title: A Crossover Design for Comparative Efficacy: A 36-Week Randomized Trial of Bevacizumab and Ranibizumab for Diabetic Macular Edema.
abstract: OBJECTIVE
  To investigate the comparative efficacy of bevacizumab (Avastin) and ranibizumab (Lucentis; both Genentech, Inc, South San Francisco, CA) for diabetic macular edema (DME) using a crossover study design.
  
  
  METHODS
  Randomized, double-masked, 36-week, 3-period crossover clinical trial.
  
  
  METHODS
  Fifty-six subjects with DME involving the center of the macula in one or both eyes.
  
  
  METHODS
  Monthly intravitreous injections of bevacizumab (1.25 mg) or ranibizumab (0.3 mg).
  
  
  METHODS
  Comparison of mean changes in visual acuity and central retinal thickness, tested using a linear mixed-effects model.
  
  
  RESULTS
  Based on the linear mixed-effects model, the 3-month estimated mean improvement in visual acuity was 5.3 letters for bevacizumab and 6.6 letters for ranibizumab (difference, 1.3 letters; P = 0.039). Estimated change in optical coherence tomography (OCT) central subfield mean thickness (CSMT) was -89 μm for bevacizumab and -137 μm for ranibizumab (difference, 48 μm; P < 0.001). Incorporating cumulative treatment benefit, the model yielded a predicted 36-week (9-month) average improvement in visual acuity of 7.1 letters (95% confidence interval [CI], 5.0-9.2) for bevacizumab and 8.4 letters (95% CI, 6.3-10.5) for ranibizumab, and a change in OCT CSMT of -128 μm (95% CI, -155 to -100) for bevacizumab and -176 μm (95% CI, -202 to -149) for ranibizumab. There was no significant treatment-by-period interaction (i.e., treatment difference was constant in all 3 periods), nor was there a significant differential carryover effect from one period to the next.
  
  
  CONCLUSIONS
  This trial demonstrated a statistically significant but small relative clinical benefit of ranibizumab compared with bevacizumab for treatment of DME, using a markedly reduced sample size relative to a full comparative efficacy study. The effects on visual acuity and central retinal thickness for the 2 drugs are consistent with those reported at 1 year for the concurrent parallel-group trial by the Diabetic Retinopathy Clinical Research Network testing bevacizumab, ranibizumab, and aflibercept for DME. The 3-period crossover design allowed for meaningful and efficient comparison, suggesting that this approach may be useful for future comparative efficacy studies of anti-vascular endothelial growth factor drugs for DME.
authors.affiliation: National Eye Institute, National Institutes of Health, Bethesda, Maryland. Electronic address: wileyhe@nei.nih.gov.
authors.forename: Henry E
authors.initials: HE
authors.lastname: Wiley
authors.affiliation: The Emmes Corporation, Rockville, Maryland.
authors.forename: Darby J S
authors.initials: DJ
authors.lastname: Thompson
authors.affiliation: University Hospitals Bristol National Health Service Foundation Trust, Bristol, United Kingdom.
authors.forename: Clare
authors.initials: C
authors.lastname: Bailey
authors.affiliation: National Eye Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Emily Y
authors.initials: EY
authors.lastname: Chew
authors.affiliation: National Eye Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Cukras
authors.affiliation: Duke Reading Center, Durham, North Carolina.
authors.forename: Glenn J
authors.initials: GJ
authors.lastname: Jaffe
authors.affiliation: University Hospitals Bristol National Health Service Foundation Trust, Bristol, United Kingdom; School of Clinical Sciences, University of Bristol, Bristol, United Kingdom; National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, National Health Service Foundation Trust, and University College London Institute of Ophthalmology, London, United Kingdom.
authors.forename: Richard W J
authors.initials: RW
authors.lastname: Lee
authors.affiliation: The Emmes Corporation, Rockville, Maryland.
authors.forename: Erin K
authors.initials: EK
authors.lastname: Loken
authors.affiliation: Wilmer Eye Institute, Johns Hopkins Hospital, Baltimore, Maryland.
authors.forename: Catherine B
authors.initials: CB
authors.lastname: Meyerle
authors.affiliation: National Eye Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Wai
authors.initials: W
authors.lastname: Wong
authors.affiliation: National Eye Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Frederick L
authors.initials: FL
authors.lastname: Ferris
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage / Q000627:therapeutic use*; D018592:Cross-Over Studies; D003922:Diabetes Mellitus, Type 1 / Q000150:complications; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000503:physiopathology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D058449:Intravitreal Injections; D008269:Macular Edema / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D000069579:Ranibizumab / Q000008:administration & dosage / Q000627:therapeutic use*; D012107:Research Design; D012160:Retina / Q000473:pathology; D041623:Tomography, Optical Coherence; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D014792:Visual Acuity / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D000069579:Ranibizumab