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    Clinical Trial Results:
    A Double-Masked, Randomized, Controlled Study of the Safety, Tolerability and Biological Effect of Repeated Intravitreal Administration of VEGF Trap-Eye in Patients with Diabetic Macular Edema (DME).

    Summary
    EudraCT number
    2008-008200-40
    Trial protocol
    AT  
    Global end of trial date
    07 Sep 2010

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

    Trial information

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    Trial identification
    Sponsor protocol code
    VGFT-OD-0706
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00789477
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Regeneron Pharmaceuticals, Inc.
    Sponsor organisation address
    777 Old Saw Mill River Road, Tarrytown, United States, 10591
    Public contact
    Clinical Trial Management, Regeneron Pharmaceuticals, Inc., clinicaltrials@regeneron.com
    Scientific contact
    Clinical Trial Management, Regeneron Pharmaceuticals, Inc., clinicaltrials@regeneron.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
    30 Nov 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Sep 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to explore the effect of various doses and dose intervals of intravitreally (IVT)-administered VEGF Trap-Eye on the best-corrected visual acuity (BCVA) in subjects with diabetic macular edema (DME).
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with the International Conference on Harmonisation (ICH) guidelines for Good Clinical Practice (GCP) and applicable regulatory requirements.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    02 Dec 2008
    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
    United States: 206
    Country: Number of subjects enrolled
    Austria: 8
    Country: Number of subjects enrolled
    Canada: 5
    Worldwide total number of subjects
    219
    EEA total number of subjects
    8
    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)
    129
    From 65 to 84 years
    86
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects with clinically significant DME with central involvement and a BCVA of 20/40 to 20/320 (letter score of 73 to 24) in the study eye were eligible to enter the study. Out of 284 screened, a total of 221 subjects were randomized at 39 centers in the US, Canada, & Austria. Of the 221 randomized subjects, 219 were treated.

    Pre-assignment
    Screening details
    Subjects were screened at visit 1 (day -21 to day -1). Eligible subjects were enrolled and randomized on day 1 (visit 2), and received treatment (active/sham) at each study visit every 4 weeks (day 1 [visit 2] to week 52 [visit 16]).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Laser Photocoagulation
    Arm description
    Focal laser using modified Early Treatment Diabetic Retinopathy Study (ETDRS) technique at week 1, and 1 week after visits at which the subject met laser re-treatment criteria to the end of the study (week 52) starting at week 16 (visit 7); laser re-treatment was permitted no more than once every 16 weeks ± 3 days. All subjects were evaluated for VEGF Trap-Eye re-treatment criteria starting at week 12 for masking purposes. Subjects randomized to the laser group received sham injection at visit 2 (day 1) and at every study visit starting at week 4 (visit 4).
    Arm type
    Reference treatment

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Intravitreal Aflibercept Injection (IAI) 0.5q4
    Arm description
    0.5 mg Intravitreal Aflibercept Injection (IAI;VEGF Trap-Eye;EYLEA®;BAY86-5321) administered every 4 weeks (0.5q4) to week 52. All subjects were evaluated for VEGF Trap-Eye re-treatment criteria starting at week 12 for masking purposes. Subjects randomized to the VEGF Trap-Eye groups received sham laser at week 1 (visit 3). Starting at week 24 (visit 9), subjects were allowed to receive active laser when they met the criteria for laser rescue.
    Arm type
    Experimental

    Investigational medicinal product name
    Aflibercept
    Investigational medicinal product code
    BAY86-5321
    Other name
    EYLEA®; VEGF Trap-Eye
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Intravitreal aflibercept injection administered at the site by IVT injection using standard ophthalmic techniques.

    Arm title
    Intravitreal Aflibercept Injection (IAI) 2q4
    Arm description
    2 mg Intravitreal Aflibercept Injection (IAI;VEGF Trap-Eye;EYLEA®;BAY86-5321) administered every 4 weeks (2q4) to week 52. All subjects were evaluated for VEGF Trap-Eye re-treatment criteria starting at week 12 for masking purposes. Subjects randomized to the VEGF Trap-Eye groups received sham laser at week 1 (visit 3). Starting at week 24 (visit 9), subjects were allowed to receive active laser when they met the criteria for laser rescue.
    Arm type
    Experimental

    Investigational medicinal product name
    Aflibercept
    Investigational medicinal product code
    BAY86-5321
    Other name
    EYLEA®; VEGF Trap-Eye
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Intravitreal aflibercept injection administered at the site by IVT injection using standard ophthalmic techniques.

    Arm title
    Intravitreal Aflibercept Injection (IAI) 2q8
    Arm description
    2 mg Intravitreal Aflibercept Injection (IAI;VEGF Trap-Eye;EYLEA®;BAY86-5321) administered every 4 weeks for 3 visits (day 1, week 4 and week 8), followed by 2 mg dosing every 8 weeks (2q8) through week 52 and sham injections at alternating visits (when study drug was not to be administered). All subjects were evaluated for VEGF Trap-Eye re-treatment criteria starting at week 12 for masking purposes. Subjects randomized to the VEGF Trap-Eye groups received sham laser at week 1 (visit 3). Starting at week 24 (visit 9), subjects were allowed to receive active laser when they met the criteria for laser rescue.
    Arm type
    Experimental

    Investigational medicinal product name
    Aflibercept
    Investigational medicinal product code
    BAY86-5321
    Other name
    EYLEA®; VEGF Trap-Eye
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Intravitreal aflibercept injection administered at the site by IVT injection using standard ophthalmic techniques.

