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    Clinical Trial Results:
    A randomized, double-masked, sham-controlled phase 3b/4 study of the efficacy, safety, and tolerability of intravitreal aflibercept monotherapy compared to aflibercept with adjunctive photodynamic therapy as indicated in subjects with polypoidal choroidal vasculopathy (PLANET)

    Summary
    EudraCT number
    		 2013-004464-54
    Trial protocol
    		 HU   DE  
    Global end of trial date
    07 Jul 2017

    Results information
    Results version number
    		 v1
    This version publication date
    18 Jul 2018
    First version publication date
    18 Jul 2018
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY86-5321/16995
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02120950
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Informal study name: PLANET
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, D-51368 Leverkusen, Germany,
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com, 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
    07 Jul 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Aug 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jul 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary objective of the study was to collect data reflecting the efficacy and safety of aflibercept with and without photodynamic therapy (PDT) rescue treatment in subjects diagnosed with the polypoidal choroidal vasculopathy (PCV) subtype of wet age-related macular degeneration (AMD) and to explore whether intravitreally administered aflibercept monotherapy is non-inferior to that of aflibercept plus PDT (as indicated) based upon best-corrected visual acuity (BCVA) in subjects diagnosed with the PCV subtype of AMD.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all 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 May 2014
    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
    Japan: 159
    Country: Number of subjects enrolled
    Australia: 24
    Country: Number of subjects enrolled
    Korea, Republic of: 72
    Country: Number of subjects enrolled
    Taiwan: 37
    Country: Number of subjects enrolled
    Hong Kong: 14
    Country: Number of subjects enrolled
    Singapore: 13
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Hungary: 13
    Worldwide total number of subjects
    333
    EEA total number of subjects
    14
    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)
    77
    From 65 to 84 years
    245
    85 years and over
    11

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study was conducted at 62 study centers in Germany, Japan, Australia, Hungary, Republic of Korea, Taiwan, Hong Kong, and Singapore between 29 May 2014 (first subject first visit) and 12 August 2016 (last subject last visit).

    Pre-assignment
    Screening details
    		 Overall, 428 subjects were screened, of them 95 were failed in screening, remaining 333 subjects were allocated to treatment, of them 15 subjects were treated as run-in treatment, until the subjects were randomized and received treatment, remaining 318 were randomized and treated.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Aflibercept + Sham Photodynamic Therapy (PDT)
    Arm description
    		 Subjects received 2 milligram (mg) [0.05 millilitre (mL)] aflibercept injection intravitreally in monthly intervals on Weeks 0, 4, and 8 (run-in treatment); subjects were randomized on Week 12 and assessed for the rescue treatment (until the visual and anatomical outcomes allowed extension of the treatment interval) and then subjects received either bi-monthly injections of aflibercept intravitreally or bi-monthly injections of aflibercept intravitreally with sham PDT (2 milligram per millilitre [mg/mL] of 5 percent [%] dextrose solution or physiological saline solution), from Week 16 to Week 52. After week 52, treat-and-extend visit were scheduled and evaluation of rescue were continued with an optional extension treatment phase, where subjects received intravitreally injections of aflibercept monthly and sham PDT intravenously up to Week 96.
    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
    Subjects received 2 mg (0.05 mL) aflibercept injection intravitreally from Week 0 to Week 96.

    Investigational medicinal product name
    Sham PDT
    Investigational medicinal product code
    Other name
    Verteporfin, Visudyne
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received sham PDT (2 mg/mL of 5% dextrose solution or physiological saline solution), from Week 16 to Week 96.

    Arm title
    		 Aflibercept + Active PDT
    Arm description
    		 Subjects received 2 mg (0.05 mL) aflibercept injection intravitreally in monthly intervals on Weeks 0, 4, and 8 (run-in treatment); subjects were randomized on Week 12 and assessed for the rescue treatment (until the visual and anatomical outcomes allowed extension of the treatment interval) and then subjects received either bi-monthly injections of aflibercept intravitreally or bi-monthly injections of aflibercept intravitreally with sham PDT (2 mg/mL of 5% dextrose solution or physiological saline solution), from Week 16 to Week 52. After week 52, treat-and-extend visit were scheduled and evaluation of rescue were continued with an optional extension treatment phase, where subjects received intravitreally injections of aflibercept monthly and sham PDT intravenously up to Week 96.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aflibercept
    Investigational medicinal product code
    BAY86-5321
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Subjects received 2 mg (0.05 mL) aflibercept injection intravitreally from Week 0 to Week 96.

