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    Clinical Trial Results:
    An open-label, randomized, active-controlled, parallel-group, Phase-3b study of the efficacy, safety, and tolerability of three different treatment regimens of 2 mg aflibercept administered by intravitreal injections to subjects with diabetic macular edema (DME)

    Summary
    EudraCT number
    		 2014-004938-25
    Trial protocol
    		 GB   SK   HU   DE   AT   ES   CZ   LT   FR   PT   PL   IT  
    Global end of trial date
    24 Sep 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Jul 2020
    First version publication date
    31 Jul 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY86-5321/17613
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02818998
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser Wilhelm Allee, Leverkusen, Germany,
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.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
    24 Sep 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Sep 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of long-term treatment with 2 mg aflibercept via different intravitreal (IVT) treatment regimens to subjects with DME pre-treated with 2 mg aflibercept every 8 weeks after 5 initial monthly injections for approximately 1 year or more (according to the European Union [EU] label for the first year of treatment)
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent was read by and explained to all the subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Nov 2016
    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
    Germany: 18
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Poland: 82
    Country: Number of subjects enrolled
    Italy: 31
    Country: Number of subjects enrolled
    Spain: 40
    Country: Number of subjects enrolled
    Canada: 15
    Country: Number of subjects enrolled
    Czech Republic: 38
    Country: Number of subjects enrolled
    Portugal: 26
    Country: Number of subjects enrolled
    Austria: 7
    Country: Number of subjects enrolled
    Hungary: 106
    Country: Number of subjects enrolled
    Slovakia: 73
    Country: Number of subjects enrolled
    Lithuania: 11
    Country: Number of subjects enrolled
    Switzerland: 5
    Worldwide total number of subjects
    463
    EEA total number of subjects
    443
    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)
    210
    From 65 to 84 years
    251
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study was conducted at multiple centers in 14 countries between 16-Nov-2016 (first participant first visit) and 24-Sep-2019 (last participant last visit).

    Pre-assignment
    Screening details
    		 A total of 500 participants were screened in this study. Of these, 37 participants did not enter the treatment period (31 were screening failures; 3 were lost to follow-up; 2 had an adverse event (AE) and 1 was not randomized due to an "other" reason). A total of 463 participants were randomized and received treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Aflibercept 2 mg fixed
    Arm description
    		 Participants received fixed dosing of 2 mg aflibercept at injection intervals of 8 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aflibercept
    Investigational medicinal product code
    BAY86-5321
    Other name
    Eylea
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    2 mg, fixed-dosing regimen every 8 weeks (2Q8fix)

    Arm title
    		 Aflibercept 2 mg extended
    Arm description
    		 Participants received flexible dosing of 2 mg aflibercept at injection intervals of ≥ 8 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aflibercept
    Investigational medicinal product code
    BAY86-5321
    Other name
    Eylea
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    2 mg, flexible-dosing regimen with gradually extended dosing interval (≥ 8 weeks, no upper limit) according to the current EU label (2Q8ext)

    Arm title
    		 Aflibercept 2 mg PRN
    Arm description
    		 Participants received monthly monitoring with 2 mg aflibercept injection pro re nata (PRN, as needed)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aflibercept
    Investigational medicinal product code
    BAY86-5321
    Other name
    Eylea
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    2 mg, pro re nata dosing regimen (2PRN)

    Number of subjects in period 1
    		Aflibercept 2 mg fixed Aflibercept 2 mg extended Aflibercept 2 mg PRN
    Started
    155
    154
    154
    Completed Week 52 visit
    144
    146
    140
    Completed
    137
    138
    136
    Not completed
    18
    16
    18
         Adverse event, serious fatal
    3
    6
    8
         Consent withdrawn by subject
    7
    6
    6
         Physician decision
    1
    -
    -
         Adverse event, non-fatal
    3
    2
    1
         Lost to follow-up
    4
    1
    2
         Withdrawal by sponsor
    -
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Aflibercept 2 mg fixed
    Reporting group description
    		 Participants received fixed dosing of 2 mg aflibercept at injection intervals of 8 weeks

