Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   36102   clinical trials with a EudraCT protocol, of which   5935   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Phase III, Randomized, Placebo-Controlled, Parallel-Group, Double-Blind Clinical Trial to Study the Efficacy and Safety of MK-8931 (SCH 900931) in Subjects with Amnestic Mild Cognitive Impairment Due to Alzheimer’s Disease (Prodromal AD)

    Summary
    EudraCT number
    2012-005542-38
    Trial protocol
    NO   ES   AT   IT   DE   GB   FI   NL   BE   HU   PL  
    Global end of trial date
    17 Apr 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    01 May 2019
    First version publication date
    01 May 2019
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    8931-019
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01953601
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Merck Protocol Number: MK-8931-019
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Apr 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Apr 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This study consists of two parts, Part 1 and Part 2. Part 1 assesses the efficacy and safety of verubecestat (MK-8931) compared with placebo administered for 104 weeks in the treatment of amnestic mild cognitive impairment (aMCI) due to Alzheimer's Disease (AD), also known as prodromal AD. Participants are randomized to receive placebo, or 12 mg or 40 mg verubecestat, once daily. The primary study hypothesis for Part 1 is that ≥1 verubecestat dose is superior to placebo with respect to the change from baseline in the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB) score at 104 weeks. Participants completing Part 1 may choose to participate in Part 2, which is a long term double-blind extension to assess efficacy and safety of verubecestat administered for up to an additional 260 weeks. In Part 2, all participants receive either 12 mg or 40 mg verubecestat, once daily.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    05 Nov 2013
    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
    Argentina: 35
    Country: Number of subjects enrolled
    Australia: 33
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Brazil: 13
    Country: Number of subjects enrolled
    Canada: 106
    Country: Number of subjects enrolled
    Finland: 12
    Country: Number of subjects enrolled
    France: 44
    Country: Number of subjects enrolled
    Germany: 25
    Country: Number of subjects enrolled
    Hungary: 14
    Country: Number of subjects enrolled
    Ireland: 10
    Country: Number of subjects enrolled
    Italy: 98
    Country: Number of subjects enrolled
    Japan: 176
    Country: Number of subjects enrolled
    Korea, Republic of: 64
    Country: Number of subjects enrolled
    Netherlands: 15
    Country: Number of subjects enrolled
    New Zealand: 13
    Country: Number of subjects enrolled
    Norway: 18
    Country: Number of subjects enrolled
    Poland: 8
    Country: Number of subjects enrolled
    Spain: 99
    Country: Number of subjects enrolled
    Switzerland: 4
    Country: Number of subjects enrolled
    United Kingdom: 81
    Country: Number of subjects enrolled
    United States: 572
    Worldwide total number of subjects
    1454
    EEA total number of subjects
    438
    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)
    243
    From 65 to 84 years
    1190
    85 years and over
    21

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    N=1454 participants with prodromal Alzheimer's Disease (AD) were randomized, with N=1451 receiving study treatment.

    Pre-assignment
    Screening details
    This trial was conducted in 2 parts: a Base Study (Part 1), followed by an Extension Study (Part 2). Participants completing Part 1 had the option to continue to Part 2.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2)
    Arm description
    [Part 1] Verubecestat 12 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Verubecestat 12 mg
    Investigational medicinal product code
    Other name
    MK-8931
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Verubecestat 12 mg oral tablet, given once daily.

    Arm title
    Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2)
    Arm description
    [Part 1] Verubecestat 40 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Verubecestat 40 mg
    Investigational medicinal product code
    Other name
    MK-8931
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Verubecestat 40 mg oral tablet, given once daily.

    Arm title
    Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Arm description
    [Part 1] Placebo once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matching verubecestat, given once daily as an oral tablet.

    Number of subjects in period 1
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Started
    485
    484
    485
    Treated
    483
    484
    484
    Completed
    234
    231
    239
    Not completed
    251
    253
    246
         Subject moved
    2
    2
    1
         Physician decision
    3
    7
    4
         Non-compliance with study drug
    -
    3
    1
         Site discontinued study participation
    2
    -
    -
         Lack of efficacy
    3
    1
    4
         Adverse event, serious fatal
    2
    -
    3
         Study terminated by sponsor
    174
    169
    179
         Adverse event, non-fatal
    24
    37
    15
         Consent withdrawn by subject
    32
    23
    22
         Screen failure
    1
    -
    1
         Discontinued due to caregiver withdrawal
    7
    8
    10
         Lost to follow-up
    1
    3
    6
    Period 2
    Period 2 title
    Part 2 (Extension Study)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2)
    Arm description
    [Part 1] Verubecestat 12 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 12 mg once daily for an additional 260 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Verubecestat 12 mg
    Investigational medicinal product code
    Other name
    MK-8931
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Verubecestat 12 mg oral tablet, given once daily.

    Arm title
    Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2)
    Arm description
    [Part 1] Verubecestat 40 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Verubecestat 40 mg
    Investigational medicinal product code
    Other name
    MK-8931
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Verubecestat 40 mg oral tablet, given once daily.

    Arm title
    Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Arm description
    [Part 1] Placebo once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Verubecestat 40 mg
    Investigational medicinal product code
    Other name
    MK-8931
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Verubecestat 40 mg oral tablet, given once daily.

    Number of subjects in period 2 [1]
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Started
    198
    191
    204
    Treated
    197
    191
    204
    Completed
    0
    0
    0
    Not completed
    198
    191
    204
         Subject moved
    -
    -
    1
         Physician decision
    2
    -
    2
         Site discontinued study participation
    -
    1
    1
         Lack of efficacy
    2
    -
    -
         Adverse event, serious fatal
    -
    3
    -
         Study terminated by sponsor
    185
    178
    187
         Adverse event, non-fatal
    1
    1
    10
         Consent withdrawn by subject
    5
    4
    2
         Discontinued due to caregiver withdrawal
    1
    3
    -
         Lost to follow-up
    2
    1
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Number completing Part 1, volunteering for Part 2

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2)
    Reporting group description
    [Part 1] Verubecestat 12 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks.

    Reporting group title
    Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2)
    Reporting group description
    [Part 1] Verubecestat 40 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.

    Reporting group title
    Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Reporting group description
    [Part 1] Placebo once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.

