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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
    		 2016-003288-20
    Trial protocol
    		 GB   ES   EE   PT   BE   DE   GR   FR   SE   DK   IT  
    Global end of trial date
    11 Jun 2019

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

    Trial information

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    Trial identification
    Sponsor protocol code
    BN29553
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03114657
    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
    11 Jun 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Jun 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
    29 Mar 2017
    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: 13
    Country: Number of subjects enrolled
    Argentina: 11
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    Brazil: 56
    Country: Number of subjects enrolled
    Canada: 32
    Country: Number of subjects enrolled
    China: 9
    Country: Number of subjects enrolled
    Germany: 33
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    Spain: 72
    Country: Number of subjects enrolled
    Estonia: 4
    Country: Number of subjects enrolled
    France: 23
    Country: Number of subjects enrolled
    United Kingdom: 27
    Country: Number of subjects enrolled
    Israel: 17
    Country: Number of subjects enrolled
    Italy: 90
    Country: Number of subjects enrolled
    Japan: 42
    Country: Number of subjects enrolled
    Korea, Republic of: 27
    Country: Number of subjects enrolled
    Norway: 7
    Country: Number of subjects enrolled
    Peru: 19
    Country: Number of subjects enrolled
    Poland: 31
    Country: Number of subjects enrolled
    Portugal: 13
    Country: Number of subjects enrolled
    Russian Federation: 30
    Country: Number of subjects enrolled
    Serbia: 11
    Country: Number of subjects enrolled
    Sweden: 8
    Country: Number of subjects enrolled
    Turkey: 9
    Country: Number of subjects enrolled
    Taiwan: 8
    Country: Number of subjects enrolled
    United States: 194
    Country: Number of subjects enrolled
    South Africa: 7
    Worldwide total number of subjects
    806
    EEA total number of subjects
    321
    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)
    164
    From 65 to 84 years
    634
    85 years and over
    8

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 209 centers in 27 countries.

    Pre-assignment
    Screening details
    		 A total of 806 participants were enrolled at 209 centers. 4 participants did not receive any study treatment meaning that the modified intent-to-treat and safety populations consisted of 802 participants.

    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
    399
    407
    Completed
    0
    0
    Not completed
    399
    407
         Adverse event, serious fatal
    4
    -
         Physician decision
    2
    2
         Consent withdrawn by subject
    28
    22
         Adverse event, non-fatal
    9
    6
         Study Terminated By Sponsor
    355
    374
         Multiple Reasons
    1
    2
         Symptomatic Deterioration
    -
    1

    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
    		 399 407 806
    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)
    		 86 78 164
        From 65-84 years
    		 310 324 634
        85 years and over
    		 3 5 8
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 70.7 ± 7.9 71.1 ± 7.5 -
    Sex: Female, Male
    Units:
        Female
    		 225 231 456
        Male
    		 174 176 350
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    		 42 35 77
        Not Hispanic or Latino
    		 334 348 682
        Not Stated
    		 15 19 34
        Unknown
    		 8 5 13
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 8 5 13
        Asian
    		 45 47 92
        Black or African American
    		 4 3 7
        Multiple
    		 4 3 7
        Unknown
    		 5 7 12
        White
    		 333 342 675

    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 = 398); Cren (n = 404)) 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 = 398); Cren (n = 404)) 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 Crenezumab 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 77 in Clinical Dementia Rating-Sum of Boxes (CDR-SB) Scale Score

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    End point title
    		 Change from Baseline to Week 77 in Clinical Dementia Rating-Sum of Boxes (CDR-SB) Scale 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 77 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, participants, 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 77
    End point values
    		 Placebo (Modified ITT) Crenezumab (Modified ITT)
    Number of subjects analysed
    15 [1]
    12 [2]
    Units: Units on a Scale
    least squares mean (standard error)
        Week 77
    3.19 ± 0.434
    1.89 ± 0.471
    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
    Crenezumab (Modified ITT) v Placebo (Modified ITT)
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 2.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.633

    Secondary: Change from Baseline to Week 77 in Alzheimer's Disease Assessment Scale-Cognition 13 (ADAS-Cog-13) Subscale Score

