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    Clinical Trial Results:
    An Eighteen-Month, Two-Arm, Randomized, Double- Masked, Multi-center, Phase III Study Assessing the Efficacy and Safety of Brolucizumab versus Aflibercept in Adult Patients with Visual Impairment due to Macular Edema secondary to Branch Retinal Vein Occlusion (RAPTOR)

    Summary
    EudraCT number
    		 2018-001842-33
    Trial protocol
    		 DE   AT   DK   ES   GB   IT   CZ  
    Global end of trial date
    26 Jul 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Jul 2022
    First version publication date
    28 Jul 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CRTH258C2301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03802630
    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
    26 Jul 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jul 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To demonstrate that brolucizumab is non-inferior to aflibercept with respect to the change in BCVA from baseline up to Month 6
    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. At the investigator's discretion, treatment with macular laser photocoagulation (focal or grid) for the study eye from Week 24 onwards was allowed in case macular edema worsened, resulting in a ≥ 10-letter loss in BCVA at 2 consecutive visits, or in a ≥ 15-letter loss in BCVA at 1 visit in the study eye, compared to best previous measurement, and the study eye BCVA value was not better than the baseline value.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Jul 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Canada: 15
    Country: Number of subjects enrolled
    China: 85
    Country: Number of subjects enrolled
    Czechia: 5
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    France: 31
    Country: Number of subjects enrolled
    Germany: 37
    Country: Number of subjects enrolled
    Hong Kong: 10
    Country: Number of subjects enrolled
    Israel: 14
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    Japan: 17
    Country: Number of subjects enrolled
    Russian Federation: 14
    Country: Number of subjects enrolled
    Slovakia: 15
    Country: Number of subjects enrolled
    Spain: 28
    Country: Number of subjects enrolled
    Switzerland: 10
    Country: Number of subjects enrolled
    Taiwan: 10
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    United States: 119
    Worldwide total number of subjects
    450
    EEA total number of subjects
    143
    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)
    214
    From 65 to 84 years
    220
    85 years and over
    16

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited from 103 sites in 18 countries

    Pre-assignment
    Screening details
    		 The study comprised a screening period of 28 days

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Brolucizumab 6 mg
    Arm description
    		 1 intravitreal injection every 4 weeks for a total of 6 injections, followed by 48 weeks of individualized flexible treatment (IFT)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brolucizumab
    Investigational medicinal product code
    RTH258
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Brolucizumab 6 mg intravitreal injection.

    Arm title
    		 Aflibercept 2 mg
    Arm description
    		 1 intravitreal injection every 4 weeks for a total of 6 injections, followed by 48 weeks of individualized flexible treatment (IFT)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Aflibercept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Aflibercept 2 mg intravitreal injection

    Number of subjects in period 1
    		Brolucizumab 6 mg Aflibercept 2 mg
    Started
    226
    224
    Completed
    73
    76
    Not completed
    153
    148
         Adverse event, serious fatal
    -
    2
         Physician decision
    2
    -
         Subject decision
    16
    9
         Adverse event, non-fatal
    3
    1
         Study terminated by sponsor
    130
    134
         Lost to follow-up
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Brolucizumab 6 mg
    Reporting group description
    		 1 intravitreal injection every 4 weeks for a total of 6 injections, followed by 48 weeks of individualized flexible treatment (IFT)

    Reporting group title
    Aflibercept 2 mg
    Reporting group description
    		 1 intravitreal injection every 4 weeks for a total of 6 injections, followed by 48 weeks of individualized flexible treatment (IFT)

    Reporting group values
    		 Brolucizumab 6 mg Aflibercept 2 mg Total
    Number of subjects
    		 226 224 450
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 106 108 214
        From 65-84 years
    		 113 107 220
        85 years and over
    		 7 9 16
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 65.4 ( 11.05 ) 65.0 ( 10.92 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 117 125 242
        Male
    		 109 99 208
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 153 153 306
        Black or African American
    		 7 4 11
        Asian
    		 65 67 132
        White/Black or African American
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Brolucizumab 6 mg
    Reporting group description
    		 1 intravitreal injection every 4 weeks for a total of 6 injections, followed by 48 weeks of individualized flexible treatment (IFT)

    Reporting group title
    Aflibercept 2 mg
    Reporting group description
    		 1 intravitreal injection every 4 weeks for a total of 6 injections, followed by 48 weeks of individualized flexible treatment (IFT)

    Primary: Change from baseline in best-corrected visual acuity (BCVA) at Week 24

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    End point title
    		 Change from baseline in best-corrected visual acuity (BCVA) at Week 24
    End point description
    BCVA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts at an initial testing distance of 4 meters. Min and max possible scores are 0-100 letters read respectively. A higher score represents better visual functioning. Missing and censored BCVA values were imputed by Last observation carried forward (LOCF) as the primary approach. Observed values from both scheduled and unscheduled post-baseline visits were used for the LOCF imputation. For subjects with no post-baseline BCVA value, the baseline value was carried forward.
    End point type
    Primary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    226
    224
    Units: Letters read
        least squares mean (standard error)
    13.1 ( 0.71 )
    15.0 ( 0.71 )
    Statistical analysis title
    		 Change from BCVA at week 24
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    450
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 = 0.018
    Method
    		 ANOVA
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.9
         upper limit
    		 0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.01
    Notes
    [1] - Non-inferiority was considered established if the lower limit of the corresponding 95% CI for the estimated between group difference (brolucizumab vs. aflibercept) on change from baseline in BCVA at Week 24 is greater than -4 letters.

