[Skip to Navigation]
Sign In
Figure 1.  Study Flow Diagram
Study Flow Diagram

Protocol-specified visits occurred at baseline (randomization), 1 month (±2 weeks), 2 months (±1 week), and 4 months (±8 weeks), then every 4 months (±12 weeks for annual visits, ±8 weeks otherwise) through 4 years.

Figure 2.  Time From Randomization to Development of Proliferative Diabetic Retinopathy (PDR) or Center-Involved Diabetic Macular Edema (CI-DME)
Time From Randomization to Development of Proliferative Diabetic Retinopathy (PDR) or Center-Involved Diabetic Macular Edema (CI-DME)

A, Time from randomization to development of PDR or CI-DME, whichever came first. B, Time from randomization to development of PDR irrespective of CI-DME. C, Time from randomization to development of CI-DME irrespective of PDR. Hazard ratios include all available data through 4 years and were adjusted for diabetic retinopathy severity at the screening visit, study eye laterality, and correlation between eyes of participants with 2 study eyes. The figure was truncated at the time point at which data from fewer than 20 eyes in each treatment group were available.

Figure 3.  Mean Change in Visual Acuity Through 2 Years
Mean Change in Visual Acuity Through 2 Years
Table 1.  Baseline Participant and Study Eye Characteristics
Baseline Participant and Study Eye Characteristics
Table 2.  Components of PDR and DME Composite Outcome Met at First Occurrence of Outcome
Components of PDR and DME Composite Outcome Met at First Occurrence of Outcome
Table 3.  Visual Acuity Outcomes at 2 Yearsa
Visual Acuity Outcomes at 2 Yearsa
1.
Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema.  Ophthalmology. 2010;117(6):1064-1077. doi:10.1016/j.ophtha.2010.02.031PubMed
2.
Wells  JA, Glassman  AR, Ayala  AR,  et al; Diabetic Retinopathy Clinical Research Network.  Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema.   N Engl J Med. 2015;372(13):1193-1203. doi:10.1056/NEJMoa1414264 PubMedGoogle Scholar
3.
Gross  JG, Glassman  AR, Jampol  LM,  et al; Writing Committee for the Diabetic Retinopathy Clinical Research Network.  Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: a randomized clinical trial.   JAMA. 2015;314(20):2137-2146. doi:10.1001/jama.2015.15217 PubMedGoogle Scholar
4.
Sivaprasad  S, Prevost  AT, Vasconcelos  JC,  et al; CLARITY Study Group.  Clinical efficacy of intravitreal aflibercept versus panretinal photocoagulation for best corrected visual acuity in patients with proliferative diabetic retinopathy at 52 weeks (CLARITY): a multicentre, single-blinded, randomised, controlled, phase 2b, non-inferiority trial.   Lancet. 2017;389(10085):2193-2203. doi:10.1016/S0140-6736(17)31193-5 PubMedGoogle ScholarCrossref
5.
Wilkinson CP, Ferris FL 3rd, Klein RE, et al. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales.  Ophthalmology. 2003;110(9):1677-1682.
6.
Regeneron Pharmaceuticals Inc. Eylea (aflibercept) injection reduced risk of developing vision-threatening events by 75% after two years in patients with diabetic retinopathy. Published February 8, 2020. Accessed January 19, 2021. https://newsroom.regeneron.com/index.php/news-releases/news-release-details/eylear-aflibercept-injection-reduced-risk-developing-vision
7.
World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.   JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053PubMedGoogle ScholarCrossref
8.
Bressler  SB, Edwards  AR, Chalam  KV,  et al; Diabetic Retinopathy Clinical Research Network Writing Committee.  Reproducibility of spectral-domain optical coherence tomography retinal thickness measurements and conversion to equivalent time-domain metrics in diabetic macular edema.   JAMA Ophthalmol. 2014;132(9):1113-1122. doi:10.1001/jamaophthalmol.2014.1698 PubMedGoogle Scholar
9.
National Institutes of Health. NIH policy and guidelines on the inclusion of women and minorities as subjects in clinical research. Accessed April 11, 2019. https://grants.nih.gov/grants/funding/women_min/guidelines.htm
10.
US Food and Drug Administration. Collection of race and ethnicity data in clinical trials: guidance for industry and Food and Drug Administration staff. Published October 26, 2016. Accessed April 11, 2019. https://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126396.pdf?source=govdelivery&utm_medium=email&utm_source=govdelivery
11.
Aiello LP, Odia I, Glassman AR, et al. Comparison of Early Treatment Diabetic Retinopathy Study standard 7-field imaging with ultrawide-field imaging for determining severity of diabetic retinopathy.  JAMA Ophthalmol. 2019;137(1):65-73.
12.
Gross  JG, Glassman  AR, Liu  D,  et al; Diabetic Retinopathy Clinical Research Network.  Five-year outcomes of panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: a randomized clinical trial.   JAMA Ophthalmol. 2018;136(10):1138-1148. doi:10.1001/jamaophthalmol.2018.3255 PubMedGoogle ScholarCrossref
13.
Wells  JA, Glassman  AR, Ayala  AR,  et al; Diabetic Retinopathy Clinical Research Network.  Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial.   Ophthalmology. 2016;123(6):1351-1359. doi:10.1016/j.ophtha.2016.02.022 PubMedGoogle ScholarCrossref
14.
Lin  DY, Wei  LJ, Ying  Z.  Checking the Cox model with cumulative sums of Martingale-based residuals.   Biometrika. 1993;80(3):557-572. doi:10.1093/biomet/80.3.557 Google ScholarCrossref
15.
Kaplan  EL, Meier  P.  Nonparametric estimation from incomplete observations.   J Am Stat Assoc. 1958;53(282):457-481. doi:10.1080/01621459.1958.10501452 Google ScholarCrossref
16.
Elman  MJ, Ayala  A, Bressler  NM,  et al; Diabetic Retinopathy Clinical Research Network.  Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year randomized trial results.   Ophthalmology. 2015;122(2):375-381. doi:10.1016/j.ophtha.2014.08.047 PubMedGoogle ScholarCrossref
17.
Early Treatment Diabetic Retinopathy Study Research Group.  Early photocoagulation for diabetic retinopathy. ETDRS report number 9.   Ophthalmology. 1991;98(5)(suppl):766-785. doi:10.1016/S0161-6420(13)38011-7 PubMedGoogle ScholarCrossref
18.
Baker  CW, Glassman  AR, Beaulieu  WT,  et al; DRCR Retina Network.  Effect of initial management with aflibercept vs laser photocoagulation vs observation on vision loss among patients with diabetic macular edema involving the center of the macula and good visual acuity: a randomized clinical trial.   JAMA. 2019;321(19):1880-1894. doi:10.1001/jama.2019.5790 PubMedGoogle ScholarCrossref
19.
Wykoff  CC, Nittala  MG, Zhou  B,  et al; Intravitreal Aflibercept for Retinal Nonperfusion in Proliferative Diabetic Retinopathy Study Group.  Intravitreal aflibercept for retinal nonperfusion in proliferative diabetic retinopathy: outcomes from the randomized RECOVERY trial.   Ophthalmol Retina. 2019;3(12):1076-1086. doi:10.1016/j.oret.2019.07.011 PubMedGoogle ScholarCrossref
20.
Couturier  A, Rey  PA, Erginay  A,  et al.  Widefield OCT-angiography and fluorescein angiography assessments of nonperfusion in diabetic retinopathy and edema treated with anti-vascular endothelial growth factor.   Ophthalmology. 2019;126(12):1685-1694. doi:10.1016/j.ophtha.2019.06.022 PubMedGoogle ScholarCrossref
21.
Nicholson  L, Crosby-Nwaobi  R, Vasconcelos  JC,  et al.  Mechanistic evaluation of panretinal photocoagulation versus aflibercept in proliferative diabetic retinopathy: CLARITY substudy.   Invest Ophthalmol Vis Sci. 2018;59(10):4277-4284. doi:10.1167/iovs.17-23509 PubMedGoogle ScholarCrossref
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    Original Investigation
    March 30, 2021

    Effect of Intravitreous Anti–Vascular Endothelial Growth Factor vs Sham Treatment for Prevention of Vision-Threatening Complications of Diabetic Retinopathy: The Protocol W Randomized Clinical Trial

    Author Affiliations
    • 1Midwest Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis
    • 2Jaeb Center for Health Research, Tampa, Florida
    • 3Charlotte Eye Ear Nose and Throat Associates, PA, Charlotte, North Carolina
    • 4Department of Ophthalmology and Visual Sciences, University of Wisconsin–Madison, Madison
    • 5Feinberg School of Medicine, Northwestern University, Chicago, Illinois
    • 6Southeast Retina Center, PC, Augusta, Georgia
    • 7Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio
    • 8Retina Associates of Southern California, Huntington Beach
    • 9Joslin Diabetes Center, Beetham Eye Institute, Harvard Department of Ophthalmology, Boston, Massachusetts
    JAMA Ophthalmol. 2021;139(7):701-712. doi:10.1001/jamaophthalmol.2021.0606
    Key Points

    Question  Does aflibercept treatment of moderate to severe nonproliferative diabetic retinopathy prevent vision-threatening complications and benefit visual acuity compared with sham treatment?

    Findings  In this randomized clinical trial of 328 adults (399 eyes) with nonproliferative diabetic retinopathy without center-involved diabetic macular edema, the 2-year rate of developing center-involved diabetic macular edema with vision loss or proliferative diabetic retinopathy was 16.3% with aflibercept vs 43.5% with sham. The difference between aflibercept and sham in 2-year mean visual acuity change was 0.5 letters.

    Meaning  In this study, aflibercept injections reduced the development of vision-threating complications; however, through 2 years, preventive treatment did not confer visual acuity benefit compared with observation plus aflibercept if complications developed.

    Abstract

    Importance  The role of anti–vascular endothelial growth factor injections for the management of nonproliferative diabetic retinopathy (NPDR) without center-involved diabetic macular edema (CI-DME) has not been clearly established.

