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    Clinical Trial Results:
    An open-label, randomized, active-controlled, parallel-group, Phase-3b study of the efficacy, safety, and tolerability of 2mg aflibercept administered by intravitreal injections using two different treatment regimens to subjects with neovascular age-related macular degeneration (nAMD)

    Summary
    EudraCT number
    		 2013-000120-33
    Trial protocol
    		 HU   CZ   SK   PT   LT   AT   GB   ES   DE   IT  
    Global end of trial date
    04 Jun 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Jun 2021
    First version publication date
    20 Jun 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY86-5321/16598
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02540954
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368
    Public contact
    Therapeutic Area Head, ​Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Jun 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Jun 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to compare the efficacy of 2 mg aflibercept administered by 2 different intravitreal (IVT) treatment regimens to subjects with nAMD.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent was read by and explained to all the subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Sep 2015
    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
    Canada: 4
    Country: Number of subjects enrolled
    Austria: 13
    Country: Number of subjects enrolled
    France: 21
    Country: Number of subjects enrolled
    Germany: 33
    Country: Number of subjects enrolled
    Hungary: 16
    Country: Number of subjects enrolled
    Italy: 48
    Country: Number of subjects enrolled
    Lithuania: 9
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Portugal: 42
    Country: Number of subjects enrolled
    Slovakia: 24
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    Switzerland: 15
    Country: Number of subjects enrolled
    Czechia: 44
    Country: Number of subjects enrolled
    United Kingdom: 58
    Worldwide total number of subjects
    335
    EEA total number of subjects
    258
    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)
    32
    From 65 to 84 years
    267
    85 years and over
    36

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study was conducted at 76 centers in 14 countries or regions, between 29-SEP-2015 (first subject first visit) and 04-JUN-2020 (last subject last visit)

    Pre-assignment
    Screening details
    		 At baseline, 336 subjects were randomized to one of 2 treatment groups; 168 subjects were randomized to the Aflibercept extended-dosing group and 168 subjects were randomized to the Aflibercept 2Q8 ((2 mg aflibercept administered every 8 weeks)) group. One subject in Aflibercept extended-dosing group did not receive any study drug.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Aflibercept extended dosing
    Arm description
    		 Aflibercept was administered 2 mg per injection intravitreal (IVT) in the study eye in Aflibercept extended dosing. Flexible dosing interval is ≥ 8 weeks (no upper limit) based on visual and anatomic outcomes as judged by the investigator. When/if visual and anatomical outcomes indicated that the disease had re-activated, the treatment interval reverted to the last treatment interval in which the disease was inactive (ie, no signs of exudation were observed).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aflibercept
    Investigational medicinal product code
    BAY86-5321
    Other name
    Eylea
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Aflibercept was injected intravitreal (IVT) at a dose of 2 mg per injection. Flexible dosing intervals of ≥ 8 weeks (no upper limit) based on visual and anatomic outcomes as judged by the investigator. Aflibercept could be treated for up to 76 weeks.

    Arm title
    		 Aflibercept 2Q8 (2 mg aflibercept administered every 8 weeks)
    Arm description
    		 Aflibercept was administered 2 mg per injection IVT in the study eye in Aflibercept 2Q8. Fixed dosing interval is 8 weeks (±3 days), modification of the treatment interval was not allowed.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Aflibercept
    Investigational medicinal product code
    BAY86-5321
    Other name
    Eylea
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Aflibercept was injected intravitreal (IVT) at a dose of 2 mg per injection. Fixed dosing intervals of 8 weeks (±3 days) with no modification of the treatment interval allowed. Aflibercept was treated up to 72 weeks.

