Effect of Intravitreal Aflibercept vs Laser Photocoagulation on Treatment Success of Retinopathy of Prematurity: The FIREFLEYE Randomized Clinical Trial

Abstract

Importance: Laser photocoagulation, which is the standard treatment for retinopathy of prematurity (ROP), can have adverse events. Studies of anti-vascular endothelial growth factor injections have suggested efficacy in the treatment of ROP, but few studies have directly compared them with laser treatments.

Objective: To compare intravitreal aflibercept vs laser photocoagulation in infants with ROP requiring treatment.

Design, setting, and participants: This noninferiority, phase 3, 24-week, randomized clinical trial was conducted in 27 countries (64 hospital sites) throughout Asia, Europe, and South America. Overall, 118 infants (gestational age ≤32 weeks at birth or birth weight ≤1500 g) with ROP severity (zone I stage 1+ [stage 1 plus increased disease activity], zone I stage 2+, zone I stage 3, zone I stage 3+, zone II stage 2+, or zone II stage 3+) requiring treatment or with aggressive posterior ROP in at least 1 eye were enrolled between September 25, 2019, and August 28, 2020 (the last visit occurred on February 12, 2021).

Interventions: Infants were randomized 2:1 to receive a 0.4-mg dose of intravitreal aflibercept (n = 75) or laser photocoagulation (n = 43) at baseline. Additional treatment was allowed as prespecified.

Main outcomes and measures: The primary outcome was the proportion of infants without active ROP and unfavorable structural outcomes 24 weeks after starting treatment (assessed by investigators). The requirement for rescue treatment was considered treatment failure. Intravitreal aflibercept was deemed noninferior if the lower limit of the 1-sided 95% bayesian credible interval for the treatment difference was greater than -5%.

Results: Among 118 infants randomized, 113 were treated (mean gestational age, 26.3 [SD, 1.9] weeks; 53 [46.9%] were female; 16.8% had aggressive posterior ROP, 19.5% had zone I ROP, and 63.7% had zone II ROP) and 104 completed the study. Treatment (intravitreal aflibercept: n = 75; laser photocoagulation: n = 38) was mostly bilateral (92.9%), and 82.2% of eyes in the intravitreal aflibercept group received 1 injection per eye. Treatment success was 85.5% with intravitreal aflibercept vs 82.1% with laser photocoagulation (between-group difference, 3.4% [1-sided 95% credible interval, -8.0% to ∞]). Rescue treatment was required in 4.8% (95% CI, 1.9% to 9.6%) of eyes in the intravitreal aflibercept group vs 11.1% (95% CI, 4.9% to 20.7%) of eyes in the laser photocoagulation group. The serious adverse event rates were 13.3% (ocular) and 24.0% (systemic) in the intravitreal aflibercept group compared with 7.9% and 36.8%, respectively, in the laser photocoagulation group. Three deaths, which occurred 4 to 9 weeks after intravitreal aflibercept treatment, were considered unrelated to aflibercept by the investigators.

Conclusions and relevance: Among infants with ROP, intravitreal aflibercept compared with laser photocoagulation did not meet criteria for noninferiority with respect to the primary outcome of the proportion of infants achieving treatment success at week 24. Further data would be required for more definitive conclusions regarding the comparative effects of intravitreal aflibercept and laser photocoagulation in this population.

Trial registration: ClinicalTrials.gov Identifier: NCT04004208.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Stahl reported serving on scientific advisory boards for Alcon, Apellis, Bayer, Novartis, and Roche; receiving speaker fees from Allergan, Bayer, and Novartis; and receiving grants and personal fees from Bayer and Novartis. Dr Sukgen reported receiving speaker fees from Allergan and receiving grants from Bayer, Novartis, and TRPharm. Dr Wu reported receiving personal fees from Allergan, Bayer, and Novartis. Dr Lepore reported receiving grants from Bayer and Novartis and serving as a paid member of the steering committee for the current trial. Dr Mazela reported receiving speaker fees from AbbVie, AstraZeneca, Draeger, HiPP, Maquet, Nestle, Nutricia, and Roche; receiving grants and personal fees from Bayer; and receiving grants from Merck Sharp & Dohme and Windtree Therapeutics. Dr Moshfeghi reported receiving personal fees from Akebia Therapeutics, Bayer, Novartis, Regeneron Pharmaceuticals, and the Shapiro Law Group; serving as a consultant to Akceso Advisors AG, Bayer, Congruence Medical Solutions, Ocular Surgery News, Praxis Inc, Retina Technologies LLC, Retina Today/Pentavision, Regeneron Pharmaceuticals, and SLACK Inc; receiving grants from Aldeyra Therapeutics, Apellis, Genentech, the National Institutes of Health, and Regeneron Pharmaceuticals; serving on a steering committee or scientific advisory or data and safety monitoring board for Akebia, Alcon, Allegro, Iconic Therapeutics, Irenix, Novartis, Pykus, and Visunex; having equity in DSentz, Grand Legend Technology, Linc, Pr3vent, Promisight, Pykus, VersI, and Visunex; serving on the board of directors for DSentz, Linc, Pr3vent, and Promisight; and receiving nonfinancial support from CMEOutfitters.com, Cole Eye Institute, Northwell Health, Prime Medical Education, Regeneron Pharmaceuticals, University of Miami, Vindico, and Visunex. Drs Vitti and Athanikar and Ms Chu reported being full-time employees of Regeneron Pharmaceuticals. Dr Athanikar reported owning stock in Regeneron Pharmaceuticals. Drs Iveli, Zhao, Schmelter, Leal, and Koefuencue reported being full-time employees of Bayer. Drs Schmelter and Leal reported owning stock in Bayer. Dr Azuma reported receiving grants from Bayer and Novartis. No other disclosures were reported.

Figures

Figure.. Screening, Randomization, and Follow-up in the FIREFLEYE Trial of Intravitreal Aflibercept for the Treatment of Retinopathy of Prematurity

FIREFLEYE indicates Aflibercept for ROP—IVT Injection versus Laser Therapy. aSee eMethods in Supplement 3 for additional details of inclusion and exclusion criteria. bOne infant with retinopathy of prematurity only in zone III was screened but not randomized. cRandomization was stratified by retinopathy of prematurity category (zones) and country of enrollment. Randomization and evaluation was by infant with each infant demonstrating retinopathy in 1 eye or both eyes. dOne infant was discontinued from the trial after an adverse event of sinus tachycardia. eOne infant was discontinued from the trial after an adverse event of retinal detachment.