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

Abstract

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.

Figure 1

Change in (A) Visual Acuity and (B) OCT Central Subfield Mean Thickness from baseline for crossover periods 1, 2, and 3 by treatment group.

Figure 2

Differential first-order carry-over effect (residual effect of the drug from the preceding period), shown as a treatment effect difference between ranibizumab and bevacizumab given in the previous period for (A) change in visual acuity and (B) central subfield mean thickness on optical coherence tomography at 4, 8, and 12 weeks after crossover. The treatment difference attributable to the first-order carry-over effect is shown in gray. The treatment difference attributable to drugs in the current period (i.e., the differential effect of the two drugs as estimated in the primary analysis of the study) is shown in black for comparison. Note that the treatment difference between ranibizumab and bevacizumab for the current period (in black) at 12 weeks after crossover (at outcome assessment) is the result estimated for 3 and 9 months in the primary analysis (1.3 letters (p=0.039) and −48 microns (p<0.001), both favoring ranibizumab).