Intravitreal Aflibercept for Neovascular Age-Related Macular Degeneration Beyond One Year of Treatment: AZURE, a Randomized Trial of Treat-and-Extend vs. Fixed Dosing. Adv Ther
NCT02540954 | AZURE | Kodjikian L et al. (2024)
Kodjikian, L., Arias Barquet, L., Papp, A., Kertes, P. J., Midena, E., Ernest, J., Silva, R., Schmelter, T., Niesen, T., Leal, S. Intravitreal Aflibercept for Neovascular Age-Related Macular Degeneration Beyond One Year of Treatment: AZURE, a Randomized Trial of Treat-and-Extend vs. Fixed Dosing. Adv Ther, 2024; 41:1010–1024.
Locations
100 study centers in 14 countries across Europe and Canada
Study Period
September 2015 to June 2020
Study Design
Phase 3b, randomized, open-label, parallel-group, noninferiority trial
Study Population
Experimental Group
Control Group
Follow-up Time: 76 weeks
Outcomes
Durability
Injection Number
At Week 52:
• T&E mean = 6.0 (SD 1.0)
• Fixed Dosing mean = 6.8 (SD 0.8)
At Week 76:
• T&E mean = 8.0 (SD 1.8); 24.2% of patients receiving 10 injections
• Fixed Dosing mean = 9.6 (SD 1.4); 83.8% of patients receiving 10 injections
Mean (SD) duration of the last treatment
interval Up to week 76:
• T&E: 11.1 (3.6) weeks
• Fixed Dosing: 8.2 (1.2) weeks
Vision
Best-Corrected Visual Acuity (BCVA)
Mean BCVA change from baseline to Week 52 (Primary Outcome):
• T&E = -0.3 ± 7.5 letters
• Fixed Dosing = -0.5 ± 8.4 letters
• Difference = 0.22 letters (95% CI: -1.51 to 1.96, p < 0.0001 for noninferiority.
Maintaining Vision
At week 52:
• T&E: 95.2% vs. Fixed Dosing: 94.0% (losing <15-letter loss). Difference = 1.1% (95% CI: -3.7 to 6.0%)
• T&E: 73.3% vs. Fixed Dosing: 78.4% (losing <5-letter loss).
At week 76:
• T&E: 92.1% vs. Fixed Dosing: 94.0%. 95%CI difference: - 7.4% to 3.6%.
• T&E: 73.3% vs. Fixed Dosing: 73.7% (losing <5-letter loss)
• T&E: 22.4% vs. Fixed Dosing: 25.7% (gained ≥5-letters)
Other
N/A
Immunognicity
Not reported
Pharmokinetics
Not reported
Anatomic
Central Subfield Thickness (CST) Mean CST change at Week 52:
• T&E = -24 ± 55 µm
• Fixed Dosing = -33 ± 47 µm.
Safety
Treatment-emergent AEs (TEAEs)
Any:
• T&E: 130/167, 77.8%
• Fixed Dosing: 124/168, 73.8%
Ocular TEAEs
Any:
• T&E: 101/167, 60.5%)
• Fixed Dosing: 95/168, 73.8%.
Ocular TEAE in the study eyes:
• T&E: 76/167, 45.5%
• Fixed Dosing: 82/168, 48.8%
Any ocular TEAE related to the study drug (study eyes):
• T&E: 9/167, 5.4%
• Fixed Dosing: 7/168, 4.2%
Cataract:
• T&E: 13/167, 7.8%
• Fixed Dosing: 18/168, 10.7%
Subretinal fluid:
• T&E: 8/167, 4.8%
• Fixed Dosing: 10/168, 6.0%
Intraocular pressure increased:
• T&E: 6/167, 3.6%
• Fixed Dosing: 11/168, 6.5%
Non-ocular TEAEs
Any:
• T&E: 83/167, 49.7%
• Fixed Dosing: 86/168, 51.2%
Serious TEAEs
Any:
• T&E: 26/167, 15.6%
• Fixed Dosing: 23/168, 13.7%
Discontinuation of study drug
Due to TEAEs:
• T&E: 3/167, 1.8%
• Fixed Dosing: 3/168, 1.8%
Due to serious TEAEs:
• T&E: 1/167, 0.6%
• Fixed Dosing: 2/168, 1.2%
Any death
• T&E: 0
• Fixed Dosing: 3/168, 1.8%
APTC-defined Cardiovascular Events
• T&E: 2.4%
• Fixed Dosing: 0.6%.
Conclusion
The treat-and-extend IVT-AFL regimen achieved similar functional and anatomical outcomes compared to the fixed dosing, with noninferiority established at 52 weeks while reducing the treatment burden. Safety outcomes were consistent between the two regimens.
Risk of Bias Assessment for Primary Outcome
Randomization Process
Low risk
Note: “…eligible patients were randomly assigned in a 1:1 ratio by central randomization to one of the two parallel treatment groups…” and “Baseline demographics and disease characteristics were similar between treatment groups.”
Missing Outcome Data
High risk
Note: There is no evidence that the result was not biased by missing outcome data. Some missingness could depend on the true value (e.g., withdrawal from study, AEs, or loss of follow-up). Besides, there are differences between intervention groups in the proportions of missing outcome data in terms of reasons (Figure 2) and proportion (11.3% vs. 8.3%). Therefore, it is likely that missingness in the outcome depended on its true value.
Selection of the Reported Results
Low risk Note: Registration with protocol.
Deviations from Intended Observations
Some concerns Note: This is an open-labeled trial with no information on deviations that arose because of the trial context. However, an mITT principle (a total 4 patients were excluded from the analysis due to lack of necessary BCVA assessment data) was applied in the analysis.
Measurement of the Outcome
Some concerns Note: This is an open-labeled trial, there is no information on whether the primary outcome assessment is different between the groups, especially, this is an international multiple-site study. However, it is unlikely that the assessment of the outcome was influenced by the knowledge of the intervention received.
Overall
High risk
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