    Investigational medicinal product name
    Active PDT
    Investigational medicinal product code
    Other name
    Verteporfin, Visudyne
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received active PDT (2 mg/mL of 5% dextrose solution or physiological saline solution), from Week 16 to Week 96.

    Arm title
    		 Aflibercept (Non-randomized)
    Arm description
    		 Subjects received 2 mg (0.05 mL) aflibercept injection intravitreally in monthly intervals on Weeks 0, 4, and 8 as run-in treatment, until the subjects were randomized and received rescue treatments.
    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
    Subjects received 3 injections of 2 mg (0.05 mL injected intravitreally) aflibercept in monthly intervals (Weeks 0, 4, and 8).

    Number of subjects in period 1
    		Aflibercept + Sham Photodynamic Therapy (PDT) Aflibercept + Active PDT Aflibercept (Non-randomized)
    Started
    157
    161
    15
    Completed
    137
    147
    0
    Not completed
    20
    14
    15
         Consent withdrawn by subject
    6
    3
    2
         Adverse Event
    5
    4
    3
         Death
    3
    -
    1
         Other
    5
    4
    1
         Lost to follow-up
    -
    2
    1
         Protocol deviation
    1
    1
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Aflibercept + Sham Photodynamic Therapy (PDT)
    Reporting group description
    		 Subjects received 2 milligram (mg) [0.05 millilitre (mL)] aflibercept injection intravitreally in monthly intervals on Weeks 0, 4, and 8 (run-in treatment); subjects were randomized on Week 12 and assessed for the rescue treatment (until the visual and anatomical outcomes allowed extension of the treatment interval) and then subjects received either bi-monthly injections of aflibercept intravitreally or bi-monthly injections of aflibercept intravitreally with sham PDT (2 milligram per millilitre [mg/mL] of 5 percent [%] dextrose solution or physiological saline solution), from Week 16 to Week 52. After week 52, treat-and-extend visit were scheduled and evaluation of rescue were continued with an optional extension treatment phase, where subjects received intravitreally injections of aflibercept monthly and sham PDT intravenously up to Week 96.

    Reporting group title
    Aflibercept + Active PDT
    Reporting group description
    		 Subjects received 2 mg (0.05 mL) aflibercept injection intravitreally in monthly intervals on Weeks 0, 4, and 8 (run-in treatment); subjects were randomized on Week 12 and assessed for the rescue treatment (until the visual and anatomical outcomes allowed extension of the treatment interval) and then subjects received either bi-monthly injections of aflibercept intravitreally or bi-monthly injections of aflibercept intravitreally with sham PDT (2 mg/mL of 5% dextrose solution or physiological saline solution), from Week 16 to Week 52. After week 52, treat-and-extend visit were scheduled and evaluation of rescue were continued with an optional extension treatment phase, where subjects received intravitreally injections of aflibercept monthly and sham PDT intravenously up to Week 96.

    Reporting group title
    Aflibercept (Non-randomized)
    Reporting group description
    		 Subjects received 2 mg (0.05 mL) aflibercept injection intravitreally in monthly intervals on Weeks 0, 4, and 8 as run-in treatment, until the subjects were randomized and received rescue treatments.

    Reporting group values
    		 Aflibercept + Sham Photodynamic Therapy (PDT) Aflibercept + Active PDT Aflibercept (Non-randomized) Total
    Number of subjects
    		 157 161 15 333
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 70.8 ± 8.4 70.4 ± 8 71.8 ± 10.2 -
    Gender categorical
    Units: Subjects
        Female
    		 47 49 8 104
        Male
    		 110 112 7 229
    Baseline BCVA score
    Visual function of the study eye and fellow eye was assessed at each study visit according to the standard procedure developed for the ETDRS adapted for AREDS, using 70 letter charts at a starting distance of 4 meters. Participants were challenged with reading letters on lines of an eye chart (5 letters per line). Lines became smaller as participants progressed from the top to the bottom of the chart. Participants read down the chart until they reached a row where a minimum of three letters on a line could be read, and were scored by how many letters could be correctly identified.
    Units: Letters
        arithmetic mean (standard deviation)
    		 57.7 ± 11.3 59.0 ± 11.5 61.8 ± 15.2 -
    Central Subfield Thickness
    Units: Micrometer
        arithmetic mean (standard deviation)
    		 347.8 ± 118.9 346.1 ± 117.5 325.8 ± 117.9 -

