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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

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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
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
     Withdrawal by parent/guardian
1
1
     Death
3
-
     COVID-19 pandemic
1
-
     Physician decision
1
-
     Adverse event, non-fatal
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
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
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
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
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
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
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
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
Crying
     subjects affected / exposed
0 / 38 (0.00%)
1 / 75 (1.33%)
     occurrences all number
0
1
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
Injury, poisoning and procedural complications
Contusion
     subjects affected / exposed
0 / 38 (0.00%)
1 / 75 (1.33%)
     occurrences all number
0
1
Multiple use of single-use product
     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
Investigations
Intraocular pressure increased
     subjects affected / exposed
0 / 38 (0.00%)
2 / 75 (2.67%)
     occurrences all number
0
3
Cardiac murmur
     subjects affected / exposed
0 / 38 (0.00%)
1 / 75 (1.33%)
     occurrences all number
0
1
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
Cardiac disorders
Tachycardia
     subjects affected / exposed
0 / 38 (0.00%)
1 / 75 (1.33%)
     occurrences all number
0
1
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
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
Respiratory, thoracic and mediastinal disorders
Cough
     subjects affected / exposed
0 / 38 (0.00%)
1 / 75 (1.33%)
     occurrences all number
0
1
Bronchopulmonary dysplasia
     subjects affected / exposed
0 / 38 (0.00%)
1 / 75 (1.33%)
     occurrences all number
0
1
Apnoea
     subjects affected / exposed
2 / 38 (5.26%)
2 / 75 (2.67%)
     occurrences all number
2
2
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
Pulmonary hypertension
     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
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
Oropharyngeal pain
     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
Blood and lymphatic system disorders
Splenomegaly
     subjects affected / exposed
0 / 38 (0.00%)
1 / 75 (1.33%)
     occurrences all number
0
1
Anaemia neonatal
     subjects affected / exposed
2 / 38 (5.26%)
0 / 75 (0.00%)
     occurrences all number
2
0
Anaemia
     subjects affected / exposed
2 / 38 (5.26%)
1 / 75 (1.33%)
     occurrences all number
3
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
Thalamus 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
Neonatal seizure
     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
Eye disorders
Conjunctival haemorrhage
     subjects affected / exposed
0 / 38 (0.00%)
4 / 75 (5.33%)
     occurrences all number
0
6
Eyelid oedema
     subjects affected / exposed
3 / 38 (7.89%)
2 / 75 (2.67%)
     occurrences all number
5
4
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
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
Retinopathy of prematurity
     subjects affected / exposed
1 / 38 (2.63%)
2 / 75 (2.67%)
     occurrences all number
2
3
Retinal haemorrhage
     subjects affected / exposed
5 / 38 (13.16%)
4 / 75 (5.33%)
     occurrences all number
6
7
Retinal vascular disorder
     subjects affected / exposed
0 / 38 (0.00%)
1 / 75 (1.33%)
     occurrences all number
0
2
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
Vitreoretinal traction syndrome
     subjects affected / exposed
0 / 38 (0.00%)
1 / 75 (1.33%)
     occurrences all number
0
2
Vitreous opacities
     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
Ear and labyrinth disorders
Auditory disorder
     subjects affected / exposed
1 / 38 (2.63%)
0 / 75 (0.00%)
     occurrences all number
1
0
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
Vomiting
     subjects affected / exposed
0 / 38 (0.00%)
1 / 75 (1.33%)
     occurrences all number
0
1
Umbilical hernia
     subjects affected / exposed
3 / 38 (7.89%)
1 / 75 (1.33%)
     occurrences all number
3
1
Inguinal hernia
     subjects affected / exposed
1 / 38 (2.63%)
2 / 75 (2.67%)
     occurrences all number
1
3
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
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
Musculoskeletal and connective tissue disorders
Extremity contracture
     subjects affected / exposed
0 / 38 (0.00%)
1 / 75 (1.33%)
     occurrences all number
0
1
Osteopenia
     subjects affected / exposed
0 / 38 (0.00%)
2 / 75 (2.67%)
     occurrences all number
0
2
Endocrine disorders
Cushingoid
     subjects affected / exposed
0 / 38 (0.00%)
1 / 75 (1.33%)
     occurrences all number
0
1
Adrenomegaly
     subjects affected / exposed
0 / 38 (0.00%)
1 / 75 (1.33%)
     occurrences all number
0
1
Metabolism and nutrition disorders
Hypoglycaemia
     subjects affected / exposed
0 / 38 (0.00%)
1 / 75 (1.33%)
     occurrences all number
0
1
Alkalosis
     subjects affected / exposed
0 / 38 (0.00%)
1 / 75 (1.33%)
     occurrences all number
0
2
Hypokalaemia
     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
Metabolic acidosis
     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
Infection
     subjects affected / exposed
0 / 38 (0.00%)
1 / 75 (1.33%)
     occurrences all number
0
1
Cytomegalovirus infection
     subjects affected / exposed
1 / 38 (2.63%)
0 / 75 (0.00%)
     occurrences all number
1
0
Conjunctivitis
     subjects affected / exposed
3 / 38 (7.89%)
3 / 75 (4.00%)
     occurrences all number
5
5
Bronchiolitis
     subjects affected / exposed
0 / 38 (0.00%)
1 / 75 (1.33%)
     occurrences all number
0
1
Ear infection
     subjects affected / exposed
0 / 38 (0.00%)
1 / 75 (1.33%)
     occurrences all number
0
1
Rhinovirus 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
Sepsis
     subjects affected / exposed
1 / 38 (2.63%)
0 / 75 (0.00%)
     occurrences all number
2
0
Rhinitis
     subjects affected / exposed
0 / 38 (0.00%)
2 / 75 (2.67%)
     occurrences all number
0
2
Nasopharyngitis
     subjects affected / exposed
0 / 38 (0.00%)
1 / 75 (1.33%)
     occurrences all number
0
1
Urinary tract 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

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

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

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