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    Clinical Trial Results:
    Open-label, randomized, two–arm, controlled study to assess the efficacy, safety, and tolerability of intravitreal (IVT) aflibercept compared to laser photocoagulation in patients with retinopathy of prematurity (ROP)

    Summary
    EudraCT number
    		 2018-002611-99
    Trial protocol
    		 CZ   SE   NL   PT   GB   BE   DE   SK   AT   BG   PL   ES   HU   LT   EE   LV   GR   IT   RO  
    Global end of trial date
    12 Feb 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Aug 2021
    First version publication date
    28 Aug 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    BAY86-5321/20090
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04004208
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000236-PIP05-18
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Feb 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Feb 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Feb 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of aflibercept in subjects diagnosed with retinopathy of prematurity (ROP) in comparison to laser
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent was read by and explained to all parent(s)/legally authorized representative(s) of the patients. Parent(s)/legally authorized representative(s) of the patients signed informed consent form and could withdraw their consent at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Sep 2019
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 3
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Bulgaria: 9
    Country: Number of subjects enrolled
    Brazil: 4
    Country: Number of subjects enrolled
    Czechia: 5
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Greece: 5
    Country: Number of subjects enrolled
    Hong Kong: 1
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Japan: 17
    Country: Number of subjects enrolled
    Korea, Republic of: 4
    Country: Number of subjects enrolled
    Malaysia: 1
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Portugal: 5
    Country: Number of subjects enrolled
    Romania: 7
    Country: Number of subjects enrolled
    Russian Federation: 18
    Country: Number of subjects enrolled
    Singapore: 1
    Country: Number of subjects enrolled
    Slovakia: 2
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    Turkey: 10
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    Ukraine: 4
    Worldwide total number of subjects
    118
    EEA total number of subjects
    50
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    118
    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)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study was conducted at 64 centers in 27 countries or regions, between 25-SEP-2019 (first subject first visit) and 12-Feb-2021 (last subject last visit)

    Pre-assignment
    Screening details
    		 121 subjects were screened. 3 subjects were screen failures. 118 subjects were enrolled, 75 subjects were randomized to the aflibercept arm and 43 to the laser arm. 113 subjects were treated, 5 subjects randomized to the laser photocoagulation arm were withdrawn before receiving any study intervention.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Aflibercept 0.4 mg
    Arm description
    		 One intravitreal injection of aflibercept 0.4 mg (0.01 mL) per eligible eye at baseline (Day 1), with up to 2 re-injections at the same single dose allowed for each eligible eye if required and interval since last aflibercept injection was 28 or more days. One or both eyes could be treated.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aflibercept
    Investigational medicinal product code
    BAY86-5321
    Other name
    Eylea
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    One intravitreal injection of aflibercept 0.4 mg (0.01 mL) per eligible eye at baseline (Day 1), with up to 2 re-injections at the same single dose allowed for each eligible eye if required and interval since last aflibercept injection was 28 or more days. One or both eyes could be treated.

    Arm title
    		 Laser photocoagulation
    Arm description
    		 Laser treatment to each eligible eye at baseline (Day 1), with supplementary laser treatments allowed. Multiple sessions within one week from baseline were counted as a single treatment. One or both eyes could be treated.
    Arm type
    		 Laser Photocoagulation

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1 [1]
    		Aflibercept 0.4 mg Laser photocoagulation
    Started
    75
    38
    Completed
    68
    36
    Not completed
    7
    2
         COVID-19 pandemic
    1
    -
         Physician decision
    1
    -
         Adverse event, non-fatal
    1
    1
         Death
    3
    -
         Withdrawal by parent/guardian
    1
    1
    Notes
    [1] - The number of subjects reported to be in the baseline 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 worldwide number of subjects enrolled was 118, however, the baseline data is presented for the 113 subjects treated.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Aflibercept 0.4 mg
    Reporting group description
    		 One intravitreal injection of aflibercept 0.4 mg (0.01 mL) per eligible eye at baseline (Day 1), with up to 2 re-injections at the same single dose allowed for each eligible eye if required and interval since last aflibercept injection was 28 or more days. One or both eyes could be treated.

    Reporting group title
    Laser photocoagulation
    Reporting group description
    		 Laser treatment to each eligible eye at baseline (Day 1), with supplementary laser treatments allowed. Multiple sessions within one week from baseline were counted as a single treatment. One or both eyes could be treated.

