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    Clinical Trial Results:
    A 24-Month, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Efficacy, Safety, Tolerability, Biomarker and Pharmacokinetics Study of AZD3293 in Early Alzheimer’s Disease (The AMARANTH Study)

    Summary
    EudraCT number
    2014-002601-38
    Trial protocol
    GB   BE   DE   ES   HU   FR  
    Global end of trial date
    04 Oct 2018

    Results information
    Results version number
    v2(current)
    This version publication date
    15 Aug 2019
    First version publication date
    27 Jun 2019
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Correction of full data set

    Trial information

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    Trial identification
    Sponsor protocol code
    I8D-MC-AZES
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02245737
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Trial Number: 16023
    Sponsors
    Sponsor organisation name
    Eli Lilly and Company
    Sponsor organisation address
    Lilly Corporate Center, Indianapolis, IN, United States, 46285
    Public contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐CTLilly,
    Scientific contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐285‐4559,
    Sponsor organisation name
    AstraZeneca UK Limited
    Sponsor organisation address
    Charter Way, Macclesfield, Cheshire, United Kingdom, SK10 2NA
    Public contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, AstraZeneca UK Limited, 44 1625-58-2828,
    Scientific contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, AstraZeneca UK Limited, 44 1625-58-2828,
    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
    04 Oct 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Oct 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The purpose of this study is to assess the efficacy and safety of lanabecestat compared with placebo administered for 104 weeks in the treatment of early Alzheimer´s disease. The study will test the hypothesis that lanabecestat is a disease-modifying treatment for participants with early Alzheimer´s disease, defined as the continuum of participants with mild cognitive impairment (MCI) due to Alzheimer´s disease and participants diagnosed with mild dementia of the Alzheimer´s type, as measured by change from baseline on the 13-item Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-Cog13) score at week 104 in each of the 2 lanabecestat treatment groups compared with placebo.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    30 Sep 2014
    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
    Romania: 5
    Country: Number of subjects enrolled
    Puerto Rico: 36
    Country: Number of subjects enrolled
    Hungary: 25
    Country: Number of subjects enrolled
    United States: 521
    Country: Number of subjects enrolled
    Japan: 183
    Country: Number of subjects enrolled
    United Kingdom: 250
    Country: Number of subjects enrolled
    Spain: 216
    Country: Number of subjects enrolled
    Canada: 180
    Country: Number of subjects enrolled
    Korea, Republic of: 70
    Country: Number of subjects enrolled
    Belgium: 50
    Country: Number of subjects enrolled
    Poland: 159
    Country: Number of subjects enrolled
    Italy: 132
    Country: Number of subjects enrolled
    Australia: 131
    Country: Number of subjects enrolled
    France: 117
    Country: Number of subjects enrolled
    Germany: 143
    Worldwide total number of subjects
    2218
    EEA total number of subjects
    1097
    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)
    423
    From 65 to 84 years
    1770
    85 years and over
    25

    Subject disposition

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    Recruitment
    Recruitment details
    No Text Available

    Pre-assignment
    Screening details
    No Text Available

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Participants received placebo film-coated oral tablets once daily.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Film-coated tablets of placebo administered orally once a day.

    Arm title
    Lanabecestat 20 mg
    Arm description
    Participants received lanabecestat 20 mg film-coated oral tablets once daily.
    Arm type
    Experimental

    Investigational medicinal product name
    Lanabecestat
    Investigational medicinal product code
    Other name
    LY3314814,AZD3293
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg film-coated tablets of lanabecestat administered orally once a day.

    Arm title
    Lanabecestat 50 mg
    Arm description
    Participants received lanabecestat 50 mg film-coated oral tablets once daily.
    Arm type
    Experimental

    Investigational medicinal product name
    Lanabecestat
    Investigational medicinal product code
    Other name
    LY3314814,AZD3293
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50 mg film-coated tablets of lanabecestat administered orally once a day.

    Number of subjects in period 1
    Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Started
    740
    739
    739
    Received at least 1 Dose of Study drug
    738
    736
    735
    Completed
    187
    184
    168
    Not completed
    553
    555
    571
         Protocol deviation
    3
    2
    3
         Physician decision
    6
    3
    6
         Condition Worsened
    9
    10
    9
         Withdrawal due to Caregiver Circumstance
    10
    20
    22
         Other Selected by Investigator
    9
    10
    10
         Eligibility Criteria No Longer Met
    2
    4
    4
         Adverse event, serious fatal
    2
    4
    4
         Adverse event, non-fatal
    23
    26
    33
         Consent withdrawn by subject
    40
    41
    44
         Sponsor Decision
    445
    430
    432
         Lost to follow-up
    2
    5
    4
         Initiation of Symptomatic AD medication
    2
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received placebo film-coated oral tablets once daily.

    Reporting group title
    Lanabecestat 20 mg
    Reporting group description
    Participants received lanabecestat 20 mg film-coated oral tablets once daily.

    Reporting group title
    Lanabecestat 50 mg
    Reporting group description
    Participants received lanabecestat 50 mg film-coated oral tablets once daily.

    Reporting group values
    Placebo Lanabecestat 20 mg Lanabecestat 50 mg Total
    Number of subjects
    740 739 739 2218
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    71.4 ± 6.9 71.2 ± 7.5 71.2 ± 7.0 -
    Gender categorical
    Units: Subjects
        Female
    398 395 384 1177
        Male
    342 344 355 1041
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    43 26 24 93
        Not Hispanic or Latino
    626 650 644 1920
        Unknown or Not Reported
    71 63 71 205
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0
        Asian
    85 85 102 272
        Native Hawaiian or Other Pacific Islander
    0 0 0 0
        Black or African American
    5 5 6 16
        White
    598 609 593 1800
        More than one race
    0 0 0 0
        Unknown or Not Reported
    52 40 38 130
    Region of Enrollment
    Units: Subjects
        Puerto Rico
    13 11 12 36
        Romania
    1 2 2 5
        Hungary
    7 12 6 25
        United States
    171 171 179 521
        Japan
    48 57 78 183
        United Kingdom
    85 87 78 250
        Spain
    74 77 65 216
        Canada
    58 59 63 180
        South Korea
    30 24 16 70
        Belgium
    20 15 15 50
        Poland
    58 51 50 159
        Italy
    45 38 49 132
        Australia
    38 55 38 131
        France
    45 36 36 117
        Germany
    47 44 52 143
    ADAS-Cog13 (13-item Alzheimer’s Disease Assessment Scale)
    ADAS-Cog13, a 13-item rating scale, measured the severity of cognitive dysfunction in persons with Alzheimer's disease (AD). Scores ranged from 0 to 85, with a higher score indicating worse cognitive functioning.
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    28.6 ± 7.9 29.0 ± 7.7 28.5 ± 8.2 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received placebo film-coated oral tablets once daily.

