Diabetic Macular Edema
Conditions
Keywords
Diabetic Macular Edema, anti-vascular endothelial growth factor
Brief summary
Although multiple studies have clearly demonstrated that ranibizumab therapy is more effective than laser alone for vision gain and avoiding vision loss in patients with central-involved Diabetic Macular Edema (DME), only eyes with poor visual acuity, such as a visual acuity letter score of 78 or worse (approximate Snellen equivalent of 20/32 or worse) were eligible. Eyes that have central-involved DME with good visual acuity (20/25 or better) have not been addressed systematically by recent studies for treatment of DME. Baseline cohort characteristics from the Early Treatment Diabetic Retinopathy Study (ETDRS) suggest that a substantial percentage of eyes with central-involved DME may retain good vision. The investigators do not know definitively whether eyes with central-involved DME and good vision do better with anti-VEGF (vascular endothelial growth factor) (e.g. aflibercept) therapy initially, or focal/grid laser treatment or observation initially followed by anti-VEGF only if vision worsens. The primary objective of the protocol is to compare the % of eyes that have lost at least 5 letters of visual acuity at 2 years compared with baseline mean visual acuity in eyes with central-involved DME and good visual acuity defined as a Snellen equivalent of 20/25 or better (electronic-ETDRS letter score of 79 or better) that receive (1) prompt focal/grid photocoagulation + deferred anti-VEGF, (2) observation + deferred anti-VEGF, or (3) prompt anti-VEGF. Secondary objectives include: * Comparing other visual acuity outcomes between treatment groups, such as the percent of eyes with at least 5, 10 and 15 letter losses in visual acuity from baseline mean visual acuity, percent of eyes with at least 5 letter gain in visual acuity from baseline, mean visual acuity, mean change in visual acuity, adjusted for baseline mean visual acuity * For eyes randomized to deferred anti-VEGF, the percentage of eyes needing anti-VEGF treatment * Comparing optical coherence tomography (OCT) outcomes, such as the mean change in OCT central subfield (CSF) thickness, adjusted for baseline mean thickness * Comparing the number of eyes with PDR at randomization, proportion of eyes avoiding vitreous hemorrhage or panretinal photocoagulation (PRP) or vitrectomy for PDR between treatment groups * Comparing safety outcomes between treatment groups * Comparing associated treatment and follow-up exam costs between treatment groups
Interventions
PROCEDUREPrompt Laser
Focal/grid laser performed at baseline and as needed during follow-up
Intravitreal injection of 2.0mg aflibercept performed on the day of randomization and up to every 4 weeks using defined treatment criteria
PROCEDUREDeferred laser
Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met
Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria
Sponsors
Regeneron Pharmaceuticals
National Eye Institute (NEI)
National Institutes of Health (NIH)
Jaeb Center for Health Research
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age \>= 18 years 2. Diagnosis of diabetes mellitus (type 1 or type 2) Any one of the following will be considered to be sufficient evidence that diabetes is present: 1. Current regular use of insulin for the treatment of diabetes 2. Current regular use of oral anti-hyperglycemia agents for the treatment of diabetes 3. Documented diabetes by American Diabetes Association (ADA) and/or World Health Organization (WHO) criteria. 3. Able and willing to provide informed consent. Meets all of the following ocular criteria in at least the one eye: 1. Best corrected E-ETDRS visual acuity letter score ≥ 79 (approximate Snellen equivalent 20/25 or better) at two consecutive visits within 1 to 28 days. 2. On clinical exam, definite retinal thickening due to DME involving the center of the macula. 3. Diabetic macular edema confirmed on OCT (equivalent to CSF thickness on OCT ≥250 microns on Zeiss Stratus or gender-specific spectral domain OCT equivalent) at two consecutive visits within 1 to 28 days. (a) Investigator must verify accuracy of OCT scan by ensuring it is centered and of adequate quality. 4. The investigator is comfortable with the eye being randomized to any of the three treatment groups (observation, laser, or anti-VEGF initially). (a) If focal/grid photocoagulation is contraindicated because all leaking microaneurysms are too close to the fovea or the investigator believes the DME that is present will not benefit from focal/grid photocoagulation, the eye should not be enrolled. 5. Media clarity, pupillary dilation, and individual cooperation sufficient for adequate OCT and fundus photographs.