    Number of subjects in period 1
    		Aflibercept extended dosing Aflibercept 2Q8 (2 mg aflibercept administered every 8 weeks)
    Started
    167
    168
    Post-baseline BCVA assessment
    165
    167
    Completed
    149
    154
    Not completed
    18
    14
         Consent withdrawn by subject
    6
    5
         Physician decision
    2
    1
         Treatment failure
    1
    -
         Adverse event, non-fatal
    4
    2
         Death
    -
    3
         Other reason
    4
    2
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Aflibercept extended dosing
    Reporting group description
    		 Aflibercept was administered 2 mg per injection intravitreal (IVT) in the study eye in Aflibercept extended dosing. Flexible dosing interval is ≥ 8 weeks (no upper limit) based on visual and anatomic outcomes as judged by the investigator. When/if visual and anatomical outcomes indicated that the disease had re-activated, the treatment interval reverted to the last treatment interval in which the disease was inactive (ie, no signs of exudation were observed).

    Reporting group title
    Aflibercept 2Q8 (2 mg aflibercept administered every 8 weeks)
    Reporting group description
    		 Aflibercept was administered 2 mg per injection IVT in the study eye in Aflibercept 2Q8. Fixed dosing interval is 8 weeks (±3 days), modification of the treatment interval was not allowed.

    Reporting group values
    		 Aflibercept extended dosing Aflibercept 2Q8 (2 mg aflibercept administered every 8 weeks) Total
    Number of subjects
    		 167 168 335
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 76.3 ( 8.3 ) 74.7 ( 7.0 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 107 108 215
        Male
    		 60 60 120
    Race
    Units: Subjects
        White
    		 139 132 271
        Black
    		 0 0 0
        Asian
    		 0 0 0
        American Indian or Alaska Native
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Not reported
    		 28 36 64
        Multiple
    		 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 0
        Not Hispanic or Latino
    		 136 128 264
        Unknown or Not Reported
    		 31 40 71
    Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual
    Visual function was assessed with the procedure from the ETDRS adapted for the Age Related Eye Disease Study using charts with 70 letters at a starting distance of 4 meters. Charts are organized in 14 lines of decreasing size with 5 letters each. Subjects reading up to 19 letters at 4 meters were tested at 1 meter to read the first 6 lines. The score equals the sum of letters read at 1 meter and 4 meters. If more than 19 letters are read at 4 meters the score equals the number of letters read plus 30. The score range is 0 to 100, and a higher score represents better visual function.
    Units: Letters read correctly
        arithmetic mean (standard deviation)
    		 69 ( 12.1 ) 70.1 ( 10.9 ) -
    Central retinal thickness (CRT) in the study eye
    Retinal characteristic was evaluated using Optical coherence tomography (OCT). Actual analysis number for both arms is 164.
    Units: μm
        arithmetic mean (standard deviation)
    		 257.3 ( 67.8 ) 264.4 ( 59.7 ) -
    Choroidal neovascularization (CNV) area in the study eye
    Choroidal neovascularization measured by optical coherence tomography (OCT). Actual analysis number for Aflibercept extended dosing is 165. Actual analysis number for Aflibercept 2Q8 (2 mg aflibercept administered every 8 weeks) is 152.
    Units: mm*2
        arithmetic mean (standard deviation)
    		 4.695 ( 4.043 ) 5.060 ( 4.105 ) -
    Total score for National Eye Institute 25-Item Visual Function
    National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) total score ranges from 0 to 100, where 100 represents the best possible score and 0 represents the worst. Actual analysis number for Aflibercept extended dosing is 163.
    Units: Score on a scale
        arithmetic mean (standard deviation)
    		 72.889 ( 18.414 ) 75.757 ( 15.495 ) -

    End points

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    End points reporting groups
    Reporting group title
    Aflibercept extended dosing
    Reporting group description
    		 Aflibercept was administered 2 mg per injection intravitreal (IVT) in the study eye in Aflibercept extended dosing. Flexible dosing interval is ≥ 8 weeks (no upper limit) based on visual and anatomic outcomes as judged by the investigator. When/if visual and anatomical outcomes indicated that the disease had re-activated, the treatment interval reverted to the last treatment interval in which the disease was inactive (ie, no signs of exudation were observed).

    Reporting group title
    Aflibercept 2Q8 (2 mg aflibercept administered every 8 weeks)
    Reporting group description
    		 Aflibercept was administered 2 mg per injection IVT in the study eye in Aflibercept 2Q8. Fixed dosing interval is 8 weeks (±3 days), modification of the treatment interval was not allowed.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All 335 subjects treated with aflibercept were included in the SAF (one randomized subject in the extended-dosing group did not receive study drug and was excluded from the SAF).

