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PANORAMA: Study of the Efficacy and Safety of Intravitreal (IVT) Aflibercept for the Improvement of Moderately Severe to Severe Nonproliferative Diabetic Retinopathy (NPDR)

Sponsor
Regeneron Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT02718326
Collaborator
(none)
402
Enrollment
89
Locations
3
Arms
39.6
Actual Duration (Months)
4.5
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary objective of the study is to assess the efficacy of intravitreal (IVT) aflibercept compared to sham treatment in the improvement of moderately severe to severe nonproliferative diabetic retinopathy (NPDR).

The secondary objectives of the study are:

  • To characterize the safety of IVT aflibercept in patients with moderately severe to severe NPDR

  • To determine if IVT aflibercept will prevent the worsening of diabetic retinopathy and reduce the incidence of DME

  • To determine the anatomic effects of IVT aflibercept in patients with moderately severe to severe NPDR

Condition or Disease Intervention/Treatment Phase
  • Drug: Intravitreal aflibercept injection [IAI]
  • Drug: Sham
 Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
402 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Phase 3, Double-Masked, Randomized Study of the Efficacy and Safety of Intravitreal Aflibercept Injection in Patients With Moderately Severe to Severe Nonproliferative Diabetic Retinopathy
Actual Study Start Date :
Mar 29, 2016
Actual Primary Completion Date :
Aug 6, 2018
Actual Study Completion Date :
Jul 16, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: Dosing regimen 1

Participants will receive IVT aflibercept dosing regimen 1

Drug: Intravitreal aflibercept injection [IAI]
Other Names:
  • EYLEA® (aflibercept) Injection
  • BAY86-5321

    		•
    Experimental: Dosing regimen 2

    Participants will receive IVT aflibercept dosing regimen 2

    Drug: Intravitreal aflibercept injection [IAI]
    Other Names:
  • EYLEA® (aflibercept) Injection
  • BAY86-5321

    		•
    Sham Comparator: Dosing regimen 3

    Participants will receive matching sham injections

    Drug: Sham

    Outcome Measures

    Primary Outcome Measures

    1. Percentage of Participants Who Improved by ≥2 Steps From Baseline in the Diabetic Retinopathy Disease Severity Scale (DRSS) Score at Week 24 in the Combined 2Q16 and 2Q8 Groups [At Week 24]

      The Diabetic Retinopathy Disease Severity Scale (DRSS) may be used to describe overall retinopathy severity as well as the change in severity over time. Severity range from level 10 (DR absent) to level 85 (advanced proliferative DR: posterior fundus obscured, or center of macula detached). Here, DRSS describes severity level 47 (moderately severe NPDR) and level 53 (severe NPDR) at week 24 from baseline.

    2. Percentage of Participants With a ≥ 2-step Change at Week 52 in Diabetic Retinopathy Severity Scale (DRSS) From Baseline [At Week 52]

      The Diabetic Retinopathy Disease Severity Scale (DRSS) may be used to describe overall retinopathy severity as well as the change in severity over time. Severity range from level 10 (DR absent) to level 85 (advanced proliferative DR: posterior fundus obscured, or center of macula detached). Here, DRSS describes severity level 47 (moderately severe NPDR) and level 53 (severe NPDR) at week 52 from baseline.

    Secondary Outcome Measures

    1. Percentage of Participants Who Developed a Vision-Threatening Complication Due to Diabetic Retinopathy at Week 52 [At Week 52]

      Vision-threatening complications are defined as the composite outcome of proliferative diabetic retinopathy (PDR) (inclusive of participants who have vitreous hemorrhage or tractional retinal detachment believed to be due to PDR) and anterior segment neovascularization (ASNV) (participants with neovascularization of the iris [at least 2 cumulative clock hours], and/or definitive neovascularization of the iridocorneal angle).

    2. Percentage of Participants Who Developed Central Involved-Diabetic Macular Edema (CI-DME) at Week 52 [At Week 52]

      The percentage of participants who developed CI-DME at week 52 were reported.

    3. Time to Development of Any Neovascular Vision Threatening Complication (PDR/ASNV) Through Week 52 [Baseline through week 52 (day 365)]

      Vision-threatening complication (VTC) is defined as the composite outcome of proliferative diabetic retinopathy (PDR) (inclusive of participants who have vitreous hemorrhage or tractional retinal detachment believed to be due to PDR) and anterior segment neovascularization (ASNV) (participants with neovascularization of the iris [at least 2 cumulative clock hours], and/or definitive neovascularization of the iridocorneal angle). Vision Threatening Complications include PDR/ASNV identified by investigators and Diabetic Retinopathy Scale Score (DRSS) >61.

    4. Time to Development of Central Involved-Diabetic Macular Edema (CI-DME) Through Week 52 [Baseline through week 52 (day 365)]

      Time to develop Central Involved-Diabetic Macular Edema (CI-DME) through week 52 reported.

    5. Percentage of Participants Who Received Panretinal Photocoagulation (PRP), Inclusive of Participants Undergoing Vitrectomy With Endolaser, at Week 52 [At Week 52]

      The percentage of participants who received panretinal photocoagulation (PRP), inclusive of participants undergoing vitrectomy with endolaser, at week 52 were reported.

    6. Area Under the Curve (AUC) for Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52 [At week 52]

      The area under the curve (AUC) is the area under the best corrected visual acuity (BCVA) versus time curve from baseline to week 52. Visual function of the study eye was assessed at a distance of 4 meters at every study visit using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. BCVA scale range is 0 (worst) to 100 (best).

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Key Inclusion Criteria:

    1. Men or women ≥18 years of age with type 1 or 2 diabetes mellitus who have moderately severe to severe nonproliferative diabetic retinopathy (NPDR) [(diabetic retinopathy severity scale (DRSS) levels 47 or 53)], confirmed by the central reading center, in whom panretinal photocoagulation (PRP) can be safely deferred for at least 6 months per the investigator

    2. Best corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score in the study eye of ≥69 letters (approximate Snellen equivalent of 20/40 or better)

    Key Exclusion Criteria:

    1. Presence of diabetic macular edema (DME) threatening the center of the macula in the study eye

    2. Evidence of retinal neovascularization on clinical examination or Fluorescein Angiography (FA)

    3. Any prior focal or grid laser photocoagulation or any prior PRP in the study eye

    4. Any prior systemic anti-vascular endothelial growth factor (VEGF) treatment or intravitreal (IVT) anti-VEGF treatment in the study eye

    5. Any prior intraocular steroid injection in the study eye

    6. Current anterior segment neovascularization (ASNV), vitreous hemorrhage, or tractional retinal detachment visible at the screening assessments in the study eye

