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    Clinical Trial Results:
    Randomized, Controlled, Multi-Center Study to Assess the Efficacy, Safety, and Tolerability of Intravitreal Aflibercept Compared to Laser Photocoagulation in Patients with Retinopathy of Prematurity

    Summary
    EudraCT number
    		 2019-001764-29
    Trial protocol
    		 HU   SK   CZ   BG   BE   PT   GR   RO  
    Global end of trial date
    18 Aug 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Mar 2023
    First version publication date
    02 Mar 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VGFTe-ROP-1920
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04101721
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Regeneron Pharmaceuticals, Inc.
    Sponsor organisation address
    777 Old Saw Mill River Rd., Tarrytown, NY, United States, 10591
    Public contact
    Clinical Trials Administrator, Regeneron Pharmaceuticals, Inc., 001 844-734-6643, clinicaltrials@regeneron.com
    Scientific contact
    Clinical Trials Administrator, Regeneron Pharmaceuticals, Inc., 001 844-734-6643, clinicaltrials@regeneron.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Aug 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Aug 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to assess the efficacy of aflibercept compared to laser in patients diagnosed with retinopathy of prematurity (ROP). The secondary objectives of the study are to assess the need for a second treatment modality, to assess the recurrence of ROP in the study and to assess the safety and tolerability of aflibercept.
    Protection of trial subjects
    It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study will be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Oct 2019
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    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
    Bulgaria: 5
    Country: Number of subjects enrolled
    Colombia: 8
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Country: Number of subjects enrolled
    Romania: 2
    Country: Number of subjects enrolled
    Russian Federation: 9
    Country: Number of subjects enrolled
    Taiwan: 1
    Country: Number of subjects enrolled
    Thailand: 50
    Country: Number of subjects enrolled
    Turkey: 9
    Country: Number of subjects enrolled
    United States: 37
    Country: Number of subjects enrolled
    Viet Nam: 5
    Worldwide total number of subjects
    127
    EEA total number of subjects
    7
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    127
    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
    		 -

    Pre-assignment
    Screening details
    		 137 participants were screened, 127 participants were randomized (94 participants to aflibercept and 33 to laser). 120 participants were treated (93 aflibercept, 27 laser), 7 were withdrawn before receiving any study intervention (aflibercept arm: 1 by parent/guardian; laser arm: 1 physician decision, 5 by parent/guardian).

    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
    		 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
    		 Procedure/surgery

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    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
    VEGF Trap-Eye
    Other name
    EYLEA
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    0.4 mg (0.01 mL) at baseline and up to 2 additional treatments

    Number of subjects in period 1 [1]
    		Laser photocoagulation Aflibercept 0.4 mg
    Started
    27
    93
    Completed
    26
    87
    Not completed
    1
    6
         Adverse event, serious fatal
    -
    1
         Withdrawal By Parent/Guardian
    1
    2
         Lost to follow-up
    -
    3
    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 participants enrolled was 127, however, the baseline data are presented for the 120 participants treated.

    Baseline characteristics

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    Baseline characteristics 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. One or both eyes could be treated.

    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 values
    		 Laser photocoagulation Aflibercept 0.4 mg Total
    Number of subjects
    		 27 93 120
    Age Categorical
    Units: Participants
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 27 93 120
        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
    Chronological Age at Randomization
    Units: weeks
        arithmetic mean (standard deviation)
    		 11.09 ( 4.338 ) 9.76 ( 3.149 ) -
    Gender Categorical
    Units: Participants
        Female
    		 10 52 62
        Male
    		 17 41 58
    Race
    Units: Subjects
        White
    		 11 26 37
        Black or African American
    		 2 6 8
        Asian
    		 13 44 57
        American Indian or Alaska Native
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Other
    		 1 12 13
        Not Reported
    		 0 5 5
    ROP Status by Investigator
    ROP (retinopathy of prematurity) classified by the investigator according to the International Classification for Retinopathy of Prematurity in at least one eye with one of the following retinal findings: Zone I, or Zone II, or AP(aggressive posterior)-ROP (Zone I, Zone II). Zone I is the innermost zone of the retina centered around the optic disc, surrounded by the more peripheral Zone II. AP-ROP is a rapidly progressive form of ROP, with posterior location, most commonly observed in Zone I, less common in posterior Zone II. AP-ROP, if untreated, usually progresses to retinal detachment.
    Units: Subjects
        Zone I
    		 5 16 21
        Zone II
    		 20 68 88
        AP-ROP
    		 2 9 11

    End points

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    End points 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. One or both eyes could be treated.

    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.

