TY - JOUR
T1 - Effect of High-Dose Intravitreal Aflibercept, 8 mg, in Patients With Neovascular Age-Related Macular Degeneration
T2 - The Phase 2 CANDELA Randomized Clinical Trial
AU - CANDELA Study Investigators
AU - Wykoff, Charles C
AU - Brown, David M
AU - Reed, Kimberly
AU - Berliner, Alyson J
AU - Gerstenblith, Adam T
AU - Breazna, Aurora
AU - Abraham, Prema
AU - Fein, Jordana G
AU - Chu, Karen W
AU - Clark, W Lloyd
AU - Leal, Sergio
AU - Schmelter, Thomas
AU - Hirshberg, Boaz
AU - Yancopoulos, George D
AU - Vitti, Robert
N1 - Publisher Copyright:
© 2023 American Medical Association. All rights reserved.
PY - 2023/9/1
Y1 - 2023/9/1
N2 - IMPORTANCE: 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.OBJECTIVE: 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.INTERVENTIONS: 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.RESULTS: 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: ClinicalTrials.gov Identifier: NCT04126317.
AB - IMPORTANCE: 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.OBJECTIVE: 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.INTERVENTIONS: 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.RESULTS: 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: ClinicalTrials.gov Identifier: NCT04126317.
KW - Angiogenesis Inhibitors/therapeutic use
KW - Diabetic Retinopathy/drug therapy
KW - Female
KW - Humans
KW - Macular Edema/drug therapy
KW - Male
KW - Receptors, Vascular Endothelial Growth Factor/therapeutic use
KW - Recombinant Fusion Proteins/adverse effects
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U2 - 10.1001/jamaophthalmol.2023.2421
DO - 10.1001/jamaophthalmol.2023.2421
M3 - Article
C2 - 37535382
SN - 2168-6165
VL - 141
SP - 834
EP - 842
JO - JAMA Ophthalmology
JF - JAMA Ophthalmology
IS - 9
ER -