Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity: A Randomized Clinical Trial | Neonatology | JAMA Pediatrics | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
Chen  J, Stahl  A, Hellstrom  A, Smith  LE.  Current update on retinopathy of prematurity: screening and treatment.  Curr Opin Pediatr. 2011;23(2):173-178.PubMedGoogle ScholarCrossref
Smith  LE, Hard  AL, Hellström  A.  The biology of retinopathy of prematurity: how knowledge of pathogenesis guides treatment.  Clin Perinatol. 2013;40(2):201-214.PubMedGoogle ScholarCrossref
Hellström  A, Smith  LE, Dammann  O.  Retinopathy of prematurity.  Lancet. 2013;382(9902):1445-1457.PubMedGoogle ScholarCrossref
Mintz-Hittner  HA, Kennedy  KA, Chuang  AZ; BEAT-ROP Cooperative Group.  Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity.  N Engl J Med. 2011;364(7):603-615.PubMedGoogle ScholarCrossref
Sato  T, Wada  K, Arahori  H,  et al.  Serum concentrations of bevacizumab (avastin) and vascular endothelial growth factor in infants with retinopathy of prematurity.  Am J Ophthalmol. 2012;153(2):327-333, e1.PubMedGoogle ScholarCrossref
Kong  L, Bhatt  AR, Demny  AB,  et al.  Pharmacokinetics of bevacizumab and its effects on serum VEGF and IGF-1 in infants with retinopathy of prematurity.  Invest Ophthalmol Vis Sci. 2015;56(2):956-961.PubMedGoogle ScholarCrossref
Avery  RL, Castellarin  AA, Steinle  NC,  et al.  Systemic pharmacokinetics and pharmacodynamics of intravitreal aflibercept, bevacizumab, and ranibizumab.  Retina. 2017;37(10):1847-1858.PubMedGoogle ScholarCrossref
Wu  W-C, Shih  C-P, Lien  R,  et al.  Serum vascular endothelial growth factor after bevacizumab or ranibizumab treatment for retinopathy of prematurity.  Retina. 2017;37(4):694-701.PubMedGoogle ScholarCrossref
Hong  YR, Kim  YH, Kim  SY, Nam  GY, Cheon  HJ, Lee  SJ.  Plasma concentrations of vascular endothelial growth factor in retinopathy of prematurity after intravitreal bevacizumab injection.  Retina. 2015;35(9):1772-1777.PubMedGoogle ScholarCrossref
Avery  RL.  Bevacizumab (Avastin) for retinopathy of prematurity: wrong dose, wrong drug, or both?  J AAPOS. 2012;16(1):2-4.PubMedGoogle ScholarCrossref
Darlow  BA, Ells  AL, Gilbert  CE, Gole  GA, Quinn  GE.  Are we there yet? Bevacizumab therapy for retinopathy of prematurity.  Arch Child Fetal Neonatal Ed. 2013;98(2):F170–F174.Google ScholarCrossref
Wallace  DK, Kraker  RT, Freedman  SF,  et al; Pediatric Eye Disease Investigator Group (PEDIG).  Assessment of lower doses of intravitreous bevacizumab for retinopathy of prematurity: a phase 1 dosing study.  JAMA Ophthalmol. 2017;135(6):654-656.PubMedGoogle ScholarCrossref
Lu  JF, Bruno  R, Eppler  S, Novotny  W, Lum  B, Gaudreault  J.  Clinical pharmacokinetics of bevacizumab in patients with solid tumors.  Cancer Chemother Pharmacol. 2008;62(5):779-786.PubMedGoogle ScholarCrossref
Xu  L, Lu  T, Tuomi  L,  et al.  Pharmacokinetics of ranibizumab in patients with neovascular age-related macular degeneration: a population approach.  Invest Ophthalmol Vis Sci. 2013;54(3):1616-1624.PubMedGoogle ScholarCrossref
Krohne  TU, Holz  FG, Meyer  CH.  Pharmacokinetics of intravitreally administered VEGF inhibitors  [in German].  Ophthalmologe. 2014;111(2):113-120.PubMedGoogle ScholarCrossref
