Flag of the European Union EU Clinical Trials Register Help

Clinical trials

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


    The EU Clinical Trials Register currently displays   39228   clinical trials with a EudraCT protocol, of which   6426   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Phase 3, Double-Masked, Randomized Study of the Efficacy and Safety of Intravitreal Aflibercept Injection in Patients with Moderately Severe to Severe Nonproliferative Diabetic Retinopathy

    Summary
    EudraCT number
    2016-002639-14
    Trial protocol
    HU   DE   GB  
    Global end of trial date
    16 Jul 2019

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

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    VGFTe-OD-1411
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02718326
    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 Trials Administrator, 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
    14 Aug 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Jul 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to assess the efficacy of intravitreal (IVT) aflibercept compared to sham treatment in the improvement of moderately severe to severe nonproliferative diabetic retinopathy (NPDR). The secondary objectives of the study were: - To characterize the safety of IVT aflibercept in subjects with moderately severe to severe NPDR - To determine if IVT aflibercept will prevent the worsening of diabetic retinopathy and reduce the incidence of DME - To determine the anatomic effects of IVT aflibercept in subjects with moderately severe to severe NPDR
    Protection of trial subjects
    It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical 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
    29 Mar 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Hungary: 10
    Country: Number of subjects enrolled
    Japan: 11
    Country: Number of subjects enrolled
    United States: 374
    Worldwide total number of subjects
    402
    EEA total number of subjects
    17
    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)
    312
    From 65 to 84 years
    89
    85 years and over
    1

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    Recruitment for this study was conducted in the following countries between 29 Mar 2016 and 07 Aug 2017: Germany, Hungary, Japan, the United Kingdom, and the United States. A total of 759 subjects were screened.

    Pre-assignment
    Screening details
    Out of 759, 402 subjects were randomized to receive 1 of 3 treatment groups in a 1:1:1 ratio stratified based on their Diabetic Retinopathy Severity Scale (DRSS) score (level 47 vs. level 53). Only 1 eye was selected as the study eye.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sham treatment
    Arm description
    All subjects received sham injections in the study eye every 4 weeks (Q4) to week 16 (after 5 initial monthly sham injections), followed by sham injections Q8 to week 96.
    Arm type
    Sham injection

    Investigational medicinal product name
    Sham injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Matching sham injections

    Arm title
    Intravitreal Aflibercept Injection (IAI) 2Q16
    Arm description
    All subjects received a 2 milligram (mg) Intravitreal Aflibercept Injection (IAI) in the study eye every 16 weeks (2Q16) (after 3 initial monthly doses and one 8-week interval) to week 96.
    Arm type
    Experimental

    Investigational medicinal product name
    Eylea
    Investigational medicinal product code
    Other name
    VEGF Trap-Eye
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    2mg every 16 weeks (2Q16)

    Arm title
    Intravitreal Aflibercept Injection (IAI) 2Q8
    Arm description
    All subjects received 2 mg IAI in the study eye every 8 weeks (2Q8) from day 1 up to week 48 (after 5 initial monthly doses), followed by a flexible treatment regimen with IAI 2 mg to week 96.
    Arm type
    Experimental

    Investigational medicinal product name
    Eylea
    Investigational medicinal product code
    Other name
    VEGF Trap-Eye
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    2 mg every 8 weeks (2Q8); PRN per protocol defined criteria from week 56 through 96

    Number of subjects in period 1
    Sham treatment Intravitreal Aflibercept Injection (IAI) 2Q16 Intravitreal Aflibercept Injection (IAI) 2Q8
    Started
    133
    135
    134
    Completed Week 52
    109
    122
    124
    Completed Week 100 (End of Study)
    97
    111
    112
    Completed
    97
    111
    112
    Not completed
    36
    24
    22
         Protocol Deviation
    1
    -
    -
         Pregnancy
    1
    -
    -
         Adverse event, serious fatal
    8
    1
    2
         Adverse event, non-fatal
    4
    9
    -
         Consent withdrawn by subject
    4
    9
    6
         Lost to follow-up
    18
    5
    14

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Sham treatment
    Reporting group description
    All subjects received sham injections in the study eye every 4 weeks (Q4) to week 16 (after 5 initial monthly sham injections), followed by sham injections Q8 to week 96.

    Reporting group title
    Intravitreal Aflibercept Injection (IAI) 2Q16
    Reporting group description
    All subjects received a 2 milligram (mg) Intravitreal Aflibercept Injection (IAI) in the study eye every 16 weeks (2Q16) (after 3 initial monthly doses and one 8-week interval) to week 96.

    Reporting group title
    Intravitreal Aflibercept Injection (IAI) 2Q8
    Reporting group description
    All subjects received 2 mg IAI in the study eye every 8 weeks (2Q8) from day 1 up to week 48 (after 5 initial monthly doses), followed by a flexible treatment regimen with IAI 2 mg to week 96.