    Reporting group title
    Lanabecestat 20 mg
    Reporting group description
    Participants received lanabecestat 20 mg film-coated oral tablets once daily.

    Reporting group title
    Lanabecestat 50 mg
    Reporting group description
    Participants received lanabecestat 50 mg film-coated oral tablets once daily.

    Primary: Change from Baseline on the 13-item Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-Cog13)

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    End point title
    Change from Baseline on the 13-item Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-Cog13)
    End point description
    ADAS-Cog13 is a psychometric instrument that evaluates word recall, ability to follow commands, constructional praxis, naming, ideational praxis, orientation, word recognition, memory, comprehension of spoken language, word-finding, and language ability, with a measure of delayed word recall and concentration/ distractibility. The total score of the 13-item scale ranges from 0 to 85, with an increase in score indicating cognitive worsening. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with factors for treatment, visit, treatment-by-visit interaction, disease status at baseline, apolipoprotein E4 (APOE4) status, acetylcholinesterase inhibitor (AChEI) use at baseline, pooled country, and covariates for baseline ADAS-Cog13 total score-by-visit interaction. Analysis Population Description: All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for ADAS-Cog13 measure.
    End point type
    Primary
    End point timeframe
    Baseline, Week 104
    End point values
    Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Number of subjects analysed
    723
    722
    708
    Units: Units on a scale
        least squares mean (standard error)
    10.31 ± 0.55
    9.38 ± 0.56
    10.72 ± 0.58
    Statistical analysis title
    ADAS-Cog13
    Comparison groups
    Placebo v Lanabecestat 20 mg
    Number of subjects included in analysis
    1445
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.232
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference (Final Values)
    Point estimate
    -0.93
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.447
         upper limit
    0.594
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.77
    Statistical analysis title
    ADAS-Cog13
    Comparison groups
    Placebo v Lanabecestat 50 mg
    Number of subjects included in analysis
    1431
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.599
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference (Final Values)
    Point estimate
    0.41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.124
         upper limit
    1.947
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.78

    Secondary: Change from Baseline on the Alzheimer´s Disease Cooperative Study Activities of Daily Living Inventory Instrumental Items (ADCS-iADL)

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    End point title
    Change from Baseline on the Alzheimer´s Disease Cooperative Study Activities of Daily Living Inventory Instrumental Items (ADCS-iADL)
    End point description
    The ADCS-ADL is a 23-item inventory developed as a rater-administered questionnaire answered by the participant's caregiver. The ADCS-ADL measures both basic and instrumental activities of daily living by participants. The range for the ADCS-iADL is 0-59 with higher scores reflecting better performance. LS Mean was determined by MMRM model with factors for treatment, visit, treatment-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, pooled country, and covariates for baseline for baseline iADL score, age at baseline, and baseline iADL score-by-visit interaction. APD: All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for ADCS-iADL measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Number of subjects analysed
    702
    700
    674
    Units: Units on a scale
        least squares mean (standard error)
    -8.87 ± 0.60
    -8.84 ± 0.61
    -8.79 ± 0.63
    Statistical analysis title
    ADCS-iADL
    Comparison groups
    Placebo v Lanabecestat 20 mg
    Number of subjects included in analysis
    1402
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.971
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference (Final Values)
    Point estimate
    0.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.609
         upper limit
    1.669
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.83
    Statistical analysis title
    ADCS-iADL
    Comparison groups
    Placebo v Lanabecestat 50 mg
    Number of subjects included in analysis
    1376
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.923
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference (Final Values)
    Point estimate
    0.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.58
         upper limit
    1.743
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.85

    Secondary: Change from Baseline on the Functional Activities Questionnaire (FAQ) Score

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    End point title
    Change from Baseline on the Functional Activities Questionnaire (FAQ) Score
    End point description
    FAQ is a 10-item, caregiver-based questionnaire and was administered to the study partner who was asked to rate the participant's ability to perform a variety of activities ranging from writing checks, assembling tax records, shopping, playing games, food preparation, traveling, keeping appointments, traveling out of neighborhood, keeping track of current events and understanding media. FAQ total score was calculated by adding the scores from each of the 10 items. Each activity is rated on a scale from 0 to 3 (Never did and would have difficulty now = 1; Never did [the activity] but could do now = 0; Normal = 0; Has difficulty but does by self = 1; Requires assistance = 2; Dependent = 3). The maximum FAQ total score is 30, with higher scores indicating greater impairment. LS Mean was calculated by MMRM. APD: All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for FAQ score.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Number of subjects analysed
    699
    697
    674
    Units: Units on a scale
        least squares mean (standard error)
    6.09 ± 0.38
    5.96 ± 0.39
    6.71 ± 0.40
    Statistical analysis title
    FAQ Score
    Comparison groups
    Placebo v Lanabecestat 20 mg
    Number of subjects included in analysis
    1396
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.796
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference (Final Values)
    Point estimate
    -0.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.172
         upper limit
    0.899
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.53
    Statistical analysis title
    FAQ Score
    Comparison groups
    Placebo v Lanabecestat 50 mg
    Number of subjects included in analysis
    1373
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.252
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference (Final Values)
    Point estimate
    0.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.437
         upper limit
    1.66
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.53

