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    Clinical Trial Results:
    A Multicenter, Open-Label Extension Study to Evaluate the Long-Term Safety and Tolerability of Faricimab in Patients with Diabetic Macular Edema

    Summary
    EudraCT number
    2020-000402-29
    Trial protocol
    PT   CZ   DE   DK   HU   GB   SK   AT   PL   BG   IT  
    Global end of trial date
    11 Oct 2023

    Results information
    Results version number
    v1(current)
    This version publication date
    23 Oct 2024
    First version publication date
    23 Oct 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GR41987
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04432831
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche, Ltd.
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, 4058
    Public contact
    F. Hoffmann-La Roche, Ltd., F. Hoffmann-La Roche, Ltd., +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche, Ltd., F. Hoffmann-La Roche, Ltd., +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Oct 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Oct 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Oct 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the long term ocular and systemic safety and tolerability of faricimab administered intravitreally in patients with DME
    Protection of trial subjects
    This study was conducted in full conformance with the ICH E6 guideline for Good Clinical Practice (GCP) and the principles of the Declaration of Helsinki, or the applicable laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. An Informed Consent Form (ICF) was required to be signed and dated by the patient or the patient's legally authorized representative before his or her participation in the study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    05 Aug 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 76
    Country: Number of subjects enrolled
    Australia: 23
    Country: Number of subjects enrolled
    Austria: 8
    Country: Number of subjects enrolled
    Bulgaria: 18
    Country: Number of subjects enrolled
    Brazil: 45
    Country: Number of subjects enrolled
    Canada: 16
    Country: Number of subjects enrolled
    Czechia: 56
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    Hong Kong: 10
    Country: Number of subjects enrolled
    Hungary: 61
    Country: Number of subjects enrolled
    Israel: 33
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    Japan: 48
    Country: Number of subjects enrolled
    Korea, Republic of: 25
    Country: Number of subjects enrolled
    Mexico: 10
    Country: Number of subjects enrolled
    Peru: 12
    Country: Number of subjects enrolled
    Poland: 166
    Country: Number of subjects enrolled
    Portugal: 20
    Country: Number of subjects enrolled
    Russian Federation: 27
    Country: Number of subjects enrolled
    Singapore: 6
    Country: Number of subjects enrolled
    Slovakia: 26
    Country: Number of subjects enrolled
    Spain: 49
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    Thailand: 14
    Country: Number of subjects enrolled
    Türkiye: 15
    Country: Number of subjects enrolled
    Taiwan: 16
    Country: Number of subjects enrolled
    United Kingdom: 43
    Country: Number of subjects enrolled
    United States: 606
    Worldwide total number of subjects
    1474
    EEA total number of subjects
    448
    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)
    750
    From 65 to 84 years
    714
    85 years and over
    10

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 1479 patients were enrolled, but 5 participants in total were excluded from the analysis populations because of Good Clinical Practice (GCP) non-compliance at a single site.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Faricimab PTI (prior Faricimab Q8W)
    Arm description
    This analysis group includes participants who were previously randomized to Arm A (faricimab 6 mg Q8W) in one of the parent studies, GR40349 (NCT03622580) and GR40398 (NCT03622593), and then enrolled in this extension study to receive faricimab 6 mg by IVT injection according to the personalized treatment interval (PTI) dosing regimen.
    Arm type
    Experimental

    Investigational medicinal product name
    Faricimab
    Investigational medicinal product code
    RO6867461
    Other name
    VABYSMO®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Participants will receive 6 mg faricimab intravitreal injections according to a personalized treatment interval (PTI) dosing regimen.

    Arm title
    Faricimab PTI (prior Faricimab PTI)
    Arm description
    This analysis group includes participants who were previously randomized to Arm B (faricimab 6 mg PTI) in one of the parent studies, GR40349 (NCT03622580) and GR40398 (NCT03622593), and then enrolled in this extension study to receive faricimab 6 mg by IVT injection according to the personalized treatment interval (PTI) dosing regimen.
    Arm type
    Experimental

    Investigational medicinal product name
    Faricimab
    Investigational medicinal product code
    RO6867461
    Other name
    VABYSMO®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Participants will receive 6 mg faricimab intravitreal injections according to a personalized treatment interval (PTI) dosing regimen.