    Reporting group values
    Sham treatment Intravitreal Aflibercept Injection (IAI) 2Q16 Intravitreal Aflibercept Injection (IAI) 2Q8 Total
    Number of subjects
    133 135 134 402
    Age categorical
    Units: Subjects
        <40 years
    11 14 10 35
        ≥40 - <65 years
    94 92 91 277
        ≥65 years
    28 29 33 90
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    55.8 ± 10.31 55.4 ± 11.13 55.8 ± 10.19 -
    Sex: Female, Male
    Units:
        Female
    64 60 53 177
        Male
    69 75 81 225
    Ethnicity (NIH/OMB)
    Units: Subjects
        Not Hispanic or Latino
    74 97 93 264
        Hispanic or Latino
    58 37 41 136
        Not Reported
    1 1 0 2
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    1 1 4 6
        Asian
    4 12 7 23
        Native Hawaiian or Other Pacific Islander
    0 1 1 2
        Black or African American
    13 16 12 41
        White
    107 99 104 310
        More than one race
    0 1 1 2
        Not Reported
    8 5 5 18
    Baseline Diabetic Retinopathy Severity Score (DRSS)
    The Diabetic Retinopathy Disease Severity Scale (DRSS) may be used to describe overall retinopathy severity as well as the change in severity over time. Severity range from level 10 (DR absent) to level 85 (advanced proliferative DR: posterior fundus obscured, or center of macula detached).
    Units: Subjects
        Level 47 (Moderately Severe)
    99 102 101 302
        Level 53 (Severe)
    34 33 33 100
    Subject analysis sets

    Subject analysis set title
    IAI 2 mg Groups Combined (2Q16 & 2Q8)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    IAI 2Q16: Subjects received a 2mg IAI in the study eye every 16 weeks (2Q16) (after 3 initial monthly doses and one 8-week interval) to week 96; IAI 2Q8: Subjects received 2mg IAI in the study eye every 8 weeks (2Q8) from day 1 up to week 48 (after 5 initial monthly doses), followed by a flexible treatment regimen with IAI 2 mg to week 96.

    Subject analysis sets values
    IAI 2 mg Groups Combined (2Q16 & 2Q8)
    Number of subjects
    269
    Age categorical
    Units: Subjects
        <40 years
    24
        ≥40 - <65 years
    183
        ≥65 years
    62
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    55.6 ± 10.66
    Sex: Female, Male
    Units:
        Female
    113
        Male
    156
    Ethnicity (NIH/OMB)
    Units: Subjects
        Not Hispanic or Latino
    190
        Hispanic or Latino
    78
        Not Reported
    1
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    5
        Asian
    19
        Native Hawaiian or Other Pacific Islander
    2
        Black or African American
    28
        White
    203
        More than one race
    2
        Not Reported
    10
    Baseline Diabetic Retinopathy Severity Score (DRSS)
    The Diabetic Retinopathy Disease Severity Scale (DRSS) may be used to describe overall retinopathy severity as well as the change in severity over time. Severity range from level 10 (DR absent) to level 85 (advanced proliferative DR: posterior fundus obscured, or center of macula detached).
    Units: Subjects
        Level 47 (Moderately Severe)
    203
        Level 53 (Severe)
    66

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    Sham treatment
    Reporting group description
    All subjects received sham injections in the study eye every 4 weeks (Q4) to week 16 (after 5 initial monthly sham injections), followed by sham injections Q8 to week 96.

    Reporting group title
    Intravitreal Aflibercept Injection (IAI) 2Q16
    Reporting group description
    All subjects received a 2 milligram (mg) Intravitreal Aflibercept Injection (IAI) in the study eye every 16 weeks (2Q16) (after 3 initial monthly doses and one 8-week interval) to week 96.

    Reporting group title
    Intravitreal Aflibercept Injection (IAI) 2Q8
    Reporting group description
    All subjects received 2 mg IAI in the study eye every 8 weeks (2Q8) from day 1 up to week 48 (after 5 initial monthly doses), followed by a flexible treatment regimen with IAI 2 mg to week 96.

    Subject analysis set title
    IAI 2 mg Groups Combined (2Q16 & 2Q8)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    IAI 2Q16: Subjects received a 2mg IAI in the study eye every 16 weeks (2Q16) (after 3 initial monthly doses and one 8-week interval) to week 96; IAI 2Q8: Subjects received 2mg IAI in the study eye every 8 weeks (2Q8) from day 1 up to week 48 (after 5 initial monthly doses), followed by a flexible treatment regimen with IAI 2 mg to week 96.