Exclusion criteria
1. History of chronic renal failure requiring dialysis or kidney transplant. 2. A condition that, in the opinion of the investigator, would preclude participation in the study (e.g., unstable medical status including blood pressure, cardiovascular disease, and glycemic control). 3. Initiation of intensive insulin treatment (a pump or multiple daily injections) within 4 months prior to randomization or plans to do so in the next 4 months. 4. Participation in an investigational trial within 30 days of randomization that involved treatment with any drug that has not received regulatory approval for the indication being studied. (a) Note: study participants cannot receive another investigational drug while participating in the study. 5. Known allergy to any component of the study drug. 6. Blood pressure \>180/110 (systolic above 180 OR diastolic above 110). If blood pressure is brought below 180/110 by anti-hypertensive treatment, individual can become eligible. 7. Systemic anti-VEGF or pro-VEGF treatment within 4 months prior to randomization. These drugs should not be used during the study. 8. For women of child-bearing potential: pregnant or lactating or intending to become pregnant within the next 24 months. (a) Women who are potential study participants should be questioned about the potential for pregnancy. Investigator judgment is used to determine when a pregnancy test is needed. 9. Individual is expecting to move out of the area of the clinical center to an area not covered by another clinical center during the 24 months of the study. Individual has any of the following ocular characteristics: 1. Macular edema is considered to be due to a cause other than DME. a) An eye should not be considered eligible if: (1) the macular edema is considered to be related to ocular surgery such as cataract extraction or (2) clinical exam and/or OCT suggest that vitreoretinal interface abnormalities (e.g., a taut posterior hyaloid or epiretinal membrane) are contributing to the macular edema. 2. An ocular condition is present such that, in the opinion of the investigator, any visual acuity loss would not improve from resolution of macular edema (e.g., foveal atrophy, pigment abnormalities, dense subfoveal hard exudates, nonretinal condition). 3. An ocular condition is present (other than DME) that, in the opinion of the investigator, might affect macular edema or alter visual acuity during the course of the study (e.g., vein occlusion, uveitis or other ocular inflammatory disease, neovascular glaucoma, etc.). 4. Cataract is present that, in the opinion of the investigator, may alter visual acuity during the course of the study. 5. Any history of prior laser or other surgical, intravitreal, or peribulbar treatment for DME (such as focal/grid macular photocoagulation, intravitreal or peribulbar corticosteroids, or anti-VEGF). 6. History of topical steroid or nonsteroidal anti-inflammatory drugs (NSAID) treatment within 30 days prior to randomization. 7. History of intravitreal or peribulbar corticosteroid within 4 months prior to randomization for an ocular condition other than DME. 8. Any history of or anticipated need for intravitreal anti-VEGF within the next 6 months for an ocular condition other than DME (e.g. choroidal neovascularization, central retinal vein occlusion, PDR). 9. History of PRP within 4 months prior to randomization or anticipated need for PRP in the 6 months following randomization. 10. Any history of vitrectomy. 11. History of major ocular surgery (cataract extraction, scleral buckle, any intraocular surgery, etc.) within prior 4 months or anticipated within the next 6 months following randomization. 12. History of YAG capsulotomy performed within 2 months prior to randomization. 13. Aphakia. 14. Exam evidence of external ocular infection, including conjunctivitis, chalazion, or significant blepharitis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Eyes With at Least 5-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline | 2 years | Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/12) to 0 letters (Snellen equivalent of 20/800). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in E-ETDRS Visual Acuity Letter Score From Baseline | 1 year | Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/12) to 0 letters (Snellen equivalent of 20/800). |
| Change in E-ETDRS Visual Acuity Letter Score From Baseline Over 2 Years (Area Under the Curve) | 2 year | Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/12) to 0 letters (Snellen equivalent of 20/800). The area under the curve (units = letters·years) was divided by 2 years (units = years) to obtain an average change in letter score (units = letters) over the 2-year follow-up. |
| Change in OCT Central Subfield Thickness From Baseline | 2 years | — |
| Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening | 1 year | Logarithmic transformation of optical coherence tomography central subfield thickness (CST) is calculated by taking the log base 10 of the ratio of the central subfield thickness divided by 200 and rounding to the nearest hundredth. The change is the change in the log values. |
