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Brief Report
June 2017

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

Author Affiliations
  • 1Duke Eye Center, Durham, North Carolina
  • 2Jaeb Center for Health Research, Tampa, Florida
  • 3Eastern Virginia Medical School, Norfolk
  • 4Emory University School of Medicine, Atlanta, Georgia
  • 5Texas Children’s Hospital, Houston
  • 6Pediatric Ophthalmology Associates Inc, Columbus, Ohio
  • 7Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
  • 8Riley Hospital for Children, Indianapolis, Indiana
  • 9Boston Children’s Hospital, Boston, Massachusetts
  • 10Dean McGee Eye Institute, University of Oklahoma, Oklahoma City
  • 11Wilmer Eye Institute, Baltimore, Maryland
  • 12Smith-Kettlewell Eye Research Institute, San Francisco, California
  • 13John A. Moran Eye Center, Salt Lake City, Utah
  • 14Baylor College of Medicine, Houston, Texas
  • 15Mayo Clinic, Rochester, Minnesota
JAMA Ophthalmol. 2017;135(6):654-656. doi:10.1001/jamaophthalmol.2017.1055
Key Points

Question  Could a lower dose of intravitreous bevacizumab effectively treat severe retinopathy of prematurity?

Findings  In this masked phase 1 dose de-escalation study, premature infants with type 1 retinopathy of prematurity were treated with bevacizumab. Success, defined as improvement by 5 days and no recurrence requiring additional treatment within 4 weeks, was achieved in 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 of bevacizumab.

Meaning  A dose of bevacizumab as low as 0.031 mg was effective in this study, and further investigation is needed to determine the optimal dose and assess effectiveness and systemic safety.

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 achieved in 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 as low as 0.031 mg was effective in 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.

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