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    End point title
    		 Change from Baseline to Week 77 in Alzheimer's Disease Assessment Scale-Cognition 13 (ADAS-Cog-13) Subscale Score
    End point description
    The ADAS-Cog-13 assesses multiple cognitive domains including memory, comprehension, praxis, orientation, and spontaneous speech. Most of these are assessed by tests although some are rated by the clinician on a 5-point scale. The ADAS-Cog-13 is the ADAS-Cog-11 with 2 further items: delayed word recall and total digit cancellation. The score range for ADAS-Cog-13 is from 0 to 85 with high scores representing severe dysfunction. The difference in mean change from Baseline to Week 77 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 77
    End point values
    		 Placebo (Modified ITT) Crenezumab (Modified ITT)
    Number of subjects analysed
    15
    12
    Units: Units on a Scale
    least squares mean (standard error)
        Week 77
    8.90 ± 1.382
    7.16 ± 1.526
    Statistical analysis title
    		 Crenezumab versus Placebo
    Comparison groups
    Placebo (Modified ITT) v Crenezumab (Modified ITT)
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    1.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.4
         upper limit
    		 5.89
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.028

    Secondary: Change from Baseline to Week 77 in Alzheimer's Disease Assessment Scale-Cognition 11 (ADAS-Cog-11) Subscale Score

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    End point title
    		 Change from Baseline to Week 77 in Alzheimer's Disease Assessment Scale-Cognition 11 (ADAS-Cog-11) Subscale Score
    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 77 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 77
    End point values
    		 Placebo (Modified ITT) Crenezumab (Modified ITT)
    Number of subjects analysed
    15
    12
    Units: Units on a Scale
    least squares mean (standard error)
        Week 77
    7.16 ± 1.452
    6.84 ± 1.592
    Statistical analysis title
    		 Crenezumab versus Placebo
    Comparison groups
    Placebo (Modified ITT) v Crenezumab (Modified ITT)
    Number of subjects included in analysis
    27
    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
    		 -4.03
         upper limit
    		 4.68
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.124

    Secondary: Change from Baseline to Week 77 on Severity of Dementia, Assessed Using the CDR-Global Score (CDR-GS)

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    End point title
    		 Change from Baseline to Week 77 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 77 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 77
    End point values
    		 Placebo (Modified ITT) Crenezumab (Modified ITT)
    Number of subjects analysed
    15
    12
    Units: Units on a Scale
    least squares mean (standard error)
        Week 77
    0.39 ± 0.096
    0.29 ± 0.102
    Statistical analysis title
    		 Crenezumab versus Placebo
    Comparison groups
    Placebo (Modified ITT) v Crenezumab (Modified ITT)
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0.39
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.141

    Secondary: Change from Baseline to Week 77 on Severity of Dementia, Assessed Using the Mini Mental State Evaluation (MMSE)

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    End point title
    		 Change from Baseline to Week 77 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 77 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 77
    End point values
    		 Placebo (Modified ITT) Crenezumab (Modified ITT)
    Number of subjects analysed
    15
    12
    Units: Units on a Scale
    least squares mean (standard error)
        Week 77
    -3.63 ± 0.672
    -3.21 ± 0.740
    Statistical analysis title
    		 Crenezumab versus Placebo
    Comparison groups
    Placebo (Modified ITT) v Crenezumab (Modified ITT)
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.42
         upper limit
    		 1.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.985

    Secondary: Change from Baseline to Week 77 on Function as assessed by (ADCS-ADL) Total Score

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    End point title
    		 Change from Baseline to Week 77 on Function as assessed by (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 77 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 77
    End point values
    		 Placebo (Modified ITT) Crenezumab (Modified ITT)
    Number of subjects analysed
    15
    12
    Units: Units on a Scale
    least squares mean (standard error)
        Week 77
    -8.83 ± 2.064
    -6.31 ± 2.278
    Statistical analysis title
    		 Crenezumab versus Placebo
    Comparison groups
    Placebo (Modified ITT) v Crenezumab (Modified ITT)
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -2.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.74
         upper limit
    		 3.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.052

    Secondary: Change from Baseline to Week 77 on Function as assessed by (ADCS-iADL) Instrumental Score

