YM-101 Eye Drops in the Treatment of Dry Eye Syndrome

This study is a single-center, randomized, double-blind, placebo-controlled clinical trial designed to evaluate the effectiveness and safety of YM-101 eye drops for the treatment of dry eye syndrome, using a placebo as a control. The treatment period lasts for 84 days. Participants are randomly assigned to in randomized sequence.

There are three sequence, including sequence 1 (YM-101 high dose in period 1 switch to placebo in period 2), sequence 2 (YM-101 low dose in period 1 swich to YM-101 high dose in period 2), and sequence 3 (placebo in period 1 switch to YM-101 high dose in period 2). Period 1 starts from 0W to 4W, then washout period lasts from 4W to 8W, and period 2 starts from 8W to 12W. Participant will need to visit the clinic at 2W, 4W 8W, 10W, 12W after enrollment for checkups and tests.

Inclusion criteria

Patients must meet all the following inclusion criteria to be enrolled in this study:

• Age ≥ 18 years, regardless of gender;
• Clearly understand and voluntarily participate in the study, with the ability and willingness to sign a written informed consent form (ICF) and comply with all study assessments and visits as instructed;
• Male and female participants of childbearing potential must agree to use medically acceptable contraception during the study and for 3 months (90 days) after the study ends. Women who are not postmenopausal or have not been menopausal for less than two years (from the last menstrual period to the signing of the ICF) must have a negative pregnancy test at Visits 0 and 1.
• A history of bilateral dry eye disease prior to the screening visit (i.e., at least one of the following subjective symptoms: ocular dryness, foreign body sensation, burning sensation, fatigue, discomfort, redness, or fluctuating vision);
• Recent use (within 30 days prior to Visit 0) of artificial tears to relieve dry eye symptoms, with discontinuation of artificial tears at least 72 hours before Visit 0;
• Ocular Surface Disease Index (OSDI) total score ≥ 13 at Visit 0;
• Best corrected visual acuity ≥ 4.3 (5-point recording method on the international standard logarithmic visual acuity chart at 5 meters) in both eyes at Visit 0;
• At least one eye must have a positive corneal fluorescein staining score (CFS) at Visits 0 and 1;
• Non-anesthetic tear secretion test (SIT) ≤ 10 mm/5 min at Visits 0 and 1;
• Tear film break-up time (BUT) ≤ 10 seconds at Visits 0 and 1.

Exclusion criteria

• **Medical History**

• History of malignant tumors in or around the eyes;
• Dry eye formed due to scarring (e.g., radiation, alkali burns, Stevens-Johnson syndrome, scarring pemphigoid) or destruction of conjunctival goblet cells (e.g., vitamin A deficiency);
• Active ocular allergy or a history of possible ocular allergy during the study period;
• Presence of ocular or systemic infection (bacterial, viral, or fungal) at Visits 0 and 1, including fever and herpetic keratitis, or currently receiving antibiotic treatment;
• History of glaucoma diagnosis;
• History of any immunodeficiency, HIV infection, hepatitis B or C, acute active hepatitis (anti-HAV IgM positive), organ or bone marrow transplantation;
• Presence of any significant chronic diseases that the investigator considers may interfere with study parameters, including but not limited to: severe pulmonary diseases, poorly controlled hypertension, and/or poorly controlled diabetes;
• Blood donation or significant blood loss (more than 400 ml) within 56 days before Visit 0;

**Physical or Laboratory Examination Abnormalities**

• Presence of active rosacea-related ocular lesions, periorbital acne, or pterygium in the eyes or eyelids;
• Anatomical abnormalities of the eyelids (e.g., eyelid laxity, entropion, or ectropion) or abnormal blinking patterns;
• Abnormal findings during slit-lamp and/or fundus examination during the screening period, which the investigator deems clinically significant (including but not limited to conjunctivitis, trichiasis, conjunctival laxity, glaucoma, uveitis), requiring pharmacological treatment and believed by the investigator to potentially interfere with trial results;

**Previous Medications and Treatments**

• Intraocular surgery or ocular laser surgery, YAG laser capsulotomy, or any surgery affecting the meibomian glands within the 180 days prior to Visit 0, or plans to undergo such surgery or treatment during the study;
• Punctal occlusion or surgical removal of plugs (resorbable plugs within 180 days) within 60 days before Visit 0, or plans to undergo punctal occlusion or surgical removal of plugs during the study;
• Use of systemic immunomodulators, oral doxycycline or tetracycline within 90 days before Visit 0, or plans to use these medications irregularly during the study;
• Local use of immunomodulators (e.g., cyclosporine A eye drops, tacrolimus eye drops) within 30 days before Visit 0;
• Use of any medications known to cause dryness of the eyes (e.g., diuretics, antidepressants, decongestants, antispasmodics, antihistamines, anesthetics, etc.) within 30 days before Visit 0, or plans to use these medications irregularly during the study;
• Active blepharitis or meibomian gland dysfunction and treatment for the eyes (e.g., eyelid scrubs, meibomian gland massage, wet compresses, hot compresses, systemic antibiotics, and other oral medications for ocular disease) within 30 days before Visit 0, or plans to treat irregularly during the study;
• Use of corticosteroids or mast cell stabilizers (including ocular) within 30 days before Visit 0;
• Use of contact lenses within 14 days before Visit 0, or plans to continue using them during the study;
• Known allergies to test drugs or their excipients, fluorescein, or other substances involved in examination;

**Other**

• Pregnant, nursing, or planning to become pregnant;
• A family member residing in the same household has already been enrolled in this study or is a direct relative of staff directly involved in the management or support of this study;
• Undergoing a drug or device trial within 30 days or 5 half-lives (whichever is longer) prior to screening, judged by the investigator to potentially affect trial results, or during the study may necessitate participation in other drug or device trials;
• Situations that the investigator/sponsor believes may expose participants to significant risk, potentially confound trial results, seriously interfere with a participant's ability to participate in the study (e.g., language barriers, illiteracy), or not be in the best interest of the participant.