Phase 3 Randomized Controlled Trial of Vitrectomy, Subretinal Alteplase, and Intravitreal Aflibercept for Submacular Hemorrhage in Exudative Age-Related Macular Degeneration

The primary objective of this study is to evaluate the **safety** and **efficacy** of a combined treatment approach involving vitrectomy, subretinal tissue plasminogen activator (TPA), intravitreal SF6 gas, and intravitreal anti-VEGF therapy for submacular hemorrhage secondary to exudative age-related macular degeneration (AMD). This is compared to the standard of care, which involves anti-VEGF monotherapy. The clinical relevance of this objective lies in potentially improving visual outcomes and reducing complications associated with submacular hemorrhage in patients with exudative AMD, a condition that can lead to significant vision loss.

Secondary objectives include:

• Achieving a gain of at least 10 ETDRS letters of vision at month 6.
• Assessing the mean ETDRS best-corrected visual acuity (BCVA).
• Evaluating Radner reading speed.
• Determining the composite score of the National Eye Institute (NEI) Visual Function Questionnaire.
• Measuring scotoma size using the Humphrey Field Analyzer 10-2.
• Assessing the presence or absence of subfoveal fibrosis and/or atrophy, and the area of fibrosis/atrophy using multimodal reading center image analysis at month 12.

The clinical trial involves a total of **80 participants** diagnosed with **exudative age-related macular degeneration**. The study population includes both **males and females** aged 50 years and older. Participants were selected based on specific criteria, including the presence of submacular hemorrhage (SMH) secondary to treatment-naïve or previously treated exudative AMD, with conditions such as choroidal neovascularization, idiopathic polypoidal choroidal vasculopathy, and retinal angiomatous proliferation. The trial population is characterized by a vulnerable group, with SMH involving the foveal center and meeting specific size and thickness requirements. The general health status of participants is not specified, but the inclusion criteria ensure that individuals have a best-corrected visual acuity (BCVA) between counting fingers and an ETDRS letter score of 70. Lifestyle considerations such as diet, physical activity, or habits are not detailed in the available data.

The clinical trial is designed to evaluate the **safety** and **efficacy** of a combined treatment approach for submacular hemorrhage secondary to **exudative age-related macular degeneration**. This is a phase 3, pan-European, two-group, active-control, observer-masked, superiority, randomized controlled surgical trial. The trial aims to compare the outcomes of vitrectomy, subretinal tissue plasminogen activator (TPA), intravitreal SF6 gas, and intravitreal anti-VEGF therapy against the standard of care with anti-VEGF monotherapy. The trial is expected to run from July 2023 to July 2025, with participant involvement lasting up to 12 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age (at least 50 years), specific characteristics of the submacular hemorrhage, and baseline best-corrected visual acuity (BCVA). Following the screening, eligible participants will be randomized into one of the two treatment groups. The primary endpoint is the gain of at least 10 ETDRS letters in BCVA at the month 12 visit. Secondary endpoints include visual acuity improvements at month 6, mean ETDRS BCVA, reading vision, visual function questionnaire scores, scotoma size, and the presence or absence of subfoveal fibrosis or atrophy at month 12.

Study visits will include baseline assessments, treatment administration, and follow-up evaluations at specified intervals to monitor safety and efficacy outcomes. The end-of-study visit will occur at the 12-month mark, where final assessments will be conducted. Participants may be withdrawn from the study early if they experience adverse events that compromise safety, fail to adhere to the study protocol, or withdraw consent. The trial's rigorous design ensures that data collected will provide valuable insights into the treatment's potential benefits and risks for patients with this condition.

The clinical trial involves the use of **Eylea**, a pharmaceutical product containing the active substance **aflibercept**. Eylea is formulated as a **solution for injection** and is administered via **intravitreal use**. The concentration of the solution is 40 mg/mL, and the maximum daily dose is 2 mg. The treatment period is limited to a maximum of one day. Aflibercept is a protein-based therapeutic agent, and its administration is intended to assess its efficacy and safety in treating submacular hemorrhage secondary to exudative age-related macular degeneration (AMD). The product is manufactured by Bayer AG and is not a pediatric formulation.

Another treatment used in the trial is **Actilyse**, which contains the active substance **alteplase**. Actilyse is provided as a **powder and solvent for solution for injection and infusion**. The administration route for this product is **subretinal use**. The maximum daily dose of alteplase is 25 micrograms, with a treatment period also limited to one day. Alteplase is a protein-based agent produced by Boehringer Ingelheim International GmbH. This product is utilized in the trial to evaluate its role in the treatment regimen for submacular hemorrhage associated with exudative AMD.

The trial is designed to compare the safety and efficacy of a combination treatment involving vitrectomy, subretinal tissue plasminogen activator (TPA), intravitreal SF6 gas, and intravitreal anti-VEGF therapy against the standard-of-care anti-VEGF monotherapy. The study is a phase 3, pan-European, two-group, active-control, observer-masked, superiority, randomized controlled surgical trial. Participant compliance with the dosing schedule and administration routes is monitored to ensure adherence to the study protocol.

Efficacy in the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is defined as the gain of at least 10 ETDRS letters in Best Corrected Visual Acuity (BCVA) in the study eye at the month 12 visit. Secondary endpoints include the gain of at least 10 ETDRS letters at month 6, mean ETDRS BCVA, Radner reading vision, and the National Eye Institute 25-item Visual Function Questionnaire composite score. Additionally, scotoma size will be evaluated using the Humphrey Field Analyser 10-2, and the presence or absence of subfoveal fibrosis and/or atrophy, as well as the area of fibrosis/atrophy, will be assessed using multimodal reading centre image analysis at month 12.