Phase III Double-Blind, Randomized, Placebo-Controlled Trial of Intravenous Tenecteplase for Visual Recovery in Acute Non-Arteritic Central Retinal Artery Occlusion

The primary objective of this study is to evaluate the **functional recovery** to best corrected visual acuity (BCVA) of Logarithm of the Minimum Angle of Resolution (LogMAR) ≤ 0.5, which corresponds to normal to mild vision impairment according to WHO ICD-11, in the affected eye at Visit 3 (30 ± 5 days). This is assessed through a dichotomized intention-to-treat (ITT) analysis, comparing functional recovery to LogMAR ≤ 0.5 versus no functional recovery, i.e., LogMAR > 0.5. This objective is clinically relevant as it aims to determine the effectiveness of early reperfusion therapy with intravenous thrombolysis in improving visual outcomes in patients with acute non-arteritic central retinal artery occlusion (CRAO).

Secondary objectives include investigating the efficacy of intravenous thrombolysis using alternative endpoints and assessing the safety of this treatment in non-arteritic CRAO. These objectives are crucial for understanding the broader impact and safety profile of the therapy beyond the primary visual acuity outcome.

The clinical trial focuses on participants diagnosed with **acute non-arteritic central retinal artery occlusion (CRAO)**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have experienced sudden, painless monocular vision loss within 12 hours of symptom onset, confirmed by an experienced ophthalmologist. The trial involves individuals who had the ability to read with the affected eye prior to the onset of CRAO. The study population is characterized by a vulnerable group, as it includes individuals with acute retinal ischemia. The sponsor has not provided information regarding the total number of participants. Key lifestyle considerations, such as diet and physical activity, are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **tenecteplase** in the treatment of acute non-arteritic central retinal artery occlusion (CRAO). This is a double-blind, randomized, placebo-controlled phase III trial. The trial aims to assess the functional recovery of best corrected visual acuity (BCVA) to a Logarithm of the Minimum Angle of Resolution (LogMAR) ≤ 0.5 in the affected eye. The study is expected to run from September 2022 to September 2027, with participants involved for a maximum of 90 days.

Participants will be randomly assigned to receive either the active treatment, Metalyse 5,000 units (25 mg) powder for solution for injection, or a placebo. The administration route is intravenous. The trial includes several key visits: an initial screening visit to confirm eligibility, followed by treatment administration. Follow-up visits are scheduled at 18-72 hours (Visit 2), 30 ± 5 days (Visit 3), and 90 ± 10 days (Visit 4) post-treatment. The primary endpoint is assessed at Visit 3, with secondary endpoints evaluated at Visits 2, 3, and 4.

Inclusion criteria require participants to be 18 years or older, with a confirmed diagnosis of acute non-arteritic CRAO within 12 hours of symptom onset. Exclusion criteria are not specified in the provided data. Participants may be withdrawn from the study if they experience adverse events or if they do not adhere to the study protocol. The trial's primary efficacy endpoint is the functional recovery of BCVA to LogMAR ≤ 0.5 at Visit 3, analyzed using an intention-to-treat approach. Secondary endpoints include visual outcome shifts, central retinal artery recanalization, and retinal arterial perfusion assessments.

The clinical trial involves the administration of **Metalyse**, a pharmaceutical product containing the active substance **tenecteplase**. Metalyse is provided as a **powder for solution for injection** and is intended for intravenous administration. The dosage is set at 25 mg, with a maximum daily and total dose of 25 mg, administered over a single treatment period. The active substance, tenecteplase, is a protein of non-human origin, classified under the ATC code B01AD11. The product is manufactured by Boehringer Ingelheim International GmbH and is authorized for use in the European Union. The administration of Metalyse is monitored to ensure compliance with the dosing schedule and to assess the therapeutic outcomes in participants.

In addition to the experimental treatment, a **placebo** is utilized in this double-blind, randomized, placebo-controlled phase III trial. The placebo is referred to as **Tenecteplase Placebo** and is used to maintain the study's blinding and control conditions. The placebo does not contain any active substance and is administered in a manner consistent with the experimental treatment to ensure the integrity of the trial's design. The use of a placebo allows for the comparison of the effects of the active treatment against a non-active control, providing a robust framework for evaluating the efficacy of tenecteplase in the recovery of vision in patients with acute central retinal artery occlusion.

Efficacy in the clinical trial titled "Early Reperfusion Therapy with Intravenous Thrombolysis for Recovery of VISION in Acute Central Retinal Artery Occlusion (REVISION)" will be assessed using several parameters. The primary efficacy endpoint is the functional recovery to best corrected visual acuity (BCVA) of Logarithm of the Minimum Angle of Resolution (LogMAR) ≤ 0.5, indicating normal to mild vision impairment according to WHO ICD-11, in the affected eye at Visit 3 (30 ± 5 days). This will be evaluated through an intention-to-treat (ITT) analysis.

Secondary endpoints include functional recovery to LogMAR ≤ 0.5 at various timepoints: Visit 2 (18 – 72 hours), Visit 3, and Visit 4 (90 ± 10 days), assessed in both dichotomized and per protocol populations. Additional assessments involve shifts in visual outcome categories, kinetic visual field using III4e mark, central retinal artery recanalization using OCTA, retinal arterial perfusion via fluorescein angiography, and patient-reported outcomes using the NEI-VFQ-25. Other measures include NIHSS at Visit 2, mRS at Visits 3 and 4, and the fraction of patients with acute ischemic lesions on follow-up diffusion-weighted MRI at Visit 2. Any bleeding events until Visit 2 will be classified according to CTCAE v5.0.