DOI: 10.1001/jamaophthalmol.2023.2421 ISSN: 2168-6165

Effect of High-Dose Intravitreal Aflibercept, 8 mg, in Patients With Neovascular Age-Related Macular Degeneration

Charles C. Wykoff, David M. Brown, Kimberly Reed, Alyson J. Berliner, Adam T. Gerstenblith, Aurora Breazna, Prema Abraham, Jordana G. Fein, Karen W. Chu, W. Lloyd Clark, Sergio Leal, Thomas Schmelter, Boaz Hirshberg, George D. Yancopoulos, Robert Vitti, Suhail Alam, Astrid Gonzalez Ramos, Daniel Virgil Alfaro, Sean Adrean, John Payne, Harold Brooks, Mark Chittum, David Callanan, Ralph Paylor, Clement Chan, John Allen, Nauman Chaudhry, Margaret Chang, Sanford Chen, William Bridges, James Dooner, Wayne Solley, Andres Emanuelli, Ronald Teed, Scott Friedman, Nader Moinfar, Ghassan Ghorayeb, Shelly Lee, Daniel Berinstein, Mitchell Goff, Harvey Reiser, Amir Guerami, Emily Ashmore, Curtis Hagedorn, Jose Martinez, Paul Hahn, Juner Colina-Biscotto, Vrinda Hershberger, Brian Joondeph, Erik Kruger, J. Shepard Bryan, Michael Lee, Mark Chiu, C. Nathaniel Roybal, Frank Wyant, James Luu, Matthew Byun, James Palmer, Mark Wieland, Joel Pearlman, Evan Berger, John Pitcher, Rajiv Rathod, Omar Punjabi, Leonard Feiner, Hema Ramkumar, Steven Lin, Rahul Reddy, Richard Dreyer, Nathan Steinle, Veeral Sheth, David Faber, Cameron Stone, Robert Engstrom, Robert Wirthlin, Mahmood El-Gasim, Robert Parnes,
  • Ophthalmology


Aflibercept, 8 mg, may have greater therapeutic benefits compared with aflibercept, 2 mg, in patients with neovascular age-related macular degeneration (nAMD), including potentially improved outcomes and decreased treatment burden.


To assess safety and efficacy of aflibercept, 8 mg, in patients with nAMD.

Design, Setting, and Participants

The CANDELA trial was a phase 2, randomized, single-masked, open-label, 44-week clinical trial conducted in the US. Treatment-naive patients with active subfoveal choroidal neovascularization secondary to nAMD and a best-corrected visual acuity score of 78 to 24 letters (approximately 20/32 to 20/320) in the study eye were enrolled between November 2019 and November 2021.


Eligible participants were randomized 1:1 to receive 3 monthly doses of 8 mg (70 μL) or 2 mg (50 μL) of aflibercept followed by doses at weeks 20 and 32.

Main Outcomes and Measures

Coprimary end points were the proportion of eyes without fluid (absence of intraretinal and subretinal fluid) in the central subfield at week 16 and safety.


All 106 eligible eyes were randomized to receive aflibercept, 8 mg (n = 53), or aflibercept, 2 mg (n = 53). Overall, 66 participants (62.3%) were female. The proportion of eyes without fluid in the central subfield with 8-mg vs 2-mg aflibercept was 50.9% (n = 27) vs 34.0% (n = 18) (difference, 17.0 [95% CI, –1.6 to 35.5] percentage points; P = .08) at week 16 and 39.6% (n = 21) vs 28.3% (n = 15) (difference, 11.3 [95% CI, –6.6 to 29.2] percentage points; nominal P = .22) at week 44. At week 44, mean (SE) change in central retinal thickness was –159.4 (16.4) vs –137.2 (22.8) μm with 8 mg vs 2 mg of aflibercept, respectively (least squares mean difference, –9.5 [95% CI, –51.4 to 32.4]; nominal P = .65) and mean (SE) change in best-corrected visual acuity score was +7.9 (1.5) vs +5.1 (1.5) letters (least squares mean difference, +2.8 [95% CI, –1.4 to +7.0]; nominal P = .20). No differences in safety profiles between the groups were observed.

Conclusions and Relevance

Although aflibercept, 8 mg, did not achieve the primary efficacy end point at week 16 at the 2-sided significance level of 5%, the observed trends in anatomic and visual improvements over 44 weeks with aflibercept, 8 mg, indicate potential additional therapeutic benefit over aflibercept, 2 mg. No new safety signals were observed over 44 weeks. These findings support further evaluation of aflibercept, 8 mg, in pivotal trials of exudative retinal diseases including nAMD and diabetic macular edema.

Trial Registration Identifier: NCT04126317

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