    Secondary: Change from Baseline on the Integrated Alzheimer's Disease Rating Scale (iADRS) Score

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    End point title
    Change from Baseline on the Integrated Alzheimer's Disease Rating Scale (iADRS) Score
    End point description
    The iADRS is a composite that measures both cognition and function. The iADRS comprises scores form the ADAS-Cog and the ADCS-iADL. The iADRS is calculated as a linear combination of the total scores of the ADAS-Cog13 (score range 0 to 85 with higher scores reflecting worse performance) and the ADCS-iADL (score range from 0-59 with higher scores reflecting better performance). The iADRS score ranges from 0 to 144 with with higher scores indicating greater impairment. LS Mean was determined by MMRM methodology with factors for treatment, visit, treatment-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, pooled country, and covariates for baseline iADRS13 total score, age at baseline, and baseline iADRS13 total score-by-visit interaction. APD: All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for iADRS.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Number of subjects analysed
    696
    689
    662
    Units: Units on a scale
        least squares mean (standard error)
    -19.56 ± 0.99
    -18.45 ± 1.02
    -19.69 ± 1.05
    Statistical analysis title
    iADRS
    Comparison groups
    Placebo v Lanabecestat 20 mg
    Number of subjects included in analysis
    1385
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.428
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference (Final Values)
    Point estimate
    1.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.637
         upper limit
    3.852
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.4
    Statistical analysis title
    iADRS
    Comparison groups
    Placebo v Lanabecestat 50 mg
    Number of subjects included in analysis
    1358
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.926
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference (Final Values)
    Point estimate
    -0.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.918
         upper limit
    2.655
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.42

    Secondary: Change from Baseline on the Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score

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    End point title
    Change from Baseline on the Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score
    End point description
    The CDR-SB is a rater administered scale and impairment is scored in of the following categories: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. Impairment is scored on a scale in which no dementia = 0, questionable dementia = 0.5, mild dementia = 1, moderate dementia = 2 and severe dementia = 3. The 6 individual category ratings, or “box scores”, were added together to give the CDR-Sum of Boxes which ranges from 0-18), with higher scores indicating greater impairment. LS Mean was determined by MMRM methodology with factors for treatment, visit, treatment-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, pooled country, and covariates for baseline CDR-SB score, age at baseline, and baseline CDR-SB score-by-visit interaction. APD: All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for CDR-SB.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Number of subjects analysed
    704
    705
    676
    Units: Units on a scale
        least squares mean (standard error)
    3.02 ± 0.17
    3.17 ± 0.17
    3.17 ± 0.18
    Statistical analysis title
    CDR-SB
    Comparison groups
    Placebo v Lanabecestat 20 mg
    Number of subjects included in analysis
    1409
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.533
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference (Final Values)
    Point estimate
    0.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.322
         upper limit
    0.622
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.24
    Statistical analysis title
    CDR-SB
    Comparison groups
    Placebo v Lanabecestat 50 mg
    Number of subjects included in analysis
    1380
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.537
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference (Final Values)
    Point estimate
    0.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.328
         upper limit
    0.63
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.24

    Secondary: Time to Progression as Measured by Loss of Clinical Dementia Rating (CDR) Global Score Stage

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    End point title
    Time to Progression as Measured by Loss of Clinical Dementia Rating (CDR) Global Score Stage
    End point description
    The CDR global score is a composite score calculated using the Washington University CDR-assignment algorithm applied to the 6 individual domain box scores (Morris 1993). The memory domain is considered the primary category that drives the CDR global outcome, and all other domains are secondary. The CDR global score ranges from 0 to 3 (0 = no dementia, 0.5 = questionable dementia, 1 = mild dementia, 2 = moderate dementia, 3 = severe dementia). APD: All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for CDR Global Score.
    End point type
    Secondary
    End point timeframe
    Baseline through Loss of 1 Global Stage or Week 104
    End point values
    Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Number of subjects analysed
    716
    714
    696
    Units: Days
        median (confidence interval 95%)
    548 (547 to 554)
    547 (545 to 550)
    548 (545 to 553)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Neuropsychiatric Inventory (NPI) Score

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    End point title
    Change from Baseline in Neuropsychiatric Inventory (NPI) Score
    End point description
    The NPI is a questionnaire administered to caregivers that quantifies behavioral changes. Each of the 12 behavioral domains the caregiver reports as present are scored for Frequency, scale: 1 (Occasionally) to 4 (Very Frequently), and Severity, scale: 1 (Mild) to 3 (Severe). If the domain is reported by the caregiver as 'Not Affected,' that domain is scored as 0. The individual domain scores are calculated by multiplying the frequency times the severity for each domain. NPI Total Score is calculated by adding the individual domain scores together for all 12 domains, with a scores range from 0 to 144, with higher scores indicated a greater severity of neuropsychiatric disturbance. LS Mean was determined by MMRM methodology. APD: All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for NPI.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Number of subjects analysed
    697
    695
    663
    Units: Units on a scale
        least squares mean (standard error)
    3.22 ± 0.81
    4.99 ± 0.83
    4.67 ± 0.85
    Statistical analysis title
    NPI
    Comparison groups
    Placebo v Lanabecestat 20 mg
    Number of subjects included in analysis
    1392
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.116
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference (Final Values)
    Point estimate
    1.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.441
         upper limit
    3.986
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.13
    Statistical analysis title
    NPI
    Comparison groups
    Placebo v Lanabecestat 50 mg
    Number of subjects included in analysis
    1360
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.208
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference (Final Values)
    Point estimate
    1.45
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.808
         upper limit
    3.704
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.15

    Secondary: Change from Baseline on the Mini-Mental State Examination (MMSE)

