A Double-Masked, Randomized, Placebo-Controlled, Parallel-Group, 12 Week Administration With Two-Week Gradual Dose Taper Phase and 38-Week Follow-Up Phase, Phase 3 Study to Investigate the Safety and Efficacy of Ripasudil (K-321) Eye Drops After Simultaneous Cataract Surgery and Descemetorhexis in Subjects with Fuchs Endothelial Corneal Dystrophy

The primary objective of this study is to evaluate the effect of **Ripasudil** (K-321) on the time to improvement in Best Corrected Visual Acuity (BCVA) by an Early Treatment Diabetic Retinopathy Study (ETDRS) letter score of ≥40 letters during the first 12 weeks following simultaneous cataract surgery and descemetorhexis in subjects with **Fuchs Endothelial Corneal Dystrophy** (FECD). This is clinically relevant as it aims to assess the potential of Ripasudil in enhancing visual recovery in patients undergoing these procedures, which could significantly impact their quality of life and visual function.

Secondary objectives include:

• Investigating the effect of K-321 on the time to improvement in BCVA by ETDRS letter score of ≥20 letters during the first 12 weeks post-surgery.
• Assessing the effect of K-321 on the time to achievement of BCVA by ETDRS letter score of ≥70 letters within the same period.
• Evaluating the impact of K-321 on central corneal endothelial cell density (ECD) at Week 12 after the surgical procedures.

The clinical trial involves a total of **64 participants** diagnosed with **Fuchs Endothelial Corneal Dystrophy** (FECD). The study population includes both male and female subjects, aged 18 years and older, who are considered part of a vulnerable population. Participants were selected based on specific criteria, including the presence of visually significant cataracts and a diagnosis of FECD with confluent central guttae in the study eye. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The selection process ensured that participants could understand and provide informed consent, and were willing to comply with the protocol requirements. The study focuses on the effect of K-321 on visual acuity improvement following simultaneous cataract surgery and descemetorhexis.

The clinical trial is designed as a **randomized**, double-masked, placebo-controlled, parallel-group study to evaluate the safety and efficacy of **Ripasudil** eye drops in subjects with **Fuchs Endothelial Corneal Dystrophy**. The trial will span a total duration of 12 weeks, followed by a two-week gradual dose taper phase and a 38-week follow-up phase. Participants will be randomly assigned to receive either the active treatment or a placebo, which is presented as sterile, non-preserved unit dose eye drops without **Ripasudil hydrochloride dihydrate**. The primary objective is to assess the time to improvement in Best Corrected Visual Acuity (BCVA) by ETDRS letter score of ≥40 letters during the first 12 weeks post-surgery.

The study will commence with an inclusion (screening) visit, where participants must meet specific criteria, including being at least 18 years old, having a diagnosis of **Fuchs Endothelial Corneal Dystrophy**, and possessing a visually significant cataract in the study eye. The study eye must have a BCVA of 75 letters or fewer by ETDRS testing. Following the screening, participants will undergo simultaneous cataract surgery and descemetorhexis, with the study eye confirmed to have excised a central area with confluent guttae and a diameter of 4.5 to 5.5 mm.

Subsequent follow-up visits will be scheduled to monitor the participants' progress and assess the primary and secondary endpoints, which include the time to ≥20 ETDRS letter improvement and central corneal endothelial cell density change from baseline at Week 12. The end-of-study visit will conclude the trial, evaluating the long-term effects of the treatment. Participant involvement is expected to last approximately 52 weeks, with conditions for early termination including non-compliance with protocol requirements or adverse events that compromise participant safety.

The clinical trial involves the administration of **Ripasudil**, an experimental medication formulated as eye drops. The active substance, **Ripasudil**, is of chemical origin and is provided by Kowa Research Institute Inc. The pharmaceutical form of the medication is eye drops, and it is administered via the eye/ear/nose drops route. The dosage is set at a maximum daily dose of 1.6% percent, with the same concentration as the total maximum dose. The treatment period is limited to a maximum of 14 days. The eye drops are not a pediatric formulation and are identified by the sponsor product code K-321. The administration schedule and participant compliance are monitored throughout the trial to ensure adherence to the dosing regimen.

The study also includes a placebo control, which is presented as sterile, non-preserved unit dose eye drops. These placebo eye drops do not contain **Ripasudil hydrochloride dihydrate** and are packaged in 0.3 ml quantities within clear, additive-free polyethylene blow-fill-seal ampoules. The placebo serves as a comparator treatment to evaluate the efficacy and safety of the experimental medication. The placebo is administered in a manner consistent with the experimental treatment to maintain the double-masked nature of the trial. Compliance with the placebo administration is similarly monitored to ensure the integrity of the study results.

The efficacy of Ripasudil (K-321) eye drops in the treatment of **Fuchs Endothelial Corneal Dystrophy (FECD)** will be assessed in a Phase 3 clinical trial. The primary endpoint for evaluating efficacy is the time to achieve an improvement of ≥40 ETDRS letters in Best Corrected Visual Acuity (BCVA) during the first 12 weeks following simultaneous cataract surgery and descemetorhexis. Secondary endpoints include the time to achieve an improvement of ≥20 ETDRS letters, the time to achieve ≥70 ETDRS letters, and the change in central corneal endothelial cell density (ECD) from baseline at Week 12.

Measurements of BCVA will be conducted using the ETDRS letter score, a validated scale for visual acuity assessment. The central corneal ECD will be measured to assess corneal health and recovery. These assessments will be performed at specified timepoints, including baseline, Week 12, and other intervals as necessary to capture the time to improvement. Data collection will be conducted in a double-masked, randomized, placebo-controlled, parallel-group design to ensure the reliability and validity of the results. The trial will include a 12-week administration phase with a two-week gradual dose taper phase, followed by a 38-week follow-up phase to monitor long-term outcomes.