A Long-Term Safety Study Evaluating the Safety and Systemic Exposure of AR-15512

Primary outcomes

1. Ocular Treatment-Emergent Adverse Events by Preferred Term With Incidence Greater Than 2 Percent

   Time frame: Day 1 post-treatment, up to Day 365

   A treatment-emergent adverse event was defined as any event that occurred or worsened on or after the day randomized study intervention was initiated. At each study visit, subjects were verbally asked by clinic staff to report any changes to any aspect of their ocular health. Ocular treatment-emergent adverse events reported by the subject or observed by the investigator were summarized by preferred term for overall incidence calculation. This was a subject-based assessment.

2. Mean Change From Baseline in Heart Rate at Each Study Visit

   Time frame: Baseline (Day 1 pretreatment), Day 14, Day 90, Day 180, Day 270, Day 365

   Heart rate was measured using manual or automated methods and recorded in beats per minute (bpm). Minimal change from the start of the study indicates a better outcome.

3. Mean Change From Baseline in Systolic Blood Pressure at Each Study Visit

   Time frame: Baseline (Day 1 pretreatment), Day 14, Day 90, Day 180, Day 270, Day 365

   Systolic blood pressure was measured using an appropriate sphygmomanometer and recorded in millimeters mercury (mmHg). Minimal change from the start of the study indicates a better outcome.

4. Mean Change From Baseline in Diastolic Blood Pressure at Each Study Visit

   Time frame: Baseline (Day 1 pretreatment), Day 14, Day 90, Day 180, Day 270, Day 365

   Diastolic blood pressure was measured using an appropriate sphygmomanometer and recorded in millimeters mercury (mmHg). Minimal change from the start of the study indicates a better outcome.

5. Mean Change From Baseline in Overall Average Endothelial Cell Density at Day 365

   Time frame: Baseline (Day 1 pretreatment), Day 365

   Cell density in the central corneal endothelium was assessed using specular microscopy imaging. Overall average cell density was calculated as the average of the average cell densities of three images and was measured in cells per millimeter squared (cells/mm^2). A negative change from baseline represents a less desirable outcome.

6. Percentage of Subjects With 10 Percent or More Decrease From Baseline in Overall Average Endothelial Cell Density at Study Exit

   Time frame: Baseline (Day 1 pretreatment), Study Exit (Day 365, early termination visit, or unscheduled visit)

   Cell density in the central corneal endothelium was assessed using specular microscopy imaging. Overall average cell density was calculated as the average of the average cell densities of three images and was measured in cells per millimeter squared (cells/mm^2). A decrease from baseline represents a less desirable outcome.

7. Mean Change From Baseline in Hematology by Visit - Basophil Level

   Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

   A small volume of blood was collected and sent to a laboratory for analysis. Basophil level was measured. Minimal change from the start of the study indicates a better outcome.

8. Mean Change From Baseline in Hematology by Visit - Basophils to Leukocytes Ratio Reported in Percentage of Cells

   Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

   A small volume of blood was collected and sent to a laboratory for analysis. The basophils to leukocytes ratio was reported as the absolute number of basophils divided by the absolute number of leukocytes multiplied by 100. Minimal change from the start of the study indicates a better outcome.

9. Mean Change From Baseline in Hematology by Visit - Eosinophil Level

   Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

   A small volume of blood was collected and sent to a laboratory for analysis. Eosinophil level was measured. Minimal change from the start of the study indicates a better outcome.

10. Mean Change From Baseline in Hematology by Visit - Eosinophils to Leukocytes Ratio Reported in Percentage of Cells

    Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

    A small volume of blood was collected and sent to a laboratory for analysis. The eosinophils to leukocytes ratio was reported as the absolute number of eosinophils divided by the absolute number of leukocytes multiplied by 100. Minimal change from the start of the study indicates a better outcome.

11. Mean Change From Baseline in Hematology by Visit - Erythrocyte Mean Corpuscular Hemoglobin Concentration Level

    Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

    A small volume of blood was collected and sent to a laboratory for analysis. Erythrocyte mean corpuscular hemoglobin concentration level was measured. Minimal change from the start of the study indicates a better outcome.

12. Mean Change From Baseline in Hematology by Visit - Erythrocyte Mean Corpuscular Hemoglobin Level

    Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

    A small volume of blood was collected and sent to a laboratory for analysis. Erythrocyte mean corpuscular hemoglobin level was measured. Minimal change from the start of the study indicates a better outcome.

13. Mean Change From Baseline in Hematology by Visit - Erythrocyte Mean Corpuscular Volume

    Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

    A small volume of blood was collected and sent to a laboratory for analysis. Erythrocyte mean corpuscular volume was measured. Minimal change from the start of the study indicates a better outcome.

14. Mean Change From Baseline in Hematology by Visit - Erythrocyte Level

    Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

    A small volume of blood was collected and sent to a laboratory for analysis. Erythrocyte level was measured. Minimal change from the start of the study indicates a better outcome.

15. Mean Change From Baseline in Hematology by Visit - Erythrocyte Distribution Width Reported as Percentage of Variation of Cells

    Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

    A small volume of blood was collected and sent to a laboratory for analysis. Erythrocyte distribution width was measured. Minimal change from the start of the study indicates a better outcome.

16. Mean Change From Baseline in Hematology by Visit - Hematocrit Level

    Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

    A small volume of blood was collected and sent to a laboratory for analysis. Hematocrit level was reported as the volume of red blood cells in liters (L) divided by the volume of blood in L. Minimal change from the start of the study indicates a better outcome.