    Note: Other inclusion/ exclusion criteria apply

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Regeneron Study Site Phoenix Arizona United States 85020
    2 Regeneron Study Site Tucson Arizona United States 85704
    3 Regeneron Study Site Arcadia California United States 91007
    4 Regeneron Study Site Beverly Hills California United States 90211
    5 Regeneron Study Site Encino California United States 91436
    6 Regeneron Study Site Fullerton California United States 92835
    7 Regeneron Study Site La Jolla California United States 92093
    8 Regeneron Study Site Mountain View California United States 94040
    9 Regeneron Study Site Oakland California United States 94609
    10 Regeneron Study Site Oceanside California United States 92056
    11 Regeneron Study Site Sacramento California United States 95841
    12 Regeneron Study Site Colorado Springs Colorado United States 80909
    13 Regeneron Study Site Golden Colorado United States 80401
    14 Regeneron Study Site New London Connecticut United States 06320
    15 Regeneron Study Site Altamonte Springs Florida United States 32701
    16 Regeneron Study Site Deerfield Beach Florida United States 33064
    17 Regeneron Study Site Fort Myers Florida United States 33912
    18 Regeneron Study Site Lakeland Florida United States 33805
    19 Regeneron Study Site Largo Florida United States 33770
    20 Regeneron Study Site Melbourne Florida United States 32901
    21 Regeneron Study Site Miami Florida United States 33126
    22 Regeneron Study Site Miami Florida United States 33143
    23 Regeneron Study Site Orlando Florida United States 32806
    24 Regeneron Study Site Plantation Florida United States 33324
    25 Regeneron Study Site Tallahassee Florida United States 32308
    26 Regeneron Study Site Tampa Florida United States 33612
    27 Regeneron Study Site Winter Haven Florida United States 33880
    28 Regeneron Study Ssites Marietta Georgia United States 30060
    29 Regeneron study Site Tucker Georgia United States 30084
    30 Regeneron Study Site Chicago Illinois United States 60612
    31 Regeneron Study Site Oak Forest Illinois United States 60452
    32 Regeneron Study Site Indianapolis Indiana United States 46290
    33 Regeneron Study Site New Albany Indiana United States 47150
    34 Regeneron Study Site Lexington Kentucky United States 40509
    35 Regeneron Study Site Baltimore Maryland United States 21204
    36 Regeneron Study Siste Baltimore Maryland United States 21209
    37 Regeneron Study Site Baltimore Maryland United States 21287
    38 Regeneron Study Site Hagerstown Maryland United States 21740
    39 Regeneron Study Site Boston Massachusetts United States 02114
    40 Regeneron Study Site Henderson Nevada United States 89052
    41 Regeneron Study Site Bloomfield New Jersey United States 07003
    42 Regeneron Study Site Albuquerque New Mexico United States 87109
    43 Regeneron Study Site Asheville North Carolina United States 28803
    44 Regeneron Study Site Charlotte North Carolina United States 28210
    45 Regeneron Study Site Columbus Ohio United States 43212
    46 Regeneron Study Site Oklahoma City Oklahoma United States 73104
    47 Regeneron Study Site Medford Oregon United States 97504
    48 Regeneron Study Site Kingston Pennsylvania United States 18704
    49 Regeneron Study Site Philadelphia Pennsylvania United States 19107
    50 Regeneron Study Site Florence South Carolina United States 29501
    51 Regeneron Study Site Ladson South Carolina United States 29456
    52 Regeneron Study Site West Columbia South Carolina United States 29169
    53 Regeneron Study Site Rapid City South Dakota United States 57701
    54 Regeneron Study Site Chattanooga Tennessee United States 37421
    55 Regeneron Study Site Germantown Tennessee United States 38138
    56 Regeneron Study Site Nashville Tennessee United States 37203
    57 Regeneron Study Site Nashville Tennessee United States 37232
    58 Regeneron Study Site Abilene Texas United States 79606
    59 Regeneron Study Site 1 Austin Texas United States 78705
    60 Regeneron Study Site 2 Austin Texas United States 78705
    61 Regeneron Study Site Dallas Texas United States 75231
    62 Regeneron Study Site Harlingen Texas United States 78559
    63 Regeneron Study Site Houston Texas United States 77030
    64 Regeneron Study Site San Antonio Texas United States 78240
    65 Regeneron Study Site The Woodlands Texas United States 77384
    66 Regeneron Study Site Willow Park Texas United States 76087
    67 Regeneron Study Site Salt Lake City Utah United States 84132
    68 Regeneron Study Site Burlington Vermont United States 05401
    69 Regeneron Study Site Fairfax Virginia United States 22031
    70 Regeneron Study Site Spokane Washington United States 99204
    71 Regeneron Study Site Morgantown West Virginia United States 26506
    72 Regeneron Study Site Marburg Hesse Germany 35043
    73 Regeneron Study Site Münster North Rhine-Westphalia Germany 48145
    74 Regeneron Study Site Leipzig Saxony Germany 04103
    75 Regeneron Study Site Szeged Csongrad Hungary 6720
    76 Regeneron Study Site Debrecen Hajdu-Bihar Hungary 4032
    77 Regeneron Study Site Budapest Pest Hungary 1062
    78 Regeneron Study Site Budapest Pest Hungary 1106
    79 Regeneron Study Site Zalaegerszeg Zala Hungary 8900
    80 Regeneron Study Site Asahikawa Hokkaido Japan 078-8510
    81 Regeneron Study Site Amagasaki Hyogo Japan 660-8550
    82 Regeneron Study Site Matsumoto Nagano Japan 390-8621
    83 Regeneron Study Site Chiyoda Tokyo Japan 101-8309
    84 Regeneron Study Site Kagoshima Japan 890-8520
    85 Regeneron Study Site Nagasaki Japan 852-8501
    86 Regeneron Study Site Arecibo Puerto Rico 00613
    87 Regeneron Study Site San Juan Puerto Rico 00907
    88 Regeneron Study Site Camberley Surrey United Kingdom GU16 7UJ
    89 Regeneron Study Site London United Kingdom EC1V 2PD

    Sponsors and Collaborators

    • Regeneron Pharmaceuticals

    Investigators

    • Study Director: Clinical Trial Management, Regeneron Pharmaceuticals

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Regeneron Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT02718326
    Other Study ID Numbers:
    • VGFTe-OD-1411
    • 2016-002639-14
    First Posted:
    Mar 24, 2016
    Last Update Posted:
    Jul 30, 2020
    Last Verified:
    Jul 1, 2020
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Retinal Diseases
    Diabetic Retinopathy
    Aflibercept

