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    Clinical Trial Results:
    A Prospective, Randomized, Double-masked, Active Comparator-controlled, Multi-center, Two-arm, Phase 3 Study to Evaluate the Efficacy and Safety of Intravitreal KSI-301 Compared with Intravitreal Aflibercept in Participants with Visual Impairment Due to Treatment-naïve Macular Edema Secondary to Retinal Vein Occlusion (RVO)

    Summary
    EudraCT number
    		 2020-001061-37
    Trial protocol
    		 LV   DE   SK   CZ   FR   HU   IT  
    Global end of trial date
    19 Jan 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jul 2024
    First version publication date
    13 Jul 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    KS301P103
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04592419
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Kodiak Sciences Inc.
    Sponsor organisation address
    1200 Page Mill Road, Palo Alto, CA, United States, 94304
    Public contact
    KSI-CL-103 Trial Information , Kodiak Sciences Inc., ksi301clinical@kodiak.com
    Scientific contact
    KSI-CL-103 Trial Information , Kodiak Sciences Inc., ksi301clinical@kodiak.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
    17 Apr 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Jun 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jan 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To demonstrate that KSI-301 5 mg administered every 8 weeks after 2 monthly doses is non-inferior to aflibercept 2 mg monthly with respect to mean change in BCVA from Day 1 to Week 24.
    Protection of trial subjects
    The study followed the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All local regulatory requirements pertinent to safety of trial subjects were followed during the conduct of the trial. At the Investigator's discretion, treatment with pan-retinal photocoagulation laser.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Sep 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Israel: 13
    Country: Number of subjects enrolled
    Spain: 31
    Country: Number of subjects enrolled
    United States: 386
    Country: Number of subjects enrolled
    Poland: 38
    Country: Number of subjects enrolled
    Slovakia: 15
    Country: Number of subjects enrolled
    Czechia: 4
    Country: Number of subjects enrolled
    France: 21
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    Hungary: 16
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Latvia: 22
    Worldwide total number of subjects
    568
    EEA total number of subjects
    169
    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)
    268
    From 65 to 84 years
    271
    85 years and over
    29

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants were recruited from 138 sites in 11 countries.

    Pre-assignment
    Screening details
    		 The study comprised a screening period of 21 days.

    Period 1
    Period 1 title
    Primary study period (Day 1 to Week 48)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 KSI-301 5 mg
    Arm description
    		 Intravitreal injection of KSI-301 (5 mg) at Day 1, Week 4, and once every 8 weeks through Week 20 followed by an individualized dosing regimen of intravitreal injection of KSI-301 (5 mg) from Week 24 to Week 44. In the Extension Phase, participants randomized to KSI-301 (5 mg) in the Primary Study will continue to receive KSI-301 (5 mg) based on protocol-defined disease activity criteria. Sham Procedure: The sham is a procedure that mimics an intravitreal injection. It involves pressing the blunt end of an empty syringe (without a needle) against the anesthetized eye. It will be administered to participants in both treatments arms at applicable visits to maintain masking.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tarcocimab tedromer
    Investigational medicinal product code
    KSI-301
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    5 mg via intravitreal injection

    Arm title
    		 Aflibercept 2 mg
    Arm description
    		 Intravitreal injection of aflibercept (2 mg) once every 4 through Week 20 followed by an individualized dosing regimen of Intravitreal injection of Aflibercept (2 mg) once every 4 weeks from Week 24 to Week 44. In the Extension Phase, participants randomized to aflibercept in the Primary Study will cross over to treatment with KSI-301 (5 mg). They will receive their first dose of KSI-301 (5 mg) at Week 48 and will receive additional treatment with KSI-301 (5 mg) based on protocol-defined disease activity criteria. Sham Procedure: The sham is a procedure that mimics an intravitreal injection. It involves pressing the blunt end of an empty syringe (without a needle) against the anesthetized eye. It will be administered to participants in both treatments arms at applicable visits to maintain masking.
    Arm type
    		 Active comparator

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

    Number of subjects in period 1
    		KSI-301 5 mg Aflibercept 2 mg
    Started
    284
    284
    Completed
    255
    255
    Not completed
    29
    29
         Adverse event, serious fatal
    3
    1
         Consent withdrawn by subject
    7
    13
         Non-compliance with study schedule
    -
    1
         Adverse event, non-fatal
    7
    2
         Participant moved cities with no available site
    -
    1
         Sponsor request
    4
    5
         Participant left the country
    2
    -
         Lost to follow-up
    5
    5
         Progressive disease
    1
    1
    Period 2
    Period 2 title
    Open label extension (Week 48 to 76)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 KSI-301 5 mg
    Arm description
    		 KSI-301 5 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tarcocimab tedromer
    Investigational medicinal product code
    KSI-301
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    5 mg via intravitreal injection

