Efficacy and Safety of Intravitreal Aflibercept Treat-and-Extend Regimens in Exudative Age-Related Macular Degeneration: 52- and 96-Week Findings from ALTAIR
NCT02305238 | ALTAIR Trial | Ohji M et al. (2020)
Ohji M, Takahashi K, Okada AA, et al. Efficacy and Safety of Intravitreal Aflibercept Treat-and-Extend Regimens in Exudative Age-Related Macular Degeneration: 52- and 96-Week Findings from ALTAIR. Adv Ther, 2020; 37(7):3501-3515.
Locations
41 sites in Japan
Study Period
December 2014 – November 2017
Study Design
Phase 4, randomized, open-label, multicenter comparative trial
Study Population
Experimental Group
Control Group
Follow-up Time: 96 weeks
Outcomes
Durability
The mean (SD) number of injections over 52 weeks:
• 2-week T&E: 7.2 (0.9)
• 4-week T&E: 6.9 (1.0) The mean (SD) number of injections over 54-96 weeks:
• 2-week T&E: 3.6 (1.6)
• 4-week T&E: 3.7 (1.4) The mean (SD) number of injections over 52 weeks:
• 2-week T&E: 10.4 (2.6)
• 4-week T&E: 10.4 (2.4) The mean (SD) last interval at week 52:
• 2-week T&E: 10.7 (2.7) weeks
• 4-week T&E: 11.8 (3.7) weeks The mean (SD) last interval at week 96:
• 2-week T&E: 12.2 (3.6) weeks
• 4-week T&E: 12.5 (3.6) weeks The proportion of patients with at least 12 weeks for the last injection interval:
• 2-week T&E: 42.3% before week 52; 56.9% before week 96
• 4-week T&E: 49.6% before week 52; 60.2% before week 96 The proportion of patients with at least 16 weeks for the last injection interval:
• 2-week T&E: 0% before week 52; 40.7% before week 96
• 4-week T&E: 41.5% before week 52; 46.3% before week 96 The proportion of patients with the intended injection interval at the last visit was at least 12 weeks:
• 2-week T&E: 56.8% up to week 52
• 4-week T&E: 57.8% up to week 52 The proportion of patients with the intended injection interval at the last visit was at least 16 weeks:
• 2-week T&E: 35.1% up to 52; 43.1% up to 96
• 4-week T&E: 40.5% up to 52; 54.5% up to 96 The proportion of patients maintained at 16 weeks until study completion:
• 2-week T&E: 41.5%
• 4-week T&E: 42.3% The proportion of patients who stayed at an 8-week injection interval and who never had an extension:
• 2-week T&E: 27.6%
• 4-week T&E: 22.0% Up to week 96, the proportion of patients with intervals of 12 weeks and beyond who maintained at least a 12-week interval:
• 2-week T&E: 48.0%
• 4-week T&E: 48.0%
Vision
Best-Corrected Visual Acuity (BCVA) The mean change in BCVA (ETDRS letters) at 52 weeks (primary outcome):
• 2-week T&E: +9.0 (95% CI: 6.4 to 11.5)
• 4-week T&E: +8.4 (95% CI: 6.0 to 10.8)
• Least squares (LS) mean difference of - 0.4 (95% CI: - 3.8 to 3.0) The mean change in BCVA (ETDRS letters) at 96 weeks:
• 2-week T&E: +7.6 (95% CI: 5.0 to 10.3)
• 4-week T&E: +6.1 (95% CI: 3.1 to 9.0)
• LS mean difference: - 1.4 (95% CI - 5.3 to 2.4) Vision Maintaining The proportion of patients losing <15 ETDRS letters at 52 weeks:
• 2-week T&E: 96.7% (95% CI: 93.6% to 99.9%)
• 4-week T&E: 95.9% (95% CI: 92.4% to 99.4%)
• Adjusted difference: - 0.9% (95% CI: - 5.7% to 4.0%) The proportion of patients losing <15 ETDRS letters at 96 weeks:
• 2-week T&E: 95.1% (95% CI: 91.3% to 98.9%)
• 4-week T&E: 91.9% (95% CI: 87.0% to 96.7%)
• Adjusted difference: - 3.1% (95% CI: - 9.5% to 3.2%) The proportion of patients losing ≥15 ETDRS letters at 52 weeks:
• 2-week T&E: 32.5% (95% CI: 24.2% to 40.8%)
• 4-week T&E: 30.9% (95% CI: 22.7% to 39.1%)
• Adjusted difference: - 1.4% (95% CI: - 12.7% to 9.8%) The proportion of patients gaining ≥15 ETDRS letters at 96 weeks:
• 2-week T&E: 28.5% (95% CI: 20.5% to 36.4%)
