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    Clinical Trial Results:
    A 64-week, two-arm, randomized, double-masked, multicenter, phase IIIb study assessing the efficacy and safety of brolucizumab 6 mg compared to aflibercept 2 mg in a treat-to-control regimen in patients with neovascular agerelated macular degeneration (TALON)

    Summary
    EudraCT number
    		 2019-000716-28
    Trial protocol
    		 PT   IT   CZ   SE   GB   ES   BE   DE   NL  
    Global end of trial date
    09 Sep 2022

    Results information
    Results version number
    		 v2(current)
    This version publication date
    13 Apr 2024
    First version publication date
    16 Sep 2023
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    CRTH258A2303
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04005352
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.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
    09 Sep 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Sep 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Sep 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of this study were: -Distribution of the last interval with no disease activity up to Week 32 (if there was disease activity, the last interval would be shortened by 4 weeks, down to a minimum of 4 weeks) -Average change in Best-corrected visual acuity (BCVA) from baseline at Weeks 28 and 32 Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com for complete trial results.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Sep 2019
    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
    Argentina: 56
    Country: Number of subjects enrolled
    Australia: 36
    Country: Number of subjects enrolled
    Austria: 11
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Canada: 17
    Country: Number of subjects enrolled
    Czechia: 54
    Country: Number of subjects enrolled
    France: 100
    Country: Number of subjects enrolled
    Germany: 65
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    Israel: 22
    Country: Number of subjects enrolled
    Italy: 28
    Country: Number of subjects enrolled
    Korea, Republic of: 52
    Country: Number of subjects enrolled
    Malaysia: 24
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Portugal: 25
    Country: Number of subjects enrolled
    Spain: 98
    Country: Number of subjects enrolled
    Sweden: 7
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    Taiwan: 29
    Country: Number of subjects enrolled
    United States: 87
    Worldwide total number of subjects
    734
    EEA total number of subjects
    396
    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)
    69
    From 65 to 84 years
    570
    85 years and over
    95

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 734 participants were treated.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Brolucizumab 6 mg
    Arm description
    		 Intra-vitreal injection
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brolucizumab
    Investigational medicinal product code
    RTH258
    Other name
    Beovu
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Brolucizumab 6 mg Intravitreal injection

    Arm title
    		 Aflibercept 2 mg
    Arm description
    		 Intra-vitreal injection
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Aflibercept
    Investigational medicinal product code
    J0178
    Other name
    Eylea and Zaltrap
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Aflibercept 2 mg

    Number of subjects in period 1
    		Brolucizumab 6 mg Aflibercept 2 mg
    Started
    366
    368
    Completed
    317
    307
    Not completed
    49
    61
         Adverse event, serious fatal
    4
    2
         Physician decision
    7
    13
         Consent withdrawn by subject
    28
    38
         Adverse event, non-fatal
    4
    5
         Lost to follow-up
    6
    2
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Brolucizumab 6 mg
    Reporting group description
    		 Intra-vitreal injection

    Reporting group title
    Aflibercept 2 mg
    Reporting group description
    		 Intra-vitreal injection

    Reporting group values
    		 Brolucizumab 6 mg Aflibercept 2 mg Total
    Number of subjects
    		 366 368 734
    Age Categorical
    Units: Participants
        <=18 years
    		 0 0 0
        Between 18 and 65 years
    		 32 37 69
        >=65 years
    		 334 331 665
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 75.5 ( 7.85 ) 75.5 ( 8.41 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 216 204 420
        Male
    		 150 164 314
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 55 55 110
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 1 1 2
        White
    		 310 312 622
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Brolucizumab 6 mg
    Reporting group description
    		 Intra-vitreal injection

    Reporting group title
    Aflibercept 2 mg
    Reporting group description
    		 Intra-vitreal injection

    Primary: Distribution of the last interval with no disease activity up to Week 32 - study eye

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    End point title
    		 Distribution of the last interval with no disease activity up to Week 32 - study eye
    End point description
    No disease activity is defined as no change in visual acuity and no change in other signs of the disease (e.g. Intraretinal Fluid (IRF), Subretinal Fluid (SRF), hemorrhage, leakage, etc.). Treatment interval distribution. Number (%) of subjects at 12/8/4-weeks intervals up to Week 32 for the study eye. If the study treatment is discontinued before Week 16, then the treatment interval is 4 weeks; otherwise. the last interval with no disease activity is used (if there was disease activity, the last interval is shortened by 4 weeks, down to a minimum of 4 weeks). If the duration of the last interval falls within the following ranges of (4-week, 8-week) or (8-week, 12-week) or ≥12-week then the floor value of these ranges was used.
    End point type
    Primary
    End point timeframe
    Up to Week 32
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    366
    368
    Units: Participants
        12 weeks
    141
    73
        8 weeks
    131
    147
        4 weeks
    94
    148
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    734
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001 [1]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [1] - with significance level of 0.025

    Primary: Average change from baseline at Week 28 and Week 32 in Best-corrected visual acuity (BCVA) - study eye

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    End point title
    		 Average change from baseline at Week 28 and Week 32 in Best-corrected visual acuity (BCVA) - study eye
    End point description
    BCVA was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. Min and max possible scores are 0-100 respectively. A higher score represents better visual functioning. Least squares mean estimate - for weeks 28 and 32 combined.
    End point type
    Primary
    End point timeframe
    Baseline, Week 28 and Week 32
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    366
    368
    Units: Scores on a scale
        least squares mean (standard error)
    5.2 ( 0.51 )
    5.1 ( 0.51 )
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    734
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 Difference
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.3
         upper limit
    		 1.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.73

    Secondary: Distribution of the last interval with no disease activity up to Week 64 - study eye

