Evaluation of Genetic Polymorphisms on Ranibizumab and Bevacizumab Efficacy in Age-Related Macular Degeneration Patients

The primary objective of this multicentre, randomised, double-blind, parallel-group, Phase III study is to determine if **Bevacizumab** is as effective as **Ranibizumab** after one year of treatment in patients with **Age-Associated Macular Degeneration** (AMD). This comparison is clinically relevant as both drugs are used to manage AMD, a leading cause of vision loss, and establishing their relative efficacy could influence treatment decisions and healthcare resource allocation.

The clinical trial involves participants diagnosed with **neovascular Age-related Macular Degeneration**. The study population includes both male and female subjects aged 50 years or older. Participants are required to have an indication for treatment with an anti-VEGF agent as determined by an ophthalmologist, and must not have received previous anti-VEGF treatment for AMD in the eye under study. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity. The selection of the trial population is based on the inclusion criteria, focusing on individuals who have not undergone prior treatment for the condition in the affected eye.

The clinical trial is a **randomized**, **double-blind**, parallel-group, Phase III study designed to evaluate the influence of genetic polymorphisms on the response to treatment with **Ranibizumab** and **Bevacizumab** in patients diagnosed with Age-Associated Macular Degeneration (AMD). The trial aims to determine if Bevacizumab is as effective as Ranibizumab after one year of treatment and to assess the impact of specific genetic polymorphisms on treatment response. The study will involve patients aged 50 years or older who have been diagnosed with neovascular AMD and have not received previous anti-VEGF treatment in the eye under study. The trial is expected to last until December 31, 2025, with participant involvement spanning up to 12 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on the principal inclusion criteria. Following randomization, participants will receive intravitreal injections of either Bevacizumab or Ranibizumab. The primary endpoint will be the change in visual acuity score, measured using the ETDRS chart at 4 meters, from baseline to the final evaluation at one year. Saliva samples will be collected for genetic analysis to explore the influence of polymorphisms in genes such as VEGFA, CFH, and others on treatment response.

Throughout the study, participants will attend regular follow-up visits to monitor treatment efficacy and safety. These visits will include assessments of visual acuity, ocular health, and any adverse events. The end-of-study visit will occur at the conclusion of the 12-month treatment period, where final evaluations will be conducted. Participants may be withdrawn from the study early if they experience significant adverse effects, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The trial is conducted under strict ethical guidelines, ensuring the safety and well-being of all participants.

The clinical trial involves the administration of **Bevacizumab**, marketed under the name Avastin, which is provided as a 25 mg/ml concentrate for solution for infusion. This pharmaceutical form is intended for **intravitreal use**. The maximum daily dose is 1.25 mg, with a total maximum dose of 15 mg over a treatment period of up to 12 months. Bevacizumab is a protein-based therapeutic agent, specifically a monoclonal antibody, and is manufactured by Roche Registration GmbH. The administration schedule and participant compliance will be closely monitored to ensure adherence to the dosing regimen.

In addition to Bevacizumab, the study includes a comparator treatment with **Ranibizumab**, which is also administered via intravitreal injection. Ranibizumab is provided as a solution for injection, with a maximum daily and total dose of 0.05 ml. This treatment is also protein-based, classified as a fragment of a monoclonal antibody. The treatment period for Ranibizumab is similarly set at 12 months. The study aims to evaluate the efficacy of Bevacizumab in comparison to Ranibizumab, with a focus on genetic polymorphisms that may influence treatment response in patients with Age-Associated Macular Degeneration. Compliance with the dosing schedule will be monitored throughout the trial to ensure accurate assessment of treatment outcomes.

Efficacy in this clinical trial will be assessed primarily through the measurement of visual acuity scores. The primary endpoint involves evaluating changes in visual acuity using the ETDRS (Early Treatment Diabetic Retinopathy Study) chart at a distance of 4 meters, or the Snellen chart with conversion to ETDRS if necessary. This assessment will be conducted between baseline and final evaluations, with the main outcome being assessed at one year. The method proposed by Rosenfeld et al. will be utilized for these measurements.

Additionally, the trial will evaluate the influence of genetic polymorphisms on treatment response. Saliva samples will be collected using oral swabs suitable for obtaining DNA. The genomic DNA will be extracted from these samples to analyze polymorphisms in specific genes, including VEGFA, CFH, CTGF/CCN2, ARMS2, HTRA1, OR52B4, LOC100287225, LEPR, and SERPINF1. This genetic analysis aims to understand the variability in response to the treatments with **Bevacizumab** and Ranibizumab in patients with Age-Related Macular Degeneration (AMD).