    Arm title
    Intravitreal Aflibercept Injection (IAI) 2PRN
    Arm description
    2 mg Intravitreal Aflibercept Injection (IAI; VEGF Trap-Eye; EYLEA®;BAY86-5321) administered every 4 weeks for 3 visits (day 1, week 4 and week 8), followed by 2 mg dosing PRN (as-needed) according to the VEGF Trap-Eye re-treatment criteria to week 52 and sham injections at visits at which VEGF Trap-Eye re-treatment criteria were not met. All subjects were evaluated for VEGF Trap-Eye re-treatment criteria starting at week 12 for masking purposes. Subjects randomized to the VEGF Trap-Eye groups received sham laser at week 1 (visit 3). Starting at week 24 (visit 9), subjects were allowed to receive active laser when they met the criteria for laser rescue.
    Arm type
    Experimental

    Investigational medicinal product name
    Aflibercept
    Investigational medicinal product code
    BAY86-5321
    Other name
    EYLEA®; VEGF Trap-Eye
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Intravitreal aflibercept injection administered at the site by IVT injection using standard ophthalmic techniques.

    Number of subjects in period 1
    Laser Photocoagulation Intravitreal Aflibercept Injection (IAI) 0.5q4 Intravitreal Aflibercept Injection (IAI) 2q4 Intravitreal Aflibercept Injection (IAI) 2q8 Intravitreal Aflibercept Injection (IAI) 2PRN
    Started
    44
    44
    44
    42
    45
    Completed
    32
    37
    32
    34
    36
    Not completed
    12
    7
    12
    8
    9
         Home hospice care
    -
    -
    -
    1
    -
         Did not return for Visit 18
    1
    -
    -
    -
    -
         Protocol deviation
    1
    -
    -
    1
    -
         Too many missed visits
    -
    -
    1
    -
    -
         Lack of efficacy
    2
    -
    -
    -
    -
         Developed CRVO in study eye-may receive avastin
    1
    -
    -
    -
    -
         Adverse event, serious fatal
    1
    1
    2
    2
    -
         Adverse event, non-fatal
    3
    3
    1
    -
    -
         Consent withdrawn by subject
    2
    2
    4
    2
    4
         Lost to follow-up
    -
    1
    4
    2
    5
         PI treating non-study eye with disallowed med.
    1
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Laser Photocoagulation
    Reporting group description
    Focal laser using modified Early Treatment Diabetic Retinopathy Study (ETDRS) technique at week 1, and 1 week after visits at which the subject met laser re-treatment criteria to the end of the study (week 52) starting at week 16 (visit 7); laser re-treatment was permitted no more than once every 16 weeks ± 3 days. All subjects were evaluated for VEGF Trap-Eye re-treatment criteria starting at week 12 for masking purposes. Subjects randomized to the laser group received sham injection at visit 2 (day 1) and at every study visit starting at week 4 (visit 4).

    Reporting group title
    Intravitreal Aflibercept Injection (IAI) 0.5q4
    Reporting group description
    0.5 mg Intravitreal Aflibercept Injection (IAI;VEGF Trap-Eye;EYLEA®;BAY86-5321) administered every 4 weeks (0.5q4) to week 52. All subjects were evaluated for VEGF Trap-Eye re-treatment criteria starting at week 12 for masking purposes. Subjects randomized to the VEGF Trap-Eye groups received sham laser at week 1 (visit 3). Starting at week 24 (visit 9), subjects were allowed to receive active laser when they met the criteria for laser rescue.

    Reporting group title
    Intravitreal Aflibercept Injection (IAI) 2q4
    Reporting group description
    2 mg Intravitreal Aflibercept Injection (IAI;VEGF Trap-Eye;EYLEA®;BAY86-5321) administered every 4 weeks (2q4) to week 52. All subjects were evaluated for VEGF Trap-Eye re-treatment criteria starting at week 12 for masking purposes. Subjects randomized to the VEGF Trap-Eye groups received sham laser at week 1 (visit 3). Starting at week 24 (visit 9), subjects were allowed to receive active laser when they met the criteria for laser rescue.

    Reporting group title
    Intravitreal Aflibercept Injection (IAI) 2q8
    Reporting group description
    2 mg Intravitreal Aflibercept Injection (IAI;VEGF Trap-Eye;EYLEA®;BAY86-5321) administered every 4 weeks for 3 visits (day 1, week 4 and week 8), followed by 2 mg dosing every 8 weeks (2q8) through week 52 and sham injections at alternating visits (when study drug was not to be administered). All subjects were evaluated for VEGF Trap-Eye re-treatment criteria starting at week 12 for masking purposes. Subjects randomized to the VEGF Trap-Eye groups received sham laser at week 1 (visit 3). Starting at week 24 (visit 9), subjects were allowed to receive active laser when they met the criteria for laser rescue.