    Reporting group values
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2) Total
    Number of subjects
    485 484 485 1454
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    85 78 80 243
        From 65-84 years
    392 398 400 1190
        85 years and over
    8 8 5 21
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    71.7 ± 7.1 71.0 ± 7.4 71.6 ± 7.1 -
    Sex: Female, Male
    Units: Subjects
        Female
    229 244 213 686
        Male
    256 240 272 768
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 2 2
        Asian
    79 85 84 248
        Native Hawaiian or Other Pacific Islander
    0 0 0 0
        Black or African American
    5 3 6 14
        White
    397 392 391 1180
        More than one race
    2 1 0 3
        Unknown or Not Reported
    2 3 2 7
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    28 29 29 86
        Not Hispanic or Latino
    441 439 441 1321
        Unknown or Not Reported
    16 16 15 47
    Geographic Region
    Units: Subjects
        United States / Canada
    226 224 226 676
        Japan
    57 60 59 176
        Europe / Australia / New Zealand
    163 163 161 487
        Other
    37 37 38 112
        Excluded (participant not treated)
    2 0 1 3
    APOE4 Genotype
    Apolipoprotein E (APOE) genotype is the strongest genetic predictor of risk for developing AD. The number of participants testing positive or negative for the APOE4 allele at baseline is presented.
    Units: Subjects
        Negative
    155 146 148 449
        Positive
    328 337 335 1000
        Missing
    0 1 1 2
        Excluded (participant not treated)
    2 0 1 3
    Baseline Use of Vitamin E
    The number of participants receiving Vitamin E (> or ≤ 400 International Units [IU] / day; or no use) is presented.
    Units: Subjects
        No Use
    351 372 355 1078
        ≤400 IU / day
    123 100 120 343
        >400 IU / day
    9 12 9 30
        Excluded (participant not treated)
    2 0 1 3
    Background Alzheimer's Disease (AD) Treatment
    The number of participants receiving acetylcholinesterase inhibitors (AChEI) and/or memantine (or no background AD treatment) is presented.
    Units: Subjects
        Use of AChEI alone
    182 191 180 553
        Use of memantine alone
    9 8 8 25
        Use of AChEI and memantine
    31 26 34 91
        No use of AChEI or memantine
    261 259 262 782
        Excluded (participant not treated)
    2 0 1 3
    Mini-Mental State Examination (MMSE) Score
    The MMSE is a cognitive assessment of 5 domains (orientation; attention; memory; language; constructional praxis), with 11 questions scored based on number of correct responses. Depending on the question, scores range from 0 (no correct response) to either 1 (4 questions), 2 (1 question), 3 (3 questions), or 5 (3 questions). Scores for each question sum to a total MMSE score (range: 0-30); lower scores indicate worse cognitive performance. Participants are stratified by MMSE score (≥24-26 or ≥27) to ensure a representative population by AD severity across study arms.
    Units: Subjects
        MMSE ≥27
    212 211 214 637
        MMSE ≥24-26
    270 271 270 811
        Missing
    1 2 0 3
        Excluded (participant not treated)
    2 0 1 3
    Clinical Dementia Rating Sum of Boxes (CDR-SB) Score
    The CDR-SB score is a clinical rating of global cognitive function, comprised of 6 domains: memory; orientation; judgment and problem solving; community affairs; home and hobbies; and personal care. For each domain, the degree of impairment is assessed by a semi-structured interview of the participant as well as the participant’s caregiver. For each domain, potential scores range from 0 (no impairment) to 3 (severe impairment). Individual domain scores are summed to a total CDR-SB score (range: 0-18). Higher scores indicate more severe cognitive impairment. (N= 465, 458, 469)
    Units: Score on a Scale
        arithmetic mean (standard deviation)
    2.7 ± 1.3 2.7 ± 1.3 2.6 ± 1.2 -
    Composite Cognition Score-3 Domain (CCS-3D)
    CCS-3D is composed of individual cognitive tests, grouped into 3 domains: 1) episodic memory; 2) executive function; and 3) attention/processing speed. For each test, a z-score (Z) is calculated at each time point [Z = (observed value - study population mean at baseline) / study population standard deviation at baseline]. Individual Zs are first combined into domain-specific Zs, and then into a composite Z, (i.e. CCS-3D). In theory, 99.9% of CCS-3D will be ± 3; more positive CCS-3D indicate greater cognitive impairment relative to the total study population at baseline. (N= 441, 424, 440)
    Units: Z-score
        arithmetic mean (standard deviation)
    0.0 ± 1.0 0.0 ± 1.0 -0.1 ± 1.0 -
    Total Hippocampal Volume (THV)
    THV was measured by volumetric magnetic resonance imaging (vMRI). (N= 168, 181, 191)
    Units: µL
        arithmetic mean (standard deviation)
    6448.4 ± 1107.1 6468.5 ± 1105.8 6435.4 ± 987.2 -
    [18F]Flutemetamol Positron Emission Tomography (PET) Standard Uptake Value Ratio (SUVR)
    [18F]Flutemetamol PET SUVR measures brain cortical amyloid load. The PET tracer [18F]Flutemetamol was given intravenously (IV). After 90 minutes uptake, participants were scanned for 20 minutes. Using the PET scan images, SUVRs, the ratio of tracer signal in a specific region compared to a reference region (RR; subcortical white matter) are calculated for brain regions of interest (ROIs). SUVRs from a selected set of brain regions are averaged to compute a composite SUVR. Higher composite SUVR values indicate increased amyloid load in selected brain regions. (N= 63, 59, 65)
    Units: Standard Uptake Value Ratio (SUVR)
        arithmetic mean (standard deviation)
    0.86 ± 0.07 0.87 ± 0.07 0.85 ± 0.06 -
    AD Cooperative Study-Activities of Daily Living, Mild Cognitive Impairment (ADCS-ADL MCI) Score
    The ADCS-ADL MCI is an 18-item assessment of recent, observed performance of activities of daily living administered to participants’ trial partners in an interview format. For the 18 items, scores range from 0 (no independence) to (depending on the item) either 2 (5 items), 3 (9 items), or 4 (4 items), with higher scores indicating greater independence in activity performance. Scores from individual items are summed for a total ADCS-ADL score (range: 0-53). Lower scores indicate less independence in activity performance and, as a result, greater AD severity. (N= 469, 462, 472)
    Units: Score on a Scale
        arithmetic mean (standard deviation)
    42.2 ± 5.9 43.1 ± 5.4 42.8 ± 5.9 -
    Cerebrospinal Fluid (CSF) Total Tau Concentration
    Total Tau concentration in the CSF was monitored as a measure of brain tau pathology. (N= 5, 6, 6)
    Units: pg/mL
        arithmetic mean (standard deviation)
    203.8 ± 129.1 159.3 ± 79.0 243.5 ± 97.0 -

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2)
    Reporting group description
    [Part 1] Verubecestat 12 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks.

