Evaluation of Aflibercept 8mg Efficacy in Extending Treatment Intervals for Neovascular Age-Related Macular Degeneration Post-Faricimab and Aflibercept 2mg Therapy

The primary objective of this study is to assess the **efficacy** of aflibercept 8mg in terms of durability at 32 weeks by extending the treatment interval in patients with neovascular age-related macular degeneration who have been previously treated with high-frequent faricimab and prior aflibercept 2mg. This is clinically relevant as it aims to determine whether a longer treatment interval can be achieved, potentially reducing the treatment burden for patients while maintaining therapeutic effectiveness.

Secondary objectives include:

• Evaluating the durability, efficacy on best-corrected visual acuity (BCVA), anatomic outcomes, and safety of aflibercept 8mg in the same patient population.
• Assessing whether systemic vascular endothelial growth factor (VEGF) levels are influenced differently under aflibercept 8mg, with optional participation for this evaluation.

The clinical trial involves participants diagnosed with **neovascular age-related macular degeneration**. The study population includes both male and female subjects aged 50 years and older. Participants are generally in a stable health condition, as the trial does not involve a vulnerable population. The total number of participants is not provided by the sponsor. Selection criteria include prior participation in the FAN study, a willingness and ability to comply with clinic visits and study-related procedures, and a history of at least four previous intravitreal injections with faricimab. Participants must have a Best Corrected Visual Acuity (BCVA) between 19 and 75 letters, which corresponds to a Snellen equivalent of approximately 20/400 to 20/32. The trial does not specify any particular lifestyle considerations such as diet or physical activity. Key inclusion criteria focus on the presence of macular neovascularization due to age-related macular degeneration and specific treatment history with faricimab.

The clinical trial is designed to evaluate the efficacy of **aflibercept** 8mg in patients with **neovascular age-related macular degeneration** who have previously been treated with high-frequency faricimab and aflibercept 2mg. This study is a monocenter, single-arm, open-label extension trial, with a primary objective to assess the durability of aflibercept 8mg over a 32-week period by extending the treatment interval. The trial is set to commence recruitment on October 30, 2024, and is expected to conclude by December 31, 2025.

Participants will be involved in the study for a maximum of 32 weeks. The trial includes a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as prior participation in the FAN study, age of 50 years or older, and specific visual acuity requirements. Follow-up visits will be conducted to monitor the treatment's efficacy and safety, with assessments including the proportion of eyes achieving extension success without retinal fluid and changes in ETDRS letter scores. The end-of-study visit will evaluate the overall outcomes and any adverse events experienced during the trial.

Participants may be withdrawn from the study if they fail to comply with study procedures, experience significant adverse events, or if the investigator deems it necessary for their safety. The trial's methodology ensures rigorous data collection and analysis, with primary and secondary endpoints focusing on the extension success rate and various measures of visual acuity and retinal health. The study's design and procedures are structured to provide comprehensive insights into the long-term benefits and safety of aflibercept 8mg in this patient population.

The clinical trial involves the administration of **Aflibercept**, an experimental medication, in the form of a **solution for injection**. The active substance, aflibercept, is a protein of other origin, specifically designed for **intravitreal use**. The dosage regimen for this study is set at a maximum daily dose of 8 mg, with a total maximum dose of 72 mg over the course of the trial. The treatment period is defined as 32 weeks, during which the efficacy of aflibercept 8 mg will be assessed in terms of its durability by extending the treatment interval in patients previously treated with high-frequency faricimab and prior aflibercept 2 mg for neovascular age-related macular degeneration.

In this single-arm, open-label extension study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus remains solely on evaluating the effects of the increased dosage of aflibercept. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment protocol. The study aims to provide insights into the potential benefits of aflibercept 8 mg in extending treatment intervals for patients with this condition.

The efficacy of **aflibercept** 8mg in the treatment of neovascular age-related macular degeneration will be assessed through a series of primary and secondary endpoints over a 32-week period. The primary endpoint is the proportion of eyes achieving at least one extension without retinal (intra- and subretinal) fluid from baseline to 32 weeks, referred to as the extension success rate. Secondary endpoints include the proportion of eyes with maximum extended intervals without retinal fluid of ≥6, ≥8, and ≥10 weeks at 32 weeks, the maximum extended treatment interval without retinal fluid at 32 weeks, and the number of injections received during the 32 weeks. Additional secondary endpoints involve the proportion of eyes maintaining a 4-weekly interval from baseline to the last visit, the proportion of eyes extended to 6 weeks without success, and various changes in ETDRS letter scores and central subfield thickness (CST) measurements.

These efficacy parameters will be measured using validated scales and clinical assessments, including the ETDRS letter score for visual acuity and CST measurements for retinal thickness. The mean change in ETDRS letter score from baseline to an averaged score between 24 and 32 weeks, as well as the mean CST change from baseline to the maximum extended interval without retinal fluid, will be analyzed. The study will also evaluate the proportion of eyes with no intraretinal or subretinal fluid at baseline and the final visit, and the incidence and severity of ocular and non-ocular adverse events. The mean change in concentration of plasma VEGF-A over time will also be monitored. These assessments will provide comprehensive data on the efficacy of aflibercept 8mg in extending treatment intervals and improving visual outcomes in patients with neovascular age-related macular degeneration.