    Objective  To determine the efficacy of intravitreous aflibercept injections compared with sham treatment in preventing potentially vision-threatening complications in eyes with moderate to severe NPDR.

    Design, Setting, and Participants  Data for this study were collected between January 15, 2016, and May 28, 2020, from the ongoing DRCR Retina Network Protocol W randomized clinical trial, conducted at 64 US and Canadian sites among 328 adults (399 eyes) with moderate to severe NPDR (Early Treatment Diabetic Retinopathy Study severity level, 43-53), without CI-DME. Analyses followed the intent-to-treat principle.

    Interventions  Eyes were randomly assigned to 2.0 mg of aflibercept injections (n = 200) or sham (n = 199) given at baseline; 1, 2, and 4 months; and every 4 months through 2 years. Between 2 and 4 years, treatment was deferred if the eye had mild NPDR or better. Aflibercept was administered in both groups if CI-DME with vision loss (≥10 letters at 1 visit or 5-9 letters at 2 consecutive visits) or high-risk proliferative diabetic retinopathy (PDR) developed.

    Main Outcomes and Measures  Development of CI-DME with vision loss or PDR through May 2020, when the last 2-year visit was completed.

    Results  Among the 328 participants (57.6% men [230 of 399 eyes]; mean [SD] age, 56 [11] years), the 2-year cumulative probability of developing CI-DME with vision loss or PDR was 16.3% with aflibercept vs 43.5% with sham. The overall hazard ratio for either outcome was 0.32 (97.5% CI, 0.21-0.50; P < .001), favoring aflibercept. The 2-year cumulative probability of developing PDR was 13.5% in the aflibercept group vs 33.2% in the sham group, and the 2-year cumulative probability of developing CI-DME with vision loss was 4.1% in the aflibercept group vs 14.8% in the sham group. The mean (SD) change in visual acuity from baseline to 2 years was −0.9 (5.8) letters with aflibercept and −2.0 (6.1) letters with sham (adjusted mean difference, 0.5 letters [97.5% CI, −1.0 to 1.9 letters]; P = .47).

    Conclusions and Relevance  In this randomized clinical trial, among eyes with moderate to severe NPDR, the proportion of eyes that developed PDR or vision-reducing CI-DME was lower with periodic aflibercept compared with sham treatment. However, through 2 years, preventive treatment did not confer visual acuity benefit compared with observation plus treatment with aflibercept only after development of PDR or vision-reducing CI-DME. The 4-year results will be important to assess longer-term visual acuity outcomes.

    Trial Registration  ClinicalTrials.gov Identifier: NCT02634333

    Introduction

    Intravitreal anti–vascular endothelial growth factor (VEGF) therapy is effective first-line treatment for vision-threatening complications of diabetes, including center-involved diabetic macular edema (CI-DME) and proliferative diabetic retinopathy (PDR).1-4 The role of anti-VEGF therapy for eyes with nonproliferative diabetic retinopathy (NPDR) in the absence of vision-threatening complications is less clear.

    In the PANORAMA (Study of the Efficacy and Safety of Intravitreal [IVT] Aflibercept for the Improvement of Moderately Severe to Severe Nonproliferative Diabetic Retinopathy [NPDR]) study, eyes with moderately severe to severe NPDR (Diabetic Retinopathy Severity Scale [DRSS] level,5 47-53) without CI-DME were randomly assigned to receive intravitreal aflibercept every 8 weeks after an initial 5 monthly doses, intravitreal aflibercept every 16 weeks after an initial 3 monthly doses, or sham injections.6 At 2 years, 62% of the eyes that received aflibercept every 8 weeks and 50% of the eyes that received aflibercept every 16 weeks had an improvement of 2 or more steps in the DRSS vs 13% of the eyes in the sham group. Through 2 years, 19% of the eyes that received aflibercept every 8 weeks and 16% of the eyes that received aflibercept every 16 weeks developed vision-threatening complications vs 50% of the eyes in the sham group. No difference was identified between groups in mean visual acuity (VA) letter score change when the study ended at 2 years (aflibercept every 8 weeks, −0.8; aflibercept every 16 weeks, 0.5; and sham, 0).

    The DRCR Retina Network Protocol W was designed as a long-term study to determine whether there is a benefit of aflibercept for a 2- and 4-year period for the prevention of PDR or CI-DME in eyes with moderate to severe NPDR, and if so, whether there is an associated visual benefit of aflibercept for the prevention of PDR or CI-DME with vision loss compared with observation and aflibercept treatment if vision-threatening complications develop.

    Methods

    Study data included in this report were collected from January 15, 2016, when the study was initiated, through May 28, 2020, when the last 2-year visit was completed. This study adhered to the tenets of the Declaration of Helsinki.7 The ethics boards associated with the following sites provided approval: Jaeb Center for Health Research; University of Wisconsin, Health Sciences Institutional review boards; Johns Hopkins Office of Human Subjects Research; Northwestern University Institutional Review Board; University of Pennsylvania, Office of Regulatory Affairs; University of North Carolina at Chapel Hill Office of Human Research Ethics; The New York Eye and Ear Infirmary; Oregon Health and Science University Institutional Review Board; Loma Linda University Health; Office for the Protection of Research Subjects, University of Illinois at Chicago; Baylor Institutional Review Board; University Health Network Research Ethics Board; University of Arizona Institutional Review Board; University of British Colombia Clinical Research Ethics Board; University of Miami Human Subjects Research Office; Nova Scotia Health Authority Research Ethics Board; WCG IRB, Canada; and University of California Davis Institutional Review Board Administration. Study participants provided written informed consent. Participants were reimbursed between $25 and $100 depending on the visit and the calendar year. An independent data and safety monitoring committee provided oversight. The study protocol and the statistical analysis plan are provided in Supplement 1. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.

    Study Population

    Protocol W recruited adults (age, ≥18 years) with type 1 or 2 diabetes and severe NPDR, as determined by the investigator, at 64 clinical sites in the US and Canada. Study eyes had moderate to severe NPDR (reading center–assessed DRSS level, 43-53; 9 months after recruitment began, the lower cutoff was modified from 47), with no evidence of neovascularization (NV) within the 7 modified Early Treatment Diabetic Retinopathy Study (ETDRS) fields detected on fluorescein angiographic image. Eyes with CI-DME detected on results of clinical examination or a central subfield thickness (CST) greater than machine and sex optical coherence tomography thresholds were excluded.8 Study eyes had a best-corrected VA letter score of 79 or greater (Snellen equivalent, ≥20/25), no history of diabetic macular edema (DME) or diabetic retinopathy (DR) treatment within the prior 12 months, and no prior panretinal photocoagulation (PRP). We collected participant-reported race/ethnicity based on fixed categories per the National Institutes of Health policy9 and consistent with US Food and Drug Administration guidelines.10

    Study Design

    Eyes were assigned randomly (1:1) on the study website to receive 2 mg of intravitreal aflibercept (Eylea; Regeneron) or sham injections. Randomization for participants with 1 study eye was stratified by DRSS5 (moderate NPDR, level 43; moderately severe, level 47A, 47B-D; severe NPDR, level 53 with NV identified outside the 7 fields on fundus photograph11; or severe NPDR, level 53 without NV identified outside the 7 fields on fundus photographs). For participants with 2 study eyes, the participant was randomly assigned to receive sham in the eye with the worse DRSS and aflibercept in the other, or aflibercept in the eye with the worse DRSS and sham in the other.

    Visits occurred at baseline and 1, 2, and 4 months, then every 4 months through 4 years. Additional visits occurred if DME or PDR treatment was initiated. Study participants, technicians for annual visits, and central reading center graders were masked to treatment assignment. Investigators were not masked.

    Study Treatment

    Quiz Ref IDPrevention injections (either aflibercept or sham) were given at randomization and at each study visit through 2 years. Thereafter, injections were deferred if DR severity was mild NPDR or better (DRSS level ≤35) based on results of clinical examination. Aflibercept was initiated for CI-DME if CST increased by 10% or more from baseline with a 10-letter or more decrease in VA at 1 visit or a 5- to 9-letter decrease at 2 consecutive visits with vision loss presumed to be due to CI-DME. Aflibercept was also initiated if high-risk PDR developed, with PRP given if aflibercept treatment failed. Once treatment was initiated, the DRCR Retina Network algorithms for anti-VEGF retreatment of CI-DME or PDR were followed.12,13

    Primary Anatomical Outcome

    The primary outcome was development of CI-DME with vision loss or PDR. Development of PDR was defined as NV within the 7 modified ETDRS fields detected on fundus photography or fluorescein angiographic image (graded by the reading center), NV of the iris or angle, neovascular glaucoma, traction retinal detachment, vitreous hemorrhage, preretinal hemorrhage greater than half the disc area, or a procedure undertaken to treat PDR. Development of CI-DME was defined as CST increased by 10% or more from baseline with vision loss (as already defined), or treatment for CI-DME.

    Statistical Analysis

    The study planned to enroll 386 eyes, which provided 89% power to reject the null hypothesis of no treatment group difference (hazard ratio, 1) for the primary anatomical outcome, assuming exponentially distributed event times consistent with rates of 15% for aflibercept and 30% for sham, 10% loss to follow-up at 2 years, and type I error rate of 5%. To preserve the type I error rate for analysis at multiple time points, a 2.5% type I error was allocated to the current analysis, and a 2.5% type I error was allocated to the final analysis to be conducted when the 4-year follow-up is completed. To preserve the type I error rate at 2 years, a hierarchical approach was used in which mean change in VA was compared only if there was a significant difference (P ≤ .025) in the primary anatomical outcome. The sample size provided 89% power to detect a difference in mean VA if the true difference was at least 3 letters with an SD of 8.

