Evaluation of Long-Term Safety and Tolerability of Ranibizumab via Port Delivery System in Neovascular Age-Related Macular Degeneration Patients

The primary objective of this study is to evaluate the long-term **safety** and tolerability of **ranibizumab** delivered via the Port Delivery System (PDS) in patients with Neovascular Age-Related Macular Degeneration (nAMD). This is clinically relevant as it aims to ensure that the PDS, which allows for sustained delivery of ranibizumab, is safe for extended use, potentially reducing the frequency of intravitreal injections required by patients.

Secondary objectives include:

• Evaluating the efficacy of ranibizumab delivered via the PDS every 24 weeks (Q24W) or every 36 weeks (Q36W) with the 100 mg/mL formulation, as assessed by visual acuity.
• Assessing the efficacy of ranibizumab, delivered via the PDS Q24W or Q36W with the 100 mg/mL formulation, as measured by center point thickness (CPT) on optical coherence tomography (OCT).
• Determining the proportion of patients who undergo supplemental treatment with intravitreal ranibizumab 0.5 mg.

The clinical trial involves a total of **666 participants** diagnosed with **Neovascular Age-Related Macular Degeneration (nAMD)**. The study population includes both male and female subjects, with an age range that encompasses adults and the elderly. Participants were selected based on their previous enrollment and completion of specific studies related to ranibizumab treatment, without early treatment or study discontinuation. The trial population includes individuals who are able and willing to attend all scheduled visits and assessments. Lifestyle considerations such as diet and physical activity are not specified. The study does not exclude vulnerable populations, indicating a diverse participant group. Key inclusion criteria include the ability to comply with study requirements and, for women of childbearing potential, agreement to use contraceptive measures or remain abstinent during the treatment period and for a specified duration after the last treatment. The trial aims to evaluate the long-term safety and tolerability of ranibizumab delivered via the Port Delivery System at specified intervals.

The clinical trial is designed to evaluate the long-term safety and tolerability of **ranibizumab** delivered via the Port Delivery System in patients with **neovascular age-related macular degeneration**. This is a multicenter, open-label extension study, following a randomized, controlled trial design. The trial will involve participants who have previously completed specific studies without early treatment or discontinuation. The trial is expected to conclude by December 31, 2029, with recruitment having commenced on August 22, 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on prior study participation and willingness to comply with study requirements. Follow-up visits will be scheduled to monitor the incidence and severity of ocular and systemic adverse events, as well as changes in best-corrected visual acuity (BCVA) over time. The end-of-study visit will assess the overall safety and tolerability outcomes. The expected length of participant involvement is up to 144 weeks, with the possibility of early termination if adverse events or other conditions arise that compromise participant safety or study integrity.

Key elements of the research methodology include the use of a combination product that includes a device, with **ranibizumab** administered via implantation. The primary endpoints focus on the incidence and severity of adverse events, while secondary endpoints include changes in BCVA and the need for supplemental treatment. Participants are required to adhere to contraceptive measures if applicable, and the study will monitor for adverse device effects throughout the trial duration.

The clinical trial involves the use of **ranibizumab**, an active substance administered through a **Port Delivery System**. The experimental medication, identified as RO4893594, is provided in the form of a **solution for injection**. This formulation is delivered via **implantation** and is designed to release the medication over an extended period. The maximum daily dose is 2 mg, with a total dose not exceeding 12 mg over a treatment period of up to 144 weeks. The administration schedule is set at intervals of every 24 weeks (Q24W) or every 36 weeks (Q36W), utilizing a 100 mg/mL formulation. The product is a combination that includes a device, specifically the Port Delivery System, which facilitates the controlled release of the medication.

Another product used in the study is Lucentis, a 10 mg/mL solution for injection provided in a pre-filled syringe. This product also contains **ranibizumab** as the active substance and is administered via **implantation**. The dosing regimen for Lucentis mirrors that of RO4893594, with a maximum daily dose of 2 mg and a total dose limit of 12 mg over a 144-week period. The administration frequency is similarly set at every 24 or 36 weeks. Lucentis is also a combination product that includes a device, ensuring precise delivery of the medication.

Both products are not pediatric formulations and are not classified as orphan drugs. The active substance, **ranibizumab**, is a protein of other origin, and the products are developed by F. Hoffmann-La Roche Ltd and Novartis Europharm Limited. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol.

The efficacy of the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoints focus on the incidence and severity of ocular and systemic adverse events, including adverse events of special interest (AESIs) and adverse device effects. These will be measured during the postoperative period and the follow-up period for patients receiving the implant. The secondary endpoints include changes in best-corrected visual acuity (BCVA) scores from baseline over time, assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart at a starting distance of 4 meters. Additionally, the percentage of patients who lose fewer than 15, 10, or 5 letters in BCVA score from baseline, as well as those with BCVA scores of 38 letters or worse and 69 letters or better, will be evaluated over time. Changes from baseline in central point thickness (CPT) and the percentage of patients undergoing supplemental treatment with intravitreal **ranibizumab** 0.5 mg during each refill-exchange interval will also be assessed.