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    Clinical Trial Results:
    56-week, phase IIIb/IV, open-label, one-arm extension study to assess the efficacy and safety of brolucizumab 6 mg in a Treat-to-Control regimen with maximum treatment intervals up to 20 weeks for the treatment of subjects with neovascular age-related macular degeneration who have completed the CRTH258A2303 (TALON) study

    Summary
    EudraCT number
    		 2020-002349-40
    Trial protocol
    		 NL   PT   CZ   SE   BE   DE   IT  
    Global end of trial date
    28 Mar 2023

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

    Trial information

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    Trial identification
    Sponsor protocol code
    CRTH258A2303E1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04597632
    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
    28 Mar 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Mar 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the extended durability of brolucizumab in a treat-to-control (TtC) regimen with respect to the duration of treatment intervals at Week 56. To evaluate the functional outcomes of brolucizumab in a TtC regimen with respect to average change in best-corrected visual acuity (BCVA) at Week 52 and Week 56.
    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
    16 Dec 2020
    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
    Australia: 16
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Czechia: 25
    Country: Number of subjects enrolled
    France: 62
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Israel: 12
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Malaysia: 4
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Portugal: 7
    Country: Number of subjects enrolled
    Korea, Republic of: 42
    Country: Number of subjects enrolled
    Spain: 36
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    Taiwan: 13
    Country: Number of subjects enrolled
    United States: 10
    Worldwide total number of subjects
    248
    EEA total number of subjects
    149
    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)
    14
    From 65 to 84 years
    199
    85 years and over
    35

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 There were 248 participants who were treated in this trial.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 brolucizumab 6 mg (Extension study total)
    Arm description
    		 Participants received brolucizumab 6 mg/0.05 mL solution by intravitreal injection in a Treat-to-Control regimen with injection intervals from 4 up to 20 weeks. Intervals could have changed in steps of 4 weeks at a time per investigators' decisions determined by the disease activity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    brolucizumab
    Investigational medicinal product code
    RTH258
    Other name
    Beovu
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    brolucizumab 6 mg that was administered via intravitreal treatment (IVT) injection. This was a Treat-to-Control regimen with injection intervals from 4 up to 20 weeks. Intervals could have changed in steps of 4 weeks at a time per investigators' decisions determined by the disease activity.

    Number of subjects in period 1
    		brolucizumab 6 mg (Extension study total)
    Started
    248
    Completed
    231
    Not completed
    17
         Adverse event, serious fatal
    1
         Consent withdrawn by subject
    10
         Adverse event, non-fatal
    5
         Lost to follow-up
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    brolucizumab 6 mg (Extension study total)
    Reporting group description
    		 Participants received brolucizumab 6 mg/0.05 mL solution by intravitreal injection in a Treat-to-Control regimen with injection intervals from 4 up to 20 weeks. Intervals could have changed in steps of 4 weeks at a time per investigators' decisions determined by the disease activity.

    Reporting group values
    		 brolucizumab 6 mg (Extension study total) Total
    Number of subjects
    		 248 248
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 14 14
        From 65-84 years
    		 199 199
        85 years and over
    		 35 35
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 75.9 ± 7.90 -
    Sex: Female, Male
    Units: Participants
        Female
    		 129 129
        Male
    		 119 119
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0
        Asian
    		 61 61
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Black or African American
    		 0 0
        White
    		 187 187
        More than one race
    		 0 0
        Unknown or Not Reported
    		 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 23 23
        Not Hispanic or Latino
    		 219 219
        Unknown or Not Reported
    		 6 6

    End points

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    End points reporting groups
    Reporting group title
    brolucizumab 6 mg (Extension study total)
    Reporting group description
    		 Participants received brolucizumab 6 mg/0.05 mL solution by intravitreal injection in a Treat-to-Control regimen with injection intervals from 4 up to 20 weeks. Intervals could have changed in steps of 4 weeks at a time per investigators' decisions determined by the disease activity.

    Subject analysis set title
    brolucizumab 6 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received brolucizumab 6 mg/0.05 mL solution by intravitreal injection in a Treat-to-Control regimen with injection intervals from 4 up to 20 weeks. Intervals could have changed in steps of 4 weeks at a time per investigators' decisions determined by the disease activity.