    The comparison of the time to PDR or DME development was performed using the marginal Cox proportional hazards regression model adjusted for baseline DRSS, study eye laterality, and correlation between eyes of participants with 2 study eyes. The proportional hazards assumption was verified using Martingale residuals.14 Data from eyes not meeting the outcome criteria were censored at the last completed visit. Two-year cumulative probabilities were calculated at the end of the 2-year visit window (815 days after randomization) using the Kaplan-Meier estimator.15

    Analyses followed the intent-to-treat principle. Descriptive statistics are reported using observed data and include data from eyes that received treatment for DME or PDR. For treatment group comparisons, missing values for VA and CST were imputed using the Markov chain Monte Carlo method (100 imputations). Secondary outcomes were analyzed using linear mixed models, logistic regression with generalized estimating equations, or marginal Cox proportional hazards regression models as appropriate.

    All P values are 2-sided, with P ≤ .025 considered significant. Analyses were completed using SAS software, version 9.4 (SAS Institute Inc). Because of the potential for type I error due to multiplicity, analyses of secondary outcomes and adverse events should be interpreted as exploratory.

    Results

    From January 2016 to March 2018, 399 eyes (328 participants) were randomly assigned to receive 2.0 mg of aflibercept (n = 200) or sham (n = 199) (Figure 1). The baseline characteristics of the participants and study eyes appeared balanced between treatment groups (Table 1). The median age was 57 years (interquartile range [IQR], 51-64 years), 57.6% were men (189 of 328), 42.4% were women (139 of 328), 46.7% were White (153 of 328), 30.5% were Hispanic or Latino (100 of 328), and 15.2% were Black or African American (50 of 328). Based on reading center assessment, 68 eyes (17.0%) had moderate NPDR (DRSS level 43), 126 eyes (31.6%) had moderately severe NPDR (DRSS level 47A), 109 eyes (27.3%) had moderately severe NPDR (DRSS level 47B-D), and 96 eyes (24.1%) had severe NPDR (DRSS level 53). The median baseline VA letter score was 88 (Snellen equivalent, 20/20) in both groups. Excluding deaths, 160 of 189 participants (84.7%) assigned to aflibercept and 167 of 191 participants (87.4%) assigned to sham completed the 2-year visit, with a mean (SD) number of visits through 2 years of 10 (3) for the aflibercept group and 11 (4) for the sham group. The median follow-up for the aflibercept group was 2.4 years (IQR, 2.0-3.0 years; maximum, 4.1 years), and the median follow-up for the sham group was 2.4 years (IQR, 2.0-3.0 years; maximum, 3.9 years). Excluding deaths, 59 of 67 participants (88.1%) with 2 study eyes completed the 2-year visit; the median follow-up duration was 2.3 years (IQR, 2.0-3.0 years).

    Treatment Effect on DR and DME

    Quiz Ref IDFor the development of CI-DME with vision loss or PDR (primary outcome), the overall adjusted hazard ratio comparing aflibercept with sham was 0.32 (97.5% CI, 0.21-0.50; P < .001) (Figure 2A). The cumulative probability of developing CI-DME with vision loss or PDR within 2 years was 16.3% with aflibercept vs 43.5% with sham. For the development of PDR, the adjusted hazard ratio was 0.34 (97.5% CI, 0.21-0.55; P < .001) (Figure 2B), and for the development of CI-DME with vision loss, the adjusted hazard ratio was 0.36 (97.5% CI, 0.17-0.77; P = .002) (Figure 2C). The cumulative probability of developing PDR within 2 years from randomization was 13.5% with aflibercept vs 33.2% with sham. The cumulative probability of developing CI-DME with vision loss within 2 years from randomization was 4.1% with aflibercept vs 14.8% with sham. The cumulative probability of developing high-risk PDR (DRSS levels of 71, 75, 81, and 85) any time within 2 years was 2.4% with aflibercept and 8.9% with sham. None of the preplanned subgroup analyses (baseline DRSS, presence of non–center-involved DME, race/ethnicity, and sex) indicated a significant subgroup effect (eTable 1 in Supplement 2).

    The details of the event of first meeting the PDR or DME development criteria are described in Table 2, with the cumulative probability of each component shown in eTable 2 in Supplement 2. The most common event, NV of the disc or elsewhere as determined by a central reading center, occurred in 20 eyes (12.4%) in the aflibercept group and 53 eyes (30.9%) in the sham group within 2 years.

    Among participants who completed the 2-year visit, DR severity improved 2 steps or more from baseline to 2 years in 69 of 154 eyes (44.8%) receiving aflibercept vs 22 of 161 eyes (13.7%) receiving sham (adjusted odds ratio, 5.91 [97.5% CI, 3.19-10.95]; P < .001); DR severity worsened 2 or more steps in 8 of 154 eyes (5.2%) receiving aflibercept vs 20 of 161 eyes (12.4%) receiving sham (adjusted odds ratio, 0.37 [97.5% CI, 0.13-1.01]; P = .03) (eTable 3 and eTable 4 in Supplement 2). Compared with baseline, the mean (SD) CST at 2 years decreased by 6 (27) μm with aflibercept vs 1 (28) μm with sham (adjusted mean difference, −4 µm [97.5% CI, −12 to 4 µm]; P = .26). Data on additional CST and optical coherence tomography retinal volume outcomes are provided in eFigure 1, eFigure 2, eTable 5, and eTable 6 in Supplement 2.

    Visual Acuity

    Quiz Ref IDThe mean (SD) change in VA from randomization to 2 years was −0.9 (5.8) letters with aflibercept and −2.0 (6.1) letters with sham (adjusted mean difference, 0.5 letters [97.5% CI, −1.0 to 1.9 letters]; P = .47) (Table 3 and Figure 3). At 2 years, 120 of 160 eyes receiving aflibercept (75.0%) and 119 of 166 eyes receiving sham (71.7%) had VA of 20/20 or better (≥84 letters); no eyes in either group had VA of 20/200 or worse (≤38 letters). Visual acuity loss of 10 or more letters at 2 years occurred in 11 of 160 eyes receiving aflibercept (6.9%) and in 14 of 166 eyes receiving sham (8.4%). Additional VA outcomes are summarized in Table 3 and eTable 7 in Supplement 2. None of the preplanned subgroup analyses (baseline DRSS, non–center-involved DME, race/ethnicity, and sex) indicated a significant subgroup effect (eTable 8 in Supplement 2).

    Treatment of DR and DME

    Among participants completing the 2-year visit, the mean (SD) number of aflibercept injections (including those given for prevention and treatment) was 8.0 (1.2) in the aflibercept group and 7.7 (0.7) for prevention alone (eTable 9 in Supplement 2); the mean (SD) number of aflibercept injections in the sham group was 1.1 (2.7), and the mean (SD) number of sham injections was 7.4 (1.1). Seven of 160 eyes (4.4%) in the aflibercept group and 32 of 167 eyes (19.2%) in the sham group received at least 1 aflibercept injection by 2 years for CI-DME or PDR. Among eyes in the sham group that received at least 1 aflibercept injection, the mean (SD) number of injections through 2 years was 5.7 (3.2).

    Safety

    There were 3 cases of endophthalmitis, all in eyes randomly assigned to aflibercept and from injections administered for prevention, among 3406 injections in study and nonstudy eyes (eTable 10 in Supplement 2). The rate of any cardiovascular or cerebrovascular adverse event was not different among the treatment groups (6 of 71 bilateral [8.5%], 11 of 129 unilateral aflibercept [8.5%], and 11 of 128 unilateral sham [8.6%]; P > .99). eTables 11, 12, 13, and 14 in Supplement 2 provide additional information on ocular and systemic adverse events.

    Discussion

    Through 2 years, the proportion of eyes with moderate to severe NPDR that developed PDR or CI-DME with vision loss was lower in the aflibercept group than in the sham group. Despite these differences in anatomical outcomes, the mean VA change from baseline to 2 years was similar between the 2 groups. Additional follow-up is needed to determine whether early treatment leads to visual benefit long term. This study will continue through 4 years.

    In this study, preventive treatment with aflibercept resulted in a more than 3-fold reduction (from 14.8% with sham to 4.1% with aflibercept) in eyes that developed CI-DME with decreased VA and a more than 2-fold reduction (from 33.2% with sham to 13.5% with aflibercept) in new-onset PDR. Eyes receiving treatment for PDR and CI-DME often have suboptimal visual outcomes; therefore, preventing these conditions may reduce vision loss over time. For example, in the DRCR Retina Network Protocol I, of eyes with CI-DME with decreased VA receiving anti-VEGF therapy, only 40% returned to VA of 20/25 or better by 5 years.16 Similarly, in Protocol S, of eyes with PDR randomized to receive anti-VEGF therapy, approximately 70% had VA of 20/25 or better by 5 years.12

    Despite the potential benefits of disease prevention, the findings from prior studies suggest that earlier treatment does not always confer long-term visual benefit. The ETDRS recommended that early PRP be deferred for eyes with mild or moderate NPDR because treatment risks outweighed functional benefits.17 In eyes with CI-DME and good VA (≥20/25), Protocol V demonstrated that initial observation, with anti-VEGF treatment given only if eyes lost VA, led to VA outcomes that were similar to those that received immediate anti-VEGF therapy.18 In this study, no statistically significant difference between aflibercept and sham was identified in mean VA through 2 years, with aflibercept treatment given for disease progression. In addition, approximately three-quarters of each group had a VA letter score of 20/20 or better and less than 10% of each group lost 2 or more lines of VA at 2 years. These data may suggest that when patients are monitored closely, with follow-up examinations performed at least every 16 weeks as was done in this protocol, treatment of vision-threatening complications after they develop may be adequate to recover lost vision or prevent VA loss, on average. Conversely, it is also possible that average VA loss stemming from higher rates of PDR and CI-DME and their complications in the sham group will increase with continued follow-up. The 4-year results from this study will provide greater clarity as to whether there is a long-term functional benefit of using anti-VEGF therapy as a preventive strategy in eyes with moderate or severe NPDR.