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    End point title
    Change from Baseline on the Mini-Mental State Examination (MMSE)
    End point description
    The MMSE is an instrument used to assess a participant's global cognitive function. The MMSE assesses orientation to time and place, immediate and delayed recall of words, attention and calculation, language (naming, comprehension and repetition), and spatial ability (copying a figure). The range for MMSE total Score is 0 to 30, with higher score indicating better cognitive performance. LS Mean was determined by MMRM methodology with factors for treatment, visit, treatment-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, pooled country, and covariates for baseline MMSE total score, age at baseline, and baseline MMSE total score-by-visit interaction. APD: All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for MMSE.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Number of subjects analysed
    723
    725
    709
    Units: Units on a scale
        least squares mean (standard error)
    -5.50 ± 0.26
    -5.18 ± 0.26
    -5.49 ± 0.27
    Statistical analysis title
    MMSE
    Comparison groups
    Placebo v Lanabecestat 20 mg
    Number of subjects included in analysis
    1448
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.379
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference (Final Values)
    Point estimate
    0.32
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.391
         upper limit
    1.027
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.36
    Statistical analysis title
    MMSE
    Comparison groups
    Placebo v Lanabecestat 50 mg
    Number of subjects included in analysis
    1432
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.992
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference (Final Values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.714
         upper limit
    0.721
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.37

    Secondary: Pharmacodynamics (PD): Percent Change from Baseline in Concentration of Cerebrospinal Fluid (CSF) Biomarker Aβ1-42

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    End point title
    Pharmacodynamics (PD): Percent Change from Baseline in Concentration of Cerebrospinal Fluid (CSF) Biomarker Aβ1-42
    End point description
    Concentration of the peptide Aβ 1-42 in plasma measured by validated immunoassay. LS Mean was determined by Analysis of covariance (ANCOVA) with LOCF (last observation carried forward), terms for treatment, baseline biomarker and age at baseline. APD: All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for Aβ1-42.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 97
    End point values
    Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Number of subjects analysed
    63
    66
    79
    Units: Percentage change in Aβ1-42
        least squares mean (standard error)
    -2.64 ± 2.07
    -53.91 ± 2.04
    -68.13 ± 1.87
    Statistical analysis title
    Aβ1-42
    Comparison groups
    Placebo v Lanabecestat 20 mg
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    LS Mean Difference (Final Values)
    Point estimate
    -51.27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -56.963
         upper limit
    -45.578
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.89
    Statistical analysis title
    Aβ1-42
    Comparison groups
    Placebo v Lanabecestat 50 mg
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    LS Mean Difference (Final Values)
    Point estimate
    -65.48
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -70.947
         upper limit
    -60.022
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.77

    Secondary: PD: Change from Baseline in Concentration of CSF Biomarker Aβ1-40

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    End point title
    PD: Change from Baseline in Concentration of CSF Biomarker Aβ1-40
    End point description
    Concentration of the peptide Aβ 1-40 in plasma measured by immunoassay. LS Mean was determined by ANCOVA with LOCF (last observation carried forward), terms for treatment, baseline biomarker and age at baseline. APD: All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for Aβ1-40.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 97
    End point values
    Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Number of subjects analysed
    64
    66
    79
    Units: Percentage change in Aβ1-40
        least squares mean (standard error)
    -1.92 ± 1.77
    -59.90 ± 1.74
    -75.17 ± 1.60
    Statistical analysis title
    Aβ1-40
    Comparison groups
    Placebo v Lanabecestat 20 mg
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    LS Mean Difference (Final Values)
    Point estimate
    -57.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -62.865
         upper limit
    -53.108
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.47
    Statistical analysis title
    Aβ1-40
    Comparison groups
    Placebo v Lanabecestat 50 mg
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    LS Mean Difference (Final Values)
    Point estimate
    -73.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -77.926
         upper limit
    -68.575
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.37

    Secondary: Change from Baseline in CSF Total Tau

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    End point title
    Change from Baseline in CSF Total Tau
    End point description
    Cerebrospinal fluid samples are collected for analysis of concentration total tau. LS Mean was determined by ANCOVA with LOCF and with factors for treatment, disease status at baseline, baseline biomarker and age at baseline. APD: All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for CSF Total Tau.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 97
    End point values
    Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Number of subjects analysed
    64
    66
    79
    Units: Picogram per milliliter (pg/mL)
        least squares mean (standard error)
    12.39 ± 8.05
    -7.48 ± 8.01
    -2.92 ± 7.30
    Statistical analysis title
    CSF Total Tau
    Comparison groups
    Placebo v Lanabecestat 20 mg
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.081
    Method
    ANCOVA
    Parameter type
    LS Mean Difference (Final Values)
    Point estimate
    -19.87
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -42.21
         upper limit
    2.464
    Variability estimate
    Standard error of the mean
    Dispersion value
    11.33
    Statistical analysis title
    CSF Total Tau
    Comparison groups
    Placebo v Lanabecestat 50 mg
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.157
    Method
    ANCOVA
    Parameter type
    LS Mean Difference (Final Values)
    Point estimate
    -15.31
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -36.555
         upper limit
    5.938
    Variability estimate
    Standard error of the mean
    Dispersion value
    10.78

    Secondary: Change from Baseline in CSF Phosphorylated Tau

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    End point title
    Change from Baseline in CSF Phosphorylated Tau
    End point description
    Cerebrospinal fluid samples are collected for analysis of concentrations of phosphorylated tau. LS Mean was determined by ANCOVA with LOCF and with factors for treatment, disease status at baseline, baseline biomarker and age at baseline. APD: All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for CSF Phosphorylated Tau.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 97
    End point values
    Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Number of subjects analysed
    63
    66
    79
    Units: Picogram per milliliter (pg/mL)
        least squares mean (standard error)
    0.47 ± 0.95
    -2.16 ± 0.94
    -1.66 ± 0.85
    Statistical analysis title
    CSF Phosphorylated Tau
    Comparison groups
    Placebo v Lanabecestat 20 mg
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.05
    Method
    ANCOVA
    Parameter type
    LS Mean Difference (Final Values)
    Point estimate
    -2.62
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.243
         upper limit
    -0.002
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.33
    Statistical analysis title
    CSF Phosphorylated Tau
    Comparison groups
    Placebo v Lanabecestat 50 mg
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.095
    Method
    ANCOVA
    Parameter type
    LS Mean Difference (Final Values)
    Point estimate
    -2.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.618
         upper limit
    0.373
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.27

