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    Clinical Trial Results:
    A Randomized, Placebo Controlled, Parallel-Group, Double Blind Efficacy and Safety Trial of MK-8931 with a Long Term Double-Blind Extension in Subjects with Mild to Moderate Alzheimer's Disease (Protocol No. MK-8931-017-10)(also known as SCH 900931, P07738)

    Summary
    EudraCT number
    		 2011-003151-20
    Trial protocol
    		 ES   NL   GB   IT   DE   PT   HU   BE   AT   DK  
    Global end of trial date
    14 Apr 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Apr 2018
    First version publication date
    27 Apr 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    8931-017
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01739348
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Merck Protocol Number: MK-8931-017
    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
    14 Apr 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Apr 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This study includes a Part I and Part II. Part I assesses efficacy and safety of verubecestat (MK-8931) compared with placebo administered for 78 weeks for treatment of Alzheimer's Disease (AD). The primary hypotheses for Part I are that ≥1 verubecestat dose is superior to placebo at 78 weeks of treatment with respect to change from baseline in: 1) AD Assessment Scale Cognitive Subscale (ADAS-Cog) score; and 2) AD Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) score. Participants completing Part I may continue to Part II, a double-blind extension to assess efficacy and safety of verubecestat given for an additional 260 weeks. Part I includes 2 substudies conducted at select sites: 1) a positron emission tomography (PET) imaging substudy evaluating changes in brain amyloid protein load using an amyloid tracer ([18F]flutemetamol); and 2) a cerebrospinal fluid (CSF) biomarker substudy to evaluate changes in amyloid-β related peptides, total tau, and phosphorylated tau.
    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
    30 Nov 2012
    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
    Australia: 35
    Country: Number of subjects enrolled
    Austria: 19
    Country: Number of subjects enrolled
    Belgium: 51
    Country: Number of subjects enrolled
    Brazil: 43
    Country: Number of subjects enrolled
    Canada: 84
    Country: Number of subjects enrolled
    Denmark: 54
    Country: Number of subjects enrolled
    Argentina: 91
    Country: Number of subjects enrolled
    France: 128
    Country: Number of subjects enrolled
    Germany: 36
    Country: Number of subjects enrolled
    Hungary: 35
    Country: Number of subjects enrolled
    Israel: 25
    Country: Number of subjects enrolled
    Italy: 27
    Country: Number of subjects enrolled
    Japan: 295
    Country: Number of subjects enrolled
    Korea, Republic of: 54
    Country: Number of subjects enrolled
    Netherlands: 43
    Country: Number of subjects enrolled
    New Zealand: 20
    Country: Number of subjects enrolled
    Portugal: 57
    Country: Number of subjects enrolled
    Spain: 102
    Country: Number of subjects enrolled
    Turkey: 56
    Country: Number of subjects enrolled
    United Kingdom: 71
    Country: Number of subjects enrolled
    United States: 885
    Worldwide total number of subjects
    2211
    EEA total number of subjects
    623
    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)
    398
    From 65 to 84 years
    1771
    85 years and over
    42

    Subject disposition

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    Recruitment
    Recruitment details
    		 Part I began by enrolling approximately 50 participants per arm (200 total). Enrollment continued until the first 200 participants reached 13 weeks treatment; total enrollment at that time: ~400. For these ~400 participants (Safety Cohort), an interim analysis (IA) was conducted to assess safety. Following IA, enrollment continued (Main Cohort).

    Pre-assignment
    Screening details
    		 2211 participants were randomized in Part I, with 2210 receiving treatment. As planned per protocol, no participants were randomized to the Verubecestat 60 mg arm (Arm C) in the Main Cohort. Participants completing Part I were eligible to continue to Part II. The trial was terminated early and did not complete as planned.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]
    Arm description
    		 [Part I] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Verubecestat
    Investigational medicinal product code
    Other name
    SCH 900931, MK-8931
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Single verubecestat tablet (12 mg, 40 mg or 60 mg) once daily, taken orally

    Arm title
    		 Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II]
    Arm description
    		 [Part I] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Verubecestat
    Investigational medicinal product code
    Other name
    SCH 900931, MK-8931
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Single verubecestat tablet (12 mg, 40 mg or 60 mg) once daily, taken orally

    Arm title
    		 Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II]
    Arm description
    		 [Part I] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Verubecestat
    Investigational medicinal product code
    Other name
    SCH 900931, MK-8931
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Single verubecestat tablet (12 mg, 40 mg or 60 mg) once daily, taken orally

    Arm title
    		 Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Arm description
    		 [Part I] Placebo once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (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
    Single placebo tablet matching verubecestat treatment once daily, taken orally

    Number of subjects in period 1
    		Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Started
    703
    700
    103
    705
    Treated
    702
    700
    103
    705
    Completed
    501
    497
    77
    516
    Not completed
    202
    203
    26
    189
         Adverse event, serious fatal
    10
    7
    2
    8
         Physician decision
    10
    7
    1
    4
         Screen Failure
    2
    -
    -
    -
         Site Discontinued Study Participation
    1
    3
    -
    -
         Participant Moved
    4
    3
    1
    7
         Study Terminated by Sponsor
    72
    73
    -
    86
         Consent withdrawn by subject
    23
    21
    7
    20
         Non-Compliance with Study Drug
    3
    2
    -
    -
         Adverse event, non-fatal
    41
    52
    8
    33
         Trial Partner/Caregiver Withdrew Consent
    27
    25
    2
    18
         Lost to follow-up
    4
    2
    4
    4
         Lack of efficacy
    3
    8
    -
    7
         Protocol deviation
    2
    -
    1
    2
    Period 2
    Period 2 title
    Part II (Extension Study)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]
    Arm description
    		 [Part I] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Verubecestat
    Investigational medicinal product code
    Other name
    SCH 900931, MK-8931
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Single verubecestat tablet (12 mg, 40 mg or 60 mg) once daily, taken orally

    Arm title
    		 Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II]
    Arm description
    		 [Part I] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Verubecestat
    Investigational medicinal product code
    Other name
    SCH 900931, MK-8931
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Single verubecestat tablet (12 mg, 40 mg or 60 mg) once daily, taken orally

    Arm title
    		 Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II]
    Arm description
    		 [Part I] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Verubecestat
    Investigational medicinal product code
    Other name
    SCH 900931, MK-8931
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Single verubecestat tablet (12 mg, 40 mg or 60 mg) once daily, taken orally

    Arm title
    		 Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Arm description
    		 [Part I] Placebo once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Verubecestat
    Investigational medicinal product code
    Other name
    SCH 900931
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Single verubecestat tablet (12 mg, 40 mg or 60 mg) once daily, taken orally

    Number of subjects in period 2 [1]
    		Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Started
    379
    366
    61
    396
    Treated
    379
    365
    61
    394
    Completed
    0
    0
    0
    0
    Not completed
    379
    366
    61
    396
         Adverse event, serious fatal
    3
    3
    2
    6
         Physician decision
    7
    11
    6
    12
         Consent withdrawn by subject
    5
    2
    4
    7
         Non-Compliance with Study Drug
    -
    -
    -
    1
         Adverse event, non-fatal
    10
    11
    7
    26
         Trial Partner/Caregiver Withdrew Consent
    18
    12
    8
    16
         Participant Moved
    3
    3
    -
    3
         Study Terminated by Sponsor
    329
    315
    34
    323
         Lost to follow-up
    3
    4
    -
    1
         Lack of efficacy
    1
    5
    -
    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 started refers to participants completing Part I, continuing to Part II

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]
    Reporting group description
    		 [Part I] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks.

    Reporting group title
    Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II]
    Reporting group description
    		 [Part I] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.

    Reporting group title
    Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II]
    Reporting group description
    		 [Part I] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.

    Reporting group title
    Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Reporting group description
    		 [Part I] Placebo once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.

