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

    Summary
    EudraCT number
    		 2018-001788-21
    Trial protocol
    		 CZ   DE   HU   NL   GR   FI   ES   GB   IT  
    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
    CRTH258C2302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03810313
    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 best-corrected visual acuity 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
    03 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
    Australia: 25
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    China: 71
    Country: Number of subjects enrolled
    Czechia: 32
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Germany: 41
    Country: Number of subjects enrolled
    Greece: 15
    Country: Number of subjects enrolled
    Hungary: 31
    Country: Number of subjects enrolled
    Israel: 21
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    Japan: 23
    Country: Number of subjects enrolled
    Malaysia: 15
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Russian Federation: 26
    Country: Number of subjects enrolled
    Spain: 25
    Country: Number of subjects enrolled
    Thailand: 8
    Country: Number of subjects enrolled
    Turkey: 2
    Country: Number of subjects enrolled
    United Kingdom: 17
    Country: Number of subjects enrolled
    United States: 97
    Worldwide total number of subjects
    493
    EEA total number of subjects
    178
    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)
    236
    From 65 to 84 years
    238
    85 years and over
    19

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited from 132 sites in 19 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 individual 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 individual 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
    247
    246
    Completed
    66
    70
    Not completed
    181
    176
         Adverse event, serious fatal
    2
    1
         Physician decision
    -
    1
         Subject decision
    10
    11
         Adverse event, non-fatal
    2
    1
         Study terminated by sponsor
    164
    159
         Lost to follow-up
    3
    3

    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 individual 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 individual flexible treatment (IFT)

    Reporting group values
    		 Brolucizumab 6 mg Aflibercept 2 mg Total
    Number of subjects
    		 247 246 493
    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)
    		 123 113 236
        From 65-84 years
    		 118 120 238
        85 years and over
    		 6 13 19
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 63.0 ( 13.69 ) 65.2 ( 12.66 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 96 96 192
        Male
    		 151 150 301
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 176 178 354
        Black or African American
    		 7 8 15
        Asian
    		 62 58 120
        Native Hawaiian or Other Pacific Islander
    		 2 0 2
        American Indian or Alaska Native
    		 0 1 1
        Unknown
    		 0 1 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 individual 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 individual 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
    247
    246
    Units: Letters read
        least squares mean (standard error)
    13.2 ( 0.85 )
    16.0 ( 0.85 )
    Statistical analysis title
    		 Change from baseline at BCVA at week 24
    Comparison groups
    Brolucizumab 6 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    493
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 = 0.173
    Method
    		 ANOVA
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.2
         upper limit
    		 -0.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.2
    Notes
    [1] - Non-inferiority was considered to be 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 > -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
    120
    120
    Units: Letters read
        arithmetic mean (standard deviation)
    13.4 ( 15.73 )
    15.4 ( 13.96 )
    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
    109
    113
    Units: Letters read
        arithmetic mean (standard deviation)
    14.0 ( 16.39 )