    Secondary: Change from baseline in BCVA averaged over Week 40 to Week 52

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    End point title
    		 Change from baseline in BCVA averaged over Week 40 to Week 52
    End point description
    An average BCVA over week 40 to week 52 was calculated. BCVA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts at an initial testing distance of 4 meters. Min and max possible scores are 0-100 letters read respectively. A higher score represents better visual functioning.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 40 to Week 52
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    123
    132
    Units: Letters read
        arithmetic mean (standard deviation)
    12.9 ( 12.81 )
    16.9 ( 10.63 )
    No statistical analyses for this end point

    Secondary: Change from baseline in BCVA averaged over Week 64 to Week 76

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    End point title
    		 Change from baseline in BCVA averaged over Week 64 to Week 76
    End point description
    An average BCVA over week 64 to week 76 was calculated. BCVA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts at an initial testing distance of 4 meters. Min and max possible scores are 0-100 letters read respectively. A higher score represents better visual functioning.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 64 to Week 76
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    110
    121
    Units: Letters read
        arithmetic mean (standard deviation)
    13.7 ( 13.33 )
    17.9 ( 10.65 )
    No statistical analyses for this end point

    Secondary: Change from baseline in BCVA by visit up to Week 76

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    End point title
    		 Change from baseline in BCVA by visit up to Week 76
    End point description
    BCVA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts at an initial testing distance of 4 meters. Min and max possible scores are 0-100 letters read respectively. A higher score represents better visual functioning.
    End point type
    Secondary
    End point timeframe
    Baseline and every 4 weeks from baseline up to Week 76
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    226
    224
    Units: Letters read
    arithmetic mean (standard deviation)
        Week 4 (n=223, 217)
    9.2 ( 8.22 )
    10.3 ( 10.13 )
        Week 8 (n=204, 199)
    11.9 ( 10.68 )
    12.8 ( 10.84 )
        Week 12 (n=185, 182)
    13.2 ( 10.22 )
    14.8 ( 11.23 )
        Week 16 (n=160, 160)
    12.2 ( 12.59 )
    16.3 ( 11.58 )
        Week 20 (n=144, 149)
    13.5 ( 10.83 )
    16.3 ( 12.15 )
        Week 24 (n=147, 144)
    12.7 ( 12.36 )
    16.6 ( 11.35 )
        Week 28 (n=135, 136)
    12.1 ( 13.88 )
    16.4 ( 10.62 )
        Week 32 (n=124, 128)
    12.2 ( 13.24 )
    15.7 ( 10.94 )
        Week 36 (n=123, 125)
    11.8 ( 14.75 )
    16.9 ( 10.95 )
        Week 40 (n=119, 124)
    12.7 ( 12.89 )
    16.9 ( 10.74 )
        Week 44 (n=116, 120)
    13.5 ( 13.28 )
    17.2 ( 11.37 )
        Week 48 (n=114, 120)
    13.3 ( 13.38 )
    17.7 ( 10.79 )
        Week 52 (n=106, 125)
    13.5 ( 13.42 )
    17.2 ( 10.46 )
        Week 56 (n=106, 122)
    14.9 ( 10.86 )
    17.7 ( 10.62 )
        Week 60 (n=105, 123)
    13.7 ( 13.67 )
    17.7 ( 10.33 )
        Week 64 (n=102, 117)
    14.1 ( 13.72 )
    18.0 ( 10.54 )
        Week 68 (n=94, 110)
    13.9 ( 13.83 )
    17.7 ( 10.75 )
        Week 72 (n=83, 92)
    13.9 ( 13.38 )
    18.4 ( 11.44 )
        Week 76 (n=68, 74)
    14.4 ( 13.72 )
    18.1 ( 11.19 )
    No statistical analyses for this end point

    Secondary: Proportion of participants with a gain ≥ 5, 10 and 15 letters in BCVA by visit compared to baseline