    Reporting group title
    Aflibercept 2 mg extended
    Reporting group description
    		 Participants received flexible dosing of 2 mg aflibercept at injection intervals of ≥ 8 weeks

    Reporting group title
    Aflibercept 2 mg PRN
    Reporting group description
    		 Participants received monthly monitoring with 2 mg aflibercept injection pro re nata (PRN, as needed)

    Reporting group values
    		 Aflibercept 2 mg fixed Aflibercept 2 mg extended Aflibercept 2 mg PRN Total
    Number of subjects
    		 155 154 154 463
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 72 70 68 210
        From 65-84 years
    		 83 84 84 251
        85 years and over
    		 0 0 2 2
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 64.3 ( 8.7 ) 64.8 ( 10.1 ) 65.4 ( 9.3 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 55 59 64 178
        Male
    		 100 95 90 285
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 1 2 4 7
        Not Hispanic or Latino
    		 144 142 142 428
        Unknown or Not Reported
    		 10 10 8 28
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 2 1 0 3
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 1 0 0 1
        White
    		 141 144 147 432
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 11 9 7 27
    Best Corrected Visual Acuity (BCVA)
    Best Corrected Visual Acuity (BCVA) was measured in the study eye by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting at 4 meters. The ETDRS chart includes 70 letters in total and the letter score ranges from 0 to 100. More letters read correctly results in a higher letter score, which represents better visual acuity.
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    		 72.8 ( 10.38 ) 72.5 ( 11.35 ) 71.0 ( 10.87 ) -
    Central Retinal Thickness (CRT)
    Central Retinal Thickness (CRT) was measured in the study eye by spectral domain optical coherence tomography (SD-OCT).
    Units: Microns
        arithmetic mean (standard deviation)
    		 289.8 ( 66.46 ) 285.3 ( 76.01 ) 294.5 ( 80.72 ) -

    End points

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    End points reporting groups
    Reporting group title
    Aflibercept 2 mg fixed
    Reporting group description
    		 Participants received fixed dosing of 2 mg aflibercept at injection intervals of 8 weeks

    Reporting group title
    Aflibercept 2 mg extended
    Reporting group description
    		 Participants received flexible dosing of 2 mg aflibercept at injection intervals of ≥ 8 weeks

    Reporting group title
    Aflibercept 2 mg PRN
    Reporting group description
    		 Participants received monthly monitoring with 2 mg aflibercept injection pro re nata (PRN, as needed)

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Included all randomized participants who received any study drug and had a baseline BCVA assessment and at least one post-baseline BCVA assessment.

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Included all participants who received any study drug under the protocol.

    Primary: Mean change from baseline in Best Corrected Visual Acuity (BCVA) at Week 52

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    End point title
    		 Mean change from baseline in Best Corrected Visual Acuity (BCVA) at Week 52
    End point description
    Best Corrected Visual Acuity (BCVA) was measured in the study eye by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting at 4 meters. The ETDRS chart includes 70 letters in total and the letter score ranges from 0 to 100. More letters read correctly results in a higher letter score, which represents better visual acuity.
    End point type
    Primary
    End point timeframe
    From baseline to Week 52
    End point values
    		 Aflibercept 2 mg fixed Aflibercept 2 mg extended Aflibercept 2 mg PRN
    Number of subjects analysed
    153
    152
    153
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    0.4 ( 6.7 )
    0.5 ( 6.7 )
    1.7 ( 6.8 )
    Statistical analysis title
    		 Analysis of covariance for BCVA change
    Statistical analysis description
    Aflibercept 2 mg fixed was regarded as the reference arm
    Comparison groups
    Aflibercept 2 mg fixed v Aflibercept 2 mg extended
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 < 0.0001 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares mean difference
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.46
         upper limit
    		 1.47
    Notes
    [1] - Non-inferiority margin: 4 letters
    [2] - Non-inferiority was demonstrated if the p-value (adjusted for multiplicity using the Hochberg procedure) was < 0.025
    Statistical analysis title
    		 Analysis of covariance for BCVA change
    Statistical analysis description
    Aflibercept 2 mg fixed was regarded as the reference arm
    Comparison groups
    Aflibercept 2 mg fixed v Aflibercept 2 mg PRN
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    P-value
    		 < 0.0001 [4]
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares mean difference
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.52
         upper limit
    		 2.42
    Notes
    [3] - Non-inferiority margin: 4 letters
    [4] - Non-inferiority was demonstrated if the p-value (adjusted for multiplicity using the Hochberg procedure) was < 0.025