    16.9 ( 13.60 )
    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
    247
    246
    Units: Letters read
    arithmetic mean (standard deviation)
        Week 4 (n= 237, 236)
    11.3 ( 12.30 )
    12.8 ( 11.00 )
        Week 8 (n= 212, 212)
    13.6 ( 13.77 )
    15.0 ( 11.78 )
        Week 12 (n= 195, 194)
    14.1 ( 14.17 )
    16.3 ( 12.78 )
        Week 16 (n= 174, 171)
    13.3 ( 15.37 )
    17.4 ( 13.54 )
        Week 20 (n= 164, 156)
    13.9 ( 14.17 )
    17.6 ( 14.68 )
        Week 24 (n= 149, 144)
    13.6 ( 14.69 )
    18.1 ( 13.83 )
        Week 28 (n= 138, 133)
    12.7 ( 15.52 )
    16.2 ( 13.55 )
        Week 32 (n= 130, 123)
    11.5 ( 15.96 )
    15.1 ( 14.58 )
        Week 36 (n= 120, 122)
    12.6 ( 17.17 )
    15.3 ( 14.05 )
        Week 40 (n= 119, 116)
    13.7 ( 15.35 )
    16.7 ( 12.62 )
        Week 44 (n= 112, 116)
    13.7 ( 16.59 )
    15.4 ( 14.50 )
        Week 48 (n= 113, 111)
    13.5 ( 17.11 )
    16.2 ( 13.14 )
        Week 52 (n= 113, 110)
    12.9 ( 18.00 )
    16.3 ( 14.13 )
        Week 56 (n= 107, 111)
    13.4 ( 16.98 )
    14.9 ( 16.43 )
        Week 60 (n= 108, 113)
    13.1 ( 18.75 )
    15.7 ( 13.93 )
        Week 64 (n= 107, 108)
    14.2 ( 17.06 )
    17.8 ( 13.54 )
        Week 68 (n= 93, 101)
    14.2 ( 16.75 )
    17.0 ( 13.88 )
        Week 72 (n= 76, 81)
    15.8 ( 14.55 )
    15.2 ( 15.09 )
        Week 76 (n= 64, 70)
    17.2 ( 13.46 )
    14.9 ( 13.76 )
    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
    247
    246
    Units: Participants
        Week4; BCVA gain from baseline >=5 (n= 237, 236)
    181
    189
        Week4; BCVA gain from baseline >=10 (n= 237, 236)
    138
    132
        Week4; BCVA gain from baseline >=15 (n= 237, 236)
    92
    86
        Week8; BCVA gain from baseline >=5 (n= 212, 212)
    177
    183
        Week8; BCVA gain from baseline >=10 (n= 212, 212)
    143
    151
        Week8; BCVA gain from baseline >=15 (n= 212, 212)
    103
    95
        Week12; BCVA gain from baseline >=5 (n= 195, 194)
    161
    164
        Week12; BCVA gain from baseline >=10 (n= 195, 194)
    134
    141
        Week12; BCVA gain from baseline >=15 (n= 195, 194)
    101
    109
        Week16; BCVA gain from baseline >=5 (n= 174, 152)
    144
    152
        Week16; BCVA gain from baseline >=10 (n= 174, 152)
    121
    134
        Week16; BCVA gain from baseline >=15 (n= 174, 152)
    91
    104
        Week20; BCVA gain from baseline >=5 (n= 164, 156)
    135
    136
        Week20; BCVA gain from baseline >=10 (n= 164, 156)
    114
    122
        Week20; BCVA gain from baseline >=15 (n= 164, 156)
    83
    101
        Week24; BCVA gain from baseline >=5 (n= 149, 144)
    125
    130
        Week24; BCVA gain from baseline >=10 (n= 149, 144)
    101
    115
        Week24; BCVA gain from baseline >=15 (n= 149, 144)
    78
    97
        Week28; BCVA gain from baseline >=5 (n= 138, 133)
    112
    116
        Week28; BCVA gain from baseline >=10 (n= 138, 133)
    91
    104
        Week28; BCVA gain from baseline >=15 (n= 138, 133)
    69
    83
        Week32; BCVA gain from baseline >=5 (n= 130, 123)
    100
    100
        Week32; BCVA gain from baseline >=10 (n= 130, 123)
    78
    89
        Week32; BCVA gain from baseline >=15 (n= 130, 123)
    58
    76
        Week36; BCVA gain from baseline >=5 (n= 120, 122)
    101
    104
        Week36; BCVA gain from baseline >=10 (n= 120, 122)
    86
    84
        Week36; BCVA gain from baseline >=15 (n= 120, 122)
    61
    69
        Week40; BCVA gain from baseline >=5 (n= 119, 116)
    101
    98
        Week40; BCVA gain from baseline >=10 (n= 119, 116)
    85
    85
        Week40; BCVA gain from baseline >=15 (n= 119, 116)
    59
    71
        Week44; BCVA gain from baseline >=5 (n= 112, 116)
    89
    99
        Week44; BCVA gain from baseline >=10 (n= 112, 116)
    75
    82
        Week44; BCVA gain from baseline >=15 (n= 112, 116)
    59
    67
        Week48; BCVA gain from baseline >=5 (n= 113, 111)
    92
    89
        Week48; BCVA gain from baseline >=10 (n= 113, 111)
    72
    79
        Week48; BCVA gain from baseline >=15 (n= 113, 111)
    56
    63
        Week52; BCVA gain from baseline >=5 (n= 113, 110)
    89
    92
