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    Clinical Trial Results:
    A 12-Month, 2-Arm, Randomized, Double-Masked, Multicenter Phase III Study Assessing the Efficacy and Safety of Brolucizumab every 4 weeks versus Aflibercept every 4 weeks in Adult Patients with Visual Impairment due to Diabetic Macular Edema (KINGFISHER)

    Summary
    EudraCT number
    		 2019-001004-37
    Trial protocol
    		 SK   HU  
    Global end of trial date
    24 Mar 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    22 May 2022
    First version publication date
    08 Apr 2022
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    CRTH258B2305
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03917472
    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
    16 Nov 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Mar 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective for this study was to demonstrate that brolucizumab is non-inferior to aflibercept with respect to the change in visual acuity (VA) from baseline compared to Week 52 summarized below along with their respective endpoints. Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com for complete trial results.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Jul 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Hungary: 51
    Country: Number of subjects enrolled
    Israel: 27
    Country: Number of subjects enrolled
    Slovakia: 47
    Country: Number of subjects enrolled
    United States: 392
    Worldwide total number of subjects
    517
    EEA total number of subjects
    98
    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)
    323
    From 65 to 84 years
    191
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study centers (no. of sites): Hungary (5), Israel (5), Slovakia (7), United States (78). Approximately, 495 subjects were planned to be randomized. Overall, 517 subjects were randomized either to brolucizumab 6 mg q4w arm (n=346) or aflibercept 2 mg q4w arm (n=171).

    Pre-assignment
    Screening details
    		 The study included a screening period of up to 2 wks to assess eligibility, followed by a double-masked treatment period (Day 1 to Wk 48). For all subjects, the last study assessment was performed at the Wk 52/end of study (EOS) visit. All subjects had study visits q4w through Wk 52. The primary analysis was performed at the EOS visit (Wk 52).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Brolucizumab 6mg q4w
    Arm description
    		 Brolucizumab 6 mg/0.05 mL every 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brolucizumab
    Investigational medicinal product code
    RTH258
    Other name
    BEOVU
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    6 mg/0.05 mL

    Arm title
    		 Aflibercept 2mg q4w
    Arm description
    		 Aflibercept 2mg/0.05 mL every 4 weeks
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Aflibercept
    Investigational medicinal product code
    Other name
    EYLEA
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    2 mg/0.05 mL

    Number of subjects in period 1
    		Brolucizumab 6mg q4w Aflibercept 2mg q4w
    Started
    346
    171
    Completed
    311
    156
    Not completed
    35
    15
         Adverse event, serious fatal
    7
    5
         Physician decision
    4
    -
         Consent withdrawn by subject
    11
    4
         Adverse event, non-fatal
    3
    1
         Lost to follow-up
    10
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Brolucizumab 6mg q4w
    Reporting group description
    		 Brolucizumab 6 mg/0.05 mL every 4 weeks.

    Reporting group title
    Aflibercept 2mg q4w
    Reporting group description
    		 Aflibercept 2mg/0.05 mL every 4 weeks

    Reporting group values
    		 Brolucizumab 6mg q4w Aflibercept 2mg q4w Total
    Number of subjects
    		 346 171 517
    Age Categorical
    Units: participants
        <=18 years
    		 0 0 0
        Between 18 and 65 years
    		 208 115 323
        >=65 years
    		 138 56 194
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.9 ( 10.59 ) 60.2 ( 9.31 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 152 66 218
        Male
    		 194 105 299
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 288 145 433
        Black or African American
    		 40 15 55
        Asian
    		 14 7 21
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        American Indian or Alaska Native
    		 0 1 1
        Unknown
    		 1 3 4
        More than one race
    		 2 0 2

    End points

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    End points reporting groups
    Reporting group title
    Brolucizumab 6mg q4w
    Reporting group description
    		 Brolucizumab 6 mg/0.05 mL every 4 weeks.

    Reporting group title
    Aflibercept 2mg q4w
    Reporting group description
    		 Aflibercept 2mg/0.05 mL every 4 weeks

    Subject analysis set title
    Brolucizumab 6mg q4w
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Brolucizumab 6mg q4w

    Subject analysis set title
    Aflibercept 2mg q4w
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Aflibercept 2mg q4w

    Primary: Change from baseline in best-corrected visual acuity (BCVA) at Week 52

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    End point title
    		 Change from baseline in best-corrected visual acuity (BCVA) at Week 52
    End point description
    BCVA will be assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. Visual function of the study eye was assessed using the ETDRS protocol. Participants with a BCVA ETDRS letter score of 73 to 23 (per the inclusion criteria) (approximate Snellen equivalent of 20/40 to 20/320) in the study eye were included. Min and max possible scores are 0-100 respectively. A higher score represents better functioning. Last observation carried forward (LOCF) was used for the imputation of missing values.
    End point type
    Primary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Brolucizumab 6mg q4w Aflibercept 2mg q4w
    Number of subjects analysed
    346
    171
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    12.2 (11.2 to 13.2)
    11.0 (9.6 to 12.4)
    Statistical analysis title
    		 Brolucizumab 6mg q4w vs. Aflibercept 2mg q4w
    Comparison groups
    Aflibercept 2mg q4w v Brolucizumab 6mg q4w
    Number of subjects included in analysis
    517
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 = 0.099
    Method
    		 ANOVA
    Parameter type
    		 LS mean difference
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 2.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.89
    Notes
    [1] - (1-sided)
    Statistical analysis title
    		 Brolucizumab 6mg q4w vs. Aflibercept 2mg q4w
    Comparison groups
    Brolucizumab 6mg q4w v Aflibercept 2mg q4w
    Number of subjects included in analysis
    517
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Confidence interval
    Notes
    [2] - (4-letter margin) (1-sided)

    Secondary: Change from baseline in central subfield thickness (CSFT) at each post-baseline visit