    Secondary: Change From Baseline in Brain Amyloid Burden Using Florbetapir Amyloid Positron Emission Tomography (PET) Scan

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    End point title
    Change From Baseline in Brain Amyloid Burden Using Florbetapir Amyloid Positron Emission Tomography (PET) Scan
    End point description
    Amyloid deposition in the brain is one of the defining neuropathologic findings of Alzheimer's disease. Florbetapir exhibits high affinity specific binding to amyloid plaques. The change from baseline was measured as average standard uptake value ratio (SUVr) in prespecified ROI assessed by florbetapir amyloid PET imaging in a subset of participants. The Centiloid scale standardizes quantitative brain amyloid PET results to allow cross-tracer and cross-methodology comparisons. 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. Florbetapir SUVr was converted to the Centiloid scale using the following conversion: Florbetapir Centiloids = 183 x SUVr - 177 LS Mean was determined by ANCOVA . APD: All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for brain amyloid burden.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Number of subjects analysed
    133
    127
    116
    Units: Units on a scale
        least squares mean (standard error)
    -2.08 ± 1.86
    -15.76 ± 1.89
    -19.74 ± 1.97
    Statistical analysis title
    Florbetapir Amyloid Scan
    Comparison groups
    Placebo v Lanabecestat 20 mg
    Number of subjects included in analysis
    260
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    LS Mean Difference (Final Values)
    Point estimate
    -13.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -18.785
         upper limit
    -8.574
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.6
    Statistical analysis title
    Florbetapir Amyloid Scan
    Comparison groups
    Placebo v Lanabecestat 50 mg
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    LS Mean Difference (Final Values)
    Point estimate
    -17.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -22.887
         upper limit
    -12.428
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.66

    Secondary: Change From Baseline in Tau PET (Flortaucipir F18)

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    End point title
    Change From Baseline in Tau PET (Flortaucipir F18)
    End point description
    Tau PET tracer (flortaucipir F18) longitudinal study measured whether lanabecestat, in patients with mild AD dementia, affected tau density and distribution over time. It was planned that up to 4 scans would be performed over 3 years at sites with access to flortaucipir F 18. The outcome reported is the composite summary of SUVRs normalized to the signal intensity in white matter. Annualized change is derived as change at LOCF divided by (LOCF date - baseline date) multiplied by 365. LS Mean was determined by ANCOVA methodology with factors for treatment, disease status at baseline, baseline biomarker and age at baseline. Baseline defined to be within 28 days of starting study drug. APD: All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for Tau PET.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Number of subjects analysed
    97
    94
    93
    Units: Standard Uptake Value ratio (SUVr)
        least squares mean (standard error)
    0.04 ± 0.01
    0.03 ± 0.01
    0.03 ± 0.01
    Statistical analysis title
    Flortaucipir F18
    Comparison groups
    Placebo v Lanabecestat 20 mg
    Number of subjects included in analysis
    191
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.426
    Method
    ANCOVA
    Parameter type
    LS Mean Difference (Final Values)
    Point estimate
    -0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.033
         upper limit
    0.014
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.01
    Statistical analysis title
    Flortaucipir F18
    Comparison groups
    Placebo v Lanabecestat 50 mg
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.66
    Method
    ANCOVA
    Parameter type
    LS Mean Difference (Final Values)
    Point estimate
    -0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.029
         upper limit
    0.018
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.01

    Secondary: Change From Baseline in Brain Metabolism Using Fluorodeoxyglucose (FDG)

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    End point title
    Change From Baseline in Brain Metabolism Using Fluorodeoxyglucose (FDG)
    End point description
    Fluorodeoxyglucose (FDG) PET evaluates the regional brain metabolic rates for glucose as a sensitive, in vivo metabolic index of brain function. The outcome reported is the composite summary of the standard uptake value ratio (SUVR) normalized to the pons + vermis assessed with composite meta and composite meta automated anatomical labeling atlas (ALL). Annualized change is derived as change at LOCF divided by (LOCF date - baseline date) multiplied by 365. LS Mean was determined by ANCOVA methodology with factors for treatment, disease status at baseline, baseline biomarker and age at baseline. Baseline defined to be within 28 days of starting study drug. APD: All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data of brain metabolism.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Number of subjects analysed
    83
    95
    82
    Units: Standard Uptake Value ratio (SUVr)
        least squares mean (standard error)
    -0.04 ± 0.00
    -0.05 ± 0.00
    -0.05 ± 0.00
    Statistical analysis title
    FDG
    Comparison groups
    Placebo v Lanabecestat 20 mg
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.21
    Method
    ANCOVA
    Parameter type
    LS Mean Difference (Final Values)
    Point estimate
    -0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.015
         upper limit
    0.003
    Variability estimate
    Standard error of the mean
    Dispersion value
    0
    Statistical analysis title
    FDG
    Comparison groups
    Lanabecestat 50 mg v Placebo
    Number of subjects included in analysis
    165
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.568
    Method
    ANCOVA
    Parameter type
    LS Mean Difference (Final Values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.013
         upper limit
    0.007
    Variability estimate
    Standard error of the mean
    Dispersion value
    0