| Number of Eyes With no Center-involved Diabetic Macular Edema and at Least 10% Central Subfield Thickness Decrease | 1 year | Center-involved diabetic macular edema defined as follows by central subfield thickness according to optical coherence tomography machine and sex: Heidelberg Spectralis ≥ 305 µm in women and ≥ 320 µm in men, and Zeiss Cirrus ≥ 290 µm in women and ≥ 305 µm in men. |
| Number of Eyes With at Least 5-letter Increase or at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline | 1 year | Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/12) to 0 letters (Snellen equivalent of 20/800). |
| Number of Eyes With ≥ 2-step Worsening of Diabetic Retinopathy | 2 years | Includes eyes with baseline severity level of 75 (high-risk proliferative diabetic retinopathy) or less based on reading center grading of color fundus photographs using the Early Treatment Diabetic Retinopathy Study severity scale. |
| For Eyes Randomized to Initial Laser Photocoagulation and Initial Observation Groups, the Percentage Receiving Aflibercept Treatment | 2 years | — |
| Number of Eyes With at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline | 2 years | Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/12) to 0 letters (Snellen equivalent of 20/800). |
| Cumulative Number of Focal/Grid Photocoagulation Sessions Performed Per Participant | 2 years | — |
| Number of Eyes With ≥ 2-step Improvement of Diabetic Retinopathy | 2 years | Includes eyes with baseline severity level of 35 (mild non-proliferative diabetic retinopathy) or greater based on reading center grading of color fundus photographs using the Early Treatment Diabetic Retinopathy Study severity scale. Excludes eyes with severity level 60 at baseline since improvement is not possible in these eyes. |
| Cumulative Number of Intraocular Injections of 2.0-mg Aflibercept Received Per Participant | 1 year | — |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Initiation With Aflibercept Intravitreal aflibercept at baseline and every 4 weeks as needed (deferred laser may be added to intravitreal aflibercept if certain criteria are met)
Prompt aflibercept: Intravitreal injection of 2.0mg aflibercept performed on the day of randomization and up to every 4 weeks using defined treatment criteria
Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met | 226 |
| Initiation With Aflibercept Intravitreal aflibercept at baseline and every 4 weeks as needed (deferred laser may be added to intravitreal aflibercept if certain criteria are met)
Prompt aflibercept: Intravitreal injection of 2.0mg aflibercept performed on the day of randomization and up to every 4 weeks using defined treatment criteria
Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met | 226 |
| Initiation With Laser Photocoagulation Focal/grid laser followed by intravitreal aflibercept if vision worsens
Prompt Laser: Focal/grid laser performed at baseline and as needed during follow-up
Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria | 240 |
| Initiation With Laser Photocoagulation Focal/grid laser followed by intravitreal aflibercept if vision worsens
Prompt Laser: Focal/grid laser performed at baseline and as needed during follow-up
Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria | 240 |
| Initiation With Observation No treatment to start followed by intravitreal aflibercept if vision worsens (deferred laser may be added to intravitreal aflibercept if certain criteria are met)
Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met
Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria | 236 |
| Initiation With Observation No treatment to start followed by intravitreal aflibercept if vision worsens (deferred laser may be added to intravitreal aflibercept if certain criteria are met)
Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met
Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria | 236 |
| Total | 1,404 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 9 | 8 | 4 |
| Overall Study | Lost to Follow-up | 5 | 11 | 10 |
| Overall Study | Missed Visit | 2 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 5 | 9 | 13 |
Baseline characteristics
| Characteristic | Total | Initiation With Laser Photocoagulation | Initiation With Aflibercept | Initiation With Observation |
|---|---|---|---|---|
| Age, Continuous | 60 years | 60 years | 59 years | 60 years |
| Arterial blood pressure | 98 mmHg | 98 mmHg | 99 mmHg | 98 mmHg |
| Body mass index | 32.2 kg/m^2 | 32.1 kg/m^2 | 32.3 kg/m^2 | 32.3 kg/m^2 |
| Central subfield thickness (time-domain equivalent) | 311 Microns STANDARD_DEVIATION 57 | 314 Microns STANDARD_DEVIATION 52 | 306 Microns STANDARD_DEVIATION 55 | 314 Microns STANDARD_DEVIATION 64 |
| Daily cigarette smoking Current | 51 Participants | 16 Participants | 15 Participants | 20 Participants |
| Daily cigarette smoking Never | 463 Participants | 157 Participants | 165 Participants | 141 Participants |