    Reporting group values
    		 Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II] Total
    Number of subjects
    		 703 700 103 705 2211
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 131 130 17 120 398
        From 65-84 years
    		 561 556 82 572 1771
        85 years and over
    		 11 14 4 13 42
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 71.2 ( 7.4 ) 71.8 ( 7.6 ) 72.3 ( 7.4 ) 72.4 ( 7.6 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 383 403 56 376 1218
        Male
    		 320 297 47 329 993
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 3 0 3 7
        Asian
    		 118 125 11 115 369
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        Black or African American
    		 8 13 2 7 30
        White
    		 566 547 88 578 1779
        More than one race
    		 4 4 2 0 10
        Unknown or Not Reported
    		 6 8 0 2 16
    Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score
    ADAS-Cog measures cognition by assessing 11 metrics impaired in Alzheimer’s Disease (AD). For each metric, scores range from 0 (no impairment) to (depending on metric) either 5 (8 metrics), 8, 10, or 12 (1 metric each); higher scores indicate more severe impairment. Individual scores sum to a total ADAS-Cog score (range: 0-70). Higher total scores indicate greater cognitive impairment. Includes all randomized participants with a baseline and ≥1 within-analysis-window, post-dose ADAS-Cog observation (Full Analysis Set [FAS] population). For Arms A, B, C, and D, N= 681, 672, 97, and 694.
    Units: Score on a Scale
        arithmetic mean (standard deviation)
    		 21.4 ( 7.5 ) 21.3 ( 7.6 ) 20.6 ( 6.2 ) 21.7 ( 7.6 ) -
    Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score
    ADCS-ADL measures performance of activities of daily living, calculated from a 24-question survey; question scores range from 0 (no independence) to either 2 (1 question), 3 (17 questions), 4 (5 questions), or 5 (1 question). Higher scores indicate greater independence in performance. Scores from questions sum to a total ADCS-ADL score (range: 0-78). Lower scores indicate less independence in performance. Includes all randomized participants with a baseline and ≥1 within-analysis-window, post-dose ADCS-ADL observation (FAS population). For Arms A, B, C, and D, N= 677, 668, 98, and 686.
    Units: Score on a Scale
        arithmetic mean (standard deviation)
    		 63.0 ( 9.5 ) 62.9 ( 9.8 ) 63.5 ( 10.3 ) 62.1 ( 10.4 ) -
    Clinical Dementia Rating Sum of Boxes (CDR-SB) Score
    CDR-SB is a clinical rating of global cognitive function, comprised of 6 domains. For each domain, degree of impairment is assessed by semi-structured interview of the participant and the participant’s caregiver. For each domain, potential scores range from 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. Includes all randomized participants with a baseline and ≥1 within-analysis-window, post-dose CDR-SB observation (FAS population). For Arms A, B, C, and D, N= 660, 643, 91, and 673.
    Units: Score on a Scale
        arithmetic mean (standard deviation)
    		 5.4 ( 2.1 ) 5.3 ( 2.1 ) 5.5 ( 2.3 ) 5.6 ( 2.3 ) -
    Total Hippocampal Volume
    Total Hippocampal Volume (THV) was measured by volumetric magnetic resonance imaging (vMRI). Analysis population: all randomized participants with a baseline and ≥1 within-analysis-window, post-dose observation for THV (FAS population). For Arms A, B, C, and D, N= 332, 307, 55, and 346.
    Units: Microliters
        arithmetic mean (standard deviation)
    		 5894.1 ( 1231.5 ) 5823.4 ( 1189.9 ) 5653.5 ( 1148.4 ) 5800.7 ( 1069.2 ) -
    Cerebrospinal Fluid (CSF) Total Tau Concentration
    Total Tau concentration in the cerebrospinal fluid (CSF) was monitored as a measure of brain tau pathology. Analysis population: all randomized participants with a baseline and ≥1 within-analysis-window, post-dose observation for CSF Total Tau (FAS population). Per protocol, CSF Total Tau concentration was analyzed as part of a substudy in Part I, with testing occurring at select trial sites. For Arms A, B, C, and D, N= 38, 57, 12, and 41.
    Units: picograms (pg)/mL
        arithmetic mean (standard deviation)
    		 206.7 ( 90.4 ) 231.5 ( 113.9 ) 268.6 ( 136.2 ) 246.2 ( 192.9 ) -
    [18F]Flutemetamol Positron Emission Tomography (PET) Standard Uptake Value Ratio (SUVR)
    Brain amyloid load assessed by SUVR of intravenous (IV) [18F]Flutemetamol. After administration and PET scan, regions of interest (ROIs) are assessed for regional SUVR, defined as ratio of pixel intensity at ROI compared to reference region (RR). Regional SUVRs are averaged for composite SUVR; higher values indicate increased amyloid load. Includes all randomized participants with a baseline and ≥1 within-analysis-window, post-dose SUVR observation (FAS population). Excludes participants enrolled before IA and to Arm C. For Arms A, B, C, and D, N= 20, 10, 0, and 14. ‘9999’: no data collected.
    Units: SUVR
        arithmetic mean (standard deviation)
    		 0.89 ( 0.10 ) 0.87 ( 0.11 ) 9999 ( 9999 ) 0.88 ( 0.11 ) -
    Neuropsychiatric Inventory (NPI) Score
    NPI assesses psychiatric status in 12 domains. After interview of participant’s caregiver, domains scored on symptom frequency [range: 1 (occasional) to 4 (very frequent)] and severity [range: 1 (mild) to 3 (severe)]. Domain scores (range: 0-12) are product of frequency and severity scores; if no symptoms, score is 0. Domain scores sum to total NPI score (range: 0-144). Higher scores reflect more severe impairment. Includes all randomized participants with a baseline and ≥1 within-analysis-window, post-dose NPI observation (FAS population). For Arms A, B, C, and D, N= 682, 679, 100, and 691.
    Units: Score on a Scale
        arithmetic mean (standard deviation)
    		 8.7 ( 10.5 ) 8.2 ( 9.8 ) 6.9 ( 9.5 ) 9.2 ( 11.6 ) -
    Mini-Mental State Examination (MMSE) Score
    MMSE is a cognitive assessment of 5 domains with 11 total questions related to the participant, scored based on the number of correct responses; depending on question, potential scores range from 0 (no correct response) to either 1 (4 questions), 2 (1 question), 3 (3 questions), or 5 (3 questions). Scores from each question sum to a total MMSE score (range: 0-30); higher scores indicate better cognitive performance. Includes all randomized participants with a baseline and ≥1 within-analysis-window, post-dose MMSE observation (FAS population). For Arms A, B, C, and D, N= 660, 648, 98, and 679.
    Units: Score on a Scale
        arithmetic mean (standard deviation)
    		 20.4 ( 3.3 ) 20.2 ( 3.3 ) 20.6 ( 3.3 ) 20.3 ( 3.2 ) -

    End points

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    End points reporting groups
    Reporting group title
    Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]
    Reporting group description
    		 [Part I] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks.

    Reporting group title
    Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II]
    Reporting group description
    		 [Part I] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.

    Reporting group title
    Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II]
    Reporting group description
    		 [Part I] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.

    Reporting group title
    Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Reporting group description
    		 [Part I] Placebo once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
    Reporting group title
    Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]
    Reporting group description
    		 [Part I] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks.

    Reporting group title
    Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II]
    Reporting group description
    		 [Part I] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.

    Reporting group title
    Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II]
    Reporting group description
    		 [Part I] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.

    Reporting group title
    Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Reporting group description
    		 [Part I] Placebo once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.