    Reporting group title
    Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2)
    Reporting group description
    [Part 1] Verubecestat 40 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.

    Reporting group title
    Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Reporting group description
    [Part 1] Placebo once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
    Reporting group title
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2)
    Reporting group description
    [Part 1] Verubecestat 12 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 12 mg once daily for an additional 260 weeks.

    Reporting group title
    Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2)
    Reporting group description
    [Part 1] Verubecestat 40 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks.

    Reporting group title
    Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Reporting group description
    [Part 1] Placebo once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks.

    Primary: Part 1 (Base Study). Least Squares Mean (LSM) Change from Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 104

    Close Top of page
    End point title
    Part 1 (Base Study). Least Squares Mean (LSM) Change from Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 104
    End point description
    LSM change from baseline at week 104 was assessed for CDR-SB score, a clinical rating of global cognitive function, comprised of 6 domains: memory; orientation; judgment and problem solving; community affairs; home and hobbies; and personal care. For each domain, the degree of impairment is assessed by a semi-structured interview of the participant as well as the participant’s caregiver. For each domain, potential scores range from 0 (no impairment) to 3 (severe impairment). Individual domain scores are summed to a total CDR-SB score (range: 0-18). Higher scores indicate more severe cognitive impairment. Further, increases in cognitive impairment would be reflected by increases in CDR-SB score. Analysis Population: Includes all participants receiving ≥1 dose of study treatment in Part 1 who: 1) had both a pre-dose baseline and ≥1 within-analysis-window, post-dose CDR-SB observation; and 2) tested positive for cortical amyloid load by PET.
    End point type
    Primary
    End point timeframe
    Baseline and Week 104 in Part 1
    End point values
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects analysed
    465
    458
    469
    Units: Score on a Scale
        least squares mean (confidence interval 95%)
    1.6 (1.4 to 1.9)
    2.0 (1.8 to 2.3)
    1.6 (1.3 to 1.8)
    Statistical analysis title
    Difference in Least Squares Mean (LSM)
    Statistical analysis description
    Difference in LSM = Arm A - Arm C
    Comparison groups
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) v Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects included in analysis
    934
    Analysis specification
    Pre-specified
    Analysis type
    [1]
    P-value
    = 0.6734
    Method
    Longitudinal ANCOVA
    Parameter type
    Difference in Least Squares Mean (LSM)
    Point estimate
    0.1
    Confidence interval
         level
    97.51%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    0.4
    Notes
    [1] - Analysis model includes categorical factors of geographic region, time, treatment, gender, APOE genotype, baseline use of Vitamin E, baseline use of AChEI, and the interaction of time by treatment, with baseline value, the interaction of baseline value and time, the baseline value of MMSE and the baseline value of age included as continuous covariates.
    Statistical analysis title
    Difference in Least Squares Means (LSM)
    Statistical analysis description
    Difference in LSM = Arm B - Arm C
    Comparison groups
    Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) v Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects included in analysis
    927
    Analysis specification
    Pre-specified
    Analysis type
    [2]
    P-value
    = 0.0141
    Method
    Longitudinal ANCOVA
    Parameter type
    Difference in Least Squares Means (LSM)
    Point estimate
    0.4
    Confidence interval
         level
    97.51%
         sides
    2-sided
         lower limit
    0
         upper limit
    0.8
    Notes
    [2] - Analysis model includes categorical factors of geographic region, time, treatment, gender, APOE genotype, baseline use of Vitamin E, baseline use of AChEI, and the interaction of time by treatment, with baseline value, the interaction of baseline value and time, the baseline value of MMSE and the baseline value of age included as continuous covariates

    Primary: Part 2 (Extension Study). Mean Change from Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 130

    Close Top of page
    End point title
    Part 2 (Extension Study). Mean Change from Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 130 [3]
    End point description
    Mean change from baseline at week 130 was assessed for CDR-SB score, a clinical rating of global cognitive function, comprised of 6 domains: memory; orientation; judgment and problem solving; community affairs; home and hobbies; and personal care. For each domain, degree of impairment is assessed by a semi-structured interview of the participant as well as their caregiver. For each domain, scores range from 0 (no impairment) to 3 (severe impairment). Individual domain scores are summed to a total CDR-SB score (range: 0-18). Higher scores indicate more severe cognitive impairment. Further, increases in cognitive impairment would be reflected by increases in CDR-SB score. Per protocol, baseline refers to the Part 1 baseline measurement. Analysis Population: All participants continuing to Part 2, with: 1) both a pre-dose baseline and ≥1 within-analysis-window, post-dose CDR-SB observation; 2) a positive test for cortical amyloid load by PET; and 3) a CDR-SB observation at week 130.
    End point type
    Primary
    End point timeframe
    Baseline and Week 130 (i.e., Week 26 of Part 2)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis not performed due to early trial termination.
    End point values
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects analysed
    120
    113
    124
    Units: Score on a Scale
        arithmetic mean (standard deviation)
    2.0 ± 2.5
    1.9 ± 2.2
    1.5 ± 2.1
    No statistical analyses for this end point

    Primary: Part 1 (Base Study). Percentage of Participants Who Experienced ≥1 Adverse Event (AE)

    Close Top of page
    End point title
    Part 1 (Base Study). Percentage of Participants Who Experienced ≥1 Adverse Event (AE)
    End point description
    The percentage of participants experiencing an AE in Part 1 was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor’s product is also an AE. Analysis Population: All randomized participants in Part 1, receiving ≥1 dose of study treatment.
    End point type
    Primary
    End point timeframe
    Up to Week 106 (up to 2 weeks following cessation of study treatment in Part 1)
    End point values
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects analysed
    483
    484
    484
    Units: Percentage of Participants
        number (not applicable)
    91.3
    92.1
    87.0
    Statistical analysis title
    Difference in % vs Placebo
    Statistical analysis description
    Difference in % = Arm A - Arm C
    Comparison groups
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) v Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects included in analysis
    967
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Difference in % vs Placebo
    Point estimate
    4.32
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.4
         upper limit
    8.31
    Statistical analysis title
    Difference in % vs Placebo
    Statistical analysis description
    Difference in % = Arm B - Arm C
    Comparison groups
    Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) v Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects included in analysis
    968
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Difference in % vs Placebo
    Point estimate
    5.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.33
         upper limit
    9.09