    Secondary: Mean change from baseline in Central Retinal Thickness (CRT) at Week 52

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    End point title
    		 Mean change from baseline in Central Retinal Thickness (CRT) at Week 52
    End point description
    Central Retinal Thickness (CRT) was measured in the study eye by spectral domain optical coherence tomography (SD-OCT).
    End point type
    Secondary
    End point timeframe
    From baseline to week 52
    End point values
    		 Aflibercept 2 mg fixed Aflibercept 2 mg extended Aflibercept 2 mg PRN
    Number of subjects analysed
    153
    152
    153
    Units: Microns
        arithmetic mean (standard deviation)
    -18.8 ( 45.5 )
    -2.1 ( 56.2 )
    2.2 ( 77.8 )
    Statistical analysis title
    		 Analysis of covariance for CRT change
    Statistical analysis description
    Aflibercept 2 mg fixed was regarded as the reference arm
    Comparison groups
    Aflibercept 2 mg fixed v Aflibercept 2 mg extended
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0105
    Method
    		 ANCOVA
    Parameter type
    		 Least Square mean difference
    Point estimate
    14.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.39
         upper limit
    		 25.37
    Statistical analysis title
    		 Analysis of covariance for CRT change
    Statistical analysis description
    Aflibercept 2 mg fixed was regarded as the reference arm
    Comparison groups
    Aflibercept 2 mg fixed v Aflibercept 2 mg PRN
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0023
    Method
    		 ANCOVA
    Parameter type
    		 Least Square mean difference
    Point estimate
    21.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.65
         upper limit
    		 34.8

    Secondary: Number of participants with categorized changes from baseline in Best Corrected Visual Acuity (BCVA) at Week 52

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    End point title
    		 Number of participants with categorized changes from baseline in Best Corrected Visual Acuity (BCVA) at Week 52
    End point description
    Best Corrected Visual Acuity (BCVA) was measured in the study eye by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting at 4 meters. The ETDRS chart includes 70 letters in total and the letter score ranges from 0 to 100. More letters read correctly results in a higher letter score, which represents better visual acuity
    End point type
    Secondary
    End point timeframe
    From baseline to week 52
    End point values
    		 Aflibercept 2 mg fixed Aflibercept 2 mg extended Aflibercept 2 mg PRN
    Number of subjects analysed
    153
    152
    153
    Units: Participants
        ≥ 15 letter gain
    4
    5
    4
        ≥ 10 letter gain
    10
    14
    13
        ≥ 30 letter loss
    1
    0
    0
    Statistical analysis title
    		 Categorized changes for ≥ 15 letter gain in BCVA
    Statistical analysis description
    Aflibercept 2 mg fixed was regarded as the reference arm
    Comparison groups
    Aflibercept 2 mg fixed v Aflibercept 2 mg extended
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.14
         upper limit
    		 4.49
    Statistical analysis title
    		 Categorized changes for ≥ 10 letter gain in BCVA
    Statistical analysis description
    Aflibercept 2 mg fixed was regarded as the reference arm
    Comparison groups
    Aflibercept 2 mg fixed v Aflibercept 2 mg extended
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    2.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.4
         upper limit
    		 8.73
    Statistical analysis title
    		 Categorized changes for ≥ 30 letter loss in BCVA
    Statistical analysis description
    Aflibercept 2 mg fixed was regarded as the reference arm
    Comparison groups
    Aflibercept 2 mg fixed v Aflibercept 2 mg extended
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.94
         upper limit
    		 0.63
    Statistical analysis title
    		 Categorized changes for ≥ 15 letter gain in BCVA
    Statistical analysis description
    Aflibercept 2 mg fixed was regarded as the reference arm
    Comparison groups
    Aflibercept 2 mg fixed v Aflibercept 2 mg PRN
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.68
         upper limit
    		 3.41
    Statistical analysis title
    		 Categorized changes for ≥ 10 letter gain in BCVA
    Statistical analysis description
    Aflibercept 2 mg fixed was regarded as the reference arm
    Comparison groups
    Aflibercept 2 mg fixed v Aflibercept 2 mg PRN
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    1.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.1
         upper limit
    		 7.54
    Statistical analysis title
    		 Categorized changes for ≥ 30 letter loss in BCVA
    Statistical analysis description
    Aflibercept 2 mg fixed was regarded as the reference arm
    Comparison groups
    Aflibercept 2 mg fixed v Aflibercept 2 mg PRN
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 0.65

