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. 2021 Jul 1;139(7):701-712.
doi: 10.1001/jamaophthalmol.2021.0606.

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

Raj K Maturi  1 , Adam R Glassman  2 , Kristin Josic  2 , Andrew N Antoszyk  3 , Barbara A Blodi  4 , Lee M Jampol  5 , Dennis M Marcus  6 , Daniel F Martin  7 , Michele Melia  2 , Hani Salehi-Had  8 , Cynthia R Stockdale  2 , Omar S Punjabi  3 , Jennifer K Sun  9 ; DRCR Retina Network
Affiliations

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

Raj K Maturi et al. JAMA Ophthalmol. .

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.

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Conflict of interest statement

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.

Figures

Figure 1.
Figure 1.. 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.
Figure 2.. 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.
Figure 3.. Mean Change in Visual Acuity Through 2 Years
See this image and copyright information in PMC

Comment in

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