    Primary: Part 1 (Base Study). Percentage of Participants Who Discontinued From Study Drug Due to an Adverse Event (AE)

    Close Top of page
    End point title
    Part 1 (Base Study). Percentage of Participants Who Discontinued From Study Drug Due to an Adverse Event (AE)
    End point description
    The percentage of participants who discontinued from study drug due to an AE in Part 1 was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor’s product is also an AE. Analysis Population: All randomized participants in Part 1, receiving ≥1 dose of study treatment.
    End point type
    Primary
    End point timeframe
    Up to Week 104 in Part 1
    End point values
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects analysed
    483
    484
    484
    Units: Percentage of Participants
        number (not applicable)
    6.6
    10.1
    4.5
    Statistical analysis title
    Difference in % vs Placebo
    Statistical analysis description
    Difference in % = Arm B - Arm C
    Comparison groups
    Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) v Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects included in analysis
    968
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Difference in % vs Placebo
    Point estimate
    5.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.35
         upper limit
    8.99
    Statistical analysis title
    Difference in % vs Placebo
    Statistical analysis description
    Difference in % = Arm A - Arm C
    Comparison groups
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) v Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects included in analysis
    967
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Difference in % vs Placebo
    Point estimate
    2.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.84
         upper limit
    5.1

    Primary: Part 2 (Extension Study). Percentage of Participants Who Experienced ≥1 Adverse Event (AE)

    Close Top of page
    End point title
    Part 2 (Extension Study). Percentage of Participants Who Experienced ≥1 Adverse Event (AE)
    End point description
    The percentage of participants experiencing an AE in Part 2 was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor’s product is also an AE. Analysis Population: All randomized participants continuing to Part 2, receiving ≥1 dose of trial treatment in Part 2. For included participants, the data reflect AEs occurring in Part 2 only.
    End point type
    Primary
    End point timeframe
    From Week 104 (start of treatment in Part 2) up to Week 210 (up to 2 weeks following cessation of study treatment in Part 2)
    End point values
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects analysed
    197
    191
    204
    Units: Percentage of Participants
        number (not applicable)
    59.4
    55.5
    66.2
    Statistical analysis title
    Difference in % vs Placebo
    Statistical analysis description
    Difference in % = Arm A - Arm C
    Comparison groups
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) v Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Difference in % vs Placebo
    Point estimate
    -6.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16.16
         upper limit
    2.68
    Statistical analysis title
    Difference in % vs Placebo
    Statistical analysis description
    Difference in % = Arm B - Arm C
    Comparison groups
    Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) v Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects included in analysis
    395
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Difference in % vs Placebo
    Point estimate
    -10.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -20.16
         upper limit
    -1.04

    Primary: Part 2 (Extension Study). Percentage of Participants Who Discontinued From Study Drug Due to an Adverse Event (AE)

    Close Top of page
    End point title
    Part 2 (Extension Study). Percentage of Participants Who Discontinued From Study Drug Due to an Adverse Event (AE)
    End point description
    The percentage of participants who discontinued from study drug due to an AE in Part 2 was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor’s product is also an AE. Analysis Population: All randomized participants continuing to Part 2, receiving ≥1 dose of trial treatment in Part 2. For included participants, the data reflect discontinuations occurring in Part 2 only.
    End point type
    Primary
    End point timeframe
    From Week 104 (start of treatment in Part 2) up to Week 208 (i.e., up to Week 104 in Part 2)
    End point values
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects analysed
    197
    191
    204
    Units: Percentage of Participants
        number (not applicable)
    1.0
    1.0
    3.4
    Statistical analysis title
    Difference in % vs Placebo
    Statistical analysis description
    Difference in % = Arm A - Arm C
    Comparison groups
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) v Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Difference in % vs Placebo
    Point estimate
    -2.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.03
         upper limit
    0.61
    Statistical analysis title
    Difference in % vs Placebo
    Statistical analysis description
    Difference in % = Arm B - Arm C
    Comparison groups
    Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) v Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects included in analysis
    395
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Difference in % vs Placebo
    Point estimate
    -2.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.01
         upper limit
    0.71

    Secondary: Part 1 (Base Study). Event-Rate per 100 Participant Years for Progression to a Clinical Diagnosis of Probable AD Dementia

    Close Top of page
    End point title
    Part 1 (Base Study). Event-Rate per 100 Participant Years for Progression to a Clinical Diagnosis of Probable AD Dementia
    End point description
    The event-rate per 100 participant-years for progression to a clinical diagnosis of probable AD dementia was calculated. Adjudication of a potential case was triggered if either: 1) in the investigator’s own expert judgment, they think the participant may have progressed to dementia and/or 2) the participant’s CDR-SB score is ≥2 points higher compared to baseline. Cases of progression to probable AD dementia confirmed by an external adjudication committee were counted as events in the analysis. The event-rate was calculated as the number of events divided by total follow-up time (participant-years) x 100; unit of measure is event-rate / 100 participant-years. Analysis Population: Includes all participants receiving ≥1 dose of study treatment in Part 1 who tested positive for cortical amyloid load by PET.
    End point type
    Secondary
    End point timeframe
    Up to Week 104 in Part 1
    End point values
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects analysed
    480
    481
    481
    Units: Event-Rate / 100 Participant-Years
        number (not applicable)
    24.5
    25.5
    19.3
    Statistical analysis title
    Hazard Ratio (HR)
    Statistical analysis description
    HR = Arm A / Arm C
    Comparison groups
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) v Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects included in analysis
    961
    Analysis specification
    Pre-specified
    Analysis type
    [4]
    P-value
    = 0.0222
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.301
    Confidence interval
         level
    97.51%
         sides
    2-sided
         lower limit
    1.005
         upper limit
    1.684
    Notes
    [4] - Based on Cox regression model with Efron′ s method of tie handling with treatment, background AD treatment (use, no use), sex, APOE4 status (carrier, non-carrier) and baseline use of Vitamin E as categorical covariates and age and baseline MMSE value as continuous covariates.
    Statistical analysis title
    Hazard Ratio (HR)
    Statistical analysis description
    HR = Arm B / Arm C
    Comparison groups
    Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) v Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects included in analysis
    962
    Analysis specification
    Pre-specified
    Analysis type
    [5]
    P-value
    = 0.005
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.382
    Confidence interval
         level
    97.51%
         sides
    2-sided
         lower limit
    1.067
         upper limit
    1.79
    Notes
    [5] - Based on Cox regression model with Efron′ s method of tie handling with treatment, background AD treatment (use, no use), sex, APOE4 status (carrier, non-carrier) and baseline use of Vitamin E as categorical covariates and age and baseline MMSE value as continuous covariates.

