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    Clinical Trial Results:
    A Placebo-Controlled, Double-Blind, Parallel-Group, 24 Month Study With an Open-Label Extension Phase to Evaluate the Efficacy and Safety of Elenbecestat (E2609) in Subjects With Early Alzheimer’s Disease

    Summary
    EudraCT number
    		 2016-003928-23
    Trial protocol
    		 GB   ES   CZ   AT   BG   GR   FR  
    Global end of trial date
    15 Jan 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Dec 2023
    First version publication date
    30 Jan 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    E2609-G000-301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02956486
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND Number: 109308
    Sponsors
    Sponsor organisation name
    Eisai Ltd.
    Sponsor organisation address
    Mosquito Way, Hatfield, Hertfordshire, United Kingdom, AL10 9SN
    Public contact
    Eisai Medical Information, Eisai Ltd., +1 888-274-2378, esi_medinfo@eisai.com
    Scientific contact
    Eisai Medical Information, Eisai Ltd., +1 888-274-2378, esi_medinfo@eisai.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Jan 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Jan 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To determine whether elenbecestat (E2609) is superior to placebo on the change from baseline in the Clinical Dementia Rating - Sum Of Boxes (CDR-SB) at 24 months in subjects with Early Alzheimer’s Disease (EAD)
    Protection of trial subjects
    This study was conducted in accordance with standard operating procedures (SOPs) of the sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines as required by the following: - Principles of the World Medical Association Declaration of Helsinki (World Medical Association, 2008). - International Council on Harmonisation (ICH) E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. - Title 21 of the United States (US) Code of Federal Regulations (US 21 CFR) regarding clinical studies, including Part 50 and Part 56 concerning informed subject consent and Institutional Review Board (IRB) regulations and applicable sections of US 21 CFR Part 312. - European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies conducted within any European Union (EU) country. All suspected unexpected serious adverse reactions were reported, as required, to the Competent Authorities of all involved EU member states. - Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP Subject Information and Informed Consent.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Oct 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 71
    Country: Number of subjects enrolled
    Spain: 101
    Country: Number of subjects enrolled
    United Kingdom: 154
    Country: Number of subjects enrolled
    Austria: 7
    Country: Number of subjects enrolled
    Bulgaria: 19
    Country: Number of subjects enrolled
    Czech Republic: 65
    Country: Number of subjects enrolled
    France: 54
    Country: Number of subjects enrolled
    Germany: 51
    Country: Number of subjects enrolled
    Greece: 15
    Country: Number of subjects enrolled
    China: 64
    Country: Number of subjects enrolled
    Croatia: 9
    Country: Number of subjects enrolled
    Hungary: 9
    Country: Number of subjects enrolled
    Russian Federation: 3
    Country: Number of subjects enrolled
    Slovakia: 38
    Country: Number of subjects enrolled
    Japan: 303
    Country: Number of subjects enrolled
    Canada: 49
    Country: Number of subjects enrolled
    United States: 823
    Country: Number of subjects enrolled
    Singapore: 11
    Country: Number of subjects enrolled
    Korea, Republic of: 84
    Country: Number of subjects enrolled
    Taiwan: 8
    Country: Number of subjects enrolled
    Argentina: 74
    Country: Number of subjects enrolled
    Chile: 17
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    Australia: 49
    Country: Number of subjects enrolled
    Denmark: 17
    Country: Number of subjects enrolled
    Finland: 4
    Country: Number of subjects enrolled
    Italy: 55
    Country: Number of subjects enrolled
    Portugal: 19
    Country: Number of subjects enrolled
    South Africa: 27
    Worldwide total number of subjects
    2204
    EEA total number of subjects
    688
    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)
    341
    From 65 to 84 years
    1841
    85 years and over
    22

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects took part at 426 investigative sites in China,Bulgaria,Croatia,Czech Republic,Greece,Hungary,Poland,Russia,Slovakia,Japan,Canada,Singapore,South Korea,Taiwan,Argentina,Chile,Mexico,Australia,Austria,Denmark,Finland,France,Germany,Italy,Portugal,South Africa,Spain,United Kingdom and United States from 20 October 2016 to 15 January 2020.

    Pre-assignment
    Screening details
    		 This study included 2 parts: Core Phase and Extension Phase. A total of 9758 subjects were screened, of which 7546 subjects were screen failures and 2212 subjects were randomized in the study. The data for the studies E2609-G000-301 (NCT02956486, MissionAD1) and E2609-G000-302 (NCT03036280, MissionAD2) was pooled.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Core Phase: Placebo
    Arm description
    		 Subjects received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Subjects were followed up for 3 months after last dose of elenbecestat matched placebo in core phase.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Subjects were followed up for 3 months after last dose of elenbecestat matched placebo in core phase.

    Arm title
    		 Core Phase: Elenbecestat 50 mg
    Arm description
    		 Subjects received one elenbecestat 50 milligram (mg) tablet, orally, once daily in the morning with or without food up to 24 months. Subjects were followed up for 3 months after last dose of elenbecestat in core phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Elenbecestat
    Investigational medicinal product code
    Other name
    E2609
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Subjects were followed up for 3 months after last dose of elenbecestat in core phase.

    Number of subjects in period 1
    		Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Started
    1105
    1099
    Full Analysis Set (FAS)
    1084
    1062
    Completed
    29
    32
    Not completed
    1076
    1067
         Consent withdrawn by subject
    99
    102
         Adverse Event
    51
    88
         Not specified
    26
    18
         Study terminated by sponsor
    888
    848
         Lost to follow-up
    8
    6
         Inadequate therapeutic effect
    4
    5
    Period 2
    Period 2 title
    Extension Phase
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Extension Phase: Elenbecestat 50 mg
    Arm description
    		 Eligible subjects who completed the core phase entered the extension phase and received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food until commercial availability of elenbecestat, or a lack of positive benefit-risk assessment was determined, whichever occurred first. Subjects were followed up for 1 month after the last dose of elenbecestat in the extension phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Elenbecestat
    Investigational medicinal product code
    Other name
    E2609
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Eligible subjects who completed the core phase entered the extension phase and received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food until commercial availability of elenbecestat, or a lack of positive benefit-risk assessment was determined, whichever occurred first (up to a maximum of 5 months). Subjects were followed up for 1 month after last dose of elenbecestat in extension phase.

    Number of subjects in period 2 [1]
    		Extension Phase: Elenbecestat 50 mg
    Started
    18
    Completed
    0
    Not completed
    18
         Adverse Event
    2
         Study terminated by sponsor
    16
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Only eligible subjects who completed core and consented for extension phase, entered extension phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Core Phase: Placebo
    Reporting group description
    		 Subjects received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Subjects were followed up for 3 months after last dose of elenbecestat matched placebo in core phase.

    Reporting group title
    Core Phase: Elenbecestat 50 mg
    Reporting group description
    		 Subjects received one elenbecestat 50 milligram (mg) tablet, orally, once daily in the morning with or without food up to 24 months. Subjects were followed up for 3 months after last dose of elenbecestat in core phase.

    Reporting group values
    		 Core Phase: Placebo Core Phase: Elenbecestat 50 mg Total
    Number of subjects
    		 1105 1099 2204
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 72.1 ( 7.09 ) 71.9 ( 7.18 ) -
    Gender categorical
    Units: Subjects
        Female
    		 592 534 1126
        Male
    		 513 565 1078
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 162 158 320
        Not Hispanic or Latino
    		 943 941 1884
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 1
        Asian
    		 233 247 480
        Native Hawaiian or Other Pacific Islander
    		 0 2 2
        Black or African American
    		 12 22 34
        White
    		 851 817 1668
        Unknown or Not Reported
    		 8 11 19

    End points

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    End points reporting groups
    Reporting group title
    Core Phase: Placebo
    Reporting group description
    		 Subjects received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Subjects were followed up for 3 months after last dose of elenbecestat matched placebo in core phase.

    Reporting group title
    Core Phase: Elenbecestat 50 mg
    Reporting group description
    		 Subjects received one elenbecestat 50 milligram (mg) tablet, orally, once daily in the morning with or without food up to 24 months. Subjects were followed up for 3 months after last dose of elenbecestat in core phase.
    Reporting group title
    Extension Phase: Elenbecestat 50 mg
    Reporting group description
    		 Eligible subjects who completed the core phase entered the extension phase and received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food until commercial availability of elenbecestat, or a lack of positive benefit-risk assessment was determined, whichever occurred first. Subjects were followed up for 1 month after the last dose of elenbecestat in the extension phase.