    Secondary: Change from Baseline in Whole Brain Volume

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    End point title
    Change from Baseline in Whole Brain Volume
    End point description
    Magnetic resonance imaging (MRI) was used to evaluate the effect of lanabecestat on whole brain volumes. Annualized change is derived as change at LOCF divided by (LOCF date - baseline date) multiplied by 365. LS Mean was determined by ANCOVA methodology with factors for treatment, baseline vMRI, intracranial volume, disease status at baseline and age at baseline. APD: All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for Whole Brain Volume.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Number of subjects analysed
    565
    582
    550
    Units: cm^3 (cubic centimeter)
        least squares mean (standard error)
    -14.16 ± 0.34
    -16.49 ± 0.33
    -17.34 ± 0.34
    Statistical analysis title
    Whole Brain Volume
    Comparison groups
    Placebo v Lanabecestat 20 mg
    Number of subjects included in analysis
    1147
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    LS Mean Difference (Final Values)
    Point estimate
    -2.34
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.258
         upper limit
    -1.413
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.47
    Statistical analysis title
    Whole Brain Volume
    Comparison groups
    Placebo v Lanabecestat 50 mg
    Number of subjects included in analysis
    1115
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    LS Mean Difference (Final Values)
    Point estimate
    -3.18
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.118
         upper limit
    -2.247
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.48

    Secondary: Pharmacokinetics (PK): Plasma Concentration of Lanabecestat

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    End point title
    Pharmacokinetics (PK): Plasma Concentration of Lanabecestat [1]
    End point description
    Plasma Concentration of Lanabecestat. APD: All randomized participants who received at least one dose of study drug and have evaluable PK data.
    End point type
    Secondary
    End point timeframe
    Week 4, post dose prior to departure from the clinic
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No arm comparison analyses were planned or conducted.
    End point values
    Lanabecestat 20 mg Lanabecestat 50 mg
    Number of subjects analysed
    697
    662
    Units: nanograms per milliliter (ng/mL)
        arithmetic mean (standard deviation)
    67.7 ± 49.1
    213 ± 149
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up To 104 weeks
    Adverse event reporting additional description
    All randomized participants who received at least one dose of study drug. There are gender specific adverse events, only occurring in male or female participants. The number of participants exposed has been adjusted accordingly.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Lanabecestat 20 mg
    Reporting group description
    Participants received lanabecestat 20 mg film-coated oral tablets once daily.

    Reporting group title
    Lanabecestat 50 mg
    Reporting group description
    Participants received lanabecestat 50 mg film-coated oral tablets once daily.

    Reporting group title
    Placebo
    Reporting group description
    Participants received placebo film-coated oral tablets once daily.