    Reporting group values
    		 Aflibercept 0.4 mg Laser photocoagulation Total
    Number of subjects
    		 75 38 113
    Age Categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 75 38 113
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous
    Gestational age at birth
    Units: weeks
        arithmetic mean (standard deviation)
    		 26.43 ( 2.1 ) 26 ( 1.6 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 34 19 53
        Male
    		 41 19 60
    RACE
    Units: Subjects
        White
    		 55 28 83
        Black or African American
    		 2 0 2
        Asian Indian
    		 0 2 2
        Chinese
    		 4 0 4
        Japanese
    		 10 6 16
        Korean
    		 2 1 3
        Asian: Other
    		 1 0 1
        American Indian or Alaska Native
    		 0 1 1
        Multiple
    		 1 0 1
    ROP classification by investigator
    Units: Subjects
        Zone I excluding AP-ROP
    		 15 7 22
        Zone II excluding AP-ROP
    		 46 26 72
        AP-ROP: Zone I
    		 12 4 16
        AP-ROP: Zone II
    		 2 1 3

    End points

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    End points reporting groups
    Reporting group title
    Aflibercept 0.4 mg
    Reporting group description
    		 One intravitreal injection of aflibercept 0.4 mg (0.01 mL) per eligible eye at baseline (Day 1), with up to 2 re-injections at the same single dose allowed for each eligible eye if required and interval since last aflibercept injection was 28 or more days. One or both eyes could be treated.

    Reporting group title
    Laser photocoagulation
    Reporting group description
    		 Laser treatment to each eligible eye at baseline (Day 1), with supplementary laser treatments allowed. Multiple sessions within one week from baseline were counted as a single treatment. One or both eyes could be treated.

    Primary: Proportion of subjects with absence of active ROP and unfavorable structural outcomes

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    End point title
    		 Proportion of subjects with absence of active ROP and unfavorable structural outcomes
    End point description
    Active ROP was defined as ROP requiring treatment. Unfavorable structural outcomes included retinal detachment, macular dragging, macular fold, or retrolental opacity.
    End point type
    Primary
    End point timeframe
    At 24 weeks after starting study treatment
    End point values
    		 Aflibercept 0.4 mg Laser photocoagulation
    Number of subjects analysed
    75
    38
    Units: Proportion of subjects
        number (not applicable)
    0.855
    0.821
    Statistical analysis title
    		 Treatment difference %
    Statistical analysis description
    Bayesian analysis with non-informative prior distributions. Calculation of two-sided 90% credible interval for the treatment difference (aflibercept – laser photocoagulation).
    Comparison groups
    Aflibercept 0.4 mg v Laser photocoagulation
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Difference in proportions
    Point estimate
    0.034
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.08
         upper limit
    		 0.162
    Notes
    [1] - Non inferiority margin is 5%. Confidence interval actually refers to a credible interval based on the Bayesian analysis.

    Secondary: Proportion of subjects requiring intervention with a second treatment modality

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    End point title
    		 Proportion of subjects requiring intervention with a second treatment modality
    End point description
    A second treatment modality for ROP was either rescue treatment or any other surgical or nonsurgical treatment for ROP
    End point type
    Secondary
    End point timeframe
    From baseline (Day 1) up to week 24.
    End point values
    		 Aflibercept 0.4 mg Laser photocoagulation
    Number of subjects analysed
    75
    38
    Units: Proportion of subjects
        number (not applicable)
    0.072
    0.096
    Statistical analysis title
    		 Treatment difference %
    Statistical analysis description
    Bayesian analysis with non-informative prior distributions. Calculation of two-sided 90% credible interval for the treatment difference (aflibercept – laser photocoagulation).
    Comparison groups
    Aflibercept 0.4 mg v Laser photocoagulation
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    Parameter type
    		 Difference in proportions
    Point estimate
    -0.023
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.11
         upper limit
    		 0.046
    Notes
    [2] - Confidence interval actually refers to a credible interval based on the Bayesian analysis.

    Secondary: Proportion of subjects with recurrence of ROP

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    End point title
    		 Proportion of subjects with recurrence of ROP
    End point description
    Subjects with recurrence of ROP were defined as subjects requiring re-treatment or rescue treatment after in the past the absence of treatment-requiring active ROP had been confirmed by the investigator.
    End point type
    Secondary
    End point timeframe
    From baseline (Day 1) up to week 24.
    End point values
    		 Aflibercept 0.4 mg Laser photocoagulation
    Number of subjects analysed
    75
    38
    Units: Proportion of subjects
        number (not applicable)
    0.161
    0.063
    Statistical analysis title
    		 Treatment difference %
    Statistical analysis description
    Bayesian analysis with non-informative prior distributions. Calculation of two-sided 90% credible interval for the treatment difference (aflibercept – laser photocoagulation).
    Comparison groups
    Aflibercept 0.4 mg v Laser photocoagulation
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    Parameter type
    		 Difference in proportions
    Point estimate
    0.096
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.019
         upper limit
    		 0.175
    Notes
    [3] - Confidence interval actually refers to a credible interval based on the Bayesian analysis.

