Short-term Outcomes After Very Low-Dose Intravitreous Bevacizumab for Retinopathy of Prematurity

Abstract

Importance: Intravitreous bevacizumab (0.25 mg to 0.625 mg) is commonly used to treat type 1 retinopathy of prematurity (ROP), but there are concerns about systemic toxicity, particularly the risk of neurodevelopmental delay. A much lower dose may be effective for ROP while reducing systemic risk. Previously, after testing doses of 0.25 mg to 0.031 mg, doses as low as 0.031 mg were found to be effective in small cohorts of infants.

Objective: To find the lowest dose of intravitreous bevacizumab effective for severe ROP.

Design, setting, and participants: Between April 2017 and May 2019, 59 premature infants with type 1 ROP in 1 or both eyes were enrolled in a masked, multicenter, dose de-escalation study. In cohorts of 10 to 14 infants, 1 eye per infant received 0.016 mg, 0.008 mg, 0.004 mg, or 0.002 mg of intravitreous bevacizumab. Diluted bevacizumab was prepared by individual research pharmacies and delivered using 300-µL syringes with 5/16-inch, 30-guage fixed needles. Analysis began July 2019.

Interventions: Bevacizumab intravitreous injections at 0.016 mg, 0.008 mg, 0.004 mg, or 0.002 mg.

Main outcomes and measures: Success was defined as improvement by 4 days postinjection and no recurrence of type 1 ROP or severe neovascularization requiring additional treatment within 4 weeks.

Results: Fifty-five of 59 enrolled infants had 4-week outcomes completed; the mean (SD) birth weight was 664 (258) g, and the mean (SD) gestational age was 24.8 (1.6) weeks. A successful 4-week outcome was achieved for 13 of 13 eyes (100%) receiving 0.016 mg, 9 of 9 eyes (100%) receiving 0.008 mg, 9 of 10 eyes (90%) receiving 0.004 mg, but only 17 of 23 eyes (74%) receiving 0.002 mg.

Conclusions and relevance: These data suggest that 0.004 mg may be the lowest dose of bevacizumab effective for ROP. Further investigation is warranted to confirm effectiveness of very low-dose intravitreous bevacizumab and its effect on plasma vascular endothelial growth factor levels and peripheral retinal vascularization.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Wallace reports grants from the National Eye Institute (NEI) during the conduct of the study and has a patent for ROPtool (FocusROP) with royalties paid. Mr Kraker and Dr Cotter report grants from the National Institutes of Health (NIH)/NEI during the conduct of the study. Dr Hartnett reports grants from NIH/NEI, book royalties from Lippincott Williams & Wilkins, and grants from Panamerica Association of Ophthalmology funded through the Retina Research Foundation during the conduct of the study; grants from Novartis and grants from Regeneron Pharmaceuticals outside the submitted work; educational support from Zeiss, Genentech, Regeneron Pharmaceuticals, and Alcon outside the submitted work; a patent to US#10 214 741 issued; honoraria for lectures given at University of Alabama at Birmingham, University of Colorado, Massachusetts Eye & Ear Infirmary, and Emory University; is on the planning committee for upcoming trials through Pediatric Eye Disease Investigator Group; and is on the board of Women in Retina. Dr Yang reports grants from Pediatric Eye Disease Investigators Group/NEI during the conduct of the study and outside the submitted work. Dr Dean reports grants from the NEI during the conduct of the study. Dr Beck reports grants from the NIH during the conduct of the study. Dr Repka reports salary from the NEI during the conduct of the study. Dr Holmes reports grants from the NIH during the conduct of the study and outside the submitted work. No other disclosures were reported.

Figures

Figure.. Success of Intravitreous Bevacizumab in the Study Eye at the 4-Week Primary Outcome Examination