    Primary: Core Phase: Change From Baseline up to Month 24 in the Clinical Dementia Rating-sum of Boxes (CDR-SB) Score

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    End point title
    		 Core Phase: Change From Baseline up to Month 24 in the Clinical Dementia Rating-sum of Boxes (CDR-SB) Score
    End point description
    Clinical dementia rating(CDR)scale is a clinical global rating scale that requires interviewing both subject and informant who knows and has contact with subject.CDR scale:clinician directed assessment of both cognition and function, and is intended to capture state and therefore disease stage of subject.CDR scale:6 domains of subject function (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, mild impairment=1, moderate impairment=2 and severe impairment=3.CDR-SB:sum of individual domain scores and ranges from 0 to 18.Higher score indicates more impairment.FAS: group of randomized subjects who received at least 1 dose of drug in core phase and had baseline and at least 1 post-dose primary efficacy measurement.Subjects analyzed:all subjects included in mixed effects model for repeated measures (MMRM) who were evaluable this specific outcome measure.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase
    End point values
    		 Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Number of subjects analysed
    1078
    1053
    Units: score on a scale
        least squares mean (standard error)
    2.17 ( 0.142 )
    1.99 ( 0.146 )
    Statistical analysis title
    		 Core Phase: Placebo,Core Phase: Elenbecestat 50 mg
    Statistical analysis description
    Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (mild cognitive impairment [MCI]/Prodromal, mild alzheimer’sdisease [AD]), concurrent AD medication use, region, apolipoprotein E (ApoE4) status (positive, negative) as fixed effects, and the baseline value and the baseline value by visit interaction as covariate.
    Comparison groups
    Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
    Number of subjects included in analysis
    2131
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.385
    Method
    		 MMRM
    Parameter type
    		 Least Square (LS) Mean Difference
    Point estimate
    -0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.57
         upper limit
    		 0.22

    Primary: Extension Phase: Number of Subjects Reporting One or More Treatment-emergent Adverse Events (TEAEs)

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    End point title
    		 Extension Phase: Number of Subjects Reporting One or More Treatment-emergent Adverse Events (TEAEs) [1]
    End point description
    A TEAE is defined as an adverse event that emerged during treatment or within 28 days following the last dose of study drug, having been absent at pretreatment (Baseline) or reemerged during treatment, having been present at pretreatment (Baseline) but stopped before treatment, or worsened in severity during treatment relative to the pretreatment state, when the adverse event was continuous. Number of subjects with TEAEs (serious and non-serious adverse events) were reported based on their safety assessments of laboratory tests, suicidal ideation and suicidal behavior, drug abuse potential, physical examination, neurological examination, regular measurement of vital signs, magnetic resonance imaging and electrocardiogram parameter values. All safety subjects was the group of subjects who enrolled into the extension phase and received at least 1 dose of study drug in the extension phase.
    End point type
    Primary
    End point timeframe
    From first dose of study drug up to approximately 6 months (including 1 month follow up) for the extension phase
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Extension Phase: Elenbecestat 50 mg
    Number of subjects analysed
    18
    Units: subjects
    6
    No statistical analyses for this end point

    Secondary: Core Phase: Change From Baseline up to Month 24 in Alzheimer’s Disease Composite Score (ADCOMS)

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    End point title
    		 Core Phase: Change From Baseline up to Month 24 in Alzheimer’s Disease Composite Score (ADCOMS)
    End point description
    ADCOMS is a weighted linear combination of 12 items from three existing clinical scales: the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog), the Mini Mental State Examination (MMSE), and the CDR. Four items are from the ADAS-cog (A4 [Delayed Word Recall], A7 [Orientation], A8 [Word Recognition], A11 [Word Finding]); 2 items are from the MMSE (M1 [Orientation Time], M7 [Drawing]); 6 items are from the CDR (C1 [Personal Care], C2 [Community Affairs], C3 [Home and Hobbies], C4 [Judgment and Problem Solving], C5 [Memory], C6 [Orientation]). Composite score is derived from the variables from the 12 items, and ranges from 0 to 1.97, where higher score indicates worse performance. The FAS was the group of randomized subjects who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here "subjects analyzed" signifies all subjects included in MMRM who were evaluable for this specific outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase
    End point values
    		 Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Number of subjects analysed
    1018
    981
    Units: score on a scale
        least squares mean (standard error)
    0.24 ( 0.014 )
    0.23 ( 0.015 )
    Statistical analysis title
    		 Core Phase: Placebo,Core Phase: Elenbecestat 50 mg
    Statistical analysis description
    Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value and the baseline value by visit interaction as covariate.
    Comparison groups
    Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
    Number of subjects included in analysis
    1999
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.345
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 0.02

    Secondary: Core Phase: Change From Baseline up to Month 24 in Amyloid Positron Emission Tomography (PET) Standardized Uptake Value Ratio (SUVR)

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    End point title
    		 Core Phase: Change From Baseline up to Month 24 in Amyloid Positron Emission Tomography (PET) Standardized Uptake Value Ratio (SUVR)
    End point description
    Amyloid PET scan assesses cerebral amyloid load using 3 tracers (florbetapir, florbetaben and flutemetamol) which is standardized into centiloids for evaluation of AD. Centiloid values on centiloid scale is based on mean composite SUVR in cingulate, frontal, parietal and temporal cortexes using whole cerebellum as reference region. SUVR is ratio of tracer uptake in each of cingulate, frontal, parietal and temporal cortexes relative to cerebellum. The centiloid scale anchor points are 0 and 100, where 0 represents a high-certainty amyloid negative scan and 100 represents the amount of global amyloid deposition found in a typical AD scans. The pharmacodynamic (PD) analysis set was the group of subjects in the core phase who had sufficient PD data to derive at least 1 PD parameter. Here "subjects analyzed" signifies all subjects included in MMRM who were evaluable for this specific outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase
    End point values
    		 Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Number of subjects analysed
    268
    248
    Units: score on a scale
        least squares mean (standard error)
    7.81 ( 2.500 )
    -5.02 ( 2.046 )
    Statistical analysis title
    		 Core Phase: Placebo,Core Phase: Elenbecestat 50 mg
    Statistical analysis description
    Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value and the baseline value by visit interaction as covariate.
    Comparison groups
    Core Phase: Elenbecestat 50 mg v Core Phase: Placebo
    Number of subjects included in analysis
    516
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -12.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18.79
         upper limit
    		 -6.88

    Secondary: Core Phase: Change From Baseline up to Month 24 in the CDR-SB Score for Subjects Enriched by Baseline Amyloid PET SUVR Between 1.2 and 1.6

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    End point title
    		 Core Phase: Change From Baseline up to Month 24 in the CDR-SB Score for Subjects Enriched by Baseline Amyloid PET SUVR Between 1.2 and 1.6
    End point description
    CDR scale: clinician directed assessment of both cognition and function, and is intended to capture state and disease stage of subject. CDR scale: 6 domains of subject function (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, mild impairment=1, moderate impairment=2 and severe impairment=3. CDR-SB: sum of individual domain scores and ranges from 0 to 18. Higher score indicates more impairment. Amyloid PET scans allow in vivo assessment of cerebral amyloid load. SUVR indicates ratio of tracer uptake in frontal cortex relative to cerebellum or ratio of tracer uptake in whole brain relative to cerebellum.FAS:group of randomized subjects who received at least 1 dose of drug in core phase and had baseline and at least 1 post-dose primary efficacy measurement.Subjects analyzed:all subjects included in MMRM who were evaluable for this specific outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase
    End point values
    		 Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Number of subjects analysed
    664
    617
    Units: score on a scale
        least squares mean (standard error)
    1.97 ( 0.157 )
    1.74 ( 0.169 )
    Statistical analysis title
    		 Core Phase: Placebo,Core Phase: Elenbecestat 50 mg
    Statistical analysis description
    Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value and the baseline value by visit interaction as covariate.
    Comparison groups
    Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
    Number of subjects included in analysis
    1281
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.316
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.67
         upper limit
    		 0.22