    Secondary: Exploration of ROP activity scale proposed by the International Neonatal Consortium

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    End point title
    		 Exploration of ROP activity scale proposed by the International Neonatal Consortium
    End point description
    Eyes were evaluated for change in ROP activitiy scale proposed by the International Neonatal Consortium (2018). ROP Activity Scale values of 0 to 7 are considered mild, 8 to 12 are moderate, and 13 to 22 are severe.
    End point type
    Secondary
    End point timeframe
    From baseline (Day 1) up to week 24.
    End point values
    		 Aflibercept 0.4 mg Laser photocoagulation
    Number of subjects analysed
    75
    38
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Baseline
    16.20 ( 2.81 )
    15.63 ( 3.53 )
        Change from baseline to Week 24
    -15.42 ( 4.46 )
    -14.77 ( 4.19 )
    No statistical analyses for this end point

    Secondary: Percentage of subjects with ocular Treatment-emergent Adverse Events (TEAEs)

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    End point title
    		 Percentage of subjects with ocular Treatment-emergent Adverse Events (TEAEs)
    End point description
    A treatment-emergent adverse event (TEAE) was defined as an adverse event (AE) that was observed or reported after the first and not later than 30 days after the last administration of study treatment.
    End point type
    Secondary
    End point timeframe
    From baseline (Day 1) up to week 24.
    End point values
    		 Aflibercept 0.4 mg Laser photocoagulation
    Number of subjects analysed
    75
    38
    Units: Percentage
        number (not applicable)
    38.7
    36.8
    No statistical analyses for this end point

    Secondary: Percentage of subjects with ocular Serious Adverse Events (SAEs)

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    End point title
    		 Percentage of subjects with ocular Serious Adverse Events (SAEs)
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline (Day 1) up to week 28
    End point values
    		 Aflibercept 0.4 mg Laser photocoagulation
    Number of subjects analysed
    75
    38
    Units: Percentage
        number (not applicable)
    13.3
    7.9
    No statistical analyses for this end point

    Secondary: Percentage of subjects with systemic TEAEs

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    End point title
    		 Percentage of subjects with systemic TEAEs
    End point description
    A treatment-emergent adverse event (TEAE) was defined as an adverse event (AE) that was observed or reported after the first and not later than 30 days after the last administration of study treatment.
    End point type
    Secondary
    End point timeframe
    From baseline (Day 1) up to week 24.
    End point values
    		 Aflibercept 0.4 mg Laser photocoagulation
    Number of subjects analysed
    75
    38
    Units: Percentage
        number (not applicable)
    52.0
    63.2
    No statistical analyses for this end point

    Secondary: Percentage of subjects with systemic SAEs

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    End point title
    		 Percentage of subjects with systemic SAEs
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline (Day 1) up to week 28
    End point values
    		 Aflibercept 0.4 mg Laser photocoagulation
    Number of subjects analysed
    75
    38
    Units: Subjects
        number (not applicable)
    24.0
    36.8
    No statistical analyses for this end point

    Secondary: Concentrations of free aflibercept in plasma

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    End point title
    		 Concentrations of free aflibercept in plasma [4]
    End point description
    Blood samples for determination of aflibercept concentrations in plasma were collected in the aflibercept 0.4 mg arm at Day 1 (within 24 hours after injection), and at weeks 2 and 4, and if feasible also at weeks 8, 12 and 24. Statistics for week 8, 12, 24 not calculated as > 1/3 of the concentrations were below the lower limit of quantification.
    End point type
    Secondary
    End point timeframe
    From baseline (Day 1) up to week 24.
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Concentrations of free aflibercept in plasma are only applicable for aflibercept 0.4 mg arm
    End point values
    		 Aflibercept 0.4 mg
    Number of subjects analysed
    75
    Units: ng/mL
    arithmetic mean (standard deviation)
        WEEK 0, DAY 1
    480.607 ( 884.724 )
        WEEK 2
    218.965 ( 358.933 )
        WEEK 4
    133.093 ( 205.052 )
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-drug antibodies (ADA)