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    End point title
    		 Change from baseline in central subfield thickness (CSFT) at each post-baseline visit
    End point description
    Central Subfield Thickness assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center.
    End point type
    Secondary
    End point timeframe
    Baselinet, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
    End point values
    		 Brolucizumab 6mg q4w Aflibercept 2mg q4w
    Number of subjects analysed
    346
    171
    Units: μm
    least squares mean (confidence interval 95%)
        Week 4
    -146.9 (-157.9 to -136.0)
    -119.5 (-135.1 to -103.9)
        Week 8
    -174.4 (-185.3 to -163.4)
    -144.1 (-159.7 to -128.5)
        Week 12
    -191.3 (-201.8 to -180.8)
    -156.7 (-171.7 to -141.8)
        Week 16
    -200.5 (-211.0 to -189.9)
    -162.4 (-177.4 to -147.4)
        Week 20
    -209.5 (-219.6 to -199.4)
    -168.7 (-183.1 to -154.2)
        Week 24
    -217.5 (-227.3 to -207.6)
    -178.8 (-192.8 to -164.7)
        Week 28
    -222.4 (-232.5 to -212.4)
    -183.6 (-197.8 to -169.3)
        Week 32
    -227.2 (-237.2 to -217.1)
    -185.9 (-200.2 to -171.6)
        Week 36
    -229.7 (-240.1 to -219.3)
    -186.7 (-201.5 to -172.0)
        Week 40
    -233.6 (-243.7 to -223.6)
    -188.4 (-202.6 to -174.1)
        Week 44
    -237.5 (-247.4 to -227.5)
    -188.1 (-202.3 to -173.9)
        Week 48
    -237.7 (-247.7 to -227.6)
    -192.0 (-206.4 to -177.7)
        Week 52
    -237.8 (-247.9 to -227.7)
    -196.5 (-210.8 to -182.1)
    Statistical analysis title
    		 Brolucizumab 6mg q4w vs. Aflibercept 2mg q4w
    Comparison groups
    Brolucizumab 6mg q4w v Aflibercept 2mg q4w
    Number of subjects included in analysis
    517
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -41.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -58.9
         upper limit
    		 -23.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.94
    Notes
    [3] - (1-sided); Week 52

    Secondary: Number of participants with fluid-free macula in the study eye at each post-baseline visit

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    End point title
    		 Number of participants with fluid-free macula in the study eye at each post-baseline visit
    End point description
    Subretinal Fluid (SRF) and Intraretinal Fluid (IRF) status in the central subfield: proportion of subjects with simultaneous absence of SRF and IRF in the study eye by visit. Events and censoring after 52 weeks are included in week 52 row.
    End point type
    Secondary
    End point timeframe
    Baselinet, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
    End point values
    		 Brolucizumab 6mg q4w Aflibercept 2mg q4w
    Number of subjects analysed
    346
    171
    Units: Participants
        Week 4
    23
    4
        Week 8
    31
    4
        Week 12
    38
    10
        Week 16
    48
    11
        Week 20
    54
    9
        Week 24
    84
    19
        Week 28
    65
    13
        Week 32
    76
    17
        Week 36
    91
    21
        Week 40
    96
    23
        Week 44
    96
    20
        week 48
    92
    23
        Week 52
    144
    38
    Statistical analysis title
    		 Brolucizumab 6mg q4w vs. Aflibercept 2mg q4w
    Comparison groups
    Brolucizumab 6mg q4w v Aflibercept 2mg q4w
    Number of subjects included in analysis
    517
    Analysis specification
    Pre-specified
    Analysis type
    		 [4]
    P-value
    		 < 0.001
    Method
    		 Clopper-Pearson exact method.
    Parameter type
    		 Difference - %
    Point estimate
    20
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 12.5
         upper limit
    		 28.6
    Notes
    [4] - (1-sided) Week 52

    Secondary: Number of participants with absence of Diabetic Macular Edema (DME) (CSFT < 280 μm) at each post-baseline visit for the study eye

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    End point title
    		 Number of participants with absence of Diabetic Macular Edema (DME) (CSFT < 280 μm) at each post-baseline visit for the study eye
    End point description
    Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center.
    End point type
    Secondary
    End point timeframe
    Baselinet, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
    End point values
    		 Brolucizumab 6mg q4w Aflibercept 2mg q4w
    Number of subjects analysed
    346
    171
    Units: Participants
        Week 4
    61
    9
        Week 8
    93
    24
        Week 12
    124
    33
        Week 16
    147
    42
        Week 20
    167
    47
        Week 24
    177
    52
        Week 28
    186
    57
        Week 32
    195
    62
        Week 36
    206
    63
        Week 40
    211
    65
        Week 44
    216
    69
        Week 48
    222
    68
        Week 52
    229
    71
    No statistical analyses for this end point

    Secondary: Time to first fluid-free macula - Time-to-first absence of Subretinal Fluid (SRF) and Intraretinal Fluid (IRF) in the study eye - Number of subjects with absence of SRF / IRF and Number of subjects censored by visit

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    End point title
    		 Time to first fluid-free macula - Time-to-first absence of Subretinal Fluid (SRF) and Intraretinal Fluid (IRF) in the study eye - Number of subjects with absence of SRF / IRF and Number of subjects censored by visit
    End point description
    Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center. Fluid status assessments after start of alternative DME treatment in the study eye are censored. Time to first fluid-free macula analysis is based on the subset of subjects with fluid present at baseline and at least one post-baseline assessment. Time (week) was calculated by (study day / 7). Events and censoring after 52 weeks were included in week 52 row.
    End point type
    Secondary
    End point timeframe
    Baselinet, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
    End point values
    		 Brolucizumab 6mg q4w Aflibercept 2mg q4w
    Number of subjects analysed
    344
    170
    Units: Participants
        N w/ absence of SRF/IRF at Wk 0 (n=344,170)
    0
    0
        N w/ absence of SRF/IRF at Wk 4 (n=344,170)
    6
    1
        N w/ absence of SRF/IRF at Wk 8 (n=335,168)
    18
    3
        N w/ absence of SRF/IRF at Wk 12 (n=314, 165)
    13
    2
        N w/ absence of SRF/IRF at Wk 16 (n=297, 161)
    17
    4
        N w/ absence of SRF/IRF at Wk 20 (n=277, 156)
    8
    6
        N w/ absence of SRF/IRF at Wk 24 (n=265,150)
    16
    2
        N w/ absence of SRF/IRF at Wk 28 (n=246,146)
    18
    7
        N w/ absence of SRF/IRF at Wk 32 (n=224,139)
    3
    1
        N w/ absence of SRF/IRF at Wk 36 (n=220,138)
    8
    2
        N w/ absence of SRF/IRF at Wk 40 (n=211, 134)
    16
    4
        N w/ absence of SRF/IRF at Wk 44 (194, 129)
    11
    2
        N w/ absence of SRF/IRF at Wk 48 (n=181, 125)
    3
    0
        N w/ absence of SRF/IRF at Wk 52 (n=177, 122)
    30
    12
        N censored at Week 0 (n=344, 170)
    0
    0
        N censored at Week 4 (n-344, 170)
    3
    1
        N censored at Week 8 (n=335,168)
    3
    0
        N censored at Week 12 (n=314, 165)
    4
    2
        N censored at Week 16 (n=297, 161)
    3
    1
        N censored at Week 20 (n=277, 156)
    4
    0
        N censored at Week 24 (n=265, 150)
    3
    2
        N censored at Week 28 (n=246, 146)
    4
    0
        N censored at Week 32 (n=224,139)
    1
    0
        N censored at Week 36 (220, 138)
    1
    2
        N censored at Week 40 (n=211,134)
    1
    1
        N censored at Week 44 (n=194,129)
    2
    2
        N censored at Week 48 (n=181, 125)
    1
    3
        N censored at Week 52 (n=177, 122)
    147
    110
    No statistical analyses for this end point

