TY - JOUR
T1 - A crossover design for comparative efficacy
T2 - A 36-week randomized trial of bevacizumab and ranibizumab for diabetic macular edema
AU - Wiley, Henry E.
AU - Thompson, Darby J.S.
AU - Bailey, Clare
AU - Chew, Emily Y.
AU - Cukras, Catherine A.
AU - Jaffe, Glenn J.
AU - Lee, Richard W.J.
AU - Loken, Erin K.
AU - Meyerle, Catherine B.
AU - Wong, Wai
AU - Ferris, Frederick L.
N1 - Funding Information:
Supported by the National Eye Institute, National Institutes of Health, Bethesda, Maryland (contract no.: HHSN263201200001C). Patient recruitment and clinical research staff costs were also supported in the United Kingdom by the National Institute for Health Research's Clinical Research Network West of England and Moorfields Biomedical Research Center as part of the Universities and National Institutes Transatlantic Eye Consortium (UNITE).
Publisher Copyright:
© 2016 by the American Academy of Ophthalmology Published by Elsevier Inc.
PY - 2016/4/1
Y1 - 2016/4/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ophtha.2015.11.021
DO - 10.1016/j.ophtha.2015.11.021
M3 - Article
C2 - 26875003
AN - SCOPUS:84957923016
SN - 0161-6420
VL - 123
SP - 841
EP - 849
JO - Ophthalmology
JF - Ophthalmology
IS - 4
ER -