    Secondary: Mean change from baseline in Best Corrected Visual Acuity (BCVA) at Week 100

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    End point title
    		 Mean change from baseline in Best Corrected Visual Acuity (BCVA) at Week 100
    End point description
    Best Corrected Visual Acuity (BCVA) was measured in the study eye by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting at 4 meters. The ETDRS chart includes 70 letters in total and the letter score ranges from 0 to 100. More letters read correctly results in a higher letter score, which represents better visual acuity.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 100
    End point values
    		 Aflibercept 2 mg fixed Aflibercept 2 mg extended Aflibercept 2 mg PRN
    Number of subjects analysed
    153
    152
    153
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    0.1 ( 7.2 )
    -0.1 ( 9.1 )
    1.8 ( 9.0 )
    Statistical analysis title
    		 Analysis of covariance for BCVA change
    Statistical analysis description
    Aflibercept 2 mg fixed was regarded as the reference arm
    Comparison groups
    Aflibercept 2 mg fixed v Aflibercept 2 mg extended
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 [5]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares mean difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.13
         upper limit
    		 1.52
    Notes
    [5] - Non-inferiority margin: 4 letters
    Statistical analysis title
    		 Analysis of covariance for BCVA change
    Statistical analysis description
    Aflibercept 2 mg fixed was regarded as the reference arm
    Comparison groups
    Aflibercept 2 mg fixed v Aflibercept 2 mg PRN
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    		 [6]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares mean difference
    Point estimate
    1.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 3.19
    Notes
    [6] - Non-inferiority margin: 4 letters

    Secondary: Mean change from baseline in Central Retinal Thickness (CRT) at Week 100

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    End point title
    		 Mean change from baseline in Central Retinal Thickness (CRT) at Week 100
    End point description
    Central Retinal Thickness (CRT) was measured in the study eye by spectral domain optical coherence tomography (SD-OCT).
    End point type
    Secondary
    End point timeframe
    From baseline to Week 100
    End point values
    		 Aflibercept 2 mg fixed Aflibercept 2 mg extended Aflibercept 2 mg PRN
    Number of subjects analysed
    153
    152
    153
    Units: Microns
        arithmetic mean (standard deviation)
    -15.5 ( 64.3 )
    2.3 ( 81.8 )
    -13.9 ( 74.4 )
    Statistical analysis title
    		 Analysis of covariance for BCVA change
    Statistical analysis description
    Aflibercept 2 mg fixed was regarded as the reference arm
    Comparison groups
    Aflibercept 2 mg fixed v Aflibercept 2 mg extended
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0416
    Method
    		 ANCOVA
    Parameter type
    		 Least Square mean difference
    Point estimate
    16.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 31.66
    Statistical analysis title
    		 Analysis of covariance for CRT change
    Statistical analysis description
    Aflibercept 2 mg fixed was regarded as the reference arm
    Comparison groups
    Aflibercept 2 mg fixed v Aflibercept 2 mg PRN
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5524
    Method
    		 ANCOVA
    Parameter type
    		 Least Square mean difference
    Point estimate
    4.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.52
         upper limit
    		 17.77