    Secondary: Part 1 (Base Study). Estimated Least Squares Mean Difference between the Last (Week 104) and First (Week 13) Post-dose CDR-SB Assessment

    Close Top of page
    End point title
    Part 1 (Base Study). Estimated Least Squares Mean Difference between the Last (Week 104) and First (Week 13) Post-dose CDR-SB Assessment
    End point description
    LSM difference between weeks 104 and 13 was estimated for CDR-SB score, a clinical rating of global cognitive function, comprised of 6 domains: memory; orientation; judgment / problem solving; community affairs; home / hobbies; and personal care. For each domain, degree of impairment is scored by a semi-structured interview of the participant and the participant’s caregiver (domain score range: 0 [no impairment] to 3 [severe impairment]). Domain scores sum to a total CDR-SB score (range: 0-18); higher scores indicate more severe cognitive impairment. Further, increased cognitive impairment is reflected by higher CDR-SB scores; larger differences between week 104 and week 13 scores indicates accelerated AD progression. Analysis Population: Includes all participants receiving ≥1 dose of study treatment in Part 1 who: 1) had both a pre-dose baseline and ≥1 within-analysis-window, post-dose CDR-SB observation; and 2) tested positive for cortical amyloid load by PET.
    End point type
    Secondary
    End point timeframe
    Week 13 and Week 104 in Part 1
    End point values
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects analysed
    465
    458
    469
    Units: Score on a Scale
        least squares mean (confidence interval 95%)
    1.5 (1.3 to 1.7)
    1.8 (1.5 to 2.0)
    1.5 (1.3 to 1.7)
    Statistical analysis title
    Difference in Least Squares Mean (LSM)
    Statistical analysis description
    Difference in LSM = Arm A - Arm C
    Comparison groups
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) v Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects included in analysis
    934
    Analysis specification
    Pre-specified
    Analysis type
    [6]
    P-value
    = 0.9109
    Method
    Longitudinal ANCOVA
    Parameter type
    Difference in Least Squares Mean (LSM)
    Point estimate
    0
    Confidence interval
         level
    97.51%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    0.4
    Notes
    [6] - Analysis model includes categorical factors of geographic region, time, treatment, gender, APOE genotype, baseline use of Vitamin E, baseline use of AChEI, and the interaction of time by treatment, with baseline value, the interaction of baseline value and time, the baseline value of MMSE and the baseline value of age included as continuous covariates.
    Statistical analysis title
    Difference in Least Squares Mean (LSM)
    Statistical analysis description
    Difference in LSM = Arm B - Arm C
    Comparison groups
    Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) v Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects included in analysis
    927
    Analysis specification
    Pre-specified
    Analysis type
    [7]
    P-value
    = 0.0824
    Method
    Longitudinal ANCOVA
    Parameter type
    Difference in Least Squares Mean (LSM)
    Point estimate
    0.3
    Confidence interval
         level
    97.51%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    0.7
    Notes
    [7] - Analysis model includes categorical factors of geographic region, time, treatment, gender, APOE genotype, baseline use of Vitamin E, baseline use of AChEI, and the interaction of time by treatment, with baseline value, the interaction of baseline value and time, the baseline value of MMSE and the baseline value of age included as continuous covariates.

    Secondary: Part 1 (Base Study). Least Squares Mean Change from Baseline in the 3-Domain Composite Cognition Score (CCS-3D) at Week 104

    Close Top of page
    End point title
    Part 1 (Base Study). Least Squares Mean Change from Baseline in the 3-Domain Composite Cognition Score (CCS-3D) at Week 104
    End point description
    CCS-3D is composed of individual cognitive tests, grouped into 3 domains: 1) episodic memory; 2) executive function; and 3) attention/processing speed. For each cognitive test, a z-score (Z) is calculated at each time point [Z = (observed value - study population mean at baseline) / study population standard deviation at baseline]. These individual Zs are first combined into domain-specific Zs, and then into a composite Z, (i.e. CCS-3D). Theoretically, 99.9% of CCS-3D will be ± 3; more positive CCS-3D indicate greater cognitive impairment relative to the total study population at baseline. Further, negative changes in CCS-3D over time indicate improved cognition relative to the total study population at baseline. Analysis Population: Includes all participants receiving ≥1 dose of study treatment who: 1) had both a pre-dose baseline and ≥1 within-analysis-window, post-dose CCS-3D observation; and 2) tested positive for cortical amyloid load by PET.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 104 in Part 1
    End point values
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects analysed
    441
    424
    440
    Units: Z-score
        least squares mean (confidence interval 95%)
    0.8 (0.7 to 0.9)
    0.8 (0.7 to 0.9)
    0.8 (0.7 to 0.9)
    Statistical analysis title
    Difference in Least Squares Mean (LSM)
    Statistical analysis description
    Difference in LSM = Arm A - Arm C
    Comparison groups
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) v Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects included in analysis
    881
    Analysis specification
    Pre-specified
    Analysis type
    [8]
    P-value
    = 0.951
    Method
    Longitudinal ANCOVA
    Parameter type
    Difference in Least Squares Mean (LSM)
    Point estimate
    0
    Confidence interval
         level
    97.51%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.2
    Notes
    [8] - Analysis model includes categorical factors of geographic region, time, treatment, gender, APOE genotype, baseline use of Vitamin E, baseline use of AChEI, and the interaction of time by treatment, with baseline value, the interaction of baseline value and time, the baseline value of MMSE and the baseline value of age included as continuous covariates.
    Statistical analysis title
    Difference in Least Squares Mean (LSM)
    Statistical analysis description
    Difference in LSM = Arm B - Arm C
    Comparison groups
    Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) v Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects included in analysis
    864
    Analysis specification
    Pre-specified
    Analysis type
    [9]
    P-value
    = 0.9392
    Method
    Longitudinal ANCOVA
    Parameter type
    Difference in Least Squares Mean (LSM)
    Point estimate
    0
    Confidence interval
         level
    97.51%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.2
    Notes
    [9] - Analysis model includes categorical factors of geographic region, time, treatment, gender, APOE genotype, baseline use of Vitamin E, baseline use of AChEI, and the interaction of time by treatment, with baseline value, the interaction of baseline value and time, the baseline value of MMSE and the baseline value of age included as continuous covariates.

