Efficacy and Safety of Intravitreal Aflibercept Using a Treat-and-Extend Regimen for Neovascular Age-Related Macular Degeneration: The ARIES Study

NCT02581891 | ARIES | Mitchell P et al. (2021)

Mitchell, P., Holz, F. G., Hykin, P., Midena, E., Souied, E., Allmeier, H., Lambrou, G., Schmelter, T., Wolf, S. Efficacy and Safety of Intravitreal Aflibercept Using a Treat-and-Extend Regimen for Neovascular Age-Related Macular Degeneration: The ARIES Study. Retina, 2021; 41(9):1911-1920.

Locations

39 centers in 8 countries (Australia, Canada, France, Germany, Hungary, Italy, Spain, United Kingdom)

Study Period

Not reported

Study Design

Phase 3b/4, randomized, open-label, multicenter trial

Study Population

Characteristic:

Type of AMD:

2 (Wet AMD)

AMD Stage:

3 (Late)

Total Sample Size:

271 randomized (Early T&E: 135, Late T&E: 136)

Age:

Phase 3b/4, randomized, open-label, multicenter trial

Sex (Male) n%:

Not reported

Experimental Group

Intervention Therapy:

Intravitreal aflibercept (IVT-AFL) 2 mg (Early Treat-and-Extend, T&E)

Dose & Frequency:

Initial fixed dosing (Week 0, 4, 8, 16), then individualized T&E dosing with 2-week interval adjustments (max 16 weeks)

Age (Years):

75.5 ±9.0 for per population set (PPS)

Number of Patients:

134 for final analysis

Male N %:

44/106 (41.5%) for PPS

Patients Followed Up:

119 (88.1%)

Control Group

Intervention Therapy:

Intravitreal aflibercept (IVT-AFL) 2 mg (Late Treat-and-Extend, T&E)

Dose & Frequency:

Fixed dosing every 8 weeks until Week 48, then T&E with 2-week interval adjustments (max 16 weeks)

Age (Years):

76.6±8.7 for PPS

Number of Patients:

135 for final analysis

Male N %:

46/104 (44.2%) for PPS

Patients Followed Up:

117 (86.0%)

Follow-up Time: 104 weeks

Outcomes

Durability

Injection Burden
The mean number of injections over 52 weeks:
• Early T&E = 7.1 (SD 0.8)
• Late T&E = 8.0 (SD 0.2)

The mean number of injections over 104 weeks:
• Early T&E = 12.0 (SD 2.3)
• Late T&E = 13.0 (SD 1.8)

Duration of the Last Treatment Interval
The mean (SD) duration of the last treatment interval up to W104:
• Early T&E = 11.5 (3.7) weeks
• Late T&E = 11.4 (3.7) weeks

Vision

Best-Corrected Visual Acuity (BCVA)
The mean BCVA change from randomization (Week 16) to Week 104 (Primary Outcome):
• Early T&E = +2.1 (SD 11.4) letters
• Late T&E = +0.4 (SD 8.4) letters
• Adjusted mean difference = -2.0 letters (95% CI: -4.75 to 0.71, p = 0.0162 for noninferiority)

The mean BCVA change from randomization (Week 16) to Week 54:
• Early T&E = +1.3 (SD 6.4) letters
• Late T&E = +2.0 (SD 5.3) letters

The mean BCVA change from baseline to Week 52:
• Early T&E = +7.8 (SD 9.4) letters
• Late T&E = +10.2 (SD 9.3) letters

The mean BCVA change from baseline to Week 104:
• Early T&E = +4.3 (SD 13.4) letters
• Late T&E = +7.9 (SD 11.9) letters

Vision Maintaining
BCVA Gain (≥15 Letters) at Week 104:
• Early T&E = 18.9%
• Late T&E = 22.1%
BCVA Maintenance (<15 Letters Loss) at Week 104:
• Early T&E = 93.4%
• Late T&E = 96.2%
• The treatment effect difference was -2.5% (95% CI: -8.46 to 3.46)

Other

N/A

Immunognicity

Not reported

Pharmokinetics

Not reported

Anatomic

Central Retinal Thickness (CRT)
Mean CRT change from baseline to Week 52:
• Early T&E = -164.9 (SD 117.3) µm
• Late T&E = -167.1 (SD 117.1) µm

Mean CRT change from baseline to Week 104:
• Early T&E = -161.6 (SD 135.6) µm
• Late T&E = -158.6 (SD 125.1) µm

Safety

Treatment-emergent AEs (TEAEs)
Patients with any TEAEs:
• Early T&E: 84.4%
• Late T&E: 82.4%
Patients with any TEAE related to the injection procedure:
• Early T&E: 30.4%
• Late T&E: 27.2%

Ocular-related TEAEs (Study Eye)
Patients with any Ocular-related TEAE:
• Early T&E: 55.6%
• Late T&E: 55.1%
Patients with any ocular TEAE related to the study drug:
• Early T&E: 4.4%
• Late T&E: 2.9%

Non-ocular TEAEs
Patients with any systemic AEs:
• Early T&E: 57.8%
• Late T&E: 63.2%

Serious AEs (SAEs)
Patients with any SAEs:
• Early T&E: 21.5%
• Late T&E: 25.7%

Discontinuation of the study drug
Discontinuation of the study drug because of TEAEs:
• Early T&E: 1.5%
• Late T&E: 3.7%
Discontinuation of the study drug because of serious TEAEs:
• Early T&E: 0
• Late T&E: 2.2%
Death Patients with treatment-emergent deaths:
• Early T&E: 1 (0.7%)
• Late T&E: 2 (1.5%)
Patients with any death:
• Early T&E: 3 (2.2%)
• Late T&E: 4 (2.9%)

Outcomes

Conclusion

The ARIES study demonstrated that an early-start T&E regimen with intravitreal aflibercept was non-inferior to a late-start T&E regimen over 104 weeks, with similar visual and anatomical outcomes but requiring one fewer injection.

Risk of Bias Assessment for Primary Outcome

Randomization Process

Some concerns

Note: There was no information on the method of the allocation concealment. However, “Baseline demographics were similar between the two arms (Table 1).”

Missing Outcome Data

Low risk

Note: The evidence that the result was not biased by missing outcome data: “A sensitivity analysis (full-analysis set population) showed a mean (SD)
BCVA change from W16 to 104…”

Selection of the Reported Results

Low risk Registration with the protocol

Deviations from Intended Observations

Some concerns Note: this is an open-labeled study. There is no information on whether there were deviations from the intended intervention that arose because of the trial context ITT principle was applied as a sensitivity analysis.

Measurement of the Outcome

Low risk Note: This is an open-label study. However, knowledge of the assigned intervention is unlikely to influence the assessment of the primary outcomes. “Morphologic outcomes were assessed by the investigator and confirmed by the central reading center before entry into the database.”

Overall

Some Concerns