        Week52; BCVA gain from baseline >=10 (n= 113, 110)
    71
    81
        Week52; BCVA gain from baseline >=15 (n= 113, 110)
    58
    67
        Week56; BCVA gain from baseline >=5 (n= 107, 111)
    88
    92
        Week56; BCVA gain from baseline >=10 (n= 107, 111)
    70
    82
        Week56; BCVA gain from baseline >=15 (n= 107, 111)
    58
    64
        Week60; BCVA gain from baseline >=5 (n= 108, 113)
    88
    91
        Week 60; BCVA gain from baseline >=10(n= 108, 113)
    72
    80
        Week60; BCVA gain from baseline >=15(n= 108, 113)
    60
    69
        Week64; BCVA gain from baseline >=5(n= 107, 108)
    88
    89
        Week64; BCVA gain from baseline >=10(n= 107, 108)
    73
    81
        Week64; BCVA gain from baseline >=15 (n= 107, 108)
    59
    65
        Week68; BCVA gain from baseline >=5 (n= 93, 101)
    76
    84
        Week68; BCVA gain from baseline >=10 (n= 93, 101)
    61
    72
        Week68; BCVA gain from baseline >=15 (n= 93, 101)
    52
    62
        Week72; BCVA gain from baseline >=5 (n= 76, 81)
    65
    63
        Week72; BCVA gain from baseline >=10 (n= 76, 81)
    53
    60
        Week72; BCVA gain from baseline >=15 (n= 76, 81)
    46
    50
        Week76; BCVA gain from baseline >=5 (n= 64, 70)
    54
    56
        Week76; BCVA gain from baseline >=10 (n= 64, 70)
    47
    49
        Week76; BCVA gain from baseline >=15 (n= 64, 70)
    36
    41
    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
    247
    246
    Units: Participants
        Week4; BCVA loss from baseline >=5 (n= 237, 236)
    10
    7
        Week4; BCVA loss from baseline >=10 (n= 237, 236)
    8
    3
        Week4; BCVA loss from baseline >=15 (n= 237, 236)
    5
    2
        Week8; BCVA loss from baseline >=5 (n= 212, 212)
    9
    6
        Week8; BCVA loss from baseline >=10 (n= 212, 212)
    7
    3
        Week8; BCVA loss from baseline >=15 (n= 212, 212)
    6
    2
        Week12; BCVA loss from baseline >=5 (n= 195, 194)
    9
    7
        Week12; BCVA loss from baseline >=10 (n= 195, 194)
    6
    5
        Week12; BCVA loss from baseline >=15 (n= 195, 194)
    5
    1
        Week16; BCVA loss from baseline >=5 (n= 174, 171)
    11
    7
        Week16; BCVA loss from baseline >=10 (n= 174, 171)
    8
    5
        Week16; BCVA loss from baseline >=15 (n= 174, 171)
    8
    2
        Week20; BCVA loss from baseline >=5 (n= 164, 156)
    6
    8
        Week20; BCVA loss from baseline >=10 (n= 164, 156)
    5
    5
        Week20; BCVA loss from baseline >=15 (n= 164, 156)
    5
    5
        Week24; BCVA loss from baseline >=5 (n= 149, 144)
    10
    7
        Week24; BCVA loss from baseline >=10 (n= 149, 144)
    8
    5
        Week24; BCVA loss from baseline >=15 (n= 149, 144)
    7
    4
        Week28; BCVA loss from baseline >=5 (n= 138, 133)
    10
    7
        Week28; BCVA loss from baseline >=10(n= 138, 133)
    6
    6
        Week28; BCVA loss from baseline >=15(n= 138, 133)
    6
    5
        Week32; BCVA loss from baseline >=5(n= 130, 123)
    11
    11
        Week32; BCVA loss from baseline >=10(n= 130, 123)
    9
    8
        Week32; BCVA loss from baseline >=15(n= 130, 123)
    5
    4
        Week36; BCVA loss from baseline >=5(n= 120, 122)
    9
    7
        Week36; BCVA loss from baseline >=10(n= 120, 122)
    8
    6
        Week36; BCVA loss from baseline >=15(n= 120, 122)
    6
    5
        Week40; BCVA loss from baseline >=5(n= 119, 116)
    7
    5
        Week40; BCVA loss from baseline >=10(n= 119, 116)
    6
    3
        Week40; BCVA loss from baseline >=15(n= 119, 116)
    4
    2
        Week44; BCVA loss from baseline >=5(n= 112, 116)
    8
    9
        Week44; BCVA loss from baseline >=10(n= 112, 116)
    7
    5
        Week44; BCVA loss from baseline >=15(n= 112, 116)
    6
    5
        Week48; BCVA loss from baseline >=5(n= 113, 111)
    9
    6
        Week48; BCVA loss from baseline >=10(n= 113, 111)
    7
    4
        Week48; BCVA loss from baseline >=15(n= 113, 111)
    6
    3
        Week52; BCVA loss from baseline >=5(n= 113, 110)
    9
    7
        Week52; BCVA loss from baseline >=10(n= 113, 110)
    7
    6
        Week52; BCVA loss from baseline >=15(n= 113, 110)
    7
    5
        Week56; BCVA loss from baseline >=5(n= 107, 111)