    Secondary: Part 1 (Base Study). Least Squares Mean Percent Change from Baseline in Total Hippocampal Volume (THV) at Week 104

    Close Top of page
    End point title
    Part 1 (Base Study). Least Squares Mean Percent Change from Baseline in Total Hippocampal Volume (THV) at Week 104
    End point description
    Least squares mean percent change from baseline at week 104 was calculated for THV as measured by volumetric magnetic resonance imaging (vMRI). Negative percent changes from baseline indicate decreases in THV (i.e. increased hippocampal atrophy). Analysis Population: Includes all participants receiving ≥1 dose of study treatment who: 1) had both a pre-dose baseline and ≥1 within-analysis-window, post-dose THV observation; and 2) tested positive for cortical amyloid load by PET.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 104 in Part 1
    End point values
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects analysed
    168
    181
    191
    Units: Percent Change
        least squares mean (confidence interval 95%)
    -6.5 (-6.9 to -6.2)
    -6.7 (-7.1 to -6.3)
    -6.1 (-6.5 to -5.7)
    Statistical analysis title
    Difference in Least Squares Mean (LSM)
    Statistical analysis description
    Difference in LSM = Arm A - Arm C
    Comparison groups
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) v Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects included in analysis
    359
    Analysis specification
    Pre-specified
    Analysis type
    [10]
    P-value
    = 0.1133
    Method
    Longitudinal ANCOVA
    Parameter type
    Difference in Least Squares Mean (LSM)
    Point estimate
    -0.4
    Confidence interval
         level
    97.51%
         sides
    2-sided
         lower limit
    -1
         upper limit
    0.2
    Notes
    [10] - Analysis model includes categorical factors of geographic region, time, treatment, gender, APOE genotype, baseline use of Vitamin E, baseline use of AChEI, and the interaction of time by treatment, with baseline value, the interaction of baseline value and time, the baseline value of MMSE and the baseline value of age included as continuous covariates.
    Statistical analysis title
    Difference in Least Squares Mean (LSM)
    Statistical analysis description
    Difference in LSM = Arm B - Arm C
    Comparison groups
    Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) v Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    [11]
    P-value
    = 0.031
    Method
    Longitudinal ANCOVA
    Parameter type
    Difference in Least Squares Mean (LSM)
    Point estimate
    -0.6
    Confidence interval
         level
    97.51%
         sides
    2-sided
         lower limit
    -1.2
         upper limit
    0
    Notes
    [11] - Analysis model includes categorical factors of geographic region, time, treatment, gender, APOE genotype, baseline use of Vitamin E, baseline use of AChEI, and the interaction of time by treatment, with baseline value, the interaction of baseline value and time, the baseline value of MMSE and the baseline value of age included as continuous covariates.

    Secondary: Part 1 (Base Study). Least Squares Mean Change from Baseline in Composite Cortical Amyloid Standard Uptake Value Ratio (SUVR) Assessed with Amyloid Tracer [18F]Flutemetamol using Positron Emission Tomography (PET) Imaging at Week 104

    Close Top of page
    End point title
    Part 1 (Base Study). Least Squares Mean Change from Baseline in Composite Cortical Amyloid Standard Uptake Value Ratio (SUVR) Assessed with Amyloid Tracer [18F]Flutemetamol using Positron Emission Tomography (PET) Imaging at Week 104
    End point description
    [18F]Flutemetamol PET SUVR measures brain cortical amyloid load. The PET tracer [18F]Flutemetamol was given intravenously (IV). After 90 minutes, participants were scanned for 20 minutes. Using the PET scan images, SUVRs, the ratio of tracer signal in a specific region compared to a reference region (RR; subcortical white matter) are calculated for brain regions of interest (ROIs). SUVRs from a selected set of brain regions are averaged to compute a composite SUVR. Higher composite SUVR values indicate increased amyloid load in selected brain regions, with negative changes in composite cortical SUVR over time indicating decreases in brain amyloid load. Analysis Population: Includes all participants receiving ≥1 dose of study treatment who: 1) had both a pre-dose baseline and ≥1 within-analysis-window, post-dose SUVR observation; and 2) tested positive for cortical amyloid load by PET.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 104 in Part 1
    End point values
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects analysed
    63
    59
    65
    Units: Standard Uptake Value Ratio (SUVR)
        least squares mean (confidence interval 95%)
    -0.03 (-0.04 to -0.03)
    -0.04 (-0.05 to -0.04)
    0.02 (0.02 to 0.03)
    Statistical analysis title
    Difference in Least Squares Mean (LSM)
    Statistical analysis description
    Difference in LSM = Arm A - Arm C
    Comparison groups
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) v Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    [12]
    P-value
    < 0.0001
    Method
    Longitudinal ANCOVA
    Parameter type
    Difference in Least Squares Mean (LSM)
    Point estimate
    -0.05
    Confidence interval
         level
    97.51%
         sides
    2-sided
         lower limit
    -0.06
         upper limit
    -0.04
    Notes
    [12] - Analysis model includes categorical factors of geographic region, time, treatment, gender, APOE genotype, baseline use of Vitamin E, baseline use of AChEI, and the interaction of time by treatment, with baseline value, the interaction of baseline value and time, the baseline value of MMSE and the baseline value of age included as continuous covariates.
    Statistical analysis title
    Difference in Least Squares Mean (LSM)
    Statistical analysis description
    Difference in LSM = Arm B - Arm C
    Comparison groups
    Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) v Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    [13]
    P-value
    < 0.0001
    Method
    Longitudinal ANCOVA
    Parameter type
    Difference in Least Squares Mean (LSM)
    Point estimate
    -0.06
    Confidence interval
         level
    97.51%
         sides
    2-sided
         lower limit
    -0.07
         upper limit
    -0.05
    Notes
    [13] - Analysis model includes categorical factors of geographic region, time, treatment, gender, APOE genotype, baseline use of Vitamin E, baseline use of AChEI, and the interaction of time by treatment, with baseline value, the interaction of baseline value and time, the baseline value of MMSE and the baseline value of age included as continuous covariates.