    Arm title
    		 Aflibercept 2 mg
    Arm description
    		 Aflibercept 2 mg
    Arm type
    		 Active comparator

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

    Number of subjects in period 2 [1]
    		KSI-301 5 mg Aflibercept 2 mg
    Started
    216
    228
    Completed
    135
    130
    Not completed
    81
    98
         Adverse event, serious fatal
    -
    2
         Consent withdrawn by subject
    5
    7
         Non-compliance with study schedule
    1
    -
         Adverse event, non-fatal
    1
    -
         Sponsor request
    73
    84
         Lost to follow-up
    1
    5
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The original intent of the open label extension was to be an optional period for all patients that completed the primary study period. However, since the open label extension was terminated prior to all patients completing the primary (masked) study period, not all patients were eligible to participate in the extension period in addition to the patients that did not want to participate.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    KSI-301 5 mg
    Reporting group description
    		 Intravitreal injection of KSI-301 (5 mg) at Day 1, Week 4, and once every 8 weeks through Week 20 followed by an individualized dosing regimen of intravitreal injection of KSI-301 (5 mg) from Week 24 to Week 44. In the Extension Phase, participants randomized to KSI-301 (5 mg) in the Primary Study will continue to receive KSI-301 (5 mg) based on protocol-defined disease activity criteria. Sham Procedure: The sham is a procedure that mimics an intravitreal injection. It involves pressing the blunt end of an empty syringe (without a needle) against the anesthetized eye. It will be administered to participants in both treatments arms at applicable visits to maintain masking.

    Reporting group title
    Aflibercept 2 mg
    Reporting group description
    		 Intravitreal injection of aflibercept (2 mg) once every 4 through Week 20 followed by an individualized dosing regimen of Intravitreal injection of Aflibercept (2 mg) once every 4 weeks from Week 24 to Week 44. In the Extension Phase, participants randomized to aflibercept in the Primary Study will cross over to treatment with KSI-301 (5 mg). They will receive their first dose of KSI-301 (5 mg) at Week 48 and will receive additional treatment with KSI-301 (5 mg) based on protocol-defined disease activity criteria. Sham Procedure: The sham is a procedure that mimics an intravitreal injection. It involves pressing the blunt end of an empty syringe (without a needle) against the anesthetized eye. It will be administered to participants in both treatments arms at applicable visits to maintain masking.

    Reporting group values
    		 KSI-301 5 mg Aflibercept 2 mg Total
    Number of subjects
    		 284 284 568
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 126 142 268
        From 65-84 years
    		 144 127 271
        85 years and over
    		 14 15 29
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 66.0 ( 11.76 ) 64.7 ( 11.32 ) -
    Gender categorical
    Units: Subjects
        Female
    		 141 138 279
        Male
    		 143 146 289
    Race/Ethnicity
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1
        Asian
    		 5 5 10
        Black or African American
    		 23 17 40
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        White
    		 240 245 485
        Multiple
    		 1 2 3
        Other
    		 4 3 7
        Missing
    		 11 11 22
    Subject analysis sets

    Subject analysis set title
    All RVO Subtypes
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set is defined as all patients who received any treatment from Day 1 through Week 48.

    Subject analysis sets values
    		 All RVO Subtypes
    Number of subjects
    568
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    268
        From 65-84 years
    271
        85 years and over
    29
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    65.3 ( 11.55 )
    Gender categorical
    Units: Subjects
        Female
    279
        Male
    289
    Race/Ethnicity
    Units: Subjects
        American Indian or Alaska Native
    1
        Asian
    10
        Black or African American
    40
        Native Hawaiian or Other Pacific Islander
    0
        White
    485
        Multiple
    3
        Other
    7
        Missing
    22

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    KSI-301 5 mg
    Reporting group description
    		 Intravitreal injection of KSI-301 (5 mg) at Day 1, Week 4, and once every 8 weeks through Week 20 followed by an individualized dosing regimen of intravitreal injection of KSI-301 (5 mg) from Week 24 to Week 44. In the Extension Phase, participants randomized to KSI-301 (5 mg) in the Primary Study will continue to receive KSI-301 (5 mg) based on protocol-defined disease activity criteria. Sham Procedure: The sham is a procedure that mimics an intravitreal injection. It involves pressing the blunt end of an empty syringe (without a needle) against the anesthetized eye. It will be administered to participants in both treatments arms at applicable visits to maintain masking.