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    End point title
    		 Distribution of the last interval with no disease activity up to Week 64 - study eye
    End point description
    No disease activity is defined as no change in visual acuity and no change in other signs of the disease (e.g. IRF, SRF, hemorrhage, leakage, etc.). Treatment interval distribution. The number of subjects at 16/12/8/4-weeks intervals as the last interval with no disease activity. If the study treatment is discontinued before Week 16, then the treatment interval is 4 weeks; otherwise. the last interval with no disease activity is used (if there was disease activity, the last interval is shortened by 4 weeks, down to a minimum of 4 weeks). If the duration of the last interval falls within the following ranges of (4-week, 8-week) or (8-week, 12-week) or (12-weeks, 16-weeks) or ≥16-week then the floor value of these ranges was used.
    End point type
    Secondary
    End point timeframe
    Up to Week 64
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    366
    368
    Units: Participants
        16 Weeks
    104
    45
        12 Weeks
    82
    88
        8 Weeks
    95
    81
        4 Weeks
    85
    154
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    734
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Distribution of the maximal intervals with no disease activity up to Week 64 - study eye

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    End point title
    		 Distribution of the maximal intervals with no disease activity up to Week 64 - study eye
    End point description
    No disease activity is defined as no change in visual acuity and no change in other signs of the disease (e.g. IRF, SRF, hemorrhage, leakage, etc.). Maximal interval distribution. Number of subjects at 16/12/8/4-weeks intervals as the last interval with no disease activity. If the study treatment is discontinued before Week 16 included, then the treatment interval is 4 weeks; otherwise, the last interval with no disease activity is used (if there was disease activity, the last interval is shortened by 4 weeks, down to a minimum of 4 weeks). If the duration of the maximal interval falls within the following ranges of [4-weeks, 8-weeks) or [8-weeks, 12-weeks) or [12-weeks, 16-weeks] or ≥16-weeks then the floor value of these ranges is used.
    End point type
    Secondary
    End point timeframe
    Up to Week 64
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    366
    368
    Units: Participants
        16 Weeks
    117
    57
        12 Weeks
    96
    92
        8 Weeks
    94
    114
        4 Weeks
    59
    105
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    734
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Number of participants with no disease activity - study eye

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    End point title
    		 Number of participants with no disease activity - study eye
    End point description
    Disease activity assessment as determined by visual acuity and assessment of other signs of the disease (e.g. IRF, SRF, hemorrhage, leakage, etc.).
    End point type
    Secondary
    End point timeframe
    Weeks 14 and 16
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    301
    296
    Units: Participants
        Week 14 (n=118, 137)
    87
    88
        Week 16 (n=301,296)
    260
    211
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    597
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    P-value
    		 < 0.0001
    Method
    		 likelihood ratio test
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.7
         upper limit
    		 3.9
    Notes
    [2] - Week 16
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    597
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    P-value
    		 = 0.051
    Method
    		 likelihood ratio test
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 2.7
    Notes
    [3] - Week 14

    Secondary: Time from Last Loading Injection to First Visit with No Disease Activity (Weeks) - 75th percentile - study eye

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    End point title
    		 Time from Last Loading Injection to First Visit with No Disease Activity (Weeks) - 75th percentile - study eye
    End point description
    Intraretinal fluid (IRF) and subretinal fluid (SRF) were assessed by Spectral Domain Optical Coherence Tomography (SD-OCT) (study eye). Please note that this endpoint can be impacted by the optional disease activity assessment visits and the flexible dosing regimen, in addition to the randomized treatment. Hence, the observed treatment effect may be confounded by the study design artifacts.
    End point type
    Secondary
    End point timeframe
    Up to Week 64
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    366
    368
    Units: weeks
    number (confidence interval 95%)
        75th percentile
    9.1 (8.9 to 10.6)
    12.1 (11.3 to 12.9)
    No statistical analyses for this end point

    Secondary: Time-to-first dry retina - time to the first visit with no Intraretinal Fluid (IRF) or Subretinal Fluid (SRF) - study eye

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    End point title
    		 Time-to-first dry retina - time to the first visit with no Intraretinal Fluid (IRF) or Subretinal Fluid (SRF) - study eye
    End point description
    Intraretinal fluid (IRF) and subretinal fluid (SRF) were assessed by Spectral Domain Optical Coherence Tomography (SD-OCT) (study eye). Includes subjects with no important protocol deviations with impact.
    End point type
    Secondary
    End point timeframe
    Up to Week 64
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    330
    337
    Units: Participants
        0 Week
    330
    337
        4 Week
    144
    138
        8 Week
    70
    86
        12 Week
    70
    86
        16 Week
    37
    67
        20 Week
    34
    55
        24 Week
    30
    47
        28 Week
    28
    38
        32 Week
    20
    25
        36 Week
    20
    23
        40 Week
    18
    22
        44 Week
    18
    22
        48 Week
    17
    20
        52 Week
    17
    20
        56 Week
    17
    20
        60 Week
    11
    14
        64 Week
    0
    0
    No statistical analyses for this end point

    Secondary: Average change from baseline at Week 60 and Week 64 in Best-corrected visual acuity (BCVA) - study eye

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    End point title
    		 Average change from baseline at Week 60 and Week 64 in Best-corrected visual acuity (BCVA) - study eye
    End point description
    BCVA was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. Min and max possible scores are 0-100 respectively. A higher score represents better visual functioning. Least squares mean estimate - for weeks 60 and 64 combined.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 60 and Week 64
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    366
    368
    Units: Scores on a scale
        least squares mean (standard error)
    4.7 ( 0.60 )
    4.9 ( 0.60 )
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    734
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.8137 [4]
    Method
    		 ANOVA
    Parameter type
    		 Difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.9
         upper limit
    		 1.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.84
    Notes
    [4] - p-value for treatment difference

    Secondary: Number of participants with best-corrected visual acuity improvements of ≥ 15 letters in BCVA from baseline or reached BCVA ≥ 84 letters up to Week 32/64 per treatment arm - study eye

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    End point title
    		 Number of participants with best-corrected visual acuity improvements of ≥ 15 letters in BCVA from baseline or reached BCVA ≥ 84 letters up to Week 32/64 per treatment arm - study eye
    End point description
    BCVA was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. Min and max possible scores are 0-100 respectively. A higher score represents better visual functioning.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 32, and Week 64
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    366
    368
    Units: participants
        Week 32
    88
    92
        Week 64
    89
    91
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    734
    Analysis specification
    Pre-specified
    Analysis type
    		 [5]
    P-value
    		 = 0.4667
    Method
    		 likelihood ratio test
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.4
    Notes
    [5] - Week 64
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    734
    Analysis specification
    Pre-specified
    Analysis type
    		 [6]
    P-value
    		 = 0.4106
    Method
    		 likelihood ratio test
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.3
    Notes
    [6] - Week 32