    Secondary: Part 1 (Base Study). Least Squares Mean Change from Baseline in Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory (Mild Cognitive Impairment version) (ADCS-ADL MCI) Score at Week 104

    Close Top of page
    End point title
    Part 1 (Base Study). Least Squares Mean Change from Baseline in Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory (Mild Cognitive Impairment version) (ADCS-ADL MCI) Score at Week 104
    End point description
    Least squares mean change from baseline at week 104 was assessed for the ADCS-ADL MCI score. The ADCS-ADL MCI is an 18-item assessment of recent, observed performance of activities of daily living administered to participants’ trial partners in an interview format. For the 18 items, scores range from 0 (no independence) to (depending on the item) either 2 (5 items), 3 (9 items), or 4 (4 items), with higher scores indicating greater independence in activity performance. Scores from individual items sum to a total ADCS-ADL score (range: 0-53). Lower scores indicate less independence in activity performance and, as a result, greater AD severity. Further, increases in AD severity over time would be reflected by decreases in ADCS-ADL score. Analysis Population: Includes all participants receiving ≥1 dose of study treatment who: 1) had both a pre-dose baseline and ≥1 within-analysis-window, post-dose ADCS-ADL MCI observation; and 2) tested positive for cortical amyloid load by PET.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 104 in Part 1
    End point values
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects analysed
    469
    462
    472
    Units: Score on a Scale
        least squares mean (confidence interval 95%)
    -5.2 (-6.1 to -4.3)
    -5.8 (-6.8 to -4.8)
    -4.1 (-5.0 to -3.3)
    Statistical analysis title
    Difference in Least Squares Mean (LSM)
    Statistical analysis description
    Difference in LSM = Arm B - Arm C
    Comparison groups
    Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) v Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects included in analysis
    934
    Analysis specification
    Pre-specified
    Analysis type
    [14]
    P-value
    = 0.011
    Method
    Longitudinal ANCOVA
    Parameter type
    Difference in Least Squares Mean (LSM)
    Point estimate
    -1.7
    Confidence interval
         level
    97.51%
         sides
    2-sided
         lower limit
    -3.2
         upper limit
    -0.2
    Notes
    [14] - Analysis model includes categorical factors of geographic region, time, treatment, gender, APOE genotype, baseline use of Vitamin E, baseline use of AChEI, and the interaction of time by treatment, with baseline value, the interaction of baseline value and time, the baseline value of MMSE and the baseline value of age included as continuous covariates.
    Statistical analysis title
    Difference in Least Squares Mean (LSM)
    Statistical analysis description
    Difference in LSM = Arm A - Arm C
    Comparison groups
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) v Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects included in analysis
    941
    Analysis specification
    Pre-specified
    Analysis type
    [15]
    P-value
    = 0.096
    Method
    Longitudinal ANCOVA
    Parameter type
    Difference in Least Squares Mean (LSM)
    Point estimate
    -1
    Confidence interval
         level
    97.51%
         sides
    2-sided
         lower limit
    -2.4
         upper limit
    0.4
    Notes
    [15] - Analysis model includes categorical factors of geographic region, time, treatment, gender, APOE genotype, baseline use of Vitamin E, baseline use of AChEI, and the interaction of time by treatment, with baseline value, the interaction of baseline value and time, the baseline value of MMSE and the baseline value of age included as continuous covariates.

    Secondary: Part 1 (Base Study). Least Squares Mean Percent Change from Baseline in Cerebrospinal Fluid (CSF) Total Tau Concentration at Week 104

    Close Top of page
    End point title
    Part 1 (Base Study). Least Squares Mean Percent Change from Baseline in Cerebrospinal Fluid (CSF) Total Tau Concentration at Week 104
    End point description
    Least squares mean percent change from baseline at week 104 was calculated for Total Tau concentration in CSF, a measure of brain tau pathology. Per protocol, CSF Total Tau concentration was analyzed as part of a substudy in Part 1, with testing occurring only at select trial sites. Analysis Population: Includes all participants receiving ≥1 dose of study treatment who: 1) had both a pre-dose baseline and ≥1 within-analysis-window, post-dose observation for CSF Total Tau concentration; and 2) tested positive for cortical amyloid load by PET. CSF Total Tau concentration was analyzed at select trial sites as a Part 1 substudy.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 104 in Part 1
    End point values
    Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
    Number of subjects analysed
    5
    6
    6
    Units: Percent Change
        arithmetic mean (standard deviation)
    33.2 ± 44.3
    42.8 ± 39.7
    10.2 ± 27.9
    No statistical analyses for this end point

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    [Part 1]: Up to Week 106 of Part 1 (up to 2 weeks following cessation of study treatment in Part 1); [Part 2]: From Week 104 (start of treatment in Part 2) up to Week 210 (up to 2 weeks following cessation of study treatment in Part 2).
    Adverse event reporting additional description
    [Part 1] all randomized participants receiving ≥1 dose of treatment. [Part 2] all participants continuing to Part 2, receiving ≥1 dose of treatment in Part 2. For Part 2 arms, only AEs occurring in Part 2 are reported. For serious AEs determined to be causally related to treatment, this reflects assessment of a blinded investigator during trial.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Arm A. Verubecestat 12 mg (Part 1)
    Reporting group description
    [Part 1] Verubecestat 12 mg once daily for 104 weeks in Part 1 (Base Study).

    Reporting group title
    Arm B. Verubecestat 40 mg (Part 1)
    Reporting group description
    [Part 1] Verubecestat 40 mg once daily for 104 weeks in Part 1 (Base Study).

    Reporting group title
    Arm C. Placebo (Part 1)
    Reporting group description
    [Part 1] Placebo once daily for 104 weeks in Part 1 (Base Study).

    Reporting group title
    Arm A. Verubecestat 12 mg (Part 2)
    Reporting group description
    [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 12 mg once daily for an additional 260 weeks.

    Reporting group title
    Arm B. Verubecestat 40 mg (Part 2)
    Reporting group description
    [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks.

    Reporting group title
    Arm C. Verubecestat 40 mg (Part 2)
    Reporting group description
    [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks.