    Arm title
    Faricimab PTI (prior Aflibercept Q8W)
    Arm description
    This analysis group includes participants who were previously randomized to Arm C (aflibercept 2 mg Q8W) in one of the parent studies, GR40349 (NCT03622580) and GR40398 (NCT03622593), and then enrolled in this extension study to receive faricimab 6 mg by IVT injection according to the personalized treatment interval (PTI) dosing regimen.
    Arm type
    Experimental

    Investigational medicinal product name
    Faricimab
    Investigational medicinal product code
    RO6867461
    Other name
    VABYSMO®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Participants will receive 6 mg faricimab intravitreal injections according to a personalized treatment interval (PTI) dosing regimen.

    Number of subjects in period 1
    Faricimab PTI (prior Faricimab Q8W) Faricimab PTI (prior Faricimab PTI) Faricimab PTI (prior Aflibercept Q8W)
    Started
    493
    506
    475
    Received at Least One Dose of Study Drug
    491
    500
    473
    Completed
    405
    407
    392
    Not completed
    88
    99
    83
         Adverse event, serious fatal
    23
    23
    17
         Consent withdrawn by subject
    24
    28
    21
         Physician decision
    1
    3
    6
         Adverse event, non-fatal
    7
    7
    7
         Final End of Study Visit Not Completed
    10
    11
    7
         Pregnancy
    -
    1
    -
         Lost to follow-up
    15
    15
    12
         Reason not specified
    7
    11
    9
         Protocol deviation
    1
    -
    2
         Lack of efficacy
    -
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Faricimab PTI (prior Faricimab Q8W)
    Reporting group description
    This analysis group includes participants who were previously randomized to Arm A (faricimab 6 mg Q8W) in one of the parent studies, GR40349 (NCT03622580) and GR40398 (NCT03622593), and then enrolled in this extension study to receive faricimab 6 mg by IVT injection according to the personalized treatment interval (PTI) dosing regimen.

    Reporting group title
    Faricimab PTI (prior Faricimab PTI)
    Reporting group description
    This analysis group includes participants who were previously randomized to Arm B (faricimab 6 mg PTI) in one of the parent studies, GR40349 (NCT03622580) and GR40398 (NCT03622593), and then enrolled in this extension study to receive faricimab 6 mg by IVT injection according to the personalized treatment interval (PTI) dosing regimen.

    Reporting group title
    Faricimab PTI (prior Aflibercept Q8W)
    Reporting group description
    This analysis group includes participants who were previously randomized to Arm C (aflibercept 2 mg Q8W) in one of the parent studies, GR40349 (NCT03622580) and GR40398 (NCT03622593), and then enrolled in this extension study to receive faricimab 6 mg by IVT injection according to the personalized treatment interval (PTI) dosing regimen.

    Reporting group values
    Faricimab PTI (prior Faricimab Q8W) Faricimab PTI (prior Faricimab PTI) Faricimab PTI (prior Aflibercept Q8W) Total
    Number of subjects
    493 506 475 1474
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    264 243 243 750
        From 65-84 years
    223 261 230 714
        85 years and over
    6 2 2 10
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    63.4 ( 9.9 ) 64.0 ( 9.8 ) 63.5 ( 9.4 ) -
    Sex: Female, Male
    Units: Participants
        Female
    191 184 205 580
        Male
    302 322 270 894
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    5 4 4 13
        Asian
    54 52 45 151
        Native Hawaiian or Other Pacific Islander
    1 0 1 2
        Black or African American
    27 32 25 84
        White
    392 406 389 1187
        More than one race
    1 0 0 1
        Unknown or Not Reported
    13 12 11 36
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    68 87 79 234
        Not Hispanic or Latino
    415 408 386 1209
        Unknown or Not Reported
    10 11 10 31

    End points

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    End points reporting groups
    Reporting group title
    Faricimab PTI (prior Faricimab Q8W)
    Reporting group description
    This analysis group includes participants who were previously randomized to Arm A (faricimab 6 mg Q8W) in one of the parent studies, GR40349 (NCT03622580) and GR40398 (NCT03622593), and then enrolled in this extension study to receive faricimab 6 mg by IVT injection according to the personalized treatment interval (PTI) dosing regimen.