    Primary: Percentage of Subjects Who Improved by ≥2 Steps from Baseline in the Diabetic Retinopathy Disease Severity Scale (DRSS) Score at Week 24 in the Combined 2Q16 and 2Q8 Groups

    Close Top of page
    End point title
    Percentage of Subjects Who Improved by ≥2 Steps from Baseline in the Diabetic Retinopathy Disease Severity Scale (DRSS) Score at Week 24 in the Combined 2Q16 and 2Q8 Groups
    End point description
    The Diabetic Retinopathy Disease Severity Scale (DRSS) may be used to describe overall retinopathy severity as well as the change in severity over time. Severity range from level 10 (DR absent) to level 85 (advanced proliferative DR: posterior fundus obscured, or center of macula detached). Here, DRSS describes severity level 47 (moderately severe NPDR) and level 53 (severe NPDR) at week 24 from baseline. FAS included all randomized subjects who received any study treatment as assigned at baseline (as randomized). The missing data were imputed using last observation carried forward (LOCF) method.
    End point type
    Primary
    End point timeframe
    At Week 24
    End point values
    Sham treatment Intravitreal Aflibercept Injection (IAI) 2Q16 Intravitreal Aflibercept Injection (IAI) 2Q8 IAI 2 mg Groups Combined (2Q16 & 2Q8)
    Number of subjects analysed
    133
    135
    134
    269
    Units: Percentage of subjects
        number (not applicable)
    6.0
    61.5
    55.2
    58.4
    Statistical analysis title
    Sham treatment, IAI 2 mg Groups Combined
    Comparison groups
    Sham treatment v IAI 2 mg Groups Combined (2Q16 & 2Q8)
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    percentage difference
    Point estimate
    52.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    45.2
         upper limit
    59.5

    Primary: Percentage of Subjects With a ≥ 2-step Change at Week 52 in Diabetic Retinopathy Severity Scale (DRSS) From Baseline

    Close Top of page
    End point title
    Percentage of Subjects With a ≥ 2-step Change at Week 52 in Diabetic Retinopathy Severity Scale (DRSS) From Baseline
    End point description
    The Diabetic Retinopathy Disease Severity Scale (DRSS) may be used to describe overall retinopathy severity as well as the change in severity over time. Severity range from level 10 (DR absent) to level 85 (advanced proliferative DR: posterior fundus obscured, or center of macula detached). Here, DRSS describes severity level 47 (moderately severe NPDR) and level 53 (severe NPDR) at week 52 from baseline. FAS included all randomized subjects who received any study treatment as assigned at baseline (as randomized). The missing data were imputed using LOCF method.
    End point type
    Primary
    End point timeframe
    At Week 52
    End point values
    Sham treatment Intravitreal Aflibercept Injection (IAI) 2Q16 Intravitreal Aflibercept Injection (IAI) 2Q8
    Number of subjects analysed
    133
    135
    134
    Units: Percentage of subjects
        number (not applicable)
    15.0
    65.2
    79.9
    Statistical analysis title
    Sham treatment, IAI 2Q16
    Comparison groups
    Sham treatment v Intravitreal Aflibercept Injection (IAI) 2Q16
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    percentage difference
    Point estimate
    50.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    40.1
         upper limit
    60.1
    Statistical analysis title
    Sham treatment, IAI 2Q18
    Comparison groups
    Sham treatment v Intravitreal Aflibercept Injection (IAI) 2Q8
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    percentage difference
    Point estimate
    64.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    55.8
         upper limit
    73.9

    Secondary: Percentage of Subjects who Developed a Vision-Threatening Complication due to Diabetic Retinopathy at Week 52

    Close Top of page
    End point title
    Percentage of Subjects who Developed a Vision-Threatening Complication due to Diabetic Retinopathy at Week 52
    End point description
    Vision-threatening complications are defined as the composite outcome of proliferative diabetic retinopathy (PDR) (inclusive of subjects who have vitreous hemorrhage or tractional retinal detachment believed to be due to PDR) and anterior segment neovascularization (ASNV) (subjects with neovascularization of the iris [at least 2 cumulative clock hours], and/or definitive neovascularization of the iridocorneal angle). FAS included all randomized subjects who received any study treatment as assigned at baseline (as randomized).
    End point type
    Secondary
    End point timeframe
    At Week 52
    End point values
    Sham treatment Intravitreal Aflibercept Injection (IAI) 2Q16 Intravitreal Aflibercept Injection (IAI) 2Q8
    Number of subjects analysed
    133
    135
    134
    Units: Percentage of subjects
        number (not applicable)
    20.3
    3.7
    3.0
    Statistical analysis title
    Sham treatment, IAI 2Q8
    Comparison groups
    Sham treatment v Intravitreal Aflibercept Injection (IAI) 2Q8
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    percentage difference
    Point estimate
    -17.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -24.7
         upper limit
    -9.9
    Statistical analysis title
    Sham treatment, IAI 2Q16
    Comparison groups
    Sham treatment v Intravitreal Aflibercept Injection (IAI) 2Q16
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    percentage difference
    Point estimate
    -16.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -24.2
         upper limit
    -9.1