    Primary: [Part I (Base Study)] Change from Baseline in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score

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    End point title
    		 [Part I (Base Study)] Change from Baseline in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score
    End point description
    Least squares mean change from baseline (CFB) at week 78 was assessed for ADAS-Cog score. ADAS-Cog measures cognition by 11 metrics impaired in AD: speech; speech comprehension; word finding; word recall; object/finger naming; orientation; obeying commands; ideational praxis; constructional praxis; word recognition; and remembering instruction. For each metric, scores range from 0 (no impairment) to (depending on metric) either 5 (8 metrics), 8, 10, or 12 (1 metric each); higher scores indicate more severe impairment. Individual scores sum to a total ADAS-Cog score (range: 0-70); higher total scores indicate greater cognitive impairment and AD severity. Further, increases in AD severity are reflected by increases in ADAS-Cog score. Analysis population: all randomized participants with a baseline and ≥1 within-analysis-window, post-dose ADAS-Cog observation (FAS population).
    End point type
    Primary
    End point timeframe
    Baseline and week 78
    End point values
    		 Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Number of subjects analysed
    631 [1]
    626 [2]
    0 [3]
    644 [4]
    Units: Score on a Scale
        least squares mean (confidence interval 95%)
    7.9 (7.2 to 8.6)
    8.0 (7.3 to 8.7)
    ( to )
    7.7 (7.0 to 8.4)
    Notes
    [1] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [2] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [3] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [4] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    Statistical analysis title
    		 ADAS-Cog CFB: Verubecestat 12 mg vs. Placebo
    Comparison groups
    Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II] v Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]
    Number of subjects included in analysis
    1275
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6287
    Method
    		 Longitudinal ANCOVA
    Parameter type
    		 Difference in Least Squares Mean
    Point estimate
    0.2
    Confidence interval
         level
    		 97.51%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 1.3
    Statistical analysis title
    		 ADAS-Cog CFB: Verubecestat 40 mg vs. Placebo
    Comparison groups
    Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] v Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Number of subjects included in analysis
    1270
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4625
    Method
    		 Longitudinal ANCOVA
    Parameter type
    		 Difference in Least Squares Mean
    Point estimate
    0.4
    Confidence interval
         level
    		 97.51%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 1.5

    Primary: [Part I (Base Study)] Change from Baseline in Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score

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    End point title
    		 [Part I (Base Study)] Change from Baseline in Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score
    End point description
    Least squares mean CFB at week 78 was assessed for ADCS-ADL score. ADCS-ADL measures performance of activities of daily living, calculated from a 24-question survey. For each of the 24 questions, scores range from 0 (no independence) to (depending on the question) either 2 (1 question), 3 (17 questions), 4 (5 questions), or 5 (1 question); higher scores indicate greater independence in activity performance. Scores from individual questions sum to a total ADCS-ADL score (range: 0 to 78); 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: all randomized participants with a baseline and ≥1 within-analysis-window, post-dose ADCS-ADL observation (FAS population).
    End point type
    Primary
    End point timeframe
    Baseline and week 78
    End point values
    		 Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Number of subjects analysed
    627 [5]
    622 [6]
    0 [7]
    636 [8]
    Units: Score on a Scale
        least squares mean (confidence interval 95%)
    -8.4 (-9.5 to -7.4)
    -8.2 (-9.2 to -7.1)
    ( to )
    -8.9 (-9.9 to -8.0)
    Notes
    [5] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [6] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [7] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [8] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    Statistical analysis title
    		 ADAS-ADL CFB: Verubecestat 12 mg vs. Placebo
    Comparison groups
    Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] v Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Number of subjects included in analysis
    1263
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4925
    Method
    		 Longitudinal ANCOVA
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    0.5
    Confidence interval
         level
    		 97.51%
         sides
    2-sided
         lower limit
    		 -1.1
         upper limit
    		 2.1
    Statistical analysis title
    		 ADAS-Cog CFB: Verubecestat 40 mg vs. Placebo
    Comparison groups
    Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] v Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Number of subjects included in analysis
    1258
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3221
    Method
    		 Longitudinal ANCOVA
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    0.7
    Confidence interval
         level
    		 97.51%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 2.3

    Primary: [Part II (Extension Study)] Change from Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score

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    End point title
    		 [Part II (Extension Study)] Change from Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score [9]
    End point description
    Mean CFB at week 104 was assessed for ADAS-Cog score. ADAS-Cog measures cognition by 11 metrics impaired in AD: speech; speech comprehension; word finding; word recall; object/finger naming; orientation; obeying commands; ideational praxis; constructional praxis; word recognition; and remembering instruction. For each metric, scores range from 0 (no impairment) to (depending on metric) either 5 (8 metrics), 8, 10, or 12 (1 metric each); higher scores indicate more severe impairment. Individual scores sum to a total ADAS-Cog score (range: 0-70); higher scores indicate greater cognitive impairment and AD severity. Further, increases in AD severity are reflected by increases in ADAS-Cog score. Analysis population: all randomized participants continuing to Part II, with a baseline (from Part I) and ≥1 within-analysis-window, post-dose ADAS-Cog observation (FAS population), having an ADAS-Cog observation at week 104.
    End point type
    Primary
    End point timeframe
    Baseline and week 104
    Notes
    [9] - 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: Given the negative results for the coprimary endpoints (base study), the analyses in the extension were not conducted.
    End point values
    		 Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Number of subjects analysed
    207 [10]
    208 [11]
    0 [12]
    216 [13]
    Units: Score on a Scale
        arithmetic mean (standard deviation)
    10.1 ( 9.9 )
    8.5 ( 9.5 )
    ( )
    9.6 ( 9.5 )
    Notes
    [10] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [11] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [12] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [13] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    No statistical analyses for this end point

    Primary: [Part II (Extension Study)] Change from Baseline in Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score

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    End point title
    		 [Part II (Extension Study)] Change from Baseline in Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score [14]
    End point description
    Mean CFB at week 104 was assessed for the ADCS-ADL score. The ADCS-ADL score measures the performance of activities of daily living, calculated from a 24-question survey. For each of the 24 questions, scores range from 0 (no independence) to (depending on the question) either 2 (1 question), 3 (17 questions), 4 (5 questions), or 5 (1 question), with higher scores indicating greater independence in activity performance. Scores from individual questions are summed into a total ADCS-ADL score, with total scores ranging from 0 to 78. 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: all randomized participants continuing to Part II, with a baseline (from Part I) and ≥1 within-analysis-window, post-dose ADAS-Cog observation (FAS population), having an ADAS-Cog observation at week 104.
    End point type
    Primary
    End point timeframe
    Baseline and week 104
    Notes
    [14] - 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: Given the negative results for the coprimary endpoints (base study), the analyses in the extension were not conducted.
    End point values
    		 Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Number of subjects analysed
    207 [15]
    209 [16]
    0 [17]
    216 [18]
    Units: Score on a Scale
        arithmetic mean (standard deviation)
    -10.7 ( 13.7 )
    -9.2 ( 12.7 )
    ( )
    -9.3 ( 12.0 )
    Notes
    [15] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [16] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [17] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [18] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    No statistical analyses for this end point

    Primary: [Part I (Base Study)] Number of Participants Who Experienced an Adverse Event

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    End point title
    		 [Part I (Base Study)] Number of Participants Who Experienced an Adverse Event [19]
    End point description
    The number of participants experiencing an adverse event (AE) in Part I 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 I receiving ≥1 dose of trial treatment.
    End point type
    Primary
    End point timeframe
    Up to week 80 (up to 2 weeks following cessation of study treatment in Part I)
    Notes
    [19] - 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: Per protocol, primary statistical analyses were not planned for this endpoint.
    End point values
    		 Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Number of subjects analysed
    702
    700
    103
    705
    Units: Participants
    630
    646
    90
    579
    No statistical analyses for this end point

    Primary: [Part II (Extension Study)] Number of Participants Who Experienced an Adverse Event

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    End point title
    		 [Part II (Extension Study)] Number of Participants Who Experienced an Adverse Event [20]
    End point description
    The number of participants experiencing an adverse event (AE) in Part II 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 II, receiving ≥1 dose of trial treatment in Part II. For included participants, the data reflect AEs occurring in Part II only.
    End point type
    Primary
    End point timeframe
    From week 78 (end of treatment in Part I) up to week 262 of Part II
    Notes
    [20] - 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: Per protocol, primary statistical analyses were not planned for this endpoint.
    End point values
    		 Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Number of subjects analysed
    379
    365
    61
    394
    Units: Participants
    240
    230
    51
    264
    No statistical analyses for this end point

    Primary: [Part I (Base Study)] Number of Participants who Discontinued from Study Drug due to an Adverse Event

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    End point title
    		 [Part I (Base Study)] Number of Participants who Discontinued from Study Drug due to an Adverse Event [21]
    End point description
    The number of participants discontinuing from study drug due to an AE in Part I 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 I receiving ≥1 dose of trial treatment.
    End point type
    Primary
    End point timeframe
    Up to week 78
    Notes
    [21] - 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: Per protocol, primary statistical analyses were not planned for this endpoint.
    End point values
    		 Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Number of subjects analysed
    702
    700
    103
    705
    Units: Participants
    57
    64
    12
    42
    No statistical analyses for this end point