    Secondary: Time to first fluid-free macula - Time-to-first absence of Subretinal Fluid (SRF) and Intraretinal Fluid (IRF) in the study eye - Kaplan-Meier analysis - Probability of absence of SRF/IRF by visit

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    End point title
    		 Time to first fluid-free macula - Time-to-first absence of Subretinal Fluid (SRF) and Intraretinal Fluid (IRF) in the study eye - Kaplan-Meier analysis - Probability of absence of SRF/IRF by visit
    End point description
    Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center. Fluid status assessments after start of alternative DME treatment in the study eye are censored. Time to first fluid-free macula analysis is based on the subset of subjects with fluid present at baseline and at least one post-baseline assessment. Time (week) was calculated by (study day / 7). Events and censoring after 52 weeks were included in week 52 row.
    End point type
    Secondary
    End point timeframe
    Baselinet, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
    End point values
    		 Brolucizumab 6mg q4w Aflibercept 2mg q4w
    Number of subjects analysed
    344
    170
    Units: Probability of absence of SRF/IRF
    number (confidence interval 95%)
        Prob. of absence of SRF/IRF at Wk 4 (n=344,170)
    0.018 (0.007 to 0.036)
    0.006 (0.001 to 0.030)
        Prob. of absence of SRF/IRF at Wk 8 (n=335,168)
    0.071 (0.047 to 0.101)
    0.024 (0.008 to 0.056)
        Prob. of absence of SRF/IRF at Wk 12 (n=314, 165)
    0.109 (0.079 to 0.145)
    0.036 (0.015 to 0.072)
        Prob. of absence of SRF/IRF at Wk 16 (n=297, 161)
    0.161 (0.124 to 0.202)
    0.060 (0.030 to 0.103)
        Prob.of absence of SRF/IRF at Wk 20 (n=277, 156)
    0.185 (0.145 to 0.228)
    0.096 (0.057 to 0.146)
        Prob. of absence of SRF/IRF at Wk 24 (n=265,150)
    0.234 (0.190 to 0.281)
    0.108 (0.067 to 0.161)
        Prob. of absence of SRF/IRF at Wk 28 (n=246,146)
    0.291 (0.243 to 0.341)
    0.151 (0.101 to 0.210)
        Prob. of absence of SRF/IRF at Wk 32 (n=224,139)
    0.300 (0.252 to 0.351)
    0.157 (0.106 to 0.217)
        Prob. of absence of SRF/IRF at Wk 36 (n=220,138)
    0.326 (0.275 to 0.377)
    0.169 (0.116 to 0.230)
        Prob. of absence of SRF/IRF at Wk 40 (n=211, 134)
    0.377 (0.324 to 0.430)
    0.194 (0.137 to 0.258)
        Prob. of absence of SRF/IRF at Wk 44 (194, 129)
    0.412 (0.358 to 0.466)
    0.206 (0.148 to 0.271)
        Prob. of absence of SRF/IRF at Wk 48 (n=181, 125)
    0.422 (0.368 to 0.476)
    0.206 (0.148 to 0.271)
        Prob. of absence of SRF/IRF at Wk 52 (n=177, 122)
    0.653 (0.540 to 0.745)
    0.328 (0.234 to 0.426)
    No statistical analyses for this end point

    Secondary: Time to first absence of Diabetic Macular Edema (DME) (CSFT < 280 μm) in the study eye at each post-baseline visit - Number of subjects with Probability of absence of DME and Number censored by visit

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    End point title
    		 Time to first absence of Diabetic Macular Edema (DME) (CSFT < 280 μm) in the study eye at each post-baseline visit - Number of subjects with Probability of absence of DME and Number censored by visit
    End point description
    Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center. CSFT assessments after start of alternative DME treatment in the study eye are censored. Time to first absence of DME based on subjects with valid baseline and at least one post-baseline CSFT assessment. Time (week) was calculated by (study day / 7). Events and censoring after 52 weeks were included in week 52 row.
    End point type
    Secondary
    End point timeframe
    Baselinet, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
    End point values
    		 Brolucizumab 6mg q4w Aflibercept 2mg q4w
    Number of subjects analysed
    346
    171
    Units: Participants
        N w/ Prob. of absence of DME at Wk 0 (n=346,171)
    0
    0
        N w/ Prob. of absence of DME at Wk 4 (n=346,171)
    14
    1
        N w/ Prob. of absence of DME at Wk 8 (n=329,169)
    54
    12
        N w/ Prob. of absence of DME at Wk 12 (n=272, 157)
    32
    13
        N w/ Prob. of absence of DME at Wk 16 (n=239, 142)
    33
    11
        N w/ Prob. of absence of DME at Wk 20 (n=204, 130)
    26
    10
        N w/ Prob. of absence of DME at Wk 24 (n=174,120)
    12
    4
        N w/ Prob. of absence of DME at Wk 28 (n=161,115)
    13
    7
        N w/ Prob. of absence of DME at Wk 32 (n=146,107)
    9
    5
        N w/ Prob. of absence of DME at Wk 36 (n=135,102)
    10
    2
        N w/ Prob. of absence of DME at Wk 40 (n=125, 98)
    7
    1
        N w/ Prob. of absence of DME at Wk 44 (117, 96)
    11
    2
        N w/ Prob. of absence of DME at Wk 48 (n=106, 92)
    6
    3
        N w/ Prob. of absence of DME at Wk 52 (n=99, 88)
    13
    4
        Number censored at Week 0 (n=346,171)
    0
    0
        Number censored at Week 4 (n=346,171)
    3
    1
        Number censored at Week 8 (n=329,169)
    3
    0
        Number censored at Week 12 (n=272, 157)
    1
    2
        Number censored at Week 16 (n=239, 142)
    2
    1
        Number censored at Week 20 (n=204, 130)
    4
    0
        Number censored at Week 24 (n=174,120)
    1
    1
        Number censored at Week 28 (n=161,115)
    2
    1
        Number censored at Week 32 (n=146,107)
    2
    0
        Number censored at Week 36 (n=135,102)
    0
    2
        Number censored at Week 40 (n=125, 98)
    1
    1
        Number censored at Week 44 (117, 96)
    0
    2
        Number censored at Week 48 (n=106, 92)
    1
    1
        Number censored at Week 52 (n=99, 88)
    86
    84
    No statistical analyses for this end point