    Despite all eyes in the aflibercept group receiving at least 1 injection per year and undergoing a mean of 8 anti-VEGF injections through 2 years, 16.3% of aflibercept group eyes developed PDR or CI-DME with VA loss by 2 years. This finding demonstrates that anti-VEGF treatment as provided in this study does not guarantee prevention of vision-threatening complications in this high-risk cohort. Continued ophthalmic follow-up and routine examinations are needed to diagnose and treat PDR and CI-DME irrespective of whether intravitreal anti-VEGF therapy is given for prevention of these conditions.

    Eyes in the Protocol W and PANORAMA aflibercept groups experienced a higher rate of DR improvement, as measured by the DRSS, compared with sham. Nonetheless, recent studies have suggested that although anti-VEGF therapy improves DR severity level, it may not substantially modify associated pathologic conditions such as retinal nonperfusion.19 Couturier et al20 imaged eyes undergoing 3 monthly anti-VEGF injections for CI-DME and did not demonstrate reperfusion of vessels or the capillary network in areas that were nonperfused at baseline. Similarly, eyes that received aflibercept vs PRP in the CLARITY (Clinical Efficacy of Intravitreal Aflibercept Versus Panretinal Photocoagulation for Best Corrected Visual Acuity in Patients With Proliferative Diabetic Retinopathy at 52 Weeks) study did not have significant differences in the retinal nonperfusion area at 52 weeks.21 Thus, the question remains whether anti-VEGF treatment delivered to specifically improve DR severity will be beneficial in the long term, especially after cessation of therapy.

    All eyes in this study were judged to have severe NPDR by the enrolling investigator. However, the reading center graded 75.9% (303 of 399) as moderate or moderately severe NPDR. This study capped enrollment of eyes at less severe levels of baseline DRSS owing to concerns that progression rates in these eyes would not be sufficient to observe a treatment effect. The 2-year progression rates of eyes receiving sham with moderate NPDR at baseline were lower (24%) than in eyes with severe NPDR (68%). However, aflibercept treatment appeared beneficial at preventing PDR or CI-DME outcomes across all DR severity levels in this study.

    Limitations

    Quiz Ref IDThis study has some limitations. First, not excluding deaths, retention through 2 years was 80.0% in the aflibercept group (160 of 200) and 83.9% in the sham group (167 of 199). Thus, although treatment adherence was excellent for participants who continued follow-up, and baseline characteristics were similar between those who completed and those who did not complete the 2-year visit, results may be biased by the loss to follow-up. Second, the primary outcome included components determined by an unmasked investigator. However, only 3.5% of the outcomes were based on investigator assessment, and if only outcomes not based on unmasked investigator assessment are evaluated, the results of the study are not substantially different. Third, although it is possible that some of the primary outcome components (eg, vitreous hemorrhage) might not be due to diabetic pathologic conditions, it was infrequent that diabetic retinopathy progression was not verified on retinal images. Fourth, this study used aflibercept as the intervention, and the treatment algorithm used to determine need for aflibercept injection was developed based on DRCR Retina Network investigator consensus. Results using another anti-VEGF agent or a different treatment approach may differ.

    Conclusions

    The proportion of eyes with moderate to severe NPDR that developed vision-threatening complications of CI-DME with vision loss or PDR was lower with aflibercept treatment compared with sham through at least 2 years. However, through 2 years, preventive treatment with aflibercept did not confer visual benefit, on average, compared with initial observation and intravitreal anti-VEGF therapy given only after PDR or DME development. The 4-year results will be critical to assess whether PDR and DME prevention with aflibercept results in long-term VA benefit.

    Back to top
    Article Information

    Accepted for Publication: February 19, 2021.

    Published Online: March 30, 2021. doi:10.1001/jamaophthalmol.2021.0606

    Corresponding Author: Adam R. Glassman, MS, Jaeb Center for Health Research, 15310 Amberly Dr, Ste 350, Tampa, FL 33647 (drcrstat2@jaeb.org).

    Author Contributions: Mr Glassman had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Glassman, Antoszyk, Blodi, Jampol, Martin, Stockdale, Punjabi, Sun.

    Acquisition, analysis, or interpretation of data: Maturi, Glassman, Josic, Antoszyk, Blodi, Jampol, Marcus, Martin, Melia, Salehi-Had, Punjabi, Sun.

    Drafting of the manuscript: Maturi, Glassman, Josic, Jampol, Sun.

    Critical revision of the manuscript for important intellectual content: Maturi, Antoszyk, Blodi, Jampol, Marcus, Martin, Melia, Salehi-Had, Stockdale, Punjabi, Sun.

    Statistical analysis: Glassman, Josic, Melia, Punjabi.

    Obtained funding: Glassman, Jampol, Martin, Sun.

    Administrative, technical, or material support: Glassman, Blodi, Salehi-Had, Stockdale, Punjabi.

    Supervision: Maturi, Glassman, Antoszyk, Blodi, Martin, Melia, Salehi-Had, Punjabi, Sun.

    Conflict of Interest Disclosures: Dr Maturi reported receiving personal fees from Jaeb Center for Health Research during the conduct of the study; personal fees from Aerpio, Allegro, Allergan, Eli Lilly, Genentech, Graybug, Kalvista, and Santen outside the submitted work. Mr Glassman reported receiving grants from the National Eye Institute, Regeneron, and JDRF during the conduct of the study; and grants from Genentech outside the submitted work. Dr Josic reported receiving grants from National Institutes of Health and JDRF; nonfinancial support and funding for clinical trial costs from Regeneron during the conduct of the study; and nonfinancial support and funding for clinical sites from Genentech outside the submitted work. Dr Antoszyk reported receiving personal fees from Jaeb Center for Health Research during the conduct of the study; grants from Jaeb Center for Health Research, Roche, and Genentech; and personal fees from Opthea and Clearside outside the submitted work. Dr Jampol reported receiving grants from the National Eye Institute during the conduct of the study. Dr Marcus reported receiving grants from Genentech/Roche, Allergan, Aiviva, Amgen, Boehringer Inglheim, Alcon, Aerpio, Kalvista, Ionis, Mylan, Samsung, Novartis, Opthea, Chenghdhu, Clearside, Astellas, Allegro, Alimera, Iveric/Opthotech, Gemini, Regeneron, Thrombogenics, Tyrogenex, Graybug, Topcon, Optos, Xplore, Gyroscope, Stealth, Aerie, Apellis, Ohr, Regenxbio, Kodiak, Zeiss, and Genentech/Roche during the conduct of the study. Ms Melia reported receiving grants from the National Eye Institute and Juvenile Diabetes Foundation; and study drug and funds to defray clinical site costs from Regeneron during the conduct of the study. Ms Stockdale reported receiving grants from the National Institutes of Health, JDRF, and Regeneron during the conduct of the study; and grants from Genentech outside the submitted work. Dr Sun reported receiving grants from Jaeb Center for Health Research during the conduct of the study; and nonfinancial support from Optovue, Boston Micromachines, Merck, Novartis, Novo Nordisk, Adaptive Sensory Technologies, Boehringer Ingelheim, Roche, and Kalvista; and grants from Physical Sciences Inc, Kalvista, Novo Nordisk, Boehringer Ingelheim, and Roche outside the submitted work. No other disclosures were reported.

    Funding/Support: This study was supported through a cooperative agreement from the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, US Department of Health and Human Services EY14231. Regeneron provided aflibercept for the study and funds to DRCR Retina Network to defray the study’s clinical site costs. Additional grants to the Jaeb Center for Health Research from the JDRF. Network chairs, coordinating center staff, committee members, and the reading center staff are all compensated for their work as members of the DRCR Retina Network.

    Role of the Funder/Sponsor: As per the DRCR Retina Network Industry Collaboration Guidelines (https://public.jaeb.org/drcrnet/view/Investig_Info) the DRCR Retina Network had complete control over the design of the protocol, ownership of the data, all editorial content of presentation and publication related to the protocol, and the decision to submit the manuscript for publication. The National Institutes of Health participated in oversight of the conduct of the study and review of the manuscript but not directly in the design or conduct of the study, nor in the collection, management, analysis, or interpretation of the data, or in the preparation of the manuscript.