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    End point title
    		 Proportion of participants with a gain ≥ 5, 10 and 15 letters in BCVA by visit compared to baseline
    End point description
    The summary by visit was conducted based on the BCVA observed from each of the corresponding visits. BCVA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts at an initial testing distance of 4 meters. Min and max possible scores are 0-100 letters read respectively. A higher score represents better visual functioning. Every 5 letters represents 1 line of vision on the reading chart.
    End point type
    Secondary
    End point timeframe
    Baseline and every 4 weeks from baseline up to Week 76
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    226
    224
    Units: Participants
        Week 4; BCVA gain from baseline >=5 (n=223, 217)
    154
    150
        Week 4; BCVA gain from baseline >=10 (n=223, 217)
    102
    110
        Week4; BCVA gain from baseline >=15(n=223, 217)
    64
    79
        Week8; BCVA gain from baseline >=5(n=204, 199)
    158
    155
        Week8; BCVA gain from baseline >=10(n=204, 199)
    117
    118
        Week8; BCVA gain from baseline >=15(n=204, 199)
    92
    93
        Week 12; BCVA gain from baseline >=5(n=185, 182)
    156
    156
        Week 12; BCVA gain from baseline >=10(n=185, 182)
    114
    125
        Week 12; BCVA gain from baseline >=15(n=185, 182)
    90
    102
        Week 16; BCVA gain from baseline >=5(n=160, 160)
    127
    143
        Week 16; BCVA gain from baseline >=10(n=160, 160)
    95
    118
        Week 16; BCVA gain from baseline >=15(n=160, 160)
    73
    100
        Week 20; BCVA gain from baseline >=5(n=144, 149)
    119
    131
        Week 20; BCVA gain from baseline >=10(n=144, 149)
    96
    108
        Week20; BCVA gain from baseline >=15 (n=144, 149)
    74
    92
        Week24; BCVA gain from baseline >=5 (n=147, 144)
    122
    126
        Week24; BCVA gain from baseline >=10 (n=147, 144)
    90
    109
        Week24; BCVA gain from baseline >=15 (n=147, 144)
    75
    91
        Week28; BCVA gain from baseline >=5 (n=135, 136)
    108
    121
        Week28; BCVA gain from baseline >=10 (n=135, 136)
    89
    107
        Week28; BCVA gain from baseline >=15 (n=135, 136)
    75
    87
        Week32; BCVA gain from baseline >=5 (n=124, 128)
    97
    110
        Week32; BCVA gain from baseline >=10 (n=124, 128)
    79
    94
        Week32; BCVA gain from baseline >=15 (n=124, 128)
    60
    78
        Week36; BCVA gain from baseline >=5 (n=123, 125)
    100
    112
        Week36; BCVA gain from baseline >=10 (n=123, 125)
    81
    98
        Week36; BCVA gain from baseline >=15 (n=123, 125)
    62
    83
        Week40; BCVA gain from baseline >=5 (n=119, 124)
    96
    114
        Week40; BCVA gain from baseline >=10 (n=119, 124)
    79
    98
        Week40; BCVA gain from baseline >=15 (n=119, 124)
    65
    85
        Week44; BCVA gain from baseline >=5 (n=116, 120)
    94
    111
        Week44; BCVA gain from baseline >=10 (n=116, 120)
    78
    97
        Week44; BCVA gain from baseline >=15 (n=116, 120)
    64
    88
        Week48; BCVA gain from baseline >=5 (n=114, 120)
    92
    112
        Week48; BCVA gain from baseline >=10 (n=114, 120)
    76
    95
        Week48; BCVA gain from baseline >=15 (n=114, 120)
    61
    80
        Week52; BCVA gain from baseline >=5 (n=106, 125)
    87
    117
        Week52; BCVA gain from baseline >=10 (n=106, 125)
    75
    99
        Week52; BCVA gain from baseline >=15 (n=106, 125)
    64
    87
        Week56; BCVA gain from baseline >=5 (n=106, 122)
    90
    113
        Week56; BCVA gain from baseline >=10 (n=106, 122)
    76
    106
        Week56; BCVA gain from baseline >=15 (n=106, 122)
    58
    84
        Week60; BCVA gain from baseline >=5 (n=105, 123)
    86
    116
        Week60; BCVA gain from baseline >=10 (n=105, 123)
    71
    104
        Week60; BCVA gain from baseline >=15 (n=105, 123)
    62
    88
        Week64; BCVA gain from baseline >=5 (n=102, 117)
    86
    112
        Week64; BCVA gain from baseline >=10 (n=102, 117)
    74
    98
        Week64; BCVA gain from baseline >=15 (n=102, 117)
    58
    82
        Week68; BCVA gain from baseline >=5 (n=94, 110)
    79
    103
        Week68; BCVA gain from baseline >=10 (n=94, 110)
    67
    88
        Week68; BCVA gain from baseline >=15 (n=94, 110)
    55
    76
        Week72; BCVA gain from baseline >=5 (n=83, 92)
    68
    89
        Week72; BCVA gain from baseline >=10 (n=83, 92)
    56
    75
        Week72; BCVA gain from baseline >=15 (n=83, 92)
    45
    63
        Week76; BCVA gain from baseline >=5 (n=68, 74)
    62
    67
        Week76; BCVA gain from baseline >=10 (n=68, 74)
    52
    61
        Week76; BCVA gain from baseline >=15 (n=68, 74)
    43
    53
    No statistical analyses for this end point

    Secondary: Proportion of participants with a loss ≥ 5, 10 and 15 letters in BCVA by visit compared to baseline