    Reporting group title
    Faricimab PTI (prior Faricimab PTI)
    Reporting group description
    This analysis group includes participants who were previously randomized to Arm B (faricimab 6 mg PTI) in one of the parent studies, GR40349 (NCT03622580) and GR40398 (NCT03622593), and then enrolled in this extension study to receive faricimab 6 mg by IVT injection according to the personalized treatment interval (PTI) dosing regimen.

    Reporting group title
    Faricimab PTI (prior Aflibercept Q8W)
    Reporting group description
    This analysis group includes participants who were previously randomized to Arm C (aflibercept 2 mg Q8W) in one of the parent studies, GR40349 (NCT03622580) and GR40398 (NCT03622593), and then enrolled in this extension study to receive faricimab 6 mg by IVT injection according to the personalized treatment interval (PTI) dosing regimen.

    Primary: Incidence and Severity of Ocular Adverse Events in the Study Eye, with Severity Determined According to Adverse Event Severity Grading Scale

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    End point title
    Incidence and Severity of Ocular Adverse Events in the Study Eye, with Severity Determined According to Adverse Event Severity Grading Scale [1]
    End point description
    This is an analysis of participants with at least one ocular adverse event (AE) that occurred in the study eye. Investigators sought information on AEs at each contact with the participants. All AEs were recorded and the investigator made an assessment of the seriousness, severity (e.g., mild, moderate, or severe intensity), and causality for each AE. AEs of special interest (AESI) included the following: Sight-threatening AEs that cause a drop in visual acuity (VA) score ≥30 letters lasting more than 1 hour, are associated with severe intraocular inflammation (IOI), or require surgical or medical intervention to prevent permanent loss of sight; suspected transmission of an infectious agent by the study drug; and, cases of potential drug-induced liver injury that include an elevated ALT or AST in combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law.
    End point type
    Primary
    End point timeframe
    From the day of the first dose of faricimab until the end of the study (up to 108 weeks)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no formal hypothesis testing planned for this study. This safety end point was assessed through descriptive summaries of the number of adverse events.
    End point values
    Faricimab PTI (prior Faricimab Q8W) Faricimab PTI (prior Faricimab PTI) Faricimab PTI (prior Aflibercept Q8W)
    Number of subjects analysed
    491
    500
    473
    Units: Participants
        Any Adverse Event (AE), Any Severity
    219
    188
    197
        AE by Severity: Mild
    119
    109
    109
        AE by Severity: Moderate
    74
    66
    74
        AE by Severity: Severe
    20
    10
    12
        AE by Severity: Missing
    6
    3
    2
        Serious Adverse Event (SAE)
    31
    15
    26
        AE Leading to Withdrawal from Study Treatment
    3
    0
    6
        Treatment-related AE
    10
    10
    11
        Treatment-related SAE
    0
    1
    1
        Any AE of Special Interest (AESI)
    30
    14
    24
        AESI: Drop in Visual Acuity Score ≥30 Letters
    23
    10
    20
        AESI: Associated with Severe IOI
    1
    1
    1
        AESI: Intervention Req. to Prev. Perm. Vision Loss
    6
    3
    3
        AESI: Suspect. Transm. of Infectious Agent by Drug
    0
    0
    0
    No statistical analyses for this end point