    Subject analysis set title
    Brolucizumab 6 mg (Core Study)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients who received brolucizumab 6 mg in the core study and continued with the same treatment in the extension study

    Subject analysis set title
    Aflibercept 2 mg (Core Study)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients who received aflibercept 2 mg in the core study and switched to brolucizumab 6 mg in the extension study

    Subject analysis set title
    brolucizumab 6 mg (Extension study total)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received brolucizumab 6 mg/0.05 mL solution by intravitreal injection in a Treat-to-Control regimen with injection intervals from 4 up to 20 weeks. Intervals could have changed in steps of 4 weeks at a time per investigators' decisions determined by the disease activity.

    Subject analysis set title
    Brolucizumab 6 mg (Core Study)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients who received brolucizumab 6 mg in the core study and continued with the same treatment in the extension study

    Subject analysis set title
    Aflibercept 2 mg (Core Study)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients who received aflibercept 2 mg in the core study and switched to brolucizumab 6 mg in the extension study

    Subject analysis set title
    brolucizumab 6 mg (Extension study total)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received brolucizumab 6 mg/0.05 mL solution by intravitreal injection in a Treat-to-Control regimen with injection intervals from 4 up to 20 weeks. Intervals could have changed in steps of 4 weeks at a time per investigators' decisions determined by the disease activity.

    Subject analysis set title
    Brolucizumab 6 mg (Core Study)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients who received brolucizumab 6 mg in the core study and continued with the same treatment in the extension study

    Subject analysis set title
    Aflibercept 2 mg (Core Study)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients who received aflibercept 2 mg in the core study and switched to brolucizumab 6 mg in the extension study

    Subject analysis set title
    brolucizumab 6 mg (Extension study total)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received brolucizumab 6 mg/0.05 mL solution by intravitreal injection in a Treat-to-Control regimen with injection intervals from 4 up to 20 weeks. Intervals could have changed in steps of 4 weeks at a time per investigators' decisions determined by the disease activity.

    Subject analysis set title
    Brolucizumab 6 mg (Core Study)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients who received brolucizumab 6 mg in the core study and continued with the same treatment in the extension study

    Subject analysis set title
    Aflibercept 2 mg (Core Study)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients who received aflibercept 2 mg in the core study and switched to brolucizumab 6 mg in the extension study

    Subject analysis set title
    brolucizumab 6 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received brolucizumab 6 mg/0.05 mL solution by intravitreal injection in a Treat-to-Control regimen with injection intervals from 4 up to 20 weeks. Intervals could have changed in steps of 4 weeks at a time per investigators' decisions determined by the disease activity.

    Primary: Duration of the last interval with no disease activity up to Week 56 - study eye

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    End point title
    		 Duration of the last interval with no disease activity up to Week 56 - study eye [1]
    End point description
    Number of subjects in every 4 weeks (q4w), every 8 weeks (q8w), every 12 weeks (q12w) and every 20 weeks (q20w) intervals at last interval with no disease activity up to Week 56. Last interval with no disease activity (number of weeks): Number of subjects at 20/16/12/8/4-weeks intervals up to Week 56 for the study eye in the extension study
    End point type
    Primary
    End point timeframe
    Up to Week 56
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Not applicable for a single arm study (for this extension study).
    End point values
    		 brolucizumab 6 mg
    Number of subjects analysed
    237
    Units: Participants
        20 weeks
    68
        16 weeks
    59
        12 weeks
    47
        8 weeks
    49
        4 weeks
    14
    No statistical analyses for this end point

    Primary: Average change in BCVA from baseline to Week 52 and Week 56 for the study eye

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    End point title
    		 Average change in BCVA from baseline to Week 52 and Week 56 for the study eye [2]
    End point description
    Best-Corrected Visual Acuity (BCVA) was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. Visual Function of the study eye was assessed using the ETDRS protocol. Min and max possible scores are 0-100 respectively. A higher score represents better visual functioning. The average change in BCVA from Baseline of the extension study at Week 52 and Week 56 was estimated by an analysis of variance (ANOVA) with baseline age categories, baseline BCVA categories and treatment arm in the core study included as fixed effects. Last observation carried forward (LOCF) was used to impute missing BCVA values.
    End point type
    Primary
    End point timeframe
    Extension study baseline, average of Week 52 and Week 56
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Not applicable for a single arm study (for this extension study).
    End point values
    		 Brolucizumab 6 mg (Core Study) Aflibercept 2 mg (Core Study) brolucizumab 6 mg (Extension study total)
    Number of subjects analysed
    135
    113
    248
    Units: Letters read
        arithmetic mean (standard deviation)
    -1.8 ± 8.29
    -2.9 ± 7.33
    -2.3 ± 7.88
    No statistical analyses for this end point

