This is a prospective, longitudinal, single-center study designed to evaluate the long-term changes in symptoms and tear production in subjects with dry eye disease. The study is randomized and investigator-masked, with subjects assigned to either the TRYPTYR (Acoltremon ophthalmic solution 0.003%) arm or the control arm (Refresh Classic Preservative-free). The study will be conducted at a single site, with subjects undergoing assessments at baseline and at months 1, 3, 6, 9, and 12.

Inclusion Criteria:

1. Male or female, 18 years of age or older at the Screening visit.

2. Have a previous history of DED, clinician diagnosed, or patient reported, within the previous 6 months prior to the Screening visit.

3. Have used, and/or desired to use artificial tears for DED symptoms within 2 months prior to the Screening visit.

4. Both of the following signs of DED in the same eye:

   1. Total corneal fluorescein staining score of >= 2 and <= 10 based on the NEI grading scheme, with no one region scoring > 3 in at least 1 eye.
   2. Unanesthetized Schirmer test score >= 2 and < 10 mm/5 min in at least 1 eye.
   3. If both eyes qualify, the eye with the lower baseline Schirmer score will be the study eye (If the Schirmer score is the same, the right eye will be the study eye).

5. Symptomatic defined as an ODS-VAS score of >=40.

6. Corrected visual acuity equal to or better than logMar +0.7 (Snellen equivalent equal to or better than 20/100), as assessed by Early Treatment of Diabetic Retinopathy Study (ETDRS) scale in both eyes.

7. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

8. Written informed consent from the subject has been obtained prior to any study related procedures.

9. Able, as assessed by the investigator, and willing to follow study instructions and likely to complete all required study visits.

Exclusion Criteria:

1. History or presence of any ocular disorder or condition (other than DED) in either eye that would, in the opinion of the investigator, interfere with the interpretation of the study results or subject safety.
2. Diagnosis of recurrent, ongoing, or active ocular infection.
3. History of ocular surgery within 1 year prior to the Screening visit.
4. Have had a corneal transplant in either or both eyes.
5. Use of contact lenses within 2 hours of any study visit.
6. Use of lid heating therapy or Meibomian gland probing/therapeutic expression within 1 year prior to the Screening visit.
7. Use of artificial tears within 24 hours of Screening visit.
8. Use of any topical ocular anti-inflammatory medication or dry eye pharmaceuticals within 30 days prior to the Screening visit.
9. Use of any topical ocular glaucoma medication within 30 days prior to the Screening visit.
10. Change in use of any other topical ocular medication within 14 days prior to the Screening visit.
11. Use of medications for the treatment of severe DED and/or Meibomian gland disease within 30 days prior to the Screening visit.
12. Initiation, discontinuation, or change in dose of a systemic medication known to cause ocular drying less than 14 days prior to the Screening visit.
13. Use of a systemic corticosteroid less than 30 days prior to the Screening visit.
14. Use of a systemic immunomodulator within 30 days prior to the Screening visit.
15. Use of an investigational product or device within 30 days prior to the Screening visit.
16. At the Screening visit, have uncontrolled or severe systemic allergy, rhinitis or sinusitis.
17. History or presence of significant systemic disease.
18. Known allergies or sensitivity to the study interventions or study diagnostic agents.
19. Women of childbearing potential who are not using a medically acceptable form of birth control.
20. The subject has a condition or is in a situation that, in the Investigator's opinion, may put the subject at significant risk.

Subjects aged 18 years or older with a history of dry eye disease (DED) will be randomized.