    Secondary: Core Phase: Change From Baseline up to Month 24 in the ADCOMS for Subjects Enriched by Baseline Amyloid PET SUVR Between 1.2 and 1.6

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    End point title
    		 Core Phase: Change From Baseline up to Month 24 in the ADCOMS for Subjects Enriched by Baseline Amyloid PET SUVR Between 1.2 and 1.6
    End point description
    ADCOMS:weighted linear combination of 12 items from 3 existing clinical scales:ADAS-cog,MMSE,and CDR.Four items are from the ADAS-cog(A4[Delayed Word Recall],A7[Orientation],A8[Word Recognition],A11[Word Finding]);2 items are from the MMSE(M1[Orientation Time],M7[Drawing]);6 items are from the CDR(C1[Personal Care],C2[Community Affairs],C3[Home and Hobbies],C4[Judgment and Problem Solving],C5[Memory],C6[Orientation]).Composite score:derived from variables from 12 items,and ranges from 0 to 1.97,where higher score indicates worse performance.Amyloid PET scans allow in vivo assessment of cerebral amyloid load.SUVR indicates ratio of tracer uptake in frontal cortex relative to cerebellum or ratio of tracer uptake in whole brain relative to cerebellum.FAS:randomized subjects who received at least 1 dose of drug in core phase and had baseline and at least 1 postdose primary efficacy measurement.Subjects analyzed:all subjects in MMRM who were evaluable for this specific outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase
    End point values
    		 Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Number of subjects analysed
    627
    571
    Units: score on a scale
        least squares mean (standard error)
    0.23 ( 0.017 )
    0.20 ( 0.018 )
    Statistical analysis title
    		 Core Phase: Placebo,Core Phase: Elenbecestat 50 mg
    Statistical analysis description
    Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value and the baseline value by visit interaction as covariate.
    Comparison groups
    Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
    Number of subjects included in analysis
    1198
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.254
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.07
         upper limit
    		 0.02

    Secondary: Core Phase: Change Per Year (Mean Slope) in CDR-SB Score up to Month 24

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    End point title
    		 Core Phase: Change Per Year (Mean Slope) in CDR-SB Score up to Month 24
    End point description
    CDR scale:clinical global rating scale that requires interviewing both the subject and an informant who knows and has contact with subject.CDR scale is a clinician directed assessment of both cognition and function,and is intended to capture state and disease stage of subject. CDR scale:6 domains of subject function(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,mild impairment=1,moderate impairment=2 and severe impairment=3.CDR-SB:sum of individual domain scores and ranges from 0 to 18.Higher score indicates more impairment.In this outcome measure,change per year(mean slope)in CDR-SB score was calculated up to month 24,where higher change indicated more impairment and lower change indicated less impairment.FAS:group of randomized subjects who received at least 1 dose of drug in core phase and had baseline and at least 1 post-dose primary efficacy measurement.
    End point type
    Secondary
    End point timeframe
    Up to Month 24 of the core phase
    End point values
    		 Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Number of subjects analysed
    1084
    1062
    Units: change in score per year
        least squares mean (confidence interval 95%)
    0.934 (0.838 to 1.030)
    0.926 (0.828 to 1.024)
    Statistical analysis title
    		 Core Phase: Placebo,Core Phase: Elenbecestat 50 mg
    Statistical analysis description
    Based on the linear mixed effects model, which included assessment time and treatment group by assessment time interaction as covariate with random intercept and slope.
    Comparison groups
    Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
    Number of subjects included in analysis
    2146
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9088
    Method
    		 Linear mixed effects model
    Parameter type
    		 Difference of Mean Slope
    Point estimate
    -0.008
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.145
         upper limit
    		 0.129

    Secondary: Core Phase: Time to Worsening of CDR Score up to Month 24

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    End point title
    		 Core Phase: Time to Worsening of CDR Score up to Month 24
    End point description
    CDR scale:requires interviewing both the subject and an informant who knows and has contact with the subject.CDR scale:clinician directed assessment of both cognition and function,and is intended to capture state and disease stage of subject. CDR scale assesses 6 domains of subject function(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,mild impairment=1,moderate impairment=2 and severe impairment=3.The global CDR score is computed via an algorithm and ranges from 0 to 3.Higher score indicates more impairment.In this outcome measure,time(in months)to worsening of CDR score(that is, an increase from baseline by at least 0.5 points on the global CDR scale on 2 consecutive scheduled visits)up to month 24 was calculated.FAS:randomized subjects who received at least 1 dose of drug in core phase and had baseline and at least 1 post dose primary efficacy measurement.
    End point type
    Secondary
    End point timeframe
    Up to Month 24 of the core phase
    End point values
    		 Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Number of subjects analysed
    1084
    1062
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (24.07 to 99999)
    Statistical analysis title
    		 Core Phase: Placebo,Core Phase: Elenbecestat 50 mg
    Statistical analysis description
    Based on a Cox regression model which included treatment group, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, APOE4 status (positive, negative) as covariate.
    Comparison groups
    Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
    Number of subjects included in analysis
    2146
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6155
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.16

    Secondary: Core Phase: Time to Conversion to Dementia for Subjects Who Were Not Clinically Staged as Having Dementia at the Core Phase Baseline up to Month 24

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    End point title
    		 Core Phase: Time to Conversion to Dementia for Subjects Who Were Not Clinically Staged as Having Dementia at the Core Phase Baseline up to Month 24
    End point description
    Time (in months) to conversion to dementia for subjects who were not clinically staged as having dementia at the core phase baseline (that is time from randomization to conversion to dementia in clinical diagnosis). The FAS was the group of randomized subjects who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here “subjects analyzed” signifies subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase
    End point values
    		 Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Number of subjects analysed
    902
    901
    Units: months
        median (confidence interval 95%)
    23.05 (21.14 to 24.66)
    21.40 (20.45 to 24.43)
    Statistical analysis title
    		 Core Phase: Placebo,Core Phase: Elenbecestat 50 mg
    Statistical analysis description
    Based on a Cox regression model which included treatment group, concurrent AD medication use, region, APOE4 status (positive, negative) as covariate.
    Comparison groups
    Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
    Number of subjects included in analysis
    1803
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1281
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 1.35

    Secondary: Core Phase: Change From Baseline up to Month 24 in the Alzheimer’s Disease Assessment Scale-cognition14 (ADAS-Cog14) Score

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    End point title
    		 Core Phase: Change From Baseline up to Month 24 in the Alzheimer’s Disease Assessment Scale-cognition14 (ADAS-Cog14) Score
    End point description
    ADAS-cog14 is a psychometric instrument that evaluates 14-items (Immediate Word-recall [0-10], Commands [0-5], Constructional Praxis [0-5], Delayed Word-recall [0-10], Naming Objects/Fingers [0-5], Ideational Praxis [0-5], Orientation[0-8], Word Recognition [0-12], Remembering Test Instructions [0-5], Comprehension[0-5], Word Finding Difficulty [0-5], Spoken Language Ability [0-5], Executive Function [0-5], and Number Cancellation [0-5] test). It is considered to be more sensitive for less impaired populations such as MCI/Prodromal and mild AD subjects. The total score ranges from 0 to 90. Higher score indicates more impairment. The FAS was the group of randomized subjects who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here “subjects analyzed” signifies all subjects included in MMRM who were evaluable for this specific outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase
    End point values
    		 Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Number of subjects analysed
    1010
    972
    Units: score on a scale
        least squares mean (standard error)
    5.38 ( 0.490 )
    4.95 ( 0.520 )
    Statistical analysis title
    		 Core Phase: Placebo,Core Phase: Elenbecestat 50 mg
    Statistical analysis description
    Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value and the baseline value by visit interaction as covariate.
    Comparison groups
    Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
    Number of subjects included in analysis
    1982
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.525
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.75
         upper limit
    		 0.9