    Secondary: Time to first absence of Diabetic Macular Edema (DME) (CSFT < 280 μm) in the study eye at each post-baseline visit - Kaplan-Meier analysis - Probability of absence of DME by visit

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    End point title
    		 Time to first absence of Diabetic Macular Edema (DME) (CSFT < 280 μm) in the study eye at each post-baseline visit - Kaplan-Meier analysis - Probability of absence of DME by visit
    End point description
    Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center. CSFT assessments after start of alternative DME treatment in the study eye are censored. Time to first absence of DME based on subjects with valid baseline and at least one post-baseline CSFT assessment. Time (week) was calculated by (study day / 7). Events and censoring after 52 weeks were included in week 52 row.
    End point type
    Secondary
    End point timeframe
    Baselinet, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
    End point values
    		 Brolucizumab 6mg q4w Aflibercept 2mg q4w
    Number of subjects analysed
    346
    171
    Units: Probability of absence of DME
    number (confidence interval 95%)
        Prob. of absence of DME at Week 4 (n=346,171)
    0.041 (0.023 to 0.066)
    0.006 (0.001 to 0.030)
        Prob. of absence of DME at Week 8 (n=329,169)
    0.199 (0.158 to 0.243)
    0.076 (0.043 to 0.123)
        Prob. of absence of DME at Week 12 (n=272, 157)
    0.293 (0.246 to 0.342)
    0.153 (0.104 to 0.212)
        Prob. of absence of DME at Week 16 (n=239, 142)
    0.391 (0.339 to 0.443)
    0.219 (0.160 to 0.284)
        Prob. of absence of DME at Week 20 (n=204, 130)
    0.470 (0.416 to 0.522)
    0.279 (0.213 to 0.348)
        Prob. of absence of DME at Week 24 (n=174,120)
    0.506 (0.452 to 0.559)
    0.303 (0.235 to 0.374)
        Prob. of absence of DME at Week 28 (n=161,115)
    0.547 (0.491 to 0.598)
    0.346 (0.274 to 0.418)
        Prob. of absence of DME at Week 32 (n=146,107)
    0.575 (0.520 to 0.626)
    0.376 (0.303 to 0.450)
        Prob. of absence of DMEE at Week 36 (n=135,102)
    0.606 (0.551 to 0.657)
    0.389 (0.314 to 0.462)
        Prob. of absence of DME at Week 40 (n=125, 98)
    0.628 (0.574 to 0.678)
    0.395 (0.320 to 0.468)
        Prob. of absence of DME at Week 44 (117, 96)
    0.663 (0.609 to 0.712)
    0.408 (0.332 to 0.482)
        Prob. of absence of DME at Week 48 (n=106, 92)
    0.682 (0.629 to 0.730)
    0.427 (0.351 to 0.501)
        Prob. of absence of DME at Week 52 (n=99, 88)
    0.866 (0.302 to 0.983)
    0.516 (0.357 to 0.654)
    No statistical analyses for this end point

    Secondary: Best Corrected Visual Acuity (letters read): Change from baseline in best-corrected visual acuity (BCVA) at each post-baseline visit for the study eye

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    End point title
    		 Best Corrected Visual Acuity (letters read): Change from baseline in best-corrected visual acuity (BCVA) at each post-baseline visit for the study eye
    End point description
    BCVA will be assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. Visual function of the study eye was assessed using the ETDRS protocol. Participants with a BCVA ETDRS letter score of 73 to 23 (per the inclusion criteria) (approximate Snellen equivalent of 20/40 to 20/320) in the study eye were included. Min and max possible scores are 0-100 respectively. A higher score represents better functioning.
    End point type
    Secondary
    End point timeframe
    Baselinet, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
    End point values
    		 Brolucizumab 6mg q4w Aflibercept 2mg q4w
    Number of subjects analysed
    346
    171
    Units: scores on a scale
    least squares mean (confidence interval 95%)
        Week 4
    5.7 (5.1 to 6.4)
    5.4 (4.5 to 6.4)
        Week 8
    7.7 (6.9 to 8.5)
    7.4 (6.4 to 8.5)
        Week 12
    9.1 (8.3 to 9.9)
    8.0 (6.9 to 9.1)
        Week 16
    9.6 (8.8 to 10.4)
    8.5 (7.3 to 9.7)
        Week 20
    10.2 (9.3 to 11.1)
    9.2 (7.9 to 10.5)
        Week 24
    10.7 (9.8 to 11.6)
    9.6 (8.3 to 10.9)
        Week 28
    10.9 (10.0 to 11.8)
    10.7 (9.3 to 12.0)
        Week 32
    11.5 (10.6 to 12.5)
    10.5 (9.2 to 11.9)
        Week 36
    11.6 (10.6 to 12.6)
    10.8 (9.4 to 12.2)
        Week 40
    11.7 (10.7 to 12.6)
    10.7 (9.4 to 12.1)
        Week 44
    12.0 (11.0 to 13.0)
    10.6 (9.2 to 12.0)
        Week 48
    12.2 (11.2 to 13.2)
    10.7 (9.3 to 12.1)
        Week 52
    12.2 (11.2 to 13.2)
    11.0 (9.6 to 12.4)
    No statistical analyses for this end point

    Secondary: Gain in best-corrected visual acuity (BCVA) (letters read): number (%) of subjects who gained ≥ 5, 10, or 15 letters in BCVA from baseline or reached BCVA ≥ 84 letters in the study eye at Week 52