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    End point title
    		 Proportion of participants with a loss ≥ 5, 10 and 15 letters in BCVA by visit compared to baseline
    End point description
    The summary by visit was conducted based on the BCVA observed from each of the corresponding visit. BCVA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts at an initial testing distance of 4 meters. Min and max possible scores are 0-100 letters read respectively. A higher score represents better visual functioning. Every 5 letters represents 1 line of vision on the reading chart.
    End point type
    Secondary
    End point timeframe
    Baseline and every 4 weeks from baseline up to Week 76
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    226
    224
    Units: Participants
        Week4; BCVA loss from baseline >=5 (n=223, 217)
    6
    7
        Week4; BCVA loss from baseline >=10 (n=223, 217)
    1
    3
        Week4; BCVA loss from baseline >=15 (n=223, 217)
    0
    0
        Week8; BCVA loss from baseline >=5 (n=204, 199)
    2
    4
        Week8; BCVA loss from baseline >=10 (n=204, 199)
    1
    2
        Week8; BCVA loss from baseline >=15 (n=204, 199)
    1
    0
        Week12; BCVA loss from baseline >=5 (n=185,182 )
    3
    2
        Week12; BCVA loss from baseline >=10 (n=185,182 )
    2
    1
        Week12; BCVA loss from baseline >=15 (n=185,182 )
    1
    0
        Week16; BCVA loss from baseline >=5 (n=160,160 )
    9
    4
        Week16; BCVA loss from baseline >=10 (n=160,160 )
    5
    2
        Week16; BCVA loss from baseline >=15 (n=160,160 )
    3
    2
        Week20; BCVA loss from baseline >=5 (n=144,149 )
    6
    4
        Week20; BCVA loss from baseline >=10 (n=144,149 )
    2
    3
        Week20; BCVA loss from baseline >=15 (n=144,149 )
    2
    1
        Week24; BCVA loss from baseline >=5 (n=147,144 )
    8
    3
        Week24; BCVA loss from baseline >=10 (n=147,144 )
    3
    3
        Week24; BCVA loss from baseline >=15 (n=147,144 )
    3
    1
        Week28; BCVA loss from baseline >=5 (n=135,136 )
    9
    2
        Week28; BCVA loss from baseline >=10 (n=135,136 )
    6
    1
        Week28; BCVA loss from baseline >=15 (n=135,136 )
    6
    1
        Week32; BCVA loss from baseline >=5 (n=124,128 )
    8
    3
        Week32; BCVA loss from baseline >=10 (n=124,128 )
    5
    2
        Week32; BCVA loss from baseline >=15 (n=124,128 )
    3
    0
        Week36; BCVA loss from baseline >=5 (n=123,125 )
    9
    2
        Week36; BCVA loss from baseline >=10 (n=123,125 )
    7
    1
        Week36; BCVA loss from baseline >=15 (n=123,125 )
    5
    1
        Week40; BCVA loss from baseline >=5 (n=119,124)
    5
    4
        Week40; BCVA loss from baseline >=10 (n=119,124)
    4
    1
        Week40; BCVA loss from baseline >=15 (n=119,124)
    2
    1
        Week44; BCVA loss from baseline >=5 (n=116,120)
    4
    5
        Week44; BCVA loss from baseline >=10 (n=116,120)
    3
    3
        Week44; BCVA loss from baseline >=15 (n=116,120)
    2
    2
        Week48; BCVA loss from baseline >=5 (n=114,120)
    5
    3
        Week48; BCVA loss from baseline >=10 (n=114,120)
    3
    1
        Week48; BCVA loss from baseline >=15 (n=114,120)
    1
    1
        Week52; BCVA loss from baseline >=5 (n=106,125)
    5
    2
        Week52; BCVA loss from baseline >=10 (n=106,125)
    3
    1
        Week52; BCVA loss from baseline >=15 (n=106,125)
    2
    1
        Week56; BCVA loss from baseline >=5 (n=106,122)
    3
    3
        Week56; BCVA loss from baseline >=10 (n=106,122)
    1
    1
        Week56; BCVA loss from baseline >=15 (n=106,122)
    0
    0
        Week60; BCVA loss from baseline >=5 (n=105, 123)
    7
    2
        Week60; BCVA loss from baseline >=10 (n=105, 123)
    3
    0
        Week60; BCVA loss from baseline >=15 (n=105, 123)
    1
    0
        Week64; BCVA loss from baseline >=5 (n=102, 117)
    5
    2
        Week64; BCVA loss from baseline >=10 (n=102, 117)
    1
    1
        Week64; BCVA loss from baseline >=15 (n=102, 117)
    1
    1
        Week68; BCVA loss from baseline >=5 (n=94, 110)
    6
    3
        Week68; BCVA loss from baseline >=10 (n=94, 110)
    3
    1
        Week68; BCVA loss from baseline >=15 (n=94, 110)
    1
    0
        Week72; BCVA loss from baseline >=5 (n=83, 92)
    1
    2
        Week72; BCVA loss from baseline >=10 (n=83, 92)
    1
    2
        Week72; BCVA loss from baseline >=15 (n=83, 92)
    1
    1
        Week76; BCVA loss from baseline >=5 (n=68, 74)
    2
    2
        Week76; BCVA loss from baseline >=10 (n=68, 74)
    1
    0
        Week76; BCVA loss from baseline >=15 (n=68, 74)
    1
    0
    No statistical analyses for this end point

    Secondary: Change from baseline in CSFT averaged over Week 40 to Week 52

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    End point title
    		 Change from baseline in CSFT averaged over Week 40 to Week 52
    End point description
    Change from baseline in central subfield thickness (CSFT) averaged over Week 40 to Week 52 , measured in µm by Spectral Domain Optical Coherence Tomography (SD-OCT)
    End point type
    Secondary
    End point timeframe
    Baseline, Week 40 to Week 52
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    123
    132
    Units: µm
        arithmetic mean (standard deviation)
    -231.8 ( 188.97 )
    -259.2 ( 190.69 )
    No statistical analyses for this end point

    Secondary: Change from baseline in CSFT averaged over Week 64 to Week 76

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    End point title
    		 Change from baseline in CSFT averaged over Week 64 to Week 76
    End point description
    Change from baseline in central subfield thickness (CSFT) averaged over Week 64 to Week 76, measured in µm by Spectral Domain Optical Coherence Tomography (SD-OCT)
    End point type
    Secondary
    End point timeframe
    Baseline, Week 64 to Week 76
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    110
    121
    Units: µm
        arithmetic mean (standard deviation)
    -243.6 ( 201.61 )
    -272.6 ( 194.29 )
    No statistical analyses for this end point