    Secondary: Core Phase: Change From Baseline up to Month 24 in the MMSE Score

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    End point title
    		 Core Phase: Change From Baseline up to Month 24 in the MMSE Score
    End point description
    MMSE:for screening purposes,staging of disease severity and measured in AD to follow disease progression and treatment effects.MMSE:composed of 30 questions grouped into domains(Orientation to Time[0-5], Orientation to Place[0-5],Registration[0-3],Attention and Calculation[0-5],Recall[0-3],Naming[0-2],Repetition[0-1],Comprehension[0-3],Reading[0-1],Writing[0-1],Drawing[0-1]).For each of MMSE domains,six items are computed(Orientation to Time[0-5],Orientation to Place[0-5],Registration[0-3],Attention and Calculation[0-5],Recall[0-3],Language:Naming,Repetition,Comprehension,Reading,Writing,and Drawing[0-9]).MMSE Total Score(ranges 0 to 30)=sum of six domains.If any domain score is missing then total score is missing.Higher score indicates better function.FAS:Subjects who received at least 1 dose of drug in core phase and had baseline and at least 1 postdose primary efficacy measurement.Subjects analyzed:signifies all subjects in MMRM who were evaluable for this specific outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase
    End point values
    		 Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Number of subjects analysed
    1056
    1017
    Units: score on a scale
        least squares mean (standard error)
    -2.87 ( 0.234 )
    -2.87 ( 0.241 )
    Statistical analysis title
    		 Core Phase: Placebo,Core Phase: Elenbecestat 50 mg
    Statistical analysis description
    Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value and the baseline value by visit interaction as covariate.
    Comparison groups
    Core Phase: Elenbecestat 50 mg v Core Phase: Placebo
    Number of subjects included in analysis
    2073
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.977
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.64
         upper limit
    		 0.62

    Secondary: Core Phase: Change From Baseline up to Month 24 in the Functional Assessment Questionnaire (FAQ) Score

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    End point title
    		 Core Phase: Change From Baseline up to Month 24 in the Functional Assessment Questionnaire (FAQ) Score
    End point description
    FAQ scores 10 items & measures activities of daily living (paying bills/balancing checkbook, assembling tax records, shopping alone for clothes or groceries, playing game of skill such as bridge or chess/working on a hobby, heating water & turning off stove, preparing balanced meal, keeping track of current events, paying attention & understanding television program, remembering appointments, driving or traveling out of neighborhood). Each item is rated as 0=Normal, 1=Has difficulty but does by self, 2=Requires assistance, 3=Dependent, or 8=Not Applicable. The Total score is the sum of all 10 items & ranges from 0 to 30. Higher score indicates more impairment. If any activity is missed, then the total score is missed. FAS: group of randomized subjects who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Subjects analyzed: all subjects included in MMRM who were evaluable for this specific outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase
    End point values
    		 Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Number of subjects analysed
    1038
    1001
    Units: score on a scale
        least squares mean (standard error)
    5.20 ( 0.448 )
    5.32 ( 0.459 )
    Statistical analysis title
    		 Core Phase: Placebo,Core Phase: Elenbecestat 50 mg
    Statistical analysis description
    Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value and the baseline value by visit interaction as covariate.
    Comparison groups
    Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
    Number of subjects included in analysis
    2039
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.854
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.09
         upper limit
    		 1.32

    Secondary: Core Phase: Change From Baseline up to Month 24 in the ADAS-cog14 Word List (Immediate Recall and Delayed Recall) Score

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    End point title
    		 Core Phase: Change From Baseline up to Month 24 in the ADAS-cog14 Word List (Immediate Recall and Delayed Recall) Score
    End point description
    The ADAS-cog14 Word List is a summation of two items: “Immediate Word-recall” and “Delayed Word-recall”. Immediate Word-recall test: Subjects are asked to recall words and the number of “No” responses for each trial (total 3 trials) are summed. Subscore: sum of scores from 3 trials, divided by 3. Score ranges from 0 to 10. Delayed Word-recall: Subjects used to recall words after a delay and the number of “No” responses are summed. Score ranges from 0 to 10. The Total Score ranges from 0 to 20. Higher score indicates more impairment. The FAS was the group of randomized subjects who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here “subjects analyzed” signifies all subjects included in MMRM who were evaluable for this specific outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase
    End point values
    		 Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Number of subjects analysed
    1050
    1005
    Units: score on a scale
        least squares mean (standard error)
    1.63 ( 0.195 )
    1.36 ( 0.207 )
    Statistical analysis title
    		 Core Phase: Placebo,Core Phase: Elenbecestat 50 mg
    Statistical analysis description
    Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value and the baseline value by visit interaction as covariate.
    Comparison groups
    Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
    Number of subjects included in analysis
    2055
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.314
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.79
         upper limit
    		 0.26

    Secondary: Core Phase: Change From Baseline up to Month 24 in the Alzheimer’s Disease Assessment Scale-cognition11 (ADAS-Cog11) Score

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    End point title
    		 Core Phase: Change From Baseline up to Month 24 in the Alzheimer’s Disease Assessment Scale-cognition11 (ADAS-Cog11) Score
    End point description
    ADAS-cog11 is a psychometric instrument that evaluates 11-items (Immediate Word-recall [0 to 10], Commands [0-5], Constructional Praxis [0-5], Naming Objects/Fingers [0-5], Ideational Praxis [0-5], Orientation[0-8], Word Recognition [0-12], Remembering Test Instructions [0-5], Comprehension[0-5], Word Finding Difficulty [0-5], Spoken Language Ability [0-5] test) and is considered more sensitive for less impaired populations such as MCI/Prodromal and mild AD subjects. The Total score ranges from 0 to 70. Higher score indicates more impairment. The FAS was the group of randomized subjects who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here “subjects analyzed” signifies all subjects included in MMRM who were evaluable for this specific outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase
    End point values
    		 Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Number of subjects analysed
    1010
    972
    Units: score on a scale
        least squares mean (standard error)
    4.11 ( 0.370 )
    4.18 ( 0.391 )
    Statistical analysis title
    		 Core Phase: Placebo,Core Phase: Elenbecestat 50 mg
    Statistical analysis description
    Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value and the baseline value by visit interaction as covariate.
    Comparison groups
    Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
    Number of subjects included in analysis
    1982
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.895
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.93
         upper limit
    		 1.07

    Secondary: Core Phase: Change From Last Dose in the CDR-SB Score

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    End point title
    		 Core Phase: Change From Last Dose in the CDR-SB Score
    End point description
    CDR scale: a clinical global rating scale that requires interviewing both the subject and an informant who knows and has contact with the subject. The CDR scale is a clinician directed assessment of both cognition and function, and is intended to capture the state and therefore the disease stage of the subject. The CDR scale assesses 6 domains of subject function (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, mild impairment=1, moderate impairment=2 and severe impairment=3. The CDR-SB is a sum of the individual domain scores and ranges from 0 to 18. Higher scores indicates more impairment. FAS: group of randomized subjects who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here “subjects analyzed” signifies subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From last dose in the core phase (up to Month 24) up to 3 months follow up (up to Month 27)
    End point values
    		 Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Number of subjects analysed
    759
    734
    Units: score on a scale
        least squares mean (standard error)
    0.40 ( 0.045 )
    0.44 ( 0.046 )
    Statistical analysis title
    		 Core Phase: Placebo,Core Phase: Elenbecestat 50 mg
    Statistical analysis description
    Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value as covariate.
    Comparison groups
    Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
    Number of subjects included in analysis
    1493
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.542
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.09
         upper limit
    		 0.17

    Secondary: Core Phase: Change From Last Dose in the ADCOMS

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    End point title
    		 Core Phase: Change From Last Dose in the ADCOMS
    End point description
    ADCOMS is a weighted linear combination of 12 items from three existing clinical scales: the ADAS-cog, the MMSE, and the CDR. Four items are from the ADAS-cog (A4 [Delayed Word Recall], A7 [Orientation], A8 [Word Recognition], A11 [Word Finding]); 2 items are from the MMSE (M1 [Orientation Time], M7 [Drawing]); 6 items are from the CDR (C1 [Personal Care], C2 [Community Affairs], C3 [Home and Hobbies], C4 [Judgment and Problem Solving], C5 [Memory], C6 [Orientation]). Composite score is derived from the variables from the 12 items, and ranges from 0 to 1.97, where higher score indicates worse performance. The FAS was the group of randomized subjects who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here “subjects analyzed” signifies subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From last dose in the core phase (up to Month 24) up to 3 months follow-up (up to Month 27)
    End point values
    		 Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Number of subjects analysed
    666
    646
    Units: score on a scale
        least squares mean (standard error)
    0.06 ( 0.005 )
    0.06 ( 0.005 )
    Statistical analysis title
    		 Core Phase: Placebo,Core Phase: Elenbecestat 50 mg
    Statistical analysis description
    Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value as covariate.
    Comparison groups
    Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
    Number of subjects included in analysis
    1312
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.38
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.01

