A Study of CA201A Eye Drops to Prevent Corneal Endothelial Cell Loss in Patients Undergoing Cataract Surgery

This is a multicenter, randomized, double-masked, vehicle-controlled, parallel-arm, Phase 2 study designed to evaluate the safety and efficacy of CA201A, a 5% ascorbic acid ophthalmic solution, for the prevention of corneal endothelial cell loss in subjects undergoing cataract surgery.

The study consists of three periods:

• Screening Period: Up to 23 days before the Baseline & treatment visit (Day -7)
• Treatment Period: Subjects will self-administer the study intervention (CA201A or vehicle) topically to the study eye, one drop four times daily (QID), beginning on Day -7 and continuing through Day 28 post-surgery. On the day of surgery (Day 0), dosing should be administered prior to surgery according to the scheduled regimen. Postoperative dosing on Day 0 may be delayed or omitted if the operated eye is padded or covered immediately following surgery, in accordance with standard surgical practice. Study intervention should be resumed as soon as clinically appropriate.
• Follow-up Period: Participants will be followed through Week 12 (day 84 ± 5 days) post-surgery for assessment of safety and efficacy endpoints.

Eligible participants planning to undergo cataract extraction by phacoemulsification will be randomized in a 1:1 ratio to one of two treatment arms. Study treatment will begin 7 days prior to cataract surgery, continue on the day of surgery, and be maintained for 4 weeks postoperatively. All participants will undergo standard-of-care phacoemulsification cataract surgery. The study intervention is administered in addition to usual perioperative management.

Surgical procedures will reflect routine clinical care, with protocol-specified documentation of key intra-operative parameters (e.g., cumulative dissipated energy, ultrasound time, irrigation volume, and intra-operative complications) to support interpretability of endothelial cell outcomes. The expected duration of participation for each participant is approximately 12 weeks post-surgery (up to approximately 16 weeks including screening).

Inclusion criteria

• The subject must voluntarily sign and date a Human Research Ethics Committee (HREC) approved informed consent form (ICF) prior to the initiation of any screening or study-specific procedures.
• In the Investigator's opinion, the subject is willing and able to comply with study instructions and complete all scheduled study visits.
• Male or female aged ≥18 and ≤85 years.
• Scheduled to undergo cataract extraction by phacoemulsification with implantation of a posterior chamber intraocular lens.
• Has the potential to improve best-corrected visual acuity (BCVA) in the study eye following surgery, as judged by the Investigator.
• Has a nuclear cataract exhibiting a nuclear opalescence of Grade 3, 4, or 5 in the study eye according to the Lens Opacities Classification System III (LOCS III) classification. This includes pure nuclear cataracts as well as mixed-type cataracts (ie, nuclear opalescence grade 3 to 5 with or without co-existing cortical and/or posterior subcapsular opacities).
• Has corneal endothelium in the study eye that can be adequately assessed using specular microscopy, with sufficient image quality for endothelial cell density analysis.
• Has a central corneal ECD ≥1000 cells/mm² in the study eye at the Screening visit, as measured by specular microscopy.
• Has a pinhole visual acuity of ≥35 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (approximately equivalent to 6/60 Snellen) in the study eye at the Screening visit, measured using an ETDRS chart at 4 meters. The fellow eye must have visual acuity sufficient, in the opinion of the Investigator, to allow safe postoperative function.
• Female subjects must be of nonchildbearing potential or have a negative pregnancy test at Screening and agree to use appropriate contraception throughout the study.
• Male subjects with female partners of childbearing potential must agree to use appropriate contraception and refrain from sperm donation during the study.

Exclusion criteria

• Ocular Exclusions (Study Eye):
• Active immunosuppressive or autoimmune disease that, in the opinion of the Investigator, could affect ocular surface integrity.
• Active or chronic/recurrent ocular or systemic disease that is uncontrolled and likely to impair wound healing.
• Intraocular pressure (IOP) ≤6 mmHg in either eye at screening.
• Clinically significant Fuchs' endothelial corneal dystrophy (Grade 4 or higher on clinical examination).
• History of corneal transplantation or other corneal surgery.
• History of intraocular surgery in the study eye within 6 months of screening (except YAG laser capsulotomy >3 months prior to screening).
• Planned combined cataract surgery with other intraocular procedures (eg, glaucoma surgery, vitrectomy).
• Active ocular infection or inflammation in either eye.
• Uncontrolled glaucoma (intraocular pressure >25 mmHg on maximum tolerated medical therapy) in the study eye.
• Significant corneal opacity, scarring, or irregularity that would interfere with accurate specular microscopy assessment (including cases where image acquisition or analysis is not feasible).
• History of uveitis or other chronic inflammatory eye disease in the study eye.
• Proliferative diabetic retinopathy or active retinal disease in the study eye, that in the Investigator's opinion, may increase surgical risk or confound postoperative assessments.
• Any other ocular condition that, in the opinion of the Investigator, may interfere with study assessments or subject safety.
• History of corneal or retinal surgery (laser or incisional) in the study eye within 6 months, or planned ocular surgery during the study period.
• Presence of severe corneal guttae or other abnormalities in the study eye that, in the opinion of the Investigator, preclude reliable endothelial cell assessment by specular microscopy.
• Anticipated complex cataract surgery in the study eye that, in the opinion of the Investigator, is likely to substantially increase endothelial injury risk or require nonstandard surgical techniques (eg, brunescent or hypermature cataract, significant zonular instability requiring planned capsular support devices, or other features expected to materially prolong phacoemulsification).
• Specular microscopy images that are not gradable at Screening despite repeat acquisition attempts.
• Systemic Exclusions:
• Known hypersensitivity to ascorbic acid or any component of the study drug or vehicle.
• Current use of systemic ascorbic acid supplementation (oral or intravenous) >500 mg/day (Subjects taking ≤500 mg/day may continue their current regimen).
• History of calcium oxalate nephrolithiasis (kidney stones) within the past 5 years.
• Severe renal impairment (estimated glomerular filtration rate <30mL/min/1.73 m²).
• Known glucose-6-phosphate dehydrogenase (G6PD) deficiency associated with clinically significant hemolytic risk.
• Pregnant or breastfeeding women.
• Females of childbearing potential unwilling to use acceptable contraception.
• Participation in another interventional clinical study or use of an investigational product within 6 weeks or 5 half-lives (whichever is longer) prior to study treatment. Observational studies and the use of over-the-counter vitamins or supplements are not exclusionary.
• Medical or psychiatric conditions that, in the opinion of the Investigator, would make consistent follow-up unlikely or pose an unacceptable medical risk.
• Clinically significant abnormalities in screening laboratory assessments (hematology, serum chemistry, or urinalysis), that, in the opinion of the Investigator, render the subject unsuitable for participation.

In general, subjects will be excluded if any of the following are present at screening:

• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 × upper limit of normal (ULN)
• Total bilirubin >1.5 × ULN (unless consistent with Gilbert's syndrome)
• Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m² Laboratory abnormalities not meeting the above thresholds may still be considered exclusionary if deemed clinically significant by the Investigator.