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All 335 subjects from the SAF were also included in the FAS except for one subject who did not have a baseline BCVA assessment and 2 subjects who had no post-baseline assessment of BCVA available. Thus, 332 subjects were included in the FAS.

    Primary: Mean change in Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) letter score for the study eye

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    End point title
    		 Mean change in Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) letter score for the study eye
    End point description
    Visual function was assessed with the procedure from the ETDRS adapted for the Age Related Eye Disease Study using charts with 70 letters at a starting distance of 4 meters. Charts are organized in 14 lines of decreasing size with 5 letters each. Subjects reading up to 19 letters at 4 meters were tested at 1 meter to read the first 6 lines. The score equals the sum of letters read at 1 meter and 4 meters. If more than 19 letters are read at 4 meters the score equals the number of letters read plus 30. The score range is 0 to 100, and a higher score represents better visual function.
    End point type
    Primary
    End point timeframe
    From baseline to Week 52
    End point values
    		 Aflibercept extended dosing Aflibercept 2Q8 (2 mg aflibercept administered every 8 weeks)
    Number of subjects analysed
    165
    167
    Units: Letters read correctly
    arithmetic mean (standard deviation)
        Mean change in ETDRS BCVA from baseline to week 52
    -0.3 ( 7.5 )
    -0.5 ( 8.4 )
    Statistical analysis title
    		 Analysis of covariance for EDTRS BCVA change
    Statistical analysis description
    Aflibercept 2QB was regarded as the reference arm
    Comparison groups
    Aflibercept extended dosing v Aflibercept 2Q8 (2 mg aflibercept administered every 8 weeks)
    Number of subjects included in analysis
    332
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 < 0.0001 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Least squares mean difference
    Point estimate
    0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.51
         upper limit
    		 1.96
    Notes
    [1] - Non-inferiority margin: 5 letters
    [2] - Non-inferiority was demonstrated if the p-value was < 0.05

    Secondary: Percentage of subjects maintaining vision in the study eye

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    End point title
    		 Percentage of subjects maintaining vision in the study eye
    End point description
    A subject was classified as maintaining vision if the subject had lost fewer than 15 letters in the ETDRS letter score compared to baseline.
    End point type
    Secondary
    End point timeframe
    At week 52
    End point values
    		 Aflibercept extended dosing Aflibercept 2Q8 (2 mg aflibercept administered every 8 weeks)
    Number of subjects analysed
    165
    167
    Units: Percentage of subjects
        number (not applicable)
    95.2
    94.0
    Statistical analysis title
    		 Treatment difference % in maintaining vision
    Statistical analysis description
    Calculation of two-sided 95% confidence intervals using normal approximation of the difference between the proportions (Aflibercept extended-dosing group minus Aflibercept 2Q8 group) of subjects maintaining vision.
    Comparison groups
    Aflibercept extended dosing v Aflibercept 2Q8 (2 mg aflibercept administered every 8 weeks)
    Number of subjects included in analysis
    332
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Treatment difference in %
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.7
         upper limit
    		 6
    Notes
    [3] - Non inferiority margin is 7%.

    Secondary: Percentage of subjects who gained from baseline 5 or more letters in the study eye

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    End point title
    		 Percentage of subjects who gained from baseline 5 or more letters in the study eye
    End point description
    End point type
    Secondary
    End point timeframe
    At week 52
    End point values
    		 Aflibercept extended dosing Aflibercept 2Q8 (2 mg aflibercept administered every 8 weeks)
    Number of subjects analysed
    165
    167
    Units: Percentage of subjects
        number (not applicable)
    24.2
    21.0
    No statistical analyses for this end point

    Secondary: Mean change from baseline in Central retinal thickness (CRT) in the study eye