    Secondary: Core Phase: Change From Last Dose in the ADAS-cog11 Score

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    End point title
    		 Core Phase: Change From Last Dose in the ADAS-cog11 Score
    End point description
    ADAS-cog11 is a psychometric instrument that evaluates 11-items (Immediate Word-recall [0 to 10], Commands [0-5], Constructional Praxis [0-5], Naming Objects/Fingers [0-5], Ideational Praxis [0-5], Orientation[0-8], Word Recognition [0-12], Remembering Test Instructions [0-5], Comprehension[0-5], Word Finding Difficulty [0-5], Spoken Language Ability [0-5] test) and is considered more sensitive for less impaired populations such as MCI/Prodromal and mild AD subjects. The Total score ranges from 0 to 70. Higher score indicates more impairment. The FAS was the group of randomized subjects who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here “subjects analyzed” signifies subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From last dose in the core phase (up to Month 24) up to 3 months follow-up (up to Month 27)
    End point values
    		 Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Number of subjects analysed
    679
    647
    Units: score on a scale
        least squares mean (standard error)
    0.95 ( 0.150 )
    0.56 ( 0.153 )
    Statistical analysis title
    		 Core Phase: Placebo,Core Phase: Elenbecestat 50 mg
    Statistical analysis description
    Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value as covariate.
    Comparison groups
    Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
    Number of subjects included in analysis
    1326
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.063
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.82
         upper limit
    		 0.02

    Secondary: Core Phase: Change From Last Dose in the ADAS-cog14 Score

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    End point title
    		 Core Phase: Change From Last Dose in the ADAS-cog14 Score
    End point description
    ADAS-cog14 is a psychometric instrument that evaluates 14-items (Immediate Word-recall [0 to 10], Commands [0-5], Constructional Praxis [0-5], Delayed Word-recall [0-10], Naming Objects/Fingers [0-5], Ideational Praxis [0-5], Orientation[0-8], Word Recognition [0-12], Remembering Test Instructions [0-5], Comprehension[0-5], Word Finding Difficulty [0-5], Spoken Language Ability [0-5], Executive Function [0-5], and Number Cancellation [0-5] test). It is considered to be more sensitive for less impaired populations such as MCI/Prodromal and mild AD subjects. The Total Score ranges from 0 to 90. Higher score indicates more impairment. The FAS was the group of randomized subjects who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here “subjects analyzed” signifies subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From last dose in the core phase (up to Month 24) up to 3 months follow-up (up to Month 27)
    End point values
    		 Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Number of subjects analysed
    679
    647
    Units: score on a scale
        least squares mean (standard error)
    0.96 ( 0.196 )
    0.40 ( 0.201 )
    Statistical analysis title
    		 Core Phase: Placebo,Core Phase: Elenbecestat 50 mg
    Statistical analysis description
    Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value as covariate.
    Comparison groups
    Core Phase: Elenbecestat 50 mg v Core Phase: Placebo
    Number of subjects included in analysis
    1326
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.045 [2]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.11
         upper limit
    		 -0.01
    Notes
    [2] - Based on a MMRM, which included baseline as a covariate with treatment groups as fixed effects.

    Secondary: Core Phase: Change From Last Dose in the MMSE Score

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    End point title
    		 Core Phase: Change From Last Dose in the MMSE Score
    End point description
    MMSE:instrument used for screening purposes,staging of disease severity and measured longitudinally in AD to follow disease progression/treatment effects.MMSE:composed of 30 questions grouped into domains(Orientation to Time[0-5],Orientation to Place[0-5],Registration[0-3],Attention and Calculation[0-5],Recall[0-3],Naming[0-2],Repetition[0-1],Comprehension[0-3],Reading[0-1],Writing[0-1],Drawing[0-1]).For each MMSE domains,six items are computed(Orientation to Time[0-5],Orientation to Place[0-5],Registration[0-3],Attention and Calculation[0-5],Recall[0-3],Language:Naming,Repetition,Comprehension,Reading,Writing,and Drawing[0-9]).MMSE Total Score(ranges from 0 to 30)=sum of six domains.If any domain score is missing then total score is missing.Higher score indicates better function.FAS:Subjects who received at least 1 dose of drug and had baseline and at least 1 post-dose primary efficacy measurement."Subjects analyzed"signifies subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From last dose in the core phase (up to Month 24) up to 3 months follow-up (up to Month 27)
    End point values
    		 Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Number of subjects analysed
    734
    719
    Units: score on a scale
        least squares mean (standard error)
    -0.22 ( 0.101 )
    -0.26 ( 0.102 )
    Statistical analysis title
    		 Core Phase: Placebo,Core Phase: Elenbecestat 50 mg
    Statistical analysis description
    Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value as covariate.
    Comparison groups
    Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
    Number of subjects included in analysis
    1453
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.799
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.32
         upper limit
    		 0.24

    Secondary: Core Phase: Change From Last Dose in the ADAS-cog14 Word List (Immediate Recall and Delayed Recall) Score

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    End point title
    		 Core Phase: Change From Last Dose in the ADAS-cog14 Word List (Immediate Recall and Delayed Recall) Score
    End point description
    The ADAS-cog14 Word List is a summation of two items: “Immediate Word-recall” and “Delayed Word-recall”. Immediate Word-recall test: Subjects are asked to recall words and the number of “No” responses for each trial (total 3 trials) are summed. Subscore: sum of scores from 3 trials, divided by 3. Score ranges from 0 to 10. Delayed Word-recall: Subjects used to recall words after a delay and the number of “No” responses are summed. Score ranges from 0 to 10. The Total Score ranges from 0 to 20. Higher score indicates more impairment. The FAS was the group of randomized subjects who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here “subjects analyzed” signifies subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From last dose in the core phase (up to Month 24) up to 3 months follow-up (up to Month 27)
    End point values
    		 Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Number of subjects analysed
    707
    685
    Units: score on a scale
        least squares mean (standard error)
    0.54 ( 0.088 )
    0.22 ( 0.090 )
    Statistical analysis title
    		 Core Phase: Placebo,Core Phase: Elenbecestat 50 mg
    Statistical analysis description
    Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value as covariate.
    Comparison groups
    Core Phase: Placebo v Core Phase: Elenbecestat 50 mg
    Number of subjects included in analysis
    1392
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.012
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.56
         upper limit
    		 -0.07

    Secondary: Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in CDR-SB Score

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    End point title
    		 Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in CDR-SB Score
    End point description
    The CDR scale is a clinical global rating scale that requires interviewing both the subject and an informant who knows and has contact with the subject. The CDR scale is a clinician directed assessment of both cognition and function, and is intended to capture the state and therefore the disease stage of the subject. The CDR scale assesses 6 domains of subject function (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, mild impairment=1, moderate impairment=2 and severe impairment=3. The CDR-SB is a sum of the individual domain scores and ranges from 0 to 18. Higher score indicates more impairment. Data could not be reported as the study was terminated prior to reaching the specified time point for assessment in the extension phase. Statistical analysis plan was modified to indicate that the extension phase analysis was not done.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase
    End point values
    		 Extension Phase: Elenbecestat 50 mg
    Number of subjects analysed
    0 [3]
    Units: score on a scale
        least squares mean (standard error)
    ( )
    Notes
    [3] - No subjects were analysed for this outcome measure.
    No statistical analyses for this end point

    Secondary: Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in ADCOMS

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    End point title
    		 Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in ADCOMS
    End point description
    ADCOMS is a weighted linear combination of 12 items from three existing clinical scales: the ADAS-cog, the MMSE, and the CDR. Four items are from the ADAS-cog (A4 [Delayed Word Recall], A7 [Orientation], A8 [Word Recognition], A11 [Word Finding]); 2 items are from the MMSE (M1 [Orientation Time], M7 [Drawing]); 6 items are from the CDR (C1 [Personal Care], C2 [Community Affairs], C3 [Home and Hobbies], C4 [Judgment and Problem Solving], C5 [Memory], C6 [Orientation]). Composite score is derived from the variables from the 12 items, and ranges from 0 to 1.97, where higher score indicates worse performance. Data could not be reported as the study was terminated prior to reaching the specified time point for assessment in the extension phase. Statistical analysis plan was modified to indicate that the extension phase analysis was not done.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase
    End point values
    		 Extension Phase: Elenbecestat 50 mg
    Number of subjects analysed
    0 [4]
    Units: score on a scale
        least squares mean (standard error)
    ( )
    Notes
    [4] - No subjects were analysed for this outcome measure.
    No statistical analyses for this end point