    Study Results

    Participant Flow

    Recruitment Details Recruitment for this study was conducted in the following countries between 29 Mar 2016 and 07 Aug 2017: Germany, Hungary, Japan, the United Kingdom, and the United States. A total of 759 participants were screened.
    Pre-assignment Detail Out of 759, 402 participants were randomized to receive 1 of 3 treatment groups in a 1:1:1 ratio stratified based on their Diabetic Retinopathy Severity Scale (DRSS) score (level 47 vs. level 53). Only 1 eye was selected as the study eye.
    Arm/Group Title Sham Treatment Intravitreal Aflibercept Injection (IAI) 2Q16 Intravitreal Aflibercept Injection (IAI) 2Q8
    Arm/Group Description All participants received sham injections in the study eye every 4 weeks (Q4) to week 16 (after 5 initial monthly sham injections), followed by sham injections Q8 to week 96. All participants received a 2 milligram (mg) Intravitreal Aflibercept Injection (IAI) in the study eye every 16 weeks (2Q16) (after 3 initial monthly doses and one 8-week interval) to week 96. All participants received 2 mg IAI in the study eye every 8 weeks (2Q8) from day 1 up to week 48 (after 5 initial monthly doses), followed by a flexible treatment regimen with IAI 2 mg to week 96.
    Period Title: Overall Study
    STARTED 133 135 134
    Completed Week 52 109 122 124
    COMPLETED 97 111 112
    NOT COMPLETED 36 24 22

    Baseline Characteristics

    Arm/Group Title Sham Treatment Intravitreal Aflibercept Injection (IAI) 2Q16 Intravitreal Aflibercept Injection (IAI) 2Q8 Total
    Arm/Group Description All participants received sham injections in the study eye every 4 weeks (Q4) to week 16 (after 5 initial monthly sham injections), followed by sham injections Q8 to week 96. All participants received a 2 milligram (mg) Intravitreal Aflibercept Injection (IAI) in the study eye every 16 weeks (2Q16) (after 3 initial monthly doses and one 8-week interval) to week 96. All participants received 2 mg IAI in the study eye every 8 weeks (2Q8) from day 1 up to week 48 (after 5 initial monthly doses), followed by a flexible treatment regimen with IAI 2 mg to week 96. Total of all reporting groups
    Overall Participants 133 135 134 402
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    55.8
    (10.31)
    55.4
    (11.13)
    55.8
    (10.19)
    55.7
    (10.53)
    Sex: Female, Male (Count of Participants)
    Female
    64
    48.1%
    60
    44.4%
    53
    39.6%
    177
    44%
    Male
    69
    51.9%
    75
    55.6%
    81
    60.4%
    225
    56%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    74
    55.6%
    97
    71.9%
    93
    69.4%
    264
    65.7%
    Not Hispanic or Latino
    58
    43.6%
    37
    27.4%
    41
    30.6%
    136
    33.8%
    Unknown or Not Reported
    1
    0.8%
    1
    0.7%
    0
    0%
    2
    0.5%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    1
    0.8%
    1
    0.7%
    4
    3%
    6
    1.5%
    Asian
    4
    3%
    12
    8.9%
    7
    5.2%
    23
    5.7%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    1
    0.7%
    1
    0.7%
    2
    0.5%
    Black or African American
    13
    9.8%
    16
    11.9%
    12
    9%
    41
    10.2%
    White
    107
    80.5%
    99
    73.3%
    104
    77.6%
    310
    77.1%
    More than one race
    0
    0%
    1
    0.7%
    1
    0.7%
    2
    0.5%
    Unknown or Not Reported
    8
    6%
    5
    3.7%
    5
    3.7%
    18
    4.5%
    Baseline Diabetic Retinopathy Severity Score (DRSS) (Count of Participants)
    Level 47 (Moderately Severe)
    99
    74.4%
    102
    75.6%
    101
    75.4%
    302
    75.1%
    Level 53 (Severe)
    34
    25.6%
    33
    24.4%
    33
    24.6%
    100
    24.9%

    Outcome Measures

    1. Primary Outcome
    Title Percentage of Participants Who Improved by ≥2 Steps From Baseline in the Diabetic Retinopathy Disease Severity Scale (DRSS) Score at Week 24 in the Combined 2Q16 and 2Q8 Groups
    Description The Diabetic Retinopathy Disease Severity Scale (DRSS) may be used to describe overall retinopathy severity as well as the change in severity over time. Severity range from level 10 (DR absent) to level 85 (advanced proliferative DR: posterior fundus obscured, or center of macula detached). Here, DRSS describes severity level 47 (moderately severe NPDR) and level 53 (severe NPDR) at week 24 from baseline.
    Time Frame At Week 24

    Outcome Measure Data

    Analysis Population Description
    FAS included all randomized participants who received any study treatment as assigned at baseline (as randomized). The missing data were imputed using last observation carried forward (LOCF) method.
    Arm/Group Title Sham Treatment Intravitreal Aflibercept Injection (IAI) 2Q16 Intravitreal Aflibercept Injection (IAI) 2Q8 IAI 2 mg Groups Combined (2Q16 & 2Q8)
    Arm/Group Description All participants received sham injections in the study eye every 4 weeks (Q4) to week 16 (after 5 initial monthly sham injections), followed by sham injections Q8 to week 96. All participants received a 2 milligram (mg) Intravitreal Aflibercept Injection (IAI) in the study eye every 16 weeks (2Q16) (after 3 initial monthly doses and one 8-week interval) to week 96. All participants received 2 mg IAI in the study eye every 8 weeks (2Q8) from day 1 up to week 48 (after 5 initial monthly doses), followed by a flexible treatment regimen with IAI 2 mg to week 96. IAI 2Q16: Participants received a 2 milligram (mg) Intravitreal Aflibercept Injection (IAI) in the study eye every 16 weeks (2Q16) (after 3 initial monthly doses and one 8-week interval) to week 96; IAI 2Q8: Participants received 2 mg IAI in the study eye every 8 weeks (2Q8) from day 1 up to week 48 (after 5 initial monthly doses), followed by a flexible treatment regimen with IAI 2 mg to week 96.
    Measure Participants 133 135 134 269
    Number [Percentage of participants]
    6.0
    4.5%
    61.5
    45.6%
    55.2
    41.2%
    58.4
    14.5%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Sham Treatment, IAI 2 mg Groups Combined (2Q16 & 2Q8)
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter percentage difference
    Estimated Value 52.3
    Confidence Interval (2-Sided) 95%
    45.2 to 59.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Primary Outcome
    Title Percentage of Participants With a ≥ 2-step Change at Week 52 in Diabetic Retinopathy Severity Scale (DRSS) From Baseline
    Description The Diabetic Retinopathy Disease Severity Scale (DRSS) may be used to describe overall retinopathy severity as well as the change in severity over time. Severity range from level 10 (DR absent) to level 85 (advanced proliferative DR: posterior fundus obscured, or center of macula detached). Here, DRSS describes severity level 47 (moderately severe NPDR) and level 53 (severe NPDR) at week 52 from baseline.
    Time Frame At Week 52