    Secondary: Percentage of Subjects who Developed Central Involved-Diabetic Macular Edema (CI-DME) at Week 52

    Close Top of page
    End point title
    Percentage of Subjects who Developed Central Involved-Diabetic Macular Edema (CI-DME) at Week 52
    End point description
    The percentage of subjects who developed CI-DME at week 52 were reported. FAS included all randomized subjects who received any study treatment as assigned at baseline (as randomized).
    End point type
    Secondary
    End point timeframe
    At Week 52
    End point values
    Sham treatment Intravitreal Aflibercept Injection (IAI) 2Q16 Intravitreal Aflibercept Injection (IAI) 2Q8
    Number of subjects analysed
    133
    135
    134
    Units: Percentage of subjects
        number (not applicable)
    25.6
    6.7
    8.2
    Statistical analysis title
    Sham treatment, IAI 2Q8
    Comparison groups
    Sham treatment v Intravitreal Aflibercept Injection (IAI) 2Q8
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    percentage difference
    Point estimate
    -17.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -26.2
         upper limit
    -8.5
    Statistical analysis title
    Sham treatment, IAI 2Q16
    Comparison groups
    Sham treatment v Intravitreal Aflibercept Injection (IAI) 2Q16
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    percentage difference
    Point estimate
    -18.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -27.5
         upper limit
    -10.4

    Secondary: Time to Development of any Neovascular Vision Threatening Complication (PDR/ASNV) through Week 52

    Close Top of page
    End point title
    Time to Development of any Neovascular Vision Threatening Complication (PDR/ASNV) through Week 52
    End point description
    Vision-threatening complication (VTC) is defined as the composite outcome of proliferative diabetic retinopathy (PDR) (inclusive of subjects who have vitreous hemorrhage or tractional retinal detachment believed to be due to PDR) and anterior segment neovascularization (ASNV) (subjects with neovascularization of the iris [at least 2 cumulative clock hours], and/or definitive neovascularization of the iridocorneal angle). Vision Threatening Complications include PDR/ASNV identified by investigators and Diabetic Retinopathy Scale Score (DRSS) >61. FAS included all randomized subjects who received any study treatment as assigned at baseline (as randomized). Subjects who did not have an event were censored at their last visit at or before the week 52 visit. Here, the value "99999" = Not evaluable due to small number of VTC events.
    End point type
    Secondary
    End point timeframe
    Baseline through week 52 (day 365)
    End point values
    Sham treatment Intravitreal Aflibercept Injection (IAI) 2Q16 Intravitreal Aflibercept Injection (IAI) 2Q8
    Number of subjects analysed
    133 [1]
    135 [2]
    134 [3]
    Units: Days
        median (inter-quartile range (Q1-Q3))
    99999 (371 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Notes
    [1] - 99999 = Not evaluable due to small number of VTC events.
    [2] - 99999 = Not evaluable due to small number of VTC events.
    [3] - 99999 = Not evaluable due to small number of VTC events.
    No statistical analyses for this end point

    Secondary: Time to Development of Central Involved-Diabetic Macular Edema (CI-DME) through Week 52

    Close Top of page
    End point title
    Time to Development of Central Involved-Diabetic Macular Edema (CI-DME) through Week 52
    End point description
    Time to develop Central Involved-Diabetic Macular Edema (CI-DME) through week 52 reported. FAS included all randomized subjects who received any study treatment as assigned at baseline (as randomized). Subjects who did not have an event were censored at their last visit, at or before the week 52 visit. Here, the value "99999" = Not evaluable due to small number of CI-DME events.
    End point type
    Secondary
    End point timeframe
    Baseline through week 52 (day 365)
    End point values
    Sham treatment Intravitreal Aflibercept Injection (IAI) 2Q16 Intravitreal Aflibercept Injection (IAI) 2Q8
    Number of subjects analysed
    133 [4]
    135 [5]
    134 [6]
    Units: Days
        median (inter-quartile range (Q1-Q3))
    99999 (333 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Notes
    [4] - 99999 = Not evaluable due to small number of CI-DME events
    [5] - 99999 = Not evaluable due to small number of CI-DME events
    [6] - 99999 = Not evaluable due to small number of CI-DME events
    No statistical analyses for this end point

    Secondary: Percentage of Subjects who Received Panretinal Photocoagulation (PRP), Inclusive of Subjects Undergoing Vitrectomy With Endolaser, at Week 52