    Secondary: Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in MMSE Score

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    End point title
    		 Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in MMSE Score
    End point description
    MMSE: cognitive instrument used for screening purposes,staging of disease severity and is often measured longitudinally in AD clinical studies to follow disease progression and treatment effects.MMSE: 30 questions grouped into domains(Orientation to Time[0-5],Orientation to Place[0-5],Registration[0-3],Attention and Calculation[0-5],Recall[0-3],Naming [0-2],Repetition[0-1],Comprehension[0-3],Reading[0-1],Writing[0-1],Drawing[0-1]).For each of MMSE domains, six items are computed(Orientation to Time[0-5],Orientation to Place [0-5],Registration[0-3],Attention and Calculation[0-5],Recall[0-3],Language:Naming,Repetition,Comprehension,Reading,Writing,and Drawing[0-9]).MMSE Total Score:sum of six domains and ranges from 0 to 30.If any domain score is missing then total score is missing.Higher score indicates better function.Data:not reported as study terminated prior to reaching specified time point.Statistical analysis plan:modified to indicate that extension phase analysis was not done.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase
    End point values
    		 Extension Phase: Elenbecestat 50 mg
    Number of subjects analysed
    0 [5]
    Units: score on a scale
        least squares mean (standard error)
    ( )
    Notes
    [5] - No subjects were analysed for this outcome measure.
    No statistical analyses for this end point

    Secondary: Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in FAQ Score

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    End point title
    		 Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in FAQ Score
    End point description
    FAQ scores 10 items & measures activities of daily living (paying bills/balancing checkbook, assembling tax records, shopping alone for clothes or groceries, playing game of skill such as bridge or chess/working on a hobby, heating water & turning off stove, preparing balanced meal, keeping track of current events, paying attention & understanding television program, remembering appointments, driving or traveling out of neighborhood). Each item is rated as follows: 0=Normal, 1=Has difficulty but does by self, 2=Requires assistance, 3=Dependent, or 8=Not Applicable. The total score is the sum of all 10 items & ranges from 0 to 30. Higher score indicates more impairment. If any activity is missed, then the total score is missed. Data could not be reported as the study was terminated prior to reaching the specified time point for assessment in the extension phase. Statistical analysis plan was modified to indicate that the extension phase analysis was not done.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase
    End point values
    		 Extension Phase: Elenbecestat 50 mg
    Number of subjects analysed
    0 [6]
    Units: score on a scale
        least squares mean (standard error)
    ( )
    Notes
    [6] - No subjects were analysed for this outcome measure.
    No statistical analyses for this end point

    Secondary: Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in ADAS-cog14 Score

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    End point title
    		 Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in ADAS-cog14 Score
    End point description
    ADAS-cog14 is a psychometric instrument that evaluates 14-items (Immediate Word-recall [0 to 10], Commands [0-5], Constructional Praxis [0-5], Delayed Word-recall [0-10], Naming Objects/Fingers [0-5], Ideational Praxis [0-5], Orientation[0-8], Word Recognition [0-12], Remembering Test Instructions [0-5], Comprehension[0-5], Word Finding Difficulty [0-5], Spoken Language Ability [0-5], Executive Function [0-5], and Number Cancellation [0-5] test). It is considered to be more sensitive for less impaired populations such as MCI/Prodromal and mild AD subjects. The total score ranges from 0 to 90. Higher score indicates more impairment. Data could not be reported as the study was terminated prior to reaching the specified time point for assessment in the extension phase. Statistical analysis plan was modified to indicate that the extension phase analysis was not done.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase
    End point values
    		 Extension Phase: Elenbecestat 50 mg
    Number of subjects analysed
    0 [7]
    Units: score on a scale
        least squares mean (standard error)
    ( )
    Notes
    [7] - No subjects were analysed for this outcome measure.
    No statistical analyses for this end point

    Secondary: Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in ADAS-cog14 Word List (Immediate Recall and Delayed Recall) Score

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    End point title
    		 Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in ADAS-cog14 Word List (Immediate Recall and Delayed Recall) Score
    End point description
    The ADAS-cog14 Word List is a summation of two items: “Immediate Word-recall” and “Delayed Word-recall”. Immediate Word-recall test: Subjects are asked to recall words and the number of “No” responses for each trial (total 3 trials) are summed. Subscore: sum of scores from 3 trials, divided by 3. Score ranges from 0 to 10. Delayed Word-recall: Subjects used to recall words after a delay and the number of “No” responses are summed. Score ranges from 0 to 10. The Total Score ranges from 0 to 20. Higher score indicates more impairment. Data could not be reported as the study was terminated prior to reaching the specified time point for assessment in the extension phase. Statistical analysis plan was modified to indicate that the extension phase analysis was not done.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase
    End point values
    		 Extension Phase: Elenbecestat 50 mg
    Number of subjects analysed
    0 [8]
    Units: score on a scale
        least squares mean (standard error)
    ( )
    Notes
    [8] - No subjects were analysed for this outcome measure.
    No statistical analyses for this end point

    Secondary: Extension Phase: Time to Conversion to Dementia for Subjects Who Were Not Clinically Staged as Having Dementia at the Core Phase Baseline up to Month 12 of the Extension Phase

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    End point title
    		 Extension Phase: Time to Conversion to Dementia for Subjects Who Were Not Clinically Staged as Having Dementia at the Core Phase Baseline up to Month 12 of the Extension Phase
    End point description
    Time (in months) to conversion to dementia for subjects who were not clinically staged as having dementia at the core phase baseline (that is time from randomization to conversion to dementia in clinical diagnosis). Data could not be reported as the study was terminated prior to reaching the specified time point for assessment in the extension phase. Statistical analysis plan was modified to indicate that the extension phase analysis was not done.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase
    End point values
    		 Extension Phase: Elenbecestat 50 mg
    Number of subjects analysed
    0 [9]
    Units: months
        median (confidence interval 95%)
    ( to )
    Notes
    [9] - No subjects were analysed for this outcome measure.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to approximately 27 months (including 3 months follow up) for the Core Phase and up to approximately 6 months (including 1 month follow up) for the Extension Phase
    Adverse event reporting additional description
    Core Phase: adverse events were reported for SAS (group of subjects who received at least 1 dose of drug and had at least 1 post-dose safety assessment). Extension Phase: adverse events were reported for All Safety Subjects analysis set: group of subjects who enrolled into extension phase and received at least 1 dose of drug in extension phase.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Core Phase: Placebo
    Reporting group description
    		 Subjects received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Subjects were followed up for 3 months after last dose of elenbecestat matched placebo in core phase.

    Reporting group title
    Core Phase: Elenbecestat 50 mg
    Reporting group description
    		 Subjects received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Subjects were followed up for 3 months after last dose of elenbecestat in core phase.

    Reporting group title
    Extension Phase: Elenbecestat 50 mg
    Reporting group description
    		 Eligible subjects who completed the core phase entered the extension phase and received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food until commercial availability of elenbecestat, or a lack of positive benefit-risk assessment was determined, whichever occurred first. Subjects were followed up for 1 month after last dose of elenbecestat in extension phase.