    9
    9
        Week56; BCVA loss from baseline >=10(n= 107, 111)
    6
    7
        Week56; BCVA loss from baseline >=15(n= 107, 111)
    5
    6
        Week60; BCVA loss from baseline >=5(n= 108, 113)
    11
    10
        Week 60; BCVA loss from baseline >=10(n= 108, 113)
    8
    6
        Week60; BCVA loss from baseline >=15(n= 108, 113)
    6
    3
        Week64; BCVA loss from baseline >=5(n= 107, 108)
    8
    4
        Week64; BCVA loss from baseline >=10(n= 107, 108)
    6
    2
        Week64; BCVA loss from baseline >=15(n= 107, 108)
    6
    2
        Week68; BCVA loss from baseline >=5(n= 93, 101)
    5
    6
        Week68; BCVA loss from baseline >=10(n= 93, 101)
    5
    3
        Week68; BCVA loss from baseline >=15(n= 93, 101)
    3
    1
        Week72; BCVA loss from baseline >=5(n= 76, 81)
    3
    7
        Week72; BCVA loss from baseline >=10(n= 76, 81)
    3
    5
        Week72; BCVA loss from baseline >=15(n= 76, 81)
    3
    3
        Week76; BCVA loss from baseline >=5(n= 64, 70)
    1
    3
        Week 76; BCVA loss from baseline >=10(n= 64, 70)
    1
    3
        Week 76; BCVA loss from baseline >=15(n= 64, 70)
    1
    3
    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
    119
    120
    Units: μm
        arithmetic mean (standard deviation)
    -399.9 ( 259.22 )
    -434.6 ( 261.71 )
    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
    108
    112
    Units: μm
        arithmetic mean (standard deviation)
    -411.6 ( 259.16 )
    -445.7 ( 259.73 )
    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
    247
    246
    Units: μm
    arithmetic mean (standard deviation)
        Week 4 (n= 235, 235)
    -429.5 ( 254.32 )
    -420.6 ( 242.68 )
        Week 8 (n= 210, 213)
    -448.8 ( 265.16 )
    -436.1 ( 255.53 )
        Week 12 (n= 194, 194)
    -468.3 ( 269.55 )
    -440.7 ( 251.74 )
        Week 16 (n= 174, 170)
    -450.1 ( 278.67 )
    -470.7 ( 255.64 )
        Week 20 (n= 163, 156)
    -458.1 ( 270.26 )
    -470.2 ( 260.46 )
        Week 24 (n= 149, 142)
    -446.8 ( 274.39 )
    -472.4 ( 249.20 )
        Week 28 (n= 137, 132)
    -383.2 ( 248.81 )
    -417.9 ( 269.03 )
        Week 32 (n= 129, 122)
    -323.5 ( 322.95 )
    -395.8 ( 299.16 )
        Week 36 (n= 116, 122)
    -387.8 ( 280.75 )
    -406.5 ( 265.67 )
        Week 40 (n= 118, 116)
    -403.9 ( 269.68 )
    -446.6 ( 270.47 )
        Week 44 (n= 111, 116)
    -404.0 ( 311.37 )
    -418.4 ( 271.33 )
        Week 48 (n= 112, 111)
    -411.5 ( 281.09 )
    -457.8 ( 261.08 )
        Week 52 (n= 112, 110)
    -411.3 ( 276.21 )
    -457.0 ( 256.40 )
        Week 56 (n= 106, 111)
    -384.6 ( 313.93 )
    -400.8 ( 298.50 )
        Week 60 (n= 107, 113)
    -396.1 ( 295.96 )
    -438.8 ( 254.36 )
        Week 64 (n= 105, 107)
    -425.2 ( 266.66 )
    -462.3 ( 258.08 )
        Week 68 (n= 91, 99)
    -396.3 ( 282.85 )
    -416.1 ( 260.79 )
        Week 72 (n= 72, 79)
    -401.5 ( 276.50 )
    -419.0 ( 252.10 )
        Week 76 (n= 63, 69)
    -421.9 ( 261.63 )
    -408.5 ( 251.12 )
    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 week 4 up to Week 76
    End point values
    		 Brolucizumab 6 mg Aflibercept 2 mg
    Number of subjects analysed
    247
    246
    Units: Participants
        Week 4 (n= 236, 235)
    101
    105
        Week 8 (n= 212, 213)
    54
    68
        Week 12 (n= 195, 194)
    38
    54
        Week 16 (n= 175, 170)
    37
    43
        Week 20 (n= 164, 156)
    34
    31
        Week 24 (n= 150, 144)
    26
    30
        Week 28 (n= 138, 133)
    44
    56
        Week 32 (n= 130, 122)
    63
    55
        Week 36 (n= 120, 122)
    43
    59
        Week 40 (n= 119, 116)
    32
    40
        Week 44 (n= 112, 116)
    38
    48
        Week 48 (n= 113, 111)
    36
    40
        Week 52 (n= 113, 110)
    35
    40
        Week 56 (n= 107, 111)
    42
    48
        Week 60 (n= 108, 113)
    36
    39
        Week 64 (n= 106, 108)
    29
    41
        Week 68 (n= 93, 100)
    36
    40
        Week 72 (n= 76, 80)
    25
    27
        Week 76 (n= 64, 70)
    24
    31
    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
    247
    246
    Units: Participants
        Week 4 (n=236 , 235)
    157
    137