    Primary: Percentage of participants with absence of active retinopathy of prematurity (ROP) and unfavorable structural outcomes from baseline to week 52 of chronological age

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    End point title
    		 Percentage of participants with absence of active retinopathy of prematurity (ROP) and unfavorable structural outcomes from baseline to week 52 of chronological age
    End point description
    Active ROP was ROP requiring treatment and unfavorable structural outcome was defined as retinal detachment, macular dragging, macular fold, or retrolental opacity. (For participants with both eyes enrolled in the study, both eyes must meet the endpoint). Full analysis set (FAS): All randomized participants who received any study treatment. Analysis on the FAS will be performed according to the treatment assigned at baseline (as randomized).
    End point type
    Primary
    End point timeframe
    Baseline to week 52 of chronological age
    End point values
    		 Laser photocoagulation Aflibercept 0.4 mg
    Number of subjects analysed
    27
    93
    Units: Percentage of participants
        number (not applicable)
    77.8
    79.6
    Statistical analysis title
    		 Treatment difference (aflibercept vs. laser)
    Statistical analysis description
    Difference with confidence interval (CI) is calculated using Mantel-Haenszel weighting scheme adjusted by baseline ROP status.
    Comparison groups
    Laser photocoagulation v Aflibercept 0.4 mg
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Adjusted difference
    Point estimate
    1.81
    Confidence interval
         level
    		 95.1%
         sides
    2-sided
         lower limit
    		 -15.71
         upper limit
    		 19.33
    Notes
    [1] - Non-inferiority margin is 5%

    Secondary: Percentage of participants requiring intervention with a second treatment modality from baseline to week 52 of chronological age

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    End point title
    		 Percentage of participants requiring intervention with a second treatment modality from baseline to week 52 of chronological age
    End point description
    Second treatment modality includes any treatment in addition to that assigned to the participant at baseline. This includes per-protocol rescue treatment (laser for aflibercept group, aflibercept for laser group), anti-VEGF agents not part of study protocol (e.g., bevacizumab, ranibizumab, commercially-available aflibercept not provided as study medication), or any ocular surgery for the management of any retinal pathology secondary to ROP (e.g., victrectomy, scleral buckle for retinal detachments). (FAS)
    End point type
    Secondary
    End point timeframe
    Baseline to to week 52 of chronological age
    End point values
    		 Laser photocoagulation Aflibercept 0.4 mg
    Number of subjects analysed
    27
    93
    Units: Percentage of participants
        number (not applicable)
    18.5
    15.1
    Statistical analysis title
    		 Treatment difference (aflibercept vs. laser)
    Statistical analysis description
    Difference with confidence interval (CI) is calculated using Mantel-Haenszel weighting scheme adjusted by baseline ROP status.
    Comparison groups
    Laser photocoagulation v Aflibercept 0.4 mg
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Adjusted difference
    Point estimate
    -3.66
    Confidence interval
         level
    		 95.1%
         sides
    2-sided
         lower limit
    		 -19.86
         upper limit
    		 12.54

    Secondary: Percentage of participants with recurrence of ROP through week 52 of chronological age

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    End point title
    		 Percentage of participants with recurrence of ROP through week 52 of chronological age
    End point description
    Recurrence of disease is defined as the reappearance of the disease requiring further treatment (including retreatment or rescue), where both "presence of ROP" and "presence of active ROP requiring treatment" are marked as "Yes", after initial regression. Here, the initial regression is defined as, at a particular visit, absence of ROP or ROP treatment not required for active ROP, i.e., presence of ROP is marked as "No" or the presence of active ROP requiring treatment is marked as "No." (FAS)
    End point type
    Secondary
    End point timeframe
    Baseline to week 52 of chronological age
    End point values
    		 Laser photocoagulation Aflibercept 0.4 mg
    Number of subjects analysed
    27
    93
    Units: Percentage of participants
        number (not applicable)
    29.6
    39.8
    Statistical analysis title
    		 Treatment difference (aflibercept vs. laser)
    Statistical analysis description
    Difference with confidence interval (CI) is calculated using Mantel-Haenszel weighting scheme adjusted by baseline ROP status
    Comparison groups
    Laser photocoagulation v Aflibercept 0.4 mg
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Adjusted difference
    Point estimate
    10.1
    Confidence interval
         level
    		 95.1%
         sides
    2-sided
         lower limit
    		 -9.83
         upper limit
    		 30.02

    Secondary: Percentage of participants with ocular treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs)

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    End point title
    		 Percentage of participants with ocular treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs)
    End point description
    Safety analysis set (SAF): All randomized participants who received any study treatment (active or laser); it is based on the treatment actually received (as treated)
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52 of chronological age
    End point values
    		 Laser photocoagulation Aflibercept 0.4 mg
    Number of subjects analysed
    27
    93
    Units: Percentage of participants
    number (not applicable)
        % Ocular TEAEs
    25.9
    18.3
        % Ocular TESAEs
    11.1
    6.5
    No statistical analyses for this end point

    Secondary: Percentage of participants with systematic (non-ocular) TEAEs and TESAEs

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    End point title
    		 Percentage of participants with systematic (non-ocular) TEAEs and TESAEs
    End point description
    SAF: All randomized participants who received any study treatment (active or laser); it is based on the treatment actually received (as treated)
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52 of chronological age
    End point values
    		 Laser photocoagulation Aflibercept 0.4 mg
    Number of subjects analysed
    27
    93
    Units: Percentage of participants
    number (not applicable)
        % Systematic TEAEs
    51.9
    47.3
        % Systematic TESAEs
    7.4
    12.9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing of ICF to end of study (week 52 of chronological age visit)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    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. One or both eyes could be treated.

    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 reinjections 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.

    Serious adverse events
    		 Laser photocoagulation Aflibercept 0.4 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 27 (44.44%)
    32 / 93 (34.41%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Investigations
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 93 (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
    Anaesthetic complication pulmonary
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative respiratory distress
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure acute
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Prophylaxis against dehydration
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Removal of foreign body from gastrointestinal tract
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Partial seizures
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Eye disorders
    Retinal detachment Study Eye
         subjects affected / exposed
    2 / 27 (7.41%)
    6 / 93 (6.45%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitreous haemorrhage Study Eye
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 93 (2.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrophy of globe Study Eye
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Maculopathy Study Eye
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Corneal infiltrates Study Eye
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal scar Study Eye
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Inguinal hernia
         subjects affected / exposed
    1 / 27 (3.70%)
    2 / 93 (2.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 93 (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
    Apnoeic attack
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Choking
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary dysplasia
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 93 (2.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Apnoea
         subjects affected / exposed
    2 / 27 (7.41%)
    2 / 93 (2.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic respiratory disease
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    1 / 27 (3.70%)
    2 / 93 (2.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 93 (2.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neonatal infection
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical device site infection
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis viral
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
         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 / 27 (0.00%)
    2 / 93 (2.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device malfunction
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Poor feeding infant
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overfeeding of infant
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Laser photocoagulation Aflibercept 0.4 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 27 (44.44%)
    40 / 93 (43.01%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 27 (7.41%)
    1 / 93 (1.08%)
         occurrences all number
    2
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    4 / 27 (14.81%)
    4 / 93 (4.30%)
         occurrences all number
    4
    6
    Eye disorders
    Conjunctival haemorrhage Study Eye
         subjects affected / exposed
    0 / 27 (0.00%)
    5 / 93 (5.38%)
         occurrences all number
    0
    7
    Strabismus Study Eye
         subjects affected / exposed
    0 / 27 (0.00%)
    6 / 93 (6.45%)
         occurrences all number
    0
    9
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    4 / 27 (14.81%)
    4 / 93 (4.30%)
         occurrences all number
    5
    4
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 27 (7.41%)
    5 / 93 (5.38%)
         occurrences all number
    2
    5
    Inguinal hernia
         subjects affected / exposed
    3 / 27 (11.11%)
    4 / 93 (4.30%)
         occurrences all number
    3
    4
    Umbilical hernia
         subjects affected / exposed
    0 / 27 (0.00%)
    5 / 93 (5.38%)
         occurrences all number
    0
    5
    Respiratory, thoracic and mediastinal disorders
    Apnoea
         subjects affected / exposed
    2 / 27 (7.41%)
    1 / 93 (1.08%)
         occurrences all number
    2
    1
    Bronchopulmonary dysplasia
         subjects affected / exposed
    0 / 27 (0.00%)
    7 / 93 (7.53%)
         occurrences all number
    0
    7
    Cough
         subjects affected / exposed
    2 / 27 (7.41%)
    3 / 93 (3.23%)
         occurrences all number
    2
    3
    Wheezing
         subjects affected / exposed
    2 / 27 (7.41%)
    1 / 93 (1.08%)
         occurrences all number
    2
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 27 (7.41%)
    5 / 93 (5.38%)
         occurrences all number
    2
    8
    Musculoskeletal and connective tissue disorders
    Osteopenia
         subjects affected / exposed
    2 / 27 (7.41%)
    2 / 93 (2.15%)
         occurrences all number
    2
    2
    Infections and infestations
    Bacterial disease carrier
         subjects affected / exposed
    2 / 27 (7.41%)
    1 / 93 (1.08%)
         occurrences all number
    2
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 27 (0.00%)
    6 / 93 (6.45%)
         occurrences all number
    0
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jul 2019
    Updated statistical sections to describe the Per Protocol Set (PPS) analysis, which is required for noninferiority studies. Removed reference to pooled analyses (with the Bayer sister study) as this is no longer planned; Clarified that collection of demographic and baseline data includes relevant maternal history; Clarified that the hearing test will be performed once only, at any time prior to discharge from the neonatal intensive care unit (NICU); Clarified that a second central nervous system imaging will be carried out prior to discharge from the NICU; Removed description of volumes for blood sampling, as this information is referenced in other study document(s); Added brief description of the RAINBOW study (in retinopathy of prematurity) for clarity

    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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