    Secondary: Number of participants with best-corrected visual acuity ≥ 69 letters - study eye

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    End point title
    		 Number of participants with best-corrected visual acuity ≥ 69 letters - study eye
    End point description
    BCVA was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. Min and max possible scores are 0-100 respectively. A higher score represents better visual functioning.
    End point type
    Secondary
    End point timeframe
    Week 32 and Week 64
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    366
    368
    Units: Participants
        Week 32
    244
    228
        Week 64
    240
    219
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    734
    Analysis specification
    Pre-specified
    Analysis type
    		 [7]
    P-value
    		 = 0.115
    Method
    		 likelihood ratio test
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 1.8
    Notes
    [7] - Week 64
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    734
    Analysis specification
    Pre-specified
    Analysis type
    		 [8]
    P-value
    		 = 0.2397
    Method
    		 likelihood ratio test
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.7
    Notes
    [8] - Week 32

    Secondary: Average change from baseline in Central Subfield Thickness (CSFT) - study eye

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    End point title
    		 Average change from baseline in Central Subfield Thickness (CSFT) - study eye
    End point description
    CSFT was measured by Spectral Domain Optical Coherence Tomography
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 28 and 32 and at Weeks 60 and 64
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    366
    368
    Units: micrometers
    least squares mean (standard error)
        Weeks 28 and 32 (average)
    -166.9 ( 6.97 )
    -140.0 ( 6.96 )
        Weeks 60 and 64 (average)
    -182.9 ( 7.72 )
    -167.5 ( 8.16 )
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    734
    Analysis specification
    Pre-specified
    Analysis type
    		 [9]
    P-value
    		 = 0.0066
    Method
    		 ANOVA
    Parameter type
    		 Difference
    Point estimate
    -26.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -46.3
         upper limit
    		 -7.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    9.87
    Notes
    [9] - Weeks 28 and 32
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    734
    Analysis specification
    Pre-specified
    Analysis type
    		 [10]
    P-value
    		 = 0.1714
    Method
    		 ANOVA
    Parameter type
    		 Difference
    Point estimate
    -15.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -37.6
         upper limit
    		 6.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    11.26
    Notes
    [10] - Weeks 60 and 64

    Secondary: Number of participants with presence of Intraretinal Fluid and/or Subretinal Fluid in the central subfield - study eye

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    End point title
    		 Number of participants with presence of Intraretinal Fluid and/or Subretinal Fluid in the central subfield - study eye
    End point description
    Intraretinal Fluid and/or Subretinal Fluid status was measured by Spectral Domain Optical Coherence Tomography (SD-OCT).
    End point type
    Secondary
    End point timeframe
    At Weeks 28, 32, 60 and 64
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    286
    289
    Units: Participants
        Week 28 (n=285,289)
    175
    198
        Week 32 (n=286, 267)
    144
    152
        Week 60 (n=269,244)
    60
    69
        Week 64 (n=271, 241)
    72
    83
    No statistical analyses for this end point

    Secondary: Number of participants with presence of sub-Retinal Pigment Epithelium fluid in the central subfield - study eye

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    End point title
    		 Number of participants with presence of sub-Retinal Pigment Epithelium fluid in the central subfield - study eye
    End point description
    Sub-Retinal Pigment Epithelium fluid status was measured by Spectral Domain Optical Coherence Tomography (SD-OCT).
    End point type
    Secondary
    End point timeframe
    At Weeks 28, 32, 60 and 64
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    288
    289
    Units: Participants
        Week 28 (n=288,289)
    173
    208
        Week 32 (n=288, 266)
    156
    175
        Week 60 (n=271,244)
    27
    31
        Week 64 (n=271, 242)
    34
    43
    No statistical analyses for this end point

    Secondary: Change from baseline in Visual Function Questionnnaire-25 (VFQ-25) - Composite scores - study eye

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    End point title
    		 Change from baseline in Visual Function Questionnnaire-25 (VFQ-25) - Composite scores - study eye
    End point description
    The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual functioning. Each item is then converted to a 0 to 100 scale so that the lowest and highest possible scores are set at 0 and 100 points, respectively. A composite score is derived based on the average of the 11 subscales.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 32, and Week 64
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    278
    261
    Units: Scores on a scale
    least squares mean (standard error)
        Week 32 (n-278, 261)
    4.09 ( 0.20 )
    3.72 ( 0.21 )
        Week 64 (n=248, 224)
    2.8 ( 0.69 )
    4.7 ( 0.73 )
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    539
    Analysis specification
    Pre-specified
    Analysis type
    		 [11]
    P-value
    		 = 0.052
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.9
         upper limit
    		 0
    Notes
    [11] - Week 64
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    539
    Analysis specification
    Pre-specified
    Analysis type
    		 [12]
    P-value
    		 = 0.193
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0.9
    Notes
    [12] - Week 32

    Secondary: Change from baseline in Visual Function Questionnnaire-25 (VFQ-25) - subscale score - General Vision - study eye

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    End point title
    		 Change from baseline in Visual Function Questionnnaire-25 (VFQ-25) - subscale score - General Vision - study eye
    End point description
    The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual functioning. Each item is then converted to a 0 to 100 scale so that the lowest and highest possible scores are set at 0 and 100 points, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 32, and Week 64
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    278
    261
    Units: Scores on a scale
    least squares mean (standard error)
        Week 32 (n-278, 261)
    7.94 ( 0.86 )
    5.79 ( 0.89 )
        Week 64 (n=248, 224)
    7.3 ( 0.87 )
    8.0 ( 0.92 )
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    539
    Analysis specification
    Pre-specified
    Analysis type
    		 [13]
    P-value
    		 = 0.081
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    2.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 4.6
    Notes
    [13] - Week 32
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    539
    Analysis specification
    Pre-specified
    Analysis type
    		 [14]
    P-value
    		 = 0.59
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.2
         upper limit
    		 1.8
    Notes
    [14] - Week 64

    Secondary: Change from baseline in Visual Function Questionnnaire-25 (VFQ-25) - subscale score - Ocular Pain - study eye