    Secondary: Number of participants with categorized changes from baseline in Best Corrected Visual Acuity (BCVA) at Week 100

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    End point title
    		 Number of participants with categorized changes from baseline in Best Corrected Visual Acuity (BCVA) at Week 100
    End point description
    Best Corrected Visual Acuity (BCVA) was measured in the study eye by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting at 4 meters. The ETDRS chart includes 70 letters in total and the letter score ranges from 0 to 100. More letters read correctly results in a higher letter score, which represents better visual acuity
    End point type
    Secondary
    End point timeframe
    From baseline to Week 100
    End point values
    		 Aflibercept 2 mg fixed Aflibercept 2 mg extended Aflibercept 2 mg PRN
    Number of subjects analysed
    153
    152
    153
    Units: Participants
        ≥ 15 letter gain
    3
    4
    6
        ≥ 10 letter gain
    10
    17
    22
        ≥ 30 letter loss
    1
    2
    2
    Statistical analysis title
    		 Categorized changes for ≥ 15 letter gain in BCVA
    Statistical analysis description
    Aflibercept 2 mg fixed was regarded as the reference arm
    Comparison groups
    Aflibercept 2 mg fixed v Aflibercept 2 mg extended
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.72
         upper limit
    		 4.05
    Statistical analysis title
    		 Categorized changes for ≥ 10 letter gain in BCVA
    Statistical analysis description
    Aflibercept 2 mg fixed was regarded as the reference arm
    Comparison groups
    Aflibercept 2 mg fixed v Aflibercept 2 mg extended
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    4.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.73
         upper limit
    		 10.98
    Statistical analysis title
    		 Categorized changes for ≥ 30 letter loss in BCVA
    Statistical analysis description
    Aflibercept 2 mg fixed was regarded as the reference arm
    Comparison groups
    Aflibercept 2 mg fixed v Aflibercept 2 mg extended
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.56
         upper limit
    		 2.87
    Statistical analysis title
    		 Categorized changes for ≥ 15 letter gain in BCVA
    Statistical analysis description
    Aflibercept 2 mg fixed was regarded as the reference arm
    Comparison groups
    Aflibercept 2 mg fixed v Aflibercept 2 mg PRN
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.89
         upper limit
    		 5.69
    Statistical analysis title
    		 Categorized changes for ≥ 10 letter gain in BCVA
    Statistical analysis description
    Aflibercept 2 mg fixed was regarded as the reference arm
    Comparison groups
    Aflibercept 2 mg fixed v Aflibercept 2 mg PRN
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    7.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 14.28
    Statistical analysis title
    		 Categorized changes for ≥ 30 letter loss in BCVA
    Statistical analysis description
    Aflibercept 2 mg fixed was regarded as the reference arm
    Comparison groups
    Aflibercept 2 mg fixed v Aflibercept 2 mg PRN
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.61
         upper limit
    		 2.88

    Secondary: Number of participants with treatment-emergent adverse event (TEAE)

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    End point title
    		 Number of participants with treatment-emergent adverse event (TEAE)
    End point description
    AEs that started after the first application of aflibercept under this protocol until 30 days after the last dose of study drug administration
    End point type
    Secondary
    End point timeframe
    Up to Week 100
    End point values
    		 Aflibercept 2 mg fixed Aflibercept 2 mg extended Aflibercept 2 mg PRN
    Number of subjects analysed
    155
    154
    154
    Units: Participants
    129
    128
    129
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    After the first application of Aflibercept under this protocol and within 30 days after the last dose of study drug administration.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Aflibercept 2 mg fixed
    Reporting group description
    		 Participants received fixed dosing of 2 mg aflibercept at injection intervals of 8 weeks

    Reporting group title
    Aflibercept 2 mg extended
    Reporting group description
    		 Participants received flexible dosing of 2 mg aflibercept at injection intervals of >=8 week

    Reporting group title
    Aflibercept 2 mg PRN
    Reporting group description
    		 Participants received monthly monitoring with 2 mg aflibercept injection pro re nata (PRN, as needed)