        Week 8 (n= 211, 213)
    168
    155
        Week 12 (n= 195, 194)
    172
    149
        Week 16 (n= 175, 170)
    153
    141
        Week 20 (n= 164, 156)
    147
    135
        Week 24 (n= 150, 142)
    135
    123
        Week 28 (n= 138, 132)
    107
    90
        Week 32 (n= 130, 122)
    81
    74
        Week 36 (n= 117, 122)
    83
    77
        Week 40 (n= 119, 116)
    94
    86
        Week 44 (n= 112, 116)
    83
    79
        Week 48 (n= 113, 111)
    82
    83
        Week 52 (n= 113, 110)
    85
    82
        Week 56 (n= 107, 111)
    74
    71
        Week 60 (n= 108, 113)
    81
    79
        Week 64 (n= 106, 107)
    85
    80
        Week 68 (n= 92, 99)
    65
    69
        Week 72 (n= 73, 79)
    59
    56
        Week 76 (n= 64, 69)
    51
    45
    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
    114
    115
    Units: Injections
    arithmetic mean (standard deviation)
        Between Week 24 and Week 52 (n= 114, 115)
    2.4 ( 1.69 )
    2.6 ( 2.02 )
        Between Week 24 and Week 72 (n=58, 67)
    4.1 ( 3.08 )
    4.4 ( 3.25 )
    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
    160
    163
    Units: Weeks
        median (confidence interval 95%)
    12.1 (12.1 to 12.4)
    12.1 (11.4 to 13.4)
    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
    247
    246
    Units: Participants
        Ocular AEs up to week 52
    105
    77
        Non-Ocular AEs up to week 52
    103
    107
        Ocular AEs up to week 76
    111
    89
        Non-Ocular AEs up to week 76
    119
    117
    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
    247
    246
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Week 24 (n= 217, 211)
    5.3 ( 13.08 )
    7.4 ( 12.46 )
        Week 52 (n= 128, 128)
    6.0 ( 14.83 )
    9.0 ( 11.10 )
        Week 76 (n= 104, 111)
    7.4 ( 14.44 )
    9.4 ( 11.66 )
    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
    247
    Units: Participants
        Baseline|Negative (n= 244)
    105
        Week 4|Negative (n= 226)
    101
        Week 12|Negative (n= 187)
    77
        Week 24|Negative (n= 146)
    51
        Week 36|Negative (n= 114)
    35
        Week 52|Negative (n= 114)
    37
        Week 76|Negative (n= 67)
    25
        Baseline|40 (n= 244)
    23
        Week 4|40 (n= 226)
    26
        Week 12|40 (n= 187)
    15
        Week 24|40 (n= 146)
    16
        Week 36|40 (n= 114)
    8
        Week 52|40 (n= 114)
    15
        Week 76|40 (n= 67)
    8
        Baseline|120 (n= 244)
    35
        Week 4|120 (n= 226)
    30
        Week 12|120 (n= 187)
    38
        Week 24|120 (n= 146)
    32
        Week 36|120 (n= 114)
    20
        Week 52|120 (n= 114)
    22
        Week 76|120 (n= 67)
    14
        Baseline|360 (n= 244)
    34
        Week 4|360 (n= 226)
    35
        Week 12|360 (n= 187)
    28
        Week 24|360 (n= 146)
    21
        Week 36|360 (n= 114)
    28
        Week 52|360 (n= 114)
    16
        Week 76|360 (n= 67)
    7
        Baseline|1080 (n= 244)
    29
        Week 4|1080 (n= 226)
    21
        Week 12|1080 (n= 187)
    12
        Week 24|1080 (n= 146)
    15
        Week 36|1080 (n= 114)
    11
        Week 52|1080 (n= 114)
    14
        Week 76|1080 (n= 67)
    7
        Baseline|3240 (n= 244)
    13
        Week 4|3240 (n= 226)
    8
        Week 12|3240 (n= 187)
    14
        Week 24|3240 (n= 146)
    8
        Week 36|3240 (n= 114)
    9
        Week 52|3240 (n= 114)
    9
        Week 76|3240 (n= 67)
    5
        Baseline|9720 (n= 244)
    4
        Week 4|9720 (n= 226)
    5
        Week 12|9720 (n= 187)
    3
        Week 24|9720 (n= 146)
    3
        Week 36|9720 (n= 114)
    3
        Week 52|9720 (n= 114)
    1
        Week 76|9720 (n= 67)
    1
        Baseline|29200 (n= 244)
    1
        Week 4|29200 (n= 226)
    0
        Week 12|29200 (n= 187)
    0
        Week 24|29200 (n= 146)
    0
        Week 36|29200 (n= 114)
    0
        Week 52|29200 (n= 114)
    0
        Week 76|29200 (n= 67)
    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
    36 / 247 (14.57%)
    55 / 493 (11.16%)
    19 / 246 (7.72%)
         number of deaths (all causes)
    2
    3
    1
         number of deaths resulting from adverse events
    1