    Primary: [Part II (Extension Study)] Number of Participants who Discontinued from Study Drug due to an Adverse Event

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    End point title
    		 [Part II (Extension Study)] Number of Participants who Discontinued from Study Drug due to an Adverse Event [22]
    End point description
    The number of participants discontinuing from study drug due to an AE in Part II 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 II, receiving ≥1 dose of trial treatment in Part II. For included participants, the data reflect treatment discontinuations occurring in Part II only.
    End point type
    Primary
    End point timeframe
    From week 78 (end of treatment in Part I) up to week 260 of Part II
    Notes
    [22] - 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: Per protocol, primary statistical analyses were not planned for this endpoint.
    End point values
    		 Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Number of subjects analysed
    379
    365
    61
    394
    Units: Participants
    10
    9
    6
    29
    No statistical analyses for this end point

    Secondary: [Part I (Base Study)] Change from Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score

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    End point title
    		 [Part I (Base Study)] Change from Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score
    End point description
    Least squares mean CFB at week 78 was assessed for CDR-SB score. CDR-SB score is a clinical rating of global cognitive function, comprised of 6 domains including: 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). Scores from each individual domain are summed to the total CDR-SB score, with total scores ranging from 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: all randomized participants (Part I) with a baseline and ≥1 within-analysis-window, post-dose observation for CDR-SB (FAS population).
    End point type
    Secondary
    End point timeframe
    Baseline and week 78
    End point values
    		 Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Number of subjects analysed
    611 [23]
    600 [24]
    0 [25]
    623 [26]
    Units: Score on a Scale
        least squares mean (confidence interval 95%)
    2.1 (1.8 to 2.3)
    2.1 (1.9 to 2.4)
    ( to )
    2.1 (1.9 to 2.3)
    Notes
    [23] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [24] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [25] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [26] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    Statistical analysis title
    		 CDR-SB CFB: Verubecestat 12 mg vs. Placebo
    Comparison groups
    Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] v Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Number of subjects included in analysis
    1234
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.8426
    Method
    		 Longitudinal ANCOVA
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    0
    Confidence interval
         level
    		 97.51%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 0.3
    Statistical analysis title
    		 CDR-SB CFB: Verubecestat 40 mg vs. Placebo
    Comparison groups
    Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] v Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Number of subjects included in analysis
    1223
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.8264
    Method
    		 Longitudinal ANCOVA
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    0
    Confidence interval
         level
    		 97.51%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.4

    Secondary: [Part I (Base Study)] Percent Change from Baseline in Total Hippocampal Volume (THV)

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    End point title
    		 [Part I (Base Study)] Percent Change from Baseline in Total Hippocampal Volume (THV)
    End point description
    Least squares mean percent CFB at week 78 was calculated for Total Hippocampal Volume (THV) as measured by volumetric magnetic resonance imaging (vMRI). Longitudinal analysis of within-participant THV is computed using a change analysis algorithm using tensor-based morphometry. This technique produces one measure of volume change calculated from the registration of serial vMRI scans at the follow-up time point relative to baseline. Negative percent changes from baseline indicate decreases in THV (i.e. increased hippocampal atrophy). Analysis population: all randomized participants with a baseline and ≥1 within-analysis-window, post-dose observation for THV (FAS population).
    End point type
    Secondary
    End point timeframe
    Baseline and week 78
    End point values
    		 Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Number of subjects analysed
    308 [27]
    281 [28]
    0 [29]
    308 [30]
    Units: Percent Change
        least squares mean (confidence interval 95%)
    -5.6 (-5.9 to -5.4)
    -5.7 (-5.9 to -5.4)
    ( to )
    -5.0 (-5.2 to -4.7)
    Notes
    [27] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [28] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [29] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [30] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    Statistical analysis title
    		 THV CFB: Verubecestat 12 mg vs. Placebo
    Comparison groups
    Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] v Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Number of subjects included in analysis
    616
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0005
    Method
    		 Longitudinal ANCOVA
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -0.6
    Confidence interval
         level
    		 97.51%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 -0.2
    Statistical analysis title
    		 THV CFB: Verubecestat 40 mg vs. Placebo
    Comparison groups
    Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] v Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Number of subjects included in analysis
    589
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0002
    Method
    		 Longitudinal ANCOVA
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -0.7
    Confidence interval
         level
    		 97.51%
         sides
    2-sided
         lower limit
    		 -1.1
         upper limit
    		 -0.3

    Secondary: [Part I (Base Study)] Fold Change from Baseline in Cerebrospinal Fluid (CSF) Total Tau

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    End point title
    		 [Part I (Base Study)] Fold Change from Baseline in Cerebrospinal Fluid (CSF) Total Tau
    End point description
    Least squares mean fold CFB at week 78 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 I, with testing occurring only at select trial sites. Least squares mean fold change from baseline >1 indicates increased Total Tau concentration in the CSF. Analysis population: all randomized participants with a baseline and ≥1 within-analysis-window, post-dose observation for CSF Total Tau (FAS population).
    End point type
    Secondary
    End point timeframe
    Baseline and week 78
    End point values
    		 Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Number of subjects analysed
    32 [31]
    46 [32]
    0 [33]
    33 [34]
    Units: Fold Change
        least squares mean (confidence interval 95%)
    1.02 (0.96 to 1.08)
    1.04 (0.99 to 1.09)
    ( to )
    1.07 (1.01 to 1.13)
    Notes
    [31] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [32] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [33] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [34] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    Statistical analysis title
    		 Total Tau CFB: Verubecestat 12 mg vs. Placebo
    Comparison groups
    Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] v Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2138
    Method
    		 Longitudinal ANCOVA
    Parameter type
    		 Ratio of Fold Change from Baseline
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 1.04
    Statistical analysis title
    		 Total Tau CFB: Verubecestat 40 mg vs. Placebo
    Comparison groups
    Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] v Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.433
    Method
    		 Longitudinal ANCOVA
    Parameter type
    		 Ratio of Fold Change from Baseline
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 1.05

    Secondary: [Part I (Base Study)] Change from Baseline in Cortical Amyloid Load assessed by [18F]Flutemetamol PET Standard Uptake Value Ratio (SUVR)

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    End point title
    		 [Part I (Base Study)] Change from Baseline in Cortical Amyloid Load assessed by [18F]Flutemetamol PET Standard Uptake Value Ratio (SUVR)
    End point description
    Least squares mean CFB at week 78 was calculated for SUVR, a measure of brain cortical amyloid load. Per protocol, SUVR was analyzed as part of a substudy in Part I, with testing occurring only at select trial sites. Participants receive the PET tracer [18F]Flutemetamol (IV) and, after 90 minutes, receive 4 PET scans (5 minutes each in duration). Using these PET scan images, brain ROIs (frontal, temporal, and parietal lobes; anterior and posterior cingulate and precuneus) are used to calculate regional SUVRs, defined as the relative ratio of pixel intensities at a ROI compared to RR (subcortical white matter). Regional SUVRs are averaged to compute a composite cortical SUVR for each participant. Higher composite cortical SUVR values indicate increased amyloid load, with negative changes indicating decreases in brain amyloid load. Analysis population: all randomized participants with a baseline and ≥1 within-analysis-window, post-dose SUVR observation (FAS population).
    End point type
    Secondary
    End point timeframe
    Baseline and week 78
    End point values
    		 Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Number of subjects analysed
    20 [35]
    10 [36]
    0 [37]
    14 [38]
    Units: SUVR
        least squares mean (confidence interval 95%)
    -0.02 (-0.04 to -0.01)
    -0.04 (-0.06 to -0.03)
    ( to )
    0.00 (-0.01 to 0.01)
    Notes
    [35] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [36] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [37] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [38] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    Statistical analysis title
    		 SUVR CFB: Verubecestat 12 mg vs. Placebo
    Comparison groups
    Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] v Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0066
    Method
    		 Longitudinal ANCOVA
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0
    Statistical analysis title
    		 SUVR CFB: Verubecestat 40 mg vs. Placebo
    Comparison groups
    Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] v Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Longitudinal ANCOVA
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 -0.02