    Reporting group title
    Intravitreal Aflibercept Injection (IAI) 2PRN
    Reporting group description
    2 mg Intravitreal Aflibercept Injection (IAI; VEGF Trap-Eye; EYLEA®;BAY86-5321) administered every 4 weeks for 3 visits (day 1, week 4 and week 8), followed by 2 mg dosing PRN (as-needed) according to the VEGF Trap-Eye re-treatment criteria to week 52 and sham injections at visits at which VEGF Trap-Eye re-treatment criteria were not met. All subjects were evaluated for VEGF Trap-Eye re-treatment criteria starting at week 12 for masking purposes. Subjects randomized to the VEGF Trap-Eye groups received sham laser at week 1 (visit 3). Starting at week 24 (visit 9), subjects were allowed to receive active laser when they met the criteria for laser rescue.

    Reporting group values
    Laser Photocoagulation Intravitreal Aflibercept Injection (IAI) 0.5q4 Intravitreal Aflibercept Injection (IAI) 2q4 Intravitreal Aflibercept Injection (IAI) 2q8 Intravitreal Aflibercept Injection (IAI) 2PRN Total
    Number of subjects
    44 44 44 42 45 219
    Age categorical
    Full analysis set (FAS)
    Units: Subjects
        In utero
    0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0 0
        Adults (18-64 years)
    24 24 29 22 30 129
        From 65-84 years
    20 18 13 20 15 86
        85 years and over
    0 2 2 0 0 4
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    64.0 ± 8.12 62.3 ± 10.70 62.1 ± 10.50 62.5 ± 11.49 60.7 ± 8.66 -
    Gender categorical
    Units: Subjects
        Male
    27 24 27 22 29 129
        Female
    17 20 17 20 16 90
    Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score
    Visual function of the study eye and the fellow eye will be assessed using the ETDRS protocol (The Early Treatment Diabetic Retinopathy Study Group, 1985) at 4 meters.
    Units: letters correctly read
        arithmetic mean (standard deviation)
    57.6 ± 12.47 59.3 ± 11.16 59.9 ± 10.07 58.8 ± 12.23 59.6 ± 11.06 -
    Central Retinal Thickness (CRT)
    Retinal and lesion characteristics will be evaluated using time domain Optical Coherence Tomography (OCT) on the study eye.
    Units: microns
        arithmetic mean (standard deviation)
    440.6 ± 145.41 426.1 ± 128.9 456.6 ± 134.95 434.8 ± 111.83 426.6 ± 152.37 -

    End points

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    End points reporting groups
    Reporting group title
    Laser Photocoagulation
    Reporting group description
    Focal laser using modified Early Treatment Diabetic Retinopathy Study (ETDRS) technique at week 1, and 1 week after visits at which the subject met laser re-treatment criteria to the end of the study (week 52) starting at week 16 (visit 7); laser re-treatment was permitted no more than once every 16 weeks ± 3 days. All subjects were evaluated for VEGF Trap-Eye re-treatment criteria starting at week 12 for masking purposes. Subjects randomized to the laser group received sham injection at visit 2 (day 1) and at every study visit starting at week 4 (visit 4).

    Reporting group title
    Intravitreal Aflibercept Injection (IAI) 0.5q4
    Reporting group description
    0.5 mg Intravitreal Aflibercept Injection (IAI;VEGF Trap-Eye;EYLEA®;BAY86-5321) administered every 4 weeks (0.5q4) to week 52. All subjects were evaluated for VEGF Trap-Eye re-treatment criteria starting at week 12 for masking purposes. Subjects randomized to the VEGF Trap-Eye groups received sham laser at week 1 (visit 3). Starting at week 24 (visit 9), subjects were allowed to receive active laser when they met the criteria for laser rescue.

    Reporting group title
    Intravitreal Aflibercept Injection (IAI) 2q4
    Reporting group description
    2 mg Intravitreal Aflibercept Injection (IAI;VEGF Trap-Eye;EYLEA®;BAY86-5321) administered every 4 weeks (2q4) to week 52. All subjects were evaluated for VEGF Trap-Eye re-treatment criteria starting at week 12 for masking purposes. Subjects randomized to the VEGF Trap-Eye groups received sham laser at week 1 (visit 3). Starting at week 24 (visit 9), subjects were allowed to receive active laser when they met the criteria for laser rescue.

    Reporting group title
    Intravitreal Aflibercept Injection (IAI) 2q8
    Reporting group description
    2 mg Intravitreal Aflibercept Injection (IAI;VEGF Trap-Eye;EYLEA®;BAY86-5321) administered every 4 weeks for 3 visits (day 1, week 4 and week 8), followed by 2 mg dosing every 8 weeks (2q8) through week 52 and sham injections at alternating visits (when study drug was not to be administered). All subjects were evaluated for VEGF Trap-Eye re-treatment criteria starting at week 12 for masking purposes. Subjects randomized to the VEGF Trap-Eye groups received sham laser at week 1 (visit 3). Starting at week 24 (visit 9), subjects were allowed to receive active laser when they met the criteria for laser rescue.