    Secondary: Change from baseline in CSFT by visit up to Week 76

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    End point title
    		 Change from baseline in CSFT by visit up to Week 76
    End point description
    Change from baseline in central subfield thickness (CSFT) measured in µm by Spectral Domain Optical Coherence Tomography (SD-OCT)
    End point type
    Secondary
    End point timeframe
    Baseline, and every 4 weeks from baseline up to Week 76
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    226
    224
    Units: µm
    arithmetic mean (standard deviation)
        Week 4 (n=223, 217)
    -247.1 ( 197.99 )
    -259.4 ( 185.11 )
        Week 8 (n=203, 201)
    -255.9 ( 206.00 )
    -270.7 ( 195.49 )
        Week 12 (n=184, 182)
    -264.5 ( 208.70 )
    -271.9 ( 194.99 )
        Week 16 (n=161, 160)
    -271.1 ( 209.38 )
    -276.1 ( 209.70 )
        Week 20 (n=143, 147)
    -257.1 ( 197.31 )
    -285.2 ( 210.32 )
        Week 24 (n=147, 143)
    -254.9 ( 203.29 )
    -286.6 ( 207.67 )
        Week 28 (n=134, 136)
    -245.4 ( 197.62 )
    -263.6 ( 197.11 )
        Week 32 (n=124, 128)
    -231.1 ( 208.02 )
    -262.1 ( 193.80 )
        Week 36 (n=123, 125)
    -234.1 ( 199.02 )
    -260.8 ( 195.03 )
        Week 40 (n=119, 124)
    -224.7 ( 190.50 )
    -259.0 ( 189.01 )
        Week 44 (n=116, 120)
    -242.8 ( 197.34 )
    -264.1 ( 192.06 )
        Week 48 (n=114, 120)
    -237.1 ( 200.64 )
    -279.4 ( 193.41 )
        Week 52 (n=106, 125)
    -243.0 ( 203.87 )
    -263.4 ( 190.36 )
        Week 56 (n=106, 122)
    -249.2 ( 206.54 )
    -271.4 ( 198.09 )
        Week 60 (n=105, 123)
    -238.3 ( 185.78 )
    -265.3 ( 187.29 )
        Week 64 (n=102, 117)
    -249.8 ( 207.86 )
    -266.1 ( 199.79 )
        Week 68 (n=93, 110)
    -247.5 ( 217.61 )
    -261.1 ( 192.30 )
        Week 72 (n=83, 92)
    -253.4 ( 211.06 )
    -279.4 ( 185.21 )
        Week 76 (n=68, 74)
    -255.6 ( 184.22 )
    -283.7 ( 197.29 )
    No statistical analyses for this end point

    Secondary: Proportion of subjects with presence of retinal fluid (intra- and/or subretinal fluid) in the study eye by visit up to Week 76

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    End point title
    		 Proportion of subjects with presence of retinal fluid (intra- and/or subretinal fluid) in the study eye by visit up to Week 76
    End point description
    Presence of retinal fluid (intra- and/or subretinal fluid) assessed by Spectral Domain Optical Coherence Tomography (SD-OCT)
    End point type
    Secondary
    End point timeframe
    Every 4 weeks from baseline up to Week 76
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    226
    224
    Units: Participants
        Week 4 (n=223, 217)
    83
    101
        Week 8 (n=204, 201)
    56
    68
        Week 12 (n=184, 182)
    41
    49
        Week 16 (n=161, 160)
    34
    50
        Week 20 (n=144, 149)
    33
    45
        Week 24 (n=147, 143)
    35
    42
        Week 28 (n=134, 136)
    47
    56
        Week 32 (n=124, 128)
    58
    50
        Week 36 (n=123, 125)
    48
    57
        Week 40 (n=119, 124)
    42
    56
        Week 44 (n=116, 120)
    43
    54
        Week 48 (n=114, 120)
    44
    49
        Week 52 (n=106, 125)
    34
    57
        Week 56 (n=106, 122)
    34
    54
        Week 60 (n=105, 123)
    39
    63
        Week 64 (n=102, 117)
    31
    52
        Week 68 (n=93, 110)
    34
    52
        Week 72 (n=83, 92)
    33
    39
        Week 76 (n=68, 74)
    16
    38
    No statistical analyses for this end point

    Secondary: Proportion of subjects with a CSFT < 300 µm for the study eye by visit up to Week 76

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    End point title
    		 Proportion of subjects with a CSFT < 300 µm for the study eye by visit up to Week 76
    End point description
    Central subfield thickness (CSFT) is measured in µm by Spectral Domain Optical Coherence Tomography (SD-OCT)
    End point type
    Secondary
    End point timeframe
    Every 4 weeks from Week 4 up to Week 76
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    226
    224
    Units: Participants
        Week 4 (n=223, 217)
    167
    153
        Week 8 (n=203, 201)
    172
    166
        Week 12 (n=184, 182)
    156
    155
        Week 16 (n=161, 160)
    137
    131
        Week 20 (n=143, 147)
    120
    118
        Week 24 (n=147, 143)
    127
    114
        Week 28 (n=134, 136)
    109
    103
        Week 32 (n=124, 128)
    92
    97
        Week 36 (n=123, 125)
    96
    91
        Week 40 (n=119, 124)
    94
    92
        Week 44 (n=116, 120)
    95
    93
        Week 48 (n=114, 120)
    89
    97
        Week 52 (n=106, 125)
    86
    95
        Week 56 (n=106, 122)
    86
    91
        Week 60 (n=105, 123)
    83
    90
        Week 64 (n=102, 117)
    85
    90
        Week 68 (n=93, 110)
    82
    79
        Week 72 (n=83, 92)
    70
    76
        Week 76 (n=68, 74)
    59
    59
    No statistical analyses for this end point

    Secondary: Number of injections between Week 24 and Week 52 and between Week 24 and Week 72

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    End point title
    		 Number of injections between Week 24 and Week 52 and between Week 24 and Week 72
    End point description
    Number of administered injections during the individualized flexible treatment (IFT) period, between Week 24 and Week 52 and between Week 24 and Week 72 are presented
    End point type
    Secondary
    End point timeframe
    Week 24 to Week 52 and Week 24 to Week 72
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    111
    126
    Units: Injections
    arithmetic mean (standard deviation)
        Between Week 24 and Week 52 (n=111, 126)
    2.2 ( 1.69 )
    2.5 ( 2.17 )
        Between Week 24 and Week 72 (n=65, 75)
    3.2 ( 2.54 )
    4.0 ( 3.28 )
    No statistical analyses for this end point