    Reporting group title
    Aflibercept 2 mg
    Reporting group description
    		 Intravitreal injection of aflibercept (2 mg) once every 4 through Week 20 followed by an individualized dosing regimen of Intravitreal injection of Aflibercept (2 mg) once every 4 weeks from Week 24 to Week 44. In the Extension Phase, participants randomized to aflibercept in the Primary Study will cross over to treatment with KSI-301 (5 mg). They will receive their first dose of KSI-301 (5 mg) at Week 48 and will receive additional treatment with KSI-301 (5 mg) based on protocol-defined disease activity criteria. Sham Procedure: The sham is a procedure that mimics an intravitreal injection. It involves pressing the blunt end of an empty syringe (without a needle) against the anesthetized eye. It will be administered to participants in both treatments arms at applicable visits to maintain masking.
    Reporting group title
    KSI-301 5 mg
    Reporting group description
    		 KSI-301 5 mg

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

    Subject analysis set title
    All RVO Subtypes
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set is defined as all patients who received any treatment from Day 1 through Week 48.

    Primary: Mean change in BCVA from Day 1 to Week 24 in BRVO Participants

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    End point title
    		 Mean change in BCVA from Day 1 to Week 24 in BRVO Participants
    End point description
    Best Corrected Visual Acuity (BCVA) as a continuous variable measured at each study visit using the Early Treatment Diabetic Retinopathy Study (ETDRS) BCVA approach.
    End point type
    Primary
    End point timeframe
    Day 1 to Week 24
    End point values
    		 KSI-301 5 mg Aflibercept 2 mg
    Number of subjects analysed
    220
    218
    Units: Letter read
        least squares mean (standard error)
    14.2 ( 0.81 )
    15.6 ( 0.79 )
    Statistical analysis title
    		 Efficacy Analysis 1 (BRVO Participants)
    Statistical analysis description
    Primary Efficacy Analysis 1- Mean Change in BCVA from Baseline to Week 24 (Full Analysis Set - BRVO)
    Comparison groups
    KSI-301 5 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    438
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 = 0.0004 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.4
    Confidence interval
         level
    		 95.02%
         sides
    2-sided
         lower limit
    		 -3.11
         upper limit
    		 0.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.87
    Notes
    [1] - If the lower limit of the two-sided 95.02% CI for the difference between the two means is >-4.5 letters, noninferiority will be demonstrated. If noninferiority is demonstrated in participants with BRVO, a second analysis will assess noninferiority in the ‘All RVO’ (BRVO+CRVO) patients.
    [2] - MMRM model with treatment, visit, treatment × visit interaction, RVO subtype, baseline BCVA, disease duration, and geographical location as covariates.

    Primary: Mean change in BCVA from Day 1 to Week 24 in All RVO Participants

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    End point title
    		 Mean change in BCVA from Day 1 to Week 24 in All RVO Participants
    End point description
    BCVA as a continuous variable measured at each study visit using the Early Treatment Diabetic Retinopathy Study (ETDRS) BCVA approach.
    End point type
    Primary
    End point timeframe
    Day 1 to Week 24
    End point values
    		 KSI-301 5 mg Aflibercept 2 mg
    Number of subjects analysed
    284
    284
    Units: Letters read
        least squares mean (standard error)
    13.0 ( 0.83 )
    15.5 ( 0.81 )
    Statistical analysis title
    		 Efficacy Analysis 2 (All RVO Participants)
    Statistical analysis description
    Primary Efficacy Analysis 2 - Mean Change in BCVA from Baseline to Week 24 (Full Analysis Set - All RVO Subtypes)
    Comparison groups
    KSI-301 5 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    568
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    P-value
    		 = 0.0243 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.5
    Confidence interval
         level
    		 95.02%
         sides
    2-sided
         lower limit
    		 -4.24
         upper limit
    		 -0.71
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.9
    Notes
    [3] - If the lower limit of the two-sided 95.02% CI for the difference between the two means is >-4.5 letters, noninferiority will be demonstrated.
    [4] - MMRM model with treatment, visit, treatment × visit interaction, RVO subtype, baseline BCVA, disease duration, and geographical location as covariates

    Secondary: Mean Change in BCVA (ETDRS Letters) from Baseline by Visit Over Time up to Week 48 for All RVO Participants