International Committee for the Classification of Retinopathy of Prematurity.  The International Classification of Retinopathy of Prematurity revisited.  Arch Ophthalmol. 2005;123(7):991-999.PubMedGoogle ScholarCrossref
Walz  JM, Bemme  S, Pielen  A,  et al.  The German ROP Registry: data from 90 infants treated for retinopathy of prematurity.  Acta Ophthalmol. 2016;94(8):e744-e752. PubMedGoogle Scholar
Hu  J, Blair  MP, Shapiro  MJ, Lichtenstein  SJ, Galasso  JM, Kapur  R.  Reactivation of retinopathy of prematurity after bevacizumab injection.  Arch Ophthalmol. 2012;130(8):1000-1006.PubMedGoogle ScholarCrossref
Wong  RK, Hubschman  S, Tsui  I.  Reactivation of retinopathy of prematurity after ranibizumab treatment.  Retina. 2015;35(4):675-680.PubMedGoogle ScholarCrossref
Snyder  LL, Garcia-Gonzalez  JM, Shapiro  MJ, Blair  MP.  Very late reactivation of retinopathy of prematurity after monotherapy with intravitreal bevacizumab.  Ophthalmic Surg Lasers Imaging Retina. 2016;47(3):280-283.PubMedGoogle ScholarCrossref
Sapieha  P, Joyal  J-S, Rivera  JC,  et al.  Retinopathy of prematurity: understanding ischemic retinal vasculopathies at an extreme of life.  J Clin Invest. 2010;120(9):3022-3032.PubMedGoogle ScholarCrossref
Pertl  L, Steinwender  G, Mayer  C,  et al.  A systematic review and meta-analysis on the safety of vascular endothelial growth factor (VEGF) inhibitors for the treatment of retinopathy of prematurity.  PLoS One. 2015;10(6):e0129383.PubMedGoogle ScholarCrossref
Lutty  GA, McLeod  DS, Bhutto  I, Wiegand  SJ.  Effect of VEGF trap on normal retinal vascular development and oxygen-induced retinopathy in the dog.  Invest Ophthalmol Vis Sci. 2011;52(7):4039-4047.PubMedGoogle ScholarCrossref
Hartnett  ME.  Vascular endothelial growth factor antagonist therapy for retinopathy of prematurity.  Clin Perinatol. 2014;41(4):925-943.PubMedGoogle ScholarCrossref
Hwang  CK, Hubbard  GB, Hutchinson  AK, Lambert  SR.  Outcomes after intravitreal bevacizumab versus laser photocoagulation for retinopathy of prematurity: a 5-year retrospective analysis.  Ophthalmology. 2015;122(5):1008-1015.PubMedGoogle ScholarCrossref
Kaakour  AH, Hansen  ED, Aziz  HA, Young  RC, Berrocal  AM.  Changing treatment patterns of ROP at a tertiary medical center between 2002 and 2012.  Ophthalmic Surg Lasers Imaging Retina. 2015;46(7):752-754.PubMedGoogle ScholarCrossref
Chan  JJ, Lam  CP, Kwok  MK,  et al.  Risk of recurrence of retinopathy of prematurity after initial intravitreal ranibizumab therapy.  Sci Rep. 2016;6:27082.PubMedGoogle ScholarCrossref
Hoerster  R, Muether  P, Dahlke  C,  et al.  Serum concentrations of vascular endothelial growth factor in an infant treated with ranibizumab for retinopathy of prematurity.  Acta Ophthalmol. 2013;91(1):e74-e75.PubMedGoogle ScholarCrossref
Walz  JM, Boehringer  D, Deissler  HL,  et al.  Pre-analytical parameters affecting vascular endothelial growth factor measurement in plasma: identifying confounders.  PLoS One. 2016;11(1):e0145375.PubMedGoogle ScholarCrossref
Avery  RL, Castellarin  AA, Steinle  NC,  et al.  Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular AMD.  Br J Ophthalmol. 2014;98(12):1636-1641.PubMedGoogle ScholarCrossref
Original Investigation
March 2018

Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity: A Randomized Clinical Trial

Author Affiliations
  • 1Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  • 2Department of Ophthalmology, University of Bonn, Bonn, Germany
  • 3Department of Ophthalmology, University of Muenster Medical Center, Muenster, Germany
  • 4Department of Ophthalmology, University of Regensburg, Regensburg, Germany
  • 5Department of Ophthalmology, Faculty of Medicine, University of Dusseldorf, Dusseldorf, Germany
  • 6Department of Ophthalmology, Otto von Guericke University, Magdeburg, Germany
  • 7Department of Ophthalmology, Ludwig-Maximilian University of Munich, Munich, Germany
  • 8University Eye Hospital, Eberhard Karls University of Tuebingen, Tuebingen, Germany
  • 9Department of Ophthalmology, University of Kiel, University Medical Center, Kiel, Germany
  • 10Augenzentrum Pallas Kliniken, Olten, Switzerland
  • 11Artemis Eye Clinic, Frankfurt, Germany
  • 12Department of Ophthalmology, Harvard Medical School, Boston Children’s Hospital, Boston, Massachusetts
  • 13Department of Pharmacology and Toxicology, University of Regensburg, Regensburg, Germany
JAMA Pediatr. 2018;172(3):278-286. doi:10.1001/jamapediatrics.2017.4838
Key Points

Question  Can anti–vascular endothelial growth factor (VEGF) therapy in retinopathy of prematurity (ROP) be improved by using ranibizumab given at lower doses than the standard treatment, bevacizumab, thus alleviating systemic safety concerns while effectively treating disease?

Findings  In this randomized clinical trial with 20 patients, both investigated ranibizumab doses were lower than the current standard bevacizumab dose for ROP. Both ranibizumab doses were effective in controlling acute ROP (17 of 18 per protocol treated eyes [94%] with 0.12 mg and 13 of 14 per protocol treated eyes [93%] with 0.20 mg); systemic VEGF levels remained unchanged.

Meaning  Low-dose ranibizumab is effective in treating acute ROP without suppressing plasma VEGF levels.


Importance  Anti–vascular endothelial growth factor (VEGF) therapies are a novel treatment option in retinopathy of prematurity (ROP). Data on dosing, efficacy, and safety are insufficient.

Objective  To investigate lower doses of anti-VEGF therapy with ranibizumab, a substance with a significantly shorter systemic half-life than the standard treatment, bevacizumab.

Design, Setting, and Participants  This randomized, multicenter, double-blind, investigator-initiated trial at 9 academic medical centers in Germany compared ranibizumab doses of 0.12 mg vs 0.20 mg in infants with bilateral aggressive posterior ROP; ROP stage 1 with plus disease, 2 with plus disease, or 3 with or without plus disease in zone I; or ROP stage 3 with plus disease in posterior zone II. Patients were recruited between September 2014 and August 2016. Twenty infants were screened and 19 were randomized.

Interventions  All infants received 1 baseline ranibizumab injection per eye. Reinjections were allowed in case of ROP recurrence after at least 28 days.

Main Outcomes and Measures  The primary end point was the number of infants who did not require rescue therapy at 24 weeks. Key secondary end points included time-to-event analyses, progression of physiologic vascularization, and plasma VEGF levels. Stages of ROP were photodocumented and reviewed by an expert committee.

Results  Nineteen infants with ROP were enrolled (9 [47.4%] female; median [range] postmenstrual age at first treatment, 36.4 [34.7-39.7] weeks), 3 of whom died during the study (1 in the 0.12-mg group and 2 in the 0.20-mg group). Of the surviving infants, 8 (88.9%) (17 eyes [94.4%]) in the 0.12-mg group and 6 (85.7%) (13 eyes [92.9%]) in the 0.20-mg group did not require rescue therapy. Both ranibizumab doses were equally successful in controlling acute ROP (Cochran-Mantel-Haenszel analysis; odds ratio, 1.88; 95% CI, 0.26-13.49; P = .53). Physiologic intraretinal vascularization was superior in the 0.12-mg group. The VEGF plasma levels were not systematically altered in either group.

Conclusions and Relevance  This pilot study demonstrates that ranibizumab is effective in controlling acute ROP and that 24% of the standard adult dose (0.12 mg) appears equally effective as 40% (0.20 mg). Superior vascularization of the peripheral retina with 0.12 mg of ranibizumab indicates that the lower dose may be favorable. Unchanged plasma VEGF levels point toward a limited systemic drug exposure after ranibizumab.

Trial Registration Identifier: NCT02134457 and Identifier: 2013-002539-13.