Assessment of Lower Doses of Intravitreous Bevacizumab for Retinopathy of Prematurity A Phase 1 Dosing Study

• Type of Material: Article
• Authors: David K. Wallace, Duke Eye Center; Raymond T. Kraker, Jaeb Center for Health Research; Sharon F. Freedman, Duke Eye Center; Eric R. Crouch, Eastern Virginia Medical School; Amy K Hutchinson, Emory University; Amit R. Bhatt, Texas Children's Hospital; David L. Rogers, Pediatric Ophthalmology Associates, Inc; Michael B. Yang, Cincinnati Children's Hospital Medical Center; Kathryn M. Haider, Riley Hospital for Children; Deborah K. VanderVeen, Boston Children's Hospital; R. Michael Siatkowski, University of Oklahoma; Trevano W. Dean, Jaeb Center for Health Research; Roy W. Beck, Jaeb Center for Health Research; Michael X. Repka, Wilmer Eye Institute; Lois Smith, Boston Children's Hospital; William V. Good, Smith Kettlewell Eye Research Institute; Mary Elizabeth Hartnett, John A Moran Eye Center; Lingkun Kong, Baylor College of Medicine; Jonathan M. Holmes, Mayo Clinic
• Language: English
• Date: 2017-06-01
• Publisher: American Medical Association (AMA)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 American Medical Association. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1001/jamaophthalmol.2017.1055
• Title of Journal or Parent Work: JAMA Ophthalmology
• ISSN: 2168-6165
• Volume: 135
• Issue: 6
• Start Page: 654
• End Page: 656
• Grant/Funding Information: Drs Rogers, Haider, VanderVeen, Repka, and Kong and Mr Dean have received grants from the National Eye Institute, National Institutes of Health.; Dr Hartnett has received a grant from the National Eye Institute and consulting fees from San Bio.; This study was supported by grants EY011751, EY023198, and EY018810 from the National Eye Institute, National Institutes of Health, Department of Health and Human Services.; Dr Holmes has received grants from the National Institutes of Health.; Mr Kraker has received grants from the National Institutes of Health.; Dr Wallace has received grants from the National Eye Institute and other compensation from FocusROP.; Dr Yang has received grants from the Jaeb Center for Health Research and National Eye Institute, National Institutes of Health.
• Keywords: Science & Technology; Life Sciences & Biomedicine; Ophthalmology
• Research Categories: Health Sciences, Opthamology; Health Sciences, Medicine and Surgery

Abstract

IMPORTANCE: Intravitreous bevacizumab (0.25 to 0.625 mg) is increasingly used to treat type 1 retinopathy of prematurity (ROP), but there remain concerns about systemic toxicity. A much lower dose may be effective while reducing systemic risk. OBJECTIVE: To find a dose of intravitreous bevacizumab that was lower than previously used for severe ROP, was effective in this study, and could be tested in future larger studies. DESIGN, SETTING, AND PARTICIPANTS: Between May 2015 and September 2016, 61 premature infants with type 1 ROP in 1 or both eyes were enrolled in a masked, multicenter, phase 1 dose de-escalation study. One eye of 10 to 14 infants received 0.25 mg of intravitreous bevacizumab. If successful, the dose was reduced for the next group of infants (to 0.125 mg, then 0.063 mg, and finally 0.031 mg). Diluted bevacizumab was delivered using 300 μL syringes with 5/16-inch, 30-gauge fixed needles. INTERVENTIONS: Bevacizumab injections at 0.25 mg, 0.125 mg, 0.063 mg, and 0.031 mg. MAIN OUTCOMES AND MEASURES: Success was defined as improvement in preinjection plus disease or zone I stage 3 ROP by 5 days after injection or sooner, and no recurrence of type 1 ROP or severe neovascularization requiring additional treatment within 4 weeks. RESULTS: Fifty-eight of 61 enrolled infants had 4-week outcomes completed; mean birth weight was 709 g and mean gestational age was 24.9 weeks. Success was achievedin 11 of 11 eyes at 0.25 mg, 14 of 14 eyes at 0.125 mg, 21 of 24 eyes at 0.063 mg, and 9 of 9 eyes at 0.031 mg. CONCLUSIONS AND RELEVANCE: A dose of bevacizumab aslow as 0.031 mgwas effectivein 9 of 9 eyes in this phase 1 study and warrants further investigation. Identifying a lower effective dose of bevacizumab may reduce the risk for neurodevelopmental disability or detrimental effects on other organs.