    Close Top of page
    End point title
    Percentage of Subjects who Received Panretinal Photocoagulation (PRP), Inclusive of Subjects Undergoing Vitrectomy With Endolaser, at Week 52
    End point description
    The percentage of subjects who received panretinal photocoagulation (PRP), inclusive of subjects undergoing vitrectomy with endolaser, at week 52 were reported. FAS included all randomized subjects who received any study treatment as assigned at baseline (as randomized).
    End point type
    Secondary
    End point timeframe
    At Week 52
    End point values
    Sham treatment Intravitreal Aflibercept Injection (IAI) 2Q16 Intravitreal Aflibercept Injection (IAI) 2Q8
    Number of subjects analysed
    133
    135
    134
    Units: Percentage of subjects
        number (not applicable)
    6.8
    0.7
    0.7
    Statistical analysis title
    Sham treatment, IAI 2Q8
    Comparison groups
    Sham treatment v Intravitreal Aflibercept Injection (IAI) 2Q8
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0096
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    percentage difference
    Point estimate
    -6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.5
         upper limit
    -1.5
    Statistical analysis title
    Sham treatment, IAI 2Q16
    Comparison groups
    Sham treatment v Intravitreal Aflibercept Injection (IAI) 2Q16
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0089
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    percentage difference
    Point estimate
    -6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.5
         upper limit
    -1.6

    Secondary: Area Under the Curve (AUC) for Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52

    Close Top of page
    End point title
    Area Under the Curve (AUC) for Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52
    End point description
    The area under the curve (AUC) is the area under the best corrected visual acuity (BCVA) versus time curve from baseline to week 52. Visual function of the study eye was assessed at a distance of 4 meters at every study visit using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. BCVA scale range is 0 (worst) to 100 (best). AUC was calculated as a weighted average based on total AUC (using the trapezoidal rule) divided by total duration in days. FAS included all randomized subjects who received any study treatment as assigned at baseline (as randomized).
    End point type
    Secondary
    End point timeframe
    At week 52
    End point values
    Sham treatment Intravitreal Aflibercept Injection (IAI) 2Q16 Intravitreal Aflibercept Injection (IAI) 2Q8
    Number of subjects analysed
    133
    135
    134
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    0.5 ± 3.01
    1.7 ± 3.50
    1.3 ± 3.49
    Statistical analysis title
    Sham treatment, IAI 2Q8
    Comparison groups
    Sham treatment v Intravitreal Aflibercept Injection (IAI) 2Q8
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0529
    Method
    ANOVA
    Parameter type
    Estimate for contrast
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.01
         upper limit
    1.6
    Statistical analysis title
    Sham treatment, IAI 2Q16
    Comparison groups
    Sham treatment v Intravitreal Aflibercept Injection (IAI) 2Q16
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0057
    Method
    ANOVA
    Parameter type
    Estimate for contrast
    Point estimate
    1.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.33
         upper limit
    1.94

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AEs) were collected from signature of the informed consent form up to week 100 regardless of seriousness or relationship to investigational product
    Adverse event reporting additional description
    Reported adverse events are treatment-emergent adverse events (TEAEs) which are AEs that developed/worsened from baseline (day1) up to end of study (week 100).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Sham Treatment
    Reporting group description
    All subjects received sham injections in the study eye every 4 weeks (Q4) to week 16 (after 5 initial monthly sham injections), followed by sham injections Q8 to week 96.

    Reporting group title
    Intravitreal Aflibercept Injection (IAI) 2Q16
    Reporting group description
    All subjects received a 2 milligram (mg) Intravitreal Aflibercept Injection (IAI) in the study eye every 16 weeks (2Q16) (after 3 initial monthly doses and one 8-week interval) to week 96.

    Reporting group title
    Intravitreal Aflibercept Injection (IAI) 2Q8
    Reporting group description
    All subjects received 2 mg IAI in the study eye every 8 weeks (2Q8) from day 1 up to week 48 (after 5 initial monthly doses), followed by a flexible treatment regimen with IAI 2 mg to week 96.

    Reporting group title
    IAI 2 mg Groups Combined (2Q16 & 2Q8)
    Reporting group description
    IAI 2Q16: Subjects received a 2mg IAI in the study eye every 16 weeks (2Q16) (after 3 initial monthly doses and one 8-week interval) to week 96; IAI 2Q8: Subjects received 2mg IAI in the study eye every 8 weeks (2Q8) from day 1 up to week 48 (after 5 initial monthly doses), followed by a flexible treatment regimen with IAI 2 mg to week 96.