    The DRCR Retina Network members: Coordinating Center staff: Jaeb Center for Health Research (JCHR), Tampa, FL (staff as of January 1, 2021): Adam R. Glassman, MS (JCHR Interim Executive Director and DRCR Retina Network Principal Investigator), Roy W. Beck, MD, PhD (JCHR President), Alyssa Baptista, BS, Wesley T. Beaulieu, PhD, Claire T. Boyle, MS, Sharon R. Constantine, BS, Isabella Correia, Brian B. Dale, Simone S. Dupre, BS, Sandra Galusic, MSPH, Meagan Huggins, BA, Paula A. Johnson, MPH, Kristin Josic, PhD, Brittany Kelly, MS, Danni Liu, MSPH, Brenda L. Loggins, BS, Maureen G. Maguire, PhD, Michele Melia, ScM, Carin M. Preston, MPH, Cynthia R. Stockdale, MSPH, and Katie Stutz, BS. Duke Reading Center staff: Katrina Postell Winter, BS (Lead Reader), Garrett Thompson, MD (Reader), Dee Busian, BA (Reader), Glenn J. Jaffe, MD (Director of Grading), Adiel Mora, BA (Project Manager), Lucia Foster, MA (Project Manager Assistant), and John Keifer McGugan, BS (Project Manager Assistant). Fundus Photograph Reading Center: University of Wisconsin–Madison: Barbara Blodi (Principal Investigator), Amitha Domalpally, Nancy Barrett, Ellie Corkery, Jim Reimers, Kristi Dohm, Ruth Shaw, Sheila Watson, Wendy Benz, Pam Vargo, Andy Ewen, and Daniel Lawrence. DRCR.net Network Chairs: Jennifer K. Sun, MD, MPH (Joslin Diabetes Center, Beetham Eye Institute, Harvard Department of Ophthalmology) (2018-present), Daniel F. Martin, MD (Cole Eye Institute, Cleveland Clinic) (2018-present), and Lee M. Jampol, MD (Feinberg School of Medicine, Northwestern University) (2013-2017). DRCR.net Vice Chairs: Carl W. Baker, MD (Paducah Retinal Center) (2011-2013, 2017-2019), Chirag Jhaveri, MD (Retina Consultants of Austin) (2016-2018), Mathew MacCumber, MD, PhD (Rush University Medical Center) (2018-2020), Andrew N. Antoszyk, MD (Charlotte Eye Ear Nose & Throat Associates, PA) (2013-2016, 2020-2020), Judy Kim, MD (Medical College of Wisconsin) (2015-2017), John A. Wells III, MD (Palmetto Retina Center) (2013-2015), and Sangeeta Bhargava, PhD (National Eye Institute/National Institutes of Health) (2016-current). Executive Committee: Andrew N. Antoszyk, MD (Charlotte Eye Ear Nose & Throat Associates, PA (2009; 2013-present), Roy W. Beck, MD, PhD (JCHR) (2002-present), Sangeeta Bhargava, PhD (National Eye Institute/National Institutes of Health) (2016-present), Barbara Blodi, MD (University of Wisconsin–Madison) (2014-present), Frederick L. Ferris III, MD (Ophthalmic Research Consultants) (2002-present), Adam R. Glassman, MS (JCHR) (2005-present), Glenn J. Jaffe, MD (Duke Reading Center) (2012-present), Lee M. Jampol, MD (Feinberg School of Medicine, Northwestern University) (2012-present), Chirag D. Jhaveri, MD (Retina Consultants of Austin) (2016-present), Judy E. Kim, MD (Medical College or Wisconsin) (2015-2017, 2020-present), Brandon Lujan, MD (Casey Eye Center) (2017-present), Mathew MacCumber, MD, PhD (Rush University Medical Center and Illinois Retina Associates, SC) (2018-present), Dennis M. Marcus, MD (Southeast Retina Center, PC) (2011-2012, 2018-present), Daniel F. Martin, MD (Cole Eye Institute at Cleveland Clinic) (2017-present), Raj K. Maturi, MD (Raj K Maturi, MD, PC) (2009-2011, 2013-present), and Jennifer K. Sun, MD, MPH (Joslin Diabetes Center, Beetham Eye Institute, Harvard Department of Ophthalmology) (2009-present). Prior members: Lloyd Paul Aiello, MD, PhD (Joslin Diabetes Center, Beetham Eye Institute, Harvard Medical School) (2002-2018; Chair 2002-2005), Carl W. Baker, MD (Paducah Retinal Center) (2009-2019), Neil M. Bressler, MD (Department of Ophthalmology, Johns Hopkins University School of Medicine) (2006-2019; Chair 2006-2008), Susan B. Bressler, MD (Wilmer Eye Institute) (2009-2019), Matthew D. Davis, MD (Medical College of Wisconsin) (2002-2017), Michael J. Elman, MD (Elman Retina Group, PA) (2006-2018; Chair 2009 and 2012), Jeffrey G. Gross, MD (Carolina Retina Center, PA) (2012-2017), Diana M. Holcomb, COA (Retina Associates of Kentucky) (2011-2012), Andreas K. Lauer, MD (Casey Eye Center) (2007-2008), Ashley A. McClain, BS, CRC (Charlotte Eye Ear Nose & Throat Associates, PA) (2013), and Brandi J. Perez (Loma Linda University Eye Institute) (2013). Data and Safety Monitoring Committee: Gary Abrams, MD (Kresge Eye Institute), Deborah R. Barnbaum, PhD (Kent State University), Harry Flynn, MD (Bascom Palmer Eye Institute), Kyle D. Rudser, PhD (University of Minnesota), Paul Sternberg Jr, MD (Vanderbilt Eye Institute), Sangeeta Bhargava, PhD (National Eye Institute/National Institutes of Health), Ruth S. Weinstock, MD, PhD (SUNY Upstate Medical University), Stephen Wisniewski, PhD (University of Pittsburgh), and Charles P. Wilkinson, MD (Greater Baltimore Medical Center) (2012-2018). Diabetic Retinopathy Clinical Research Network clinical sites that participated in this protocol: sites are listed in order by number of participants enrolled into the study. The number of participants enrolled is noted in parentheses preceded by the site location and the site name. Personnel are listed as (I) for Study Investigator, (C) for Coordinator, (V) for Visual Acuity Technician, and (P) for Photographer. Charlotte, North Carolina: Southeast Clinical Research Associates, LLC (32): Omar S. Punjabi, MD (I); David Browning, MD, PhD (I); John Bradley Allen, MD (I); Andrew N. Antoszyk, MD (I); Angela K. Price, MPH (C, V); Taylor S. Jones (C, V); Sherry L. Fredenberg (C, V); Christina J. Fleming, BS, CCRP (C, V); Brittany A Murphy, BA, COT (C, V); Courtney Mahr (C); Erica Breglio (V); Kaitlin T. McShea, MS (V); Christina Mutch (V); Angella K. Gentile (V); Kayla A Bratcher (V); Sarah A. Ennis (V); Uma M. Balasubramaniam (P); Carol A Shore (P); Lisa A. Jackson (P); Loraine M. Clark, COA (P); Lynn Watson (P); Michael D. McOwen (P); Shannon Stobbe (P); Donna McClain, COA (P); and Tracy A. Ross (P). Huntington Beach, California: Salehi Retina Institute Inc (23): Hani Salehi-Had, MD (I); Evelyn Ceja (C); Sara Ahmed, BS (C); Stephanie Ramirez (C, P, V); Scott F. Lee, OD (V); Mary Ma, OD (V); Mailan Tran, OD (V); Undariya Boldbaatar (P); Nikki Nguyen, BS (P); Lily Castillo (P); Janet Reyes (P); and Karen Gasperian (P). Hagerstown, Maryland: Mid Atlantic Retina Specialists (16): Adam T. Gerstenblith, MD (I); Robert E. Parnes, MD (I); April L. Stockman (C, P, V); Jennifer Shirey (V); Kylie Stambaugh (V); Angie Goldizen (P); Leslie Toomey (P); and Lora Glaspell (P). Houston, Texas: Retina Consultants of Texas, PA (13): Charles C. Wykoff, MD, PhD (I); Rosa Y. Kim, MD (I); Tien P. Wong, MD (I); James C. Major, MD (I); Matthew S. Benz, MD (I); David M. Brown, MD (I); Richard H. Fish, MD (I); Eric Chen, MD (I); Ankoor R. Shah, MD (I); Amy C. Schefler, MD (I); Tyneisha McCoy (C); Jose Munoz (C); Sadia Y Karani (C); Stacy M. Supapo (C); Garret L Twining (C); Diana Rodriguez (C); Maura A Estes (C); Daniel Park (C); Amy Hutson (C); Calley N. Smith (C); Danee Foerster (C); Lindsay Burt (V); Melina Vela (V); Miguel Oviedo (V); Ilsa Ortega (V); Heather Koger-Grifaldo (V); Nina A. Webb (V); Veronica A. Sneed (V); Lisa M Wolff (V); Elizabeth Quellar (V); Belinda A. Almanza (V); Rebecca Yee (V); Eric N. Kegley (P); Miranda F James (P); Cary A. Stoever (P); Beau A Richter (P); David Garcia (P); and Luis R. Salinas (P). Santa Barbara, California: California Retina Consultants (13): Dante J. Pieramici, MD (I); Alessandro A. Castellarin, MD (I); Daniel L. Learned, MD (I); Nathan Steinle, MD (I); Dilsher Dhoot, MD (I); Carmen Carbajal (C); Libby Dahlberg (C); Gina Hong, BS, BA (C, P, V); Marco A Munoz (C, V); Jack Giust, BS (C, P); Jamison C Ray, BS (C, V); John McDermott (C, V); Kate M McKee, BS (C, P, V); Kevin Card (C, V); Kelly Avery (V); Laura Budvytyte (V); Jerry Smith (V); Nancy Castillo (P); Aimee H. Shook, BS (P); and Susan Spaeth (P). Augusta, Georgia: Southeast Retina Center, PC (12): Dennis M. Marcus, MD (I); Harinderjit Singh, MD (I); Siobhan O. Ortiz (C); Amina Farooq, MD (C); Thomas Bailey (V); Lindsay Allison Foster (V); Michele Woodward (V); and Ken Ivey, COA (P). Oakland, California: East Bay Retina Consultants Inc (12): Soraya Rofagha, MD, MPH (I); Jesse J. Jung, MD (I); Eugene Stephen Lit, MD (I); Heidi A. Winje (C, P); Maria Zamora (C); Renjini Balakrishnan, MSc (C); Caroline Frambach (V); Denise Joy Bustamante (V); Joshua R Machacon (V); Mae Kwan (V); Helen Ricks (V); Afsoon Jamali (P); and Maria Miranda (P). Indianapolis, Indiana: Raj K. Maturi, MD, PC (10): Raj K. Maturi, MD (I); David A. Lightman, MD (I); Stephen J Saxe (I); Lorraine White (C, P, V); Ashley M. Harless (C, P, V); Carolee K. Novak, CRC (V); Erin Brown (V); Myra K Retrum (V); Thomas