    Serious adverse events
    		 Core Phase: Placebo Core Phase: Elenbecestat 50 mg Extension Phase: Elenbecestat 50 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    117 / 1105 (10.59%)
    134 / 1099 (12.19%)
    0 / 18 (0.00%)
         number of deaths (all causes)
    6
    3
    0
         number of deaths resulting from adverse events
    3
    2
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 1105 (0.00%)
    2 / 1099 (0.18%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    3 / 1105 (0.27%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Benign gastric neoplasm
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder adenocarcinoma stage unspecified
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric adenoma
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastatic malignant melanoma
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Salivary gland cancer
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    2 / 1105 (0.18%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mucinous adenocarcinoma of appendix
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of pharynx
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vulval neoplasm
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Waldenstrom's macroglobulinaemia
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 1105 (0.09%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic aneurysm
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive urgency
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood pressure inadequately controlled
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 1105 (0.09%)
    2 / 1099 (0.18%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 1105 (0.09%)
    2 / 1099 (0.18%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    0 / 1105 (0.00%)
    2 / 1099 (0.18%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical polyp
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystocele
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 1105 (0.18%)
    2 / 1099 (0.18%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 1105 (0.09%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 1105 (0.09%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 1105 (0.18%)
    2 / 1099 (0.18%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aggression
         subjects affected / exposed
    0 / 1105 (0.00%)
    2 / 1099 (0.18%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 1105 (0.00%)
    2 / 1099 (0.18%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delusion
         subjects affected / exposed
    1 / 1105 (0.09%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychotic behaviour
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hallucination, visual
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood potassium decreased
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Heart rate irregular
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatic enzymes increased
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    White blood cell count increased
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    4 / 1105 (0.36%)
    7 / 1099 (0.64%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 1105 (0.09%)
    3 / 1099 (0.27%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 1105 (0.00%)
    3 / 1099 (0.27%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 1105 (0.00%)
    2 / 1099 (0.18%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    2 / 1105 (0.18%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 1105 (0.09%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 1105 (0.09%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaw fracture
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous haematoma
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Accidental overdose
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary vascular graft stenosis
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Type V hyperlipidaemia
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    3 / 1105 (0.27%)
    2 / 1099 (0.18%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 1105 (0.09%)
    2 / 1099 (0.18%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 1105 (0.00%)
    2 / 1099 (0.18%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 1105 (0.00%)
    2 / 1099 (0.18%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    3 / 1105 (0.27%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    2 / 1105 (0.18%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 1105 (0.09%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    3 / 1105 (0.27%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paroxysmal atrioventricular block
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus arrest
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 1105 (0.09%)
    4 / 1099 (0.36%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 1105 (0.09%)
    2 / 1099 (0.18%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 1105 (0.09%)
    2 / 1099 (0.18%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 1105 (0.09%)
    2 / 1099 (0.18%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 1105 (0.00%)
    2 / 1099 (0.18%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Normal pressure hydrocephalus
         subjects affected / exposed
    0 / 1105 (0.00%)
    2 / 1099 (0.18%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    2 / 1105 (0.18%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 1105 (0.09%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Unresponsive to stimuli
         subjects affected / exposed
    1 / 1105 (0.09%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Altered state of consciousness
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain injury
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cerebral ventricle dilatation
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myoclonus
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parkinsonism
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Petit mal epilepsy
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dementia Alzheimer's type
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lacunar stroke
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphopenia
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 1105 (0.09%)
    3 / 1099 (0.27%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Idiopathic orbital inflammation
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal artery occlusion
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diplopia
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 1105 (0.27%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    2 / 1105 (0.18%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal spasm
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis acute
         subjects affected / exposed
    1 / 1105 (0.09%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic mass
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug eruption
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug reaction with eosinophilia and systemic symptoms
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity vasculitis
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxic skin eruption
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Actinic keratosis
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 1105 (0.00%)
    2 / 1099 (0.18%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urethral meatus stenosis
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Thyroid mass
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    0 / 1105 (0.00%)
    2 / 1099 (0.18%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    6 / 1105 (0.54%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle twitching
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc degeneration
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 1105 (0.27%)
    5 / 1099 (0.45%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    2 / 1105 (0.18%)
    5 / 1099 (0.45%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 1105 (0.18%)
    3 / 1099 (0.27%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 1105 (0.09%)
    2 / 1099 (0.18%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 1105 (0.00%)
    2 / 1099 (0.18%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 1105 (0.00%)
    2 / 1099 (0.18%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 1105 (0.00%)
    2 / 1099 (0.18%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 1105 (0.09%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Alpha haemolytic streptococcal infection
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis viral
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colonic abscess
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection viral
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 1105 (0.18%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enteritis infectious
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ophthalmic herpes zoster
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    1 / 1105 (0.09%)
    2 / 1099 (0.18%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 1105 (0.18%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 1105 (0.00%)
    1 / 1099 (0.09%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 1105 (0.18%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acidosis
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 1105 (0.09%)
    0 / 1099 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Core Phase: Placebo Core Phase: Elenbecestat 50 mg Extension Phase: Elenbecestat 50 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    292 / 1105 (26.43%)
    391 / 1099 (35.58%)
    6 / 18 (33.33%)
    Investigations
    Blood sodium decreased
         subjects affected / exposed
    0 / 1105 (0.00%)
    0 / 1099 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    55 / 1105 (4.98%)
    66 / 1099 (6.01%)
    0 / 18 (0.00%)
         occurrences all number
    79
    101
    0
    Fall
         subjects affected / exposed
    60 / 1105 (5.43%)
    61 / 1099 (5.55%)
    0 / 18 (0.00%)
         occurrences all number
    71
    79
    0
    Vascular disorders
    Varicose vein
         subjects affected / exposed
    0 / 1105 (0.00%)
    0 / 1099 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Cerebral microhaemorrhage
         subjects affected / exposed
    0 / 1105 (0.00%)
    0 / 1099 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Cognitive disorder
         subjects affected / exposed
    0 / 1105 (0.00%)
    0 / 1099 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    0
    2
    Dizziness
         subjects affected / exposed
    45 / 1105 (4.07%)
    57 / 1099 (5.19%)
    0 / 18 (0.00%)
         occurrences all number
    49
    61
    0
    Somnolence
         subjects affected / exposed
    0 / 1105 (0.00%)
    0 / 1099 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    18 / 1105 (1.63%)
    70 / 1099 (6.37%)
    0 / 18 (0.00%)
         occurrences all number
    18
    89
    0
    General disorders and administration site conditions
    Gait disturbance
         subjects affected / exposed
    0 / 1105 (0.00%)
    0 / 1099 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 1105 (0.00%)
    0 / 1099 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Rash
         subjects affected / exposed
    22 / 1105 (1.99%)
    60 / 1099 (5.46%)
    0 / 18 (0.00%)
         occurrences all number
    26
    78
    0
    Psychiatric disorders
    Abnormal dreams
         subjects affected / exposed
    36 / 1105 (3.26%)
    57 / 1099 (5.19%)
    0 / 18 (0.00%)
         occurrences all number
    42
    66
    0
    Nightmare
         subjects affected / exposed
    0 / 1105 (0.00%)