    Serious adverse events
    Sham Treatment Intravitreal Aflibercept Injection (IAI) 2Q16 Intravitreal Aflibercept Injection (IAI) 2Q8 IAI 2 mg Groups Combined (2Q16 & 2Q8)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    38 / 133 (28.57%)
    38 / 135 (28.15%)
    47 / 134 (35.07%)
    85 / 269 (31.60%)
         number of deaths (all causes)
    8
    1
    3
    4
         number of deaths resulting from adverse events
    Vascular disorders
    Peripheral ischaemia
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cervix carcinoma stage 0
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 135 (0.74%)
    0 / 134 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transitional cell carcinoma metastatic
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 135 (0.74%)
    0 / 134 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Bipolar disorder
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 135 (0.74%)
    0 / 134 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anaemia postoperative
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 135 (0.74%)
    0 / 134 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 135 (0.74%)
    0 / 134 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 135 (0.74%)
    0 / 134 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative respiratory failure
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative thoracic procedure complication
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 135 (0.74%)
    0 / 134 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic arthropathy
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 135 (0.74%)
    0 / 134 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumocephalus
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic fracture Study Eye
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood glucose increased
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood sodium decreased
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Coronary artery disease
         subjects affected / exposed
    1 / 133 (0.75%)
    5 / 135 (3.70%)
    4 / 134 (2.99%)
    9 / 269 (3.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 4
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 133 (0.75%)
    2 / 135 (1.48%)
    3 / 134 (2.24%)
    5 / 269 (1.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 133 (0.75%)
    2 / 135 (1.48%)
    1 / 134 (0.75%)
    3 / 269 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    2 / 133 (1.50%)
    2 / 135 (1.48%)
    0 / 134 (0.00%)
    2 / 269 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 135 (0.74%)
    1 / 134 (0.75%)
    2 / 269 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 133 (0.00%)
    2 / 135 (1.48%)
    0 / 134 (0.00%)
    2 / 269 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 135 (0.74%)
    0 / 134 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Cardiac failure chronic
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 135 (0.74%)
    0 / 134 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 135 (0.74%)
    0 / 134 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    2 / 133 (1.50%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulseless electrical activity
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    2 / 134 (1.49%)
    2 / 269 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 133 (1.50%)
    1 / 135 (0.74%)
    1 / 134 (0.75%)
    2 / 269 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory acidosis
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 135 (0.74%)
    0 / 134 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 135 (0.74%)
    0 / 134 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary congestion
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    2 / 133 (1.50%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 133 (0.00%)
    2 / 135 (1.48%)
    0 / 134 (0.00%)
    2 / 269 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 133 (0.00%)
    3 / 135 (2.22%)
    1 / 134 (0.75%)
    4 / 269 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    1 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain stem stroke
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 135 (0.74%)
    0 / 134 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 135 (0.74%)
    0 / 134 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemic unconsciousness
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    3 / 133 (2.26%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Visual acuity reduced Fellow Eye
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    3 / 134 (2.24%)
    3 / 269 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic retinal oedema Fellow Eye
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Macular fibrosis Fellow Eye
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Macular hole Fellow Eye
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal vein occlusion Fellow Eye
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 135 (0.74%)
    0 / 134 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Visual impairment Fellow Eye
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vitreous adhesions Fellow Eye
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vitreous haemorrhage Fellow Eye
         subjects affected / exposed
    1 / 133 (0.75%)
    1 / 135 (0.74%)
    0 / 134 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cataract Fellow Eye
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Iris neovascularisation Fellow Eye
         subjects affected / exposed
    2 / 133 (1.50%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystoid macular oedema Study Eye