    Outcome Measure Data

    Analysis Population Description
    FAS included all randomized participants who received any study treatment as assigned at baseline (as randomized). The missing data were imputed using LOCF method.
    Arm/Group Title Sham Treatment Intravitreal Aflibercept Injection (IAI) 2Q16 Intravitreal Aflibercept Injection (IAI) 2Q8
    Arm/Group Description All participants received sham injections in the study eye every 4 weeks (Q4) to week 16 (after 5 initial monthly sham injections), followed by sham injections Q8 to week 96. All participants received a 2 milligram (mg) Intravitreal Aflibercept Injection (IAI) in the study eye every 16 weeks (2Q16) (after 3 initial monthly doses and one 8-week interval) to week 96. All participants received 2 mg IAI in the study eye every 8 weeks (2Q8) from day 1 up to week 48 (after 5 initial monthly doses), followed by a flexible treatment regimen with IAI 2 mg to week 96.
    Measure Participants 133 135 134
    Number [Percentage of participants]
    15.0
    11.3%
    65.2
    48.3%
    79.9
    59.6%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Sham Treatment, Intravitreal Aflibercept Injection (IAI) 2Q16
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter percentage difference
    Estimated Value 50.1
    Confidence Interval (2-Sided) 95%
    40.1 to 60.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Sham Treatment, Intravitreal Aflibercept Injection (IAI) 2Q8
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter percentage difference
    Estimated Value 64.8
    Confidence Interval (2-Sided) 95%
    55.8 to 73.9
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    Title Percentage of Participants Who Developed a Vision-Threatening Complication Due to Diabetic Retinopathy at Week 52
    Description Vision-threatening complications are defined as the composite outcome of proliferative diabetic retinopathy (PDR) (inclusive of participants who have vitreous hemorrhage or tractional retinal detachment believed to be due to PDR) and anterior segment neovascularization (ASNV) (participants with neovascularization of the iris [at least 2 cumulative clock hours], and/or definitive neovascularization of the iridocorneal angle).
    Time Frame At Week 52

    Outcome Measure Data

    Analysis Population Description
    FAS included all randomized participants who received any study treatment as assigned at baseline (as randomized).
    Arm/Group Title Sham Treatment Intravitreal Aflibercept Injection (IAI) 2Q16 Intravitreal Aflibercept Injection (IAI) 2Q8
    Arm/Group Description All participants received sham injections in the study eye every 4 weeks (Q4) to week 16 (after 5 initial monthly sham injections), followed by sham injections Q8 to week 96. All participants received a 2 milligram (mg) Intravitreal Aflibercept Injection (IAI) in the study eye every 16 weeks (2Q16) (after 3 initial monthly doses and one 8-week interval) to week 96. All participants received 2 mg IAI in the study eye every 8 weeks (2Q8) from day 1 up to week 48 (after 5 initial monthly doses), followed by a flexible treatment regimen with IAI 2 mg to week 96.
    Measure Participants 133 135 134
    Number [Percentage of participants]
    20.3
    15.3%
    3.7
    2.7%
    3.0
    2.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Sham Treatment, Intravitreal Aflibercept Injection (IAI) 2Q8
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter percentage difference
    Estimated Value -17.3
    Confidence Interval (2-Sided) 95%
    -24.7 to -9.9
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Sham Treatment, Intravitreal Aflibercept Injection (IAI) 2Q16
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter percentage difference
    Estimated Value -16.6
    Confidence Interval (2-Sided) 95%
    -24.2 to -9.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Secondary Outcome
    Title Percentage of Participants Who Developed Central Involved-Diabetic Macular Edema (CI-DME) at Week 52
    Description The percentage of participants who developed CI-DME at week 52 were reported.
    Time Frame At Week 52

    Outcome Measure Data

    Analysis Population Description
    FAS included all randomized participants who received any study treatment as assigned at baseline (as randomized).
    Arm/Group Title Sham Treatment Intravitreal Aflibercept Injection (IAI) 2Q16 Intravitreal Aflibercept Injection (IAI) 2Q8
    Arm/Group Description All participants received sham injections in the study eye every 4 weeks (Q4) to week 16 (after 5 initial monthly sham injections), followed by sham injections Q8 to week 96. All participants received a 2 milligram (mg) Intravitreal Aflibercept Injection (IAI) in the study eye every 16 weeks (2Q16) (after 3 initial monthly doses and one 8-week interval) to week 96. All participants received 2 mg IAI in the study eye every 8 weeks (2Q8) from day 1 up to week 48 (after 5 initial monthly doses), followed by a flexible treatment regimen with IAI 2 mg to week 96.
    Measure Participants 133 135 134
    Number [Percentage of participants]
    25.6
    19.2%
    6.7
    5%
    8.2
    6.1%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Sham Treatment, Intravitreal Aflibercept Injection (IAI) 2Q8
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0002
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter percentage difference
    Estimated Value -17.3
    Confidence Interval (2-Sided) 95%
    -26.2 to -8.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Sham Treatment, Intravitreal Aflibercept Injection (IAI) 2Q16
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter percentage difference
    Estimated Value -18.9
    Confidence Interval (2-Sided) 95%
    -27.5 to -10.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    5. Secondary Outcome
    Title Time to Development of Any Neovascular Vision Threatening Complication (PDR/ASNV) Through Week 52
    Description Vision-threatening complication (VTC) is defined as the composite outcome of proliferative diabetic retinopathy (PDR) (inclusive of participants who have vitreous hemorrhage or tractional retinal detachment believed to be due to PDR) and anterior segment neovascularization (ASNV) (participants with neovascularization of the iris [at least 2 cumulative clock hours], and/or definitive neovascularization of the iridocorneal angle). Vision Threatening Complications include PDR/ASNV identified by investigators and Diabetic Retinopathy Scale Score (DRSS) >61.
    Time Frame Baseline through week 52 (day 365)