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    End point title
    		 Number of subjects with anti-drug antibodies (ADA) [5]
    End point description
    Immunogenicity was characterized by anti-drug antibody (ADA) responses in patients in the aflibercept 0.4 mg arm. Serum samples were taken at baseline prior to the injection and at 12 weeks after injection. ADA titers were summarized for 3 categories: Low (titer <1,000); Moderate (1,000 ≤ titer ≤ 10,000); High (titer >10,000).
    End point type
    Secondary
    End point timeframe
    Baseline and 12 weeks after aflibercept injection
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Number of subjects with anti-drug antibodies (ADA) is only applicable for aflibercept 0.4 mg arm
    End point values
    		 Aflibercept 0.4 mg
    Number of subjects analysed
    75
    Units: Subjects
        Baseline
    0
        Week 12
    1
    No statistical analyses for this end point

    Secondary: Number of subjects with potential neutralizing antibodies (NAb)

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    End point title
    		 Number of subjects with potential neutralizing antibodies (NAb) [6]
    End point description
    NAb status was evaluated for the samples that were positive in the ADA assay and had sufficient volume to analyze.
    End point type
    Secondary
    End point timeframe
    At 12 weeks after aflibercept injection
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Number of subjects with potential neutralizing antibodies (NAb) is only applicable for aflibercept 0.4 mg arm
    End point values
    		 Aflibercept 0.4 mg
    Number of subjects analysed
    1
    Units: Subjects
        Week 12
    0
    No statistical analyses for this end point

    Secondary: Number of aflibercept administrations

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    End point title
    		 Number of aflibercept administrations
    End point description
    Total number of injections in both eyes.
    End point type
    Secondary
    End point timeframe
    From baseline (Day 1) up to week 24.
    End point values
    		 Aflibercept 0.4 mg Laser photocoagulation
    Number of subjects analysed
    75
    38
    Units: Subjects
        0 aflibercept administration
    0
    34
        1 aflibercept administration
    4
    0
        2 aflibercept administrations
    55
    3
        3 aflibercept administrations
    6
    1
        4 aflibercept administrations
    10
    0
    No statistical analyses for this end point

    Secondary: Number of laser treatments

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    End point title
    		 Number of laser treatments
    End point description
    Total number of laser treatment in both eyes. If multiple sessions of laser treatment were necessary within 1 week from baseline, they were counted as a single treatment.
    End point type
    Secondary
    End point timeframe
    From baseline (Day 1) up to week 24.
    End point values
    		 Aflibercept 0.4 mg Laser photocoagulation
    Number of subjects analysed
    75
    38
    Units: Subjects
        0 laser treatment
    70
    0
        1 laser treatment
    3
    4
        2 laser treatments
    2
    30
        3 laser treatments
    0
    1
        4 laser treatments
    0
    2
        6 laser treatments
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Laser photocoagulation
    Reporting group description
    		 Laser treatment to each eligible eye at baseline (Day 1),with supplementary laser treatments allowed.Multiple sessions within one week from baseline were counted as a single treatment.

    Reporting group title
    Aflibercept 0.4 mg
    Reporting group description
    		 One intravitreal injection of aflibercept 0.4 mg (0.01 mL) per eligible eye at baseline (Day 1), with up to 2 re-injections at the same single dose allowed for each eligible eye if required and interval since last aflibercept injection was 28 or more days.