    0 / 1099 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Urine flow decreased
         subjects affected / exposed
    0 / 1105 (0.00%)
    0 / 1099 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 1105 (0.00%)
    0 / 1099 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Osteoarthritis
         subjects affected / exposed
    0 / 1105 (0.00%)
    0 / 1099 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 1105 (0.00%)
    0 / 1099 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    67 / 1105 (6.06%)
    71 / 1099 (6.46%)
    0 / 18 (0.00%)
         occurrences all number
    80
    86
    0
    Upper respiratory tract infection
         subjects affected / exposed
    50 / 1105 (4.52%)
    58 / 1099 (5.28%)
    0 / 18 (0.00%)
         occurrences all number
    56
    63
    0
    Viral infection
         subjects affected / exposed
    0 / 1105 (0.00%)
    0 / 1099 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 1105 (0.00%)
    0 / 1099 (0.00%)
    1 / 18 (5.56%)
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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Nov 2016
    Amendment 01 to study E2609-G000-301 (2016-003928-23): -Added that randomization was stratified according to region, disease status, and use of concomitant medications. Randomization was no longer to be stratified by apolipoprotein E (ApoE) genotype. -Added the requirement for central reading of ECG recordings for consistency. -Added a secondary objective to determine whether elenbecestat was superior to placebo on the ADAS-cog14 Word List (immediate recall and delayed recall) at 24 months in subjects with EAD. -Added a secondary objective to determine whether elenbecestat was superior to placebo on the change from baseline in CDR-SB at 27 months (ie, 24 months of treatment plus 3 months posttreatment follow-up). -Additional instructions were provided regarding temporary suspension of study drug following lymphocytopenia and subsequent rechallenge. -Administration of the Modified Hachinski Scale was moved to Tier 1 instead of Tier 2 to identify those subjects with vascular dementia and exclude them earlier in the screening process. -Addition of sleep/dream questionnaire for subjects reporting AEs of abnormal dreams, nightmares or sleep terrors. -Added requirement to measure absolute lymphocyte count (ALC) every 4 weeks for subjects who had a Grade 2 or greater lymphocytopenia during the follow-up period. -Clinical chemistry and hematology test were made mandatory at the second Follow-up Visit. -Added clarification regarding testing of blood samples for immunological assessments. - Malignant neoplasms within 5 years of Screening were excluded from the study (changed from 3 years). - Clarified that subjects who were illiterate were excluded from participation in the study. - Additional blood samples for PD evaluation were added at follow up.
    06 Feb 2017
    Amendment 02 to study E2609-G000-301 (2016-003928-23) and amendment 01 to study E2609-G000-302 (2016-004128-42): -Added China to the list of regions to participate in the study and changed the number of levels of stratification by region from 6 to 7 (added by Amendment 02 to Study 301 only: China was already included in Study 302). -Added an exclusion for moderate to severe hepatic impairment and provided specific criteria. -Prothrombin time and International Normalized Ratio (INR) (derived from prothrombin time) were added as a required part of Screening. -Added that subjects who developed moderate to severe hepatic impairment during the study were to discontinue study drug. -Removed exclusion of subjects undergoing lumbar puncture (LP) procedure with a medical condition with bleeding risk that is not under adequate control and provided additional guidance for subjects receiving concomitant anticoagulation/antiplatelet therapy. These subjects were to have prothrombin time and INR prior to CSF LP; if they were assessed by the investigator to be at risk for bleeding, they were to be excluded from CSF collection. -Added clarification to the exclusion criteria to specify that ALC was derived from the complete blood count with differential representing the normal lymphocytes (with atypical lymphocytes removed and presented as a separate count if they were present) and calculated by the white blood cell count × percentage of lymphocytes. -Added that subjects who were assessed by both amyloid PET and CSF were required to wait for a minimum of 48 hours between the 2 procedures and deleted that CSF must be collected before PET assessment. -Completion of the Sleep/Dream Questionnaire when triggered by AEs related to abnormal dreams, nightmares, or sleep terror was added for all study visits.
    04 Apr 2017
    Amendment 03 to study E2609-G000-301 (2016-003928-23) and amendment 02 to study E2609-G000-302 (2016-004128-42): -Added that start of open-label Extension Phase would require a protocol amendment with prior approval from applicable Health Authorities. -Added that the end of the study for the double-blind Randomization Phase would be the date of the last study visit (Visit 15) for the last subject in the double-blind Randomization Phase. -Extended the requirement of compliance with local standard of care for concomitant use of AChEI or memantine for symptomatic treatment of AD to include initiation or changing dose of AChEI or memantine during the study. -Revised the description of blood/CSF collection and assay for PD and exploratory biomarkers. -Specified that PBMCs were to be stored for testing as required. -Added that subjects who develop seizures were to be discontinued from study drug. -Defined severe infection as follows: sepsis; deep tissue (invasive) infection; any infection requiring intravenous (IV) antibiotics; any infection requiring hospitalization (if outpatient at onset); any infection leading to need for oxygen, pressors or fluids to support blood pressure (BP), or intubation; any infection that requires major surgical intervention; pseudomembranous colitis due to C. difficile; typhlitis; osteomyelitis; and meningitis. -Added guidance to action to be taken with drug administration for subjects who developed severe infections. -Revised study drug interruption and discontinuation criteria for skin rash and herpes infections. Added instructions for drug consultation with medical monitor and potential rechallenge. -Corrected description for calculating immediate memory score on ADAS-cog14. -Added measurement of prothrombin time, INR (derived from prothrombin time), and activated partial thromboplastin time to each study visit.
    28 Jun 2017
    Amendment 04 to study E2609-G000-301 (2016-003928-23) and amendment 03 to study E2609-G000-302 (2016-004128-42): -Specified the duration of the Prerandomization Phase and that randomization was to occur no more than 10 days after completion of all screening Added that for any given subject, every effort was to be made to ensure that the diagnosing clinician (responsible for the initial diagnosis and for disease staging) and the CDR rater remained unchanged throughout the study. -Removed PD blood specimen collection from the Screening Period and stipulated that Baseline blood draws for PD assessment were to be performed predose at Visit 2 (Randomization Phase) rather than during Screening. -Specified that safety assessments of immune status were to be performed throughout the study. -Specified that the MMSE and CDR requirements are to be met at Screening. -Listed CSF Aβ(1-42) and tau:Aβ (1-42) ratio as examples of AD biomarkers for brain amyloid pathology. -Added that PET scans performed at the ED Visit should only be performed if 6 months has elapsed since the prior PET scan. -Specified that historical PET scans must have been positive for amyloid in order to be considered for eligibility purposes. -Added that subjects must have the capacity to provide informed consent (as determined in accordance with applicable professional standards and local laws/regulations) to enroll in the study. -Added that the study partner must be literate. -Specified that findings of “diffuse” white matter disease “as defined by a score of 3 on the age-related white matter changes score” on centrally read brain MRI scan at Screening were exclusionary. Clarified that evidence of multiple lacunar infarcts was exclusionary, regardless of region, whereas evidence of stroke was exclusionary when it involved a major vascular territory. -Provided guidance for possible inclusion of subjects successfully treated for hepatitis C.
    19 Jul 2018
    Amendment 05 to study E2609-G000-301 (2016-003928-23) and Amendment 04 to study E2609-G000-302 (2016-004128-42): -An optional tau PET longitudinal substudy was added for study eligible subjects from select geographical sites in the US (based on the proximity to the tau PET ligand manufacturing sites) that have had an amyloid positive study specific PET scan and consented to participate in the optional amyloid PET longitudinal substudy.
    21 Jan 2019
    Amendment 06 to study E2609-G000-301 (2016-003928-23) and Amendment 05 to study E2609-G000-302 (2016-004128-42): -Added details for the open-label Extension Phase. -Added the plan for pooling of Studies 301 and 302 analysis, with decreased subjects and sites in each study. -Key secondary objectives were defined among the multiple secondary objectives, indicating those of most importance that were tested in a hierarchical manner. -Added Alzheimer's Disease Composite Score (ADCOMS) as a secondary objective for the Core Studies. -Added of CDR-SB and ADCOMS enriched by baseline amyloid PET standardized uptake value ratio (SUVR) as a secondary objective for the Core Studies. -Added a biomarker objective and endpoints for the Core Studies. -Revised the country list to reflect that South Africa was a participating country. -Added that if subjects had non MRI compatible devices fitted during treatment, then a computed tomography scan could be utilized to assess safety, if deemed appropriate by the investigator. -Added that CSF was to be used to assess PD, PK, and exploratory biomarkers. -Added that CSF and PET assessments were to be conducted before any other visit assessments and while the study was still study drug -Added that new AEs were to be collected for 4 weeks post last dose and followed-up for 12 weeks, or until resolution, whichever came first. AEs relating to study procedures were to be collected until the end of study participation. -Allowed for historical CSF samples, if collected, processed, and stored under appropriate conditions and approved by the sponsor, to be analyzed to determine CSF amyloid positivity. -Added that levels of Vitamin B12 may be confirmed with reflex testing to include methylmalonic acid analysis, if available in region. -Revised exclusion criterion to specify that if the QTcF machine read was greater than 440 ms on the first single 12-lead ECG, 2 additional 12-lead ECGs were to be performed.
    23 May 2019
    Amendment 07 to study E2609-G000-301 (2016-003928-23) and Amendment 06 to study E2609-G000-302 (2016-004128-42): -To comply with applicable professional standards and local laws/regulations, added that subjects in Japan who lost the capacity to provide informed consent during the Core Studies were eligible for inclusion in the Extension Phase if the investigators obtain subject assent and consent of the legal representative.

    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.
    Study terminated early due to unfavorable risk-benefit ratio including no evidence of potential efficacy and adverse event profile with drug was worse than placebo.Small sample size at 24 month timepoint of core phase limits interpretability of data.
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