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 493 (0.20%)
    0 / 246 (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
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 493 (0.20%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Prostate cancer
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 493 (0.20%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 493 (0.20%)
    0 / 246 (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
    Waldenstrom's macroglobulinaemia
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 493 (0.20%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aneurysm
         subjects affected / exposed
    2 / 247 (0.81%)
    2 / 493 (0.41%)
    0 / 246 (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
    Peripheral ischaemia
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 493 (0.20%)
    0 / 246 (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
    Hypertensive crisis
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 493 (0.20%)
    0 / 246 (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
    Varicose vein
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 493 (0.20%)
    0 / 246 (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
    Reproductive system and breast disorders
    Cervical dysplasia
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 493 (0.20%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 493 (0.20%)
    0 / 246 (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
    Dyspnoea
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 493 (0.20%)
    0 / 246 (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 / 247 (0.00%)
    1 / 493 (0.20%)
    1 / 246 (0.41%)
         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
    Suicidal ideation
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 493 (0.20%)
    0 / 246 (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
    Femoral neck fracture
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 493 (0.20%)
    0 / 246 (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 haematoma
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 493 (0.20%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 493 (0.20%)
    0 / 246 (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
    Cardiac failure congestive
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 493 (0.20%)
    0 / 246 (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
    Hypertensive heart disease
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 493 (0.20%)
    0 / 246 (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
    Myocardial infarction
         subjects affected / exposed
    1 / 247 (0.40%)
    2 / 493 (0.41%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 493 (0.20%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 493 (0.20%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 493 (0.20%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 493 (0.20%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 493 (0.20%)
    0 / 246 (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
    Hemiparesis
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 493 (0.20%)
    1 / 246 (0.41%)
         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 / 247 (0.40%)
    2 / 493 (0.41%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Sudden hearing loss
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 493 (0.20%)
    0 / 246 (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
    Cataract - Fellow eye
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 493 (0.20%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cataract - Study eye
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 493 (0.20%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epiretinal membrane - Fellow eye
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 493 (0.20%)
    0 / 246 (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 hypertension - Study eye
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 493 (0.20%)
    0 / 246 (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 / 247 (0.81%)
    2 / 493 (0.41%)
    0 / 246 (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 ischaemia - Study eye
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 493 (0.20%)