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    End point title
    		 Mean change from baseline in Central retinal thickness (CRT) in the study eye
    End point description
    Retinal characteristic was evaluated using Optical coherence tomography (OCT).
    End point type
    Secondary
    End point timeframe
    From baseline to week 52
    End point values
    		 Aflibercept extended dosing Aflibercept 2Q8 (2 mg aflibercept administered every 8 weeks)
    Number of subjects analysed
    165
    167
    Units: μm
    arithmetic mean (standard deviation)
        Mean change in CRT from baseline to week 52
    -24.4 ( 55.2 )
    -33.4 ( 47.1 )
    No statistical analyses for this end point

    Secondary: Mean change from baseline in Choroidal neovascularization (CNV) area in the study eye

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    End point title
    		 Mean change from baseline in Choroidal neovascularization (CNV) area in the study eye
    End point description
    Choroidal neovascularization measured by optical coherence tomography (OCT).
    End point type
    Secondary
    End point timeframe
    From baseline to week 52
    End point values
    		 Aflibercept extended dosing Aflibercept 2Q8 (2 mg aflibercept administered every 8 weeks)
    Number of subjects analysed
    121
    120
    Units: mm*2
    arithmetic mean (standard deviation)
        Mean change in CNV from baseline to week 52
    0.274 ( 2.723 )
    0.204 ( 2.813 )
    No statistical analyses for this end point

    Secondary: Percentage of subjects who lost from baseline 30 or more letters in the study eye

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    End point title
    		 Percentage of subjects who lost from baseline 30 or more letters in the study eye
    End point description
    End point type
    Secondary
    End point timeframe
    At week 52
    End point values
    		 Aflibercept extended dosing Aflibercept 2Q8 (2 mg aflibercept administered every 8 weeks)
    Number of subjects analysed
    165
    167
    Units: Percentage of Subjects
        number (not applicable)
    0
    0.6
    No statistical analyses for this end point

    Secondary: Mean change from baseline in total score for National Eye Institute 25-Item Visual Function (NEI VFQ-25) Questionnaire

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    End point title
    		 Mean change from baseline in total score for National Eye Institute 25-Item Visual Function (NEI VFQ-25) Questionnaire
    End point description
    National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) total score ranges from 0 to 100, where 100 represents the best possible score and 0 represents the worst.
    End point type
    Secondary
    End point timeframe
    From baseline to week 52
    End point values
    		 Aflibercept extended dosing Aflibercept 2Q8 (2 mg aflibercept administered every 8 weeks)
    Number of subjects analysed
    143
    157
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Mean change in NEI VFQ-25 from baseline to week 52
    0.186 ( 9.601 )
    -1.694 ( 10.328 )
    Statistical analysis title
    		 Treatment difference in NEI VFQ-25 score
    Comparison groups
    Aflibercept extended dosing v Aflibercept 2Q8 (2 mg aflibercept administered every 8 weeks)
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment difference in score
    Point estimate
    -1.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.152
         upper limit
    		 0.392

    Secondary: Number of subjects with Treatment-emergent adverse events(TEAE)

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    End point title
    		 Number of subjects with Treatment-emergent adverse events(TEAE)
    End point description
    End point type
    Secondary
    End point timeframe
    Started after the first application of aflibercept in the study and less than or equal to 30 days after the last dose of study drug over approximate 1.5 years
    End point values
    		 Aflibercept extended dosing Aflibercept 2Q8 (2 mg aflibercept administered every 8 weeks)
    Number of subjects analysed
    167
    168
    Units: Subjects
        Any TEAE
    130
    124
        Any serious TEAE
    26
    23
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From after the first application of aflibercept in the study to 30 days after the last dose of study drug over approximate 1.5 years
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Aflibercept 2Q8 (2 mg aflibercept administered every 8 weeks)
    Reporting group description
    		 Aflibercept was administered 2 mg per injection IVT in the study eye in Aflibercept 2Q8. Fixed dosing interval is 8 weeks (±3 days), modification of the treatment interval was not allowed.