    Serious adverse events
    		 Aflibercept 2 mg fixed Aflibercept 2 mg extended Aflibercept 2 mg PRN
    Total subjects affected by serious adverse events
         subjects affected / exposed
    35 / 155 (22.58%)
    38 / 154 (24.68%)
    37 / 154 (24.03%)
         number of deaths (all causes)
    3
    6
    8
         number of deaths resulting from adverse events
    1
    3
    4
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (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 lung neoplasm
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer stage III
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (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
    Bronchial carcinoma
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (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
    Meningioma
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer stage IV
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastatic bronchial carcinoma
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (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
    Benign spleen tumour
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic cancer
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (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
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (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
    Hypertension
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (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 ischaemia
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         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
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (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
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (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
    Arterial occlusive disease
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (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
    Surgical and medical procedures
    Angioplasty
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         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 pacemaker insertion
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (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
    Toe amputation
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary arterial stent insertion
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (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 rehabilitation therapy
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rehabilitation therapy
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal hernia repair
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (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
    Heart valve replacement
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cataract operation
         subjects affected / exposed
    2 / 155 (1.29%)
    1 / 154 (0.65%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intraocular lens implant
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (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 artery bypass
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (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
    Death
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Fatigue
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (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
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (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
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine prolapse
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Product issues
    Device loosening
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         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
    Angiocardiogram
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 154 (1.30%)
    0 / 154 (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
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (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
    Femoral neck fracture
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (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
    Femur fracture
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (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
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaw fracture
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         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 disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 155 (0.65%)
    2 / 154 (1.30%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (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
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (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 / 155 (0.65%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (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
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         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 arrest
         subjects affected / exposed
    0 / 155 (0.00%)
    3 / 154 (1.95%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Cardiac failure
         subjects affected / exposed
    1 / 155 (0.65%)
    2 / 154 (1.30%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (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 chronic
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 154 (1.30%)
    0 / 154 (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
    Cardiogenic shock
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         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 occlusion
         subjects affected / exposed
    2 / 155 (1.29%)
    0 / 154 (0.00%)
    0 / 154 (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
    Myocardial infarction
         subjects affected / exposed
    5 / 155 (3.23%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    2 / 155 (1.29%)
    0 / 154 (0.00%)
    0 / 154 (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
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Transient ischaemic attack
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lacunar stroke
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (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
    Thrombocytopenia
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (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
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (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
    Neurosensory hypoacusis
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (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
         subjects affected / exposed
    0 / 155 (0.00%)
    3 / 154 (1.95%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cataract nuclear
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (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 subcapsular
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (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
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (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
    Choroidal neovascularisation
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (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
    Macular fibrosis
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (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
    Inguinal hernia
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (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