    1 / 246 (0.41%)
         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 vasculitis - Study eye
         subjects affected / exposed
    2 / 247 (0.81%)
    2 / 493 (0.41%)
    0 / 246 (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
    Uveitis - Study eye
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 493 (0.20%)
    0 / 246 (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 vein occlusion - Study eye
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 493 (0.20%)
    0 / 246 (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
    Ascites
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 493 (0.20%)
    0 / 246 (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
    Diabetic nephropathy
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 493 (0.20%)
    0 / 246 (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
    Endocrine disorders
    Adrenal mass
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 493 (0.20%)
    0 / 246 (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
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 493 (0.20%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoporotic fracture
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 493 (0.20%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 493 (0.20%)
    0 / 246 (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
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 493 (0.20%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    4 / 247 (1.62%)
    6 / 493 (1.22%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    2 / 247 (0.81%)
    2 / 493 (0.41%)
    0 / 246 (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
    Cellulitis
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 493 (0.20%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dacryocystitis - Study eye
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 493 (0.20%)
    0 / 246 (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
    Emphysematous cystitis
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 493 (0.20%)
    0 / 246 (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
    Endocarditis
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 493 (0.20%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endophthalmitis - Study eye
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 493 (0.20%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 493 (0.20%)
    0 / 246 (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
    Gastroenteritis viral
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 493 (0.20%)
    1 / 246 (0.41%)
         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 cyst infection
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 493 (0.20%)
    0 / 246 (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
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 493 (0.20%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 493 (0.20%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 493 (0.20%)
    0 / 246 (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
    Vestibular neuronitis
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 493 (0.20%)
    0 / 246 (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
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 493 (0.20%)
    1 / 246 (0.41%)
         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: 2%
    Non-serious adverse events
    		 Brolucizumab 6mg Overall Aflibercept 2mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    104 / 247 (42.11%)
    191 / 493 (38.74%)
    87 / 246 (35.37%)
    Investigations
    Intraocular pressure increased - Study eye
         subjects affected / exposed
    10 / 247 (4.05%)
    23 / 493 (4.67%)
    13 / 246 (5.28%)
         occurrences all number
    14
    37
    23
    Vascular disorders
    Hypertension
         subjects affected / exposed
    19 / 247 (7.69%)
    29 / 493 (5.88%)
    10 / 246 (4.07%)
         occurrences all number
    19
    29
    10
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 247 (1.21%)
    11 / 493 (2.23%)
    8 / 246 (3.25%)
         occurrences all number
    3
    13
    10
    Eye disorders
    Cataract - Study eye
         subjects affected / exposed
    8 / 247 (3.24%)