    Serious adverse events
    Arm A. Verubecestat 12 mg (Part 1) Arm B. Verubecestat 40 mg (Part 1) Arm C. Placebo (Part 1) Arm A. Verubecestat 12 mg (Part 2) Arm B. Verubecestat 40 mg (Part 2) Arm C. Verubecestat 40 mg (Part 2)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    124 / 483 (25.67%)
    101 / 484 (20.87%)
    96 / 484 (19.83%)
    10 / 197 (5.08%)
    22 / 191 (11.52%)
    24 / 204 (11.76%)
         number of deaths (all causes)
    3
    1
    3
    0
    3
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arterial stenosis
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive episode
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intermittent claudication
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral obliterative arteriopathy
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    1 / 191 (0.52%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma of prostate
         subjects affected / exposed
    0 / 483 (0.00%)
    2 / 484 (0.41%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atypical fibroxanthoma
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    13 / 483 (2.69%)
    8 / 484 (1.65%)
    6 / 484 (1.24%)
    4 / 197 (2.03%)
    2 / 191 (1.05%)
    3 / 204 (1.47%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 10
    1 / 7
    0 / 4
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder neoplasm
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer metastatic
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer recurrent
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carcinoma in situ of breast ductal
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical cancer
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clear cell renal cell carcinoma
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colonic tubular adenoma
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Follicular thyroid cancer
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric adenoma
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lentigo melanoma
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lip basal cell carcinoma
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma metastatic
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Melanoma
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Melanoma in situ
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to lymph nodes
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic gastric cancer
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple myeloma
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nodular basal cell carcinoma
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreas cancer
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    3 / 483 (0.62%)
    2 / 484 (0.41%)
    5 / 484 (1.03%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 5
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer recurrent
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    1 / 191 (0.52%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate carcinoma
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin cancer
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin carcinoma
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    3 / 483 (0.62%)
    2 / 484 (0.41%)
    2 / 484 (0.41%)
    1 / 197 (0.51%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of head and neck
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    5 / 483 (1.04%)
    3 / 484 (0.62%)
    5 / 484 (1.03%)
    1 / 197 (0.51%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 4
    0 / 5
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin in situ
         subjects affected / exposed
    1 / 483 (0.21%)
    2 / 484 (0.41%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    1 / 191 (0.52%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin well differentiated
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of the nasal cavity
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Superficial basal cell carcinoma
         subjects affected / exposed
    3 / 483 (0.62%)
    0 / 484 (0.00%)
    3 / 484 (0.62%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    1 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Throat cancer
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urothelial carcinoma
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    2 / 484 (0.41%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity reaction
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Acute chest pain
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    3 / 483 (0.62%)
    2 / 484 (0.41%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain aggravated
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pressure
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fever of unknown origin
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gait abnormal
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute mania
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusion aggravated
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    3 / 483 (0.62%)
    1 / 484 (0.21%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Delusion
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychosis aggravated
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic episode
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somatisation disorder
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Unsuccessful suicide
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute delirium
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    1 / 191 (0.52%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Bartholin's cyst
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign prostatic hypertrophy
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystocele
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urogenital prolapse
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Alcohol intoxication
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arm fracture
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bimalleolar fracture
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bruise of head
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic subdural haematoma
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 483 (0.21%)
    1 / 484 (0.21%)
    3 / 484 (0.62%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    1 / 191 (0.52%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Finger injury
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fracture of intertrochanteric section of femur, closed
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fractured mandible
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    1 / 191 (0.52%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 483 (0.21%)
    2 / 484 (0.41%)
    2 / 484 (0.41%)
    0 / 197 (0.00%)
    1 / 191 (0.52%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint ligament rupture
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar spine compression fracture
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Near drowning
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Olecranon fracture
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain trauma activated
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural pain
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative haematoma
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative hypotension
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    1 / 191 (0.52%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Scapula fracture
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid bleeding
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma (traumatic)
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thoracic vertebral fracture T12
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traffic accident
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Trochanteric femoral fracture
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertebral fracture
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    1 / 191 (0.52%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    1 / 191 (0.52%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic fracture
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Creatinine increased
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Faecal occult blood
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostatic specific antigen increased
         subjects affected / exposed
    1 / 483 (0.21%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    1 / 191 (0.52%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 483 (0.21%)
    1 / 484 (0.21%)
    2 / 484 (0.41%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris aggravated
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    1 / 191 (0.52%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    2 / 484 (0.41%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation aggravated
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation with rapid ventricular response
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 483 (0.21%)
    1 / 484 (0.21%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    1 / 191 (0.52%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease aggravated
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 483 (0.00%)
    2 / 484 (0.41%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    1 / 191 (0.52%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Non ST segment elevation myocardial infarction
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paroxysmal supraventricular tachycardia
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Recurrent atrial fibrillation
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sick sinus syndrome
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular bigeminy
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    1 / 191 (0.52%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Right coronary artery stenosis
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Bronchogenic cyst
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Pancytopenia
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease exacerbation
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Collapse of lung
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal haematoma
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 483 (0.00%)
    2 / 484 (0.41%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 483 (0.41%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    1 / 191 (0.52%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    1 / 191 (0.52%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    1 / 191 (0.52%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    1 / 483 (0.21%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 483 (0.00%)
    2 / 484 (0.41%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular insufficiency
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Complex partial seizures
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dementia aggravated
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 483 (0.21%)
    1 / 484 (0.21%)
    1 / 484 (0.21%)
    1 / 197 (0.51%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epileptic seizure
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Felt faint
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lightheadedness
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neurocardiogenic syncope
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nonconvulsive status epilepticus
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 483 (0.41%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    1 / 197 (0.51%)
    1 / 191 (0.52%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stroke
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncopal attack
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    5 / 483 (1.04%)
    1 / 484 (0.21%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    1 / 191 (0.52%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thalamic infarction
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient cerebral ischaemia
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient global amnesia
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 483 (0.00%)
    3 / 484 (0.62%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tremor aggravated
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Unconsciousness
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neurologic reaction
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    1 / 191 (0.52%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cataract bilateral NOS
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Right cataract
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Benign paroxysmal positional vertigo
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 483 (0.21%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute enterocolitis
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    1 / 191 (0.52%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal upset
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids aggravated
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Indirect inguinal hernia
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left inguinal hernia
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left upper quadrant pain
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal ulcer
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal prolapse
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reflux oesophagitis
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Right inguinal hernia
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tenderness epigastric
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 484 (0.21%)
    1 / 484 (0.21%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 483 (0.00%)
    2 / 484 (0.41%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticular disease
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 484 (0.00%)
    0 / 484 (0.00%)
    0 / 197 (0.00%)
    0 / 191 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0