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    End point title
    		 Gain in best-corrected visual acuity (BCVA) (letters read): number (%) of subjects who gained ≥ 5, 10, or 15 letters in BCVA from baseline or reached BCVA ≥ 84 letters in the study eye at Week 52
    End point description
    BCVA will be assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. Visual function of the study eye was assessed using the ETDRS protocol. Participants with a BCVA ETDRS letter score of 73 to 23 (per the inclusion criteria) (approximate Snellen equivalent of 20/40 to 20/320) in the study eye were included. Min and max possible scores are 0-100 respectively. A higher score represents better functioning.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Brolucizumab 6mg q4w Aflibercept 2mg q4w
    Number of subjects analysed
    346
    171
    Units: Participants
        ≥5 letters gain from b/l or BCVA≥84letters at Wk52
    286
    127
        ≥10 letters gain from b/l or BCVA≥84letters at W52
    211
    95
        ≥15 letters gain from b/l or BCVA≥84letters at W52
    151
    69
    Statistical analysis title
    		 Brolucizumab 6mg q4w vs. Aflibercept 2mg q4w
    Statistical analysis description
    ≥ 5 letters gain from baseline or BCVA ≥ 84 letters at Week 52
    Comparison groups
    Brolucizumab 6mg q4w v Aflibercept 2mg q4w
    Number of subjects included in analysis
    517
    Analysis specification
    Pre-specified
    Analysis type
    		 [5]
    Method
    		 Clopper-Pearson exact method
    Parameter type
    		 Difference - %
    Point estimate
    9.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.7
         upper limit
    		 17
    Notes
    [5] - Descriptive
    Statistical analysis title
    		 Brolucizumab 6mg q4w vs. Aflibercept 2mg q4w
    Statistical analysis description
    ≥ 15 letters gain from baseline or BCVA ≥ 84 letters at Week 52
    Comparison groups
    Brolucizumab 6mg q4w v Aflibercept 2mg q4w
    Number of subjects included in analysis
    517
    Analysis specification
    Pre-specified
    Analysis type
    		 [6]
    Method
    		 Clopper-Pearson exact method
    Parameter type
    		 Difference - %
    Point estimate
    5.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.7
         upper limit
    		 14.3
    Notes
    [6] - Descriptive
    Statistical analysis title
    		 Brolucizumab 6mg q4w vs. Aflibercept 2mg q4w
    Statistical analysis description
    ≥ 10 letters gain from baseline or BCVA ≥ 84 letters at Week 52
    Comparison groups
    Brolucizumab 6mg q4w v Aflibercept 2mg q4w
    Number of subjects included in analysis
    517
    Analysis specification
    Pre-specified
    Analysis type
    		 [7]
    Method
    		 Clopper-Pearson exact method
    Parameter type
    		 Difference - %
    Point estimate
    7.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5
         upper limit
    		 17
    Notes
    [7] - Descriptive

    Secondary: Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic retinopathy severity scale (DRSS): proportion of subjects with >=2-step improvement from baseline in the DRSS score at each assessment visit for the study eye

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    End point title
    		 Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic retinopathy severity scale (DRSS): proportion of subjects with >=2-step improvement from baseline in the DRSS score at each assessment visit for the study eye
    End point description
    The Diabetic Retinopathy Disease Severity Scale measures the 5 levels of diabetic retinopathy - none, mild, moderate, severe, and proliferative. Severity of Diabetic retinopathy was evaluated using the ETDRS DRSS score assessed by the Central Reading Center based on color fundus photography images in the study eye. When the ETDRS-DR severities were evaluable, they were categorized on the original scale with scores varying from 10 (DR absent) to 85 (very advanced PDR). All DRSS values were then converted into a 12-level scale, allowing the derivation of the ≥2-step and ≥3-step change from baseline for each post-baseline assessment”. A lower score represents better functioning. Subjects who had full/partial panretinal photocoagulation or local photocoagulation for new vessel (DRSS score 60) at any visit were excluded. DRSS scores after start of alternative DME treatment in the study eye are censored and replaced by the last value prior to start of this alternative treatment.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24 and 52
    End point values
    		 Brolucizumab 6mg q4w Aflibercept 2mg q4w
    Number of subjects analysed
    221
    118
    Units: Participants
        Week 12
    56
    21
        Week 24
    82
    38
        Week 52
    95
    45
    Statistical analysis title
    		 Brolucizumab 6mg q4w vs. Aflibercept 2mg q4w
    Comparison groups
    Brolucizumab 6mg q4w v Aflibercept 2mg q4w
    Number of subjects included in analysis
    339
    Analysis specification
    Pre-specified
    Analysis type
    		 [8]
    Method
    		 Clopper-Pearson exact method
    Parameter type
    		 Difference - %
    Point estimate
    8.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 16.5
    Notes
    [8] - descriptive; week 12
    Statistical analysis title
    		 Brolucizumab 6mg q4w vs. Aflibercept 2mg q4w
    Comparison groups
    Brolucizumab 6mg q4w v Aflibercept 2mg q4w
    Number of subjects included in analysis
    339
    Analysis specification
    Pre-specified
    Analysis type
    		 [9]
    P-value
    		 = 0.002 [10]
    Method
    		 Clopper-Pearson exact method
    Parameter type
    		 Difference - %
    Point estimate
    6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.9
         upper limit
    		 16.1
    Notes
    [9] - (10% margin); week 52
    [10] - (10% margin) (1-sided)
    Statistical analysis title
    		 Brolucizumab 6mg q4w vs. Aflibercept 2mg q4w
    Comparison groups
    Brolucizumab 6mg q4w v Aflibercept 2mg q4w
    Number of subjects included in analysis
    339
    Analysis specification
    Pre-specified
    Analysis type
    		 [11]
    Method
    		 Clopper-Pearson exact method
    Parameter type
    		 Difference - %
    Point estimate
    6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3
         upper limit
    		 14.9
    Notes
    [11] - descriptive; week 24

    Secondary: Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic retinopathy severity scale (DRSS): proportion of subjects with >=3-step improvement from baseline in the DRSS score at each assessment visit for the study eye