| Daily cigarette smoking Prior | 188 Participants | 67 Participants | 46 Participants | 75 Participants |
| Diabetes type Type 1 | 49 Participants | 18 Participants | 13 Participants | 18 Participants |
| Diabetes type Type 2 | 642 Participants | 221 Participants | 211 Participants | 210 Participants |
| Diabetes type Uncertain | 11 Participants | 1 Participants | 2 Participants | 8 Participants |
| Diabetic retinopathy severity level Diabetic Retinopathy absent or questionable | 7 Eyes | 4 Eyes | 2 Eyes | 1 Eyes |
| Diabetic retinopathy severity level Inactive PDR | 20 Eyes | 7 Eyes | 6 Eyes | 7 Eyes |
| Diabetic retinopathy severity level Microaneurysms only | 27 Eyes | 8 Eyes | 13 Eyes | 6 Eyes |
| Diabetic retinopathy severity level Mild to moderate NPDR | 393 Eyes | 132 Eyes | 119 Eyes | 142 Eyes |
| Diabetic retinopathy severity level Mild to moderate PDR | 35 Eyes | 12 Eyes | 14 Eyes | 9 Eyes |
| Diabetic retinopathy severity level Moderately severe to severe NPDR | 184 Eyes | 64 Eyes | 58 Eyes | 62 Eyes |
| Duration of diabetes | 15 years | 15 years | 15 years | 16 years |
| E-ETDRS visual acuity letter score | 85.2 units on a scale STANDARD_DEVIATION 3.7 | 85.2 units on a scale STANDARD_DEVIATION 3.8 | 85.2 units on a scale STANDARD_DEVIATION 3.5 | 85.2 units on a scale STANDARD_DEVIATION 3.8 |
| Hemoglobin A1c | 7.6 Hemoglobin A1c percentage | 7.6 Hemoglobin A1c percentage | 7.6 Hemoglobin A1c percentage | 7.6 Hemoglobin A1c percentage |
| Insulin used | 466 Participants | 145 Participants | 161 Participants | 160 Participants |
| Intraocular pressure | 15 mmHg | 15 mmHg | 15 mmHg | 15 mmHg |
| Lens status at clinical examination Phakic (natural lens) | 550 Eyes | 188 Eyes | 180 Eyes | 182 Eyes |
| Lens status at clinical examination Prosthetic intraocular lens | 152 Eyes | 52 Eyes | 46 Eyes | 54 Eyes |
| Macular volume (time-domain equivalent) | 8.0 mm^3 STANDARD_DEVIATION 1 | 8.0 mm^3 STANDARD_DEVIATION 1.2 | 7.9 mm^3 STANDARD_DEVIATION 1.1 | 8.0 mm^3 STANDARD_DEVIATION 1.1 |
| Optical coherence tomography machine used to measure central subfield thickness Heidelberg Spectralis | 450 Eyes | 151 Eyes | 148 Eyes | 151 Eyes |
| Optical coherence tomography machine used to measure central subfield thickness Zeiss Cirrus | 252 Eyes | 89 Eyes | 78 Eyes | 85 Eyes |
| Patient-reported visual complaints presumed to be from diabetic macular edema | 333 Eyes | 116 Eyes | 99 Eyes | 118 Eyes |
| Prior anti-VEGF for diabetic macular edema | 38 Eyes | 14 Eyes | 11 Eyes | 13 Eyes |
| Prior focal/grid laser photocoagulation for diabetic macular edema | 74 Eyes | 24 Eyes | 26 Eyes | 24 Eyes |
| Prior myocardial infarction | 51 Participants | 21 Participants | 11 Participants | 19 Participants |
| Prior panretinal photocoagulation | 36 Eyes | 12 Eyes | 15 Eyes | 9 Eyes |
| Prior stroke | 31 Participants | 6 Participants | 16 Participants | 9 Participants |
| Prior treatment for diabetic macular edema | 99 Eyes | 31 Eyes | 34 Eyes | 34 Eyes |
| Race/Ethnicity, Customized Race/ethnicity American Indian or Alaskan Native | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race/ethnicity Asian | 12 Participants | 1 Participants | 6 Participants | 5 Participants |
| Race/Ethnicity, Customized Race/ethnicity Hispanic or Latino | 91 Participants | 35 Participants | 31 Participants | 25 Participants |
| Race/Ethnicity, Customized Race/ethnicity More than one race | 7 Participants | 2 Participants | 4 Participants | 1 Participants |
| Race/Ethnicity, Customized Race/ethnicity Native Hawaiian or other Pacific Islander | 4 Participants | 3 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race/ethnicity Non-Hispanic Black/African American | 114 Participants | 36 Participants | 37 Participants | 41 Participants |
| Race/Ethnicity, Customized Race/ethnicity Non-Hispanic White | 466 Participants | 160 Participants | 145 Participants | 161 Participants |
| Race/Ethnicity, Customized Race/ethnicity Unknown or not reported | 6 Participants | 2 Participants | 2 Participants | 2 Participants |
| Recent or planned diabetic macular edema treatment in non-study eye | 268 Eyes | 90 Eyes | 86 Eyes | 92 Eyes |
| Region of Enrollment Canada | 7 Participants | 2 Participants | 1 Participants | 4 Participants |
| Region of Enrollment United States | 695 Participants | 238 Participants | 225 Participants | 232 Participants |
| Sex: Female, Male Female | 264 Participants | 82 Participants | 95 Participants | 87 Participants |
| Sex: Female, Male Male | 438 Participants | 158 Participants | 131 Participants | 149 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 10 / 226 | 9 / 240 | 5 / 236 |
| other Total, other adverse events | 194 / 240 | 197 / 236 | 185 / 226 |
| serious Total, serious adverse events | 64 / 240 | 77 / 236 | 69 / 226 |
Outcome results
Primary
Number of Eyes With at Least 5-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline
Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/12) to 0 letters (Snellen equivalent of 20/800).