    Primary: Incidence of Ocular Adverse Events in the Fellow Eye

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    End point title
    Incidence of Ocular Adverse Events in the Fellow Eye [2]
    End point description
    This is an analysis of participants with at least one ocular adverse event (AE) that occurred in the fellow eye (i.e., non-study eye). Investigators sought information on AEs at each contact with the participants. All AEs were recorded and the investigator made an assessment of the seriousness, severity, and causality for each AE. AEs of special interest (AESI) included the following: Sight-threatening AEs that cause a drop in visual acuity (VA) score ≥30 letters lasting more than 1 hour, are associated with severe intraocular inflammation (IOI), or require surgical or medical intervention to prevent permanent loss of sight; suspected transmission of an infectious agent by the study drug; and, cases of potential drug-induced liver injury that include an elevated ALT or AST in combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law.
    End point type
    Primary
    End point timeframe
    From the day of the first dose of faricimab until the end of the study (up to 108 weeks)
    Notes
    [2] - 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: There was no formal hypothesis testing planned for this study. This safety end point was assessed through descriptive summaries of the number of adverse events.
    End point values
    Faricimab PTI (prior Faricimab Q8W) Faricimab PTI (prior Faricimab PTI) Faricimab PTI (prior Aflibercept Q8W)
    Number of subjects analysed
    491
    500
    473
    Units: Participants
        Any Adverse Event (AE)
    186
    185
    179
        Serious Adverse Event (SAE)
    16
    17
    15
        Any AE of Special Interest (AESI)
    13
    16
    14
        AESI: Drop in Visual Acuity Score ≥30 Letters
    6
    9
    10
        AESI: Associated with Severe IOI
    0
    1
    1
        AESI: Intervention Req. to Prev. Perm. Vision Loss
    7
    6
    4
        AESI: Suspect. Transm. of Infectious Agent by Drug
    0
    0
    0
    No statistical analyses for this end point

    Primary: Incidence and Severity of Non-Ocular Adverse Events, with Severity Determined According to Adverse Event Severity Grading Scale

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    End point title
    Incidence and Severity of Non-Ocular Adverse Events, with Severity Determined According to Adverse Event Severity Grading Scale [3]
    End point description
    This is an analysis of participants with at least one non-ocular (systemic) adverse event (AE). Investigators sought information on AEs at each contact with the participants. All AEs were recorded and the investigator made an assessment of the seriousness, severity (e.g., mild, moderate, or severe intensity), and causality for each AE. AEs of special interest (AESI) included the following: Sight-threatening AEs that cause a drop in visual acuity (VA) score ≥30 letters lasting more than 1 hour, are associated with severe intraocular inflammation (IOI), or require surgical or medical intervention to prevent permanent loss of sight; suspected transmission of an infectious agent by the study drug; and, cases of potential drug-induced liver injury that include an elevated ALT or AST in combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law.
    End point type
    Primary
    End point timeframe
    From the day of the first dose of faricimab until the end of the study (up to 108 weeks)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no formal hypothesis testing planned for this study. This safety end point was assessed through descriptive summaries of the number of adverse events.
    End point values
    Faricimab PTI (prior Faricimab Q8W) Faricimab PTI (prior Faricimab PTI) Faricimab PTI (prior Aflibercept Q8W)
    Number of subjects analysed
    491
    500
    473
    Units: Participants
        Any Adverse Event (AE), Any Severity
    317
    295
    297
        AE by Severity: Mild
    91
    94
    97
        AE by Severity: Moderate
    124
    124
    115
        AE by Severity: Severe
    102
    77
    85
        Serious Adverse Event (SAE)
    122
    100
    112
        AE Leading to Withdrawal from Study Treatment
    2
    7
    4
        Any AE of Special Interest (AESI)
    0
    0
    1
        AESI: Drop in Visual Acuity Score ≥30 Letters
    0
    0
    1
        AESI: High ALT/AST & High Bilir. or Clin. Jaundice
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the day of the first dose of faricimab until the end of the study (up to 108 weeks)
    Adverse event reporting additional description
    Total number of deaths and adverse events (AEs) are reported for the Safety-Evaluable Population, which included all participant who enrolled and received at least one dose of faricimab during the study. For ocular AEs, the number of participants and events reported per term are specified to have occurred in the study eye or the fellow eye.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Faricimab PTI (prior Faricimab Q8W)
    Reporting group description
    This analysis group includes participants who were previously randomized to Arm A (faricimab 6 mg Q8W) in one of the parent studies, GR40349 (NCT03622580) and GR40398 (NCT03622593), and then enrolled in this extension study to receive faricimab 6 mg by IVT injection according to the personalized treatment interval (PTI) dosing regimen.

    Reporting group title
    Faricimab PTI (prior Faricimab PTI)
    Reporting group description
    This analysis group includes participants who were previously randomized to Arm B (faricimab 6 mg PTI) in one of the parent studies, GR40349 (NCT03622580) and GR40398 (NCT03622593), and then enrolled in this extension study to receive faricimab 6 mg by IVT injection according to the personalized treatment interval (PTI) dosing regimen.