Steele, CRA (P); Holly Fiscus (P); Yesenia Sarmiento (P); Stephanie J. Morrow, COA (P); and Charlotte Harris (P). Paducah, Kentucky: The Ophthalmology Group LLC (10): Carl W. Baker, MD (I); Ron H. Tilford, MD (I); Jil D Baker, MT, ASCP (C); Tracey M. Caldwell, CCRC (C); Margaret J. Orr, COA (V); Mary J. Sharp, COA (V); Samantha Kettler (P); Sonya L Alcaraz (P); Kylie S. Sedberry (P); and Alecia B. Camp (P). Austin, Texas: Retina Research Center (8): Brian B. Berger, MD (I); Chirag D. Jhaveri, MD (I); Saradha Chexal, MD (I); Gowtham Jonna, MD (I); Daniela Vega Pereira (C); Daniela Mariel Wilson (C); Tina A Seidu (C); Ivana Gunderson (C, V); Ryan M. Reid (C, P); Valerie Gatavaski (V); Abla M Harara (V); Boris Corak, BS (P); Yong Ren (P); and Christopher C. Stovall (P). Austin, Texas: Austin Retina Associates (8): Robert W. Wong, MD (I); Jose A. Martinez, MD (I); Peter A. Nixon, MD (I); Margaret A. Rodriguez, COA (C); Phillip V. Le (C, P, V); Corinne C Vargas (C, P, V); Gopal Karsaliya (C, P, V); Chris A. Montesclaros (C, P); and Cory Mangham (P). Boston, Massachusetts: Joslin Diabetes Center (8): Lloyd Paul Aiello, MD, PhD (I); Miin Irene Roh, MD, PhD (I); Sabera T. Shah, MD (I); Jennifer K. Sun, MD, MPH (I); Paolo S. Silva, MD (I); George S. Sharuk, MD (I); Paul G. Arrigg, MD (I); Margaret E. Stockman (C, V); Jae W Rhee (C); Tanya Olesker, BS (C); Leila Bestourous (V); Mina Sehizadeh, OD (V); Jerry D. Cavallerano, OD, PhD (V); William Carli, COA (V); Steve L. Papaconstantinou, COT (V); Elizabeth S. Weimann, COT, BS (V); Michael N. Krigman (V); Robert W. Cavicchi (P); and Konstantina Sampani (P). Knoxville, Tennessee: Southeastern Retina Associates, PC (8): Joseph M. Googe, MD (I); R. Keith Shuler, MD (I); Nicholas G. Anderson, MD (I); Kristina Oliver (C); Steve Morris (C); Vicky L. Seitz (C); Julie Asher (C, V); Summer McCoy (V); Katie Milstead (V); Jeff Wheeler (V); Caitlin Gilbreath (P); Justin Walsh (P); Raul E. Lince (P); Hodge A. Griffone (P); and Sarah M. Oelrich (P). Marietta, Georgia: Marietta Eye Clinic (8): Annal Dhanu Meleth, MD, MS (I); Lakshmana Murthy Kooragayala, MD (I); Chigozie Nkemka (C); Chenavia Lewis, MS, CCRP (C, P, V); Meuzette White-Walker (C); Minuette S Jackson, BA, COA (C, V); Shakirah J Sewell (C); Samantha Sircar (P); Adam Goff (P); and Kenneth Thompson (P). Loma Linda, California: Loma Linda University (7): Joseph T. Fan, MD (I); Kakarla V. Chalam, MD (I); Samuel C. Kim, MD (I); Michael E. Rauser, MD (I); David Isaiah Sierpina, MD (I); Tina L Ramirez (C); Vivian L Garcia (C); Raquel Hernandez (C, V); Anthoni Tampubolon (C, P, V); Jayson S Paw (C); Jacqueline V Midgett, MPH (C); Marcia Easterly (P); Adel E Alset, COA (P); and Moises Tellez (P). North York, Toronto, Ontario: Chow Berger Koushan Medicine Professional Corporation o/a Toronto Retina Institute (7): Keyvan Koushan, MD, FRCSC (I); Myuri Jeyabalachandran (C); Pauline Fung (C); Arman Amiri (C); Stephanie Hegarty (V); Parita Thakker (P); Jennifer Wong (P); Devjani Dutta (P); and Gloria Leung (P). Toronto, Ontario: University Health Network (7): Michael Henry Brent, MD, FRCSC (I); Efrem D. Mandelcorn, MD, FRCSC (I); Olivera Sutakovic, MD, CCRCII (C, P, V); Michelle Moon (C, P, V); Lindsay Hampton-Hampejskova (C, P); Lina Chen (C, P, V); Bilgin Turhal, MD (C, P, V); Claire Mowatt (P); Susan Bolychuk (P); Ian Brown (P); and Isaac A Kotei (P). Ayer, Massachusetts: Valley Eye Physicians and Surgeons (6): Gisela Velez, MD, MPH, MA (I); Oksana Mykhaylyk (C, V); Madeline Leon (C, P); Elizabeth I. Johnson, MS (C); Maa Ahema Parry, OD, MEd (C); Travis Sweeney (C); Nicholas Chang (V); Nicholas R Mastrodomenico (V); Michael D. Ortega, CMA (P); Amanda Aho (P); Jean Larkin (P); Jhan Carlos Caro (P); Christine Manuel (P); Joseph A. Myers (P); Beatriz LaFountain (P); Crystal Girard (P); Armando Saez (P); Chandapilla C. Pallipeedikayil (P); and Thomas Taylor (P). Houston, Texas: Baylor College of Medicine, Baylor Eye Physicians and Surgeons (6): Christina Y. Weng, MD, MBA (I); Tahira Scholle, MD (I); Laura A Baker (C, V); Becky R. Chatham (C, V); Wendy Blacutt, MD (C, V); Jiping Cai, MD (C, V); Annika S. Joshi, COA, CCRC (C, V); April Leger, COT (V); Joseph F. Morales (P); and Dana B. Barnett (P). Orlando, Florida: Florida Retina Institute, James A. Staman, MD, PA (6): Matthew A. Cunningham, MD (I); Elias C. Mavrofrides, MD (I); Jaya B. Kumar, MD (I); Samuel K. S. Houston, III, MD (I); Elaine Rodriguez-Roman, OD (C); Alma Rodriguez (P); Chanell Thomas (P); Dianelis Figueroa (P); Francisco Pineda (P); and Timothy S Holle (P). Baltimore, Maryland: Elman Retina Group, PA (5): Michael J. Elman, MD (I); Henry A. Leder, MD (I); JoAnn Starr (C); Twyla J Robinson (C); Travis J. Smalls, BA, MS (C); Kate N Kreis (C); Jennifer L. Belz (C); Alesia K McCalla (V); Christine Ringrose (V); Teresa Coffey (V); Perel M. Simpson, COA (V); Pamela V. Singletary, COA (V); Katherine L Wentz (V); Amy Thompson (V); Dallas R. Sandler (V); Ashley M. Metzger (P); Peter Sotirakos (P); and Terri Cain (P). Eugene, Oregon: Sterling Vision DBA Oregon Retina (5): Albert O. Edwards, MD, PhD (I); Allan A. Hunter III, MD (I); Jessica Zuniga (C, V); Jonathan Wallace (C, V); Natalie W. Kogutkiewicz (C, V); Nicole M Gregorich (C, V); Ryan G. Lebien, BS (C, P, V); Nicole Muhlnickel (V); and Andrew G. Everett (P). New York, New York: Macula Care (5): Daniel F. Rosberger, MD, PhD, MPH (I); Nneka O. Brooks, MD (I); Phuntsho Wangmo, BA (C); Mohammed Yaseen (C, P, V); Sandra Acevedo, BS (C, V); Sarah Bendarkawi, BS (C); Joshua A Pickell, BA (C); Sonam Gyaltshen (P); and Yenelda M. Gomez (P). Philadelphia, Pennsylvania: The Trustees of the University of Pennsylvania (5): Alexander J. Brucker, MD (I); Sheri Drossner, MSW (C, V); Joan C. DuPont, CRC (C, V); Devica L Bhutani (V); Kennedy N Johnson (V); Judy Chen (P); Jim M. Berger (P); Cheryl Devine (P); and Sara Freeman (P). Phoenix, Arizona: Arizona Retina and Vitreous Consultants and Doc Trials, LLC (5): Shabari S. Seetharam, MD (I); Anita Prasad, MD (I); Ramin Schadlu, MD (I); Brigid Smith, BS (C); Lindsey Butler, BSN (C); Juan Tonche (P); and Jacob Michael Hylands (P). Sandy Springs, Georgia: Thomas Eye Group (5): Paul L. Kaufman, MD (I); Jessica D. McCluskey, MD (I); Kathy T. Wynne, BS, COT (C, V); Cynthia Weaver, COT (V); Rosario Romero (P); Brandun Watson, BS, COT (P); Kristin Gilbert (P); Carlos R. Cook (P); and Sarah Matloff, COA (P). Chattanooga, Tennessee: Southeastern Retina Associates (4): Richard I. Breazeale, MD (I); Francis C. DeCroos, MD (I); Devon Ghodasra, MD (I); Rohan J. Shah, MD (I); Steve W. McBee, Jr. (C); Elizabeth Lisa McDonald (C, P); Courtney Duncan (V); Brianna J Lewis (V); Kate Menefee (V); David Woods, CRA, COA, CST (P); and Roger P. Melendrez (P). Sacramento, California: Regents of the University of California, Davis, DBA University of California, Davis (4): Ala Moshiri, MD, PhD (I); Glenn C. Yiu, MD, PhD (I); Cynthia Wallace (C); Denise C Macias (C); Angela M. Beliveau (C); Susan Garcia (V); Marisa E. Salvador (V); Karishma Chandra (P); Sashi Deo (P); John Peterson (P); and Igor Slabosnitskiy (P). Chapel Hill, North Carolina: University of North Carolina at Chapel Hill (3): Jan Niklas Ulrich, MD (I); Seema Garg, MD, PhD (I); Cassandra J. Barnhart, MPH (C); Elizabeth L. DuBose, MPH (C, V); Kanika A Bhansali (C, V); Debra Cantrell (P); Veronica Jones (P); Rona Lyn Esquejo (P); Sean Grout (P); and Houston P Sharpe (P). Columbia, South Carolina: Carolina Retina Center (3): Jeffrey G. Gross, MD (I); Victor A. Neamtu, MD (I); Joel Gross (C); Vincent Klapper (C, V); Amy M. Flowers, BA (C, V); Angelique SA McDowell, BS (V); and Randall L. Price, BA (P). Fort Myers, Florida: National Ophthalmic Research Institute (3): A. Thomas Ghuman, MD (I); Paul A. Raskauskas, MD (I); Ashish G. Sharma, MD (I); Joseph P. Walker, MD (I); Kristi Maro (C); Cheryl Kiesel, COA, ROUB (C); Eileen Knips, RN, COA, CRA (C, P); Cheryl Ryan (C); Crystal Y. Peters, CCRC (C); Anita H. Leslie (V); and Raymond K. Kiesel (P). Lakeland, Florida: Florida Retina Consultants (3): Nader Moinfar, MD, MPH (I); Scott M. Friedman, MD (I); Shannon M Rehling (C, V); Damanda F. Fagan (C, P, V); Kimberly A. Williamson (C); Ceara L Wendel (C); Jacqueline Andrews (V); Karen Seyez, COT (V); Shana E Williams (P); Allen McKinney (P); and Brenda J. Bobbitt (P). McAllen, Texas: Valley Retina Institute (3): Victor Hugo Gonzalez, MD (I); Nehal R. Patel, MD (I); Rohit Adyanthaya, MD (I); Yesenia Salinas, CRC (C); David A. Reyes, BS (C); Nancy L Salinas (C); Angelina Garza, BS (C); Ana L Pina, BA (C); Amber B Ibarra, BS (C); Elyssa Navarro (C); Janette Arredondo (V); Isaac