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_UNITS) |
|---|---|---|
| Initiation With Aflibercept | Number of Eyes With at Least 5-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline | 33 Eyes |
| Initiation With Laser Photocoagulation | Number of Eyes With at Least 5-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline | 36 Eyes |
| Initiation With Observation | Number of Eyes With at Least 5-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline | 39 Eyes |
Secondary
Change in E-ETDRS Visual Acuity Letter Score From Baseline
Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/12) to 0 letters (Snellen equivalent of 20/800).
Time frame: 2 years
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Initiation With Aflibercept | Change in E-ETDRS Visual Acuity Letter Score From Baseline | 0.9 units on a scale | Standard Deviation 6.4 |
| Initiation With Laser Photocoagulation | Change in E-ETDRS Visual Acuity Letter Score From Baseline | 0.1 units on a scale | Standard Deviation 6.3 |
| Initiation With Observation | Change in E-ETDRS Visual Acuity Letter Score From Baseline | -0.4 units on a scale | Standard Deviation 6.4 |
Secondary
Change in E-ETDRS Visual Acuity Letter Score From Baseline
Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/12) to 0 letters (Snellen equivalent of 20/800).
Time frame: 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Initiation With Aflibercept | Change in E-ETDRS Visual Acuity Letter Score From Baseline | 2.1 units on a scale | Standard Deviation 5 |
| Initiation With Laser Photocoagulation | Change in E-ETDRS Visual Acuity Letter Score From Baseline | 0.1 units on a scale | Standard Deviation 5.5 |
| Initiation With Observation | Change in E-ETDRS Visual Acuity Letter Score From Baseline | 0.0 units on a scale | Standard Deviation 5.4 |
Secondary
Change in E-ETDRS Visual Acuity Letter Score From Baseline Over 2 Years (Area Under the Curve)
Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/12) to 0 letters (Snellen equivalent of 20/800). The area under the curve (units = letters·years) was divided by 2 years (units = years) to obtain an average change in letter score (units = letters) over the 2-year follow-up.
Time frame: 2 year
Population: Best-corrected visual acuity letter score as measured by a certified tester using an electronic visual acuity testing machine based on the early treatment diabetic retinopathy study method . Best value on the scale 100, worst 0.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Initiation With Aflibercept | Change in E-ETDRS Visual Acuity Letter Score From Baseline Over 2 Years (Area Under the Curve) | 1.5 units on a scale | Standard Deviation 4 |
| Initiation With Laser Photocoagulation | Change in E-ETDRS Visual Acuity Letter Score From Baseline Over 2 Years (Area Under the Curve) | 0.0 units on a scale | Standard Deviation 3.9 |
| Initiation With Observation | Change in E-ETDRS Visual Acuity Letter Score From Baseline Over 2 Years (Area Under the Curve) | -0.4 units on a scale | Standard Deviation 4.2 |
Secondary
Change in OCT Central Subfield Thickness From Baseline
Time frame: 2 years
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Initiation With Aflibercept | Change in OCT Central Subfield Thickness From Baseline | -48 microns | Standard Deviation 65 |
| Initiation With Laser Photocoagulation | Change in OCT Central Subfield Thickness From Baseline | -41 microns | Standard Deviation 75 |
| Initiation With Observation | Change in OCT Central Subfield Thickness From Baseline | -42 microns | Standard Deviation 75 |
Secondary
Change in OCT Central Subfield Thickness From Baseline
Measured using spectral-domain optical coherence tomography (OCT).