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    End point title
    		 Mean Change in BCVA (ETDRS Letters) from Baseline by Visit Over Time up to Week 48 for All RVO Participants
    End point description
    BCVA as a continuous variable measured at each study visit using the Early Treatment Diabetic Retinopathy Study (ETDRS) BCVA approach.
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 48
    End point values
    		 KSI-301 5 mg Aflibercept 2 mg
    Number of subjects analysed
    284
    284
    Units: ETDRS letters read
    arithmetic mean (standard deviation)
        Week 1 (n = 280, 275)
    7.7 ( 9.25 )
    7.9 ( 7.74 )
        Week 4 (n = 279, 275)
    8.9 ( 9.89 )
    11.2 ( 10.01 )
        Week 8 (n = 273, 278)
    11.4 ( 10.38 )
    13.5 ( 9.78 )
        Week 12 (n = 276, 277)
    10.0 ( 12.58 )
    14.2 ( 10.05 )
        Week 16 (n = 270, 272)
    12.7 ( 11.99 )
    14.9 ( 10.52 )
        Week 20 (n = 263, 269)
    12.4 ( 12.29 )
    15.3 ( 11.86 )
        Week 24 (n = 261, 267)
    14.0 ( 11.42 )
    15.6 ( 11.54 )
        Week 28 (n = 257, 264)
    12.8 ( 11.85 )
    14.1 ( 12.9 )
        Week 32 (n = 250, 257)
    13.3 ( 11.55 )
    13.8 ( 12.46 )
        Week 36 (n = 252, 259)
    13.1 ( 11.52 )
    13.5 ( 11.96 )
        Week 40 (n = 252, 257)
    13.9 ( 11.51 )
    13.9 ( 12.87 )
        Week 44 (n = 244, 256)
    13.6 ( 11.26 )
    13.7 ( 13.11 )
        Week 48 (n = 247, 252)
    13.5 ( 12.10 )
    14.2 ( 13.64 )
    No statistical analyses for this end point

    Secondary: Proportion of Participants Who Gain ≥5, ≥10 and ≥15 Letters from Baseline Over Time up to Week 48 for All RVO Participants

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    End point title
    		 Proportion of Participants Who Gain ≥5, ≥10 and ≥15 Letters from Baseline Over Time up to Week 48 for All RVO Participants
    End point description
    Number of participants in each treatment arm who meet specified criteria at each visit from Week 1 through Week 48.
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 48
    End point values
    		 KSI-301 5 mg Aflibercept 2 mg
    Number of subjects analysed
    284
    284
    Units: Participants
        Gain ≥5 letters, Week 1 (n = 280, 275)
    176
    176
        Gain ≥5 letters, Week 4 (n = 279, 275)
    197
    202
        Gain ≥5 letters, Week 8 (n = 273, 278)
    211
    233
        Gain ≥5 letters, Week 12 (n =276, 277)
    198
    237
        Gain ≥5 letters, Week 16 (n =270, 272)
    222
    240
        Gain ≥5 letters, Week 20 (n =263, 269)
    199
    235
        Gain ≥5 letters, Week 24 (n =261, 267)
    215
    233
        Gain ≥5 letters, Week 28 (n =257, 264)
    206
    211
        Gain ≥5 letters, Week 32 (n =250, 257)
    200
    213
        Gain ≥5 letters, Week 36 (n =252, 259)
    205
    212
        Gain ≥5 letters, Week 40 (n =252, 257)
    210
    215
        Gain ≥5 letters, Week 44 (n =244, 256)
    196
    211
        Gain ≥5 letters, Week 48 (n =247, 252)
    199
    206
        Gain ≥10 letters, Week 1 (n = 280, 275)
    94
    91
        Gain ≥10 letters, Week 4 (n = 279, 275)
    120
    145
        Gain ≥10 letters, Week 8 (n = 273, 278)
    151
    175
        Gain ≥10 letters, Week 12 (n = 276, 277)
    141
    179
        Gain ≥10 letters, Week 16 (n = 270, 272)
    168
    181
        Gain ≥10 letters, Week 20 (n = 263, 269)
    168
    183
        Gain ≥10 letters, Week 24 (n = 261, 267)
    177
    188
        Gain ≥10 letters, Week 28 (n = 257, 264)
    160
    168
        Gain ≥10 letters, Week 32 (n = 250, 257)
    164
    172
        Gain ≥10 letters, Week 36 (n = 252, 259)
    158
    162
        Gain ≥10 letters, Week 40 (n = 252, 257)
    167
    162
        Gain ≥10 letters, Week 44 (n = 244, 256)
    156
    164
        Gain ≥10 letters, Week 48 (n = 247, 252)
    159
    164
        Gain ≥15 letters, Week 1 (n = 280, 275)
    46
    49
        Gain ≥15 letters, Week 4 (n = 279, 275)
    69
    85
        Gain ≥15 letters, Week 8 (n = 273, 278)
    92
    111
        Gain ≥15 letters, Week 12 (n = 276, 277)
    83
    119
        Gain ≥15 letters, Week 16 (n = 270, 272)
    109
    131
        Gain ≥15 letters, Week 20 (n = 263, 269)
    109
    137
        Gain ≥15 letters, Week 24 (n = 261, 267)
    121
    138
        Gain ≥15 letters, Week 28 (n = 257, 264)
    111
    118
        Gain ≥15 letters, Week 32 (n = 250, 257)
    113
    113
        Gain ≥15 letters, Week 36 (n = 252, 259)
    108
    112
        Gain ≥15 letters, Week 40 (n = 252, 257)
    107
    120
        Gain ≥15 letters, Week 44 (n = 244, 256)
    111
    116
        Gain ≥15 letters, Week 48 (n = 247, 252)
    112
    120
    No statistical analyses for this end point