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    End point title
    		 Change from baseline in Visual Function Questionnnaire-25 (VFQ-25) - subscale score - Ocular Pain - study eye
    End point description
    The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual functioning. Each item is then converted to a 0 to 100 scale so that the lowest and highest possible scores are set at 0 and 100 points, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 32, and Week 64
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    278
    261
    Units: Scores on a scale
    least squares mean (standard error)
        Week 32 (n-278, 261)
    3.55 ( 0.92 )
    2.78 ( 0.94 )
        Week 64 (n=248, 224)
    3.1 ( 0.89 )
    5.0 ( 0.94 )
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    539
    Analysis specification
    Pre-specified
    Analysis type
    		 [15]
    P-value
    		 = 0.138
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.5
         upper limit
    		 0.6
    Notes
    [15] - Week 64
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    539
    Analysis specification
    Pre-specified
    Analysis type
    		 [16]
    P-value
    		 = 0.558
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 3.4
    Notes
    [16] - Week 32

    Secondary: Change from baseline n Visual Function Questionnnaire-25 (VFQ-25) - subscale score - Near Activities - study eye

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    End point title
    		 Change from baseline n Visual Function Questionnnaire-25 (VFQ-25) - subscale score - Near Activities - study eye
    End point description
    The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual functioning. Each item is then converted to a 0 to 100 scale so that the lowest and highest possible scores are set at 0 and 100 points, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 32, and Week 64
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    278
    261
    Units: Scores on a scale
    least squares mean (standard error)
        Week 32 (n-278, 261)
    7.46 ( 1.05 )
    5.86 ( 1.08 )
        Week 64 (n=248, 224)
    4.9 ( 1.12 )
    7.9 ( 1.18 )
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    539
    Analysis specification
    Pre-specified
    Analysis type
    		 [17]
    P-value
    		 = 0.07
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.2
         upper limit
    		 0.2
    Notes
    [17] - Week 64
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    539
    Analysis specification
    Pre-specified
    Analysis type
    		 [18]
    P-value
    		 = 0.287
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 4.6
    Notes
    [18] - Week 32

    Secondary: Change from baseline in Visual Function Questionnnaire-25 (VFQ-25) - subscale score - Distance Activities - study eye

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    End point title
    		 Change from baseline in Visual Function Questionnnaire-25 (VFQ-25) - subscale score - Distance Activities - study eye
    End point description
    The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual functioning. Each item is then converted to a 0 to 100 scale so that the lowest and highest possible scores are set at 0 and 100 points, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 32, and Week 64
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    278
    261
    Units: Scores on a scale
    least squares mean (standard error)
        Week 32 (n-278, 261)
    3.06 ( 0.95 )
    3.78 ( 0.98 )
        Week 64 (n=248, 224)
    2.5 ( 0.99 )
    5.0 ( 1.04 )
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    539
    Analysis specification
    Pre-specified
    Analysis type
    		 [19]
    P-value
    		 = 0.086
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.3
         upper limit
    		 0.4
    Notes
    [19] - Week 64
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    539
    Analysis specification
    Pre-specified
    Analysis type
    		 [20]
    P-value
    		 = 0.602
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.4
         upper limit
    		 2
    Notes
    [20] - Week 32

    Secondary: Change from baseline in Visual Function Questionnnaire-25 (VFQ-25) - subscale score - Social Functioning - study eye

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    End point title
    		 Change from baseline in Visual Function Questionnnaire-25 (VFQ-25) - subscale score - Social Functioning - study eye
    End point description
    The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual functioning or outcome. Each item is then converted to a 0 to 100 scale so that the lowest and highest possible scores are set at 0 and 100 points, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 32, and Week 64
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    278
    261
    Units: Scores on a scale
    least squares mean (standard error)
        Week 32 (n-278, 261)
    1.99 ( 0.79 )
    0.43 ( 0.82 )
        Week 64 (n=248, 224)
    0.2 ( 0.81 )
    1.7 ( 0.85 )
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    539
    Analysis specification
    Pre-specified
    Analysis type
    		 [21]
    P-value
    		 = 0.21
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.8
         upper limit
    		 0.8
    Notes
    [21] - Week 64
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    539
    Analysis specification
    Pre-specified
    Analysis type
    		 [22]
    P-value
    		 = 0.174
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    1.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 3.8
    Notes
    [22] - Week 32

    Secondary: Change from baseline in Visual Function Questionnnaire-25 (VFQ-25) - subscale score - Mental Health - study eye

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    End point title
    		 Change from baseline in Visual Function Questionnnaire-25 (VFQ-25) - subscale score - Mental Health - study eye
    End point description
    The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual functioning or outcome. Each item is then converted to a 0 to 100 scale so that the lowest and highest possible scores are set at 0 and 100 points, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 32, and Week 64
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    278
    261
    Units: Scores on a scale
    least squares mean (standard error)
        Week 32 (n-278, 261)
    5.83 ( 0.99 )
    6.79 ( 1.02 )
        Week 64 (n=248, 224)
    5.0 ( 1.08 )
    7.2 ( 1.14 )
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    539
    Analysis specification
    Pre-specified
    Analysis type
    		 [23]
    P-value
    		 = 0.147
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.4
         upper limit
    		 0.8
    Notes
    [23] - Week 64
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    539
    Analysis specification
    Pre-specified
    Analysis type
    		 [24]
    P-value
    		 = 0.499
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.8
         upper limit
    		 1.8
    Notes
    [24] - Week 32

    Secondary: Change from baseline in Visual Function Questionnnaire-25 (VFQ-25) - subscale score - Role Difficulties - study eye

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    End point title
    		 Change from baseline in Visual Function Questionnnaire-25 (VFQ-25) - subscale score - Role Difficulties - study eye
    End point description
    The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual functioning or outcome. Each item is then converted to a 0 to 100 scale so that the lowest and highest possible scores are set at 0 and 100 points, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 32, and Week 64
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    278
    261
    Units: Scores on a scale
    least squares mean (standard error)
        Week 32 (n-278, 261)
    5.17 ( 1.31 )
    4.30 ( 1.35 )
        Week 64 (n=248, 224)
    4.7 ( 1.31 )
    5.9 ( 1.38 )
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    539
    Analysis specification
    Pre-specified
    Analysis type
    		 [25]
    P-value
    		 = 0.507
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5
         upper limit
    		 2.5
    Notes
    [25] - Week 64
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    539
    Analysis specification
    Pre-specified
    Analysis type
    		 [26]
    P-value
    		 = 0.643
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.8
         upper limit
    		 4.6
    Notes
    [26] - Week 32

