Intravitreal aflibercept 8 mg in neovascular age-related macular degeneration (PULSAR): 48-week results from a randomised, double-masked, non-inferiority, phase 3 trial
NCT04423718 | PULSAR | Lanzetta P et al. (2024)
Lanzetta, P., Korobelnik, J-F., Heier, J. S., Leal, S., Holz, F. G., Clark, W. L., et al. Intravitreal aflibercept 8 mg in neovascular age-related macular degeneration (PULSAR): 48-week results from a randomised, double-masked, non-inferiority, phase 3 trial. The Lancet, 2024; 403(10344):1141-1152.
Locations
223 sites across 27 countries worldwide
Study Period
August 2020 – July 2021 (48-week results)
Study Design
Phase 3, multicenter, randomized, double-masked, non-inferiority trial
Study Population
Experimental Group
Control Group
Follow-up Time: 48 weeks
Outcomes
Durability
• A total of 251 (79%) of 316 patients in the aflibercept 8q12 group and 239 (77%) of 312 patients in the aflibercept 8q16 group maintained their assigned dosing regimen up to week 48.
• Overall, 523 (83%) of 628 patients who received aflibercept 8 mg maintained at least 12-week dosing intervals up to week 48.
Vision
Best-Corrected Visual Acuity (BCVA)
Mean BCVA change at 48 weeks (Primary Outcome):
• 8q12 = +6.7 ± 12.6 letters
• 8q16 = +6.2 ± 11.7 letters
• 2q8 = +7.6 ± 12.2 letters
• Differences: 8q12 vs 2q8 = -0.97 letters (95% CI: -2.87 to 0.92, p=0.0009)
• Difference: 8q16 vs 2q8 = -1.14 letters (95% CI: -2.97 to 0.69, p=0.0011).
Other
N/A
Immunognicity
Not reported
Pharmokinetics
Not reported
Anatomic
Change in Central Retinal Thickness (CRT)
Mean CRT reduction at 48 weeks:
• 8q12 = -147.4 µm (95% CI: -155.2 to -139.5, p=0.012)
• 8q16 = -146.8 µm (95% CI: -154.2 to -139.4, p=0.014)
• 2q8 = -136.3 µm (95% CI: -144.6 to -127.9, p=0.031).
Choroidal neovascularisation (CNV)
At week 48, least squares mean change of CNV:
• 8q12 = -3.7 (SE 0.3) mm²
• 8q16 = -2.9 (0.3) mm²
• 2q8 = -2.4 (0.3) mm²
The least squares mean change in total lesion area at week 48:
• 8q12 = -0.46 (SE 0.19) mm²
• 8q16 = -0.35 (0.20) mm²
• 2q8 = 0.09 (0.22) mm²
Proportion of Patients with No Retinal Fluid
At Week 16
• 8q12 = 62%
• 8q16 = 65%
• 2q8 = 52%
• Difference: Pooled 8 mg vs. 2q8 = 12% (95% CI: 5% to 18%, p=0.0002).
Safety
Ocular Treatment-emergent AEs (TEAEs) Any:
• 8q12: 129 (39%)
• 8q16: 127 (38%)
• 2q8: 130 (39%)
Intraocular inflammation in the study eye:
• 8q12: 4 cases
• 8q16: 1 cases
• 2q8: 2 cases
Non-ocular TEAEs
Any:
• 8q12: 175 (52%)
• 8q16: 182 (54%)
• 2q8: 178 (53%)
Any adjudicated treatment-emergent Anti-Platelet Trialists’ Collaboration events:
• 8q12: 1 case
• 8q16: 2 cases
• 2q8: 5 cases
Hypertension:
• 8q12: 16 (5%)
• 8q16: 16 (5%)
• 2q8: 12 (4%))
Serious TEAEs
Ocular
• 8q12: 6 (2%)
• 8q16: 5 (1%)
• 2q8: 2 (1%)
Non-Ocular:
• 8q12: 34 (10%)
• 8q16: 32 (9%)
• 2q8: 46 (14%)
Deaths
• 8q12: 3 (1%)
• 8q16: 1 (<1%)
• 2q8: 5 (1%).
Conclusion
Aflibercept 8 mg administered every 12 or 16 weeks was non-inferior to aflibercept 2 mg every 8 weeks in terms of BCVA improvement, with superior anatomic outcomes and a similar safety profile, potentially reducing treatment burden for nAMD patients.
Risk of Bias Assessment for Primary Outcome
Randomization Process
Low risk
Note: “Eligible patients were randomly assigned, using an interactive web response system…” There is no information that suggestion of the baseline characteristics unbalanced.
Missing Outcome Data
Low risk
Note: “Sensitivity and supplementary analyses were performed including multiple imputation and tipping point analyses to assess the effect of potential deviations from the missing at random assumption.”
Selection of the Reported Results
Low risk Note: Registration with the protocol.
Deviations from Intended Observations
Low risk Note: “Patients, all study personnel (other than those performing unmasked roles), and the central reading centre were masked to treatment assignment.” “All efficacy analyses were conducted in the full analysis set (all randomised patients who received at least one dose of the study treatment) according to original randomisation…”
Measurement of the Outcome
Low risk Note: “Patients, all study personnel (other than those performing unmasked roles), and the central reading centre were masked to treatment assignment.” “The same certified BCVA examiner performed assessments for each patient, whenever possible, to ensure consistent measurement.”
Overall
Low risk
Categories: Wet AMD