    Reporting group title
    Intravitreal Aflibercept Injection (IAI) 2PRN
    Reporting group description
    2 mg Intravitreal Aflibercept Injection (IAI; VEGF Trap-Eye; EYLEA®;BAY86-5321) administered every 4 weeks for 3 visits (day 1, week 4 and week 8), followed by 2 mg dosing PRN (as-needed) according to the VEGF Trap-Eye re-treatment criteria to week 52 and sham injections at visits at which VEGF Trap-Eye re-treatment criteria were not met. All subjects were evaluated for VEGF Trap-Eye re-treatment criteria starting at week 12 for masking purposes. Subjects randomized to the VEGF Trap-Eye groups received sham laser at week 1 (visit 3). Starting at week 24 (visit 9), subjects were allowed to receive active laser when they met the criteria for laser rescue.

    Primary: Change in Best Corrected Visual Acuity (BCVA) From Baseline to Week 24 - Last Observation Carried Forward (LOCF)

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    End point title
    Change in Best Corrected Visual Acuity (BCVA) From Baseline to Week 24 - Last Observation Carried Forward (LOCF)
    End point description
    Visual function of the study eye was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol at 4 meters. Measurements were taken at every study visit. Missing values were imputed with post-baseline values during on-treatment period by using last observation carried forward (LOCF). Full analysis set (FAS): included all randomized subjects who received any study drug, had baseline assessments, and had at least 1 post-baseline assessment.
    End point type
    Primary
    End point timeframe
    Baseline to Week 24
    End point values
    Laser Photocoagulation Intravitreal Aflibercept Injection (IAI) 0.5q4 Intravitreal Aflibercept Injection (IAI) 2q4 Intravitreal Aflibercept Injection (IAI) 2q8 Intravitreal Aflibercept Injection (IAI) 2PRN
    Number of subjects analysed
    44
    44
    44
    42
    45
    Units: letters correctly read
        arithmetic mean (standard deviation)
    2.5 ± 16.14
    8.6 ± 14.64
    11.4 ± 8.67
    8.5 ± 7.50
    10.3 ± 7.52
    Statistical analysis title
    IAI 0.5q4 vs Laser
    Statistical analysis description
    Difference in Least Squares (LS) Means
    Comparison groups
    Intravitreal Aflibercept Injection (IAI) 0.5q4 v Laser Photocoagulation
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0054
    Method
    ANCOVA
    Parameter type
    LS means
    Point estimate
    6.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.6
         upper limit
    8.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.36
    Statistical analysis title
    IAI 2q4 vs Laser
    Statistical analysis description
    Difference in LS Means
    Comparison groups
    Laser Photocoagulation v Intravitreal Aflibercept Injection (IAI) 2q4
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    LS means
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    9.6
         upper limit
    11.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.36
    Statistical analysis title
    IAI 2q8 vs Laser
    Statistical analysis description
    Difference in LS Means
    Comparison groups
    Laser Photocoagulation v Intravitreal Aflibercept Injection (IAI) 2q8
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0085
    Method
    ANCOVA
    Parameter type
    LS means
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.3
         upper limit
    8.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.38
    Statistical analysis title
    IAI 2PRN vs Laser
    Statistical analysis description
    Difference in LS Means
    Comparison groups
    Laser Photocoagulation v Intravitreal Aflibercept Injection (IAI) 2PRN
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0004
    Method
    ANCOVA
    Parameter type
    LS means
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    8.4
         upper limit
    10.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.34

    Secondary: Change in BCVA From Baseline to Week 52 - LOCF

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    End point title
    Change in BCVA From Baseline to Week 52 - LOCF
    End point description
    Visual function of the study eye was assessed using the ETDRS protocol at 4 meters. Missing values were imputed with post-baseline values during on-treatment period by using LOCF. Analysis was performed on FAS population.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Laser Photocoagulation Intravitreal Aflibercept Injection (IAI) 0.5q4 Intravitreal Aflibercept Injection (IAI) 2q4 Intravitreal Aflibercept Injection (IAI) 2q8 Intravitreal Aflibercept Injection (IAI) 2PRN
    Number of subjects analysed
    44
    44
    44
    42
    45
    Units: letters correctly read
        arithmetic mean (standard deviation)
    -1.3 ± 20.72
    11.0 ± 15.40
    13.1 ± 10.54
    9.7 ± 8.93
    12.0 ± 11.09
    Statistical analysis title
    IAI 0.5q4 vs Laser
    Statistical analysis description
    Difference in LS Means
    Comparison groups
    Laser Photocoagulation v Intravitreal Aflibercept Injection (IAI) 0.5q4
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    LS means
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    11.1
         upper limit
    12.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.86
    Statistical analysis title
    IAI 2q4 vs Laser
    Statistical analysis description
    Difference in LS Means
    Comparison groups
    Laser Photocoagulation v Intravitreal Aflibercept Injection (IAI) 2q4
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    LS means
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    13.4
         upper limit
    15.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.86
    Statistical analysis title
    IAI 2q8 vs Laser
    Statistical analysis description
    Difference in LS Means
    Comparison groups
    Laser Photocoagulation v Intravitreal Aflibercept Injection (IAI) 2q8
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001
    Method
    ANCOVA
    Parameter type
    LS means
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    9.6
         upper limit
    11.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.89
    Statistical analysis title
    IAI 2PRN vs Laser
    Statistical analysis description
    Difference in LS Means
    Comparison groups
    Laser Photocoagulation v Intravitreal Aflibercept Injection (IAI) 2PRN
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    12.2
         upper limit
    14
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.84

    Secondary: Subjects with Gains in Early Treatment Diabetic Retinopathy (ETDRS) Letter Score of at Least 15 Letters at Week 24 and at Week 52 - LOCF