    End points

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    End points reporting groups
    Reporting group title
    Aflibercept + Sham Photodynamic Therapy (PDT)
    Reporting group description
    		 Subjects received 2 milligram (mg) [0.05 millilitre (mL)] aflibercept injection intravitreally in monthly intervals on Weeks 0, 4, and 8 (run-in treatment); subjects were randomized on Week 12 and assessed for the rescue treatment (until the visual and anatomical outcomes allowed extension of the treatment interval) and then subjects received either bi-monthly injections of aflibercept intravitreally or bi-monthly injections of aflibercept intravitreally with sham PDT (2 milligram per millilitre [mg/mL] of 5 percent [%] dextrose solution or physiological saline solution), from Week 16 to Week 52. After week 52, treat-and-extend visit were scheduled and evaluation of rescue were continued with an optional extension treatment phase, where subjects received intravitreally injections of aflibercept monthly and sham PDT intravenously up to Week 96.

    Reporting group title
    Aflibercept + Active PDT
    Reporting group description
    		 Subjects received 2 mg (0.05 mL) aflibercept injection intravitreally in monthly intervals on Weeks 0, 4, and 8 (run-in treatment); subjects were randomized on Week 12 and assessed for the rescue treatment (until the visual and anatomical outcomes allowed extension of the treatment interval) and then subjects received either bi-monthly injections of aflibercept intravitreally or bi-monthly injections of aflibercept intravitreally with sham PDT (2 mg/mL of 5% dextrose solution or physiological saline solution), from Week 16 to Week 52. After week 52, treat-and-extend visit were scheduled and evaluation of rescue were continued with an optional extension treatment phase, where subjects received intravitreally injections of aflibercept monthly and sham PDT intravenously up to Week 96.

    Reporting group title
    Aflibercept (Non-randomized)
    Reporting group description
    		 Subjects received 2 mg (0.05 mL) aflibercept injection intravitreally in monthly intervals on Weeks 0, 4, and 8 as run-in treatment, until the subjects were randomized and received rescue treatments.

    Subject analysis set title
    Safety Analysis Set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    SAF (N=333) included all subjects who received any study drug under this protocol.

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    FAS (N=318) included all randomized subjects.

    Primary: Mean change in Best Corrected Visual Acuity (BCVA) as measured by Early Treatment of Diabetic Retinopathy Study (ETDRS) letter scores from baseline to Week 52 - Last observation carried forward (LOCF)

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    End point title
    		 Mean change in Best Corrected Visual Acuity (BCVA) as measured by Early Treatment of Diabetic Retinopathy Study (ETDRS) letter scores from baseline to Week 52 - Last observation carried forward (LOCF) [1]
    End point description
    Visual function of the study eye and fellow eye was assessed at each study visit according to the standard procedure developed for the ETDRS adapted for Age Related Eye Disease Study (AREDS), using 70 letter charts at a starting distance of 4 meters. Participants were challenged with reading letters on lines of an eye chart (5 letters per line). Lines became smaller as participants progressed from the top to the bottom of the chart. Participants read down the chart until they reached a row where a minimum of three letters on a line could be read, and were scored by how many letters could be correctly identified.
    End point type
    Primary
    End point timeframe
    From Baseline to Week 52
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint reports only the data for the randomized subjects (N=318), excluding the non-randomized reporting group.
    End point values
    		 Aflibercept + Sham Photodynamic Therapy (PDT) Aflibercept + Active PDT
    Number of subjects analysed
    157 [2]
    161 [3]
    Units: Letters correctly read
        arithmetic mean (standard deviation)
    10.7 ± 11.3
    10.8 ± 10.7
    Notes
    [2] - FAS
    [3] - FAS
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Aflibercept + Sham Photodynamic Therapy (PDT) v Aflibercept + Active PDT
    Number of subjects included in analysis
    318
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.548
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.9
         upper limit
    		 1.6

    Secondary: Percentage of Subjects Who Avoided at Least 15 Letters Loss in Early Treatment of Diabetic Retinopathy Study (ETDRS) From Baseline to Week 52