    Serious adverse events
    Lanabecestat 20 mg Lanabecestat 50 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    117 / 736 (15.90%)
    147 / 735 (20.00%)
    108 / 738 (14.63%)
         number of deaths (all causes)
    4
    4
    2
         number of deaths resulting from adverse events
    0
    1
    0
    Vascular disorders
    aortic aneurysm
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 736 (0.27%)
    0 / 735 (0.00%)
    0 / 738 (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
    granulomatosis with polyangiitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    haematoma
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    hypertension
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    hypertensive crisis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    hypotension
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    1 / 735 (0.14%)
    2 / 738 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    orthostatic hypotension
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    peripheral artery stenosis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    temporal arteritis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 736 (0.27%)
    0 / 735 (0.00%)
    0 / 738 (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
    thrombophlebitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    venous thrombosis limb
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    Surgical and medical procedures
    cardiac pacemaker insertion
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    cataract operation
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    hip arthroplasty
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    inguinal hernia repair
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    spinal operation
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    synovial cyst removal
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    tumour excision
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    urethral repair
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    vocal cord operation
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    acoustic neuroma
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    acute myeloid leukaemia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    adenocarcinoma of colon
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    1 / 735 (0.14%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    basal cell carcinoma
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    1 / 735 (0.14%)
    0 / 738 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    bile duct adenocarcinoma
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    bladder neoplasm
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    breast cancer male
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed [1]
    1 / 344 (0.29%)
    0 / 354 (0.00%)
    0 / 341 (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
    breast cancer
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    breast cancer recurrent
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    colon cancer
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    2 / 735 (0.27%)
    0 / 738 (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
    endometrial adenocarcinoma
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed [2]
    0 / 392 (0.00%)
    0 / 381 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    haemangioma
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    invasive ductal breast carcinoma
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 736 (0.27%)
    2 / 735 (0.27%)
    0 / 738 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    laryngeal squamous cell carcinoma
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    lentigo maligna
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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 adenocarcinoma
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    3 / 735 (0.41%)
    2 / 738 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    lung neoplasm
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    lymphoma
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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 neoplasm malignant
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 736 (0.27%)
    0 / 735 (0.00%)
    0 / 738 (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
    malignant melanoma
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    malignant melanoma in situ
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    malignant neoplasm of unknown primary site
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    metastases to bone
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    metastases to lymph nodes
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    neuroendocrine tumour
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ovarian adenoma
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed [3]
    0 / 392 (0.00%)
    1 / 381 (0.26%)
    0 / 397 (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 carcinoma
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    prostate cancer
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed [4]
    2 / 344 (0.58%)
    2 / 354 (0.56%)
    2 / 341 (0.59%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    prostatic adenoma
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed [5]
    0 / 344 (0.00%)
    0 / 354 (0.00%)
    1 / 341 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    rectal adenoma
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    rectal adenocarcinoma
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    rectal cancer
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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 cell lung cancer
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    transitional cell carcinoma
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    drug hypersensitivity
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    seasonal allergy
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    asthenia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    1 / 735 (0.14%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    chest pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    4 / 736 (0.54%)
    4 / 735 (0.54%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    non-cardiac chest pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 736 (0.27%)
    1 / 735 (0.14%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pyrexia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    sudden death
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    systemic inflammatory response syndrome
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    abnormal behaviour
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    1 / 735 (0.14%)
    2 / 738 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    acute psychosis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 736 (0.27%)
    0 / 735 (0.00%)
    0 / 738 (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
    aggression
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    2 / 735 (0.27%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    agitation
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    2 / 735 (0.27%)
    2 / 738 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    anxiety
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    2 / 735 (0.27%)
    0 / 738 (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
    confusional state
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    2 / 738 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    delirium
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 736 (0.27%)
    5 / 735 (0.68%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    depression
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    4 / 735 (0.54%)
    0 / 738 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    depressive symptom
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    3 / 735 (0.41%)
    0 / 738 (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
    device failure
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    hallucination
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    hallucination, auditory
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    hallucination, olfactory
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    paranoia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    2 / 738 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    psychotic disorder
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    2 / 738 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    schizophrenia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    1 / 735 (0.14%)
    0 / 738 (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
    suicide attempt
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    Reproductive system and breast disorders
    benign prostatic hyperplasia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed [6]
    1 / 344 (0.29%)
    1 / 354 (0.28%)
    2 / 341 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    postmenopausal haemorrhage
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed [7]
    1 / 392 (0.26%)
    0 / 381 (0.00%)
    0 / 397 (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
    Injury, poisoning and procedural complications
    accidental overdose
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    accidental poisoning
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    alcohol poisoning
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    ankle fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    1 / 735 (0.14%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    cervical vertebral fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    chemical burn of gastrointestinal tract
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    clavicle fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    contusion
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    1 / 735 (0.14%)
    0 / 738 (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
    fall
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    8 / 736 (1.09%)
    4 / 735 (0.54%)
    6 / 738 (0.81%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    femur fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 736 (0.27%)
    1 / 735 (0.14%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    femoral neck fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    2 / 735 (0.27%)
    0 / 738 (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
    fibula fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    forearm fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    head injury
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    hip fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    3 / 736 (0.41%)
    2 / 735 (0.27%)
    0 / 738 (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
    humerus fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    2 / 735 (0.27%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    jaw fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    lacrimal structure injury
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    ligament rupture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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 vertebral fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    2 / 738 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    multiple injuries
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    overdose
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pelvic fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    periprosthetic fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    post procedural haemorrhage
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    pubis fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    2 / 735 (0.27%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    rib fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    2 / 738 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    road traffic accident
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    skin laceration
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    skull fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    spinal compression fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    3 / 738 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    spinal fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    3 / 735 (0.41%)
    3 / 738 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    subdural haemorrhage
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    tibia fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    2 / 738 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ulna fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    upper limb fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    wrist fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    blood potassium decreased
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    acute coronary syndrome
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    acute myocardial infarction
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    2 / 735 (0.27%)
    2 / 738 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    angina pectoris
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    1 / 735 (0.14%)
    2 / 738 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    angina unstable
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    atrial fibrillation
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 736 (0.27%)
    1 / 735 (0.14%)
    2 / 738 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    atrial flutter
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    1 / 735 (0.14%)
    0 / 738 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    bifascicular block
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    bradycardia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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 failure
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 736 (0.27%)
    2 / 735 (0.27%)
    0 / 738 (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
    cardio-respiratory arrest
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    2 / 738 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    cardiac tamponade
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    coronary artery disease
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    coronary artery thrombosis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    myocardial infarction
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 736 (0.27%)
    0 / 735 (0.00%)
    4 / 738 (0.54%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    sinus node dysfunction
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    sinus bradycardia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    stress cardiomyopathy
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    supraventricular extrasystoles
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    supraventricular tachycardia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    tachycardia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    tricuspid valve incompetence
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    gastrointestinal arteriovenous malformation
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    acute respiratory distress syndrome
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    asthma
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    cystic lung disease
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    dyspnoea
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 736 (0.27%)
    1 / 735 (0.14%)
    0 / 738 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    obstructive airways disorder
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pneumonia aspiration
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    pneumothorax
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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 embolism
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    2 / 735 (0.27%)
    0 / 738 (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