    Secondary: [Part I (Base Study)] Percentage of Participants Achieving Responder Status

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    End point title
    		 [Part I (Base Study)] Percentage of Participants Achieving Responder Status
    End point description
    The percentage of participants achieving responder status at week 78 was assessed. To determine which participants were considered responders, a linear regression was conducted at the participant level, yielding an estimated 78-week rate of change (i.e., a slope) for each participant with respect to ADAS-Cog and ADCS-ADL. To be declared a responder, a participant must have: 1) ADAS-Cog and ADCS-ADL observations at baseline and 78 weeks of treatment; 2) an ADAS-Cog slope > 4.0 over 78 weeks, and 3) an ADCS-ADL slope > -6.3 over 78 weeks. A participant failing to meet any of these criteria was designated as a non-responder at Week 78. Analysis population: All randomized participants in Part I receiving ≥1 dose of trial treatment.
    End point type
    Secondary
    End point timeframe
    Week 78
    End point values
    		 Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Number of subjects analysed
    652 [39]
    652 [40]
    0 [41]
    653 [42]
    Units: Percentage of Participants
        number (not applicable)
    20.1
    19.6
    19.3
    Notes
    [39] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [40] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [41] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [42] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    No statistical analyses for this end point

    Secondary: [Part I (Base Study)] Change from Baseline in Neuropsychiatric Inventory (NPI) Score

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    End point title
    		 [Part I (Base Study)] Change from Baseline in Neuropsychiatric Inventory (NPI) Score
    End point description
    Least squares mean CFB at week 78 was assessed for NPI score. NPI is a clinical assessment of psychiatric status covering 12 domains: delusion; hallucination; agitation/aggression; depression/dysphoria; anxiety; elation/euphoria; apathy/indifference; disinhibition; irritability/lability; aberrant motor behavior; sleep/nighttime behavior; and appetite/eating disorders. Based on interview of participant’s caregiver, domains are scored for symptom frequency [range: 1 (occasional) to 4 (very frequent)] and severity [range: 1 (mild) to 3 (severe)]. Frequency and severity scores are multiplied (frequency x severity) to compute domain scores [range: 0 (no symptoms) to 12] The 12 domain scores sum to total NPI score [range: 0-144]. Higher scores reflect more severe psychiatric impairment, with increased impairment reflected by increased NPI score. Analysis population: all randomized participants with a baseline and ≥1 within-analysis-window, post-dose NPI observation (FAS population).
    End point type
    Secondary
    End point timeframe
    Baseline and week 78
    End point values
    		 Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Number of subjects analysed
    632 [43]
    631 [44]
    0 [45]
    639 [46]
    Units: Score on a Scale
        least squares mean (confidence interval 95%)
    3.4 (2.5 to 4.4)
    3.8 (2.8 to 4.8)
    ( to )
    2.7 (1.7 to 3.7)
    Notes
    [43] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [44] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [45] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [46] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    Statistical analysis title
    		 NPI CFB: Verubecestat 12 mg vs. Placebo
    Comparison groups
    Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] v Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Number of subjects included in analysis
    1271
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2949
    Method
    		 Longitudinal ANCOVA
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 2.1
    Statistical analysis title
    		 NPI CFB: Verubecestat 40 mg vs. Placebo
    Comparison groups
    Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] v Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Number of subjects included in analysis
    1270
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1372
    Method
    		 Longitudinal ANCOVA
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 2.6

    Secondary: [Part I (Base Study)] Change from Baseline in Mini-Mental State Examination (MMSE) Score

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    End point title
    		 [Part I (Base Study)] Change from Baseline in Mini-Mental State Examination (MMSE) Score
    End point description
    Least squares mean CFB at week 78 was assessed for MMSE score. MMSE is a cognitive assessment of 5 domains: orientation; attention; memory; language; and constructional praxis. These domains are assessed over the course of 11 total questions related to the participant. Participants are scored based on the number of correct responses; depending on the question, potential scores range from 0 (no correct response) to either 1 (4 questions), 2 (1 question), 3 (3 questions), or 5 (3 questions). Scores from each question are summed to the total MMSE score, with total scores ranging from 0-30. Higher scores indicate better cognitive performance. Further, deterioration in cognitive performance would be reflected by decreases in MMSE score. Analysis population: all randomized participants with a baseline and ≥1 within-analysis-window, post-dose MMSE observation (FAS population).
    End point type
    Secondary
    End point timeframe
    Baseline and week 78
    End point values
    		 Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Number of subjects analysed
    610 [47]
    600 [48]
    0 [49]
    628 [50]
    Units: Score on a Scale
        least squares mean (confidence interval 95%)
    -3.9 (-4.3 to -3.6)
    -3.6 (-4.0 to -3.3)
    ( to )
    -4.1 (-4.5 to -3.8)
    Notes
    [47] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [48] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [49] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    [50] - Per protocol, analysis excludes 200 participants enrolled before IA (all arms) and all in Arm C.
    Statistical analysis title
    		 MMSE CFB: Verubecestat 12 mg vs. Placebo
    Comparison groups
    Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] v Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Number of subjects included in analysis
    1238
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4721
    Method
    		 Longitudinal ANCOVA
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.7
    Statistical analysis title
    		 MMSE CFB: Verubecestat 40 mg vs. Placebo
    Comparison groups
    Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] v Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
    Number of subjects included in analysis
    1228
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0599
    Method
    		 Longitudinal ANCOVA
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 1

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    [Part I]: Up to week 80 of Part I (up to 2 weeks following cessation of study treatment in Part I); [Part II]: From week 78 (end of treatment in Part I) up to week 262 of Study Part II
    Adverse event reporting additional description
    [Part I] Includes all randomized participants in Study Part I (Base Study) receiving ≥1 dose of trial treatment. [Part II] Includes all randomized participants continuing to Study Part II (Extension Study) receiving ≥1 dose of trial treatment in Part II. For Part II-specific arms, only the AEs occurring during study Part II are reported.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 20.0
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Arm A. Verubecestat 12 mg [Part I]
    Reporting group description
    		 [Part I] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study).

    Reporting group title
    Arm B. Verubecestat 40 mg [Part I]
    Reporting group description
    		 [Part I] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study).

    Reporting group title
    Arm C. Verubecestat 60mg/40mg [Part I]
    Reporting group description
    		 [Part I] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks).

    Reporting group title
    Arm D. Placebo [Part I]
    Reporting group description
    		 [Part I] Placebo once daily for 78 weeks in Study Part I (Base Study).