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    End point title
    		 Percentage of Subjects Who Avoided at Least 15 Letters Loss in Early Treatment of Diabetic Retinopathy Study (ETDRS) From Baseline to Week 52 [4]
    End point description
    Visual function of the study eye and fellow eye was assessed at each study visit according to the standard procedure developed for the ETDRS adapted for Age Related Eye Disease Study (AREDS), using 70 letter charts at a starting distance of 4 meters. Participants were challenged with reading letters on lines of an eye chart (5 letters per line). Lines became smaller as participants progressed from the top to the bottom of the chart. Participants read down the chart until they reached a row where a minimum of three letters on a line could be read, and were scored by how many letters could be correctly identified.
    End point type
    Secondary
    End point timeframe
    Baseline up to week 52
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint reports only the data for the randomized subjects (N=318), excluding the non-randomized reporting group.
    End point values
    		 Aflibercept + Sham Photodynamic Therapy (PDT) Aflibercept + Active PDT
    Number of subjects analysed
    157
    161
    Units: percentage of subjects
        number (not applicable)
    97.5
    96.9
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Aflibercept + Active PDT v Aflibercept + Sham Photodynamic Therapy (PDT)
    Number of subjects included in analysis
    318
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7402
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment difference
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.1
         upper limit
    		 4.3

    Other pre-specified: Percentage of subjects who never need rescue therapy in the first year

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    End point title
    		 Percentage of subjects who never need rescue therapy in the first year [5]
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 52
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint reports only the data for the randomized subjects (N=318), excluding the non-randomized reporting group.
    End point values
    		 Aflibercept + Sham Photodynamic Therapy (PDT) Aflibercept + Active PDT
    Number of subjects analysed
    157
    161
    Units: Percentage of subjects
        number (not applicable)
    87.9
    85.7
    No statistical analyses for this end point

    Other pre-specified: Number of PDT treatments in the study eye before Week 52

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    End point title
    		 Number of PDT treatments in the study eye before Week 52 [6]
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 52
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint reports only the data for the randomized subjects (N=318), excluding the non-randomized reporting group.
    End point values
    		 Aflibercept + Sham Photodynamic Therapy (PDT) Aflibercept + Active PDT
    Number of subjects analysed
    157
    161
    Units: PDT administrations
        arithmetic mean (standard deviation)
    0.2 ± 0.7
    0.2 ± 0.4
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Aflibercept + Sham Photodynamic Therapy (PDT) v Aflibercept + Active PDT
    Number of subjects included in analysis
    318
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0682
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Confidence interval
         level
    		 95%

    Other pre-specified: Number of aflibercept treatments in the study eye (after randomization) before Week 52

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    End point title
    		 Number of aflibercept treatments in the study eye (after randomization) before Week 52 [7]
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 52
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint reports only the data for the randomized subjects (N=318), excluding the non-randomized reporting group.
    End point values
    		 Aflibercept + Sham Photodynamic Therapy (PDT) Aflibercept + Active PDT
    Number of subjects analysed
    154
    160 [8]
    Units: Aflibercept injections
        arithmetic mean (standard deviation)
    5.2 ± 1.1
    5.1 ± 0.8
    Notes
    [8] - FAS with evaluable subjects for this outcome measure
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Aflibercept + Sham Photodynamic Therapy (PDT) v Aflibercept + Active PDT
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.164
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    0.164
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.3

    Other pre-specified: Time to first administration of PDT in the study eye before Week 52

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    End point title
    		 Time to first administration of PDT in the study eye before Week 52 [9]
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 52
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint reports only the data for the randomized subjects (N=318), excluding the non-randomized reporting group.
    End point values
    		 Aflibercept + Sham Photodynamic Therapy (PDT) Aflibercept + Active PDT
    Number of subjects analysed
    157
    161
    Units: Days
        arithmetic mean (full range (min-max))
    131.2 (80 to 278)
    128.2 (80 to 315)
    No statistical analyses for this end point

    Other pre-specified: Change of visual acuity (letters) from baseline over time (week) in the study eye

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    End point title
    		 Change of visual acuity (letters) from baseline over time (week) in the study eye [10]
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 52
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint reports only the data for the randomized subjects (N=318), excluding the non-randomized reporting group.
    End point values
    		 Aflibercept + Sham Photodynamic Therapy (PDT) Aflibercept + Active PDT
    Number of subjects analysed
    157
    161
    Units: Letters
        arithmetic mean (standard deviation)
    10.7 ± 11.3
    10.8 ± 10.7
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who gained ≥5, 10, or 15 letters at Week 52