    pulmonary oedema
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    respiratory arrest
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    sleep apnoea syndrome
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    stridor
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    1 / 735 (0.14%)
    2 / 738 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    altered state of consciousness
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    amyloid related imaging abnormality-microhaemorrhages and haemosiderin deposits
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    central nervous system lesion
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    cerebral haemorrhage
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    2 / 735 (0.27%)
    3 / 738 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    cerebral haematoma
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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 microhaemorrhage
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    1 / 735 (0.14%)
    0 / 738 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    cerebrovascular accident
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    3 / 736 (0.41%)
    1 / 735 (0.14%)
    2 / 738 (0.27%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    cervical radiculopathy
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    cholinergic syndrome
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    cognitive disorder
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    1 / 735 (0.14%)
    0 / 738 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    dementia with lewy bodies
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    dizziness
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    1 / 735 (0.14%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    dyskinesia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    epilepsy
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    generalised tonic-clonic seizure
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    headache
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    hypertensive encephalopathy
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    hypoaesthesia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    intraventricular haemorrhage
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    partial seizures
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    petit mal epilepsy
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    presyncope
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    sciatica
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    seizure
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    2 / 735 (0.27%)
    0 / 738 (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
    subarachnoid haemorrhage
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    2 / 738 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    syncope
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    6 / 736 (0.82%)
    7 / 735 (0.95%)
    2 / 738 (0.27%)
         occurrences causally related to treatment / all
    3 / 6
    2 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    thalamic infarction
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 736 (0.27%)
    2 / 735 (0.27%)
    2 / 738 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ulnar nerve palsy
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    vasogenic cerebral oedema
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    vocal cord paresis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    Eye disorders
    cataract
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 736 (0.27%)
    1 / 735 (0.14%)
    0 / 738 (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
    pterygium
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    retinal detachment
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    2 / 738 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    retinal haemorrhage
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    vestibular disorder
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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 discomfort
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    alcoholic pancreatitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    anal incontinence
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    coeliac artery stenosis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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 microscopic
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    colitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    constipation
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    diarrhoea
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    enlarged uvula
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    faecaloma
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    femoral hernia incarcerated
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    food poisoning
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    gastric ulcer
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    gastrointestinal haemorrhage
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    1 / 735 (0.14%)
    2 / 738 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    gastrooesophageal reflux disease
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    haemorrhoids
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    inguinal hernia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 736 (0.27%)
    3 / 735 (0.41%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    intestinal mass
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    intestinal obstruction
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    3 / 735 (0.41%)
    0 / 738 (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
    large intestine polyp
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    2 / 735 (0.27%)
    0 / 738 (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
    lower gastrointestinal haemorrhage
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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 prolapse
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 736 (0.27%)
    0 / 735 (0.00%)
    0 / 738 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    small intestinal obstruction
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    cholelithiasis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    drug-induced liver injury
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    Renal and urinary disorders
    acute kidney injury
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    calculus bladder
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    urinary retention
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    1 / 735 (0.14%)
    0 / 738 (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
    urge incontinence
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    Skin and subcutaneous tissue disorders
    angioedema
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    drug eruption
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    psoriasis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    arthritis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    2 / 735 (0.27%)
    0 / 738 (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
    back pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    bone lesion
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    foot deformity
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    infrapatellar fat pad inflammation
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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 compression
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    intervertebral disc protrusion
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    mobility decreased
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    musculoskeletal pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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 chest pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    myofascial pain syndrome
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    osteoarthritis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 736 (0.27%)
    1 / 735 (0.14%)
    4 / 738 (0.54%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    osteolysis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    osteoporotic fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    pain in extremity
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    spinal column stenosis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    vertebral foraminal stenosis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    dehydration
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    4 / 736 (0.54%)
    5 / 735 (0.68%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    electrolyte imbalance
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    hypercalcaemia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    hyperglycaemia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    hypoglycaemia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    hyponatraemia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 736 (0.27%)
    1 / 735 (0.14%)
    0 / 738 (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
    hypokalaemia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    hypophosphataemia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    lactic acidosis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    2 / 738 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    appendicitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    bone abscess
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    bronchitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    cellulitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    2 / 735 (0.27%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    clostridium difficile colitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    diverticulitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    3 / 735 (0.41%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    endocarditis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    hepatic cyst infection
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    human anaplasmosis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    infection
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    influenza
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 736 (0.27%)
    4 / 735 (0.54%)
    0 / 738 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    intervertebral discitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    lower respiratory tract infection
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    lower respiratory tract infection viral
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    peritonsillitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    pneumonia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    3 / 736 (0.41%)
    3 / 735 (0.41%)
    6 / 738 (0.81%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    sepsis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    2 / 738 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    septic arthritis streptococcal
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    0 / 735 (0.00%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    septic shock
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    1 / 738 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    urinary tract infection
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    3 / 735 (0.41%)
    6 / 738 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    urinary tract infection pseudomonal
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 736 (0.00%)
    1 / 735 (0.14%)
    0 / 738 (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
    vestibular neuronitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 736 (0.14%)
    0 / 735 (0.00%)
    0 / 738 (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
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.
    [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.
    [6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.
    [7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Lanabecestat 20 mg Lanabecestat 50 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    357 / 736 (48.51%)
    361 / 735 (49.12%)
    340 / 738 (46.07%)
    Injury, poisoning and procedural complications
    fall
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    71 / 736 (9.65%)
    73 / 735 (9.93%)
    69 / 738 (9.35%)
         occurrences all number
    95
    111
    86
    Respiratory, thoracic and mediastinal disorders
    cough
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    46 / 736 (6.25%)
    25 / 735 (3.40%)
    25 / 738 (3.39%)
         occurrences all number
    49
    29
    25
    Nervous system disorders
    dizziness
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    43 / 736 (5.84%)
    51 / 735 (6.94%)
    42 / 738 (5.69%)
         occurrences all number
    52
    61
    48
    headache
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    40 / 736 (5.43%)
    46 / 735 (6.26%)
    52 / 738 (7.05%)
         occurrences all number
    50
    72
    56
    Gastrointestinal disorders
    diarrhoea
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    62 / 736 (8.42%)
    54 / 735 (7.35%)
    39 / 738 (5.28%)
         occurrences all number
    81
    62
    44
    nausea
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    33 / 736 (4.48%)
    41 / 735 (5.58%)
    32 / 738 (4.34%)
         occurrences all number
    39
    50
    38
    Psychiatric disorders
    anxiety
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    57 / 736 (7.74%)
    48 / 735 (6.53%)
    34 / 738 (4.61%)
         occurrences all number
    63
    50
    40
    depression
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    36 / 736 (4.89%)
    46 / 735 (6.26%)
    31 / 738 (4.20%)
         occurrences all number
    39
    49
    32
    Musculoskeletal and connective tissue disorders
    back pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    36 / 736 (4.89%)
    33 / 735 (4.49%)
    40 / 738 (5.42%)
         occurrences all number
    38
    35
    50
    Infections and infestations
    nasopharyngitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    78 / 736 (10.60%)
    76 / 735 (10.34%)
    60 / 738 (8.13%)
         occurrences all number
    94
    89
    69
    upper respiratory tract infection
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    39 / 736 (5.30%)
    44 / 735 (5.99%)
    46 / 738 (6.23%)
         occurrences all number
    43
    50
    57
    urinary tract infection
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    36 / 736 (4.89%)
    32 / 735 (4.35%)
    56 / 738 (7.59%)
         occurrences all number
    53
    36
    70

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Mar 2015
    Amendment (04): Protocol amended to specify -Co-administration of AZD3293 with food is now permitted. -Wording for permitted dose changes for cholinesterase inhibitors has been modified from “reductions” to “adjustments” to allow increases in dose if medically necessary. -Antipsychotic are no longer prohibited to allow treatment of patients if medically necessary.
    30 Jun 2016
    Amendment (07): - Changed the primary endpoint CDR-SB to ADAS-Cog13. -Updated potential risks to be consistent with the Investigator’s Brochure (IB): Initiation of symptomatic treatments for patient progression (including acetylcholinesterase inhibitors [AChEI] and memantine) to now to be permitted at specific time intervals. -Broadened classes of applicable medications and added clinical judgment to Exclusion Criterion [26] about use of concomitant medications during study participation.
    12 Jul 2017
    Amendment (7.1): Added a fourth interim analysis with description. Clarified timing of third and fourth interim analysis.

    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.
    An independent assessment concluded the trial was not likely to meet the primary endpoint upon completion and therefore, trial stopped for futility. Due to early termination of the study the planned population PK analysis was not performed.