    Outcome Measure Data

    Analysis Population Description
    FAS included all randomized participants who received any study treatment as assigned at baseline (as randomized). Participants who did not have an event were censored at their last visit at or before the week 52 visit. Here, the value "NA" = Not evaluable due to small number of VTC events.
    Arm/Group Title Sham Treatment Intravitreal Aflibercept Injection (IAI) 2Q16 Intravitreal Aflibercept Injection (IAI) 2Q8
    Arm/Group Description All participants received sham injections in the study eye every 4 weeks (Q4) to week 16 (after 5 initial monthly sham injections), followed by sham injections Q8 to week 96. All participants received a 2 milligram (mg) Intravitreal Aflibercept Injection (IAI) in the study eye every 16 weeks (2Q16) (after 3 initial monthly doses and one 8-week interval) to week 96. All participants received 2 mg IAI in the study eye every 8 weeks (2Q8) from day 1 up to week 48 (after 5 initial monthly doses), followed by a flexible treatment regimen with IAI 2 mg to week 96.
    Measure Participants 133 135 134
    Median (Inter-Quartile Range) [Days]
    NA
    NA
    NA
    6. Secondary Outcome
    Title Time to Development of Central Involved-Diabetic Macular Edema (CI-DME) Through Week 52
    Description Time to develop Central Involved-Diabetic Macular Edema (CI-DME) through week 52 reported.
    Time Frame Baseline through week 52 (day 365)

    Outcome Measure Data

    Analysis Population Description
    FAS included all randomized participants who received any study treatment as assigned at baseline (as randomized). Participants who did not have an event were censored at their last visit, at or before the week 52 visit. Here, the value "NA" = Not evaluable due to small number of CI-DME events.
    Arm/Group Title Sham Treatment Intravitreal Aflibercept Injection (IAI) 2Q16 Intravitreal Aflibercept Injection (IAI) 2Q8
    Arm/Group Description All participants received sham injections in the study eye every 4 weeks (Q4) to week 16 (after 5 initial monthly sham injections), followed by sham injections Q8 to week 96. All participants received a 2 milligram (mg) Intravitreal Aflibercept Injection (IAI) in the study eye every 16 weeks (2Q16) (after 3 initial monthly doses and one 8-week interval) to week 96. All participants received 2 mg IAI in the study eye every 8 weeks (2Q8) from day 1 up to week 48 (after 5 initial monthly doses), followed by a flexible treatment regimen with IAI 2 mg to week 96.
    Measure Participants 133 135 134
    Median (Inter-Quartile Range) [Days]
    NA
    NA
    NA
    7. Secondary Outcome
    Title Percentage of Participants Who Received Panretinal Photocoagulation (PRP), Inclusive of Participants Undergoing Vitrectomy With Endolaser, at Week 52
    Description The percentage of participants who received panretinal photocoagulation (PRP), inclusive of participants undergoing vitrectomy with endolaser, at week 52 were reported.
    Time Frame At Week 52

    Outcome Measure Data

    Analysis Population Description
    FAS included all randomized participants who received any study treatment as assigned at baseline (as randomized).
    Arm/Group Title Sham Treatment Intravitreal Aflibercept Injection (IAI) 2Q16 Intravitreal Aflibercept Injection (IAI) 2Q8
    Arm/Group Description All participants received sham injections in the study eye every 4 weeks (Q4) to week 16 (after 5 initial monthly sham injections), followed by sham injections Q8 to week 96. All participants received a 2 milligram (mg) Intravitreal Aflibercept Injection (IAI) in the study eye every 16 weeks (2Q16) (after 3 initial monthly doses and one 8-week interval) to week 96. All participants received 2 mg IAI in the study eye every 8 weeks (2Q8) from day 1 up to week 48 (after 5 initial monthly doses), followed by a flexible treatment regimen with IAI 2 mg to week 96.
    Measure Participants 133 135 134
    Number [Percentage of participants]
    6.8
    5.1%
    0.7
    0.5%
    0.7
    0.5%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Sham Treatment, Intravitreal Aflibercept Injection (IAI) 2Q8
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0096
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter percentage difference
    Estimated Value -6.0
    Confidence Interval (2-Sided) 95%
    -10.5 to -1.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Sham Treatment, Intravitreal Aflibercept Injection (IAI) 2Q16
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0089
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter percentage difference
    Estimated Value -6.0
    Confidence Interval (2-Sided) 95%
    -10.5 to -1.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    8. Secondary Outcome
    Title Area Under the Curve (AUC) for Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52
    Description The area under the curve (AUC) is the area under the best corrected visual acuity (BCVA) versus time curve from baseline to week 52. Visual function of the study eye was assessed at a distance of 4 meters at every study visit using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. BCVA scale range is 0 (worst) to 100 (best).
    Time Frame At week 52

    Outcome Measure Data

    Analysis Population Description
    AUC was calculated as a weighted average based on total AUC (using the trapezoidal rule) divided by total duration in days. FAS included all randomized participants who received any study treatment as assigned at baseline (as randomized).
    Arm/Group Title Sham Treatment Intravitreal Aflibercept Injection (IAI) 2Q16 Intravitreal Aflibercept Injection (IAI) 2Q8
    Arm/Group Description All participants received sham injections in the study eye every 4 weeks (Q4) to week 16 (after 5 initial monthly sham injections), followed by sham injections Q8 to week 96. All participants received a 2 milligram (mg) Intravitreal Aflibercept Injection (IAI) in the study eye every 16 weeks (2Q16) (after 3 initial monthly doses and one 8-week interval) to week 96. All participants received 2 mg IAI in the study eye every 8 weeks (2Q8) from day 1 up to week 48 (after 5 initial monthly doses), followed by a flexible treatment regimen with IAI 2 mg to week 96.
    Measure Participants 133 135 134
    Mean (Standard Deviation) [scores on a scale]
    0.5
    (3.01)
    1.7
    (3.50)
    1.3
    (3.49)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Sham Treatment, Intravitreal Aflibercept Injection (IAI) 2Q8
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0529
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Estimate for contrast
    Estimated Value 0.80
    Confidence Interval (2-Sided) 95%
    -0.01 to 1.60
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Sham Treatment, Intravitreal Aflibercept Injection (IAI) 2Q16
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0057
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Estimate for contrast
    Estimated Value 1.14
    Confidence Interval (2-Sided) 95%
    0.33 to 1.94
    Parameter Dispersion Type:
    Value:
    Estimation Comments