    Reporting group title
    Faricimab PTI (prior Aflibercept Q8W)
    Reporting group description
    This analysis group includes participants who were previously randomized to Arm C (aflibercept 2 mg Q8W) in one of the parent studies, GR40349 (NCT03622580) and GR40398 (NCT03622593), and then enrolled in this extension study to receive faricimab 6 mg by IVT injection according to the personalized treatment interval (PTI) dosing regimen.

    Serious adverse events
    Faricimab PTI (prior Faricimab Q8W) Faricimab PTI (prior Faricimab PTI) Faricimab PTI (prior Aflibercept Q8W)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    158 / 491 (32.18%)
    124 / 500 (24.80%)
    134 / 473 (28.33%)
         number of deaths (all causes)
    22
    20
    17
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clear cell renal cell carcinoma
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Benign anorectal neoplasm
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon cancer metastatic
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 491 (0.00%)
    4 / 500 (0.80%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast neoplasm
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervix carcinoma
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometrial cancer stage III
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer stage IV
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic cancer
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukaemia
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasm malignant
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuroendocrine carcinoma of the skin
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal cancer metastatic
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Ovarian fibroma
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    2 / 491 (0.41%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 491 (0.00%)
    2 / 500 (0.40%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal cancer stage IV
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Spinal cord neoplasm
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Angiopathy
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Hypertensive urgency
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    2 / 491 (0.41%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 491 (0.41%)
    1 / 500 (0.20%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive emergency
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 491 (0.20%)
    3 / 500 (0.60%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Organ failure
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    3 / 491 (0.61%)
    5 / 500 (1.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 5
    0 / 2
    Hernia
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 491 (0.00%)
    2 / 500 (0.40%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Food allergy
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Contrast media allergy
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Allergy to arthropod sting
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Orchitis noninfective
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic cyst
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 491 (0.20%)
    1 / 500 (0.20%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Chronic respiratory failure
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 491 (0.00%)
    2 / 500 (0.40%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    2 / 491 (0.41%)
    1 / 500 (0.20%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    2 / 491 (0.41%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 491 (0.41%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Psychiatric disorders
    Substance-induced psychotic disorder
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device leakage
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Ammonia increased
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Glycosylated haemoglobin abnormal
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Heart rate increased
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SARS-CoV-2 test positive
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Precancerous cells present
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intraocular pressure increased
    Additional description: SAEs occurred in the fellow eye
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Red blood cell count decreased
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Corneal abrasion
    Additional description: SAEs occurred in the fellow eye
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cataract traumatic
    Additional description: SAEs occurred the study eye
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Comminuted fracture
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye injury
    Additional description: SAEs occurred the study eye
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 491 (0.20%)
    1 / 500 (0.20%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 491 (0.00%)
    2 / 500 (0.40%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    2 / 491 (0.41%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    2 / 491 (0.41%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foreign body
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fracture displacement
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ocular procedural complication
    Additional description: SAEs occurred in the fellow eye
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritoneal dialysis complication
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural constipation
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural inflammation
    Additional description: SAEs occurred in the fellow eye
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Shoulder fracture