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    End point title
    		 Change from Baseline to Week 77 on Function as assessed by (ADCS-iADL) Instrumental Score
    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 77 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 77
    End point values
    		 Placebo (Modified ITT) Crenezumab (Modified ITT)
    Number of subjects analysed
    15
    12
    Units: Units on a Scale
    least squares mean (standard error)
        Week 77
    -6.69 ± 1.692
    -5.51 ± 1.872
    Statistical analysis title
    		 Crenezumab versus Placebo
    Comparison groups
    Placebo (Modified ITT) v Crenezumab (Modified ITT)
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -1.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.29
         upper limit
    		 3.92
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.501

    Secondary: Change from Baseline to Week 77 on Function as assessed by the Functional Activities Questionnaire (FAQ) total score

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    End point title
    		 Change from Baseline to Week 77 on Function as assessed by the Functional Activities Questionnaire (FAQ) total score
    End point description
    The Functional Activities Questionnaire (FAQ) is an instrument consisting of 10 items and assesses instrumental, social and cognitive functioning. The score range is from 0 to 30 with higher scores representing higher impairment. The difference in mean change from Baseline to Week 77 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 77
    End point values
    		 Placebo (Modified ITT) Crenezumab (Modified ITT)
    Number of subjects analysed
    15
    12
    Units: Units on a Scale
    least squares mean (standard error)
        Week 77
    5.00 ± 0.991
    4.37 ± 1.059
    Statistical analysis title
    		 Crenezumab versus Placebo
    Comparison groups
    Placebo (Modified ITT) v Crenezumab (Modified ITT)
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.25
         upper limit
    		 3.51
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.42

    Secondary: Change from Baseline to Week 77 on a Measure of Dependence Level Assessed from the ADCS-ADL Score

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    End point title
    		 Change from Baseline to Week 77 on a Measure of Dependence Level Assessed 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 77
    End point values
    		 Placebo Crenezumab
    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 53 on Behavior in Neuropsychiatric Inventory Questionnaire (NPI-Q) Total Score

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    End point title
    		 Change from Baseline to Week 53 on Behavior in Neuropsychiatric Inventory Questionnaire (NPI-Q) Total Score
    End point description
    The NPI-Q 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/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. Difference in mean change from Baseline to Week 53 between Crenezumab and Placebo treated subjects was estimated. Mixed model repeated measures adjusting for disease severity, APOEe4 status, geographic region and the use/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 53
    End point values
    		 Placebo (Modified ITT) Crenezumab (Modified ITT)
    Number of subjects analysed
    102
    110
    Units: Units on a Scale
    least squares mean (standard error)
        Week 53
    -0.00 ± 0.852
    0.76 ± 0.886
    Statistical analysis title
    		 Crenezumab versus Placebo
    Comparison groups
    Placebo (Modified ITT) v Crenezumab (Modified ITT)
    Number of subjects included in analysis
    212
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.75
         upper limit
    		 0.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.502

    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 77 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 77
    End point values
    		 Placebo (Modified ITT) Crenezumab (Modified ITT)
    Number of subjects analysed
    15
    11
    Units: Units on a Scale
    least squares mean (standard error)
        Week 77
    -1.61 ± 1.310
    -1.16 ± 1.432
    Statistical analysis title
    		 Crenezumab versus Placebo
    Comparison groups
    Placebo (Modified ITT) v Crenezumab (Modified ITT)
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.3
         upper limit
    		 2.39
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.383

    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 53 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 53
    End point values
    		 Placebo (Modified ITT) Crenezumab (Modified ITT)
    Number of subjects analysed
    101
    108
    Units: Units on a Scale
    least squares mean (standard error)
        Week 53
    9.20 ± 9.292
    2.65 ± 9.643
    Statistical analysis title
    		 Crenezumab versus Placebo
    Comparison groups
    Placebo (Modified ITT) v Crenezumab (Modified ITT)
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    6.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.35
         upper limit
    		 17.44
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.527

    Secondary: European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Domain Scores for Subjects