    12 / 493 (2.43%)
    4 / 246 (1.63%)
         occurrences all number
    9
    13
    4
    Conjunctival haemorrhage - Study eye
         subjects affected / exposed
    16 / 247 (6.48%)
    27 / 493 (5.48%)
    11 / 246 (4.47%)
         occurrences all number
    25
    49
    24
    Dry eye - Fellow eye
         subjects affected / exposed
    5 / 247 (2.02%)
    10 / 493 (2.03%)
    5 / 246 (2.03%)
         occurrences all number
    6
    11
    5
    Eye pain - Study eye
         subjects affected / exposed
    9 / 247 (3.64%)
    15 / 493 (3.04%)
    6 / 246 (2.44%)
         occurrences all number
    12
    18
    6
    Dry eye - Study eye
         subjects affected / exposed
    6 / 247 (2.43%)
    12 / 493 (2.43%)
    6 / 246 (2.44%)
         occurrences all number
    7
    13
    6
    Glaucoma - Fellow eye
         subjects affected / exposed
    5 / 247 (2.02%)
    10 / 493 (2.03%)
    5 / 246 (2.03%)
         occurrences all number
    5
    10
    5
    Glaucoma - Study eye
         subjects affected / exposed
    5 / 247 (2.02%)
    10 / 493 (2.03%)
    5 / 246 (2.03%)
         occurrences all number
    5
    10
    5
    Macular oedema - Study eye
         subjects affected / exposed
    18 / 247 (7.29%)
    29 / 493 (5.88%)
    11 / 246 (4.47%)
         occurrences all number
    27
    41
    14
    Ocular hypertension - Study eye
         subjects affected / exposed
    6 / 247 (2.43%)
    9 / 493 (1.83%)
    3 / 246 (1.22%)
         occurrences all number
    7
    10
    3
    Retinal ischaemia - Study eye
         subjects affected / exposed
    6 / 247 (2.43%)
    7 / 493 (1.42%)
    1 / 246 (0.41%)
         occurrences all number
    6
    7
    1
    Retinal vein occlusion - Study eye
         subjects affected / exposed
    7 / 247 (2.83%)
    8 / 493 (1.62%)
    1 / 246 (0.41%)
         occurrences all number
    7
    8
    1
    Uveitis - Study eye
         subjects affected / exposed
    8 / 247 (3.24%)
    8 / 493 (1.62%)
    0 / 246 (0.00%)
         occurrences all number
    10
    10
    0
    Vitreous detachment - Study eye
         subjects affected / exposed
    11 / 247 (4.45%)
    22 / 493 (4.46%)
    11 / 246 (4.47%)
         occurrences all number
    11
    22
    11
    Visual acuity reduced - Study eye
         subjects affected / exposed
    22 / 247 (8.91%)
    31 / 493 (6.29%)
    9 / 246 (3.66%)
         occurrences all number
    33
    47
    14
    Vitreous floaters - Study eye
         subjects affected / exposed
    5 / 247 (2.02%)
    16 / 493 (3.25%)
    11 / 246 (4.47%)
         occurrences all number
    6
    19
    13
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 247 (0.40%)
    6 / 493 (1.22%)
    5 / 246 (2.03%)
         occurrences all number
    1
    7
    6
    Arthralgia
         subjects affected / exposed
    9 / 247 (3.64%)
    16 / 493 (3.25%)
    7 / 246 (2.85%)
         occurrences all number
    9
    16
    7
    Infections and infestations
    COVID-19
         subjects affected / exposed
    5 / 247 (2.02%)
    11 / 493 (2.23%)
    6 / 246 (2.44%)
         occurrences all number
    5
    11
    6
    Nasopharyngitis
         subjects affected / exposed
    8 / 247 (3.24%)
    14 / 493 (2.84%)
    6 / 246 (2.44%)
         occurrences all number
    9
    16
    7
    Tooth abscess
         subjects affected / exposed
    1 / 247 (0.40%)
    6 / 493 (1.22%)
    5 / 246 (2.03%)
         occurrences all number
    1
    7
    6
    Urinary tract infection
         subjects affected / exposed
    7 / 247 (2.83%)
    10 / 493 (2.03%)
    3 / 246 (1.22%)
         occurrences all number
    8
    13
    5

    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 this amendment is to provide clarification and guidance on safety assessments in accordance to the urgent safety measure regarding the post-marketing reports with brolucizumab (Beovu®) in the treatment of neovascular age-related macular degeneration (nAMD), which were identified as retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation, that may result in severe vision loss. In addition, the amendment includes modifications due to the Coronavirus disease 2019 (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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