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    Clinical Trial Results:
    A 52-week multicenter, randomized, double-masked, 2-arm parallel study to compare efficacy, safety and immunogenicity of SOK583A1 to Eylea®, administered intravitreally, in patients with neovascular age-related macular degeneration.

    Summary
    EudraCT number
    		 2019-004838-41
    Trial protocol
    		 DE   LT   LV   FR   SK   BG   HU   PT   AT   CZ  
    Global end of trial date
    10 May 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 May 2024
    First version publication date
    08 May 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CSOK583A12301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04864834
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Hexal AG
    Sponsor organisation address
    Industriestr. 25, Holzkirchen, Germany, 83607
    Public contact
    Clinical Disclosure Office, Hexal AG, +49  8024 / 908 0 ,
    Scientific contact
    Clinical Disclosure Office, Hexal AG, +49  8024 / 908 0 ,
    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
    10 May 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 May 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate similar efficacy of SOK583A1 and Eylea EU in terms of BCVA.
    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
    12 May 2021
    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: 23
    Country: Number of subjects enrolled
    Israel: 27
    Country: Number of subjects enrolled
    Japan: 26
    Country: Number of subjects enrolled
    Spain: 38
    Country: Number of subjects enrolled
    United States: 89
    Country: Number of subjects enrolled
    Poland: 34
    Country: Number of subjects enrolled
    Portugal: 10
    Country: Number of subjects enrolled
    Slovakia: 35
    Country: Number of subjects enrolled
    Austria: 9
    Country: Number of subjects enrolled
    Bulgaria: 9
    Country: Number of subjects enrolled
    Czechia: 29
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    Germany: 14
    Country: Number of subjects enrolled
    Hungary: 78
    Country: Number of subjects enrolled
    Latvia: 32
    Country: Number of subjects enrolled
    Lithuania: 20
    Worldwide total number of subjects
    485
    EEA total number of subjects
    320
    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)
    44
    From 65 to 84 years
    376
    85 years and over
    65

    Subject disposition

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    Recruitment
    Recruitment details
    		 In total 723 subjects were screened in 16 countries and 119 sites, 485 patients were randomized in 103 sites.

    Pre-assignment
    Screening details
    		 A total of 723 subjects were screened. 485 subjects were randomized. 431 of the 485 randomized subjects completed treatment, and 438 subjects completed the study.

    Pre-assignment period milestones
    Number of subjects started
    		 723 [1]
    Number of subjects completed
    		 485

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Screening failures: 238
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The total numbers per country (485) are the number of randomized patients and not the number of screened patients (723).
    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 SOK583A1 (40 mg/mL)
    Arm description
    		 Intravitreal (IVT) administration of 2 mg of SOK583A1 in the study eye, every 4 weeks (q4w) at Baseline, Week 4 and Week 8, and thereafter every 8 weeks (q8w) at week 16, 24, 32, 40 and 48.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SOK583A1
    Investigational medicinal product code
    Other name
    proposed biosimilar aflibercept
    Pharmaceutical forms
    Solution for injection in vial
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Intravitreal (IVT) administration of 2 mg of SOK583A1 in the study eye, every 4 weeks (q4w) at Baseline, Week 4 and Week 8, and thereafter every 8 weeks (q8w) at week 16, 24, 32, 40 and 48.

    Arm title
    		 Eylea EU (40 mg/mL)
    Arm description
    		 IVT administration of 2 mg of Eylea EU in the study eye, every 4 weeks (q4w) at Baseline, Week 4 and Week 8, and thereafter every 8 weeks (q8w) at week 16, 24, 32, 40 and 48. EU: European
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Eylea EU
    Investigational medicinal product code
    Other name
    aflibercept
    Pharmaceutical forms
    Solution for injection in vial
    Routes of administration
    Intravitreal use
    Dosage and administration details
    IVT administration of 2 mg of Eylea EU in the study eye, every 4 weeks (q4w) at Baseline, Week 4 and Week 8, and thereafter every 8 weeks (q8w) at week 16, 24, 32, 40 and 48. EU: European

    Number of subjects in period 1
    		SOK583A1 (40 mg/mL) Eylea EU (40 mg/mL)
    Started
    245
    240
    Completed
    220
    218
    Not completed
    25
    22
         Adverse event, serious fatal
    5
    1
         Physician decision
    4
    3
         Consent withdrawn by subject
    8
    11
         Adverse event, non-fatal
    4
    3
         Randomized by mistake without study treatment
    1
    -
         Lost to follow-up
    2
    3
         Protocol deviation
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SOK583A1 (40 mg/mL)
    Reporting group description
    		 Intravitreal (IVT) administration of 2 mg of SOK583A1 in the study eye, every 4 weeks (q4w) at Baseline, Week 4 and Week 8, and thereafter every 8 weeks (q8w) at week 16, 24, 32, 40 and 48.