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    End point title
    		 European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Domain Scores 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 77 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 77
    End point values
    		 Placebo (Modified ITT) Crenezumab (Modified ITT)
    Number of subjects analysed
    15
    12
    Units: Units on a Scale
    least squares mean (standard error)
        Week 77
    -3.69 ± 3.961
    -3.39 ± 4.392
    Statistical analysis title
    		 Crenezumab versus Placebo
    Comparison groups
    Placebo (Modified ITT) v Crenezumab (Modified ITT)
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.31
         upper limit
    		 11.71
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.831

    Secondary: European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Domain Scores for Caregivers

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    End point title
    		 European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Domain Scores 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 77 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 77
    End point values
    		 Placebo (Modified ITT) Crenezumab (Modified ITT)
    Number of subjects analysed
    15
    12
    Units: Units on a Scale
    least squares mean (standard error)
        Week 77
    -4.07 ± 2.724
    -0.68 ± 3.031
    Statistical analysis title
    		 Crenezumab versus Placebo
    Comparison groups
    Placebo (Modified ITT) v Crenezumab (Modified ITT)
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -3.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.5
         upper limit
    		 4.73
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.94

    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
    398
    404
    Units: Percentage
    number (not applicable)
        AEs
    73.1
    73.5
        SAEs
    10.6
    8.2
    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
    Please note that for this Outcome Measure, no Subjects were evaluated at all as the existing immunogenicity data from an identical study (Study BN29552) showed a low potential of Crenezumab to induce Anti-Drug Antibodies (ADAs).
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 105
    End point values
    		 Placebo (Safety) Crenezumab (Safety)
    Number of subjects analysed
    0 [5]
    0 [6]
    Units: Percentage
        number (not applicable)
    Notes
    [5] - ADAs were not collected in this study due to low induction potential of Crenezumab.
    [6] - ADAs were not collected in this study due to low induction potential of Crenezumab.
    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 5, 13, 37, 53 and 77. 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 (Pre-dose), 37 (Pre-dose), 53 (Pre-dose) and 77 (Pre-dose) (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
    404
    Units: ug/mL
    arithmetic mean (standard deviation)
        Week 1 Day 1 Predose (n=138)
    999 ± 999
        Week 1 Day 1 Postdose (n=110)
    1260 ± 437
        Week 5 Predose (n=138)
    246 ± 128
        Week 13 Predose (n=128)
    360 ± 162
        Week 25 Predose (n=125)
    401 ± 196
        Week 25 Postdose (n=106)
    1650 ± 443
        Week 37 Predose (n=97)
    456 ± 351
        Week 53 Predose (n=32)
    401 ± 130
        Week 77 Predose (n=3)
    357 ± 94.2
    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 Pre-dose samples were only collected at Weeks 1 and 53. (n=X) refers to Number of Subjects analysed at each timepoint.
    End point type
    Secondary
    End point timeframe
    Week 1 Day 1; Weeks 53
    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
    36
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 1 Day 1 Predose (n=36)
    0.415 ± 0.0687
        Week 53 Predose (n=13)
    46.6 ± 6.91
    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 Pre-dose samples were only collected at Weeks 1 and 53. (n=X) refers to Number of Subjects analysed at each timepoint.
    End point type
    Secondary
    End point timeframe
    Week 1 Day 1; Weeks 53
    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
    36
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 1 Day 1 Predose (n=36)
    0.0331 ± 0.00463
        Week 53 Predose (n=13)
    2.94 ± 0.473
    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
    4
    4
    Units: Percentage
    least squares mean (standard error)
        Week 105
    -2.71 ± 0.444
    -2.15 ± 0.345
    Statistical analysis title
    		 Crenezumab versus Placebo
    Comparison groups
    Placebo (Modified ITT) v Crenezumab (Modified ITT)
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.01
         upper limit
    		 0.89
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.622

    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
    4
    4
    Units: Percentage
    least squares mean (standard error)
        Week 105
    18.78 ± 1.343
    17.18 ± 1.145
    Statistical analysis title
    		 Crenezumab versus Placebo
    Comparison groups
    Placebo (Modified ITT) v Crenezumab (Modified ITT)
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.7
         upper limit
    		 4.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.668