    Secondary: Change from baseline in Visual Function Questionnnaire-25 (VFQ-25) - subscale score - Dependency - study eye

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    End point title
    		 Change from baseline in Visual Function Questionnnaire-25 (VFQ-25) - subscale score - Dependency - study eye
    End point description
    The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual functioning or outcome. Each item is then converted to a 0 to 100 scale so that the lowest and highest possible scores are set at 0 and 100 points, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 32, and Week 64
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    278
    261
    Units: Scores on a scale
    least squares mean (standard error)
        Week 32 (n-278, 261)
    2.71 ( 0.88 )
    2.22 ( 0.91 )
        Week 64 (n=248, 224)
    -0.6 ( 1.09 )
    2.2 ( 1.14 )
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    539
    Analysis specification
    Pre-specified
    Analysis type
    		 [27]
    P-value
    		 = 0.07
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6
         upper limit
    		 0.2
    Notes
    [27] - Week 64
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    539
    Analysis specification
    Pre-specified
    Analysis type
    		 [28]
    P-value
    		 = 0.7
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 3
    Notes
    [28] - Week 32

    Secondary: Change from baseline in Visual Function Questionnnaire-25 (VFQ-25) - subscale score - Driving - study eye

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    End point title
    		 Change from baseline in Visual Function Questionnnaire-25 (VFQ-25) - subscale score - Driving - study eye
    End point description
    The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual functioning. Each item is then converted to a 0 to 100 scale so that the lowest and highest possible scores are set at 0 and 100 points, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 32, and Week 64
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    278
    261
    Units: Scores on a scale
    least squares mean (standard error)
        Week 32 (n-278, 261)
    4.92 ( 1.56 )
    4.19 ( 1.57 )
        Week 64 (n=248, 224)
    1.3 ( 1.74 )
    3.0 ( 1.79 )
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    539
    Analysis specification
    Pre-specified
    Analysis type
    		 [29]
    P-value
    		 = 0.494
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.6
         upper limit
    		 3.2
    Notes
    [29] - Week 64
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    539
    Analysis specification
    Pre-specified
    Analysis type
    		 [30]
    P-value
    		 = 0.741
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.6
         upper limit
    		 5.1
    Notes
    [30] - Week 32

    Secondary: Change from baseline in Visual Function Questionnnaire-25 (VFQ-25) - subscale score - Color Vision - study eye

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    End point title
    		 Change from baseline in Visual Function Questionnnaire-25 (VFQ-25) - subscale score - Color Vision - study eye
    End point description
    The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual functioning. Each item is then converted to a 0 to 100 scale so that the lowest and highest possible scores are set at 0 and 100 points, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 32, and Week 64
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    278
    261
    Units: Scores on a scale
    least squares mean (standard error)
        Week 32 (n-278, 261)
    1.78 ( 0.63 )
    0.02 ( 0.65 )
        Week 64 (n=248, 224)
    0.1 ( 0.80 )
    1.2 ( 0.84 )
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    539
    Analysis specification
    Pre-specified
    Analysis type
    		 [31]
    P-value
    		 = 0.331
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.4
         upper limit
    		 1.2
    Notes
    [31] - Week 64
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    539
    Analysis specification
    Pre-specified
    Analysis type
    		 [32]
    P-value
    		 = 0.054
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    1.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 3.5
    Notes
    [32] - Week 32

    Secondary: Change from baseline in Visual Function Questionnnaire-25 (VFQ-25) - subscale score - Peripheral Vision - study eye

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    End point title
    		 Change from baseline in Visual Function Questionnnaire-25 (VFQ-25) - subscale score - Peripheral Vision - study eye
    End point description
    The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual functioning. Each item is then converted to a 0 to 100 scale so that the lowest and highest possible scores are set at 0 and 100 points, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 32, and Week 64
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    278
    261
    Units: Scores on a scale
    least squares mean (standard error)
        Week 32 (n-278, 261)
    3.24 ( 1.01 )
    2.00 ( 1.04 )
        Week 64 (n=248, 224)
    2.5 ( 1.08 )
    3.0 ( 1.13 )
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    539
    Analysis specification
    Pre-specified
    Analysis type
    		 [33]
    P-value
    		 = 0.728
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.6
         upper limit
    		 2.5
    Notes
    [33] - Week 64
    Statistical analysis title
    		 Brolucizumab 6 mg v Aflibercept 2 mg
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    539
    Analysis specification
    Pre-specified
    Analysis type
    		 [34]
    P-value
    		 = 0.394
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    1.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 4.1
    Notes
    [34] - Week 32

    Secondary: Number of participants with treatment emergent ocular adverse events (greater than or equal to 1% in any treatment arm) by preferred term for the study eye

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    End point title
    		 Number of participants with treatment emergent ocular adverse events (greater than or equal to 1% in any treatment arm) by preferred term for the study eye
    End point description
    An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign (including abnormal laboratory findings), symptom or disease) in a subject or clinical investigation subject.
    End point type
    Secondary
    End point timeframe
    Adverse events are reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of 483 days, approx. 69 weeks, 1.3 years.
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    366
    368
    Units: Participants
        Number of subjects with at least one event
    114
    102
        Conjunctival haemorrhage
    23
    13
        Visual acuity reduced
    16
    18
        Eye pain
    17
    13
        Vitreous floaters
    12
    6
        Intraocular pressure increased
    5
    11
        Subretinal fluid
    5
    11
        Vitreous detachment
    10
    3
        Retinal haemorrhage
    4
    7
        Cataract
    5
    5
        Foreign body sensation in eyes
    4
    6
        Intra-ocular injection complication
    6
    3
        Retinal pigment epithelial tear
    5
    4
        Macular oedema
    3
    4
        Posterior capsule opacification
    2
    5
        Dry eye
    2
    4
        Hordeolum
    4
    2
        Neovascular age-related macular degeneration
    2
    4
        Retinal oedema
    1
    4
        Uveitis
    4
    1
        Vision blurred
    4
    1
        Detachment of retinal pigment epithelium
    0
    4
        Retinal artery occlusion
    4
    0
        Subretinal fibrosis
    4
    0
    No statistical analyses for this end point