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound necrosis
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular procedure complication
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrioventricular block complete
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 491 (0.20%)
    1 / 500 (0.20%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 491 (0.20%)
    1 / 500 (0.20%)
    4 / 473 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 491 (0.20%)
    4 / 500 (0.80%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    0 / 491 (0.00%)
    2 / 500 (0.40%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute left ventricular failure
         subjects affected / exposed
    2 / 491 (0.41%)
    2 / 500 (0.40%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiac discomfort
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 491 (0.41%)
    2 / 500 (0.40%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 491 (0.20%)
    1 / 500 (0.20%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradyarrhythmia
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    7 / 491 (1.43%)
    3 / 500 (0.60%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac valve disease
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    Cardiogenic shock
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 491 (0.00%)
    3 / 500 (0.60%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    6 / 491 (1.22%)
    5 / 500 (1.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular hypokinesia
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 491 (0.20%)
    1 / 500 (0.20%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    9 / 491 (1.83%)
    3 / 500 (0.60%)
    8 / 473 (1.69%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 3
    0 / 8
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    0 / 3
    Ischaemic cardiomyopathy
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    1 / 491 (0.20%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Amyotrophic lateral sclerosis
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalomalacia
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    4 / 491 (0.81%)
    3 / 500 (0.60%)
    10 / 473 (2.11%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    Cerebral infarction
         subjects affected / exposed
    2 / 491 (0.41%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemic unconsciousness
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 491 (0.20%)
    1 / 500 (0.20%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Optic neuritis
    Additional description: SAEs occurred in the fellow eye
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukoencephalopathy
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxic encephalopathy
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 491 (0.20%)
    2 / 500 (0.40%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 491 (0.41%)
    1 / 500 (0.20%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vertebral artery stenosis
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vocal cord paralysis
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 491 (0.41%)
    2 / 500 (0.40%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrogenic anaemia
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Normocytic anaemia
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
    Additional description: SAEs occurred in both the study eye (subjects affected [exposed] occurrences = 11[491]11, 8[500]8, 15[473]15) and the fellow eye (subjects affected [exposed] occurrences = 1[491]1, 6[500]6, 0[473]0)
         subjects affected / exposed
    12 / 491 (2.44%)
    14 / 500 (2.80%)
    15 / 473 (3.17%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 14
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic retinal oedema
    Additional description: SAEs occurred in both the study eye (subjects affected [exposed] occurrences = 7[491]8, 0[500]0, 2[473]2) and the fellow eye (subjects affected [exposed] occurrences = 1[491]1, 1[500]1, 2[473]2)
         subjects affected / exposed
    8 / 491 (1.63%)
    1 / 500 (0.20%)
    4 / 473 (0.85%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cataract nuclear
    Additional description: SAEs occurred in the study eye
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cataract cortical
    Additional description: SAEs occurred in the fellow eye
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angle closure glaucoma
    Additional description: SAEs occurred in the fellow eye
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neovascular age-related macular degeneration
    Additional description: SAEs occurred in the fellow eye
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Posterior capsule opacification
    Additional description: SAEs occurred in the study eye
         subjects affected / exposed
    2 / 491 (0.41%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Iridocyclitis
    Additional description: SAEs occurred in the study eye
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Iridocele
    Additional description: SAEs occurred in the study eye
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Glaucoma
    Additional description: SAEs occurred in the study eye
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhegmatogenous retinal detachment
    Additional description: SAEs occurred in the study eye
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal tear
    Additional description: SAEs occurred in both the study eye (subjects affected [exposed] occurrences = 0[491]0, 1[500]1, 0[473]0) and the fellow eye (subjects affected [exposed] occurrences = 0[491]0, 1[500]1, 0[473]0)
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal neovascularisation
    Additional description: SAEs occurred in the fellow eye
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tractional retinal detachment