    Secondary: Time to recurrence after Week 20 and up to Week 76

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    End point title
    		 Time to recurrence after Week 20 and up to Week 76
    End point description
    Recurrence is defined as the need for injection while showing a lack of disease stability for the first time after Week 20 and up to Week 76. For subjects with recurrence after the Week 20 visit, time-to-event is calculated as (first time with the lack of disease stability – the injection date on Week 20 visit + 1). For subjects without recurrence after Week 20, the censoring time will be calculated as (last visit with disease stability assessment – the injection date on Week 20 visit + 1).
    End point type
    Secondary
    End point timeframe
    Week 20 to Week 76
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    157
    159
    Units: Weeks
        median (confidence interval 95%)
    12.9 (12.1 to 14.4)
    13.1 (11.3 to 17.4)
    No statistical analyses for this end point

    Secondary: Number of subjects with ocular and non-ocular AEs up to Week 52 and Week 76

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    End point title
    		 Number of subjects with ocular and non-ocular AEs up to Week 52 and Week 76
    End point description
    Number of subjects with at least one ocular or non-ocular Adverse Events (AEs).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 76
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    226
    224
    Units: Participants
        Ocular AEs up to week 52
    93
    72
        Non-Ocular AEs up to week 52
    94
    112
        Ocular AEs up to week 76
    98
    75
        Non-Ocular AEs up to week 76
    103
    120
    No statistical analyses for this end point

    Secondary: Change from baseline in patient reported outcomes (NEI VFQ-25) at Week 24, Week 52 and Week 76

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    End point title
    		 Change from baseline in patient reported outcomes (NEI VFQ-25) at Week 24, Week 52 and Week 76
    End point description
    The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures a patient's subjective assessment of vision-related Quality of Life (QoL). The 11 subscales in the VFQ-25 are general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, color vision, and peripheral vision. The scores on the subscales were added together for a total score, which ranged from 0 to 100. A higher score indicated better vision-related quality of life.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, Week 52 and Week 76
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    226
    224
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 24 (n=193, 192)
    5.6 ( 11.51 )
    6.4 ( 11.92 )
        Week 52 (n=119, 125)
    6.9 ( 13.21 )
    7.6 ( 10.47 )
        Week 76 (n=95, 114)
    8.6 ( 13.89 )
    7.5 ( 11.55 )
    No statistical analyses for this end point

    Secondary: Number of subjects according to their Anti-drug antibody (ADA) titer at screening and Week 4, Week 12, Week 24, Week 36, Week 52 and Week 76

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    End point title
    		 Number of subjects according to their Anti-drug antibody (ADA) titer at screening and Week 4, Week 12, Week 24, Week 36, Week 52 and Week 76 [2]
    End point description
    Anti-drug antibodies (ADA) levels were assessed from subjects assigned to brolucizumab treatment only.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, Week 12, Week 24, Week 36, Week 52 and Week 76
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this secondary outcome
    End point values
    		 Brolucizumab 6 mg
    Number of subjects analysed
    226
    Units: Participants
        Baseline|Negative (n=219)
    67
        Week 4|Negative (n=208)
    76
        Week 12|Negative (n=170)
    58
        Week 24|Negative (n=134)
    44
        Week 36|Negative (n=114)
    33
        Week 52|Negative (n=101)
    28
        Week 76|Negative (n=68)
    17
        Baseline|40 (n=219)
    29
        Week 4|40 (n=208)
    29
        Week 12|40 (n=170)
    17
        Week 24|40 (n=134)
    14
        Week 36|40 (n=114)
    18
        Week 52|40 (n=101)
    18
        Week 76|40 (n=68)
    6
        Baseline|120 (n=219)
    33
        Week 4|120 (n=208)
    31
        Week 12|120 (n=170)
    31
        Week 24|120 (n=134)
    23
        Week 36|120 (n=114)
    19
        Week 52|120 (n=101)
    19
        Week 76|120 (n=68)
    18
        Baseline|360 (n=219)
    37
        Week 4|360 (n=208)
    28
        Week 12|360 (n=170)
    25
        Week 24|360 (n=134)
    17
        Week 36|360 (n=114)
    17
        Week 52|360 (n=101)
    16
        Week 76|360 (n=68)
    14
        Baseline|1080 (n=219)
    31
        Week 4|1080 (n=208)
    27
        Week 12|1080 (n=170)
    19
        Week 24|1080 (n=134)
    19
        Week 36|1080 (n=114)
    17
        Week 52|1080 (n=101)
    14
        Week 76|1080 (n=68)
    10
        Baseline|3240 (n=219)
    15
        Week 4|3240 (n=208)
    9
        Week 12|3240 (n=170)
    11
        Week 24|3240 (n=134)
    11
        Week 36|3240 (n=114)
    8
        Week 52|3240 (n=101)
    5
        Week 76|3240 (n=68)
    2
        Baseline|9720 (n=219)
    1
        Week 4|9720 (n=208)
    6
        Week 12|9720 (n=170)
    7
        Week 24|9720 (n=134)
    5
        Week 36|9720 (n=114)
    1
        Week 52|9720 (n=101)
    1
        Week 76|9720 (n=68)
    1
        Baseline|29200 (n=219)
    6
        Week 4|29200 (n=208)
    2
        Week 12|29200 (n=170)
    2
        Week 24|29200 (n=134)
    1
        Week 36|29200 (n=114)
    1
        Week 52|29200 (n=101)
    0
        Week 76|29200 (n=68)
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from first dose of study treatment until end of study treatment plus 4 weeks post treatment, up to maximum duration of 76 weeks
    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
    24.1
    Reporting groups
    Reporting group title
    Brolucizumab 6mg
    Reporting group description
    		 Brolucizumab 6mg