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    End point title
    Subjects with Gains in Early Treatment Diabetic Retinopathy (ETDRS) Letter Score of at Least 15 Letters at Week 24 and at Week 52 - LOCF
    End point description
    Missing values were imputed with post-baseline values during on-treatment period by using LOCF. Analysis was performed on FAS population.
    End point type
    Secondary
    End point timeframe
    At Week 24 and At Week 52
    End point values
    Laser Photocoagulation Intravitreal Aflibercept Injection (IAI) 0.5q4 Intravitreal Aflibercept Injection (IAI) 2q4 Intravitreal Aflibercept Injection (IAI) 2q8 Intravitreal Aflibercept Injection (IAI) 2PRN
    Number of subjects analysed
    44
    44
    44
    42
    45
    Units: Subjects
    number (not applicable)
        At Week 24
    9
    15
    14
    7
    12
        At Week 52
    5
    18
    20
    10
    19
    No statistical analyses for this end point

    Secondary: Change From Baseline in Central Retinal Thickness (CRT) as Assessed by Optical Coherence Tomography (OCT) at Week 24 and Week 52- LOCF

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    End point title
    Change From Baseline in Central Retinal Thickness (CRT) as Assessed by Optical Coherence Tomography (OCT) at Week 24 and Week 52- LOCF
    End point description
    Retinal thickness was evaluated using OCT at every visit except Week 1. Missing values were imputed with post-baseline values during on-treatment period by using LOCF. Analysis was performed on FAS population.
    End point type
    Secondary
    End point timeframe
    At Week 24 and At Week 52
    End point values
    Laser Photocoagulation Intravitreal Aflibercept Injection (IAI) 0.5q4 Intravitreal Aflibercept Injection (IAI) 2q4 Intravitreal Aflibercept Injection (IAI) 2q8 Intravitreal Aflibercept Injection (IAI) 2PRN
    Number of subjects analysed
    43
    44
    44
    42
    45
    Units: microns
    arithmetic mean (standard deviation)
        Week 24
    -67.9 ± 135.17
    -144.6 ± 110.65
    -194.5 ± 143.04
    -127.3 ± 141.78
    -153.3 ± 132.17
        Week 52
    -58.4 ± 177.6
    -165.4 ± 135.72
    -227.4 ± 148.96
    -187.8 ± 135.01
    -180.3 ± 124.43
    No statistical analyses for this end point

    Secondary: Number of Focal Laser Treatments in the First 48 Weeks

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    End point title
    Number of Focal Laser Treatments in the First 48 Weeks
    End point description
    For the first 24 weeks, the Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) groups did not receive laser treatment. From Week 24 onward, subjects in the Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) groups were allowed to receive laser rescue treatment. Analysis was performed on FAS population.
    End point type
    Secondary
    End point timeframe
    Week 1 to Week 48
    End point values
    Laser Photocoagulation Intravitreal Aflibercept Injection (IAI) 0.5q4 Intravitreal Aflibercept Injection (IAI) 2q4 Intravitreal Aflibercept Injection (IAI) 2q8 Intravitreal Aflibercept Injection (IAI) 2PRN
    Number of subjects analysed
    44
    44
    44
    42
    45
    Units: Treatments
        arithmetic mean (standard deviation)
    2.5 ± 0.87
    0.8 ± 0.83
    0.5 ± 0.66
    0.8 ± 0.86
    0.7 ± 0.77
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 to Week 52
    Adverse event reporting additional description
    Safety analysis set (SAF): included all subjects who received any study drug. The SAF was used for all safety and tolerability assessments. Safety analysis included subjects as treated.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Laser Photocoagulation
    Reporting group description
    Focal laser using modified Early Treatment Diabetic Retinopathy Study (ETDRS) technique at week 1, and 1 week after visits at which the subject met laser re-treatment criteria to the end of the study (week 52) starting at week 16 (visit 7); laser re-treatment was permitted no more than once every 16 weeks ± 3 days. All subjects were evaluated for VEGF Trap-Eye re-treatment criteria starting at week 12 for masking purposes. Subjects randomized to the laser group received sham injection at visit 2 (day 1) and at every study visit starting at week 4 (visit 4).

    Reporting group title
    Intravitreal Aflibercept Injection (IAI) 0.5q4
    Reporting group description
    0.5 mg Intravitreal Aflibercept Injection (IAI;VEGF Trap-Eye;EYLEA®;BAY86-5321) administered every 4 weeks (0.5q4) to week 52. All subjects were evaluated for VEGF Trap-Eye re-treatment criteria starting at week 12 for masking purposes. Subjects randomized to the VEGF Trap-Eye groups received sham laser at week 1 (visit 3). Starting at week 24 (visit 9), subjects were allowed to receive active laser when they met the criteria for laser rescue.

    Reporting group title
    Intravitreal Aflibercept Injection (IAI) 2q4
    Reporting group description
    2 mg Intravitreal Aflibercept Injection (IAI;VEGF Trap-Eye;EYLEA®;BAY86-5321) administered every 4 weeks (2q4) to week 52. All subjects were evaluated for VEGF Trap-Eye re-treatment criteria starting at week 12 for masking purposes. Subjects randomized to the VEGF Trap-Eye groups received sham laser at week 1 (visit 3). Starting at week 24 (visit 9), subjects were allowed to receive active laser when they met the criteria for laser rescue.