Time frame: 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Initiation With Aflibercept | Change in OCT Central Subfield Thickness From Baseline | -50 microns | Standard Deviation 55 |
| Initiation With Laser Photocoagulation | Change in OCT Central Subfield Thickness From Baseline | -30 microns | Standard Deviation 69 |
| Initiation With Observation | Change in OCT Central Subfield Thickness From Baseline | -25 microns | Standard Deviation 73 |
Secondary
Cumulative Number of Focal/Grid Photocoagulation Sessions Performed Per Participant
Time frame: 2 years
Population: The initial laser session was completed for all eyes in the initial laser group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Initiation With Aflibercept | Cumulative Number of Focal/Grid Photocoagulation Sessions Performed Per Participant | 0.1 Focal/grid photocoagulation session | Standard Deviation 0.4 |
| Initiation With Laser Photocoagulation | Cumulative Number of Focal/Grid Photocoagulation Sessions Performed Per Participant | 1.5 Focal/grid photocoagulation session | Standard Deviation 0.9 |
| Initiation With Observation | Cumulative Number of Focal/Grid Photocoagulation Sessions Performed Per Participant | 0.0 Focal/grid photocoagulation session | Standard Deviation 0.3 |
Secondary
Cumulative Number of Intraocular Injections of 2.0-mg Aflibercept Received Per Participant
Time frame: 2 years
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Initiation With Aflibercept | Cumulative Number of Intraocular Injections of 2.0-mg Aflibercept Received Per Participant | 8.3 Injections | Standard Deviation 4.2 |
| Initiation With Laser Photocoagulation | Cumulative Number of Intraocular Injections of 2.0-mg Aflibercept Received Per Participant | 2.1 Injections | Standard Deviation 4 |
| Initiation With Observation | Cumulative Number of Intraocular Injections of 2.0-mg Aflibercept Received Per Participant | 3.1 Injections | Standard Deviation 4.9 |
Secondary
Cumulative Number of Intraocular Injections of 2.0-mg Aflibercept Received Per Participant
Time frame: 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Initiation With Aflibercept | Cumulative Number of Intraocular Injections of 2.0-mg Aflibercept Received Per Participant | 6.0 Injections | Standard Deviation 2.5 |
| Initiation With Laser Photocoagulation | Cumulative Number of Intraocular Injections of 2.0-mg Aflibercept Received Per Participant | 0.7 Injections | Standard Deviation 2.1 |
| Initiation With Observation | Cumulative Number of Intraocular Injections of 2.0-mg Aflibercept Received Per Participant | 1.4 Injections | Standard Deviation 2.6 |
Secondary
For Eyes Randomized to Initial Laser Photocoagulation and Initial Observation Groups, the Percentage Receiving Aflibercept Treatment
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_UNITS) |
|---|---|---|
| Initiation With Aflibercept | For Eyes Randomized to Initial Laser Photocoagulation and Initial Observation Groups, the Percentage Receiving Aflibercept Treatment | 60 Eyes |
| Initiation With Laser Photocoagulation | For Eyes Randomized to Initial Laser Photocoagulation and Initial Observation Groups, the Percentage Receiving Aflibercept Treatment | 80 Eyes |
Secondary
Number of Eyes With ≥ 2-step Improvement of Diabetic Retinopathy
Includes eyes with baseline severity level of 35 (mild non-proliferative diabetic retinopathy) or greater based on reading center grading of color fundus photographs using the Early Treatment Diabetic Retinopathy Study severity scale. Excludes eyes with severity level 60 at baseline since improvement is not possible in these eyes.
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_UNITS) |
|---|---|---|
| Initiation With Aflibercept | Number of Eyes With ≥ 2-step Improvement of Diabetic Retinopathy | 23 Eyes |
| Initiation With Laser Photocoagulation | Number of Eyes With ≥ 2-step Improvement of Diabetic Retinopathy | 21 Eyes |
| Initiation With Observation | Number of Eyes With ≥ 2-step Improvement of Diabetic Retinopathy | 18 Eyes |
Secondary
Number of Eyes With ≥ 2-step Worsening of Diabetic Retinopathy
Includes eyes with baseline severity level of 75 (high-risk proliferative diabetic retinopathy) or less based on reading center grading of color fundus photographs using the Early Treatment Diabetic Retinopathy Study severity scale.