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Visual acuity reduced Study Eye
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vitreous haemorrhage Study Eye
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic retinopathy Study Eye
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Iris neovascularisation Study Eye
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal neovascularisation Study Eye
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diabetic gastroparesis
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 135 (0.74%)
    0 / 134 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 133 (1.50%)
    1 / 135 (0.74%)
    3 / 134 (2.24%)
    4 / 269 (1.49%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 135 (0.74%)
    0 / 134 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    End stage renal disease
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urge incontinence
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 135 (0.74%)
    0 / 134 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 133 (0.75%)
    1 / 135 (0.74%)
    0 / 134 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 135 (0.74%)
    2 / 134 (1.49%)
    3 / 269 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Photosensitivity reaction
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    3 / 134 (2.24%)
    3 / 269 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 133 (0.00%)
    2 / 135 (1.48%)
    0 / 134 (0.00%)
    2 / 269 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 133 (0.00%)
    2 / 135 (1.48%)
    0 / 134 (0.00%)
    2 / 269 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 135 (0.74%)
    0 / 134 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 133 (0.75%)
    2 / 135 (1.48%)
    5 / 134 (3.73%)
    7 / 269 (2.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 6
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 133 (1.50%)
    3 / 135 (2.22%)
    3 / 134 (2.24%)
    6 / 269 (2.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 5
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic foot infection
         subjects affected / exposed
    0 / 133 (0.00%)
    3 / 135 (2.22%)
    0 / 134 (0.00%)
    3 / 269 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    3 / 134 (2.24%)
    3 / 269 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    2 / 134 (1.49%)
    2 / 269 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterococcal bacteraemia
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    4 / 133 (3.01%)
    1 / 135 (0.74%)
    0 / 134 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis acute
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis syndrome
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 135 (0.74%)
    0 / 134 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 135 (0.74%)
    0 / 134 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal osteomyelitis
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal skin infection
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 135 (0.00%)
    1 / 134 (0.75%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 135 (0.74%)
    0 / 134 (0.00%)
    1 / 269 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic gangrene
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 135 (0.00%)
    0 / 134 (0.00%)
    0 / 269 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Sham Treatment Intravitreal Aflibercept Injection (IAI) 2Q16 Intravitreal Aflibercept Injection (IAI) 2Q8 IAI 2 mg Groups Combined (2Q16 & 2Q8)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    104 / 133 (78.20%)
    104 / 135 (77.04%)
    106 / 134 (79.10%)
    210 / 269 (78.07%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    25 / 133 (18.80%)
    28 / 135 (20.74%)
    20 / 134 (14.93%)
    48 / 269 (17.84%)
         occurrences all number
    28
    32
    23
    55
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    5 / 133 (3.76%)
    5 / 135 (3.70%)
    8 / 134 (5.97%)
    13 / 269 (4.83%)
         occurrences all number
    5
    7
    11
    18
    Investigations
    Blood glucose increased
         subjects affected / exposed
    7 / 133 (5.26%)
    3 / 135 (2.22%)
    7 / 134 (5.22%)
    10 / 269 (3.72%)
         occurrences all number
    8
    3
    7
    10
    Glycosylated haemoglobin increased
         subjects affected / exposed
    7 / 133 (5.26%)
    9 / 135 (6.67%)
    9 / 134 (6.72%)
    18 / 269 (6.69%)
         occurrences all number
    7
    9
    9
    18
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 133 (1.50%)
    7 / 135 (5.19%)
    8 / 134 (5.97%)
    15 / 269 (5.58%)
         occurrences all number
    2
    9
    8
    17
    Eye disorders
    Blepharitis Fellow Eye
         subjects affected / exposed
    1 / 133 (0.75%)
    3 / 135 (2.22%)
    7 / 134 (5.22%)
    10 / 269 (3.72%)
         occurrences all number
    1
    3
    7
    10
    Cataract Fellow Eye
         subjects affected / exposed
    4 / 133 (3.01%)
    9 / 135 (6.67%)
    4 / 134 (2.99%)
    13 / 269 (4.83%)
         occurrences all number
    4
    9
    4
    13
    Conjunctival haemorrhage Fellow Eye
         subjects affected / exposed
    6 / 133 (4.51%)
    5 / 135 (3.70%)
    8 / 134 (5.97%)
    13 / 269 (4.83%)
         occurrences all number
    7
    14
    14
    28
    Diabetic retinal oedema Fellow Eye
         subjects affected / exposed
    19 / 133 (14.29%)
    17 / 135 (12.59%)
    23 / 134 (17.16%)
    40 / 269 (14.87%)
         occurrences all number
    25
    24
    27
    51
    Diabetic retinopathy Fellow Eye
         subjects affected / exposed
    12 / 133 (9.02%)
    13 / 135 (9.63%)
    10 / 134 (7.46%)
    23 / 269 (8.55%)