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    End point title
    		 Percentage of subjects who gained ≥5, 10, or 15 letters at Week 52 [11]
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 52
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint reports only the data for the randomized subjects (N=318), excluding the non-randomized reporting group.
    End point values
    		 Aflibercept + Sham Photodynamic Therapy (PDT) Aflibercept + Active PDT
    Number of subjects analysed
    157
    161
    Units: Percentage of subjects
    number (not applicable)
        Gained ≥ 5
    73.9
    78.9
        Gained ≥ 10
    55.4
    57.1
        Gained ≥ 15
    33.1
    36.6
    Statistical analysis title
    		 Category of Gained ≥ 5
    Statistical analysis description
    The p-value is calculated from the 2-sided Cochran-Mantel-Haenszel test adjusted by ethnicity and qualification for rescue therapy at Week 12. CI is based on the treatment difference in % (AFL-sham – AFL-PDT) using the Mantel-Haenszel weighting scheme adjusted by ethnicity and qualification for rescue therapy at Week 12.
    Comparison groups
    Aflibercept + Sham Photodynamic Therapy (PDT) v Aflibercept + Active PDT
    Number of subjects included in analysis
    318
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2348
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 treatment difference in %
    Point estimate
    -5.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.9
         upper limit
    		 3.7
    Statistical analysis title
    		 Category of Gained ≥ 10
    Statistical analysis description
    The p-value is calculated from the 2-sided Cochran-Mantel-Haenszel test adjusted by ethnicity and qualification for rescue therapy at Week 12. CI is based on the treatment difference in % (AFL-sham – AFL-PDT) using the Mantel-Haenszel weighting scheme adjusted by ethnicity and qualification for rescue therapy at Week 12.
    Comparison groups
    Aflibercept + Sham Photodynamic Therapy (PDT) v Aflibercept + Active PDT
    Number of subjects included in analysis
    318
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.6877
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 treatment difference in %
    Point estimate
    -2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.1
         upper limit
    		 8.6
    Statistical analysis title
    		 Category of Gained ≥ 15
    Statistical analysis description
    The p-value is calculated from the 2-sided Cochran-Mantel-Haenszel test adjusted by ethnicity and qualification for rescue therapy at Week 12. CI is based on the treatment difference in % (AFL-sham – AFL-PDT) using the Mantel-Haenszel weighting scheme adjusted by ethnicity and qualification for rescue therapy at Week 12.
    Comparison groups
    Aflibercept + Sham Photodynamic Therapy (PDT) v Aflibercept + Active PDT
    Number of subjects included in analysis
    318
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4556
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 treatment difference in %
    Point estimate
    -4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.5
         upper limit
    		 6.5

    Other pre-specified: Percentage of subjects who lost ≥5, 10, or 15 letters at Week 52

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    End point title
    		 Percentage of subjects who lost ≥5, 10, or 15 letters at Week 52 [12]
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 52
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint reports only the data for the randomized subjects (N=318), excluding the non-randomized reporting group.
    End point values
    		 Aflibercept + Sham Photodynamic Therapy (PDT) Aflibercept + Active PDT
    Number of subjects analysed
    157
    161
    Units: Percentage of subjects
    number (not applicable)
        Lost ≥ 5
    7.0
    5.6
        Lost ≥ 10
    3.8
    3.1
        Lost ≥ 15
    2.5
    3.1
    Statistical analysis title
    		 Category of Lost ≥ 5
    Statistical analysis description
    The p-value is calculated from the 2-sided Cochran-Mantel-Haenszel test adjusted by ethnicity and qualification for rescue therapy at Week 12. CI is based on the treatment difference in % (AFL-sham – AFL-PDT) using the Mantel-Haenszel weighting scheme adjusted by ethnicity and qualification for rescue therapy at Week 12.
    Comparison groups
    Aflibercept + Sham Photodynamic Therapy (PDT) v Aflibercept + Active PDT
    Number of subjects included in analysis
    318
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5372
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 treatment difference in %
    Point estimate
    1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.7
         upper limit
    		 7.2
    Statistical analysis title
    		 Category of Lost ≥ 10
    Statistical analysis description
    The p-value is calculated from the 2-sided Cochran-Mantel-Haenszel test adjusted by ethnicity and qualification for rescue therapy at Week 12. CI is based on the treatment difference in % (AFL-sham – AFL-PDT) using the Mantel-Haenszel weighting scheme adjusted by ethnicity and qualification for rescue therapy at Week 12.
    Comparison groups
    Aflibercept + Sham Photodynamic Therapy (PDT) v Aflibercept + Active PDT
    Number of subjects included in analysis
    318
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7569
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 treatment difference in %
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.4
         upper limit
    		 4.7
    Statistical analysis title
    		 Category of Lost ≥ 15
    Statistical analysis description
    The p-value is calculated from the 2-sided Cochran-Mantel-Haenszel test adjusted by ethnicity and qualification for rescue therapy at Week 12. CI is based on the treatment difference in % (AFL-sham – AFL-PDT) using the Mantel-Haenszel weighting scheme adjusted by ethnicity and qualification for rescue therapy at Week 12.
    Comparison groups
    Aflibercept + Active PDT v Aflibercept + Sham Photodynamic Therapy (PDT)
    Number of subjects included in analysis
    318
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7402
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 treatment difference in %
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.3
         upper limit
    		 3.1