    Large intestine polyp
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (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
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (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
    Cholelithiasis
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic neuropathic ulcer
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    1 / 155 (0.65%)
    2 / 154 (1.30%)
    0 / 154 (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
    Diabetic foot
         subjects affected / exposed
    1 / 155 (0.65%)
    1 / 154 (0.65%)
    3 / 154 (1.95%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic skin ulcer
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephropathy
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (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
    Urinary retention
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         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 nephropathy
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (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 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 155 (0.65%)
    1 / 154 (0.65%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (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
    End stage renal disease
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Dupuytren's contracture
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (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
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    2 / 155 (1.29%)
    1 / 154 (0.65%)
    0 / 154 (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
    Cystitis
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (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
    Gangrene
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    2 / 155 (1.29%)
    0 / 154 (0.00%)
    0 / 154 (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
    Pneumonia
         subjects affected / exposed
    1 / 155 (0.65%)
    2 / 154 (1.30%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 155 (0.65%)
    1 / 154 (0.65%)
    0 / 154 (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
    Pyelonephritis acute
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (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
    Sepsis
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         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
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (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
    Wound infection
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (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
    Peritonsillitis
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (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
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Biliary sepsis
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 154 (0.00%)
    0 / 154 (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 foot infection
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    3 / 155 (1.94%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (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
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (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
    Hyperglycaemia
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 154 (0.00%)
    1 / 154 (0.65%)
         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
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (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
    Obesity
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (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
    Tetany
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (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 metabolic decompensation
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiometabolic syndrome
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 154 (0.65%)
    0 / 154 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Aflibercept 2 mg fixed Aflibercept 2 mg extended Aflibercept 2 mg PRN
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    97 / 155 (62.58%)
    85 / 154 (55.19%)
    98 / 154 (63.64%)
    Investigations
    Intraocular pressure increased
         subjects affected / exposed
    11 / 155 (7.10%)
    4 / 154 (2.60%)
    11 / 154 (7.14%)
         occurrences all number
    14
    5
    14
    Eye disorders
    Cataract
         subjects affected / exposed
    27 / 155 (17.42%)
    29 / 154 (18.83%)
    24 / 154 (15.58%)
         occurrences all number
    37
    41
    35
    Cataract cortical
         subjects affected / exposed
    8 / 155 (5.16%)
    7 / 154 (4.55%)
    6 / 154 (3.90%)
         occurrences all number
    11
    10
    10
    Cataract nuclear
         subjects affected / exposed
    9 / 155 (5.81%)
    0 / 154 (0.00%)
    7 / 154 (4.55%)
         occurrences all number
    11
    0
    8
    Cataract subcapsular
         subjects affected / exposed
    7 / 155 (4.52%)
    9 / 154 (5.84%)
    8 / 154 (5.19%)
         occurrences all number
    10
    10
    10
    Diabetic retinal oedema
         subjects affected / exposed
    12 / 155 (7.74%)
    13 / 154 (8.44%)
    14 / 154 (9.09%)
         occurrences all number
    15
    17
    17
    Diabetic retinopathy
         subjects affected / exposed
    14 / 155 (9.03%)
    14 / 154 (9.09%)
    18 / 154 (11.69%)
         occurrences all number
    18
    18
    23
    Macular oedema
         subjects affected / exposed
    8 / 155 (5.16%)
    11 / 154 (7.14%)
    17 / 154 (11.04%)
         occurrences all number
    10
    14
    32
    Maculopathy
         subjects affected / exposed
    3 / 155 (1.94%)
    1 / 154 (0.65%)
    13 / 154 (8.44%)
         occurrences all number
    4
    2
    20
    Posterior capsule opacification
         subjects affected / exposed
    5 / 155 (3.23%)
    9 / 154 (5.84%)
    10 / 154 (6.49%)
         occurrences all number
    6
    9
    12
    Retinal haemorrhage
         subjects affected / exposed
    4 / 155 (2.58%)
    3 / 154 (1.95%)
    10 / 154 (6.49%)
         occurrences all number
    7
    3
    21
    Visual acuity reduced
         subjects affected / exposed
    25 / 155 (16.13%)
    22 / 154 (14.29%)
    22 / 154 (14.29%)
         occurrences all number
    42
    30
    30
    Cystoid macular oedema
         subjects affected / exposed
    14 / 155 (9.03%)
    12 / 154 (7.79%)
    10 / 154 (6.49%)
         occurrences all number
    25
    17
    15
    Macular fibrosis
         subjects affected / exposed
    7 / 155 (4.52%)
    6 / 154 (3.90%)
    10 / 154 (6.49%)
         occurrences all number
    7
    7
    11
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    4 / 155 (2.58%)
    1 / 154 (0.65%)
    8 / 154 (5.19%)
         occurrences all number
    7
    1
    12
    Influenza
         subjects affected / exposed
    8 / 155 (5.16%)
    3 / 154 (1.95%)
    8 / 154 (5.19%)
         occurrences all number
    8
    3
    8
    Nasopharyngitis
         subjects affected / exposed
    14 / 155 (9.03%)
    14 / 154 (9.09%)
    17 / 154 (11.04%)
         occurrences all number
    18
    18
    24
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    24 / 155 (15.48%)
    10 / 154 (6.49%)
    15 / 154 (9.74%)
         occurrences all number
    26
    10
    15

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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