    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
    2
    2
    Units: Percentage
    least squares mean (standard error)
        Week 105
    -6.34 ± 0.338
    -5.98 ± 0.290
    Statistical analysis title
    		 Crenezumab versus Placebo
    Comparison groups
    Placebo (Modified ITT) v Crenezumab (Modified ITT)
    Number of subjects included in analysis
    4
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.13
         upper limit
    		 0.41
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.373

    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
    42 / 398 (10.55%)
    33 / 404 (8.17%)
         number of deaths (all causes)
    6
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    BONE GIANT CELL TUMOUR MALIGNANT
         subjects affected / exposed
    1 / 398 (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
    CLEAR CELL ENDOMETRIAL CARCINOMA
         subjects affected / exposed
    1 / 398 (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
    LUNG ADENOCARCINOMA
         subjects affected / exposed
    0 / 398 (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
    0 / 398 (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
    PROSTATE CANCER
         subjects affected / exposed
    1 / 398 (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
    Vascular disorders
    ARTERIOVENOUS FISTULA
         subjects affected / exposed
    1 / 398 (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
    HYPERTENSIVE CRISIS
         subjects affected / exposed
    1 / 398 (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
    HYPOTENSION
         subjects affected / exposed
    1 / 398 (0.25%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIPHERAL VASCULAR DISORDER
         subjects affected / exposed
    0 / 398 (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
    SHOCK HAEMORRHAGIC
         subjects affected / exposed
    1 / 398 (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
    Surgical and medical procedures
    CARDIAC ABLATION
         subjects affected / exposed
    0 / 398 (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
    KNEE ARTHROPLASTY
         subjects affected / exposed
    0 / 398 (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
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    1 / 398 (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
    CHEST DISCOMFORT
         subjects affected / exposed
    0 / 398 (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
    CHEST PAIN
         subjects affected / exposed
    0 / 398 (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
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    0 / 398 (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
    PYREXIA
         subjects affected / exposed
    1 / 398 (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
    SUDDEN DEATH
         subjects affected / exposed
    2 / 398 (0.50%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ASTHMA
         subjects affected / exposed
    1 / 398 (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
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    0 / 398 (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
    COUGH
         subjects affected / exposed
    1 / 398 (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
    DYSPNOEA
         subjects affected / exposed
    2 / 398 (0.50%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTERSTITIAL LUNG DISEASE
         subjects affected / exposed
    1 / 398 (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
    PULMONARY EMBOLISM
         subjects affected / exposed
    1 / 398 (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
    Psychiatric disorders
    AGGRESSION
         subjects affected / exposed
    1 / 398 (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
    1 / 398 (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
    DEPRESSIVE SYMPTOM
         subjects affected / exposed
    0 / 398 (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
    SUICIDE THREAT
         subjects affected / exposed
    0 / 398 (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
    Investigations
    ARTHROSCOPY
         subjects affected / exposed
    0 / 398 (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
    ANKLE FRACTURE
         subjects affected / exposed
    0 / 398 (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
    CLAVICLE FRACTURE
         subjects affected / exposed
    1 / 398 (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
    CRANIOCEREBRAL INJURY
         subjects affected / exposed
    1 / 398 (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
    FALL
         subjects affected / exposed
    6 / 398 (1.51%)
    2 / 404 (0.50%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    HIP FRACTURE
         subjects affected / exposed
    3 / 398 (0.75%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HUMERUS FRACTURE
         subjects affected / exposed
    0 / 398 (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 LIMB FRACTURE
         subjects affected / exposed
    0 / 398 (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
    MENISCUS INJURY
         subjects affected / exposed
    1 / 398 (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
    PUBIS FRACTURE
         subjects affected / exposed
    1 / 398 (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
    RIB FRACTURE
         subjects affected / exposed
    1 / 398 (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
    SUBDURAL HAEMATOMA
         subjects affected / exposed
    0 / 398 (0.00%)
    3 / 404 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    ATRIAL FIBRILLATION
         subjects affected / exposed
    2 / 398 (0.50%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CORONARY ARTERY DISEASE
         subjects affected / exposed
    1 / 398 (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
    PALPITATIONS
         subjects affected / exposed