    Reporting group title
    Overall
    Reporting group description
    		 Overall

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

    Serious adverse events
    		 Brolucizumab 6mg Overall Aflibercept 2mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    32 / 226 (14.16%)
    48 / 450 (10.67%)
    16 / 224 (7.14%)
         number of deaths (all causes)
    0
    2
    2
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder neoplasm
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 450 (0.22%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eyelid seborrhoeic keratosis - Fellow eye
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 450 (0.22%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    2 / 226 (0.88%)
    2 / 450 (0.44%)
    0 / 224 (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
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 450 (0.22%)
    0 / 224 (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
    Vasospasm
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 450 (0.22%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 226 (0.44%)
    2 / 450 (0.44%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 450 (0.22%)
    0 / 224 (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
    Pleural mass
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 450 (0.22%)
    1 / 224 (0.45%)
         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
    Depression
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 450 (0.22%)
    0 / 224 (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
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 450 (0.22%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Weight increased
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 450 (0.22%)
    0 / 224 (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
    Injury, poisoning and procedural complications
    Dislocation of vertebra
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 450 (0.22%)
    1 / 224 (0.45%)
         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
    1 / 226 (0.44%)
    1 / 450 (0.22%)
    0 / 224 (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
    Subdural haemorrhage
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 450 (0.22%)
    0 / 224 (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
    Congenital, familial and genetic disorders
    Atrial septal defect
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 450 (0.22%)
    0 / 224 (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
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 450 (0.22%)
    0 / 224 (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
    Atrial fibrillation
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 450 (0.22%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 450 (0.22%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Cardiac failure
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 450 (0.22%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 450 (0.22%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac valve disease
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 450 (0.22%)
    1 / 224 (0.45%)
         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
    0 / 226 (0.00%)
    1 / 450 (0.22%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 450 (0.22%)
    0 / 224 (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
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 450 (0.22%)
    1 / 224 (0.45%)
         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 / 226 (0.00%)
    1 / 450 (0.22%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Ischaemic stroke
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 450 (0.22%)
    0 / 224 (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
    Syncope
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 450 (0.22%)
    0 / 224 (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
    Transient ischaemic attack
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 450 (0.22%)
    0 / 224 (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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 450 (0.22%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 450 (0.22%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract - Fellow eye
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 450 (0.22%)
    0 / 224 (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
    Cataract - Study eye
         subjects affected / exposed
    2 / 226 (0.88%)
    2 / 450 (0.44%)
    0 / 224 (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
    Glaucoma - Study eye
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 450 (0.22%)
    0 / 224 (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
    Glaucoma - Fellow eye
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 450 (0.22%)
    0 / 224 (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 / 226 (0.44%)
    1 / 450 (0.22%)
    0 / 224 (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 aneurysm - Study eye
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 450 (0.22%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal artery occlusion - Fellow eye
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 450 (0.22%)
    0 / 224 (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
    Retinal artery occlusion - Study eye
         subjects affected / exposed
    2 / 226 (0.88%)
    2 / 450 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal detachment - Study eye
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 450 (0.22%)
    0 / 224 (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
    Retinal occlusive vasculitis - Study eye
         subjects affected / exposed
    2 / 226 (0.88%)
    2 / 450 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal vasculitis - Study eye
         subjects affected / exposed
    2 / 226 (0.88%)
    2 / 450 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal vascular occlusion - Study eye
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 450 (0.22%)
    0 / 224 (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 / 226 (1.33%)
    3 / 450 (0.67%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vitreous haemorrhage - Study eye
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 450 (0.22%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vitreous opacities - Study eye
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 450 (0.22%)
    0 / 224 (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
    Vitritis - Study eye
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 450 (0.22%)
    0 / 224 (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
    Gastrointestinal disorders
    Mallory-Weiss syndrome
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 450 (0.22%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 450 (0.22%)
    0 / 224 (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 acute
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 450 (0.22%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 450 (0.22%)
    0 / 224 (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
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 226 (0.44%)
    2 / 450 (0.44%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 450 (0.22%)