    Secondary: Number of participants with treatment emergent non-ocular adverse events (greater than or equal to 2% in any treatment arm) - summary table

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    End point title
    		 Number of participants with treatment emergent non-ocular adverse events (greater than or equal to 2% in any treatment arm) - summary table
    End point description
    An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign (including abnormal laboratory findings), symptom or disease) in a subject or clinical investigation subject.
    End point type
    Secondary
    End point timeframe
    Adverse events are reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of 483 days, approx. 69 weeks, 1.3 years.
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    366
    368
    Units: Participants
    182
    185
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of 483 days, approx. 69 weeks, 1.3 years.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Brolucizumab 6mg
    Reporting group description
    		 Brolucizumab 6mg

    Reporting group title
    All Patients
    Reporting group description
    		 All Patients

    Reporting group title
    Aflibercept 2mg
    Reporting group description
    		 Aflibercept 2mg

    Serious adverse events
    		 Brolucizumab 6mg All Patients Aflibercept 2mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    58 / 366 (15.85%)
    111 / 734 (15.12%)
    53 / 368 (14.40%)
         number of deaths (all causes)
    4
    6
    2
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatic cancer
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Colon cancer
         subjects affected / exposed
    1 / 366 (0.27%)
    3 / 734 (0.41%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 366 (0.27%)
    2 / 734 (0.27%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal cancer
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma gastric
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Lung neoplasm
         subjects affected / exposed
    1 / 366 (0.27%)
    2 / 734 (0.27%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tongue neoplasm malignant stage unspecified
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-small cell lung cancer metastatic
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Neoplasm
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastatic squamous cell carcinoma
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Renal neoplasm
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    1 / 366 (0.27%)
    2 / 734 (0.27%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery aneurysm rupture
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Dyspnoea exertional
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Epistaxis
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Hypercapnia
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Pneumonitis
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Pulmonary embolism
         subjects affected / exposed
    0 / 366 (0.00%)
    2 / 734 (0.27%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychotic disorder due to a general medical condition
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abnormal behaviour
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Intraocular pressure increased - Study Eye
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Face injury
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 366 (0.00%)
    2 / 734 (0.27%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    2 / 366 (0.55%)
    3 / 734 (0.41%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Concussion
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 366 (0.27%)
    2 / 734 (0.27%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 366 (0.00%)
    2 / 734 (0.27%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Forearm fracture
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Hip fracture
         subjects affected / exposed
    1 / 366 (0.27%)
    2 / 734 (0.27%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Meniscus injury
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 366 (0.27%)
    2 / 734 (0.27%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stress fracture
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Wrist fracture
         subjects affected / exposed
    2 / 366 (0.55%)
    2 / 734 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    2 / 366 (0.55%)
    2 / 734 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    3 / 366 (0.82%)
    4 / 734 (0.54%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 8
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Angina pectoris
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Arrhythmia
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 366 (0.55%)
    2 / 734 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 366 (0.27%)
    3 / 734 (0.41%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Sinus node dysfunction
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Myocardial ischaemia
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 366 (0.55%)
    3 / 734 (0.41%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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 disease
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Basal ganglia infarction
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Cerebral infarction
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Speech disorder
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Eye disorders
    Glaucoma - Study Eye
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye inflammation - Study Eye
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Iridocyclitis - Study Eye
         subjects affected / exposed
    1 / 366 (0.27%)
    2 / 734 (0.27%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Visual acuity reduced - Study Eye
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uveitis - Study Eye
         subjects affected / exposed
    3 / 366 (0.82%)
    3 / 734 (0.41%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal vein occlusion - Study Eye
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal vascular occlusion - Study Eye
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal artery occlusion - Study Eye
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Macular hole - Study Eye
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ocular discomfort - Study Eye
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Ocular discomfort - Fellow Eye
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Gastrointestinal disorders
    Abdominal adhesions
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Ileus paralytic
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gingival bleeding
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Renal and urinary disorders
    Ureterolithiasis
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Haematuria