    Secondary: Average change in central subfield thickness (CSFT) from baseline to Week 52 and Week 56 - study eye

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    End point title
    		 Average change in central subfield thickness (CSFT) from baseline to Week 52 and Week 56 - study eye
    End point description
    Central Subfield Thickness (μm): Analysis of Variance (ANOVA) results for the average change from extension study Baseline at Week 52 and Week 56 for the study eye in the extension study by core study treatment arm. Central Subfield Thickness was assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center.
    End point type
    Secondary
    End point timeframe
    Extension study baseline, average of Week 52 and Week 56
    End point values
    		 Brolucizumab 6 mg (Core Study) Aflibercept 2 mg (Core Study) brolucizumab 6 mg (Extension study total)
    Number of subjects analysed
    105
    89
    194
    Units: μm
        arithmetic mean (standard deviation)
    5.9 ± 24.43
    -14.1 ± 60.67
    -3.3 ± 45.83
    No statistical analyses for this end point

    Secondary: Number (%) of subjects with presence of IRF and/or SRF, and sub-RPE fluid in the study eye at Week 52 and Week 56 overall and by core study treatment arm

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    End point title
    		 Number (%) of subjects with presence of IRF and/or SRF, and sub-RPE fluid in the study eye at Week 52 and Week 56 overall and by core study treatment arm
    End point description
    Intraretinal Fluid (IRF) and Subretinal Fluid (SRF) status in the central subfield as assessed by Spectral Domain Ocular Coherence Tomography (SD-OCT): Number (%) of subjects with presence of IRF and/or SRF, and sub-Retinal Pigment Epithelium (RPE) fluid in the study eye at Week 52 and Week 56 overall and by core study treatment arm
    End point type
    Secondary
    End point timeframe
    Weeks 52 and 56
    End point values
    		 Brolucizumab 6 mg (Core Study) Aflibercept 2 mg (Core Study) brolucizumab 6 mg (Extension study total)
    Number of subjects analysed
    106
    94
    200
    Units: Participants
        Week 52 IRF assessment - Present (n=103,90,193)
    10
    14
    24
        Week 52 IRF assessment - Absent (n=103,90,193)
    93
    76
    169
        Week 52 SRF assessment - Present (n=103,90,193)
    14
    9
    23
        Week 52 SRF assessment - Absent (n=103,90,193)
    89
    81
    170
        Week 52 Sub-RPE fluid - Present (n=103,90,193)
    52
    44
    96
        Week 52 Sub-RPE fluid - Absent (n=103,90,193)
    51
    46
    97
        Week 52 IRF and/or SRF - Present (n=103,90,193)
    23
    22
    45
        Week 52 IRF and/or SRF - Absent (n=103,90,193)
    102
    89
    191
        Week 52 IRF and SRF - Present (n=103,90,193)
    1
    1
    2
        Week 52 IRF and SRF - Absent (n=103,90,193)
    80
    68
    148
        Week 56 IRF assessment - Present
    13
    12
    25
        Week 56 IRF assessment - Absent
    93
    82
    175
        Week 56 SRF assessment - Present
    11
    7
    18
        Week 56 SRF assessment - Absent
    95
    87
    182
        Week 56 Sub-RPE fluid - Present
    51
    49
    100
        Week 56 Sub-RPE fluid - Absent
    55
    45
    100
        Week 56 IRF and/or SRF - Present
    23
    17
    40
        Week 56 IRF and/or SRF - Absent
    105
    92
    197
        Week 56 IRF and SRF - Present
    1
    2
    3
        Week 56 IRF and SRF - Absent
    83
    77
    160
    No statistical analyses for this end point

    Secondary: Last interval with no disease activity (number of weeks): Number (%) of subjects at 20/16/12/8/4-weeks intervals up to Week 56 for the study eye in the Extension Study by core study randomized treatment arm

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    End point title
    		 Last interval with no disease activity (number of weeks): Number (%) of subjects at 20/16/12/8/4-weeks intervals up to Week 56 for the study eye in the Extension Study by core study randomized treatment arm
    End point description
    Duration of the last interval with no disease activity up to Week 52 by core study treatment arm.
    End point type
    Secondary
    End point timeframe
    up to Week 56
    End point values
    		 Brolucizumab 6 mg (Core Study) Aflibercept 2 mg (Core Study)
    Number of subjects analysed
    130
    107
    Units: Participants
        20 Weeks
    49
    19
        16 Weeks
    29
    30
        12 Weeks
    21
    26
        8 Weeks
    23
    26
        4 Weeks
    8
    6
    No statistical analyses for this end point