    Reporting group title
    Intravitreal Aflibercept Injection (IAI) 2q8
    Reporting group description
    2 mg Intravitreal Aflibercept Injection (IAI;VEGF Trap-Eye;EYLEA®;BAY86-5321) administered every 4 weeks for 3 visits (day 1, week 4 and week 8), followed by 2 mg dosing every 8 weeks (2q8) through week 52 and sham injections at alternating visits (when study drug was not to be administered). All subjects were evaluated for VEGF Trap-Eye re-treatment criteria starting at week 12 for masking purposes. Subjects randomized to the VEGF Trap-Eye groups received sham laser at week 1 (visit 3). Starting at week 24 (visit 9), subjects were allowed to receive active laser when they met the criteria for laser rescue.

    Reporting group title
    Intravitreal Aflibercept Injection (IAI) 2PRN
    Reporting group description
    2 mg Intravitreal Aflibercept Injection (IAI; VEGF Trap-Eye; EYLEA®;BAY86-5321) administered every 4 weeks for 3 visits (day 1, week 4 and week 8), followed by 2 mg dosing PRN (as-needed) according to the VEGF Trap-Eye re-treatment criteria to week 52 and sham injections at visits at which VEGF Trap-Eye re-treatment criteria were not met. All subjects were evaluated for VEGF Trap-Eye re-treatment criteria starting at week 12 for masking purposes. Subjects randomized to the VEGF Trap-Eye groups received sham laser at week 1 (visit 3). Starting at week 24 (visit 9), subjects were allowed to receive active laser when they met the criteria for laser rescue.