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Spondylolisthesis
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Osteoarthritis
         subjects affected / exposed
    1 / 366 (0.27%)
    2 / 734 (0.27%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 366 (0.27%)
    2 / 734 (0.27%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 366 (0.55%)
    2 / 734 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Escherichia sepsis
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Diverticulitis
         subjects affected / exposed
    0 / 366 (0.00%)
    2 / 734 (0.27%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    5 / 366 (1.37%)
    6 / 734 (0.82%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    COVID-19
         subjects affected / exposed
    2 / 366 (0.55%)
    2 / 734 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Endophthalmitis - Study Eye
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Urosepsis
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Hyperkalaemia
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 734 (0.14%)
    0 / 368 (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
    Hyponatraemia
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 734 (0.14%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Brolucizumab 6mg All Patients Aflibercept 2mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    172 / 366 (46.99%)
    349 / 734 (47.55%)
    177 / 368 (48.10%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    18 / 366 (4.92%)
    35 / 734 (4.77%)
    17 / 368 (4.62%)
         occurrences all number
    19
    37
    18
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 366 (1.09%)
    7 / 734 (0.95%)
    3 / 368 (0.82%)
         occurrences all number
    4
    7
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    5 / 366 (1.37%)
    5 / 734 (0.68%)
    0 / 368 (0.00%)
         occurrences all number
    6
    6
    0
    Investigations
    Intraocular pressure increased - Study Eye
         subjects affected / exposed
    5 / 366 (1.37%)
    15 / 734 (2.04%)
    10 / 368 (2.72%)
         occurrences all number
    6
    22
    16
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    4 / 366 (1.09%)
    7 / 734 (0.95%)
    3 / 368 (0.82%)
         occurrences all number
    4
    7
    3
    Injury, poisoning and procedural complications
    Vaccination complication
         subjects affected / exposed
    3 / 366 (0.82%)
    7 / 734 (0.95%)
    4 / 368 (1.09%)
         occurrences all number
    3
    7
    4
    Intra-ocular injection complication - Study Eye
         subjects affected / exposed
    6 / 366 (1.64%)
    9 / 734 (1.23%)
    3 / 368 (0.82%)
         occurrences all number
    7
    11
    4
    Fall
         subjects affected / exposed
    6 / 366 (1.64%)
    15 / 734 (2.04%)
    9 / 368 (2.45%)
         occurrences all number
    6
    18
    12
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    6 / 366 (1.64%)
    7 / 734 (0.95%)
    1 / 368 (0.27%)
         occurrences all number
    6
    7
    1
    Nervous system disorders
    Carpal tunnel syndrome
         subjects affected / exposed
    4 / 366 (1.09%)
    4 / 734 (0.54%)
    0 / 368 (0.00%)
         occurrences all number
    4
    4
    0
    Dizziness
         subjects affected / exposed
    4 / 366 (1.09%)
    6 / 734 (0.82%)
    2 / 368 (0.54%)
         occurrences all number
    5
    7
    2
    Headache
         subjects affected / exposed
    10 / 366 (2.73%)
    21 / 734 (2.86%)
    11 / 368 (2.99%)
         occurrences all number
    10
    23
    13
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 366 (0.00%)
    4 / 734 (0.54%)
    4 / 368 (1.09%)
         occurrences all number
    0
    4
    4
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    4 / 366 (1.09%)
    8 / 734 (1.09%)
    4 / 368 (1.09%)
         occurrences all number
    4
    9
    5
    Eye disorders
    Cataract - Study Eye
         subjects affected / exposed
    5 / 366 (1.37%)
    12 / 734 (1.63%)
    7 / 368 (1.90%)
         occurrences all number
    5
    12
    7
    Eye pain - Study Eye
         subjects affected / exposed
    17 / 366 (4.64%)
    30 / 734 (4.09%)
    13 / 368 (3.53%)
         occurrences all number
    20
    37
    17
    Detachment of retinal pigment epithelium - Study Eye
         subjects affected / exposed
    0 / 366 (0.00%)
    4 / 734 (0.54%)
    4 / 368 (1.09%)
         occurrences all number
    0
    4
    4
    Conjunctival haemorrhage - Study Eye
         subjects affected / exposed
    23 / 366 (6.28%)
    36 / 734 (4.90%)
    13 / 368 (3.53%)
         occurrences all number
    26
    46
    20
    Foreign body sensation in eyes - Study Eye
         subjects affected / exposed
    5 / 366 (1.37%)
    13 / 734 (1.77%)
    8 / 368 (2.17%)
         occurrences all number
    5
    16
    11
    Macular oedema - Study Eye
         subjects affected / exposed
    3 / 366 (0.82%)
    7 / 734 (0.95%)
    4 / 368 (1.09%)
         occurrences all number
    4
    8
    4
    Neovascular age-related macular degeneration - Study Eye
         subjects affected / exposed
    3 / 366 (0.82%)
    7 / 734 (0.95%)
    4 / 368 (1.09%)
         occurrences all number
    4
    8
    4
    Posterior capsule opacification - Study Eye
         subjects affected / exposed
    3 / 366 (0.82%)
    8 / 734 (1.09%)
    5 / 368 (1.36%)
         occurrences all number
    3
    8
    5
    Dry eye - Study Eye
         subjects affected / exposed
    8 / 366 (2.19%)
    26 / 734 (3.54%)
    18 / 368 (4.89%)
         occurrences all number
    8
    26
    18
    Vitreous floaters - Study Eye
         subjects affected / exposed
    14 / 366 (3.83%)
    20 / 734 (2.72%)
    6 / 368 (1.63%)
         occurrences all number
    16
    23
    7
    Vitreous detachment - Study Eye
         subjects affected / exposed
    11 / 366 (3.01%)
    14 / 734 (1.91%)
    3 / 368 (0.82%)
         occurrences all number
    12
    15
    3
    Visual acuity reduced - Study Eye
         subjects affected / exposed
    18 / 366 (4.92%)
    37 / 734 (5.04%)
    19 / 368 (5.16%)
         occurrences all number
    20
    43
    23
    Vision blurred - Study Eye
         subjects affected / exposed
    4 / 366 (1.09%)
    5 / 734 (0.68%)
    1 / 368 (0.27%)
         occurrences all number
    4
    5
    1
    Subretinal fluid - Study Eye
         subjects affected / exposed
    5 / 366 (1.37%)
    16 / 734 (2.18%)
    11 / 368 (2.99%)
         occurrences all number
    5
    20
    15
    Subretinal fibrosis - Study Eye
         subjects affected / exposed
    4 / 366 (1.09%)
    4 / 734 (0.54%)
    0 / 368 (0.00%)
         occurrences all number
    4
    4
    0
    Retinal pigment epithelial tear - Study Eye
         subjects affected / exposed
    5 / 366 (1.37%)
    9 / 734 (1.23%)
    4 / 368 (1.09%)
         occurrences all number
    5
    9
    4
    Retinal oedema - Study Eye