    Secondary: Maximal interval with no disease activity (number of weeks): Number (%) of subjects at 20/16/12/8/4-weeks intervals up to Week 56 for the study eye in the extension study

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    End point title
    		 Maximal interval with no disease activity (number of weeks): Number (%) of subjects at 20/16/12/8/4-weeks intervals up to Week 56 for the study eye in the extension study
    End point description
    Duration of the maximal intervals with no disease activity up to Week 52 by core study treatment arm.
    End point type
    Secondary
    End point timeframe
    up to Week 56
    End point values
    		 Brolucizumab 6 mg (Core Study) Aflibercept 2 mg (Core Study)
    Number of subjects analysed
    130
    107
    Units: Participants
        20 Weeks
    54
    20
        16 Weeks
    28
    31
        12 Weeks
    23
    34
        8 Weeks
    22
    18
        4 Weeks
    3
    4
    No statistical analyses for this end point

    Secondary: Number (%) of subjects with change in duration of last interval with no disease activity between Baseline of the extension study and Week 56 by core study treatment arm

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    End point title
    		 Number (%) of subjects with change in duration of last interval with no disease activity between Baseline of the extension study and Week 56 by core study treatment arm
    End point description
    Change in last interval with no disease activity
    End point type
    Secondary
    End point timeframe
    Extension study baseline, up to Week 56
    End point values
    		 Brolucizumab 6 mg (Core Study) Aflibercept 2 mg (Core Study)
    Number of subjects analysed
    130
    107
    Units: Participants
        16 Weeks
    0
    2
        12 Weeks
    8
    5
        8 Weeks
    21
    32
        4 Weeks
    49
    28
        0 Weeks
    41
    31
        - 4 Weeks
    8
    7
        -8 Weeks
    2
    2
        -12 Weeks
    1
    0
    No statistical analyses for this end point

    Secondary: Treatment-emergent ocular adverse events (greater than or equal to 1.0%) by preferred term for the study eye

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    End point title
    		 Treatment-emergent ocular adverse events (greater than or equal to 1.0%) by preferred term for the study eye
    End point description
    An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study.
    End point type
    Secondary
    End point timeframe
    Adverse events are reported from the first dose of study-drug until the end of treatment at week 52, plus 4 weeks safety follow-up, for a maximum timeframe of approximately 56 weeks.
    End point values
    		 brolucizumab 6 mg
    Number of subjects analysed
    248
    Units: Participants
        Number of subjects with at least one AE
    63
        Cataract
    9
        Eye pain
    6
        Visual acuity reduced
    6
        Intraocular pressure increased
    5
        Retinal haemorrhage
    4
        Ocular discomfort
    3
        Vitreous floaters
    3
    No statistical analyses for this end point

    Secondary: Treatment-emergent non-ocular adverse events (greater than or equal to 2%) by preferred term

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    End point title
    		 Treatment-emergent non-ocular adverse events (greater than or equal to 2%) by preferred term
    End point description
    An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study.
    End point type
    Secondary
    End point timeframe
    Adverse events are reported from the first dose of study-drug until the end of treatment at week 52, plus 4 weeks safety follow-up, for a maximum timeframe of approximately 56 weeks.
    End point values
    		 brolucizumab 6 mg
    Number of subjects analysed
    248
    Units: Participants
        Number of subjects with at least one AE
    82
        COVID-19
    10
        Nasopharyngitis
    8
        Fall
    7
        Basal cell carcinoma
    5
    No statistical analyses for this end point

    Post-hoc: All Collected Deaths

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    End point title
    		 All Collected Deaths
    End point description
    On treatment death monitoring occurred after the first dose of study drug in the extension study until 30 days after the last administration of study drug for a maximum timeframe of approximately 56 weeks. Post-treatment death monitoring occurred greater than 30 days after the last administration of study drug.
    End point type
    Post-hoc
    End point timeframe
    On-treatment death reporting - from first dose until 30 days after last dose for a maximum timeframe of approximately 56 weeks. Post-treatment death reporting - greater than 30 days after the last dose of study drug.
    End point values
    		 brolucizumab 6 mg
    Number of subjects analysed
    248
    Units: Participants
        On-treatment Deaths
    0
        Post-treatment Deaths
    1
        Total Deaths
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are reported from the first dose of study-drug until the end of the treatment period (at Week 208) plus 16 weeks additional follow up reporting, for a maximum timeframe of approximately 224 weeks.
    Adverse event reporting additional description
    Treatment emergent adverse events in this study are events that started after the first dose of study treatment and until 84 days after the last study treatment, or events present prior to the first dose of treatment which increased in severity based on preferred term within 84 days after the last study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Brolucizumab 6mg
    Reporting group description
    		 Brolucizumab 6mg