    Additional description: SAEs occurred in the fellow eye
         subjects affected / exposed
    2 / 491 (0.41%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic retinopathy
    Additional description: SAEs occurred in both the study eye (subjects affected [exposed] occurrences = 0[491]0, 0[500]0, 1[473]1) and the fellow eye (subjects affected [exposed] occurrences = 2[491]2, 3[500]3, 2[473]2)
         subjects affected / exposed
    2 / 491 (0.41%)
    3 / 500 (0.60%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epiretinal membrane
    Additional description: SAEs occurred in both the study eye (subjects affected [exposed] occurrences = 0[491]0, 0[500]0, 1[473]1) and the fellow eye (subjects affected [exposed] occurrences = 0[491]0, 0[500]0, 2[473]2)
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal artery occlusion
    Additional description: SAEs occurred in both the study eye (subjects affected [exposed] occurrences = 0[491]0, 1[500]1, 2[473]2) and the fellow eye (subjects affected [exposed] occurrences = 1[491]1, 0[500]0, 1[473]1)
         subjects affected / exposed
    1 / 491 (0.20%)
    1 / 500 (0.20%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal detachment
    Additional description: SAEs occurred in both the study eye (subjects affected [exposed] occurrences = 2[491]2, 0[500]0, 0[473]0) and the fellow eye (subjects affected [exposed] occurrences = 1[491]1, 0[500]0, 1[473]1)
         subjects affected / exposed
    3 / 491 (0.61%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal vein occlusion
    Additional description: SAEs occurred in the study eye
         subjects affected / exposed
    2 / 491 (0.41%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vitreous haemorrhage
    Additional description: SAEs occurred in both the study eye (subjects affected [exposed] occurrences = 1[491]1, 1[500]1, 2[473]2) and the fellow eye (subjects affected [exposed] occurrences = 4[491]4, 3[500]3, 6[473]6)
         subjects affected / exposed
    5 / 491 (1.02%)
    4 / 500 (0.80%)
    8 / 473 (1.69%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uveitis
    Additional description: SAEs occurred in the study eye
         subjects affected / exposed
    1 / 491 (0.20%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Faecaloma
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oral mucosal hypertrophy
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Portal vein thrombosis
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Gallbladder rupture
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Biliary tract disorder
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 491 (0.20%)
    1 / 500 (0.20%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 491 (0.20%)
    1 / 500 (0.20%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Cellulite
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic foot
         subjects affected / exposed
    2 / 491 (0.41%)
    3 / 500 (0.60%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    3 / 491 (0.61%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Diabetic nephropathy
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    2 / 491 (0.41%)
    3 / 500 (0.60%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    8 / 491 (1.63%)
    5 / 500 (1.00%)
    5 / 473 (1.06%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    End stage renal disease
         subjects affected / exposed
    1 / 491 (0.20%)
    2 / 500 (0.40%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subcapsular renal haematoma
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal haemorrhage
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    3 / 491 (0.61%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephropathy
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 491 (0.20%)
    3 / 500 (0.60%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuropathic arthropathy
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    1 / 491 (0.20%)
    1 / 500 (0.20%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal infection
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    10 / 491 (2.04%)
    9 / 500 (1.80%)
    5 / 473 (1.06%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 9
    0 / 5
         deaths causally related to treatment / all
    0 / 3
    0 / 3
    0 / 0
    Arthritis infective
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    2 / 491 (0.41%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic gangrene
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis intestinal haemorrhagic
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic foot infection
         subjects affected / exposed
    2 / 491 (0.41%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    1 / 491 (0.20%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 491 (0.61%)
    4 / 500 (0.80%)
    6 / 473 (1.27%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    4 / 491 (0.81%)
    2 / 500 (0.40%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocarditis bacterial
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endophthalmitis
    Additional description: SAEs occurred in both the study eye (subjects affected [exposed] occurrences = 2[491]2, 0[500]0, 1[473]1) and the fellow eye (subjects affected [exposed] occurrences = 2[491]2, 0[500]0, 1[473]1)
         subjects affected / exposed
    4 / 491 (0.81%)
    0 / 500 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    2 / 491 (0.41%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 491 (0.20%)
    2 / 500 (0.40%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infected dermal cyst
         subjects affected / exposed
    0 / 491 (0.00%)
    2 / 500 (0.40%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    7 / 491 (1.43%)
    0 / 500 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Labyrinthitis
