A Crossover Design for Comparative Efficacy: A 36-Week Randomized Trial of Bevacizumab and Ranibizumab for Diabetic Macular Edema.

Publication Type
Journal Article
Year of Publication
Wiley, Henry E; Thompson, Darby J S; Bailey, Clare; Chew, Emily Y; Cukras, Catherine A; Jaffe, Glenn J; Lee, Richard W J; Loken, Erin K; Meyerle, Catherine B; Wong, Wai; Ferris, Frederick L
Date Published
2016 Apr
Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Bevacizumab; Cross-Over Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Double-Blind Method; Female; Humans; Intravitreal Injections; macular edema; Male; Middle Aged; Ranibizumab; Research Design; retina; Tomography, Optical Coherence; Vascular Endothelial Growth Factor A; visual acuity

PURPOSE: 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.

DESIGN: Randomized, double-masked, 36-week, 3-period crossover clinical trial.

PARTICIPANTS: 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).

MAIN OUTCOME MEASURES: 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.