point description
    Percentage Change in Hippocampal Volume will be measured over time and descriptive summary statistics will include the arithmetic mean, median, range, SD, and coefficient of variation, as appropriate. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline. Data presented below is only for subjects that were included in the actual analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 105
    End point values
    		 Placebo (Modified ITT) Crenezumab (Modified ITT)
    Number of subjects analysed
    169
    160
    Units: Percentage
    least squares mean (standard error)
        Week 105
    -6.57 ± 0.200
    -6.97 ± 0.203
    Statistical analysis title
    		 Crenezumab versus Placebo
    Comparison groups
    Placebo (Modified ITT) v Crenezumab (Modified ITT)
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.89
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.253

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up until 16 weeks after the last dose of study drug (up to 117 weeks).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks.

    Reporting group title
    Crenezumab
    Reporting group description
    		 Subjects received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.

    Serious adverse events
    		 Placebo Crenezumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    63 / 405 (15.56%)
    67 / 404 (16.58%)
         number of deaths (all causes)
    5
    8
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    ADENOCARCINOMA
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ADENOCARCINOMA GASTRIC
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    BREAST CANCER
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIFFUSE LARGE B-CELL LYMPHOMA
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INVASIVE DUCTAL BREAST CARCINOMA
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG ADENOCARCINOMA
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG NEOPLASM MALIGNANT
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LYMPHOPROLIFERATIVE DISORDER
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    PROSTATE CANCER
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    HYPOTENSION
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIPHERAL ARTERIAL OCCLUSIVE DISEASE
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    CORONARY ARTERY BYPASS
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SKIN NEOPLASM EXCISION
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URETHRAL STENT INSERTION
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    CHEST PAIN
         subjects affected / exposed
    0 / 405 (0.00%)
    2 / 404 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEATH
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    2 / 405 (0.49%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    ANAPHYLACTIC REACTION
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    OVARIAN CYST
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ACUTE INTERSTITIAL PNEUMONITIS
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    PNEUMONIA ASPIRATION
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    ACUTE PSYCHOSIS
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    AGITATION
         subjects affected / exposed
    1 / 405 (0.25%)
    2 / 404 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DELIRIUM
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DELUSION
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HALLUCINATION, VISUAL
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERSONALITY CHANGE
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SCHIZOPHRENIA
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    DEVICE FAILURE
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    CLAVICLE FRACTURE
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONCUSSION
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FACIAL BONES FRACTURE
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FALL
         subjects affected / exposed
    1 / 405 (0.25%)
    4 / 404 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEMUR FRACTURE
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HIP FRACTURE
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RADIUS FRACTURE
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RIB FRACTURE
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ROAD TRAFFIC ACCIDENT
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SKIN LACERATION
         subjects affected / exposed
    0 / 405 (0.00%)
    2 / 404 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SKULL FRACTURED BASE
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SOFT TISSUE INJURY
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUBDURAL HAEMATOMA
         subjects affected / exposed
    3 / 405 (0.74%)
    4 / 404 (0.99%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    SUBDURAL HAEMORRHAGE
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRAUMATIC INTRACRANIAL HAEMORRHAGE
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ULNA FRACTURE
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UPPER LIMB FRACTURE
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WRIST FRACTURE
         subjects affected / exposed
    2 / 405 (0.49%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    ACUTE CORONARY SYNDROME
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANGINA UNSTABLE
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL FLUTTER
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIOVENTRICULAR BLOCK COMPLETE
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRADYCARDIA
         subjects affected / exposed
    2 / 405 (0.49%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC ARREST
         subjects affected / exposed
    1 / 405 (0.25%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    CARDIAC FAILURE ACUTE
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    CORONARY ARTERY DISEASE
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYOCARDIAL INFARCTION
         subjects affected / exposed
    2 / 405 (0.49%)
    2 / 404 (0.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    MYOCARDIAL ISCHAEMIA
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    CAROTID ARTERY STENOSIS
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CENTRAL NERVOUS SYSTEM LESION
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    CEREBRAL HAEMORRHAGE
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBRAL ISCHAEMIA
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    1 / 405 (0.25%)
    2 / 404 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBROVASCULAR DISORDER
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEMENTIA ALZHEIMER'S TYPE
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEPRESSED LEVEL OF CONSCIOUSNESS
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYDROCEPHALUS
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ISCHAEMIC STROKE
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOSS OF CONSCIOUSNESS
         subjects affected / exposed
    2 / 405 (0.49%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PARAESTHESIA
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEIZURE
         subjects affected / exposed
    0 / 405 (0.00%)
    2 / 404 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUBARACHNOID HAEMORRHAGE
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    4 / 405 (0.99%)
    3 / 404 (0.74%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    VERTIGO
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL DISCOMFORT
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHRONIC GASTRITIS
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COLITIS
         subjects affected / exposed
    1 / 405 (0.25%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COLITIS ISCHAEMIC
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONSTIPATION
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIVERTICULUM
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 405 (0.00%)
    2 / 404 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL PERFORATION
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL ULCER HAEMORRHAGE
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL VASCULAR MALFORMATION
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INGUINAL HERNIA
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOWER GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RECTAL HAEMORRHAGE
         subjects affected / exposed
    0 / 405 (0.00%)
    2 / 404 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    CHOLECYSTITIS ACUTE
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLELITHIASIS
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    ANGIOEDEMA
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEPHROLITHIASIS
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    AUTOIMMUNE THYROIDITIS
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERPARATHYROIDISM PRIMARY
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ARTHRITIS
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTERVERTEBRAL DISC PROTRUSION
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUMBAR SPINAL STENOSIS
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OSTEOARTHRITIS
         subjects affected / exposed
    2 / 405 (0.49%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SYSTEMIC SCLERODERMA
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    APPENDICITIS
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIVERTICULITIS
         subjects affected / exposed
    3 / 405 (0.74%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ERYSIPELAS
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HERPES ZOSTER
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERITONITIS
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERITONSILLAR ABSCESS
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    3 / 405 (0.74%)
    5 / 404 (1.24%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    PNEUMONIA BACTERIAL
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYELONEPHRITIS
         subjects affected / exposed
    0 / 405 (0.00%)
    2 / 404 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SKIN INFECTION
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TUBERCULOSIS OF CENTRAL NERVOUS SYSTEM
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 405 (0.00%)
    2 / 404 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UROSEPSIS
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIRAL INFECTION
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    0 / 405 (0.00%)
    3 / 404 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIABETIC KETOACIDOSIS
         subjects affected / exposed
    2 / 405 (0.49%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Crenezumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    214 / 405 (52.84%)
    225 / 404 (55.69%)
    Investigations
    WEIGHT DECREASED
         subjects affected / exposed
    11 / 405 (2.72%)
    22 / 404 (5.45%)
         occurrences all number
    11
    22
    Injury, poisoning and procedural complications
    FALL
         subjects affected / exposed
    33 / 405 (8.15%)
    42 / 404 (10.40%)
         occurrences all number
    42
    60
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    22 / 405 (5.43%)
    27 / 404 (6.68%)
         occurrences all number
    22
    29
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    27 / 405 (6.67%)
    23 / 404 (5.69%)
         occurrences all number
    34
    28
    HEADACHE
         subjects affected / exposed
    45 / 405 (11.11%)
    39 / 404 (9.65%)
         occurrences all number
    60
    48
    Gastrointestinal disorders
    DIARRHOEA
         subjects affected / exposed
    26 / 405 (6.42%)
    25 / 404 (6.19%)
         occurrences all number
    42
    27
    Skin and subcutaneous tissue disorders
    RASH
         subjects affected / exposed
    22 / 405 (5.43%)
    7 / 404 (1.73%)
         occurrences all number
    26
    8
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    21 / 405 (5.19%)
    28 / 404 (6.93%)
         occurrences all number
    24
    31
    DEPRESSION
         subjects affected / exposed
    27 / 405 (6.67%)
    28 / 404 (6.93%)
         occurrences all number
    27
    28
    Musculoskeletal and connective tissue disorders
    BACK PAIN
         subjects affected / exposed
    31 / 405 (7.65%)
    26 / 404 (6.44%)
         occurrences all number
    36
    38
    Infections and infestations
    BRONCHITIS
         subjects affected / exposed
    13 / 405 (3.21%)
    21 / 404 (5.20%)
         occurrences all number
    13
    21
    NASOPHARYNGITIS
         subjects affected / exposed
    33 / 405 (8.15%)
    40 / 404 (9.90%)
         occurrences all number
    41
    50
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    29 / 405 (7.16%)
    33 / 404 (8.17%)
         occurrences all number
    38
    36
    URINARY TRACT INFECTION
         subjects affected / exposed
    22 / 405 (5.43%)
    20 / 404 (4.95%)
         occurrences all number
    29
    22

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Oct 2015
    Following updates were made: [1] Clarification to background information on Crenezumab; [2] Update to data on dose rationale; [3] Addition of section describing exploratory substudies; [4] Clarification that the Independent Data Monitoring Committee may evaluate any planned interim efficacy or futility analyses; [5] Update to Inclusion Criteria; [6] Explanation for procedure for blinding around PK samples; [7] Clarification of Patient Centred Outcomes language; [8] Clarification of procedure around Brain MRI; [9] Updates to Safety Information and [10] Update to Primary Efficacy Endpoint rationale.
    10 Mar 2018
    Following updates were made: [1] Restructuring and clarification of Secondary Efficacy, Pharmacokinetic and Biomarker Objectives/Endpoints; [2] Revisions to Statistical Considerations and Analysis Plan and [3] Minor updates made to other sections including Background on Alzheimer's Disease, Biomarkers section, Overall Benefit-Risk Summary, Overview of Study Design, Permitted Therapy, PD Biomarkers, Amyloid-related imaging abnormalities (ARIA) text and the Schedule of Activities.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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