    Serious adverse events
    		 Laser photocoagulation Aflibercept 0.4 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 38 (26.32%)
    9 / 75 (12.00%)
         number of deaths (all causes)
    0
    3
         number of deaths resulting from adverse events
    0
    1
    Investigations
    Intraocular pressure increased
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Pulmonary valve stenosis
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Corneal oedema
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    2 / 38 (5.26%)
    3 / 75 (4.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal haemorrhage
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 75 (2.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinopathy of prematurity
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Necrotising colitis
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Apnoea
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary dysplasia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infantile apnoea
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 75 (2.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Conjunctivitis
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinitis
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         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: 0%
    Non-serious adverse events
    		 Laser photocoagulation Aflibercept 0.4 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 38 (60.53%)
    53 / 75 (70.67%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haemangioma
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Haemangioma of liver
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Crying
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Injection site haemorrhage
         subjects affected / exposed
    0 / 38 (0.00%)
    3 / 75 (4.00%)
         occurrences all number
    0
    3
    Injection site reaction
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    2
    Pain
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 38 (0.00%)
    3 / 75 (4.00%)
         occurrences all number
    0
    3
    Respiratory, thoracic and mediastinal disorders
    Apnoea
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 75 (2.67%)
         occurrences all number
    2
    2
    Bronchopulmonary dysplasia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Cough
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Laryngeal stenosis
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    Nasal obstruction
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Tachypnoea
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Stridor
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    Rhonchi
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Respiratory distress
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Pulmonary hypertension
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Chronic respiratory disease
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Investigations
    Cardiac murmur
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Intraocular pressure increased
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 75 (2.67%)
         occurrences all number
    0
    3
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 38 (0.00%)
    3 / 75 (4.00%)
         occurrences all number
    0
    4
    Brain stem auditory evoked response abnormal
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 75 (2.67%)
         occurrences all number
    0
    3
    Otoacoustic emissions test abnormal
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 75 (2.67%)
         occurrences all number
    0
    3
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Post procedural oedema
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 75 (0.00%)
         occurrences all number
    2
    0
    Multiple use of single-use product
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Congenital, familial and genetic disorders
    Cryptorchism
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Ankyloglossia congenital
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Congenital arterial malformation
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Laryngomalacia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 75 (2.67%)
         occurrences all number
    0
    2
    Sinus tachycardia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Tachycardia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Nervous system disorders
    Developmental coordination disorder
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Intraventricular haemorrhage
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Intraventricular haemorrhage neonatal
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 75 (1.33%)
         occurrences all number
    1
    1
    Thalamus haemorrhage
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 75 (2.67%)
         occurrences all number
    0
    2
    Neonatal seizure
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 75 (1.33%)
         occurrences all number
    3
    1
    Anaemia neonatal
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 75 (0.00%)
         occurrences all number
    2
    0
    Splenomegaly
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Auditory disorder
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 38 (0.00%)
    4 / 75 (5.33%)
         occurrences all number
    0
    6
    Conjunctival oedema
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 75 (2.67%)
         occurrences all number
    0
    4
    Corneal oedema
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 75 (0.00%)
         occurrences all number
    2
    0
    Eyelid oedema
         subjects affected / exposed
    3 / 38 (7.89%)
    2 / 75 (2.67%)
         occurrences all number
    5
    4
    Iris adhesions
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    Keratitis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    2
    Retinal artery occlusion
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    2
    Lenticular opacities
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    2
    Retinal detachment
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    2
    Retinal vascular disorder
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    2
    Retinal haemorrhage
         subjects affected / exposed
    5 / 38 (13.16%)
    4 / 75 (5.33%)
         occurrences all number
    6
    7
    Retinopathy of prematurity
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 75 (2.67%)
         occurrences all number
    2
    3
    Swelling of eyelid
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    2
    Vitreous haemorrhage
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    Vitreous opacities
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    2
    Vitreoretinal traction syndrome
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    2
    Macular fibrosis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Abdominal pain
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    Cheilitis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 75 (1.33%)
         occurrences all number
    1
    1
    Dysphagia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Enterocolitis
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    Flatulence
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 75 (1.33%)
         occurrences all number
    1
    1
    Inguinal hernia
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 75 (2.67%)
         occurrences all number
    1
    3
    Umbilical hernia
         subjects affected / exposed
    3 / 38 (7.89%)
    1 / 75 (1.33%)
         occurrences all number
    3
    1
    Vomiting
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Hepatic lesion
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Eczema infantile
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Dermatitis diaper
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 75 (2.67%)
         occurrences all number
    1
    2
    Dermatitis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Haemorrhage subcutaneous
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 75 (0.00%)
         occurrences all number
    3
    0
    Intertrigo
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Glycosuria
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Haematuria
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    Proteinuria
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 75 (1.33%)
         occurrences all number
    1
    1
    Leukocyturia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Adrenomegaly
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Cushingoid
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Osteopenia
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 75 (2.67%)
         occurrences all number
    0
    2
    Extremity contracture
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Infections and infestations
    Bacterial disease carrier
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 75 (0.00%)
         occurrences all number
    2
    0
    Bacteriuria
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    Bronchiolitis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Conjunctivitis
         subjects affected / exposed
    3 / 38 (7.89%)
    3 / 75 (4.00%)
         occurrences all number
    5
    5
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    Ear infection
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Infection
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Rhinitis
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 75 (2.67%)
         occurrences all number
    0
    2
    Sepsis
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 75 (0.00%)
         occurrences all number
    2
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    Oral fungal infection
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 75 (1.33%)
         occurrences all number
    1
    1
    Rhinovirus infection
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Alkalosis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    2
    Hypoglycaemia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Hypokalaemia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Metabolic acidosis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Hypomagnesaemia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Jun 2020
    Pharmacokinetic samples were added at weeks 8, 12, and 24 to further characterize the PK profile in subjects treated with aflibercept, document the further elimination of free (pharmacologically active) aflibercept and bound aflibercept from plasma, and provide estimates of the elimination half-life.

    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
    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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