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

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

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

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

    Serious adverse events
    		 Arm A. Verubecestat 12 mg [Part I] Arm B. Verubecestat 40 mg [Part I] Arm C. Verubecestat 60mg/40mg [Part I] Arm D. Placebo [Part I] Arm A. Verubecestat 12 mg [Part II] Arm B. Verubecestat 40 mg [Part II] Arm C. Verubecestat 40 mg [Part II] Arm D. Verubecestat 40 mg [Part II]
    Total subjects affected by serious adverse events
         subjects affected / exposed
    134 / 702 (19.09%)
    162 / 700 (23.14%)
    24 / 103 (23.30%)
    121 / 705 (17.16%)
    57 / 379 (15.04%)
    56 / 365 (15.34%)
    22 / 61 (36.07%)
    69 / 394 (17.51%)
         number of deaths (all causes)
    9
    13
    3
    6
    6
    4
    4
    8
         number of deaths resulting from adverse events
    1
    1
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Adenocarcinoma pancreas
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Atypical fibroxanthoma
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    1 / 103 (0.97%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    9 / 702 (1.28%)
    9 / 700 (1.29%)
    1 / 103 (0.97%)
    15 / 705 (2.13%)
    2 / 379 (0.53%)
    3 / 365 (0.82%)
    1 / 61 (1.64%)
    2 / 394 (0.51%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 14
    0 / 1
    0 / 17
    0 / 3
    0 / 3
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma stage II
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Borderline mucinous tumour of ovary
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    2 / 702 (0.28%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    3 / 705 (0.43%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 4
    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
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    Breast cancer recurrent
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Cholangiocarcinoma
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 1
    Colon adenoma
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    Extradural neoplasm
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    1 / 702 (0.14%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    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
    0 / 1
    0 / 0
    Glioma
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Hepatic cancer
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 1
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Kaposi's sarcoma
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Keratoacanthoma
         subjects affected / exposed
    1 / 702 (0.14%)
    3 / 700 (0.43%)
    0 / 103 (0.00%)
    3 / 705 (0.43%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    1 / 3
    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
    0 / 0
    0 / 0
    Lentigo maligna
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    1 / 103 (0.97%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 702 (0.14%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    3 / 705 (0.43%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 3
    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
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm of renal pelvis
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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 / 1
    0 / 0
    0 / 0
    0 / 0
    Metastatic malignant melanoma
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Metastatic squamous cell carcinoma
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myelofibrosis
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    Neuroendocrine tumour
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Oesophageal adenocarcinoma
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 702 (0.14%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    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
    0 / 0
    0 / 0
    Prostate cancer metastatic
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostatic adenoma
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 1
    Sarcoma uterus
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin squamous cell carcinoma metastatic
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestine carcinoma
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    5 / 702 (0.71%)
    3 / 700 (0.43%)
    2 / 103 (1.94%)
    3 / 705 (0.43%)
    5 / 379 (1.32%)
    1 / 365 (0.27%)
    2 / 61 (3.28%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 4
    0 / 2
    0 / 3
    0 / 5
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of head and neck
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    1 / 103 (0.97%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    3 / 702 (0.43%)
    2 / 700 (0.29%)
    1 / 103 (0.97%)
    4 / 705 (0.57%)
    1 / 379 (0.26%)
    1 / 365 (0.27%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 1
    0 / 4
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    1 / 103 (0.97%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    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
    0 / 0
    0 / 0
    Uterine cancer
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    1 / 702 (0.14%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    1 / 103 (0.97%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 702 (0.14%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    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
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 702 (0.00%)
    2 / 700 (0.29%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    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
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 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
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    2 / 705 (0.28%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    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
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 702 (0.14%)
    4 / 700 (0.57%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    1 / 379 (0.26%)
    2 / 365 (0.55%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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 / 1
    0 / 0
    0 / 0
    0 / 0
    Drowning
         subjects affected / exposed
    1 / 702 (0.14%)
    2 / 700 (0.29%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Euthanasia
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 1
    Gait disturbance
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    1 / 103 (0.97%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incarcerated hernia
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Mass
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    2 / 705 (0.28%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    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
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 702 (0.28%)
    0 / 700 (0.00%)
    1 / 103 (0.97%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    3 / 394 (0.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    1 / 103 (0.97%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 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
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    3 / 702 (0.43%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    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
    0 / 0
    0 / 0
    Breast pain
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Cystocele
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Prostatomegaly
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    Rectocele
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Noninfective bronchitis
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Pharyngeal pouch
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    1 / 61 (1.64%)
    2 / 394 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 702 (0.14%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    1 / 103 (0.97%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 1
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    1 / 702 (0.14%)
    2 / 700 (0.29%)
    0 / 103 (0.00%)
    2 / 705 (0.28%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    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
    0 / 0
    0 / 0
    Aggression
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    2 / 705 (0.28%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    2 / 394 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    4 / 702 (0.57%)
    4 / 700 (0.57%)
    1 / 103 (0.97%)
    0 / 705 (0.00%)
    5 / 379 (1.32%)
    0 / 365 (0.00%)
    1 / 61 (1.64%)
    2 / 394 (0.51%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 4
    0 / 1
    0 / 0
    0 / 6
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    2 / 702 (0.28%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    3 / 705 (0.43%)
    2 / 379 (0.53%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 3
    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
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 702 (0.00%)
    4 / 700 (0.57%)
    1 / 103 (0.97%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
    1 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Delusion
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    2 / 379 (0.53%)
    1 / 365 (0.27%)
    1 / 61 (1.64%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    1 / 2
    0 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Delusional disorder, persecutory type
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Delusional disorder, unspecified type
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Emotional distress
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    1 / 61 (1.64%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hallucination, auditory
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Hallucination, visual
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 702 (0.14%)
    1 / 700 (0.14%)
    1 / 103 (0.97%)
    1 / 705 (0.14%)
    3 / 379 (0.79%)
    1 / 365 (0.27%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    1 / 1
    0 / 1
    0 / 3
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuropsychiatric symptoms
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    3 / 394 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paranoia
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Psychogenic movement disorder
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    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
    0 / 0
    0 / 0
    Restlessness
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Sleep disorder
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Suicidal behaviour
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    2 / 702 (0.28%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    1 / 103 (0.97%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Ammonia increased
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    1 / 103 (0.97%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 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
    0 / 0
    0 / 0
    Blood glucose decreased
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Blood glucose fluctuation
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 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
    0 / 0
    0 / 0
    Heart rate irregular
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Lipoprotein (a) increased
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Prostatic specific antigen increased
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Anastomotic leak
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 702 (0.14%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    2 / 394 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carbon monoxide poisoning
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Comminuted fracture
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    3 / 702 (0.43%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    2 / 365 (0.55%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    1 / 103 (0.97%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 702 (0.14%)
    1 / 700 (0.14%)
    1 / 103 (0.97%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    2 / 365 (0.55%)
    0 / 61 (0.00%)
    2 / 394 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Fracture displacement
         subjects affected / exposed
    0 / 702 (0.00%)
    2 / 700 (0.29%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    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
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    1 / 103 (0.97%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 702 (0.00%)
    5 / 700 (0.71%)
    1 / 103 (0.97%)
    1 / 705 (0.14%)
    2 / 379 (0.53%)
    2 / 365 (0.55%)
    2 / 61 (3.28%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
    0 / 1
    0 / 1
    0 / 2
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    2 / 702 (0.28%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle strain
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    1 / 103 (0.97%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Prescribed overdose
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 702 (0.14%)
    2 / 700 (0.29%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    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
    0 / 0
    0 / 0
    Skin abrasion
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 702 (0.14%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    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
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    2 / 702 (0.28%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    2 / 379 (0.53%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Traumatic fracture
         subjects affected / exposed
    0 / 702 (0.00%)
    2 / 700 (0.29%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Vaccination complication
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    2 / 705 (0.28%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    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 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 702 (0.43%)
    2 / 700 (0.29%)
    3 / 103 (2.91%)
    1 / 705 (0.14%)
    1 / 379 (0.26%)
    2 / 365 (0.55%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    1 / 3
    0 / 1
    0 / 1
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 702 (0.14%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    2 / 365 (0.55%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 702 (0.00%)
    2 / 700 (0.29%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    2 / 394 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    1 / 702 (0.14%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    1 / 379 (0.26%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    1 / 702 (0.14%)
    2 / 700 (0.29%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    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
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    1 / 702 (0.14%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    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
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    2 / 365 (0.55%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Torsade de pointes
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Conduction disorder
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    1 / 702 (0.14%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carotid artery occlusion
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Cerebellar infarction
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 702 (0.14%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 702 (0.28%)
    6 / 700 (0.86%)
    0 / 103 (0.00%)
    4 / 705 (0.57%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
    0 / 0
    0 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Dementia Alzheimer's type
         subjects affected / exposed
    1 / 702 (0.14%)
    1 / 700 (0.14%)
    1 / 103 (0.97%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    5 / 394 (1.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 3
    Depressed level of consciousness
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Diplegia
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    2 / 702 (0.28%)
    2 / 700 (0.29%)
    0 / 103 (0.00%)
    3 / 705 (0.43%)
    0 / 379 (0.00%)
    2 / 365 (0.55%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
    0 / 0
    0 / 4
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 702 (0.14%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 702 (0.00%)
    2 / 700 (0.29%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    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