    Secondary: Proportion of Participants Who Lost ≥5, ≥10 and ≥15 Letters from Baseline Over Time up to Week 48 for All RVO Participants

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    End point title
    		 Proportion of Participants Who Lost ≥5, ≥10 and ≥15 Letters from Baseline Over Time up to Week 48 for All RVO Participants
    End point description
    Number of participants (n) in each treatment arm who meet specified criteria at each visit from Week 1 through Week 48.
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 48
    End point values
    		 KSI-301 5 mg Aflibercept 2 mg
    Number of subjects analysed
    284
    284
    Units: Participants
        Lost ≥5 letters, Week 1 (n=280, 275)
    5
    6
        Lost ≥5 letters, Week 4 (n=279, 275)
    19
    7
        Lost ≥5 letters, Week 8 (n=273, 278)
    14
    3
        Lost ≥5 letters, Week 12 (n=276, 277)
    18
    3
        Lost ≥5 letters, Week 16 (n=270, 272)
    13
    5
        Lost ≥5 letters, Week 20 (n=263, 269)
    17
    8
        Lost ≥5 letters, Week 24 (n=261, 267)
    13
    7
        Lost ≥5 letters, Week 28 (n=257, 264)
    16
    10
        Lost ≥5 letters, Week 32 (n=250, 257)
    14
    9
        Lost ≥5 letters, Week 36 (n=252, 259)
    16
    11
        Lost ≥5 letters, Week 40 (n=252, 257)
    13
    14
        Lost ≥5 letters, Week 44 (n=244, 256)
    10
    15
        Lost ≥5 letters, Week 48 (n=247, 252)
    18
    15
        Lost ≥10 letters, Week 1 (n=280, 275)
    3
    1
        Lost ≥10 letters, Week 4 (n=279, 275)
    4
    1
        Lost ≥10 letters, Week 8 (n=273, 278)
    6
    1
        Lost ≥10 letters, Week 12 (n=276, 277)
    9
    0
        Lost ≥10 letters, Week 16 (n=270, 272)
    6
    2
        Lost ≥10 letters, Week 20 (n=263, 269)
    10
    5
        Lost ≥10 letters, Week 24 (n=261, 267)
    4
    4
        Lost ≥10 letters, Week 28 (n=257, 264)
    9
    8
        Lost ≥10 letters, Week 32 (n=250, 257)
    9
    7
        Lost ≥10 letters, Week 36 (n=252, 259)
    10
    4
        Lost ≥10 letters, Week 40 (n=252, 257)
    9
    8
        Lost ≥10 letters, Week 44 (n=244, 256)
    6
    9
        Lost ≥10 letters, Week 48 (n=247, 252)
    9
    9
        Lost ≥15 letters, Week 1 (n=280, 275)
    2
    0
        Lost ≥15 letters, Week 4 (n=279, 275)
    2
    1
        Lost ≥15 letters, Week 8 (n=273, 278)
    1
    0
        Lost ≥15 letters, Week 12 (n=276, 277)
    6
    0
        Lost ≥15 letters, Week 16 (n=270, 272)
    5
    1
        Lost ≥15 letters, Week 20 (n=263, 269)
    4
    2
        Lost ≥15 letters, Week 24 (n=261, 267)
    1
    2
        Lost ≥15 letters, Week 28 (n=257, 264)
    5
    5
        Lost ≥15 letters, Week 32 (n=250, 257)
    4
    6
        Lost ≥15 letters, Week 36 (n=252, 259)
    2
    2
        Lost ≥15 letters, Week 40 (n=252, 257)
    3
    5
        Lost ≥15 letters, Week 44 (n=244, 256)
    3
    6
        Lost ≥15 letters, Week 48 (n=247, 252)
    5
    8
    No statistical analyses for this end point

    Secondary: Proportion of Participants with BCVA Snellen Equivalent of 20/40 or Better from Baseline Over Time up to Week 48 for All RVO Participants

