(22153) Randomized, Double-Masked, Active-Controlled, Phase 3 Study of the Efficacy and Safety of Aflibercept 8 mg in Macular Edema Secondary to Retinal Vein Occlusion

The primary objective of this study is to determine if treatment with **aflibercept** 8 mg every 8 weeks (Q8W) provides non-inferior best-corrected visual acuity (BCVA) change compared to aflibercept 2 mg every 4 weeks (Q4W) in patients with macular edema secondary to retinal vein occlusion. This is clinically relevant as it may offer a less frequent dosing regimen while maintaining visual outcomes, potentially improving patient compliance and reducing treatment burden.

Secondary objectives include:

• Determining if treatment with aflibercept 8 mg Q8W requires fewer injections compared to aflibercept 2 mg Q4W.
• Assessing the effect of aflibercept 8 mg Q8W compared to aflibercept 2 mg Q4W on other visual and anatomic measures of response.
• Evaluating the efficacy of aflibercept 8 mg Q8W compared to aflibercept 2 mg Q4W on vision-related quality of life (QoL).
• Evaluating the safety of aflibercept 8 mg Q8W compared to aflibercept 2 mg Q4W.
• Evaluating the duration of effect of aflibercept 8 mg Q8W compared to aflibercept 2 mg Q4W.
• Evaluating the pharmacokinetics (PK) of aflibercept 8 mg Q8W compared to aflibercept 2 mg Q4W.

The clinical trial involves a total of **615 participants** diagnosed with **macular edema secondary to retinal vein occlusion**. The study population includes both male and female adults aged 18 years and older, with the age range extending to include older adults. Participants were selected based on specific inclusion criteria, such as being treatment-naïve and having a diagnosis of macular edema involving the foveal center secondary to retinal vein occlusion within 16 weeks prior to the screening visit. The trial population is characterized by a decrease in best-corrected visual acuity primarily due to retinal vein occlusion, with a mean central subfield thickness of at least 300 µm on optical coherence tomography. Participants are required to be capable of providing informed consent and, if applicable, comply with local regulations regarding contraception. The study includes a vulnerable population, ensuring that ethical considerations are addressed. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the **efficacy** and safety of **aflibercept** 8 mg in patients with **macular edema** secondary to **retinal vein occlusion**. This is a randomized, double-masked, active-controlled, Phase 3 study. The trial aims to determine if treatment with aflibercept 8 mg every 8 weeks provides non-inferior best-corrected visual acuity (BCVA) change compared to aflibercept 2 mg every 4 weeks. The primary endpoint is the change from baseline in BCVA measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score at Week 36. Secondary endpoints include the number of active injections from baseline to Week 64, changes in BCVA at Weeks 44 and 64, and the occurrence of treatment-emergent adverse events through Weeks 36 and 64.

The trial is expected to last until May 2025, with an estimated recruitment start date in September 2023. Participants will be involved in the study for a maximum treatment period of 60 weeks. The study includes several key visits: an initial screening visit to confirm eligibility, baseline visits to establish initial measurements, and follow-up visits at specified intervals to monitor progress and collect data. The end-of-study visit will conclude the participant's involvement, assessing final outcomes and any long-term effects.

Participants are required to meet specific inclusion criteria, such as being adults aged 18 years or older, having treatment-naïve macular edema involving the foveal center secondary to retinal vein occlusion, and a BCVA letter score of 73 to 24 at screening and baseline visits. Conditions that may lead to early termination from the study include non-compliance with the study protocol, withdrawal of consent, or the occurrence of adverse events that necessitate discontinuation. The study is conducted under strict adherence to ethical guidelines, ensuring the safety and well-being of all participants throughout the trial duration.

The clinical trial involves the administration of **Aflibercept**, a **solution for injection** used in the treatment of macular edema secondary to retinal vein occlusion. Aflibercept is administered via **intravitreal use**. The experimental medication is provided in two dosing regimens: 8 mg every 8 weeks (Q8W) and 2 mg every 4 weeks (Q4W). The maximum daily dose is 8 mg, with a total maximum dose of 120 mg over a treatment period of 60 weeks. The solution is supplied in vials and is extracted using a BD Blunt Fill Needle, which is not intended for injection. The trial aims to assess the non-inferiority of the 8 mg Q8W regimen compared to the 2 mg Q4W regimen in terms of best-corrected visual acuity (BCVA) change.

**Eylea 40 mg/mL solution for injection in a vial** is used as a comparator in the study. It contains the active substance **Aflibercept** and is also administered via **intravitreal use**. The pharmaceutical form is a solution for injection, and the dosing regimen is 2 mg every 4 weeks (Q4W), with a maximum daily dose of 2 mg and a total maximum dose of 32 mg over a 60-week treatment period. The solution is extracted from the vial using a BD Blunt Fill Needle, which is not intended for injection. This comparator treatment is used to evaluate the efficacy and safety of the experimental dosing regimen.

**Fluorescein Sodium** is utilized as an auxiliary treatment in the trial. It is a chemical substance administered via **intravenous injection**. The pharmaceutical form is denoted as PHF00231MIG. The maximum daily dose is 500 mg, with a total maximum dose of 2000 mg over a 60-week treatment period. Fluorescein Sodium is used to assist in diagnostic procedures related to the study but is not the primary focus of the trial.

**Eylea**, another formulation of **Aflibercept**, is also included in the study as an auxiliary treatment. It is provided as a **solution for injection** and administered via **intravitreal use**. The dosing regimen is 8 mg every 8 weeks (Q8W), with a maximum daily dose of 8 mg and a total maximum dose of 120 mg over a 60-week treatment period. The solution is extracted using a BD Blunt Fill Needle, which is not intended for injection. This formulation supports the evaluation of the experimental treatment's efficacy and safety.

The efficacy of the clinical trial will be assessed primarily through the change from baseline in **best-corrected visual acuity (BCVA)**, measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score at Week 36. Secondary endpoints include the number of active injections from baseline to Weeks 36 and 64, changes in BCVA at Weeks 44 and 64, and the number of participants gaining at least 15 letters in BCVA from baseline at Weeks 36 and 64. Additional secondary endpoints involve achieving an ETDRS letter score of at least 69 at Weeks 36 and 64, and the absence of intraretinal fluid (IRF) and sub-retinal fluid (SRF) in the center subfield at these timepoints.

Further assessments will include changes from baseline in central subfield thickness (CST) and the National Eye Institute Visual Functioning Questionnaire-25 (NEI-VFQ-25) total score at Weeks 36 and 64. The occurrence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) will be monitored through Weeks 36 and 64. The trial will also evaluate systemic exposure to **aflibercept** by measuring plasma concentrations of free, adjusted bound, and total aflibercept from baseline through Weeks 36 and 64. The efficacy parameters will be collected and analyzed at specified timepoints to determine the non-inferiority of aflibercept 8 mg administered every 8 weeks compared to aflibercept 2 mg administered every 4 weeks.