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 702 (0.00%)
    2 / 700 (0.29%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbosacral radiculopathy
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Memory impairment
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 702 (0.14%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    3 / 379 (0.79%)
    0 / 365 (0.00%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychomotor skills impaired
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    2 / 365 (0.55%)
    1 / 61 (1.64%)
    3 / 394 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    2 / 705 (0.28%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    7 / 702 (1.00%)
    13 / 700 (1.86%)
    0 / 103 (0.00%)
    5 / 705 (0.71%)
    1 / 379 (0.26%)
    3 / 365 (0.82%)
    2 / 61 (3.28%)
    2 / 394 (0.51%)
         occurrences causally related to treatment / all
    1 / 7
    2 / 15
    0 / 0
    0 / 5
    0 / 1
    0 / 4
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    3 / 702 (0.43%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    1 / 61 (1.64%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    2 / 103 (1.94%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    2 / 365 (0.55%)
    2 / 61 (3.28%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic anaemia
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 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
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Meniere's disease
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Vertigo positional
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 702 (0.14%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    2 / 705 (0.28%)
    0 / 379 (0.00%)
    2 / 365 (0.55%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Corneal oedema
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Glaucoma
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Keratitis
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Macular oedema
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Trichiasis
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    2 / 394 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    2 / 702 (0.28%)
    0 / 700 (0.00%)
    1 / 103 (0.97%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    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
    0 / 0
    0 / 0
    Anal prolapse
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 702 (0.00%)
    2 / 700 (0.29%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    2 / 365 (0.55%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 702 (0.28%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    3 / 394 (0.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Diverticulum oesophageal
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    1 / 103 (0.97%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 702 (0.14%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 702 (0.00%)
    2 / 700 (0.29%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    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
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Incarcerated umbilical hernia
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 702 (0.14%)
    2 / 700 (0.29%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    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
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Large intestinal stenosis
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 702 (0.14%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Oesophageal spasm
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Retroperitoneal haematoma
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 702 (0.00%)
    2 / 700 (0.29%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    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
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    2 / 702 (0.28%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 702 (0.14%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    Hepatic cyst
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dermal cyst
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Erythema
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Petechiae
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    1 / 103 (0.97%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Rash macular
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    1 / 103 (0.97%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 702 (0.14%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    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
    0 / 0
    0 / 0
    Bladder spasm
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    1 / 103 (0.97%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Calculus bladder
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    End stage renal disease
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Incontinence
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    1 / 103 (0.97%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    2 / 702 (0.28%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Stress urinary incontinence
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    2 / 702 (0.28%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urethral disorder
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    1 / 61 (1.64%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Thyroid cyst
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    1 / 103 (0.97%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthropathy
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Chondrocalcinosis pyrophosphate
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fracture pain
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Gouty arthritis
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Muscle spasms
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 702 (0.14%)
    3 / 700 (0.43%)
    1 / 103 (0.97%)
    3 / 705 (0.43%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    2 / 61 (3.28%)
    2 / 394 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
    0 / 3
    0 / 1
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Tendonitis
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 702 (0.14%)
    1 / 700 (0.14%)
    1 / 103 (0.97%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    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
    0 / 0
    0 / 0
    Bronchitis viral
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 702 (0.00%)
    2 / 700 (0.29%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    2 / 379 (0.53%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    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
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    1 / 103 (0.97%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Gallbladder empyema
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 702 (0.00%)
    2 / 700 (0.29%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Haematoma infection
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Helicobacter gastritis
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Meningoencephalitis herpetic
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Neurosyphilis
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Otitis media acute
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    2 / 702 (0.28%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 702 (0.71%)
    6 / 700 (0.86%)
    3 / 103 (2.91%)
    5 / 705 (0.71%)
    3 / 379 (0.79%)
    5 / 365 (1.37%)
    3 / 61 (4.92%)
    4 / 394 (1.02%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
    0 / 3
    0 / 5
    0 / 3
    0 / 5
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retroperitoneal infection
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    1 / 103 (0.97%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Tuberculous pleurisy
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 702 (0.14%)
    1 / 700 (0.14%)
    1 / 103 (0.97%)
    2 / 705 (0.28%)
    2 / 379 (0.53%)
    1 / 365 (0.27%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 2
    1 / 2
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    3 / 702 (0.43%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    2 / 705 (0.28%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    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
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    3 / 365 (0.82%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    1 / 702 (0.14%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Hypercalcaemia
         subjects affected / exposed
    1 / 702 (0.14%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 702 (0.14%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Hypokalaemic syndrome
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    1 / 379 (0.26%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 702 (0.00%)
    3 / 700 (0.43%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    2 / 365 (0.55%)
    0 / 61 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    1 / 702 (0.14%)
    2 / 700 (0.29%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    1 / 61 (1.64%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Starvation
         subjects affected / exposed
    0 / 702 (0.00%)
    0 / 700 (0.00%)
    0 / 103 (0.00%)
    1 / 705 (0.14%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 702 (0.00%)
    1 / 700 (0.14%)
    0 / 103 (0.00%)
    0 / 705 (0.00%)
    0 / 379 (0.00%)
    0 / 365 (0.00%)
    0 / 61 (0.00%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A. Verubecestat 12 mg [Part I] Arm B. Verubecestat 40 mg [Part I] Arm C. Verubecestat 60mg/40mg [Part I] Arm D. Placebo [Part I] Arm A. Verubecestat 12 mg [Part II] Arm B. Verubecestat 40 mg [Part II] Arm C. Verubecestat 40 mg [Part II] Arm D. Verubecestat 40 mg [Part II]
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    408 / 702 (58.12%)
    440 / 700 (62.86%)
    66 / 103 (64.08%)
    337 / 705 (47.80%)
    135 / 379 (35.62%)
    102 / 365 (27.95%)
    37 / 61 (60.66%)
    144 / 394 (36.55%)
    Investigations
    Weight decreased
         subjects affected / exposed
    47 / 702 (6.70%)
    44 / 700 (6.29%)
    7 / 103 (6.80%)
    21 / 705 (2.98%)
    10 / 379 (2.64%)
    8 / 365 (2.19%)
    2 / 61 (3.28%)
    13 / 394 (3.30%)
         occurrences all number
    48
    44
    7
    22
    10
    8
    2
    13
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    25 / 702 (3.56%)
    30 / 700 (4.29%)
    7 / 103 (6.80%)
    21 / 705 (2.98%)
    14 / 379 (3.69%)
    8 / 365 (2.19%)
    2 / 61 (3.28%)
    5 / 394 (1.27%)
         occurrences all number
    31
    33
    9
    27
    21
    8
    2
    5
    Fall
         subjects affected / exposed
    56 / 702 (7.98%)
    59 / 700 (8.43%)
    8 / 103 (7.77%)
    39 / 705 (5.53%)
    31 / 379 (8.18%)
    19 / 365 (5.21%)
    7 / 61 (11.48%)
    22 / 394 (5.58%)
         occurrences all number
    84
    75
    8
    51
    37
    25
    14
    27
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    33 / 702 (4.70%)
    56 / 700 (8.00%)
    12 / 103 (11.65%)
    32 / 705 (4.54%)
    9 / 379 (2.37%)
    3 / 365 (0.82%)
    1 / 61 (1.64%)
    8 / 394 (2.03%)
         occurrences all number
    34
    70
    15
    35
    9
    3
    1
    10
    Headache
         subjects affected / exposed
    42 / 702 (5.98%)
    52 / 700 (7.43%)
    5 / 103 (4.85%)
    41 / 705 (5.82%)
    4 / 379 (1.06%)
    5 / 365 (1.37%)
    2 / 61 (3.28%)
    6 / 394 (1.52%)
         occurrences all number
    48
    59
    7
    58
    6
    5
    2
    9
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 702 (1.14%)
    11 / 700 (1.57%)
    1 / 103 (0.97%)
    6 / 705 (0.85%)
    5 / 379 (1.32%)
    1 / 365 (0.27%)
    4 / 61 (6.56%)
    5 / 394 (1.27%)
         occurrences all number
    8
    11
    1
    6
    5
    1
    5
    5
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    30 / 702 (4.27%)
    27 / 700 (3.86%)
    9 / 103 (8.74%)
    20 / 705 (2.84%)
    13 / 379 (3.43%)
    3 / 365 (0.82%)
    4 / 61 (6.56%)
    10 / 394 (2.54%)
         occurrences all number
    32
    29
    9
    20
    14
    3
    5
    10
    Diarrhoea
         subjects affected / exposed
    56 / 702 (7.98%)
    60 / 700 (8.57%)
    4 / 103 (3.88%)
    42 / 705 (5.96%)
    8 / 379 (2.11%)
    8 / 365 (2.19%)
    4 / 61 (6.56%)
    9 / 394 (2.28%)
         occurrences all number
    65
    70
    9
    45
    9
    8
    5
    10
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    32 / 702 (4.56%)
    26 / 700 (3.71%)
    6 / 103 (5.83%)
    22 / 705 (3.12%)
    7 / 379 (1.85%)
    9 / 365 (2.47%)
    1 / 61 (1.64%)
    13 / 394 (3.30%)
         occurrences all number
    38
    27
    6
    23
    9
    10
    1
    14
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    33 / 702 (4.70%)
    26 / 700 (3.71%)
    6 / 103 (5.83%)
    25 / 705 (3.55%)
    7 / 379 (1.85%)
    3 / 365 (0.82%)
    1 / 61 (1.64%)
    8 / 394 (2.03%)
         occurrences all number
    38
    31
    6
    31
    7
    3
    1
    8
    Psychiatric disorders
    Abnormal dreams
         subjects affected / exposed
    11 / 702 (1.57%)
    15 / 700 (2.14%)
    6 / 103 (5.83%)
    6 / 705 (0.85%)
    1 / 379 (0.26%)
    1 / 365 (0.27%)
    0 / 61 (0.00%)
    3 / 394 (0.76%)
         occurrences all number
    11
    16
    6
    6
    2
    1
    0
    3
    Agitation
         subjects affected / exposed
    31 / 702 (4.42%)
    16 / 700 (2.29%)
    5 / 103 (4.85%)
    19 / 705 (2.70%)
    8 / 379 (2.11%)
    5 / 365 (1.37%)
    5 / 61 (8.20%)
    10 / 394 (2.54%)
         occurrences all number
    32
    17
    7
    20
    8
    5
    6
    11
    Anxiety
         subjects affected / exposed
    40 / 702 (5.70%)
    47 / 700 (6.71%)
    8 / 103 (7.77%)
    27 / 705 (3.83%)
    6 / 379 (1.58%)
    6 / 365 (1.64%)
    6 / 61 (9.84%)
    8 / 394 (2.03%)
         occurrences all number
    41
    51
    10
    29
    6
    6
    6
    8
    Depression
         subjects affected / exposed
    47 / 702 (6.70%)
    46 / 700 (6.57%)
    9 / 103 (8.74%)
    38 / 705 (5.39%)
    5 / 379 (1.32%)
    6 / 365 (1.64%)
    5 / 61 (8.20%)
    8 / 394 (2.03%)
         occurrences all number
    52
    48
    9
    38
    5
    6
    5
    9
    Insomnia
         subjects affected / exposed
    41 / 702 (5.84%)
    33 / 700 (4.71%)
    6 / 103 (5.83%)
    21 / 705 (2.98%)
    12 / 379 (3.17%)
    8 / 365 (2.19%)
    2 / 61 (3.28%)
    10 / 394 (2.54%)
         occurrences all number
    42
    33
    6
    23
    12
    8
    2
    10
    Suicidal ideation
         subjects affected / exposed
    39 / 702 (5.56%)
    45 / 700 (6.43%)
    4 / 103 (3.88%)
    24 / 705 (3.40%)
    12 / 379 (3.17%)
    9 / 365 (2.47%)
    2 / 61 (3.28%)
    12 / 394 (3.05%)
         occurrences all number
    42
    55
    4
    26
    14
    9
    2
    13
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    36 / 702 (5.13%)
    26 / 700 (3.71%)
    4 / 103 (3.88%)
    21 / 705 (2.98%)
    8 / 379 (2.11%)
    7 / 365 (1.92%)
    5 / 61 (8.20%)
    3 / 394 (0.76%)
         occurrences all number
    41
    26
    5
    23
    11
    8
    5
    3
    Back pain
         subjects affected / exposed
    36 / 702 (5.13%)
    46 / 700 (6.57%)
    6 / 103 (5.83%)
    30 / 705 (4.26%)
    8 / 379 (2.11%)
    7 / 365 (1.92%)
    2 / 61 (3.28%)
    6 / 394 (1.52%)
         occurrences all number
    39
    49
    6
    34
    8
    7
    3
    6
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    24 / 702 (3.42%)
    10 / 700 (1.43%)
    6 / 103 (5.83%)
    19 / 705 (2.70%)
    9 / 379 (2.37%)
    5 / 365 (1.37%)
    2 / 61 (3.28%)
    4 / 394 (1.02%)
         occurrences all number
    28
    11
    7
    19
    12
    5
    2
    5
    Urinary tract infection
         subjects affected / exposed
    61 / 702 (8.69%)
    71 / 700 (10.14%)
    15 / 103 (14.56%)
    56 / 705 (7.94%)
    20 / 379 (5.28%)
    18 / 365 (4.93%)
    5 / 61 (8.20%)
    28 / 394 (7.11%)
         occurrences all number
    79
    93
    18
    68
    25
    21
    6
    34
    Viral upper respiratory tract infection
         subjects affected / exposed
    60 / 702 (8.55%)
    50 / 700 (7.14%)
    5 / 103 (4.85%)
    42 / 705 (5.96%)
    21 / 379 (5.54%)
    11 / 365 (3.01%)
    2 / 61 (3.28%)
    10 / 394 (2.54%)
         occurrences all number
    81
    60
    5
    49
    27
    12
    2
    11
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    19 / 702 (2.71%)
    30 / 700 (4.29%)
    6 / 103 (5.83%)
    16 / 705 (2.27%)
    4 / 379 (1.06%)
    0 / 365 (0.00%)
    1 / 61 (1.64%)
    10 / 394 (2.54%)
         occurrences all number
    20
    31
    7
    16
    4
    0
    1
    10