         occurrences all number
    13
    14
    10
    24
    Macular oedema Fellow Eye
         subjects affected / exposed
    4 / 133 (3.01%)
    7 / 135 (5.19%)
    6 / 134 (4.48%)
    13 / 269 (4.83%)
         occurrences all number
    4
    7
    6
    13
    Retinal exudates Fellow Eye
         subjects affected / exposed
    8 / 133 (6.02%)
    2 / 135 (1.48%)
    6 / 134 (4.48%)
    8 / 269 (2.97%)
         occurrences all number
    9
    2
    7
    9
    Vitreous haemorrhage Fellow Eye
         subjects affected / exposed
    4 / 133 (3.01%)
    8 / 135 (5.93%)
    3 / 134 (2.24%)
    11 / 269 (4.09%)
         occurrences all number
    4
    12
    3
    15
    Blepharitis Study Eye
         subjects affected / exposed
    1 / 133 (0.75%)
    2 / 135 (1.48%)
    7 / 134 (5.22%)
    9 / 269 (3.35%)
         occurrences all number
    1
    2
    7
    9
    Cataract Study Eye
         subjects affected / exposed
    5 / 133 (3.76%)
    8 / 135 (5.93%)
    8 / 134 (5.97%)
    16 / 269 (5.95%)
         occurrences all number
    5
    8
    8
    16
    Conjunctival haemorrhage Study Eye
         subjects affected / exposed
    8 / 133 (6.02%)
    18 / 135 (13.33%)
    25 / 134 (18.66%)
    43 / 269 (15.99%)
         occurrences all number
    14
    27
    34
    61
    Diabetic retinal oedema Study Eye
         subjects affected / exposed
    43 / 133 (32.33%)
    14 / 135 (10.37%)
    19 / 134 (14.18%)
    33 / 269 (12.27%)
         occurrences all number
    54
    22
    25
    47
    Diabetic retinopathy Study Eye
         subjects affected / exposed
    22 / 133 (16.54%)
    3 / 135 (2.22%)
    5 / 134 (3.73%)
    8 / 269 (2.97%)
         occurrences all number
    25
    4
    5
    9
    Eye pain Study Eye
         subjects affected / exposed
    6 / 133 (4.51%)
    11 / 135 (8.15%)
    5 / 134 (3.73%)
    16 / 269 (5.95%)
         occurrences all number
    8
    13
    5
    18
    Retinal exudates Study Eye
         subjects affected / exposed
    6 / 133 (4.51%)
    5 / 135 (3.70%)
    9 / 134 (6.72%)
    14 / 269 (5.20%)
         occurrences all number
    7
    5
    9
    14
    Vitreous detachment Study Eye
         subjects affected / exposed
    4 / 133 (3.01%)
    7 / 135 (5.19%)
    7 / 134 (5.22%)
    14 / 269 (5.20%)
         occurrences all number
    4
    7
    9
    16
    Vitreous floaters Study Eye
         subjects affected / exposed
    3 / 133 (2.26%)
    7 / 135 (5.19%)
    13 / 134 (9.70%)
    20 / 269 (7.43%)
         occurrences all number
    3
    8
    13
    21
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    3 / 133 (2.26%)
    5 / 135 (3.70%)
    7 / 134 (5.22%)
    12 / 269 (4.46%)
         occurrences all number
    3
    5
    7
    12
    Nausea
         subjects affected / exposed
    8 / 133 (6.02%)
    5 / 135 (3.70%)
    6 / 134 (4.48%)
    11 / 269 (4.09%)
         occurrences all number
    9
    5
    14
    19
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    13 / 133 (9.77%)
    11 / 135 (8.15%)
    8 / 134 (5.97%)
    19 / 269 (7.06%)
         occurrences all number
    15
    11
    8
    19
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    7 / 133 (5.26%)
    9 / 135 (6.67%)
    5 / 134 (3.73%)
    14 / 269 (5.20%)
         occurrences all number
    7
    10
    5
    15
    Cellulitis
         subjects affected / exposed
    6 / 133 (4.51%)
    5 / 135 (3.70%)
    7 / 134 (5.22%)
    12 / 269 (4.46%)
         occurrences all number
    6
    10
    7
    17
    Influenza
         subjects affected / exposed
    8 / 133 (6.02%)
    10 / 135 (7.41%)
    4 / 134 (2.99%)
    14 / 269 (5.20%)
         occurrences all number
    8
    12
    4
    16
    Nasopharyngitis
         subjects affected / exposed
    15 / 133 (11.28%)
    11 / 135 (8.15%)
    11 / 134 (8.21%)
    22 / 269 (8.18%)
         occurrences all number
    16
    16
    12
    28
    Urinary tract infection
         subjects affected / exposed
    16 / 133 (12.03%)
    12 / 135 (8.89%)
    11 / 134 (8.21%)
    23 / 269 (8.55%)
         occurrences all number
    22
    13
    13
    26

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Dec 2015
    The purpose of this amendment was to incorporate the following changes and clarifications following discussions with the FDA: The primary outcome measure of the study became the proportion of patients who have improved by ≥2 steps from baseline in the Diabetic Retinopathy Severity Scale (DRSS) score at week 24 in the combined 2Q8 and 2Q16 groups, and at week 52 for each group separately. Secondary endpoints were modified slightly; a few have been separated into 2 endpoints. The 2Q8 group transitioned to a flexible dosing regimen based on the investigator's assessment of DRSS score beginning at week 56.
    12 Feb 2016
    The purpose of this amendment was to incorporate the following revisions in response to feedback from the Food and Drug Administration (FDA) and the Pharmaceuticals and Medical Devices Agency (PMDA): Revised the significance levels for testing of the secondary efficacy endpoints, per FDA feedback; Added a hemoglobin A1c (HbA1c) assessment at week 24, and fundus photography (FP) at week 8, per PMDA feedback
    20 Oct 2016
    The purpose of this amendment was to update exclusion criterion #16 to exclude women who were breastfeeding from participation in the study.
    24 Jul 2018
    The purpose of this amendment was to change the time point for evaluation of the secondary endpoints from week 100 to week 52.

    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
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2021 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA