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    Clinical Trial Results:
    A Longitudinal, Biomarker Study of Anti-VEGF, to Explore the Relationship Between Aqueous Humor Composition and Multimodal Retinal Imaging in Neovascular Age-related Macular Degeneration and Diabetic Macular Edema

    Summary
    EudraCT number
    		 2020-003515-10
    Trial protocol
    		 CZ   PL   IT  
    Global end of trial date
    19 Dec 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Aug 2025
    First version publication date
    28 Aug 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BP41783
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche Ltd.
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4058
    Public contact
    F. Hoffmann-La Roche Ltd., F. Hoffmann-La Roche Ltd., +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche Ltd., F. Hoffmann-La Roche Ltd., +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    19 Dec 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Dec 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study was to explore the aqueous humor (AH) biomarkers and multimodal retinal imaging features before and during a six-month treatment period with aflibercept in subjects with neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME).
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form (ICF).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Apr 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 106
    Country: Number of subjects enrolled
    Korea, Republic of: 62
    Country: Number of subjects enrolled
    Colombia: 10
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Poland: 16
    Country: Number of subjects enrolled
    Czechia: 4
    Worldwide total number of subjects
    209
    EEA total number of subjects
    31
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    60
    From 65 to 84 years
    133
    85 years and over
    16

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 116 subjects with nAMD and 93 subjects with DME took part in the study across 36 sites in the United States, the Republic of Korea, Colombia, Italy, Poland, and the Czech Republic from 12 April 2021 to 19 December 2022.

    Pre-assignment
    Screening details
    		 Subjects with nAMD and DME who were treatment-naïve in the study eye received aflibercept as an intravitreal (IVT) injection.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 nAMD-treatment Naive
    Arm description
    		 Subjects received aflibercept, 2 milligrams (mg), as an IVT injection, every 4 weeks (Q4W) for the first 3 doses, and thereafter once every 8 weeks (Q8W) up to Week 24.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aflibercept
    Investigational medicinal product code
    Other name
    Eylea®
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Aflibercept, 2 mg, as an IVT injection, Q4W for the first 3 doses, and thereafter once Q8W up to Week 24.

    Arm title
    		 DME-treatment Naive
    Arm description
    		 Subjects received aflibercept, 2 mg, as an IVT injection, Q4W for the first 5 doses, and thereafter once Q8W up to Week 24.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aflibercept
    Investigational medicinal product code
    Other name
    Eylea®
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Aflibercept, 2 mg, as an IVT injection, Q4W for the first 5 doses, and thereafter once Q8W up to Week 24.

    Number of subjects in period 1
    		nAMD-treatment Naive DME-treatment Naive
    Started
    116
    93
    Completed
    112
    82
    Not completed
    4
    11
         Adverse event, serious fatal
    1
    1
         Consent withdrawn by subject
    1
    3
         Adverse event, non-fatal
    1
    4
         Lost to follow-up
    1
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    nAMD-treatment Naive
    Reporting group description
    		 Subjects received aflibercept, 2 milligrams (mg), as an IVT injection, every 4 weeks (Q4W) for the first 3 doses, and thereafter once every 8 weeks (Q8W) up to Week 24.

    Reporting group title
    DME-treatment Naive
    Reporting group description
    		 Subjects received aflibercept, 2 mg, as an IVT injection, Q4W for the first 5 doses, and thereafter once Q8W up to Week 24.

    Reporting group values
    		 nAMD-treatment Naive DME-treatment Naive Total
    Number of subjects
    		 116 93 209
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 75.2 ( 8.6 ) 63.7 ( 8.6 ) -
    Gender Categorical
    Units: subjects
        Female
    		 60 43 103
        Male
    		 56 50 106

    End points

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    End points reporting groups
    Reporting group title
    nAMD-treatment Naive
    Reporting group description
    		 Subjects received aflibercept, 2 milligrams (mg), as an IVT injection, every 4 weeks (Q4W) for the first 3 doses, and thereafter once every 8 weeks (Q8W) up to Week 24.

    Reporting group title
    DME-treatment Naive
    Reporting group description
    		 Subjects received aflibercept, 2 mg, as an IVT injection, Q4W for the first 5 doses, and thereafter once Q8W up to Week 24.

    Primary: Best Corrected Visual Acuity (BCVA) Scores at the Specified Timepoints

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    End point title
    		 Best Corrected Visual Acuity (BCVA) Scores at the Specified Timepoints [1]
    End point description
    BCVA was measured using the set of three Precision Vision^TM or Lighthouse distance acuity charts (modified Early Treatment Diabetic Retinopathy Study [ETDRS] Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity (VA) examiner. The BCVA letter score ranges from 0 to 100. Higher scores and a gain in BCVA letter score from baseline indicated an improvement in VA. Intent-to-treat (ITT) population included all subjects enrolled in the study. Number analyzed is the number of subjects with data available for analysis. n = number of subjects with data available for analysis at the specified time point. 9999 = No subjects were analyzed at the specified time point.
    End point type
    Primary
    End point timeframe
    nAMD: Baseline, Day 56 and Day 168; DME: Baseline, Day 112 and Day 168
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This was an exploratory study that was not designed for formal hypothesis testing. No comparisons were made between the nAMD and DME cohorts.
    End point values
    		 nAMD-treatment Naive DME-treatment Naive
    Number of subjects analysed
    114
    93
    Units: letters
    arithmetic mean (standard deviation)
        Baseline (n=114, 93)
    57.78 ( 14.39 )
    61.76 ( 11.29 )
        Day 56 (n=113,0)
    62.93 ( 15.6 )
    9999 ( 9999 )
        Day 112 (n=0, 84)
    9999 ( 9999 )
    69 ( 11.03 )
        Day 168 (n=112, 82)
    64.12 ( 16.46 )
    68.67 ( 11.04 )
    No statistical analyses for this end point

    Primary: Change From Baseline in BCVA Scores at the Specified Timepoints

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    End point title
    		 Change From Baseline in BCVA Scores at the Specified Timepoints [2]
    End point description
    BCVA was measured using the set of three Precision Vision^TM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified VA examiner. The BCVA letter score ranges from 0 to 100. Higher scores and a gain in BCVA letter score from baseline indicated an improvement in VA. ITT population included all subjects enrolled in the study. Number analyzed is the number of subjects with data available for analysis. n = number of subjects with data available for analysis at the specified time point. 9999 = No subjects were analyzed at the specified time point.
    End point type
    Primary
    End point timeframe
    nAMD: Day 56 and Day 168; DME: Day 112 and Day 168
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This was an exploratory study that was not designed for formal hypothesis testing. No comparisons were made between the nAMD and DME cohorts.
    End point values
    		 nAMD-treatment Naive DME-treatment Naive
    Number of subjects analysed
    112
    84
    Units: letters
    arithmetic mean (standard deviation)
        Day 56 (n=112,0)
    5.24 ( 7.52 )
    9999 ( 9999 )
        Day 112 (n=0,84)
    9999 ( 9999 )
    6.92 ( 6.68 )
        Day 168 (n=111, 82)
    6.19 ( 9.22 )
    6.61 ( 7.37 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in BCVA Scores Based on Mixed-effect Model of Repeated Measures (MMRM) Over Time

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    End point title
    		 Change From Baseline in BCVA Scores Based on Mixed-effect Model of Repeated Measures (MMRM) Over Time
    End point description
    BCVA was measured using the set of three Precision Vision^TM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified VA examiner. The BCVA letter score ranges from 0 to 100. Higher scores and a gain in BCVA letter score from baseline indicated an improvement in VA. The analysis was performed using an MMRM. Adjusted mean is reported here. ITT population included all subjects enrolled in the study. Number analyzed is the number of subjects with data available for analysis. n = number of subjects with data available for analysis at the specified time point. 9999 = No subjects were analyzed at the specified time point.
    End point type
    Secondary
    End point timeframe
    nAMD: Day 56, and Day 168; DME: Day 112, Day 168, and Early Termination Visit
    End point values
    		 nAMD-treatment Naive DME-treatment Naive
    Number of subjects analysed
    112
    84
    Units: letters
    arithmetic mean (standard error)
        Day 56 (n = 112, 0)
    5.0 ( 0.85 )
    9999 ( 9999 )
        Day 112 (n = 0, 84)
    9999 ( 9999 )
    6.4 ( 0.78 )
        Day 168 (n = 111, 82)
    5.9 ( 0.96 )
    6.2 ( 0.81 )
        Early Termination (n = 0, 4)
    9999 ( 9999 )
    13.6 ( 3.85 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Absence of Intraretinal Fluid (IRF) in the Central Subfield Over Time

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    End point title
    		 Percentage of Subjects With Absence of Intraretinal Fluid (IRF) in the Central Subfield Over Time
    End point description
    The absence of IRF in the study eye (defined as IRF absent or definite outside center subfield only) was assessed by the central reading center using Spectral Domain-Optical Coherence Tomography (SD-OCT). The percentage of subjects with absence of IRF and a two-sided 95% Clopper-Pearson exact confidence interval (CI) was reported. ITT population included all subjects enrolled in the study. 9999 = No subjects were analyzed at the specified time point.
    End point type
    Secondary
    End point timeframe
    nAMD: Baseline, Day 56 and Day 168; DME: Baseline, Day 112 and Day 168
    End point values
    		 nAMD-treatment Naive DME-treatment Naive
    Number of subjects analysed
    116
    93
    Units: percentage of subjects
    number (confidence interval 95%)
        Baseline
    36.2 (27.5 to 45.6)
    0.0 (0.0 to 3.9)
        Day 56
    59.5 (50.0 to 68.5)
    9999 (9999 to 9999)
        Day 112
    9999 (9999 to 9999)
    9.7 (4.5 to 17.6)
        Day 168
    64.7 (55.2 to 73.3)
    11.8 (6.1 to 20.2)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Absence of Subretinal Fluid (SRF) in the Central Subfield Over Time

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    End point title
    		 Percentage of Subjects With Absence of Subretinal Fluid (SRF) in the Central Subfield Over Time
    End point description
    The absence of SRF in the study eye (defined as SRF absent or definite outside center subfield only) was assessed by the central reading center using SD-OCT. The percentage of subjects with absence of SRF and a two-sided 95% Clopper-Pearson exact CI was reported. ITT population included all subjects enrolled in the study. 9999 = No subjects were analyzed at the specified time point.
    End point type
    Secondary
    End point timeframe
    nAMD: Baseline, Day 56 and Day 168; DME: Baseline, Day 112 and Day 168
    End point values
    		 nAMD-treatment Naive DME-treatment Naive
    Number of subjects analysed
    116
    93
    Units: percentage of subjects
    number (confidence interval 95%)
        Baseline
    9.5 (4.8 to 16.3)
    66.7 (56.1 to 76.1)
        Day 56
    65.5 (56.1 to 74.1)
    9999 (9999 to 9999)
        Day 112
    9999 (9999 to 9999)
    83.9 (74.8 to 90.7)
        Day 168
    56.0 (46.5 to 65.2)
    82.8 (73.6 to 89.8)
    No statistical analyses for this end point

    Secondary: Central Subfield Thickness (CST) Assessed From Internal Limiting Membrane to Bruch's Membrane (ILM-BM) Over Time

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    End point title
    		 Central Subfield Thickness (CST) Assessed From Internal Limiting Membrane to Bruch's Membrane (ILM-BM) Over Time
    End point description
    CST was defined as an objective measurement of retinal thickness in the central 1 millimeter (mm) diameter of macula. It is the distance between the ILM (inner layer of retina) and the BM (outer layer) and was assessed using SD-OCT by the central reading center. ITT population included all subjects enrolled in the study. Number analyzed is the number of subjects with data available for analysis. n = number of subjects with data available for analysis at the specified time point. 9999 = No subjects were analyzed at the specified time point.
    End point type
    Secondary
    End point timeframe
    nAMD: Baseline, Day 56 and Day 168; DME: Baseline, Day 112 and Day 168
    End point values
    		 nAMD-treatment Naive DME-treatment Naive
    Number of subjects analysed
    116
    92
    Units: mm
    arithmetic mean (standard deviation)
        Baseline (n = 116, 92)
    0.46 ( 0.2 )
    0.47 ( 0.11 )
        Day 56 (n = 111, 0)
    0.3 ( 0.11 )
    9999 ( 9999 )
        Day 112 (n = 0, 82)
    9999 ( 9999 )
    0.33 ( 0.07 )
        Day 168 (n = 111, 81)
    0.33 ( 0.12 )
    0.33 ( 0.09 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in CST Assessed From ILM-BM Over Time

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    End point title
    		 Change From Baseline in CST Assessed From ILM-BM Over Time
    End point description
    CST was defined as an objective measurement of retinal thickness in the central 1 mm diameter of macula. It is the distance between the ILM (inner layer of retina) and the BM (outer layer) and was assessed using SD-OCT by the central reading center. ITT population included all subjects enrolled in the study. Number analyzed is the number of subjects with data available for analysis. n = number of subjects with data available for analysis at the specified time point. 9999 = No subjects were analyzed at the specified time point.
    End point type
    Secondary
    End point timeframe
    nAMD: Day 56 and Day 168; DME: Day 112 and Day 168
    End point values
    		 nAMD-treatment Naive DME-treatment Naive
    Number of subjects analysed
    111
    82
    Units: mm
    arithmetic mean (standard deviation)
        Day 56 (n = 111, 0)
    -0.16 ( 0.15 )
    9999 ( 9999 )
        Day 112 (n = 0, 82)
    9999 ( 9999 )
    -0.13 ( 0.1 )
        Day 168 (n = 111, 81)
    -0.14 ( 0.17 )
    -0.13 ( 0.11 )
    No statistical analyses for this end point

    Secondary: CST Assessed From ILM to Retinal Pigment Epithelium (RPE) Over Time

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    End point title
    		 CST Assessed From ILM to Retinal Pigment Epithelium (RPE) Over Time
    End point description
    CST was defined as an objective measurement of retinal thickness in the central 1 mm diameter of macula. It is the distance between the ILM (inner layer of retina) and the RPE (outer layer) and was assessed using SD-OCT by the central reading center. ITT population included all subjects enrolled in the study. Number analyzed is the number of subjects with data available for analysis. n = number of subjects with data available for analysis at the specified time point. 9999 = No subjects were analyzed at the specified time point.
    End point type
    Secondary
    End point timeframe
    nAMD: Baseline, Day 56 and Day 168; DME: Baseline, Day 112 and Day 168
    End point values
    		 nAMD-treatment Naive DME-treatment Naive
    Number of subjects analysed
    115
    93
    Units: mm
    arithmetic mean (standard deviation)
        Baseline (n = 115, 93)
    0.34 ( 0.1 )
    0.44 ( 0.11 )
        Day 56 (n = 110, 0)
    0.23 ( 0.05 )
    9999 ( 9999 )
        Day 112 (n = 0, 83)
    9999 ( 9999 )
    0.31 ( 0.07 )
        Day 168 (n = 110, 81)
    0.24 ( 0.07 )
    0.31 ( 0.09 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in CST Assessed From ILM-RPE Over Time

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    End point title
    		 Change From Baseline in CST Assessed From ILM-RPE Over Time
    End point description
    CST was defined as an objective measurement of retinal thickness in the central 1 mm diameter of macula. It is the distance between the ILM (inner layer of retina) and the RPE (outer layer) and was assessed using SD-OCT by the central reading center. ITT population included all subjects enrolled in the study. Number analyzed is the number of subjects with data available for analysis. n = number of subjects with data available for analysis at the specified time point. 9999 = No subjects were analyzed at the specified time point.
    End point type
    Secondary
    End point timeframe
    nAMD: Day 56 and Day 168; DME: Day 112 and Day 168
    End point values
    		 nAMD-treatment Naive DME-treatment Naive
    Number of subjects analysed
    110
    83
    Units: mm
    arithmetic mean (standard deviation)
        Day 56 (n = 110, 0)
    -0.12 ( 0.1 )
    9999 ( 9999 )
        Day 112 (n = 0, 83)
    9999 ( 9999 )
    -0.13 ( 0.1 )
        Day 168 (n = 110, 81)
    -0.1 ( 0.11 )
    -0.13 ( 0.11 )
    No statistical analyses for this end point

    Secondary: Center Point Thickness (CPT) Assessed From ILM-BM Over Time

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    End point title
    		 Center Point Thickness (CPT) Assessed From ILM-BM Over Time
    End point description
    CPT was defined as the measurement of retinal thickness at the very center of the fovea. It is the distance between the ILM (inner layer of retina) and the BM (outer layer) and was assessed using SD-OCT by the central reading center. ITT population included all subjects enrolled in the study. n = number of subjects with data available for analysis at the specified time point. 9999 = No subjects were analyzed at the specified time point.
    End point type
    Secondary
    End point timeframe
    nAMD: Baseline, Day 56 and Day 168; DME: Baseline, Day 112 and Day 168
    End point values
    		 nAMD-treatment Naive DME-treatment Naive
    Number of subjects analysed
    116
    93
    Units: mm
    arithmetic mean (standard deviation)
        Baseline (n = 116, 93)
    0.43 ( 0.21 )
    0.46 ( 0.13 )
        Day 56 (n = 112, 0)
    0.26 ( 0.11 )
    9999 ( 9999 )
        Day 112 (n = 0, 83)
    9999 ( 9999 )
    0.3 ( 0.1 )
        Day 168 (n = 112, 81)
    0.28 ( 0.13 )
    0.3 ( 0.11 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in CPT Assessed From ILM-BM Over Time

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    End point title
    		 Change From Baseline in CPT Assessed From ILM-BM Over Time
    End point description
    CPT was defined as the measurement of retinal thickness at the very center of the fovea. It is the distance between the ILM (inner layer of retina) and the BM (outer layer) and was assessed using SD-OCT by the central reading center. ITT population included all subjects enrolled in the study. Number analyzed is the number of subjects with data available for analysis. n = number of subjects with data available for analysis at the specified time point. 9999 = No subjects were analyzed at the specified time point.
    End point type
    Secondary
    End point timeframe
    nAMD: Day 56 and Day 168; DME: Day 112 and Day 168
    End point values
    		 nAMD-treatment Naive DME-treatment Naive
    Number of subjects analysed
    112
    83
    Units: mm
    arithmetic mean (standard deviation)
        Day 56 (n = 112, 0)
    -0.17 ( 0.17 )
    9999 ( 9999 )
        Day 112 (n = 0, 83)
    9999 ( 9999 )
    -0.15 ( 0.12 )
        Day 168 (n = 112, 81)
    -0.15 ( 0.19 )
    -0.15 ( 0.13 )
    No statistical analyses for this end point

    Secondary: CPT Assessed From ILM-RPE Over Time

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    End point title
    		 CPT Assessed From ILM-RPE Over Time
    End point description
    CPT was defined as the measurement of retinal thickness at the very center of the fovea. It is the distance between the ILM (inner layer of retina) and the RPE (outer layer) and was assessed using SD-OCT by the central reading center. ITT population included all subjects enrolled in the study. Number analyzed is the number of subjects with data available for analysis. n = number of subjects with data available for analysis at the specified time point. 9999 = No subjects were analyzed at the specified time point.
    End point type
    Secondary
    End point timeframe
    nAMD: Baseline, Day 56 and Day 168; DME: Baseline, Day 112 and Day 168
    End point values
    		 nAMD-treatment Naive DME-treatment Naive
    Number of subjects analysed
    115
    93
    Units: mm
    arithmetic mean (standard deviation)
        Baseline (n = 115, 93)
    0.31 ( 0.13 )
    0.43 ( 0.13 )
        Day 56 (n = 110, 0)
    0.18 ( 0.06 )
    9999 ( 9999 )
        Day 112 (n = 0, 83)
    9999 ( 9999 )
    0.28 ( 0.09 )
        Day 168 (n = 110, 81)
    0.19 ( 0.08 )
    0.28 ( 0.12 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in CPT Assessed From ILM-RPE Over Time

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    End point title
    		 Change From Baseline in CPT Assessed From ILM-RPE Over Time
    End point description
    CPT was defined as the measurement of retinal thickness at the very center of the fovea. It is the distance between the ILM (inner layer of retina) and the RPE (outer layer) and was assessed using SD-OCT by the central reading center. ITT population included all subjects enrolled in the study. Number analyzed is the number of subjects with data available for analysis. n = number of subjects with data available for analysis at the specified time point. 9999 = No subjects were analyzed at the specified time point.
    End point type
    Secondary
    End point timeframe
    nAMD: Day 56 and Day 168; DME: Day 112 and Day 168
    End point values
    		 nAMD-treatment Naive DME-treatment Naive
    Number of subjects analysed
    110
    83
    Units: mm
    arithmetic mean (standard deviation)
        Day 56 (n = 110, 0)
    -0.13 ( 0.13 )
    9999 ( 9999 )
        Day 112 (n = 0, 83)
    9999 ( 9999 )
    -0.14 ( 0.12 )
        Day 168 (n = 110, 81)
    -0.12 ( 0.14 )
    -0.15 ( 0.13 )
    No statistical analyses for this end point

    Secondary: Percentage of DME Subjects With ≥2-Step Improvement From Baseline on the ETDRS-Diabetic Retinopathy Severity Scale (DRSS) Over Time

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    End point title
    		 Percentage of DME Subjects With ≥2-Step Improvement From Baseline on the ETDRS-Diabetic Retinopathy Severity Scale (DRSS) Over Time [3]
    End point description
    The ETDRS-DRSS classifies diabetic retinopathy into 12 severity steps ranging from absence of retinopathy to advanced proliferative diabetic retinopathy. The DRSS ranges from level 10 (no diabetic retinopathy) to level 85 (advanced diabetic retinopathy), where higher scores indicate a higher risk of vision loss. The ETDRS-DRSS score of each subject's study eye was assessed using fundus photography-7 modified fields (FP-7M) taken by trained personnel by the central reading center. The percentage of subjects with a ≥2-step improvement from baseline was summarized along with a two-sided 95% Clopper-Pearson exact CI. ITT population included all subjects enrolled in the DME-treatment naïve arm.
    End point type
    Secondary
    End point timeframe
    At Day 168
    Notes
    [3] - 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: This end point was only applicable to the cohort of patients with DME.
    End point values
    		 DME-treatment Naive
    Number of subjects analysed
    93
    Units: percentage of subjects
        number (confidence interval 95%)
    25.8 (17.3 to 35.9)
    No statistical analyses for this end point

    Secondary: Percentage of DME Subjects With ≥3-Step Improvement From Baseline on the ETDRS-DRSS Over Time

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    End point title
    		 Percentage of DME Subjects With ≥3-Step Improvement From Baseline on the ETDRS-DRSS Over Time [4]
    End point description
    The ETDRS-DRSS classifies diabetic retinopathy into 12 severity steps ranging from absence of retinopathy to advanced proliferative diabetic retinopathy. The DRSS ranges from level 10 (no diabetic retinopathy) to level 85 (advanced diabetic retinopathy), where higher scores indicate a higher risk of vision loss. The ETDRS-DRSS score of each subject's study eye was assessed using FP-7M taken by trained personnel by the central reading center. The percentage of subjects with a ≥3-step improvement from baseline was summarized along with a two-sided 95% Clopper-Pearson exact CI. ITT population included all subjects enrolled in the DME-treatment naïve arm.
    End point type
    Secondary
    End point timeframe
    At Day 168
    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: This end point was only applicable to the cohort of patients with DME.
    End point values
    		 DME-treatment Naive
    Number of subjects analysed
    93
    Units: percentage of subjects
        number (confidence interval 95%)
    8.6 (3.8 to 16.2)
    No statistical analyses for this end point

    Secondary: Retinal Volume Between ILM-BM Over Time in DME Subjects

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    End point title
    		 Retinal Volume Between ILM-BM Over Time in DME Subjects [5]
    End point description
    The retinal volume between ILM and BM in the study eye was assessed using SD-OCT. Volume of retinal thickness within the central 3 mm radius is presented here. ITT population included all subjects enrolled in the DME-treatment naïve arm. n = number of subjects with data available for analysis at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 112 and Day 168
    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: This end point was only applicable to the cohort of patients with DME.
    End point values
    		 DME-treatment Naive
    Number of subjects analysed
    93
    Units: mm^3
    arithmetic mean (standard deviation)
        Baseline (n=93)
    8.38 ( 2.17 )
        Day 112 (n=83)
    6.86 ( 1.36 )
        Day 168 (n=81)
    6.91 ( 1.46 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Retinal Volume Between ILM-BM Over Time in DME Subjects

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    End point title
    		 Change From Baseline in Retinal Volume Between ILM-BM Over Time in DME Subjects [6]
    End point description
    The retinal volume between ILM and BM, in the study eye, was assessed using SD-OCT. Change from baseline in volume of retinal thickness within the central 3 mm radius is presented here. ITT population included all subjects enrolled in the DME-treatment naïve arm. Number analyzed is the number of subjects with data available for analysis. n = number of subjects with data available for analysis at the specified time point.
    End point type
    Secondary
    End point timeframe
    Day 112 and Day 168
    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: This end point was only applicable to the cohort of patients with DME.
    End point values
    		 DME-treatment Naive
    Number of subjects analysed
    83
    Units: mm^3
    arithmetic mean (standard deviation)
        Day 112 (n=83)
    -1.51 ( 1.95 )
        Day 168 (n=81)
    -1.48 ( 2.11 )
    No statistical analyses for this end point

    Secondary: Retinal Volume Between ILM-RPE Over Time in DME Subjects

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    End point title
    		 Retinal Volume Between ILM-RPE Over Time in DME Subjects [7]
    End point description
    The retinal volume between ILM and RPE in the study eye was assessed using SD-OCT. Volume of retinal thickness within the central 3 mm radius is presented here. ITT population included all subjects enrolled in the DME-treatment naïve arm. n = number of subjects with data available for analysis at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 112 and Day 168
    Notes
    [7] - 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: This end point was only applicable to the cohort of patients with DME.
    End point values
    		 DME-treatment Naive
    Number of subjects analysed
    93
    Units: cubic millimeters (mm^3)
    arithmetic mean (standard deviation)
        Baseline (n=93)
    9.56 ( 1.71 )
        Day 112 (n=83)
    8.59 ( 1.2 )
        Day 168 (n=81)
    8.3 ( 1.22 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Retinal Volume Between ILM-RPE Over Time in DME Subjects

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    End point title
    		 Change From Baseline in Retinal Volume Between ILM-RPE Over Time in DME Subjects [8]
    End point description
    The retinal volume between ILM and RPE, in the study eye, was assessed using SD-OCT. Change from baseline in volume of retinal thickness within the central 3 mm radius is presented here. ITT population included all subjects enrolled in the DME-treatment naïve arm. Number analyzed is the number of subjects with data available for analysis. n = number of subjects with data available for analysis at the specified time point.
    End point type
    Secondary
    End point timeframe
    Day 112 and Day 168
    Notes
    [8] - 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: This end point was only applicable to the cohort of patients with DME.
    End point values
    		 DME-treatment Naive
    Number of subjects analysed
    83
    Units: mm^3
    arithmetic mean (standard deviation)
        Day 112 (n=83)
    -0.99 ( 1.3 )
        Day 168 (n=81)
    -1.22 ( 1.32 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 8.5 months
    Adverse event reporting additional description
    Safety population included all subjects enrolled in the study who performed at least one study assessment or had one sample taken on Day 1.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    DME-treatment Naive
    Reporting group description
    		 Subjects received aflibercept, 2 mg, as an IVT injection, Q4W for the first 5 doses, and thereafter once Q8W up to Week 24.

    Reporting group title
    nAMD-treatment Naive
    Reporting group description
    		 Subjects received aflibercept, 2 mg, as an IVT injection, Q4W for the first 3 doses, and thereafter once Q8W up to Week 24.

    Serious adverse events
    		 DME-treatment Naive nAMD-treatment Naive
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 93 (11.83%)
    11 / 116 (9.48%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Leg amputation
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 116 (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
    Fall
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural Pain
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ileus
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash erythematous
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    2 / 93 (2.15%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 DME-treatment Naive nAMD-treatment Naive
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 93 (19.35%)
    14 / 116 (12.07%)
    Injury, poisoning and procedural complications
    Corneal abrasion
         subjects affected / exposed
    2 / 93 (2.15%)
    0 / 116 (0.00%)
         occurrences all number
    2
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 93 (0.00%)
    3 / 116 (2.59%)
         occurrences all number
    0
    3
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    2 / 93 (2.15%)
    0 / 116 (0.00%)
         occurrences all number
    2
    0
    Eye disorders
    Dry Eye
         subjects affected / exposed
    0 / 93 (0.00%)
    3 / 116 (2.59%)
         occurrences all number
    0
    6
    Cataract
         subjects affected / exposed
    3 / 93 (3.23%)
    2 / 116 (1.72%)
         occurrences all number
    4
    2
    Vitreous floaters
         subjects affected / exposed
    0 / 93 (0.00%)
    3 / 116 (2.59%)
         occurrences all number
    0
    3
    Vitreous detachment
         subjects affected / exposed
    1 / 93 (1.08%)
    3 / 116 (2.59%)
         occurrences all number
    1
    4
    Eye pain
         subjects affected / exposed
    0 / 93 (0.00%)
    3 / 116 (2.59%)
         occurrences all number
    0
    3
    Conjunctival hyperaemia
         subjects affected / exposed
    2 / 93 (2.15%)
    0 / 116 (0.00%)
         occurrences all number
    2
    0
    Conjunctival haemorrhage
         subjects affected / exposed
    2 / 93 (2.15%)
    2 / 116 (1.72%)
         occurrences all number
    2
    2
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 93 (2.15%)
    0 / 116 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    4 / 93 (4.30%)
    2 / 116 (1.72%)
         occurrences all number
    4
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Mar 2021
    The following updates were made as per the amendment, version 2: The Schedule of Activities for nAMD and DME was updated, anthropometric measures and a clarification on when to perform the pregnancy test were added; An inclusion criterion for all subjects was added to align female participation with the recommendation of the local prescribing information; Exclusion criteria for all subjects were updated to align with the recommendation of the local prescribing information with additional examples of excluded diseases and information about exclusion of COVID-19 positive subjects, and to exclude subjects with aphakia or implantation of intraocular lens outside of the capsular bag in the study eye; An exclusion criterion for nAMD population was updated with additional examples of excluded ocular diseases other than nAMD; Exclusion criteria for DME population were updated with a clarification that one rescreening is permitted and with additional examples of ocular diseases other than DME; Reporting of post-study AEs and serious adverse events (SAEs) were updated.

    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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