Cabrera (V); Rebecca R. Flores, COA (V); Yvonne Diaz (V); Brenda Velasquez (V); Enrique Chavez (V); Monica R. Cantu, COT (V); Monique Montemayor, COA (P); Stephanie Tamez (P); Santos Garza (P); and Samuel Alonso (P). Miami, Florida: University of Miami (3): Justin H. Townsend, MD (I); Jessica Taha (C); Belen Rodriguez, CCRP (C); Ailen E Gutierrez, BA (C); Alexey Gomez Rodriguez (V); Enelda Idalia Mendoza (V); Liliana P. Perez (V); Megan Mawdesley (P); Ailen Graces Fernandez (P); Tanya Nicole Rego (P); Shannon B Asklar (P); and Brandon Michael Sparling (P). Portland, Oregon: Oregon Health & Science University (3): J. Peter Campbell, MD, MPH (I); Andreas K. Lauer, MD (I); Christina J Flaxel, MD (I); Steven T. Bailey, MD (I); Thomas S. Hwang, MD (I); Mitchell Schain, BS (C, P, V); Ann D. Lundquist, BA (C, V); Jennifer K Maykoski, BS (V); Shirley D. Ira, COT (V); Chris S Howell, BA (P); Dawn M. Ryan, CRA (P); Jocelyn T. Hui, BS (P); Jordan Barth, AA (P); Chiedozie Ukachukwu (P); and Scott R. Pickell, BS (P). Syracuse, New York: Retina-Vitreous Surgeons of Central NY, PC (3): Jamin S. Brown, MD (I); G. Robert Hampton, MD (I); Laurie J. Sienkiewycz (C); Christine M. Dorr (C); Lisa Spuches (V); Lynn M. Kwasniewski (V); Michelle L. Manley (V); Abigail Miller (P); Nicole E. Robarge (P); Stefanie R. DeSantis, BS (P); Teresa M. DeForge (P); and Jeffrey P Barker (P). West Monroe, Louisiana: Joseph E. Humble and Raymond Haik PTRS DBA Eye Center Eye Assoc of Northeast Louisiana (3): Ruben A. Grigorian, MD (I); Latha M Jois (C, P); Rebecca Morris (C, P, V); Rebecca Webb, BS, CRC (C, P, V); Dusti D Douglas (V); Sharoon David, MBBS (P); and Faith Pena, BS (P). Asheville, North Carolina: Western Carolina Clinical Research, LLC (2): Cameron McLure Stone, MD (I); McCayla Elise Hall (C); Andrea K. Menzel, COA (C); Monica Hamrick (C); Lea R. Raymer, BS (C); Leslie D. Rickman, COA (V); Julia Crokett Overbey (V); Donna Machen (V); Lisa H. Hawkins, COA (P); Melissa Smith (P); and Paula A. Price, COT (P). Halifax, Nova Scotia: Nova Scotia Health Authority (2): Alan F. Cruess, MD (I); R. Rishi Gupta, MD, DABO (I); John D. Dickinson, MD (I); Alec M. Cranston (C); Meggie D. Caldwell (C); Stacey Durling (V); Mitzi Hynes, COT (P); and Trina MacDonnell, OC (C), COMT (P). Lubbock, Texas: Texas Retina Associates (2): Michel Shami, MD (I); Yolanda Saldivar (C); Ashaki Meeks (V); and Glenn R. Gardner, CRA (P). Monroeville, Pennsylvania: Retina-Vitreous Consultants, Inc. (2): Karl R. Olsen, MD (I); Jared E. Knickelbein, MD, PhD (I); Robert L. Bergren, MD (I); Bernard H. Doft, MD (I); Lori A. Merlotti (C); Julie Walter (V); Lois Stepansky (V); Dawn Diperna (P); and Phyllis P Ostroska (P). Palm Desert, California: Southern California Desert Retina Consultants, Inc (2): Clement K. Chan, MD (I); Maziar Lalezary, MD (I); Tiana Gonzales (C); Kimberly S. Walther (C); Tonya M Gieser (C); Isela Aldana (C, V); Lenise E. Myers, COA (V); Kristina Pettit (P); and Kenneth M. Huff, COA (P). Pinellas Park, Florida: Southeast Eye Institute, P.A. dba–Eye Associates of Pinellas (2): Jason M. Handza, DO (I); Bronson Oudshoff, CCRC (C); Corey T. McGahee, COA (P); Christina Glover (P); nd Annette M. Carey, COA (P). Plantation, Florida: Eye Physicians of Florida LLC DBA Fort Lauderdale Eye Institute LLC (2): Tirso M. Lara, MD (I); Stuart K. Burgess, MD (I); Noel H. Pereda, MD (C, V); Deborah Davis (V); Adriana Villa (V); Mark Oberlander (P); and Karen Workman (P). Portland, Oregon: Retina Northwest, PC (2): Apurva K. Patel, MD (I); Paul S. Tlucek, MD (I); Mark A. Peters, MD (I); Colin Ma, MD (I); Brian S Puckett (C); Pualani Smith (C); Stephanie L. Ho, BA (C, P, V); Margaret E Charpentier (V); Marcia Kopfer, BS, COT (V); and Christine Hoerner (P). Sarasota, Florida: Sarasota Retina Institute (2): Melvin Chen, MD (I); Peggy A. Jelemensky (C, V); Samantha R. Basham (V); Tara L. Raphael (V); Mark Sneath, COA (P); and Rosa Miller (P). Shawnee Mission, Kansas: Retina Associates, PA (2): Gregory M. Fox, MD (I); Ryan D. Christensen, MD (I); David S. Dyer, MD (I); Ivan R. Batlle, MD (I); Ravi S. J. Singh, MD (I); Lexie R. Ainley (C); Karla A. Batlle, BS (C); Amber R. VandeVelde, RN (V); Holly Wyrick (V); Frank T. Yeager (P); and Katherine Pippin (P). Southlake, Texas: Jawad A. Qureshi MD, PA DBA Retina Center of Texas (2): Jawad A. Qureshi, MD (I); Kruti P. Dajee, MD (I); Johnathan D. Warminski, MD (I); Pualani Smith (C, V); Victoria E. Cowart (C); Andre Watkins (P); Denise Ortiz (P); and Diana Murillo (P). Vancouver, British Columbia: University of British Columbia and Vancouver Coastal Health Authority and Eduardo Navajas, MD, PhD (2): Eduardo Vitor Navajas, MD, PhD (I); Sijia Cao (C); Mira Jovanovic, Msci (C, V); Theresa Wiens, MSc, CCRP (C); Sherry Han, MSc (V); Bryan Harrison (P); Anne-Marie Godfrey (P); and Kelly Grant (P). Baltimore, Maryland: Johns Hopkins University (1): Sharon D. Solomon, MD (I); Susan Bressler, MD (I); Deborah Donohue (C, V); Lisa K. Levin (C); Mary Frey, BSc, CCRP (V); Russ Distle (P); and Dennis Cain, CRA (P). Chicago, Illinois: Northwestern University (1): Alice T. Lyon, MD (I); Manjot K. Gill, MD (I); Chisomo Mwale (C, V); Carmen Ramirez (C, V); Crystal Santillanes (C, V); Evan C. Davies (C); Nicole M Seddon (C); Priya M Thakkar, BS (C); Anson Moore (V); Cason Moore (P); Maritza Barragan (P); and Evica Simjanoski, BFA (P). Chicago, Illinois: The Board of Trustees of the University of Illinois (1): Jennifer I. Lim, MD (I); Felix Y. Chau, MD (I); Jie Sun, MD (C); Tametha Johnson (V); Natasa Stankovic, AAS, COT (V); Ben Martinez (V); Mark Janowicz, BS (P); and Andrea Degillio, CRA, CDOS (P). Jacksonville, Florida: University of Florida–Jacksonville (1): Sandeep Grover, MD (I); Ghulam Shabbir Hamdani, MBBS, MSH, CCRP (C); Bharani Krishna Mynampati A, PhD (C, P, V); Romesh Babaria, MS (C, V); and Jazzmin N Smith (C, P). Madison, Wisconsin: The Board of Regents of the University of Wisconsin System (1): Justin Gottlieb, MD (I); Barbara A. Blodi, MD (I); Kristine A. Dietzman, BS, CCRC (C); Christopher M. Smith, COA (C, V); Angela M. Adler, BS, CCRC (V); Denise A. Krolnik, MS (P); and Sandie L. Reed, AD (P). Minneapolis, Minnesota: Retina Center, PA DBA Retina Center of Minnesota (1): Abdhish R. Bhavsar, MD (I); Andrea Gilchrist (C); Matt D. Peloquin, AA (V); Jason R Sweet (V); Denise Vang (P); Erin C. Kinney (P); and Alanna C. Evans (P). New York, New York: The New York Eye and Ear Infirmary (1): Ronald C Gentile, MD (I); Melissa Rivas (C, V); John Bo Soo Choi (C, V); Wanda Carrasquillo-Boyd (P); and Robert Masini (P). Orlando, Florida: Magruder Eye Institute (1): John T. Lehr, MD (I); Brittany M. Pendarvis (C); Elaine Rodriguez-Roman, OD (C); Mari Delgado (C, P, V); Atira Bramble, COA (V); Robert Atnip (V); Patricia Lynch (V); Martha Eileen Haddox (V); Julian Rodriguez (P); Kyle Dreessen (P); Ashley E Willer (P); Mark Pena (P); and Chase Hutchings, COA (P). Overland Park, Kansas: Mid-America Retina Consultants, PA (1): William N. Rosenthal, MD (I); Elizabeth N. Heim, BSN, RN (C); Sarah N. Lamaster, RN, BSN (C, V); Courtney J. Dunn (P); R. Scott Varner (P); and Mary C. Stewart, RN (P). San Antonio, Texas: Retinal Consultants of San Antonio (1): Moises A. Chica, MD (I); Calvin E. Mein, MD (I); Lydia Adams (C); Jenny M Bermea (C); Sara L Cloudt (C); Lita Kirschbaum, COA (C); Victoria Lopez (V); Jonathan San Roman (V); Samantha Bankston (P); Brenda Nakoski (P); and Christopher Sean Wienecke (P). Springfield, Illinois: Springfield Clinic, LLP (1): Ramanath Bhandari, MD (I); Jennifer Shaw (C, P); Bradley C. Evans, LPN, COA (C); Braden Anderson (V); Gaylan W Moushon, OD (V); Kris Karrick, COA (P); Caitlyn Wessel (P); and Dennis Frye (P). Trumbull, Connecticut: New England Retina Associates, PC (1): Gregory M. Haffner, MD (I); Andrea L. DeClement (C); Leslie D. Hurst, MS (C); Patricia L Anderson (C); Adriana N. Enxuto (V); Stephanie Esteves (V); and Emily Morse, BS (P). Tucson, Arizona: University of Arizona Medical Center/Department of Ophthalmology (1): John B. Christoforidis, MD (I); Jill Brickman-Kelleher, BS, AAS (C); Sue A. Bulau (C, V); Patricia H. Fryer (V); and Dennis Haymore (P). West Columbia, South Carolina: John A. Wells, III MD DBA Palmetto Retina Center, LLC (1): John A. Wells, III, MD (I); Tiffany R. Swinford (C, V); Tiffany N. Ogbuewu (V); Robbin Spivey (P); and Ashley Studebaker (P). West Des Moines, Iowa: Wolfe Eye Clinic, PC (1): Jared S. Nielsen, MD (I); Kyle J. Alliman, MD (I); Tami Jo Woehl (C); Marianne Parker (C); Erin L. Riley (C); Jack Bowers (V); Jamie Spillman (V); Paula L. Bix (V); Spencer D. Ridgway (P); and Lisa M. Boender (P).