    Reporting group title
    Eylea EU (40 mg/mL)
    Reporting group description
    		 IVT administration of 2 mg of Eylea EU in the study eye, every 4 weeks (q4w) at Baseline, Week 4 and Week 8, and thereafter every 8 weeks (q8w) at week 16, 24, 32, 40 and 48. EU: European

    Reporting group values
    		 SOK583A1 (40 mg/mL) Eylea EU (40 mg/mL) Total
    Number of subjects
    		 245 240 485
    Age categorical
    Units: Subjects
        Adults: >=50
    		 245 240 485
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 75.8 ( 7.82 ) 75.7 ( 7.72 ) -
    Gender categorical
    Units: Subjects
        Female
    		 139 136 275
        Male
    		 106 104 210

    End points

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    End points reporting groups
    Reporting group title
    SOK583A1 (40 mg/mL)
    Reporting group description
    		 Intravitreal (IVT) administration of 2 mg of SOK583A1 in the study eye, every 4 weeks (q4w) at Baseline, Week 4 and Week 8, and thereafter every 8 weeks (q8w) at week 16, 24, 32, 40 and 48.

    Reporting group title
    Eylea EU (40 mg/mL)
    Reporting group description
    		 IVT administration of 2 mg of Eylea EU in the study eye, every 4 weeks (q4w) at Baseline, Week 4 and Week 8, and thereafter every 8 weeks (q8w) at week 16, 24, 32, 40 and 48. EU: European

    Primary: Mean change from baseline in BCVA score using ETDRS testing charts at Week 8

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    End point title
    		 Mean change from baseline in BCVA score using ETDRS testing charts at Week 8
    End point description
    The primary aim of the study is to demonstrate equivalence of change in BCVA score from Baseline at Week 8 between participants with nAMD treated with SOK583A1 and participants treated with Eylea EU. The primary analysis will be performed on the Per-Protocol Set (PPS), which is the most appropriate analysis set to use when testing for equivalence. ETDRS: Early Treatment Diabetic Retinopathy Study EU: European
    End point type
    Primary
    End point timeframe
    Change from baseline in mean BCVA score at Week 8
    End point values
    		 SOK583A1 (40 mg/mL) Eylea EU (40 mg/mL)
    Number of subjects analysed
    235
    226
    Units: letters
        arithmetic mean (standard deviation)
    6.5 ( 8.98 )
    6.8 ( 7.46 )
    Statistical analysis title
    		 SOK583A1 vs Eylea EU
    Comparison groups
    SOK583A1 (40 mg/mL) v Eylea EU (40 mg/mL)
    Number of subjects included in analysis
    461
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 1.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.77

    Secondary: Mean change in CSFT using SD-OCT from Baseline to Week 1, 4, 8, 24 and 52

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    End point title
    		 Mean change in CSFT using SD-OCT from Baseline to Week 1, 4, 8, 24 and 52
    End point description
    End point type
    Secondary
    End point timeframe
    Week 1, 4, 8, 24 and 52
    End point values
    		 SOK583A1 (40 mg/mL) Eylea EU (40 mg/mL)
    Number of subjects analysed
    243
    238
    Units: μm
    arithmetic mean (standard deviation)
        Week 1
    -103.6 ( 89.91 )
    -99.2 ( 86.18 )
        Week 4
    -152.9 ( 123.55 )
    -140.7 ( 120.25 )
        Week 8
    -165.7 ( 144.35 )
    -154.2 ( 133.43 )
        Week 24
    -136.4 ( 140.19 )
    -127.5 ( 137.87 )
        Week 52
    -187.9 ( 150.7 )
    -172.9 ( 142.74 )
    No statistical analyses for this end point

    Secondary: Mean change of CNV lesion

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    End point title
    		 Mean change of CNV lesion
    End point description
    End point type
    Secondary
    End point timeframe
    Week 8 and 52
    End point values
    		 SOK583A1 (40 mg/mL) Eylea EU (40 mg/mL)
    Number of subjects analysed
    242
    237
    Units: mm^2
    arithmetic mean (standard deviation)
        Week 8
    -1.7877 ( 3.97567 )
    -1.7274 ( 3.77398 )
        Week 52
    -3.7845 ( 5.21911 )
    -3.5026 ( 4.96036 )
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in BCVA score using EDTRS testing charts at Week 24 and 52

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    End point title
    		 Mean change from Baseline in BCVA score using EDTRS testing charts at Week 24 and 52
    End point description
    End point type
    Secondary
    End point timeframe
    Week 24 and 52
    End point values
    		 SOK583A1 (40 mg/mL) Eylea EU (40 mg/mL)
    Number of subjects analysed
    243
    240
    Units: Letters
    arithmetic mean (standard deviation)
        Week 24
    6.9 ( 8.93 )
    7.4 ( 9.95 )
        Week 52
    6.4 ( 11.91 )
    7.7 ( 11.62 )
    No statistical analyses for this end point

    Secondary: Similarity Between SOK583A1 and Eylea EU in Terms of Safety

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    End point title
    		 Similarity Between SOK583A1 and Eylea EU in Terms of Safety
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 SOK583A1 (40 mg/mL) Eylea EU (40 mg/mL)
    Number of subjects analysed
    244
    240
    Units: Participants
        Ocular AEs in the study eye
    84
    78
        Ocular AEs in the fellow eye
    55
    51
        Non-ocular AEs
    141
    141
    No statistical analyses for this end point