    0 / 398 (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
    TACHYCARDIA
         subjects affected / exposed
    0 / 398 (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
    TRIFASCICULAR BLOCK
         subjects affected / exposed
    0 / 398 (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
    AMYOTROPHIC LATERAL SCLEROSIS
         subjects affected / exposed
    1 / 398 (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
    CEREBRAL ARTERIOSCLEROSIS
         subjects affected / exposed
    1 / 398 (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
    ISCHAEMIC CEREBRAL INFARCTION
         subjects affected / exposed
    0 / 398 (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
    SPEECH DISORDER
         subjects affected / exposed
    0 / 398 (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
    SUBARACHNOID HAEMORRHAGE
         subjects affected / exposed
    0 / 398 (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
    SUPERIOR SAGITTAL SINUS THROMBOSIS
         subjects affected / exposed
    1 / 398 (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
    SYNCOPE
         subjects affected / exposed
    2 / 398 (0.50%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    1 / 398 (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
    Ear and labyrinth disorders
    TINNITUS
         subjects affected / exposed
    1 / 398 (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
    VERTIGO
         subjects affected / exposed
    2 / 398 (0.50%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    COLITIS ISCHAEMIC
         subjects affected / exposed
    1 / 398 (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 / 398 (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 HAEMORRHAGE
         subjects affected / exposed
    1 / 398 (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
    UPPER GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    1 / 398 (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
    SKIN ULCER
         subjects affected / exposed
    0 / 398 (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
    ARTHRITIS
         subjects affected / exposed
    0 / 398 (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 / 398 (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 PAIN
         subjects affected / exposed
    1 / 398 (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
    Infections and infestations
    BACTERAEMIA
         subjects affected / exposed
    1 / 398 (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
    BRONCHITIS
         subjects affected / exposed
    0 / 398 (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
    CELLULITIS STAPHYLOCOCCAL
         subjects affected / exposed
    1 / 398 (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
    CLOSTRIDIUM DIFFICILE INFECTION
         subjects affected / exposed
    1 / 398 (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
    ENTEROBACTER PNEUMONIA
         subjects affected / exposed
    1 / 398 (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
    ENDOCARDITIS
         subjects affected / exposed
    0 / 398 (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
    GASTROENTERITIS
         subjects affected / exposed
    2 / 398 (0.50%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LIVER ABSCESS
         subjects affected / exposed
    0 / 398 (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
    NEUROSYPHILIS
         subjects affected / exposed
    0 / 398 (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
    PHARYNGITIS STREPTOCOCCAL
         subjects affected / exposed
    0 / 398 (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
    2 / 398 (0.50%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    PNEUMONIA INFLUENZAL
         subjects affected / exposed
    0 / 398 (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
    STAPHYLOCOCCAL BACTERAEMIA
         subjects affected / exposed
    1 / 398 (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
    URINARY TRACT INFECTION
         subjects affected / exposed
    1 / 398 (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 / 398 (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
    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
    77 / 398 (19.35%)
    85 / 404 (21.04%)
    Injury, poisoning and procedural complications
    FALL
         subjects affected / exposed
    20 / 398 (5.03%)
    19 / 404 (4.70%)
         occurrences all number
    34
    26
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    15 / 398 (3.77%)
    27 / 404 (6.68%)
         occurrences all number
    18
    29
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    22 / 398 (5.53%)
    25 / 404 (6.19%)
         occurrences all number
    28
    30
    Infections and infestations
    NASOPHARYNGITIS
         subjects affected / exposed
    25 / 398 (6.28%)
    24 / 404 (5.94%)
         occurrences all number
    32
    28

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Mar 2018
    Following updates were made: [1] Restructuring of Secondary Efficacy objectives; [2] Restructuring and updating of PK and Biomarker objectives; [3] Revision of the Statistical Considerations and Analysis plan section and [4] Minor updates made to other sections including Background on Alzheimer’s disease, alignment with latest Investigator's Brochure, Biomarkers, Overall Benefit-Risk Summary, Overview of Study Design, use of medical food supplements, requirements for the removal of no planned changes of Alzheimer’s medications for 6 months post-randomization, screening window duration, exclusion criteria, Permitted Therapies, 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.
    This study was discontinued due to an interim analysis in the BN29552 study, which indicated that Crenezumab was unlikely to meet its primary endpoint. No subjects reached Week 105 for primary and secondary efficacy endpoints.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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