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_UNITS) |
|---|---|---|
| Initiation With Aflibercept | Number of Eyes With ≥ 2-step Worsening of Diabetic Retinopathy | 7 Eyes |
| Initiation With Laser Photocoagulation | Number of Eyes With ≥ 2-step Worsening of Diabetic Retinopathy | 18 Eyes |
| Initiation With Observation | Number of Eyes With ≥ 2-step Worsening of Diabetic Retinopathy | 20 Eyes |
Secondary
Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening
Logarithmic transformation of optical coherence tomography central subfield thickness is calculated by taking the log base 10 of the ratio of the central subfield thickness divided by 200 and rounding to the nearest hundredth. The change is the change in the log values.
Time frame: 2 years
| Arm | Measure | Group | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Initiation With Aflibercept | Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening | ≥ 2 log-step CST decrease (improvement) | 12 Eyes |
| Initiation With Aflibercept | Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening | ≥ 1 log-step CST decrease (improvement) | 57 Eyes |
| Initiation With Aflibercept | Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening | ≥ 1 log-step CST increase (worsening) | 6 Eyes |
| Initiation With Aflibercept | Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening | ≥ 2 log-step CST increase (worsening) | 1 Eyes |
| Initiation With Laser Photocoagulation | Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening | ≥ 2 log-step CST increase (worsening) | 1 Eyes |
| Initiation With Laser Photocoagulation | Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening | ≥ 2 log-step CST decrease (improvement) | 18 Eyes |
| Initiation With Laser Photocoagulation | Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening | ≥ 1 log-step CST increase (worsening) | 10 Eyes |
| Initiation With Laser Photocoagulation | Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening | ≥ 1 log-step CST decrease (improvement) | 56 Eyes |
| Initiation With Observation | Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening | ≥ 2 log-step CST increase (worsening) | 2 Eyes |
| Initiation With Observation | Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening | ≥ 1 log-step CST decrease (improvement) | 61 Eyes |
| Initiation With Observation | Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening | ≥ 1 log-step CST increase (worsening) | 11 Eyes |
| Initiation With Observation | Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening | ≥ 2 log-step CST decrease (improvement) | 13 Eyes |
Secondary
Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening
Logarithmic transformation of optical coherence tomography central subfield thickness (CST) is calculated by taking the log base 10 of the ratio of the central subfield thickness divided by 200 and rounding to the nearest hundredth. The change is the change in the log values.
Time frame: 1 year
| Arm | Measure | Group | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Initiation With Aflibercept | Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening | ≥ 2 log-step CST decrease (improvement) | 7 Eyes |
| Initiation With Aflibercept | Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening | ≥ 1 log-step CST decrease (improvement) | 56 Eyes |
| Initiation With Aflibercept | Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening | ≥ 1 log-step CST increase (worsening) | 1 Eyes |
| Initiation With Aflibercept | Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening | ≥ 2 log-step CST increase (worsening) | 0 Eyes |
| Initiation With Laser Photocoagulation | Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening | ≥ 2 log-step CST increase (worsening) | 3 Eyes |
| Initiation With Laser Photocoagulation | Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening | ≥ 2 log-step CST decrease (improvement) | 11 Eyes |
| Initiation With Laser Photocoagulation | Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening | ≥ 1 log-step CST increase (worsening) | 12 Eyes |
| Initiation With Laser Photocoagulation | Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening | ≥ 1 log-step CST decrease (improvement) | 45 Eyes |
| Initiation With Observation | Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening | ≥ 2 log-step CST increase (worsening) | 3 Eyes |
| Initiation With Observation | Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening | ≥ 1 log-step CST decrease (improvement) | 39 Eyes |
| Initiation With Observation | Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening | ≥ 1 log-step CST increase (worsening) | 14 Eyes |
| Initiation With Observation | Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening | ≥ 2 log-step CST decrease (improvement) | 8 Eyes |
Secondary
Number of Eyes With at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline
Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/12) to 0 letters (Snellen equivalent of 20/800).
Time frame: 2 years
| Arm | Measure | Group | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Initiation With Aflibercept | Number of Eyes With at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline | ≥ 10-Letter Worsening | 18 Eyes |
| Initiation With Aflibercept | Number of Eyes With at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline | ≥ 5-Letter Improvement | 55 Eyes |
| Initiation With Aflibercept | Number of Eyes With at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline | ≥ 15-Letter Worsening | 5 Eyes |
| Initiation With Laser Photocoagulation | Number of Eyes With at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline | ≥ 10-Letter Worsening | 14 Eyes |
| Initiation With Laser Photocoagulation | Number of Eyes With at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline | ≥ 5-Letter Improvement | 53 Eyes |
| Initiation With Laser Photocoagulation | Number of Eyes With at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline | ≥ 15-Letter Worsening | 8 Eyes |
| Initiation With Observation | Number of Eyes With at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline | ≥ 5-Letter Improvement | 43 Eyes |
| Initiation With Observation | Number of Eyes With at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline | ≥ 15-Letter Worsening | 8 Eyes |
| Initiation With Observation | Number of Eyes With at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline | ≥ 10-Letter Worsening | 14 Eyes |
Secondary
Number of Eyes With at Least 5-letter Increase or at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline
Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/12) to 0 letters (Snellen equivalent of 20/800).
