Phase 3 Evaluation of Ripasudil (K-321) Eye Drops on Visual Acuity Post-Descemetorhexis in Fuchs Endothelial Corneal Dystrophy Patients

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 descemetorhexis in subjects with **Fuchs Endothelial Corneal Dystrophy** (FECD). This is clinically relevant as it aims to assess the potential of K-321 to enhance visual acuity, which is a critical outcome for patients with FECD undergoing descemetorhexis.

The secondary objectives focus on both efficacy and safety aspects of K-321. Key secondary efficacy 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.
• The time to achieve a BCVA by ETDRS letter score of ≥70 letters during the first 12 weeks.
• Central corneal endothelial cell density (ECD) at Week 12.
• The time to achieve no corneal edema in both epithelial and stromal areas during the first 12 weeks and over a 52-week period.
• The time to return of central corneal thickness to baseline levels during the first 12 weeks and over a 52-week period.
• The time to therapy failure, defined as events such as rescue keratoplasty or other rescue treatments, study drug discontinuation due to lack of efficacy, and withdrawal from the study due to lack of efficacy, over a 52-week period.
• The time to undergo rescue therapy or treatment over a 52-week period.

The clinical trial investigating the effect of K-321 on **Fuchs Endothelial Corneal Dystrophy** involves a total of 14 participants. The study population includes both male and female subjects, aged 18 years and older, who are diagnosed with Fuchs Endothelial Corneal Dystrophy. Participants were selected based on specific criteria, including the presence of confluent central guttae in the study eye that can be removed by descemetorhexis. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The study includes a vulnerable population, indicating that additional ethical considerations are in place to protect the participants. The selection process ensures that all participants have provided informed consent and are willing to comply with the protocol requirements.

The clinical trial is designed to evaluate the **safety** and **efficacy** of Ripasudil (K-321) eye drops in subjects with **Fuchs Endothelial Corneal Dystrophy** following descemetorhexis. This is a double-masked, randomized, placebo-controlled, parallel-group study. The trial consists of a 12-week administration phase with a two-week gradual dose taper, followed by a 38-week follow-up phase, making the overall trial duration approximately 52 weeks. Participants will be randomly assigned to receive either the active treatment or a placebo ophthalmic solution, which is formulated with the same excipients as the active product.

The study involves several key visits. The inclusion visit, or screening visit (Visit 1), is where eligibility is assessed based on criteria such as age, diagnosis of Fuchs Endothelial Corneal Dystrophy, and visual acuity. Following the screening, participants will undergo descemetorhexis (Visit 2), where the excision of a central area with confluent guttae is confirmed. Subsequent follow-up visits will monitor the primary endpoint, which is the time to improvement in best corrected visual acuity (BCVA) by 40 ETDRS letters within the first 12 weeks post-descemetorhexis. Secondary endpoints include time to 20 ETDRS letter improvement, achievement of 70 ETDRS letters, changes in central corneal endothelial cell density, and resolution of corneal edema.

Participants are expected to be involved in the study for the entire duration of the trial, approximately one year. However, early termination from the study may occur if participants do not comply with protocol requirements, experience adverse events that necessitate withdrawal, or if the study is discontinued for any reason. The trial aims to provide comprehensive data on the therapeutic potential of Ripasudil in improving visual outcomes for patients with Fuchs Endothelial Corneal Dystrophy.

The clinical trial involves the administration of **Ripasudil**, an investigational medication formulated as eye drops. Ripasudil is chemically derived and is provided by Kowa Research Institute Inc. The pharmaceutical form of Ripasudil is specifically designed for **ocular use**. The dosage of Ripasudil is set at a maximum daily dose of 1.6% percent, with the same concentration being the maximum total dose amount. The treatment period for Ripasudil is limited to a maximum of 14 days. The administration schedule and participant compliance are closely monitored to ensure adherence to the dosing regimen.

In addition to the experimental treatment, a **placebo** is utilized in this study. The placebo is a matching sterile ophthalmic solution, formulated with the same excipients as the active K-321 product, ensuring that it is indistinguishable from the investigational medication in appearance and administration. The placebo is also administered via ocular use, following the same dosing schedule as Ripasudil. This placebo-controlled design is integral to maintaining the study's double-masked methodology, ensuring unbiased assessment of the investigational product's efficacy and safety.

The efficacy of Ripasudil (K-321) Eye Drops in the treatment of **Fuchs Endothelial Corneal Dystrophy** will be assessed through a series of primary and secondary endpoints. The primary endpoint is 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 descemetorhexis. This will be measured using the ETDRS letter score, a validated scale for assessing visual acuity.

Secondary endpoints include the time to a ≥20 ETDRS letter improvement, the time to achieve ≥70 ETDRS letters, changes in central corneal endothelial cell density (ECD) from baseline at Week 12, the time to achieve no corneal edema in both epithelial and stromal areas, and the time to exceed the pre-descemetorhexis ETDRS letter score in BCVA. These parameters will be evaluated during the first 12 weeks post-descemetorhexis.

The study is designed as a double-masked, randomized, placebo-controlled, parallel-group trial with a 12-week administration phase, followed by a two-week gradual dose taper phase and a 38-week follow-up phase. Efficacy assessments will be conducted at specified intervals throughout the study to ensure comprehensive data collection and analysis.