    Serious adverse events
    		 Brolucizumab 6mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    26 / 248 (10.48%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    5 / 248 (2.02%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Spinal compression fracture
         subjects affected / exposed
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fall
         subjects affected / exposed
    2 / 248 (0.81%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Procedural vomiting
         subjects affected / exposed
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Meniscus injury
         subjects affected / exposed
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 248 (0.81%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Retinal detachment - Fellow eye
         subjects affected / exposed
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Retinal occlusive vasculitis - Study eye
         subjects affected / exposed
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vitreal cells - Study eye
         subjects affected / exposed
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vitreal cells - Fellow eye
         subjects affected / exposed
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Uveitis - Study eye
         subjects affected / exposed
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Inguinal hernia
         subjects affected / exposed
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory arrest
         subjects affected / exposed
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Chondropathy
         subjects affected / exposed
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Whipple's disease
         subjects affected / exposed
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Brolucizumab 6mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    58 / 248 (23.39%)
    Investigations
    Intraocular pressure increased - Study eye
         subjects affected / exposed
    5 / 248 (2.02%)
         occurrences all number
    6
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    7 / 248 (2.82%)
         occurrences all number
    7
    Eye disorders
    Cataract - Fellow eye
         subjects affected / exposed
    7 / 248 (2.82%)
         occurrences all number
    7
    Cataract - Study eye
         subjects affected / exposed
    9 / 248 (3.63%)
         occurrences all number
    9
    Eye pain - Study eye
         subjects affected / exposed
    6 / 248 (2.42%)
         occurrences all number
    6
    Neovascular age-related macular degeneration - Fellow eye
         subjects affected / exposed
    10 / 248 (4.03%)
         occurrences all number
    10
    Visual acuity reduced - Study eye
         subjects affected / exposed
    6 / 248 (2.42%)
         occurrences all number
    6
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    8 / 248 (3.23%)
         occurrences all number
    8
    COVID-19
         subjects affected / exposed
    10 / 248 (4.03%)
         occurrences all number
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Aug 2021
    To provide clarification and guidance on the early discontinuation of study treatment that was required for those subjects who were currently on q4w dosing beyond the first 3 monthly loading doses (“loading phase”) or would need q4w dosing beyond the “loading phase” based on the Investigator’s assessment. This was as per the USM dated 27-May-2021 (based on CTH258AUS04 (MERLIN) Year 1 first interpretable results (FIR) indicating a higher frequency of intraocular inflammation (IOI) including retinal vasculitis (RV), and retinal vascular occlusion (RO) in brolucizumab 6 mg q4w when compared to aflibercept 2 mg q4w (IOI: 9.3% vs 4.5% of which RV: 0.8% vs 0.0%; RO: 2.0% vs 0.0%, respectively). To provide clarification and guidance on the early discontinuation of study treatment that was required for those subjects with RV and RO events. This was as per the USM dated 10-Aug-2021 (based on the results of the mechanistic study BASICHR0049 which identified a causal link with an immune-mediated mechanism of the previously identified risk of RV and/or RO, typically in the presence of IOI). To update safety sections throughout the protocol including updates to the Risks and Benefits section and the creation of a new section under Safety Monitoring which consolidated all risk mitigation information into one section of the protocol.
    20 Oct 2021
    The main purpose of this amendment was to reduce the sample size for this study. The initial sample size calculation for this open-label, one-arm extension study was mainly based on the assumption that all eligible subjects completing the core study could be enrolled. Following the USM dated 27-May-2021, subjects requiring study treatment every 4 weeks were discontinued, therefore, the originally planned number of subjects transitioning from the core study into the extension study was reduced. Consequently, the sample size was re-assessed with the focus on the estimation of subjects who would be on a q20w interval. This estimation could be achieved with acceptable precision with a sample size of 250. The study objectives were still assessed with the revised sample size. In addition, information was included on the gender imbalance in the reported rates of IOI-related adverse events following brolucizumab treatment.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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