    Adverse Events

    Time Frame All Adverse Events (AEs) were collected from signature of the informed consent form up to week 100 regardless of seriousness or relationship to investigational product
    Adverse Event Reporting Description Reported adverse events are treatment-emergent adverse events (TEAEs) which are AEs that developed/worsened from baseline (day1) up to end of study (week 100).
    Arm/Group Title Sham Treatment Intravitreal Aflibercept Injection (IAI) 2Q16 Intravitreal Aflibercept Injection (IAI) 2Q8 IAI 2 mg Groups Combined (2Q16 & 2Q8)
    Arm/Group Description All participants received sham injections in the study eye every 4 weeks (Q4) to week 16 (after 5 initial monthly sham injections), followed by sham injections Q8 to week 96. All participants received a 2 milligram (mg) Intravitreal Aflibercept Injection (IAI) in the study eye every 16 weeks (2Q16) (after 3 initial monthly doses and one 8-week interval) to week 96. All participants received 2 mg IAI in the study eye every 8 weeks (2Q8) from day 1 up to week 48 (after 5 initial monthly doses), followed by a flexible treatment regimen with IAI 2 mg to week 96. IAI 2Q16: Participants received a 2 milligram (mg) Intravitreal Aflibercept Injection (IAI) in the study eye every 16 weeks (2Q16) (after 3 initial monthly doses and one 8-week interval) to week 96; IAI 2Q8: Participants received 2 mg IAI in the study eye every 8 weeks (2Q8) from day 1 up to week 48 (after 5 initial monthly doses), followed by a flexible treatment regimen with IAI 2 mg to week 96.
    All Cause Mortality
    Sham Treatment Intravitreal Aflibercept Injection (IAI) 2Q16 Intravitreal Aflibercept Injection (IAI) 2Q8 IAI 2 mg Groups Combined (2Q16 & 2Q8)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 8/133 (6%) 1/135 (0.7%) 3/134 (2.2%) 4/269 (1.5%)
    Serious Adverse Events
    Sham Treatment Intravitreal Aflibercept Injection (IAI) 2Q16 Intravitreal Aflibercept Injection (IAI) 2Q8 IAI 2 mg Groups Combined (2Q16 & 2Q8)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 38/133 (28.6%) 38/135 (28.1%) 47/134 (35.1%) 85/269 (31.6%)
    Blood and lymphatic system disorders
    Anaemia 0/133 (0%) 0 2/135 (1.5%) 2 0/134 (0%) 0 2/269 (0.7%) 2
    Cardiac disorders
    Coronary artery disease 1/133 (0.8%) 1 5/135 (3.7%) 5 4/134 (3%) 4 9/269 (3.3%) 9
    Cardiac failure congestive 1/133 (0.8%) 1 2/135 (1.5%) 2 3/134 (2.2%) 3 5/269 (1.9%) 5
    Myocardial infarction 1/133 (0.8%) 1 2/135 (1.5%) 2 1/134 (0.7%) 1 3/269 (1.1%) 3
    Acute myocardial infarction 2/133 (1.5%) 2 2/135 (1.5%) 2 0/134 (0%) 0 2/269 (0.7%) 2
    Cardiac failure acute 0/133 (0%) 0 1/135 (0.7%) 2 1/134 (0.7%) 1 2/269 (0.7%) 3
    Coronary artery stenosis 0/133 (0%) 0 2/135 (1.5%) 2 0/134 (0%) 0 2/269 (0.7%) 2
    Atrial fibrillation 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Atrial flutter 0/133 (0%) 0 1/135 (0.7%) 1 0/134 (0%) 0 1/269 (0.4%) 1
    Cardiac arrest 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Cardiac failure chronic 0/133 (0%) 0 1/135 (0.7%) 1 0/134 (0%) 0 1/269 (0.4%) 1
    Myocardial ischaemia 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Supraventricular tachycardia 0/133 (0%) 0 1/135 (0.7%) 1 0/134 (0%) 0 1/269 (0.4%) 1
    Acute coronary syndrome 1/133 (0.8%) 1 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Cardiac failure 1/133 (0.8%) 1 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Ischaemic cardiomyopathy 1/133 (0.8%) 1 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Left ventricular dysfunction 1/133 (0.8%) 1 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Left ventricular failure 2/133 (1.5%) 2 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Pulseless electrical activity 1/133 (0.8%) 1 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Eye disorders
    Visual acuity reduced Fellow Eye 1/133 (0.8%) 1 0/135 (0%) 0 3/134 (2.2%) 3 3/269 (1.1%) 3
    Diabetic retinal oedema Fellow Eye 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Macular fibrosis Fellow Eye 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Macular hole Fellow Eye 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Retinal vein occlusion Fellow Eye 0/133 (0%) 0 1/135 (0.7%) 1 0/134 (0%) 0 1/269 (0.4%) 1
    Visual impairment Fellow Eye 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Vitreous adhesions Fellow Eye 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Vitreous haemorrhage Fellow Eye 1/133 (0.8%) 1 1/135 (0.7%) 1 0/134 (0%) 0 1/269 (0.4%) 1
    Cataract Fellow Eye 1/133 (0.8%) 1 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Iris neovascularisation Fellow Eye 2/133 (1.5%) 2 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Cystoid macular oedema Study Eye 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 2 1/269 (0.4%) 2
    Visual acuity reduced Study Eye 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Vitreous haemorrhage Study Eye 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Diabetic retinopathy Study Eye 1/133 (0.8%) 2 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Iris neovascularisation Study Eye 1/133 (0.8%) 1 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Retinal neovascularisation Study Eye 1/133 (0.8%) 1 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Gastrointestinal disorders
    Diabetic gastroparesis 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Dysphagia 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Faecaloma 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Impaired gastric emptying 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 5 1/269 (0.4%) 5
    Small intestinal obstruction 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Upper gastrointestinal haemorrhage 0/133 (0%) 0 1/135 (0.7%) 1 0/134 (0%) 0 1/269 (0.4%) 1