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    End point title
    		 Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic retinopathy severity scale (DRSS): proportion of subjects with >=3-step improvement from baseline in the DRSS score at each assessment visit for the study eye
    End point description
    The Diabetic Retinopathy Disease Severity Scale measures the 5 levels of diabetic retinopathy - none, mild, moderate, severe, and proliferative. Severity of Diabetic retinopathy was evaluated using the ETDRS DRSS score assessed by the Central Reading Center based on color fundus photography images in the study eye. When the ETDRS-DR severities were evaluable, they were categorized on the original scale with scores varying from 10 (DR absent) to 85 (very advanced PDR). All DRSS values were then converted into a 12-level scale, allowing the derivation of the ≥2-step and ≥3-step change from baseline for each post-baseline assessment”. A lower score represents better functioning. Subjects who had full/partial panretinal photocoagulation or local photocoagulation for new vessel (DRSS score 60) at any visit were excluded. DRSS scores after start of alternative DME treatment in the study eye are censored and replaced by the last value prior to start of this alternative treatment.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24 and 52
    End point values
    		 Brolucizumab 6mg q4w Aflibercept 2mg q4w
    Number of subjects analysed
    221
    118
    Units: Participants
        Week 12
    18
    8
        Week 24
    33
    16
        Week 52
    40
    18
    Statistical analysis title
    		 Brolucizumab 6mg q4w vs. Aflibercept 2mg q4w
    Comparison groups
    Brolucizumab 6mg q4w v Aflibercept 2mg q4w
    Number of subjects included in analysis
    339
    Analysis specification
    Pre-specified
    Analysis type
    		 [12]
    Method
    		 Clopper-Pearson exact method
    Parameter type
    		 Difference - %
    Point estimate
    2.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3
         upper limit
    		 7.7
    Notes
    [12] - descriptive; week 24
    Statistical analysis title
    		 Brolucizumab 6mg q4w vs. Aflibercept 2mg q4w
    Comparison groups
    Brolucizumab 6mg q4w v Aflibercept 2mg q4w
    Number of subjects included in analysis
    339
    Analysis specification
    Pre-specified
    Analysis type
    		 [13]
    Method
    		 Clopper-Pearson exact method
    Parameter type
    		 Difference - %
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.5
         upper limit
    		 6.6
    Notes
    [13] - descriptive; week 12
    Statistical analysis title
    		 Brolucizumab 6mg q4w vs. Aflibercept 2mg q4w
    Comparison groups
    Brolucizumab 6mg q4w v Aflibercept 2mg q4w
    Number of subjects included in analysis
    339
    Analysis specification
    Pre-specified
    Analysis type
    		 [14]
    Method
    		 Clopper-Pearson exact method
    Parameter type
    		 Difference - %
    Point estimate
    3.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 9.8
    Notes
    [14] - descriptive; week 52

    Secondary: Anti-Drug Antibody (ADA): frequency distribution of pre-existing ADA status in the Brolucizumab arm

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    End point title
    		 Anti-Drug Antibody (ADA): frequency distribution of pre-existing ADA status in the Brolucizumab arm
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Brolucizumab 6mg q4w Aflibercept 2mg q4w
    Number of subjects analysed
    342
    0 [15]
    Units: Participants
        Negative
    112
        Positive
    230
    Notes
    [15] - Endpoint only defined for the Brolucizumab 6mg q4w arm
    No statistical analyses for this end point

    Post-hoc: Ocular AEs (greater than or equal to 2% in any treatment arm) by preferred term in the study eye

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    End point title
    		 Ocular AEs (greater than or equal to 2% in any treatment arm) by preferred term in the study eye
    End point description
    End point type
    Post-hoc
    End point timeframe
    Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of approximately 52 weeks.
    End point values
    		 Brolucizumab 6mg q4w Aflibercept 2mg q4w
    Number of subjects analysed
    346
    171
    Units: Participants
        Number of subjects with at least one AE
    105
    59
        Vitreous detachment
    10
    7
        Cataract
    9
    6
        Conjunctival haemorrhage
    9
    7
        Punctate keratitis
    9
    2
        Uveitis
    8
    1
        Vitreous floaters
    8
    5
        Dry eye
    7
    4
        Eye pain
    6
    5
        Corneal abrasion
    0
    5
        Diabetic retinal oedema
    0
    4
    No statistical analyses for this end point

    Post-hoc: Number of subjects with non-ocular AEs (greater than or equal to 2% in any treatment arm)