         subjects affected / exposed
    1 / 366 (0.27%)
    5 / 734 (0.68%)
    4 / 368 (1.09%)
         occurrences all number
    1
    6
    5
    Retinal haemorrhage - Study Eye
         subjects affected / exposed
    4 / 366 (1.09%)
    11 / 734 (1.50%)
    7 / 368 (1.90%)
         occurrences all number
    4
    11
    7
    Conjunctival haemorrhage - Fellow Eye
         subjects affected / exposed
    3 / 366 (0.82%)
    7 / 734 (0.95%)
    4 / 368 (1.09%)
         occurrences all number
    4
    8
    4
    Choroidal neovascularisation - Fellow Eye
         subjects affected / exposed
    5 / 366 (1.37%)
    12 / 734 (1.63%)
    7 / 368 (1.90%)
         occurrences all number
    5
    12
    7
    Vitreous detachment - Fellow Eye
         subjects affected / exposed
    5 / 366 (1.37%)
    6 / 734 (0.82%)
    1 / 368 (0.27%)
         occurrences all number
    5
    6
    1
    Visual acuity reduced - Fellow Eye
         subjects affected / exposed
    4 / 366 (1.09%)
    8 / 734 (1.09%)
    4 / 368 (1.09%)
         occurrences all number
    7
    11
    4
    Retinal depigmentation - Study Eye
         subjects affected / exposed
    1 / 366 (0.27%)
    5 / 734 (0.68%)
    4 / 368 (1.09%)
         occurrences all number
    1
    5
    4
    Neovascular age-related macular degeneration - Fellow Eye
         subjects affected / exposed
    22 / 366 (6.01%)
    39 / 734 (5.31%)
    17 / 368 (4.62%)
         occurrences all number
    22
    40
    18
    Lacrimation increased - Fellow Eye
         subjects affected / exposed
    1 / 366 (0.27%)
    5 / 734 (0.68%)
    4 / 368 (1.09%)
         occurrences all number
    1
    5
    4
    Eye pruritus - Study Eye
         subjects affected / exposed
    4 / 366 (1.09%)
    5 / 734 (0.68%)
    1 / 368 (0.27%)
         occurrences all number
    4
    5
    1
    Eye pain - Fellow Eye
         subjects affected / exposed
    2 / 366 (0.55%)
    6 / 734 (0.82%)
    4 / 368 (1.09%)
         occurrences all number
    2
    6
    4
    Dry eye - Fellow Eye
         subjects affected / exposed
    6 / 366 (1.64%)
    22 / 734 (3.00%)
    16 / 368 (4.35%)
         occurrences all number
    6
    22
    16
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    5 / 366 (1.37%)
    5 / 734 (0.68%)
    0 / 368 (0.00%)
         occurrences all number
    5
    5
    0
    Diarrhoea
         subjects affected / exposed
    7 / 366 (1.91%)
    9 / 734 (1.23%)
    2 / 368 (0.54%)
         occurrences all number
    7
    9
    2
    Constipation
         subjects affected / exposed
    4 / 366 (1.09%)
    4 / 734 (0.54%)
    0 / 368 (0.00%)
         occurrences all number
    4
    4
    0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    6 / 366 (1.64%)
    8 / 734 (1.09%)
    2 / 368 (0.54%)
         occurrences all number
    6
    8
    2
    Back pain
         subjects affected / exposed
    8 / 366 (2.19%)
    16 / 734 (2.18%)
    8 / 368 (2.17%)
         occurrences all number
    8
    17
    9
    Infections and infestations
    COVID-19
         subjects affected / exposed
    9 / 366 (2.46%)
    25 / 734 (3.41%)
    16 / 368 (4.35%)
         occurrences all number
    9
    25
    16
    Nasopharyngitis
         subjects affected / exposed
    12 / 366 (3.28%)
    23 / 734 (3.13%)
    11 / 368 (2.99%)
         occurrences all number
    15
    29
    14
    Hordeolum - Study Eye
         subjects affected / exposed
    4 / 366 (1.09%)
    6 / 734 (0.82%)
    2 / 368 (0.54%)
         occurrences all number
    4
    6
    2
    Cystitis
         subjects affected / exposed
    3 / 366 (0.82%)
    8 / 734 (1.09%)
    5 / 368 (1.36%)
         occurrences all number
    4
    16
    12
    Urinary tract infection
         subjects affected / exposed
    11 / 366 (3.01%)
    21 / 734 (2.86%)
    10 / 368 (2.72%)
         occurrences all number
    15
    29
    14
    Conjunctivitis - Fellow Eye
         subjects affected / exposed
    4 / 366 (1.09%)
    8 / 734 (1.09%)
    4 / 368 (1.09%)
         occurrences all number
    4
    8
    4
    Conjunctivitis - Study Eye
         subjects affected / exposed
    5 / 366 (1.37%)
    10 / 734 (1.36%)
    5 / 368 (1.36%)
         occurrences all number
    6
    12
    6
    Metabolism and nutrition disorders
    Hyperuricaemia
         subjects affected / exposed
    1 / 366 (0.27%)
    5 / 734 (0.68%)
    4 / 368 (1.09%)
         occurrences all number
    1
    5
    4
    Hypercholesterolaemia
         subjects affected / exposed
    4 / 366 (1.09%)
    10 / 734 (1.36%)
    6 / 368 (1.63%)
         occurrences all number
    4
    10
    6
    Diabetes mellitus
         subjects affected / exposed
    4 / 366 (1.09%)
    5 / 734 (0.68%)
    1 / 368 (0.27%)
         occurrences all number
    4
    5
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Jun 2020
    To provide clarification and guidance on safety assessments in accordance to the USM regarding the post-marketing reports with brolucizumab (Beovu ®) in the treatment of nAMD, which were identified as retinal vasculitis (RV) and/or retinal vascular occlusion (RO), typically in the presence of IOI, that may result in severe vision loss. In addition, the amendment included the modifications due to COVID-19 pandemic.
    13 Aug 2021
    To provide clarification and guidance on the early discontinuation of study treatment that was required for those subjects who were currently on q4w dosing beyond the first 3 monthly loading doses (“loading phase”) or would need q4w dosing beyond the “loading phase” based on the investigator’s assessment. This was as per the USM dated 27-May- 2021 (based on CTH258AUS04 (MERLIN) Year 1 FIR indicating a higher frequency of IOI including RV, and RO in brolucizumab 6 mg q4w when compared to aflibercept 2 mg q4w (IOI: 9.3% vs 4.5% of which RV: 0.8% vs 0.0%; RO: 2.0% vs 0.0%, respectively). To provide clarification and guidance on the early discontinuation of study treatment that was required for those subjects with RV and RO events. This was as per the USM dated 10-Aug-2021 (based on the results of the mechanistic study BASICHR0049 which identified a causal link with an immune-mediated mechanism of the previously identified risk of RV and/or RO, typically in the presence of IOI). To update safety sections throughout the protocol including updates to the Risks and Benefits section and the creation of a new section under Safety Monitoring which consolidated all risk mitigation information into one section of the protocol.
    23 Sep 2021
    To include information on the gender imbalance in the reported rates of IOI-related adverse events following brolucizumab treatment.

    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.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com for complete trial results.
    For support, Contact us.
    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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