    Vomiting 1/133 (0.8%) 1 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Gastrointestinal haemorrhage 1/133 (0.8%) 1 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Ileus 1/133 (0.8%) 1 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Nausea 1/133 (0.8%) 1 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    General disorders
    Chest pain 0/133 (0%) 0 1/135 (0.7%) 1 0/134 (0%) 0 1/269 (0.4%) 1
    Non-cardiac chest pain 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Asthenia 1/133 (0.8%) 1 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Generalised oedema 1/133 (0.8%) 1 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Pyrexia 1/133 (0.8%) 1 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Hepatobiliary disorders
    Cholecystitis 1/133 (0.8%) 1 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Cholecystitis chronic 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Cholelithiasis 1/133 (0.8%) 1 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Infections and infestations
    Cellulitis 1/133 (0.8%) 1 2/135 (1.5%) 2 5/134 (3.7%) 6 7/269 (2.6%) 8
    Pneumonia 2/133 (1.5%) 2 3/135 (2.2%) 3 3/134 (2.2%) 5 6/269 (2.2%) 8
    Diabetic foot infection 0/133 (0%) 0 3/135 (2.2%) 3 0/134 (0%) 0 3/269 (1.1%) 3
    Sepsis 1/133 (0.8%) 1 0/135 (0%) 0 3/134 (2.2%) 3 3/269 (1.1%) 3
    Abscess limb 0/133 (0%) 0 0/135 (0%) 0 2/134 (1.5%) 2 2/269 (0.7%) 2
    Arthritis bacterial 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Enterococcal bacteraemia 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Gastroenteritis viral 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Influenza 1/133 (0.8%) 1 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Osteomyelitis 4/133 (3%) 4 1/135 (0.7%) 1 0/134 (0%) 0 1/269 (0.4%) 1
    Osteomyelitis acute 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Pneumonia bacterial 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Sepsis syndrome 0/133 (0%) 0 1/135 (0.7%) 1 0/134 (0%) 0 1/269 (0.4%) 1
    Staphylococcal infection 0/133 (0%) 0 1/135 (0.7%) 1 0/134 (0%) 0 1/269 (0.4%) 1
    Staphylococcal osteomyelitis 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Staphylococcal skin infection 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Urinary tract infection 0/133 (0%) 0 1/135 (0.7%) 2 0/134 (0%) 0 1/269 (0.4%) 2
    Appendicitis 1/133 (0.8%) 1 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Diabetic gangrene 1/133 (0.8%) 1 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Infected skin ulcer 1/133 (0.8%) 1 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Septic shock 1/133 (0.8%) 1 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Injury, poisoning and procedural complications
    Anaemia postoperative 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Ankle fracture 0/133 (0%) 0 1/135 (0.7%) 1 0/134 (0%) 0 1/269 (0.4%) 1
    Fall 0/133 (0%) 0 1/135 (0.7%) 1 0/134 (0%) 0 1/269 (0.4%) 1
    Femur fracture 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Fibula fracture 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Meniscus injury 0/133 (0%) 0 1/135 (0.7%) 1 0/134 (0%) 0 1/269 (0.4%) 1
    Postoperative respiratory failure 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Postoperative thoracic procedure complication 0/133 (0%) 0 1/135 (0.7%) 1 0/134 (0%) 0 1/269 (0.4%) 1
    Radius fracture 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Skin laceration 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Tibia fracture 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Traumatic arthropathy 0/133 (0%) 0 1/135 (0.7%) 1 0/134 (0%) 0 1/269 (0.4%) 1
    Ulna fracture 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Limb injury 1/133 (0.8%) 1 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Pneumocephalus 1/133 (0.8%) 1 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Subdural haematoma 1/133 (0.8%) 1 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Traumatic fracture Study Eye 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Investigations
    Blood glucose increased 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Blood sodium decreased 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Metabolism and nutrition disorders
    Dehydration 1/133 (0.8%) 1 0/135 (0%) 0 3/134 (2.2%) 3 3/269 (1.1%) 3
    Diabetic ketoacidosis 0/133 (0%) 0 2/135 (1.5%) 2 0/134 (0%) 0 2/269 (0.7%) 2
    Hypoglycaemia 0/133 (0%) 0 2/135 (1.5%) 2 0/134 (0%) 0 2/269 (0.7%) 2
    Diabetes mellitus 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Gout 0/133 (0%) 0 1/135 (0.7%) 1 0/134 (0%) 0 1/269 (0.4%) 1
    Hyperglycaemia 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Hypokalaemia 1/133 (0.8%) 1 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Hypomagnesaemia 1/133 (0.8%) 1 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cervix carcinoma stage 0 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Gastric cancer 0/133 (0%) 0 1/135 (0.7%) 1 0/134 (0%) 0 1/269 (0.4%) 1
    Malignant melanoma 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Pancreatic carcinoma 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Transitional cell carcinoma metastatic 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Uterine leiomyoma 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Basal cell carcinoma 1/133 (0.8%) 1 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Papillary thyroid cancer 1/133 (0.8%) 2 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Squamous cell carcinoma of skin 1/133 (0.8%) 1 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Nervous system disorders
    Cerebrovascular accident 0/133 (0%) 0 3/135 (2.2%) 3 1/134 (0.7%) 1 4/269 (1.5%) 4
    Brain stem stroke 0/133 (0%) 0 1/135 (0.7%) 1 0/134 (0%) 0 1/269 (0.4%) 1
    Cerebral infarction 0/133 (0%) 0 1/135 (0.7%) 1 0/134 (0%) 0 1/269 (0.4%) 1
    Hepatic encephalopathy 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Hypoglycaemic unconsciousness 1/133 (0.8%) 1 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Ischaemic stroke 3/133 (2.3%) 3 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Psychiatric disorders