    Other pre-specified: Percentage of subjects with complete polyp regression at Week 52

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    End point title
    		 Percentage of subjects with complete polyp regression at Week 52 [13]
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 52
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint reports only the data for the randomized subjects (N=318), excluding the non-randomized reporting group.
    End point values
    		 Aflibercept + Sham Photodynamic Therapy (PDT) Aflibercept + Active PDT
    Number of subjects analysed
    126 [14]
    134 [15]
    Units: Percetage of subjects
        number (not applicable)
    38.9
    44.8
    Notes
    [14] - FAS with evaluable subjects for this outcome measure.
    [15] - FAS with evaluable subjects for this outcome measure.
    Statistical analysis title
    		 Statistical analysis title 1
    Statistical analysis description
    The p-value is calculated from the 2-sided Cochran-Mantel-Haenszel test adjusted by ethnicity and qualification for rescue therapy at Week 12. CI is based on the treatment difference in % (AFL-sham – AFL-PDT) using the Mantel-Haenszel weighting scheme adjusted by ethnicity and qualification for rescue therapy at Week 12.
    Comparison groups
    Aflibercept + Sham Photodynamic Therapy (PDT) v Aflibercept + Active PDT
    Number of subjects included in analysis
    260
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3244
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 treatment difference in %
    Point estimate
    -6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.8
         upper limit
    		 5.9

    Other pre-specified: Change of leakage area in Fluorescein angiography (FA) in the study eye at Week 52

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    End point title
    		 Change of leakage area in Fluorescein angiography (FA) in the study eye at Week 52 [16]
    End point description
    Leakage is the release of fluorescein dye from diseased retinal vessels. Leakage area is defined as the area showing presence of fluorescein dye in the late stages of fluorescein angiography.
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 52
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint reports only the data for the randomized subjects (N=318), excluding the non-randomized reporting group.
    End point values
    		 Aflibercept + Sham Photodynamic Therapy (PDT) Aflibercept + Active PDT
    Number of subjects analysed
    140 [17]
    149 [18]
    Units: Square millimeter
        arithmetic mean (standard deviation)
    -1.3 ± 3.6
    -1.2 ± 3.7
    Notes
    [17] - FAS with evaluable subjects for this outcome measure.
    [18] - FAS with evaluable subjects for this outcome measure.
    Statistical analysis title
    		 Statistical analysis title 1
    Statistical analysis description
    The analysis population included only subjects with leakage in FA at baseline and Week 52. Baseline values were not carried forward. Point estimate, 95% CI and p-value are based on difference (AFL-sham – AFL-PDT) of LS mean changes using an ANCOVA model with treatment group and ethnicity and qualification for rescue therapy at Week 12 as fixed effects, baseline value as covariate.
    Comparison groups
    Aflibercept + Sham Photodynamic Therapy (PDT) v Aflibercept + Active PDT
    Number of subjects included in analysis
    289
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7109
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 0.6

    Other pre-specified: Change of Central subfield thickness (CST) on Optical coherence tomography (OCT) from baseline to Week 52