• 4-week T&E: 31.7% (95% CI: 23.5% to 39.9%)
• Adjusted difference: - 3.4% (95% CI: - 7.9% to 14.7%)
Other
N/A
Immunognicity
Not reported
Pharmokinetics
Not reported
Anatomic
Central Retinal Thickness (CRT) The mean change in CRT (µm) at 52 weeks:
• 2-week T&E: -134.4 (95% CI: -162.2 to -106.6)
• 4-week T&E: -126.1 (95% CI: -147.1 to -105.1)
• Least squares (LS) mean difference of – 5.8 (95% CI: - 24.3 to 12.7) The mean change in CRT (µm) at 96 weeks:
• 2-week T&E: -130.5 (95% CI: -158.7 to -102.4)
• 4-week T&E: -125.3 (95% CI: -146.6 to -104.1)
• LS mean difference: - 9.0 (95% CI – 27.7 to 9.7) Retinal Fluid The proportion of patients without fluid on OCT at week 16:
• 2-week T&E: 53.7%
• 4-week T&E: 62.6% The proportion of patients without fluid on OCT at 52 weeks:
• 2-week T&E: 68.3% (95% CI: 60.1% to 76.5%)
• 4-week T&E: 69.1% (95% CI: 60.9% to 77.3%)
• Adjusted difference: 1.0% (95% CI: - 10.6% to 12.7%) The proportion of patients without fluid on OCT at 96 weeks:
• 2-week T&E: 67.5% (95% CI: 59.2% to 75.8%)
• 4-week T&E: 67.5% (95% CI: 59.2% to 75.8%)
• Adjusted difference: 0.4% (95% CI: - 11.4% to 12.2%)
Safety
Treatment-emergent AEs (TEAEs) Patients with any TEAEs:
• 2-week T&E: 68.5%
• 4-week T&E: 69.9% Patients with any mild, moderate, and severe TEAEs:
• 2-week T&E: 50.0%, 12.1%, and 6.5%
• 4-week T&E: 44.7%, 17.9%, and 7.3% Ocular TEAEs Patients with any ocular TEAEs (study eye) ≥2%:
• 2-week T&E: 21.0%
• 4-week T&E: 30.9%
• Common ocular AEs: Cataract; Conjunctival hemorrhage; Dry eye; Retinal pigment epithelium tear Non-ocular TEAEs Patients with any non-ocular TEAEs ≥3%:
• 2-week T&E: 52.4%
• 4-week T&E: 56.1%
• Common ocular AEs: Constipation; Large intestine polyp; Nasopharyngitis; Influenza Contusion; Hypertension Patients with APTC arterial thromboembolic events:
• 2-week T&E: 0.8%
• 4-week T&E: 1.6% Serious AEs Patients with any serious TEAEs:
• 2-week T&E: 15.3%
• 4-week T&E: 16.3% Patients with any serious ocular TEAEs:
• 2-week T&E: 2.4%
• 4-week T&E: 1.6% Patients with any serious non-ocular TEAEs:
• 2-week T&E: 12.9%
• 4-week T&E: 13.0% Study Discontinuation Patients with any TEAE leading to discontinuation of the study drug:
• 2-week T&E: 0.8%
• 4-week T&E: 1.6% Death
• 2-week T&E: 1.6%
• 4-week T&E: 0.8%
Conclusion
Both aflibercept T&E regimens (2-week and 4-week interval adjustments) maintained BCVA gains and anatomic outcomes at 96 weeks. The 4-week T&E group had a slightly longer mean last injection interval, with no significant differences in safety outcomes.
Risk of Bias Assessment for Primary Outcome
Randomization Process
Low risk
Note: “Block randomization was stratified by baseline BCVA…” “Patient baseline demographics were similar between the two groups.”
Missing Outcome Data
Some concerns
Note: Patients who withdrew from the studies were unbalanced for each of the two assessment periods, with no adjustment. However, it is unlikely that missingness is dependent on true value.
Selection of the Reported Results
Low risk The protocol was publicly available.
Deviations from Intended Observations
Some concerns Note: This is an open-labeled study. There is no information on whether the deviation arose because of the trial context. According to Figure 3, information mITT was applied.
Measurement of the Outcome
Some concerns Note: As this is a multiple-site study, the BCVA measurement may be different among different sites. In addition, the outcome assessors were aware of the intervention, although it is unlikely that the assessment was influenced by knowledge of the intervention.
Overall
High risk
Categories: Wet AMD