    Serious adverse events
    Laser Photocoagulation Intravitreal Aflibercept Injection (IAI) 0.5q4 Intravitreal Aflibercept Injection (IAI) 2q4 Intravitreal Aflibercept Injection (IAI) 2q8 Intravitreal Aflibercept Injection (IAI) 2PRN
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 44 (31.82%)
    16 / 44 (36.36%)
    14 / 44 (31.82%)
    15 / 42 (35.71%)
    7 / 45 (15.56%)
         number of deaths (all causes)
    1
    1
    3
    2
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    2 / 44 (4.55%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive emergency
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer stage iii
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-Small cell lung cancer
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Renal cell carcinoma stage iv
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    2 / 44 (4.55%)
    0 / 42 (0.00%)
    3 / 45 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Multi-Organ failure
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Non-Cardiac chest pain
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Joint capsule rupture
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative ileus
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic brain injury
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Corneal abrasion
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood pressure increased
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    3 / 44 (6.82%)
    1 / 42 (2.38%)
    2 / 45 (4.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 44 (4.55%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sick sinus syndrome
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Silent myocardial infarction
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wolff-Parkinson-White syndrome
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    2 / 44 (4.55%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coagulopathy
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic anaemia
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 44 (2.27%)
    2 / 44 (4.55%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cystoid macular oedema
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic retinopathy
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Maculopathy
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal tear
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Visual acuity reduced
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vitreous adhesions
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    4 / 44 (9.09%)
    1 / 44 (2.27%)
    1 / 44 (2.27%)
    2 / 42 (4.76%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angle closure glaucoma
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic retinal oedema
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uveitis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diverticulum
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varices oesophageal
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephropathy
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stress urinary incontinence
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    2 / 42 (4.76%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    2 / 44 (4.55%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 44 (2.27%)
    1 / 44 (2.27%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 44 (0.00%)
    3 / 44 (6.82%)
    2 / 44 (4.55%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endophthalmitis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Laser Photocoagulation Intravitreal Aflibercept Injection (IAI) 0.5q4 Intravitreal Aflibercept Injection (IAI) 2q4 Intravitreal Aflibercept Injection (IAI) 2q8 Intravitreal Aflibercept Injection (IAI) 2PRN
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 44 (72.73%)
    34 / 44 (77.27%)
    33 / 44 (75.00%)
    34 / 42 (80.95%)
    35 / 45 (77.78%)
    Injury, poisoning and procedural complications
    Corneal abrasion
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    2 / 44 (4.55%)
    2 / 42 (4.76%)
    3 / 45 (6.67%)
         occurrences all number
    0
    0
    3
    2
    3
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 44 (11.36%)
    5 / 44 (11.36%)
    5 / 44 (11.36%)
    6 / 42 (14.29%)
    5 / 45 (11.11%)
         occurrences all number
    7
    5
    5
    7
    5
    Investigations
    Blood glucose increased
         subjects affected / exposed
    1 / 44 (2.27%)
    4 / 44 (9.09%)
    3 / 44 (6.82%)
    6 / 42 (14.29%)
    6 / 45 (13.33%)
         occurrences all number
    1
    4
    3
    6
    6
    Blood potassium increased
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    3 / 42 (7.14%)
    3 / 45 (6.67%)
         occurrences all number
    0
    1
    0
    3
    3
    Blood pressure increased
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 44 (2.27%)
    4 / 44 (9.09%)
    1 / 42 (2.38%)
    1 / 45 (2.22%)
         occurrences all number
    1
    1
    4
    1
    1
    Blood urine present
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    1 / 42 (2.38%)
    3 / 45 (6.67%)
         occurrences all number
    0
    1
    0
    1
    3
    Glucose urine present
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    3 / 42 (7.14%)
    4 / 45 (8.89%)
         occurrences all number
    1
    1
    0
    3
    4
    Glycosylated haemoglobin increased
         subjects affected / exposed
    2 / 44 (4.55%)
    6 / 44 (13.64%)
    5 / 44 (11.36%)
    5 / 42 (11.90%)
    2 / 45 (4.44%)
         occurrences all number
    2
    7
    5
    5
    2
    Haematocrit decreased
         subjects affected / exposed
    2 / 44 (4.55%)
    2 / 44 (4.55%)
    4 / 44 (9.09%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    2
    2
    4
    0
    0
    Haemoglobin decreased
         subjects affected / exposed
    2 / 44 (4.55%)
    2 / 44 (4.55%)
    3 / 44 (6.82%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    2
    2
    3
    0
    0
    Protein urine present
         subjects affected / exposed
    2 / 44 (4.55%)
    1 / 44 (2.27%)
    1 / 44 (2.27%)
    4 / 42 (9.52%)
    3 / 45 (6.67%)
         occurrences all number
    2
    1
    1
    4
    3
    Red blood cell count decreased
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    3 / 44 (6.82%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    3
    0
    1
    Intraocular pressure increased
         subjects affected / exposed
    1 / 44 (2.27%)
    8 / 44 (18.18%)
    7 / 44 (15.91%)
    5 / 42 (11.90%)
    4 / 45 (8.89%)
         occurrences all number
    1
    8
    7
    5
    4
    Urine protein/creatinine ratio increased
         subjects affected / exposed
    2 / 44 (4.55%)
    6 / 44 (13.64%)
    4 / 44 (9.09%)
    5 / 42 (11.90%)
    4 / 45 (8.89%)
         occurrences all number
    3
    7
    4
    5
    5
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    3 / 42 (7.14%)
    1 / 45 (2.22%)
         occurrences all number
    0
    0
    0
    3
    1
    Oropharyngeal pain
         subjects affected / exposed
    3 / 44 (6.82%)
    1 / 44 (2.27%)
    1 / 44 (2.27%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences all number
    3
    1
    1
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 44 (4.55%)
    1 / 44 (2.27%)
    3 / 44 (6.82%)
    4 / 42 (9.52%)
    3 / 45 (6.67%)
         occurrences all number