    Data Sharing Statement: See Supplement 3.

    Additional Information: The data collected for this study, including deidentified participant data and a data dictionary defining each filed in the data set, will be made available at https://public.jaeb.org/drcrnet/stdy no later than 12 months after publication of the final 4-year primary results. At that time, the data will be made available to anyone requesting the data.

    References
    1.
    Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema.  Ophthalmology. 2010;117(6):1064-1077. doi:10.1016/j.ophtha.2010.02.031PubMed
    2.
    Wells  JA, Glassman  AR, Ayala  AR,  et al; Diabetic Retinopathy Clinical Research Network.  Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema.   N Engl J Med. 2015;372(13):1193-1203. doi:10.1056/NEJMoa1414264 PubMedGoogle Scholar
    3.
    Gross  JG, Glassman  AR, Jampol  LM,  et al; Writing Committee for the Diabetic Retinopathy Clinical Research Network.  Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: a randomized clinical trial.   JAMA. 2015;314(20):2137-2146. doi:10.1001/jama.2015.15217 PubMedGoogle Scholar
    4.
    Sivaprasad  S, Prevost  AT, Vasconcelos  JC,  et al; CLARITY Study Group.  Clinical efficacy of intravitreal aflibercept versus panretinal photocoagulation for best corrected visual acuity in patients with proliferative diabetic retinopathy at 52 weeks (CLARITY): a multicentre, single-blinded, randomised, controlled, phase 2b, non-inferiority trial.   Lancet. 2017;389(10085):2193-2203. doi:10.1016/S0140-6736(17)31193-5 PubMedGoogle ScholarCrossref
    5.
    Wilkinson CP, Ferris FL 3rd, Klein RE, et al. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales.  Ophthalmology. 2003;110(9):1677-1682.
    6.
    Regeneron Pharmaceuticals Inc. Eylea (aflibercept) injection reduced risk of developing vision-threatening events by 75% after two years in patients with diabetic retinopathy. Published February 8, 2020. Accessed January 19, 2021. https://newsroom.regeneron.com/index.php/news-releases/news-release-details/eylear-aflibercept-injection-reduced-risk-developing-vision
    7.
    World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.   JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053PubMedGoogle ScholarCrossref
    8.
    Bressler  SB, Edwards  AR, Chalam  KV,  et al; Diabetic Retinopathy Clinical Research Network Writing Committee.  Reproducibility of spectral-domain optical coherence tomography retinal thickness measurements and conversion to equivalent time-domain metrics in diabetic macular edema.   JAMA Ophthalmol. 2014;132(9):1113-1122. doi:10.1001/jamaophthalmol.2014.1698 PubMedGoogle Scholar
    9.
    National Institutes of Health. NIH policy and guidelines on the inclusion of women and minorities as subjects in clinical research. Accessed April 11, 2019. https://grants.nih.gov/grants/funding/women_min/guidelines.htm
    10.
    US Food and Drug Administration. Collection of race and ethnicity data in clinical trials: guidance for industry and Food and Drug Administration staff. Published October 26, 2016. Accessed April 11, 2019. https://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126396.pdf?source=govdelivery&utm_medium=email&utm_source=govdelivery
    11.
    Aiello LP, Odia I, Glassman AR, et al. Comparison of Early Treatment Diabetic Retinopathy Study standard 7-field imaging with ultrawide-field imaging for determining severity of diabetic retinopathy.  JAMA Ophthalmol. 2019;137(1):65-73.
    12.
    Gross  JG, Glassman  AR, Liu  D,  et al; Diabetic Retinopathy Clinical Research Network.  Five-year outcomes of panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: a randomized clinical trial.   JAMA Ophthalmol. 2018;136(10):1138-1148. doi:10.1001/jamaophthalmol.2018.3255 PubMedGoogle ScholarCrossref
    13.
    Wells  JA, Glassman  AR, Ayala  AR,  et al; Diabetic Retinopathy Clinical Research Network.  Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial.   Ophthalmology. 2016;123(6):1351-1359. doi:10.1016/j.ophtha.2016.02.022 PubMedGoogle ScholarCrossref
    14.
    Lin  DY, Wei  LJ, Ying  Z.  Checking the Cox model with cumulative sums of Martingale-based residuals.   Biometrika. 1993;80(3):557-572. doi:10.1093/biomet/80.3.557 Google ScholarCrossref
    15.
    Kaplan  EL, Meier  P.  Nonparametric estimation from incomplete observations.   J Am Stat Assoc. 1958;53(282):457-481. doi:10.1080/01621459.1958.10501452 Google ScholarCrossref
    16.
    Elman  MJ, Ayala  A, Bressler  NM,  et al; Diabetic Retinopathy Clinical Research Network.  Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year randomized trial results.   Ophthalmology. 2015;122(2):375-381. doi:10.1016/j.ophtha.2014.08.047 PubMedGoogle ScholarCrossref
    17.
    Early Treatment Diabetic Retinopathy Study Research Group.  Early photocoagulation for diabetic retinopathy. ETDRS report number 9.   Ophthalmology. 1991;98(5)(suppl):766-785. doi:10.1016/S0161-6420(13)38011-7 PubMedGoogle ScholarCrossref
    18.
    Baker  CW, Glassman  AR, Beaulieu  WT,  et al; DRCR Retina Network.  Effect of initial management with aflibercept vs laser photocoagulation vs observation on vision loss among patients with diabetic macular edema involving the center of the macula and good visual acuity: a randomized clinical trial.   JAMA. 2019;321(19):1880-1894. doi:10.1001/jama.2019.5790 PubMedGoogle ScholarCrossref
    19.
    Wykoff  CC, Nittala  MG, Zhou  B,  et al; Intravitreal Aflibercept for Retinal Nonperfusion in Proliferative Diabetic Retinopathy Study Group.  Intravitreal aflibercept for retinal nonperfusion in proliferative diabetic retinopathy: outcomes from the randomized RECOVERY trial.   Ophthalmol Retina. 2019;3(12):1076-1086. doi:10.1016/j.oret.2019.07.011 PubMedGoogle ScholarCrossref
    20.
    Couturier  A, Rey  PA, Erginay  A,  et al.  Widefield OCT-angiography and fluorescein angiography assessments of nonperfusion in diabetic retinopathy and edema treated with anti-vascular endothelial growth factor.   Ophthalmology. 2019;126(12):1685-1694. doi:10.1016/j.ophtha.2019.06.022 PubMedGoogle ScholarCrossref
    21.
    Nicholson  L, Crosby-Nwaobi  R, Vasconcelos  JC,  et al.  Mechanistic evaluation of panretinal photocoagulation versus aflibercept in proliferative diabetic retinopathy: CLARITY substudy.   Invest Ophthalmol Vis Sci. 2018;59(10):4277-4284. doi:10.1167/iovs.17-23509 PubMedGoogle ScholarCrossref
    ×