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    7 / 491 (1.43%)
    4 / 500 (0.80%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paronychia
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis chronic
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis acute
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Systemic bacterial infection
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic endocarditis
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 491 (0.81%)
    2 / 500 (0.40%)
    4 / 473 (0.85%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    Staphylococcal infection
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 491 (0.00%)
    2 / 500 (0.40%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 491 (1.02%)
    8 / 500 (1.60%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 9
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 491 (0.41%)
    0 / 500 (0.00%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 491 (0.20%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 491 (0.20%)
    1 / 500 (0.20%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Hypervolaemia
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 491 (0.20%)
    2 / 500 (0.40%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemic hyperosmolar nonketotic syndrome
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 491 (0.00%)
    0 / 500 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 491 (0.20%)
    0 / 500 (0.00%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 491 (0.00%)
    1 / 500 (0.20%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    Faricimab PTI (prior Faricimab Q8W) Faricimab PTI (prior Faricimab PTI) Faricimab PTI (prior Aflibercept Q8W)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    233 / 491 (47.45%)
    213 / 500 (42.60%)
    219 / 473 (46.30%)
    Investigations
    Intraocular pressure increased
    Additional description: AEs occurred in the study eye
         subjects affected / exposed
    16 / 491 (3.26%)
    12 / 500 (2.40%)
    12 / 473 (2.54%)
         occurrences all number
    20
    15
    13
    Vascular disorders
    Hypertension
         subjects affected / exposed
    18 / 491 (3.67%)
    20 / 500 (4.00%)
    23 / 473 (4.86%)
         occurrences all number
    18
    20
    24
    Eye disorders
    Cataract
    Additional description: AEs occurred in both the study eye (subjects affected [exposed] occurrences = 65[491]65, 60[500]60, 63[473]63) and the fellow eye (subjects affected [exposed] occurrences = 56[491]56, 41[500]41, 51[473]52)
         subjects affected / exposed
    90 / 491 (18.33%)
    72 / 500 (14.40%)
    84 / 473 (17.76%)
         occurrences all number
    115
    91
    110
    Posterior capsule opacification
    Additional description: AEs occurred in both the study eye (subjects affected [exposed] occurrences = 16[491]17, 17[500]17, 14[473]14) and the fellow eye (subjects affected [exposed] occurrences = 13[491]14, 20[500]20, 13[473]13)
         subjects affected / exposed
    19 / 491 (3.87%)
    29 / 500 (5.80%)
    20 / 473 (4.23%)
         occurrences all number
    27
    34
    27
    Diabetic retinal oedema
    Additional description: AEs occurred in the fellow eye
         subjects affected / exposed
    22 / 491 (4.48%)
    27 / 500 (5.40%)
    24 / 473 (5.07%)
         occurrences all number
    22
    31
    27
    Conjunctival haemorrhage
    Additional description: AEs occurred in the study eye
         subjects affected / exposed
    16 / 491 (3.26%)
    9 / 500 (1.80%)
    5 / 473 (1.06%)
         occurrences all number
    17
    9
    5
    Diabetic retinopathy
    Additional description: AEs occurred in the fellow eye
         subjects affected / exposed
    17 / 491 (3.46%)
    8 / 500 (1.60%)
    12 / 473 (2.54%)
         occurrences all number
    17
    8
    12
    Vitreous detachment
    Additional description: AEs occurred in the study eye
         subjects affected / exposed
    16 / 491 (3.26%)
    12 / 500 (2.40%)
    6 / 473 (1.27%)
         occurrences all number
    16
    12
    6
    Vitreous floaters
    Additional description: AEs occurred in the study eye
         subjects affected / exposed
    16 / 491 (3.26%)
    7 / 500 (1.40%)
    8 / 473 (1.69%)
         occurrences all number
    18
    7
    8
    Infections and infestations
    COVID-19
         subjects affected / exposed
    63 / 491 (12.83%)
    49 / 500 (9.80%)
    46 / 473 (9.73%)
         occurrences all number
    70
    50
    49
    Nasopharyngitis
         subjects affected / exposed
    18 / 491 (3.67%)
    12 / 500 (2.40%)
    23 / 473 (4.86%)
         occurrences all number
    21
    12
    27
    Urinary tract infection
         subjects affected / exposed
    16 / 491 (3.26%)
    15 / 500 (3.00%)
    16 / 473 (3.38%)
         occurrences all number
    19
    17
    18

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 May 2020
    Protocol Version 2: An exclusion criterion was added relating to a history of reaction or hypersensitivity to biologic agents including any component of the faricimab injection or study treatment procedures.
    13 Dec 2021
    Protocol Version 3: -A Final End-of-Study (FEOS) visit, to be completed 28-35 days after the last PTI dosing visit, was included for all patients. Therefore, the study was extended to a maximum of 108 weeks for patients who received their final dose of faricimab at Week 104; -The list of prohibited therapies was amended to clarify that continuous usage of topical ophthalmic corticosteroids for 100 days or more is considered prohibited therapy, and to add the use of kallidinogenase and other medications claiming to have an effect on macular pathology to the list of prohibited therapies.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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