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    End point title
    		 Proportion of Participants with BCVA Snellen Equivalent of 20/40 or Better from Baseline Over Time up to Week 48 for All RVO Participants
    End point description
    Number of participants (n) with BCVA Snellen Equivalent of 20/40 or Better from Baseline to Week 48. Snellen Equivalent of 20/40 is 69 ETDRS letters. Number of participants in each treatment arm who meet specified criteria at each visit from Baseline through Week 48.
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 48
    End point values
    		 KSI-301 5 mg Aflibercept 2 mg
    Number of subjects analysed
    284
    284
    Units: Participants
        Baseline (n=284,284)
    92
    90
        Week 1 (n=280,275)
    168
    153
        Week 4 (n=279,275)
    173
    182
        Week 8 (n=273,278)
    185
    198
        Week 12 (n=276,277)
    186
    199
        Week 16 (n=270,272)
    200
    209
        Week 20 (n=263,269)
    189
    207
        Week 24 (n=261,267)
    196
    205
        Week 28 (n=257,264)
    192
    197
        Week 32 (n=250,257)
    182
    190
        Week 36 (n=252,259)
    188
    192
        Week 40 (n=252,257)
    191
    193
        Week 44 (n=244,256)
    184
    191
        Week 48 (n=247,252)
    182
    190
    No statistical analyses for this end point

    Secondary: Proportion of Participants with BCVA Snellen Equivalent of 20/200 or Worse from Baseline Over Time up to Week 48 for All RVO Participants)

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    End point title
    		 Proportion of Participants with BCVA Snellen Equivalent of 20/200 or Worse from Baseline Over Time up to Week 48 for All RVO Participants)
    End point description
    Number of Participants (n) with BCVA Snellen Equivalent of 20/200 or Worse from Baseline to Week 48. Snellen Equivalent of 20/200 is 38 ETDRS letters. Number of participants in each treatment arm who meet specified criteria at each visit from Baseline through Week 48.
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 48
    End point values
    		 KSI-301 5 mg Aflibercept 2 mg
    Number of subjects analysed
    284
    284
    Units: Participants
        Baseline (n=284, 284)
    22
    31
        Week 1 (n=280, 275)
    9
    12
        Week 4 (n=279, 275)
    10
    9
        Week 8 (n=273, 278)
    6
    5
        Week 12 (n=276, 277)
    11
    4
        Week 16 (n=270, 272)
    7
    7
        Week 20 (n=263, 269)
    7
    5
        Week 24 (n=261, 267)
    2
    4
        Week 28 (n=257, 264)
    5
    6
        Week 32 (n=250, 257)
    3
    5
        Week 36 (n=252, 259)
    2
    3
        Week 40 (n=252, 257)
    2
    7
        Week 44 (n=244, 256)
    2
    6
        Week 48 (n=247, 252)
    5
    8
    No statistical analyses for this end point

    Secondary: Proportion of Participants with Absence of Macular Edema from Baseline Over Time up to Week 48 for All RVO Participants

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    End point title
    		 Proportion of Participants with Absence of Macular Edema from Baseline Over Time up to Week 48 for All RVO Participants
    End point description
    Macular Edema (ME) is assessed by optical coherence tomography (OCT) central subfield thickness (CST). A thickness of less than 325 microns is considered absence of ME. Proportion of participants with Absence of Macular Edema from Baseline to Week 48. Number of participants in each treatment arm who meet specified criteria at each visit from Week 1 through Week 48.
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 48
    End point values
    		 KSI-301 5 mg Aflibercept 2 mg
    Number of subjects analysed
    284
    284
    Units: Participants
        Baseline (n=284,284)
    4
    7
        Week 1 (n=278,274)
    156
    150
        Week 4 (n=279,276)
    174
    225
        Week 8 (n=273,277)
    205
    247
        Week 12 (n=275,276)
    160
    252
        Week 16 (n=270,272)
    218
    245
        Week 20 (n=262,268)
    174
    240
        Week 24 (n=261,266)
    221
    247
        Week 28 (n=258,263)
    185
    196
        Week 32 (n=252,256)
    168
    173
        Week 36 (n=249,258)
    172
    172
        Week 40 (n=252,255)
    179
    188
        Week 44 (n=240,255)
    160
    177
        Week 48 (n=245,251)
    166
    187
    No statistical analyses for this end point

    Secondary: Mean Change in OCT Central Subfield Retinal Thickness (CST) from Baseline Over Time up to Week 48 for All RVO Participants