    0 / 224 (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
    Infections and infestations
    COVID-19
         subjects affected / exposed
    2 / 226 (0.88%)
    2 / 450 (0.44%)
    0 / 224 (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
    Bronchitis
         subjects affected / exposed
    1 / 226 (0.44%)
    2 / 450 (0.44%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 450 (0.22%)
    0 / 224 (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
    Endophthalmitis - Study eye
         subjects affected / exposed
    2 / 226 (0.88%)
    2 / 450 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Brolucizumab 6mg Overall Aflibercept 2mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    109 / 226 (48.23%)
    204 / 450 (45.33%)
    95 / 224 (42.41%)
    Investigations
    Intraocular pressure increased - Fellow eye
         subjects affected / exposed
    3 / 226 (1.33%)
    9 / 450 (2.00%)
    6 / 224 (2.68%)
         occurrences all number
    3
    10
    7
    Intraocular pressure increased - Study eye
         subjects affected / exposed
    4 / 226 (1.77%)
    12 / 450 (2.67%)
    8 / 224 (3.57%)
         occurrences all number
    4
    25
    21
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    3 / 226 (1.33%)
    8 / 450 (1.78%)
    5 / 224 (2.23%)
         occurrences all number
    4
    10
    6
    Vascular disorders
    Hypertension
         subjects affected / exposed
    26 / 226 (11.50%)
    45 / 450 (10.00%)
    19 / 224 (8.48%)
         occurrences all number
    28
    48
    20
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 226 (1.77%)
    11 / 450 (2.44%)
    7 / 224 (3.13%)
         occurrences all number
    4
    13
    9
    Eye disorders
    Cataract - Study eye
         subjects affected / exposed
    9 / 226 (3.98%)
    11 / 450 (2.44%)
    2 / 224 (0.89%)
         occurrences all number
    9
    11
    2
    Dry eye - Fellow eye
         subjects affected / exposed
    5 / 226 (2.21%)
    14 / 450 (3.11%)
    9 / 224 (4.02%)
         occurrences all number
    5
    14
    9
    Dry eye - Study eye
         subjects affected / exposed
    6 / 226 (2.65%)
    15 / 450 (3.33%)
    9 / 224 (4.02%)
         occurrences all number
    8
    17
    9
    Eye pain - Study eye
         subjects affected / exposed
    4 / 226 (1.77%)
    15 / 450 (3.33%)
    11 / 224 (4.91%)
         occurrences all number
    6
    23
    17
    Conjunctival haemorrhage - Study eye
         subjects affected / exposed
    11 / 226 (4.87%)
    23 / 450 (5.11%)
    12 / 224 (5.36%)
         occurrences all number
    11
    27
    16
    Macular oedema - Study eye
         subjects affected / exposed
    15 / 226 (6.64%)
    25 / 450 (5.56%)
    10 / 224 (4.46%)
         occurrences all number
    25
    38
    13
    Foreign body sensation in eyes - Study eye
         subjects affected / exposed
    5 / 226 (2.21%)
    6 / 450 (1.33%)
    1 / 224 (0.45%)
         occurrences all number
    5
    6
    1
    Retinal haemorrhage - Study eye
         subjects affected / exposed
    2 / 226 (0.88%)
    10 / 450 (2.22%)
    8 / 224 (3.57%)
         occurrences all number
    2
    10
    8
    Uveitis - Study eye
         subjects affected / exposed
    5 / 226 (2.21%)
    5 / 450 (1.11%)
    0 / 224 (0.00%)
         occurrences all number
    6
    6
    0
    Visual acuity reduced - Study eye
         subjects affected / exposed
    15 / 226 (6.64%)
    27 / 450 (6.00%)
    12 / 224 (5.36%)
         occurrences all number
    19
    33
    14
    Retinal exudates - Study eye
         subjects affected / exposed
    5 / 226 (2.21%)
    13 / 450 (2.89%)
    8 / 224 (3.57%)
         occurrences all number
    5
    13
    8
    Vitreous detachment - Study eye
         subjects affected / exposed
    5 / 226 (2.21%)
    10 / 450 (2.22%)
    5 / 224 (2.23%)
         occurrences all number
    5
    12
    7
    Vitreous floaters - Study eye
         subjects affected / exposed
    11 / 226 (4.87%)
    16 / 450 (3.56%)
    5 / 224 (2.23%)
         occurrences all number
    12
    18
    6
    Vitritis - Study eye
         subjects affected / exposed
    5 / 226 (2.21%)
    5 / 450 (1.11%)
    0 / 224 (0.00%)
         occurrences all number
    5
    5
    0
    Vitreous opacities - Study eye
         subjects affected / exposed
    5 / 226 (2.21%)
    6 / 450 (1.33%)
    1 / 224 (0.45%)
         occurrences all number
    5
    6
    1
    Gastrointestinal disorders
    Toothache
         subjects affected / exposed
    5 / 226 (2.21%)
    8 / 450 (1.78%)
    3 / 224 (1.34%)
         occurrences all number
    7
    10
    3
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    6 / 226 (2.65%)
    8 / 450 (1.78%)
    2 / 224 (0.89%)
         occurrences all number
    7
    10
    3
    Back pain
         subjects affected / exposed
    2 / 226 (0.88%)
    9 / 450 (2.00%)
    7 / 224 (3.13%)
         occurrences all number
    2
    9
    7
    Arthralgia
         subjects affected / exposed
    2 / 226 (0.88%)
    8 / 450 (1.78%)
    6 / 224 (2.68%)
         occurrences all number
    2
    9
    7
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    5 / 226 (2.21%)
    11 / 450 (2.44%)
    6 / 224 (2.68%)
         occurrences all number
    5
    12
    7
    COVID-19
         subjects affected / exposed
    7 / 226 (3.10%)
    14 / 450 (3.11%)
    7 / 224 (3.13%)
         occurrences all number
    7
    14
    7
    Nasopharyngitis
         subjects affected / exposed
    6 / 226 (2.65%)
    13 / 450 (2.89%)
    7 / 224 (3.13%)
         occurrences all number
    6
    14
    8
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 226 (0.88%)
    9 / 450 (2.00%)
    7 / 224 (3.13%)
         occurrences all number
    2
    11
    9
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    5 / 226 (2.21%)
    8 / 450 (1.78%)
    3 / 224 (1.34%)
         occurrences all number
    5
    8
    3
    Type 2 diabetes mellitus
         subjects affected / exposed
    5 / 226 (2.21%)
    5 / 450 (1.11%)
    0 / 224 (0.00%)
         occurrences all number
    5
    5
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Jun 2020
    The main purpose of the amendment was to provide clarification and guidance on safety assessments in accordance to the urgent safety measure regarding the postmarketing reports with brolucizumab in the treatment of nAMD, which were identified as retinal vasculitis and/or retinal vascular occlusion, typically in the presence of IOI, that may result in severe vision loss. In addition, the amendment included modifications (exclusion criteria, prohibited medications/procedures, informed consent procedures, visit schedule and assessments, safety, laboratory evaluations, data analysis and statistical methods) due to the COVID-19 pandemic.

    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.
    Study was terminated by sponsor due to increased incidences of AEs of special interest (intraocular inflammation including retinal vasculitis and retinal vascular occlusion), in patients dosed brolucizumab 6mg every 4 weeks beyond 3 initial doses
    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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