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    End point title
    		 Change of Central subfield thickness (CST) on Optical coherence tomography (OCT) from baseline to Week 52 [19]
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 52
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint reports only the data for the randomized subjects (N=318), excluding the non-randomized reporting group.
    End point values
    		 Aflibercept + Sham Photodynamic Therapy (PDT) Aflibercept + Active PDT
    Number of subjects analysed
    136 [20]
    150 [21]
    Units: millimeter(s)
        arithmetic mean (standard deviation)
    -137.7 ± 116.0
    -143.5 ± 110.5
    Notes
    [20] - FAS with evaluable subjects for this outcome measure
    [21] - FAS with evaluable subjects for this outcome measure
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The analysis population included only subjects with values for CST at baseline and Week 52. Baseline values were not carried forward. Point estimate, 95% CI and p-value are based on difference (AFL-sham – AFL-PDT) of LS mean changes using an ANCOVA model with treatment group and ethnicity and qualification for rescue therapy at Week 12 as fixed effects, baseline value as covariate.
    Comparison groups
    Aflibercept + Sham Photodynamic Therapy (PDT) v Aflibercept + Active PDT
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8355
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.2
         upper limit
    		 11.3

    Other pre-specified: Change in National Eye Institute 25-item visual function questionnaire (NEI VFQ-25) total score from baseline to Week 52

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    End point title
    		 Change in National Eye Institute 25-item visual function questionnaire (NEI VFQ-25) total score from baseline to Week 52 [22]
    End point description
    The NEI VFQ-25 total score ranges from 0-100 with a score of 0 being the worst outcome and 100 being the best outcome. The NEI VFQ questionnaire is organized as a collection of subscales which are all scored from 0-100. To reach the overall composite score, each sub-scale score is averaged in order to give each sub-scale equal weight.
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 52
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint reports only the data for the randomized subjects (N=318), excluding the non-randomized reporting group.
    End point values
    		 Aflibercept + Sham Photodynamic Therapy (PDT) Aflibercept + Active PDT
    Number of subjects analysed
    143 [23]
    153 [24]
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    4.7 ± 10.3
    7.3 ± 12.5
    Notes
    [23] - FAS with evaluable subjects for this outcome measure.
    [24] - FAS with evaluable subjects for this outcome measure.
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Aflibercept + Sham Photodynamic Therapy (PDT) v Aflibercept + Active PDT
    Number of subjects included in analysis
    296
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5069
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.9
         upper limit
    		 1.4

    Other pre-specified: Percentage of subjects for whom rescue therapy is indicated over the course till Week 52

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    End point title
    		 Percentage of subjects for whom rescue therapy is indicated over the course till Week 52 [25]
    End point description
    Evaluations for qualification for rescue were conducted at each visit from Week 12 to Week 52. Intensified aflibercept treatment plus active or sham PDT treatments were given at any of these visits if treatment criteria were met. Qualification for rescue was based upon insufficient gain of BCVA, leakage, and presence of active polyps.
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 52
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint reports only the data for the randomized subjects (N=318), excluding the non-randomized reporting group.
    End point values
    		 Aflibercept + Sham Photodynamic Therapy (PDT) Aflibercept + Active PDT
    Number of subjects analysed
    157
    161
    Units: Percentage of subjects
        number (not applicable)
    12.1
    14.3
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The p-value is calculated from the 2-sided Cochran-Mantel-Haenszel test adjusted by ethnicity and qualification for rescue therapy at Week 12. CI is based on the treatment difference in % (AFL-sham – AFL-PDT) using the Mantel-Haenszel weighting scheme adjusted by ethnicity and qualification for rescue therapy at Week 12.
    Comparison groups
    Aflibercept + Sham Photodynamic Therapy (PDT) v Aflibercept + Active PDT
    Number of subjects included in analysis
    318
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8423
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference %
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.3
         upper limit
    		 5.1

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study treatment up to 30 days after the last treatment. Approximately 100 weeks.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Aflibercept + Sham PDT
    Reporting group description
    		 Subjects received 2 milligram (mg) Intravitreal aflibercept injection (IAI) (Eylea, VEGF Trap-Eye, BAY86-5321) every month for the first 3 months (run-in period).At Week 12, subjects were assessed for the rescue treatment and randomized to receive Aflibercept injection plus sham photodynamic therapy (only in subjects qualifying for rescue therapy) until Week 52. Between Week 52 and Week 96, the treatment interval could have been extended (typically in increments of 1 or 2 weeks) at the discretion of the investigator when the visual and anatomic outcomes allowed.