    2
    1
    3
    4
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 44 (0.00%)
    2 / 44 (4.55%)
    3 / 42 (7.14%)
    2 / 45 (4.44%)
         occurrences all number
    2
    0
    3
    3
    2
    Eye disorders
    Blepharitis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    4 / 44 (9.09%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    0
    5
    0
    2
    Cataract
         subjects affected / exposed
    2 / 44 (4.55%)
    2 / 44 (4.55%)
    4 / 44 (9.09%)
    2 / 42 (4.76%)
    8 / 45 (17.78%)
         occurrences all number
    2
    2
    4
    2
    9
    Conjunctival haemorrhage
         subjects affected / exposed
    8 / 44 (18.18%)
    13 / 44 (29.55%)
    7 / 44 (15.91%)
    16 / 42 (38.10%)
    14 / 45 (31.11%)
         occurrences all number
    21
    40
    9
    39
    33
    Diabetic retinal oedema
         subjects affected / exposed
    0 / 44 (0.00%)
    5 / 44 (11.36%)
    6 / 44 (13.64%)
    1 / 42 (2.38%)
    5 / 45 (11.11%)
         occurrences all number
    0
    6
    6
    2
    8
    Eye pain
         subjects affected / exposed
    5 / 44 (11.36%)
    7 / 44 (15.91%)
    5 / 44 (11.36%)
    7 / 42 (16.67%)
    7 / 45 (15.56%)
         occurrences all number
    5
    17
    5
    10
    16
    Macular oedema
         subjects affected / exposed
    3 / 44 (6.82%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    3
    1
    0
    0
    1
    Posterior capsule opacification
         subjects affected / exposed
    4 / 44 (9.09%)
    3 / 44 (6.82%)
    2 / 44 (4.55%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences all number
    4
    3
    4
    1
    0
    Retinal aneurysm
         subjects affected / exposed
    1 / 44 (2.27%)
    3 / 44 (6.82%)
    0 / 44 (0.00%)
    4 / 42 (9.52%)
    3 / 45 (6.67%)
         occurrences all number
    1
    4
    0
    5
    3
    Retinal haemorrhage
         subjects affected / exposed
    3 / 44 (6.82%)
    1 / 44 (2.27%)
    3 / 44 (6.82%)
    3 / 42 (7.14%)
    5 / 45 (11.11%)
         occurrences all number
    4
    1
    3
    5
    8
    Retinal neovascularisation
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 44 (0.00%)
    2 / 44 (4.55%)
    1 / 42 (2.38%)
    3 / 45 (6.67%)
         occurrences all number
    4
    0
    3
    2
    3
    Vitreous detachment
         subjects affected / exposed
    5 / 44 (11.36%)
    3 / 44 (6.82%)
    3 / 44 (6.82%)
    5 / 42 (11.90%)
    0 / 45 (0.00%)
         occurrences all number
    5
    3
    3
    6
    0
    Vitreous floaters
         subjects affected / exposed
    3 / 44 (6.82%)
    5 / 44 (11.36%)
    4 / 44 (9.09%)
    4 / 42 (9.52%)
    2 / 45 (4.44%)
         occurrences all number
    3
    5
    4
    4
    2
    Vitreous haemorrhage
         subjects affected / exposed
    9 / 44 (20.45%)
    3 / 44 (6.82%)
    6 / 44 (13.64%)
    4 / 42 (9.52%)
    3 / 45 (6.67%)
         occurrences all number
    12
    3
    8
    7
    4
    Anterior chamber cell
         subjects affected / exposed
    0 / 44 (0.00%)
    4 / 44 (9.09%)
    0 / 44 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences all number
    0
    5
    0
    1
    0
    Diabetic retinopathy
         subjects affected / exposed
    3 / 44 (6.82%)
    2 / 44 (4.55%)
    2 / 44 (4.55%)
    1 / 42 (2.38%)
    1 / 45 (2.22%)
         occurrences all number
    3
    2
    2
    1
    1
    Foreign body sensation in eyes
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    1 / 44 (2.27%)
    1 / 42 (2.38%)
    3 / 45 (6.67%)
         occurrences all number
    0
    1
    1
    2
    4
    Maculopathy
         subjects affected / exposed
    2 / 44 (4.55%)
    2 / 44 (4.55%)
    2 / 44 (4.55%)
    4 / 42 (9.52%)
    3 / 45 (6.67%)
         occurrences all number
    2
    2
    2
    4
    3
    Ocular hyperaemia
         subjects affected / exposed
    2 / 44 (4.55%)
    5 / 44 (11.36%)
    2 / 44 (4.55%)
    3 / 42 (7.14%)
    3 / 45 (6.67%)
         occurrences all number
    2
    8
    2
    5
    6
    Punctate keratitis
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    3 / 42 (7.14%)
    0 / 45 (0.00%)
         occurrences all number
    5
    1
    0
    12
    0
    Retinal exudates
         subjects affected / exposed
    2 / 44 (4.55%)
    5 / 44 (11.36%)
    2 / 44 (4.55%)
    3 / 42 (7.14%)
    3 / 45 (6.67%)
         occurrences all number
    2
    5
    2
    4
    7
    Vision blurred
         subjects affected / exposed
    1 / 44 (2.27%)
    5 / 44 (11.36%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    2
    7
    1
    0
    4
    Visual acuity reduced
         subjects affected / exposed
    0 / 44 (0.00%)
    3 / 44 (6.82%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    3
    1
    0
    0
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    3 / 44 (6.82%)
    1 / 44 (2.27%)
    1 / 44 (2.27%)
    2 / 42 (4.76%)
    2 / 45 (4.44%)
         occurrences all number
    3
    1
    1
    2
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 44 (2.27%)
    2 / 44 (4.55%)
    3 / 44 (6.82%)
    4 / 42 (9.52%)
    4 / 45 (8.89%)
         occurrences all number
    1
    2
    3
    4
    4
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 44 (2.27%)
    3 / 44 (6.82%)
    3 / 42 (7.14%)
    1 / 45 (2.22%)
         occurrences all number
    1
    1
    3
    3
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 44 (2.27%)
    3 / 44 (6.82%)
    2 / 44 (4.55%)
    0 / 42 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    1
    3
    2
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    4 / 44 (9.09%)
    4 / 44 (9.09%)
    3 / 44 (6.82%)
    1 / 42 (2.38%)
    3 / 45 (6.67%)
         occurrences all number
    4
    4
    3
    2
    4
    Sinusitis
         subjects affected / exposed
    2 / 44 (4.55%)
    3 / 44 (6.82%)
    0 / 44 (0.00%)
    2 / 42 (4.76%)
    2 / 45 (4.44%)
         occurrences all number
    2
    3
    0
    2
    2
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 44 (9.09%)
    4 / 44 (9.09%)
    2 / 44 (4.55%)
    4 / 42 (9.52%)
    4 / 45 (8.89%)
         occurrences all number
    4
    4
    3
    5
    4
    Urinary tract infection
         subjects affected / exposed
    4 / 44 (9.09%)
    2 / 44 (4.55%)
    5 / 44 (11.36%)
    1 / 42 (2.38%)
    1 / 45 (2.22%)
         occurrences all number
    5
    2
    7
    1
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Nov 2008
    Following changes were made: • Clarified the treatment requirements for the fellow eye • Revised visits, where applicable, to include a post-dose indirect ophthalmoscopy • Revised the role of the unmasked physician to include post-dose indirect ophthalmoscopy but not pre-dose ophthalmoscopy • Revised the screening range to allow for same day enrollment.
    27 Jan 2009
    Following changes were made: • Revised the protocol to exclude subjects with only 1 functional eye or subjects with ocular conditions with a poorer prognosis in the fellow eye • Clarified that multiple, repeated use of the same vial of VEGF Trap-Eye was prohibited • Included Health Canada as a regulatory authority for the study • Changed the technical procedure for microperimetry
    24 Feb 2009
    Changed the needle used to withdraw VEGF Trap-Eye from the vial into the syringe

    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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