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    End point title
    		 Number of subjects with non-ocular AEs (greater than or equal to 2% in any treatment arm)
    End point description
    End point type
    Post-hoc
    End point timeframe
    Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of approximately 52 weeks.
    End point values
    		 Brolucizumab 6mg q4w Aflibercept 2mg q4w
    Number of subjects analysed
    346
    171
    Units: Participants
        Number of subjects with at least one AE
    209
    96
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of approximately 52 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
    24.0
    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
    74 / 346 (21.39%)
    110 / 517 (21.28%)
    36 / 171 (21.05%)
         number of deaths (all causes)
    7
    12
    5
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adrenal adenoma
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Bladder cancer
         subjects affected / exposed
    0 / 346 (0.00%)
    1 / 517 (0.19%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Leukaemia
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric neoplasm
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Extremity necrosis
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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 emergency
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Hypertension
         subjects affected / exposed
    1 / 346 (0.29%)
    3 / 517 (0.58%)
    2 / 171 (1.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive urgency
         subjects affected / exposed
    0 / 346 (0.00%)
    1 / 517 (0.19%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 346 (0.29%)
    2 / 517 (0.39%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Peripheral vascular disorder
         subjects affected / exposed
    0 / 346 (0.00%)
    1 / 517 (0.19%)
    1 / 171 (0.58%)
         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
    Peripheral swelling
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Chest pain
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Generalised oedema
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Oedema peripheral
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Sudden death
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 346 (0.29%)
    2 / 517 (0.39%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Dyspnoea
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Interstitial lung disease
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    1 / 346 (0.29%)
    2 / 517 (0.39%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Pulmonary oedema
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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 failure
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Investigations
    Blood potassium increased
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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 glucose increased
         subjects affected / exposed
    0 / 346 (0.00%)
    1 / 517 (0.19%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Ankle fracture
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Anastomotic ulcer haemorrhage
         subjects affected / exposed
    0 / 346 (0.00%)
    1 / 517 (0.19%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Forearm fracture
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Contusion
         subjects affected / exposed
    0 / 346 (0.00%)
    1 / 517 (0.19%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    2 / 346 (0.58%)
    2 / 517 (0.39%)
    0 / 171 (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
    Cataract operation complication - Fellow eye
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Rib fracture
         subjects affected / exposed
    2 / 346 (0.58%)
    2 / 517 (0.39%)
    0 / 171 (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
    Postoperative ileus
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Post-traumatic neck syndrome
         subjects affected / exposed
    0 / 346 (0.00%)
    1 / 517 (0.19%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Acute coronary syndrome
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Acute left ventricular failure
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Acute myocardial infarction
         subjects affected / exposed
    1 / 346 (0.29%)
    2 / 517 (0.39%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    2 / 346 (0.58%)
    2 / 517 (0.39%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    4 / 346 (1.16%)
    4 / 517 (0.77%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    3 / 346 (0.87%)
    4 / 517 (0.77%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    Cardiac arrest
         subjects affected / exposed
    0 / 346 (0.00%)
    1 / 517 (0.19%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    3 / 346 (0.87%)
    4 / 517 (0.77%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 346 (0.00%)
    1 / 517 (0.19%)
    1 / 171 (0.58%)
         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
    3 / 346 (0.87%)
    4 / 517 (0.77%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    2 / 346 (0.58%)
    3 / 517 (0.58%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 346 (0.00%)
    1 / 517 (0.19%)
    1 / 171 (0.58%)
         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
    6 / 346 (1.73%)
    12 / 517 (2.32%)
    6 / 171 (3.51%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 12
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Lacunar stroke
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Ischaemic stroke
         subjects affected / exposed
    1 / 346 (0.29%)
    2 / 517 (0.39%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Thrombotic stroke
         subjects affected / exposed
    0 / 346 (0.00%)
    1 / 517 (0.19%)
    1 / 171 (0.58%)
         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 / 346 (0.29%)
    2 / 517 (0.39%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Hypochromic anaemia
         subjects affected / exposed
    0 / 346 (0.00%)
    1 / 517 (0.19%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 346 (0.29%)
    2 / 517 (0.39%)
    1 / 171 (0.58%)
         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
    Vertigo
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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 / 346 (0.00%)
    1 / 517 (0.19%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic retinopathy - Fellow eye
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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 subcapsular - Study eye
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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 vasculitis - Study eye
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Vitreous haemorrhage - Study eye
         subjects affected / exposed
    2 / 346 (0.58%)
    2 / 517 (0.39%)
    0 / 171 (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
    Vitreous haemorrhage - Fellow eye
         subjects affected / exposed
    2 / 346 (0.58%)
    2 / 517 (0.39%)
    0 / 171 (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
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 346 (0.00%)
    1 / 517 (0.19%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic gastroparesis
         subjects affected / exposed
    0 / 346 (0.00%)
    1 / 517 (0.19%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Vomiting
         subjects affected / exposed
    0 / 346 (0.00%)
    1 / 517 (0.19%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Liver disorder
         subjects affected / exposed
    0 / 346 (0.00%)
    1 / 517 (0.19%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Cholecystitis
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    0 / 346 (0.00%)
    1 / 517 (0.19%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic wound
         subjects affected / exposed
    0 / 346 (0.00%)
    1 / 517 (0.19%)
    1 / 171 (0.58%)
         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
    Acute kidney injury
         subjects affected / exposed
    4 / 346 (1.16%)
    5 / 517 (0.97%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 346 (0.58%)
    2 / 517 (0.39%)
    0 / 171 (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
    Renal colic
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Hydronephrosis
         subjects affected / exposed
    0 / 346 (0.00%)
    1 / 517 (0.19%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Renal impairment
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Chronic kidney disease
         subjects affected / exposed
    3 / 346 (0.87%)
    3 / 517 (0.58%)
    0 / 171 (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
    Renal mass
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Pathological fracture
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Abscess bacterial
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Bronchitis viral
         subjects affected / exposed
    0 / 346 (0.00%)
    1 / 517 (0.19%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 346 (0.00%)
    1 / 517 (0.19%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    COVID-19
         subjects affected / exposed