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    End point title
    		 Mean Change in OCT Central Subfield Retinal Thickness (CST) from Baseline Over Time up to Week 48 for All RVO Participants
    End point description
    Mean change in OCT central subfield retinal thickness (CST) from baseline by visit over time (up to Week 48) for all RVO participants.
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 48
    End point values
    		 KSI-301 5 mg Aflibercept 2 mg
    Number of subjects analysed
    284
    284
    Units: micrometers (um)
    arithmetic mean (standard deviation)
        Week 1 (n = 278, 274)
    -225.2 ( 152.87 )
    -255.9 ( 168.25 )
        Week 4 (n = 279, 276)
    -230.8 ( 181.37 )
    -294.2 ( 195.07 )
        Week 8 (n = 273, 277)
    -255.6 ( 190.4 )
    -310.1 ( 203.17 )
        Week 12 (n = 275, 276)
    -195.8 ( 213.7 )
    -314.8 ( 208.68 )
        Week 16 (n = 270, 272)
    -264.9 ( 204.77 )
    -321.0 ( 209.89 )
        Week 20 (n = 262, 268)
    -218.1 ( 203.88 )
    -323.0 ( 209.89 )
        Week 24 (n = 261, 266)
    -278.9 ( 192.68 )
    -326.6 ( 210.78 )
        Week 28 (n = 258, 263)
    -240.4 ( 200.78 )
    -273.9 ( 218.56 )
        Week 32 (n = 252, 256)
    -246.6 ( 200.99 )
    -269.7 ( 213.89 )
        Week 36 (n = 249, 258)
    -243.4 ( 198.13 )
    -258.6 ( 213.44 )
        Week 40 (n = 252, 255)
    -246.9 ( 193.79 )
    -274.9 ( 229.38 )
        Week 44 (n = 240, 255)
    -237.5 ( 189.3 )
    -258.3 ( 216.49 )
        Week 48 (n = 245, 251)
    -240.0 ( 203.97 )
    -278.8 ( 224.13 )
    No statistical analyses for this end point

    Secondary: Mean Change in OCT Center Point Retinal Thickness (CPT) From Baseline Over Time up to Week 48 for All RVO Participants

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    End point title
    		 Mean Change in OCT Center Point Retinal Thickness (CPT) From Baseline Over Time up to Week 48 for All RVO Participants
    End point description
    Mean change in OCT center point retinal thickness (CPT) from baseline by visit over time (up to Week 48) for all RVO participants.
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 48
    End point values
    		 KSI-301 5 mg Aflibercept 2 mg
    Number of subjects analysed
    284
    284
    Units: micrometers (um)
    arithmetic mean (standard deviation)
        Week 1 (n = 278, 274)
    -278.7 ( 186.23 )
    -320.9 ( 200.0 )
        Week 4 (n = 279, 276)
    -278.5 ( 212.92 )
    -358.4 ( 224.51 )
        Week 8 (n = 273, 277)
    -301.4 ( 220.72 )
    -373.9 ( 235.35 )
        Week 12 (n = 275, 276)
    -230.3 ( 248.92 )
    -377.6 ( 239.01 )
        Week 16 (n = 270, 272)
    -311.5 ( 237.01 )
    -381.3 ( 240.74 )
        Week 20 (n = 262, 268)
    -258.1 ( 236.58 )
    -385.4 ( 238.61 )
        Week 24 (n = 261, 266)
    -327.9 ( 223.13 )
    -387.5 ( 240.42 )
        Week 28 (n = 258, 263)
    -280.5 ( 232.22 )
    -328.0 ( 249.96 )
        Week 32 (n = 252, 256)
    -288.9 ( 229.60 )
    -322.4 ( 244.98 )
        Week 36 (n = 249, 258)
    -286.8 ( 229.63 )
    -308.1 ( 247.22 )
        Week 40 (n = 252, 255)
    -290.7 ( 220.56 )
    -328.7 ( 261.26 )
        Week 44 (n = 240, 255)
    -281.5 ( 221.38 )
    -306.6 ( 252.79 )
        Week 48 (n = 245, 251)
    -279.6 ( 231.43 )
    -331.6 ( 259.43 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From 1st dose of study drug to 76 weeks. Only SAEs caused by a protocol-mandated intervention were reported from time of ICD through 1st study intervention. From Day 1 through final safety follow up visit, all AE and SAE information were collected.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, the Sponsor has reported under the Serious adverse events field “number of deaths resulting from adverse events” all 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
    23.1
    Reporting groups
    Reporting group title
    KSI-301 5 mg
    Reporting group description
    		 Intravitreal injection of KSI-301 (5 mg) at Day 1, Week 4, and once every 8 weeks through Week 20 followed by an individualized dosing regimen of intravitreal injection of KSI-301 (5 mg) from Week 24 to Week 44. In the Extension Phase, participants randomized to KSI-301 (5 mg) in the Primary Study will continue to receive KSI-301 (5 mg) based on protocol-defined disease activity criteria. Sham Procedure: The sham is a procedure that mimics an intravitreal injection. It involves pressing the blunt end of an empty syringe (without a needle) against the anesthetized eye. It will be administered to participants in both treatments arms at applicable visits to maintain masking.