    Reporting group title
    Aflibercept extended dosing
    Reporting group description
    		 Aflibercept was administered 2 mg per injection intravitreal (IVT) in the study eye in Aflibercept extended dosing. Flexible dosing interval is ≥ 8 weeks (no upper limit) based on visual and anatomic outcomes as judged by the investigator. When/if visual and anatomical outcomes indicated that the disease had re-activated, the treatment interval reverted to the last treatment interval in which the disease was inactive (ie, no signs of exudation were observed).

    Serious adverse events
    		 Aflibercept 2Q8 (2 mg aflibercept administered every 8 weeks) Aflibercept extended dosing
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 168 (13.69%)
    26 / 167 (15.57%)
         number of deaths (all causes)
    3
    0
         number of deaths resulting from adverse events
    2
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Breast neoplasm
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal cancer
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine cancer
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal tract adenoma
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Oesophageal prosthesis insertion
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Facial bones fracture
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 168 (0.00%)
    3 / 167 (1.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 168 (0.60%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract operation complication
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial reocclusion
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 168 (0.60%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 168 (0.00%)
    3 / 167 (1.80%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Sciatica
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 168 (1.19%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal haemorrhage
         subjects affected / exposed
    0 / 168 (0.00%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal tear
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedematous pancreatitis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal vascular malformation haemorrhagic
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 168 (1.19%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endophthalmitis
         subjects affected / exposed
    1 / 168 (0.60%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 168 (0.00%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Aflibercept 2Q8 (2 mg aflibercept administered every 8 weeks) Aflibercept extended dosing
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    70 / 168 (41.67%)
    60 / 167 (35.93%)
    Investigations
    Intraocular pressure increased
         subjects affected / exposed
    11 / 168 (6.55%)
    7 / 167 (4.19%)
         occurrences all number
    19
    12
    Eye disorders
    Cataract
         subjects affected / exposed
    19 / 168 (11.31%)
    17 / 167 (10.18%)
         occurrences all number
    27
    22
    Visual acuity reduced
         subjects affected / exposed
    4 / 168 (2.38%)
    14 / 167 (8.38%)
         occurrences all number
    6
    18
    Choroidal neovascularisation
         subjects affected / exposed
    9 / 168 (5.36%)
    9 / 167 (5.39%)
         occurrences all number
    9
    10
    Subretinal fluid
         subjects affected / exposed
    14 / 168 (8.33%)
    14 / 167 (8.38%)
         occurrences all number
    16
    17
    Neovascular age-related macular degeneration
         subjects affected / exposed
    10 / 168 (5.95%)
    8 / 167 (4.79%)
         occurrences all number
    12
    9
    Infections and infestations
    Influenza
         subjects affected / exposed
    9 / 168 (5.36%)
    9 / 167 (5.39%)
         occurrences all number
    9
    9
    Nasopharyngitis
         subjects affected / exposed
    12 / 168 (7.14%)
    4 / 167 (2.40%)
         occurrences all number
    15
    5

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Dec 2015
    Amendment 2: 1-Update of approval status. 2-Clarification of duration of the periods. 3-Time windows and schedule of visits. 4-Selection of study eye. 5-Clarifications of inclusion criteria. 6-Time periods for inclusion criteria 1 and 2. 7-Study manual. 8-Inclusion criterion 8. 9-Clarifications in second set of exclusion criteria. 10-Re-screening criteria. 11-Subject identification number. 12-Identity of study drug. 13-EU SmPC and other updates for safety reasons to dosage and administration. 14-Treatment posology. 15-Drug storage. 16-Final visit or early termination visit. 17-Specification of pregnancy testing. 18-Timing of pregnancy testing. 19-Order of footnotes and minor clarifications in schedule of evaluations. 20-Removal of sample study drug injection protocol from appendix. 21-Re-check of eligibility criteria. 22-Post-injection ocular assessments. 23-Conduct of visits. 24-OCT. 25-FA and FP. 26-ECG. 27-Actions taken with study treatment. 28-Expected adverse events. 29-Pregnancies. 30-Time point of blood withdrawal. 31-NEI VFQ-25 questionnaire. 32-Data processing. 33-Subject information and consent process. 34-Fellow eye treatment. 35-Efficacy analyses – sensitivity analyses.

    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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