Time frame: 1 year
| Arm | Measure | Group | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Initiation With Aflibercept | Number of Eyes With at Least 5-letter Increase or at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline | ≥ 5-Letter Decrease | 19 Eyes |
| Initiation With Aflibercept | Number of Eyes With at Least 5-letter Increase or at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline | ≥ 10-Letter Decrease | 6 Eyes |
| Initiation With Aflibercept | Number of Eyes With at Least 5-letter Increase or at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline | ≥ 5-Letter Increase | 61 Eyes |
| Initiation With Aflibercept | Number of Eyes With at Least 5-letter Increase or at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline | ≥ 15-Letter Decrease | 3 Eyes |
| Initiation With Laser Photocoagulation | Number of Eyes With at Least 5-letter Increase or at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline | ≥ 5-Letter Decrease | 36 Eyes |
| Initiation With Laser Photocoagulation | Number of Eyes With at Least 5-letter Increase or at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline | ≥ 5-Letter Increase | 44 Eyes |
| Initiation With Laser Photocoagulation | Number of Eyes With at Least 5-letter Increase or at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline | ≥ 10-Letter Decrease | 9 Eyes |
| Initiation With Laser Photocoagulation | Number of Eyes With at Least 5-letter Increase or at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline | ≥ 15-Letter Decrease | 4 Eyes |
| Initiation With Observation | Number of Eyes With at Least 5-letter Increase or at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline | ≥ 10-Letter Decrease | 7 Eyes |
| Initiation With Observation | Number of Eyes With at Least 5-letter Increase or at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline | ≥ 5-Letter Increase | 33 Eyes |
| Initiation With Observation | Number of Eyes With at Least 5-letter Increase or at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline | ≥ 5-Letter Decrease | 25 Eyes |
| Initiation With Observation | Number of Eyes With at Least 5-letter Increase or at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline | ≥ 15-Letter Decrease | 6 Eyes |
Secondary
Number of Eyes With no Center-involved Diabetic Macular Edema and at Least 10% Central Subfield Thickness Decrease
Center-involved diabetic macular edema defined as follows by central subfield thickness according to optical coherence tomography machine and sex: Heidelberg Spectralis ≥ 305 µm in women and ≥ 320 µm in men, and Zeiss Cirrus ≥ 290 µm in women and ≥ 305 µm in men.
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_UNITS) |
|---|---|---|
| Initiation With Aflibercept | Number of Eyes With no Center-involved Diabetic Macular Edema and at Least 10% Central Subfield Thickness Decrease | 95 Eyes |
| Initiation With Laser Photocoagulation | Number of Eyes With no Center-involved Diabetic Macular Edema and at Least 10% Central Subfield Thickness Decrease | 90 Eyes |
| Initiation With Observation | Number of Eyes With no Center-involved Diabetic Macular Edema and at Least 10% Central Subfield Thickness Decrease | 74 Eyes |
Secondary
Number of Eyes With no Center-involved Diabetic Macular Edema and at Least 10% Central Subfield Thickness Decrease
Center-involved diabetic macular edema defined as follows by central subfield thickness according to optical coherence tomography machine and sex: Heidelberg Spectralis ≥ 305 µm in women and ≥ 320 µm in men, and Zeiss Cirrus ≥ 290 µm in women and ≥ 305 µm in men.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_UNITS) |
|---|---|---|
| Initiation With Aflibercept | Number of Eyes With no Center-involved Diabetic Macular Edema and at Least 10% Central Subfield Thickness Decrease | 93 Eyes |
| Initiation With Laser Photocoagulation | Number of Eyes With no Center-involved Diabetic Macular Edema and at Least 10% Central Subfield Thickness Decrease | 58 Eyes |
| Initiation With Observation | Number of Eyes With no Center-involved Diabetic Macular Edema and at Least 10% Central Subfield Thickness Decrease | 67 Eyes |