Long-term Evaluation of Aflibercept in Retinopathy of Prematurity: An Extension Study of Visual Function and Safety Outcomes

The primary objective of this study is to evaluate the long-term **safety** outcomes and visual function of subjects who received treatment for **retinopathy of prematurity** (ROP) in Study 20090. This is clinically relevant as it aims to assess the enduring effects and potential risks associated with the treatment, providing critical insights into the management of ROP, a condition that can lead to blindness in premature infants if not adequately addressed.

Secondary objectives include describing the visual function and overall development of subjects included in Study 20090 for treatment for ROP. This will help in understanding the broader impact of the treatment on the developmental trajectory of the affected individuals.

The clinical trial involves a total of **58 participants** who were previously treated in Study 20090 for **retinopathy of prematurity**. The study population includes both male and female subjects, all of whom are less than 13 months of chronological age. Participants were selected based on their prior involvement in the aforementioned study and the acquisition of signed informed consent from their parent(s) or legally authorized representative(s). The trial population is considered a vulnerable group due to the young age of the participants. No specific lifestyle considerations such as diet or physical activity are highlighted in the trial data provided.

The clinical trial is designed to evaluate the long-term safety outcomes and visual function of subjects who previously received treatment for **retinopathy of prematurity** in a prior study. This is a phase 3, randomized, double-blind, controlled extension study. The trial is expected to span from March 30, 2020, to July 3, 2025, with the primary endpoint being the binocular best-corrected visual acuity in Snellen equivalent score at 5 years of age. Secondary endpoints include the proportion of subjects with ocular and systemic adverse events, unfavorable ocular structural outcomes, and neurodevelopmental outcomes at various time points up to 5 years of age.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as previous treatment in Study 20090, age less than 13 months, and signed informed consent from a parent or legally authorized representative. Follow-up visits will be scheduled at 1, 3, and 5 years of age to assess visual acuity, ocular health, and neurodevelopmental progress. The end-of-study visit will occur at the 5-year mark, concluding the participant's involvement in the trial.

The expected length of participant involvement is up to 5 years, with conditions for early termination including withdrawal of consent, non-compliance with study procedures, or the occurrence of significant adverse events. The investigational product, **aflibercept**, is administered via intravitreal injection, with the study ensuring adherence to safety protocols and monitoring for any adverse effects throughout the trial duration.

The clinical trial involves the administration of **Eylea**, a pharmaceutical product containing the active substance **aflibercept**. Eylea is formulated as a **solution for injection** in a vial, with a concentration of 40 mg/mL. The route of administration is **intravitreal use**, which involves injecting the solution directly into the eye. The product is supplied with a filter needle, specifically the BD Blunt Fill Needle, which is used to extract the injection solution from the vial into the injection syringe. It is important to note that the filter needle is not intended for injection. The product is manufactured by Bayer AG and is authorized for use in the European Union under the marketing authorization number EU/1/12/797/002. The product has been modified compared to its marketing authorization with regards to secondary packaging.

In this clinical trial, Eylea is used to evaluate long-term safety outcomes and visual function in subjects who previously received treatment for **retinopathy of prematurity**. The trial is an extension study following Study 20090. The maximum treatment period for the trial is set at an extensive duration, allowing for comprehensive evaluation of long-term effects. The trial does not specify a maximum daily or total dose amount, indicating that dosing will be determined based on clinical judgment and participant response. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment protocol.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified for use in this study. The focus remains solely on the administration of Eylea to assess its efficacy and safety in the specified patient population. The trial does not involve a pediatric formulation, and the product is not classified as an orphan drug. The study aims to provide valuable insights into the long-term management of retinopathy of prematurity using aflibercept.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the binocular best-corrected visual acuity in Snellen equivalent score at 5 years of age. Secondary endpoints include the proportion of subjects with ocular adverse events (AEs) and serious AEs (SAEs) through 5 years of age, as well as systemic AEs and SAEs within the same timeframe. Additionally, the trial will evaluate the proportion of subjects developing unfavorable ocular structural outcomes, such as retinal detachment, macular dragging, macular fold, and retrolental opacity at 1, 3, and 5 years of age. The absence of active **retinopathy of prematurity (ROP)** and unfavorable structural outcomes at 1 year of age will also be assessed.

Further secondary endpoints include best-corrected visual acuity in each eye at 3 and 5 years of age, refractive spherical equivalent in each eye at these timepoints, and neurodevelopmental outcomes at 2 and 5 years of age using standardized development tests such as the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), the Differential Ability Scales® II (DAS-II®), the Wechsler Preschool and Primary Scale of Intelligence™, Fourth Edition (WPSSI-IV), and the Vineland Adaptive Behavior Scales, Second Edition (VABS-II). The trial will also measure the proportion of subjects with recurrence of ROP at 3 and 5 years of age, and those requiring treatment for ROP or ophthalmological treatment during the extension study.