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 May 2012
    Amendment 01: The primary purpose of this amendment was to: 1) include ophthalmologic assessments to monitor for retinal effects and to provide long-term ocular safety data in the Safety and Main Cohorts; 2) exclude the first 200 participants enrolled from the primary efficacy analyses; and 3) clarify the IA process.
    20 Jun 2012
    Amendment 02: The primary purpose of this amendment was to add language whereby the external data monitoring committee (eDMC) may recommend reducing or dropping the requirements for MRI monitoring if indicated or increasing the frequency of MRI scans for the Main Cohort if a safety signal emerges in the Safety Cohort.
    24 Jun 2013
    Amendment 05: The primary purpose of this amendment was to add ophthalmologic assessments to monitor the iris and potential complications of iris pigment loss in the Safety and Main Cohorts.
    10 Oct 2013
    Amendment 07: The primary purpose of this amendment was to: 1) exclude the use of digoxin for all participants; 2) drop the 60 mg Verubecestat dose from the Main Cohort; 3) revise the primary analysis approach, analysis populations, and analytical model; and 4) update trial procedures, monitoring, and guidance.
    25 Mar 2014
    Amendment 08: The primary purpose of this amendment was to create and describe a long term, double-blind extension phase (i.e. Part II), outlining study objectives, procedures, and statistical analysis plan for Part II.
    19 Feb 2015
    Amendment 10: The primary purpose of this amendment was to: 1) discontinue iris and intraocular pressure monitoring; and 2) remove routine MRI safety monitoring in response to updated Food and Drug Administration (FDA) guidance.
    06 May 2015
    Amendment 13: The primary purpose of this amendment was to discontinue ophthalmic monitoring and remove opthamology-related exclusion criteria for new participants at the recommendation of the eDMC.
    05 Aug 2016
    Amendment 17: The primary purpose of this amendment was to: 1) modify criteria for futility interim analysis; 2) update the statistical analysis plan with respect to sensitivity analysis; and 3) reinstate the collection of plasma pharmacokinetic sampling.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    14 Feb 2017
    Trial was terminated early
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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