    Secondary: Similarity Between SOK583A1 and Eylea EU in Terms of Immunogenicity

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    End point title
    		 Similarity Between SOK583A1 and Eylea EU in Terms of Immunogenicity
    End point description
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 SOK583A1 (40 mg/mL) Eylea EU (40 mg/mL)
    Number of subjects analysed
    234
    231
    Units: Participants
        ADA positive
    2
    6
        ADA negative
    232
    225
    No statistical analyses for this end point

    Secondary: Systemic Exposure to SOK583A1 and Eylea EU in Participants of the Pharmacokinetic (PK) Assessment

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    End point title
    		 Systemic Exposure to SOK583A1 and Eylea EU in Participants of the Pharmacokinetic (PK) Assessment
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline (pre-dose) and 24 hours after the first injection (day 2) and third injection (day 58)
    End point values
    		 SOK583A1 (40 mg/mL) Eylea EU (40 mg/mL)
    Number of subjects analysed
    23
    20
    Units: mg/mL
    arithmetic mean (standard deviation)
        Day 1 (Baseline)
    0.0 ( 0.0 )
    0.0 ( 0.0 )
        Day 2
    32.0 ( 24.0 )
    33.3 ( 24.6 )
        Day 58
    31.7 ( 21.9 )
    33.6 ( 25.8 )
    No statistical analyses for this end point

    Secondary: Analysis Systemic VEGF Concentrations in Patients Treated With Aflibercept

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    End point title
    		 Analysis Systemic VEGF Concentrations in Patients Treated With Aflibercept
    End point description
    End point type
    Secondary
    End point timeframe
    Assessment at Week 48 (pre-dose) and Week 52
    End point values
    		 SOK583A1 (40 mg/mL) Eylea EU (40 mg/mL)
    Number of subjects analysed
    60
    67
    Units: mg/mL
    arithmetic mean (standard deviation)
        Week 48 (pre-dose)
    86.44 ( 77.962 )
    80.09 ( 92.155 )
        Week 52
    75.14 ( 20.892 )
    73.38 ( 20.169 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From study treatment start date to the end of the study participation.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Eylea EU
    Reporting group description
    		 Eylea EU

    Reporting group title
    SOK583
    Reporting group description
    		 SOK583

    Serious adverse events
    		 Eylea EU SOK583
    Total subjects affected by serious adverse events
         subjects affected / exposed
    30 / 240 (12.50%)
    39 / 244 (15.98%)
         number of deaths (all causes)
    1
    5
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Renal cancer stage IV
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant fibrous histiocytoma
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cancer
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 240 (0.42%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic aneurysm
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 240 (0.00%)
    3 / 244 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Immune system disorders
    Sarcoidosis
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary oedema
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 240 (0.83%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 240 (0.42%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Product issues
    Device malfunction
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood pressure increased
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 240 (0.00%)
    2 / 244 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 240 (0.00%)
    2 / 244 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 240 (0.42%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 240 (0.83%)
    4 / 244 (1.64%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 240 (0.42%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 240 (0.00%)
    2 / 244 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine with aura
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 240 (0.42%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitreoretinal traction syndrome
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visual impairment
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visual acuity reduced
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal haemorrhage
         subjects affected / exposed
    1 / 240 (0.42%)
    2 / 244 (0.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenal obstruction
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    1 / 240 (0.42%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal adhesions
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary obstruction
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 240 (0.42%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 240 (0.83%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ophthalmic herpes zoster
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 240 (0.83%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Eylea EU SOK583
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    63 / 240 (26.25%)
    58 / 244 (23.77%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    16 / 240 (6.67%)
    11 / 244 (4.51%)
         occurrences all number
    17
    12
    Eye disorders
    Neovascular age-related macular degeneration
         subjects affected / exposed
    25 / 240 (10.42%)
    25 / 244 (10.25%)
         occurrences all number
    25
    25
    Visual acuity reduced
         subjects affected / exposed
    12 / 240 (5.00%)
    11 / 244 (4.51%)
         occurrences all number
    13
    13
    Infections and infestations
    COVID-19
         subjects affected / exposed
    23 / 240 (9.58%)
    19 / 244 (7.79%)
         occurrences all number
    23
    19

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Jun 2022
    This amendment to version 3.0 of the protocol of Study CSOK583A12301 includes the evaluation of systemic VEGF concentrations at Week 48 (pre-dose) and Week 52. The aim of this assessment is to evaluate the concentrations of systemic VEGF in the 2 treatment groups at Week 52, i.e. 4 weeks after IVA treatment with aflibercept. VEGF concentration at Week 48 (pre-dose) will be used as baseline value to calculate the relative change in VEGF between Week 48 and Week 52. The VEGF evaluation was recommended by EMA in a scientific advice. This amendment applies to those participants who agree to additional blood collection for the evaluation of systemic VEGF concentrations. They will document their agreement by signing the corresponding ICF.

    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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