    8 / 346 (2.31%)
    9 / 517 (1.74%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 9
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 3
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    4 / 346 (1.16%)
    4 / 517 (0.77%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 346 (0.87%)
    3 / 517 (0.58%)
    0 / 171 (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
    Chest wall abscess
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Cholecystitis infective
         subjects affected / exposed
    0 / 346 (0.00%)
    1 / 517 (0.19%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 346 (0.00%)
    1 / 517 (0.19%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Diabetic foot infection
         subjects affected / exposed
    1 / 346 (0.29%)
    3 / 517 (0.58%)
    2 / 171 (1.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    2 / 346 (0.58%)
    3 / 517 (0.58%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic gangrene
         subjects affected / exposed
    0 / 346 (0.00%)
    1 / 517 (0.19%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Lymphangitis
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Osteomyelitis
         subjects affected / exposed
    3 / 346 (0.87%)
    5 / 517 (0.97%)
    2 / 171 (1.17%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 346 (0.87%)
    5 / 517 (0.97%)
    2 / 171 (1.17%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Sepsis
         subjects affected / exposed
    2 / 346 (0.58%)
    3 / 517 (0.58%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Subcutaneous abscess
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Urinary tract infection
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Wound infection staphylococcal
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    Fluid retention
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 346 (0.29%)
    2 / 517 (0.39%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 346 (0.00%)
    1 / 517 (0.19%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 346 (0.29%)
    1 / 517 (0.19%)
    0 / 171 (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
    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
    144 / 346 (41.62%)
    236 / 517 (45.65%)
    92 / 171 (53.80%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    18 / 346 (5.20%)
    31 / 517 (6.00%)
    13 / 171 (7.60%)
         occurrences all number
    19
    32
    13
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    3 / 346 (0.87%)
    7 / 517 (1.35%)
    4 / 171 (2.34%)
         occurrences all number
    3
    7
    4
    Pyrexia
         subjects affected / exposed
    4 / 346 (1.16%)
    8 / 517 (1.55%)
    4 / 171 (2.34%)
         occurrences all number
    6
    10
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 346 (0.87%)
    12 / 517 (2.32%)
    9 / 171 (5.26%)
         occurrences all number
    4
    13
    9
    Investigations
    Blood pressure increased
         subjects affected / exposed
    7 / 346 (2.02%)
    12 / 517 (2.32%)
    5 / 171 (2.92%)
         occurrences all number
    7
    12
    5
    Blood creatinine increased
         subjects affected / exposed
    4 / 346 (1.16%)
    11 / 517 (2.13%)
    7 / 171 (4.09%)
         occurrences all number
    4
    11
    7
    Injury, poisoning and procedural complications
    Corneal abrasion - Study eye
         subjects affected / exposed
    0 / 346 (0.00%)
    5 / 517 (0.97%)
    5 / 171 (2.92%)
         occurrences all number
    0
    5
    5
    Fall
         subjects affected / exposed
    9 / 346 (2.60%)
    13 / 517 (2.51%)
    4 / 171 (2.34%)
         occurrences all number
    10
    14
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 346 (0.87%)
    10 / 517 (1.93%)
    7 / 171 (4.09%)
         occurrences all number
    3
    11
    8
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 346 (2.31%)
    12 / 517 (2.32%)
    4 / 171 (2.34%)
         occurrences all number
    8
    12
    4
    Eye disorders
    Cataract - Fellow eye
         subjects affected / exposed
    6 / 346 (1.73%)
    10 / 517 (1.93%)
    4 / 171 (2.34%)
         occurrences all number
    6
    10
    4
    Cataract - Study eye
         subjects affected / exposed
    9 / 346 (2.60%)
    15 / 517 (2.90%)
    6 / 171 (3.51%)
         occurrences all number
    9
    15
    6
    Conjunctival haemorrhage - Fellow eye
         subjects affected / exposed
    4 / 346 (1.16%)
    9 / 517 (1.74%)
    5 / 171 (2.92%)
         occurrences all number
    4
    10
    6
    Conjunctival haemorrhage - Study eye
         subjects affected / exposed
    9 / 346 (2.60%)
    16 / 517 (3.09%)
    7 / 171 (4.09%)
         occurrences all number
    10
    20
    10
    Diabetic retinal oedema - Fellow eye
         subjects affected / exposed
    10 / 346 (2.89%)
    17 / 517 (3.29%)
    7 / 171 (4.09%)
         occurrences all number
    10
    17
    7
    Diabetic retinal oedema - Study eye
         subjects affected / exposed
    0 / 346 (0.00%)
    4 / 517 (0.77%)
    4 / 171 (2.34%)
         occurrences all number
    0
    4
    4
    Dry eye - Fellow eye
         subjects affected / exposed
    6 / 346 (1.73%)
    12 / 517 (2.32%)
    6 / 171 (3.51%)
         occurrences all number
    6
    12
    6
    Dry eye - Study eye
         subjects affected / exposed
    7 / 346 (2.02%)
    11 / 517 (2.13%)
    4 / 171 (2.34%)
         occurrences all number
    7
    11
    4
    Eye pain - Fellow eye
         subjects affected / exposed
    3 / 346 (0.87%)
    7 / 517 (1.35%)
    4 / 171 (2.34%)
         occurrences all number
    3
    7
    4
    Vitreous detachment - Study eye
         subjects affected / exposed
    10 / 346 (2.89%)
    17 / 517 (3.29%)
    7 / 171 (4.09%)
         occurrences all number
    10
    17
    7
    Uveitis - Study eye
         subjects affected / exposed
    8 / 346 (2.31%)
    9 / 517 (1.74%)
    1 / 171 (0.58%)
         occurrences all number
    9
    10
    1
    Punctate keratitis - Study eye
         subjects affected / exposed
    9 / 346 (2.60%)
    11 / 517 (2.13%)
    2 / 171 (1.17%)
         occurrences all number
    12
    15
    3
    Eye pain - Study eye
         subjects affected / exposed
    6 / 346 (1.73%)
    11 / 517 (2.13%)
    5 / 171 (2.92%)
         occurrences all number
    6
    11
    5
    Vitreous floaters - Study eye
         subjects affected / exposed
    8 / 346 (2.31%)
    13 / 517 (2.51%)
    5 / 171 (2.92%)
         occurrences all number
    8
    13
    5
    Vitreous haemorrhage - Fellow eye
         subjects affected / exposed
    10 / 346 (2.89%)
    14 / 517 (2.71%)
    4 / 171 (2.34%)
         occurrences all number
    11
    15
    4
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 346 (0.87%)
    7 / 517 (1.35%)
    4 / 171 (2.34%)
         occurrences all number
    3
    8
    5
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    8 / 346 (2.31%)
    12 / 517 (2.32%)
    4 / 171 (2.34%)
         occurrences all number
    9
    13
    4
    Chronic kidney disease
         subjects affected / exposed
    8 / 346 (2.31%)
    12 / 517 (2.32%)
    4 / 171 (2.34%)
         occurrences all number
    9
    13
    4
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 346 (0.87%)
    7 / 517 (1.35%)
    4 / 171 (2.34%)
         occurrences all number
    3
    7
    4
    Infections and infestations
    COVID-19
         subjects affected / exposed
    11 / 346 (3.18%)
    22 / 517 (4.26%)
    11 / 171 (6.43%)
         occurrences all number
    12
    23
    11
    Cellulitis
         subjects affected / exposed
    7 / 346 (2.02%)
    11 / 517 (2.13%)
    4 / 171 (2.34%)
         occurrences all number
    8
    12
    4
    Influenza
         subjects affected / exposed
    2 / 346 (0.58%)
    6 / 517 (1.16%)
    4 / 171 (2.34%)
         occurrences all number
    2
    6
    4
    Urinary tract infection
         subjects affected / exposed
    11 / 346 (3.18%)
    13 / 517 (2.51%)
    2 / 171 (1.17%)
         occurrences all number
    12
    14
    2
    Nasopharyngitis
         subjects affected / exposed
    8 / 346 (2.31%)
    14 / 517 (2.71%)
    6 / 171 (3.51%)
         occurrences all number
    8
    14
    6
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    7 / 346 (2.02%)
    7 / 517 (1.35%)
    0 / 171 (0.00%)
         occurrences all number
    7
    7
    0
    Type 2 diabetes mellitus
         subjects affected / exposed
    5 / 346 (1.45%)
    9 / 517 (1.74%)
    4 / 171 (2.34%)
         occurrences all number
    5
    9
    4

    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 was to provide clarification and guidance on safety assessments in accordance with the urgent safety measure regarding the post-marketing reports with brolucizumab (Beovu®) in the treatment of nAMD, which were identified as retinal vasculitis and/or retinal vascular occlusion, typically in the presence of IOI, that could result in severe vision loss. In addition, the amendment included the modifications due to 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.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com for complete trial results.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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