    Reporting group title
    Aflibercept 2 mg
    Reporting group description
    		 Intravitreal injection of aflibercept (2 mg) once every 4 through Week 20 followed by an individualized dosing regimen of Intravitreal injection of Aflibercept (2 mg) once every 4 weeks from Week 24 to Week 44. In the Extension Phase, participants randomized to aflibercept in the Primary Study will cross over to treatment with KSI-301 (5 mg). They will receive their first dose of KSI-301 (5 mg) at Week 48 and will receive additional treatment with KSI-301 (5 mg) based on protocol-defined disease activity criteria. Sham Procedure: The sham is a procedure that mimics an intravitreal injection. It involves pressing the blunt end of an empty syringe (without a needle) against the anesthetized eye. It will be administered to participants in both treatments arms at applicable visits to maintain masking.

    Reporting group title
    KSI-301 5mg Extension Phase
    Reporting group description
    		 In the Extension Phase, participants randomized to KSI-301 (5 mg) in the Primary Study will continue to receive KSI-301 (5 mg) based on protocol-defined disease activity criteria. In the Extension Phase, participants randomized to aflibercept in the Primary Study will cross over to treatment with KSI-301 (5 mg). They will receive their first dose of KSI-301 (5 mg) at Week 48 and will receive additional treatment with KSI-301 (5 mg) based on protocol-defined disease activity criteria.

    Serious adverse events
    		 KSI-301 5 mg Aflibercept 2 mg KSI-301 5mg Extension Phase
    Total subjects affected by serious adverse events
         subjects affected / exposed
    36 / 284 (12.68%)
    23 / 284 (8.10%)
    18 / 444 (4.05%)
         number of deaths (all causes)
    3
    1
    2
         number of deaths resulting from adverse events
    3
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Waldenstrom's macroglobulinaemia
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma pancreas
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 284 (0.35%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 284 (0.35%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer metastatic
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 284 (0.35%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine cancer
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 284 (0.35%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchial neoplasm
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 284 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 284 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 284 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sarcomatoid carcinoma of the lung
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 284 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 284 (0.35%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    1 / 284 (0.35%)
    1 / 284 (0.35%)
    0 / 444 (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
    Giant cell arteritis
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Essential hypertension
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 284 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 284 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 284 (0.00%)
    2 / 284 (0.70%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 284 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea exertional
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 284 (0.35%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 284 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 284 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device malfunction
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Intraocular pressure increased - Study Eye
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Arthropod sting
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fractured sacrum
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 284 (0.00%)
    2 / 284 (0.70%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 284 (0.35%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 284 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 284 (0.70%)
    2 / 284 (0.70%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    2 / 284 (0.70%)
    0 / 284 (0.00%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 284 (0.00%)
    2 / 284 (0.70%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 284 (0.35%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 284 (0.35%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 284 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 284 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhagic stroke
         subjects affected / exposed
    2 / 284 (0.70%)
    0 / 284 (0.00%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 284 (0.35%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 284 (0.35%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 284 (0.35%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myelopathy
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 284 (0.35%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 284 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 284 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 284 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nerve compression
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 284 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 284 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 284 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Glaucoma - Study Eye
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lens dislocation - Study Eye
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal detachment - Study Eye
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhegmatogenous retinal detachment - Study Eye
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vitritis - Study Eye
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal vein occlusion - Study Eye
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 284 (0.35%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal detachment - Fellow Eye
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 284 (0.35%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 284 (0.35%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 284 (0.35%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 284 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 284 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 284 (0.35%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 284 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 284 (0.35%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 284 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 284 (0.35%)
    2 / 284 (0.70%)
    0 / 444 (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
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 284 (0.35%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    3 / 284 (1.06%)
    1 / 284 (0.35%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Furuncle
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 284 (0.00%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 284 (0.35%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 284 (0.35%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 KSI-301 5 mg Aflibercept 2 mg KSI-301 5mg Extension Phase
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    73 / 284 (25.70%)
    66 / 284 (23.24%)
    53 / 444 (11.94%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    30 / 284 (10.56%)
    26 / 284 (9.15%)
    13 / 444 (2.93%)
         occurrences all number
    31
    28
    13
    Eye disorders
    Conjunctival haemorrhage - Study Eye
         subjects affected / exposed
    24 / 284 (8.45%)
    22 / 284 (7.75%)
    8 / 444 (1.80%)
         occurrences all number
    27
    24
    8
    Infections and infestations
    COVID-19
         subjects affected / exposed
    30 / 284 (10.56%)
    23 / 284 (8.10%)
    32 / 444 (7.21%)
         occurrences all number
    30
    23
    33

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Jul 2020
    Protocol Version 1.1 Changes from Version 1.0 include administrative revisions based on IRB pre-submission feedback of Version 1.0.
    02 Jun 2021
    Protocol Version 2.0 Changes from Version 1.1 include addition of a 20-week Extension Period; and addition of a China-specific enrolment plan.

    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.
    The open-label extension period of the study was terminated by the Sponsor once all participants had completed the last follow-up visit of the primary study (Week 52).
    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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