    Bipolar disorder 0/133 (0%) 0 1/135 (0.7%) 1 0/134 (0%) 0 1/269 (0.4%) 1
    Renal and urinary disorders
    Acute kidney injury 2/133 (1.5%) 2 1/135 (0.7%) 1 3/134 (2.2%) 3 4/269 (1.5%) 4
    Chronic kidney disease 0/133 (0%) 0 1/135 (0.7%) 1 0/134 (0%) 0 1/269 (0.4%) 1
    End stage renal disease 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Urge incontinence 0/133 (0%) 0 1/135 (0.7%) 1 0/134 (0%) 0 1/269 (0.4%) 1
    Urinary retention 1/133 (0.8%) 1 1/135 (0.7%) 1 0/134 (0%) 0 1/269 (0.4%) 1
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure 1/133 (0.8%) 1 0/135 (0%) 0 2/134 (1.5%) 2 2/269 (0.7%) 2
    Pleural effusion 2/133 (1.5%) 2 1/135 (0.7%) 1 1/134 (0.7%) 1 2/269 (0.7%) 2
    Chronic obstructive pulmonary disease 1/133 (0.8%) 1 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Pulmonary arterial hypertension 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Respiratory acidosis 0/133 (0%) 0 1/135 (0.7%) 1 0/134 (0%) 0 1/269 (0.4%) 1
    Respiratory failure 0/133 (0%) 0 1/135 (0.7%) 1 0/134 (0%) 0 1/269 (0.4%) 1
    Pulmonary congestion 1/133 (0.8%) 1 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Pulmonary hypertension 2/133 (1.5%) 2 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Skin and subcutaneous tissue disorders
    Diabetic foot 0/133 (0%) 0 1/135 (0.7%) 1 2/134 (1.5%) 2 3/269 (1.1%) 3
    Photosensitivity reaction 1/133 (0.8%) 1 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Vascular disorders
    Peripheral ischaemia 0/133 (0%) 0 0/135 (0%) 0 1/134 (0.7%) 1 1/269 (0.4%) 1
    Arteriosclerosis 1/133 (0.8%) 1 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Hypotension 1/133 (0.8%) 1 0/135 (0%) 0 0/134 (0%) 0 0/269 (0%) 0
    Other (Not Including Serious) Adverse Events
    Sham Treatment Intravitreal Aflibercept Injection (IAI) 2Q16 Intravitreal Aflibercept Injection (IAI) 2Q8 IAI 2 mg Groups Combined (2Q16 & 2Q8)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 104/133 (78.2%) 104/135 (77%) 106/134 (79.1%) 210/269 (78.1%)
    Eye disorders
    Blepharitis Fellow Eye 1/133 (0.8%) 1 3/135 (2.2%) 3 7/134 (5.2%) 7 10/269 (3.7%) 10
    Cataract Fellow Eye 4/133 (3%) 4 9/135 (6.7%) 9 4/134 (3%) 4 13/269 (4.8%) 13
    Conjunctival haemorrhage Fellow Eye 6/133 (4.5%) 7 5/135 (3.7%) 14 8/134 (6%) 14 13/269 (4.8%) 28
    Diabetic retinal oedema Fellow Eye 19/133 (14.3%) 25 17/135 (12.6%) 24 23/134 (17.2%) 27 40/269 (14.9%) 51
    Diabetic retinopathy Fellow Eye 12/133 (9%) 13 13/135 (9.6%) 14 10/134 (7.5%) 10 23/269 (8.6%) 24
    Macular oedema Fellow Eye 4/133 (3%) 4 7/135 (5.2%) 7 6/134 (4.5%) 6 13/269 (4.8%) 13
    Retinal exudates Fellow Eye 8/133 (6%) 9 2/135 (1.5%) 2 6/134 (4.5%) 7 8/269 (3%) 9
    Vitreous haemorrhage Fellow Eye 4/133 (3%) 4 8/135 (5.9%) 12 3/134 (2.2%) 3 11/269 (4.1%) 15
    Blepharitis Study Eye 1/133 (0.8%) 1 2/135 (1.5%) 2 7/134 (5.2%) 7 9/269 (3.3%) 9
    Cataract Study Eye 5/133 (3.8%) 5 8/135 (5.9%) 8 8/134 (6%) 8 16/269 (5.9%) 16
    Conjunctival haemorrhage Study Eye 8/133 (6%) 14 18/135 (13.3%) 27 25/134 (18.7%) 34 43/269 (16%) 61
    Diabetic retinal oedema Study Eye 43/133 (32.3%) 54 14/135 (10.4%) 22 19/134 (14.2%) 25 33/269 (12.3%) 47
    Diabetic retinopathy Study Eye 22/133 (16.5%) 25 3/135 (2.2%) 4 5/134 (3.7%) 5 8/269 (3%) 9
    Eye pain Study Eye 6/133 (4.5%) 8 11/135 (8.1%) 13 5/134 (3.7%) 5 16/269 (5.9%) 18
    Retinal exudates Study Eye 6/133 (4.5%) 7 5/135 (3.7%) 5 9/134 (6.7%) 9 14/269 (5.2%) 14
    Vitreous detachment Study Eye 4/133 (3%) 4 7/135 (5.2%) 7 7/134 (5.2%) 9 14/269 (5.2%) 16
    Vitreous floaters Study Eye 3/133 (2.3%) 3 7/135 (5.2%) 8 13/134 (9.7%) 13 20/269 (7.4%) 21
    Gastrointestinal disorders
    Constipation 3/133 (2.3%) 3 5/135 (3.7%) 5 7/134 (5.2%) 7 12/269 (4.5%) 12
    Nausea 8/133 (6%) 9 5/135 (3.7%) 5 6/134 (4.5%) 14 11/269 (4.1%) 19
    Infections and infestations
    Bronchitis 7/133 (5.3%) 7 9/135 (6.7%) 10 5/134 (3.7%) 5 14/269 (5.2%) 15
    Cellulitis 6/133 (4.5%) 6 5/135 (3.7%) 10 7/134 (5.2%) 7 12/269 (4.5%) 17
    Influenza 8/133 (6%) 8 10/135 (7.4%) 12 4/134 (3%) 4 14/269 (5.2%) 16
    Nasopharyngitis 15/133 (11.3%) 16 11/135 (8.1%) 16 11/134 (8.2%) 12 22/269 (8.2%) 28
    Urinary tract infection 16/133 (12%) 22 12/135 (8.9%) 13 11/134 (8.2%) 13 23/269 (8.6%) 26
    Injury, poisoning and procedural complications
    Fall 5/133 (3.8%) 5 5/135 (3.7%) 7 8/134 (6%) 11 13/269 (4.8%) 18
    Investigations
    Blood glucose increased 7/133 (5.3%) 8 3/135 (2.2%) 3 7/134 (5.2%) 7 10/269 (3.7%) 10
    Glycosylated haemoglobin increased 7/133 (5.3%) 7 9/135 (6.7%) 9 9/134 (6.7%) 9 18/269 (6.7%) 18
    Metabolism and nutrition disorders
    Diabetes mellitus 13/133 (9.8%) 15 11/135 (8.1%) 11 8/134 (6%) 8 19/269 (7.1%) 19
    Nervous system disorders
    Headache 2/133 (1.5%) 2 7/135 (5.2%) 9 8/134 (6%) 8 15/269 (5.6%) 17
    Vascular disorders
    Hypertension 25/133 (18.8%) 28 28/135 (20.7%) 32 20/134 (14.9%) 23 48/269 (17.8%) 55

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The investigator has the right to independently publish study results from the investigator's site after a multi-center publication, or a defined period after the completion of the study by all sites. The investigator must provide the sponsor a copy of any such publication derived from the study for review and comment in advance of any submission, and delay publication, if requested, to allow the Sponsor to preserve its proprietary rights.

    Results Point of Contact

    Name/Title Clinical Trial Management
    Organization Regeneron Pharmaceuticals, Inc.
    Phone 844-734-6643
    Email clinicaltrials@regeneron.com
    Responsible Party:
    Regeneron Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT02718326
    Other Study ID Numbers:
    • VGFTe-OD-1411
    • 2016-002639-14
    First Posted:
    Mar 24, 2016
    Last Update Posted:
    Jul 30, 2020
    Last Verified:
    Jul 1, 2020