    Reporting group title
    Aflibercept + Active PDT
    Reporting group description
    		 Subjects received 2 mg Intravitreal aflibercept injection (IAI) (Eylea, VEGF Trap-Eye, BAY86-5321) every month for the first 3 months (run-in period). At Week 12, subjects were assessed for the rescue treatment and randomized to receive Aflibercept injection plus active photodynamic therapy (only in subjects qualifying for rescue therapy) until Week 52. Between Week 52 and Week 96, the treatment interval could have been extended (typically in increments of 1 or 2 weeks) at the discretion of the investigator when the visual and anatomic outcomes allowed.

    Reporting group title
    Aflibercept (Non-randomized)
    Reporting group description
    		 Subjects received 2 mg Intravitreal aflibercept injection (IAI) (Eylea, VEGF Trap-Eye, BAY86-5321) every month for the first 3 months (run-in period), but discontinued study participation before randomization.

    Serious adverse events
    		 Aflibercept + Sham PDT Aflibercept + Active PDT Aflibercept (Non-randomized)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 157 (17.20%)
    25 / 161 (15.53%)
    4 / 15 (26.67%)
         number of deaths (all causes)
    3
    0
    1
         number of deaths resulting from adverse events
    1
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acoustic neuroma
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 161 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma gastric
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 161 (0.62%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 161 (0.62%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasm
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thyroid neoplasm
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 161 (0.62%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric adenoma
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 161 (0.62%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 161 (0.62%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Varicose vein
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Transcatheter arterial chemoembolisation
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 161 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 161 (0.62%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystocele
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 161 (0.62%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 13
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 161 (0.62%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 161 (0.62%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Scapula fracture
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Afferent loop syndrome
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 161 (0.62%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Traumatic haemothorax
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 161 (0.62%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 161 (0.62%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Senile dementia
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 161 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eyelid ptosis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 161 (0.62%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal artery occlusion
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 161 (0.62%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal haemorrhage
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 161 (0.62%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Visual acuity reduced
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 161 (1.24%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal pigment epithelial tear
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 161 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ileus
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 161 (0.62%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 161 (0.62%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 161 (0.62%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia strangulated
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 161 (0.62%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Cervical spinal stenosis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 161 (0.62%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Exostosis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 161 (0.62%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Ear infection
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endophthalmitis
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 161 (0.62%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 157 (0.00%)
    3 / 161 (1.86%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 161 (0.62%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Iron deficiency
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Aflibercept + Sham PDT Aflibercept + Active PDT Aflibercept (Non-randomized)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    59 / 157 (37.58%)
    49 / 161 (30.43%)
    3 / 15 (20.00%)
    Investigations
    Intraocular pressure increased
         subjects affected / exposed
    6 / 157 (3.82%)
    9 / 161 (5.59%)
    0 / 15 (0.00%)
         occurrences all number
    18
    20
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 157 (3.82%)
    13 / 161 (8.07%)
    2 / 15 (13.33%)
         occurrences all number
    6
    13
    2
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    10 / 157 (6.37%)
    5 / 161 (3.11%)
    0 / 15 (0.00%)
         occurrences all number
    31
    8
    0
    Dry eye
         subjects affected / exposed
    6 / 157 (3.82%)
    11 / 161 (6.83%)
    0 / 15 (0.00%)
         occurrences all number
    11
    22
    0
    Ocular hypertension
         subjects affected / exposed
    3 / 157 (1.91%)
    1 / 161 (0.62%)
    1 / 15 (6.67%)
         occurrences all number
    4
    1
    1
    Visual acuity reduced
         subjects affected / exposed
    7 / 157 (4.46%)
    9 / 161 (5.59%)
    0 / 15 (0.00%)
         occurrences all number
    7
    10
    0
    Vitreous floaters
         subjects affected / exposed
    9 / 157 (5.73%)
    1 / 161 (0.62%)
    0 / 15 (0.00%)
         occurrences all number
    10
    1
    0
    Retinal pigment epithelial tear
         subjects affected / exposed
    4 / 157 (2.55%)
    0 / 161 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    4
    0
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 161 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    1
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    25 / 157 (15.92%)
    18 / 161 (11.18%)
    0 / 15 (0.00%)
         occurrences all number
    41
    25
    0

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

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Decimal places were automatically truncated if last decimal equals zero.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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