17. Mean Change From Baseline in Hematology by Visit - Hemoglobin Level

    Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

    A small volume of blood was collected and sent to a laboratory for analysis. Hemoglobin level was measured. Minimal change from the start of the study indicates a better outcome.

18. Mean Change From Baseline in Hematology by Visit - Leukocyte Level

    Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

    A small volume of blood was collected and sent to a laboratory for analysis. Leukocyte level was measured. Minimal change from the start of the study indicates a better outcome.

19. Mean Change From Baseline in Hematology by Visit - Lymphocyte Level

    Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

    A small volume of blood was collected and sent to a laboratory for analysis. Lymphocyte level was measured. Minimal change from the start of the study indicates a better outcome.

20. Mean Change From Baseline in Hematology by Visit - Lymphocytes to Leukocytes Ratio Reported in Percentage of Cells

    Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

    A small volume of blood was collected and sent to a laboratory for analysis. The lymphocytes to leukocytes ratio was reported as the absolute number of lymphocytes divided by the absolute number of leukocytes multiplied by 100. Minimal change from the start of the study indicates a better outcome.

21. Mean Change From Baseline in Hematology by Visit - Monocyte Level

    Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

    A small volume of blood was collected and sent to a laboratory for analysis. Monocyte level was measured. Minimal change from the start of the study indicates a better outcome.

22. Mean Change From Baseline in Hematology by Visit - Monocytes to Leukocytes Ratio Reported in Percentage of Cells

    Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

    A small volume of blood was collected and sent to a laboratory for analysis. The monocytes to leukocytes ratio was reported as the absolute number of monocytes divided by the absolute number of leukocytes multiplied by 100. Minimal change from the start of the study indicates a better outcome.

23. Mean Change From Baseline in Hematology by Visit - Neutrophil Level

    Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

    A small volume of blood was collected and sent to a laboratory for analysis. Neutrophil level was measured. Minimal change from the start of the study indicates a better outcome.

24. Mean Change From Baseline in Hematology by Visit - Neutrophils to Leukocytes Ratio Reported in Percentage of Cells

    Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

    A small volume of blood was collected and sent to a laboratory for analysis. The neutrophils to leukocytes ratio was reported as the absolute number of neutrophils divided by the absolute number of leukocytes multiplied by 100. Minimal change from the start of the study indicates a better outcome.

25. Mean Change From Baseline in Hematology by Visit - Platelet Level

    Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

    A small volume of blood was collected and sent to a laboratory for analysis. Platelet level was measured. Minimal change from the start of the study indicates a better outcome.

26. Mean Change From Baseline in Hematology by Visit - Mean Platelet Volume

    Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

    A small volume of blood was collected and sent to a laboratory for analysis. Platelet volume was measured. Minimal change from the start of the study indicates a better outcome.

27. Mean Change From Baseline in Chemistry by Visit - Alanine Aminotransferase Level

    Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

    A small volume of blood was collected and sent to a laboratory for analysis. Alanine aminotransferase level was measured. Minimal change from the start of the study indicates a better outcome.

28. Mean Change From Baseline in Chemistry by Visit - Albumin Level

    Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

    A small volume of blood was collected and sent to a laboratory for analysis. Albumin level was measured. Minimal change from the start of the study indicates a better outcome.

29. Mean Change From Baseline in Chemistry by Visit - Alkaline Phosphatase Level

    Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

    A small volume of blood was collected and sent to a laboratory for analysis. Alkaline phosphatase level was measured. Minimal change from the start of the study indicates a better outcome.

30. Mean Change From Baseline in Chemistry by Visit - Aspartate Aminotransferase Level

    Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

    A small volume of blood was collected and sent to a laboratory for analysis. Aspartate aminotransferase level was measured. Minimal change from the start of the study indicates a better outcome.

31. Mean Change From Baseline in Chemistry by Visit - Calcium Level

    Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

    A small volume of blood was collected and sent to a laboratory for analysis. Calcium level was measured. Minimal change from the start of the study indicates a better outcome.

32. Mean Change From Baseline in Chemistry by Visit - Creatinine Level

    Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

    A small volume of blood was collected and sent to a laboratory for analysis. Creatinine level was measured. Minimal change from the start of the study indicates a better outcome.

33. Mean Change From Baseline in Chemistry by Visit - Globulin Level

    Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

    A small volume of blood was collected and sent to a laboratory for analysis. Globulin level was measured. Minimal change from the start of the study indicates a better outcome.

34. Mean Change From Baseline in Chemistry by Visit - Potassium Level

    Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

    A small volume of blood was collected and sent to a laboratory for analysis. Potassium level was measured. Minimal change from the start of the study indicates a better outcome.

35. Mean Change From Baseline in Chemistry by Visit - Protein Level

    Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

    A small volume of blood was collected and sent to a laboratory for analysis. Protein level was measured. Minimal change from the start of the study indicates a better outcome.

36. Mean Change From Baseline in Chemistry by Visit - Sodium Level

    Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

    A small volume of blood was collected and sent to a laboratory for analysis. Sodium level was measured. Minimal change from the start of the study indicates a better outcome.

37. Mean Change From Baseline in Chemistry by Visit - Triglyceride Level

    Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

    A small volume of blood was collected and sent to a laboratory for analysis. Triglyceride level was measured. Minimal change from the start of the study indicates a better outcome.

38. Mean Change From Baseline in Chemistry by Visit - Urea Nitrogen Level

    Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

    A small volume of blood was collected and sent to a laboratory for analysis. Urea nitrogen level was measured. Minimal change from the start of the study indicates a better outcome.

39. Mean Change From Baseline in Urinalysis by Visit - Specific Gravity Level

    Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

    A small volume of blood was collected and sent to a laboratory for analysis. Specific gravity level was calculated by dividing the sample's density by the density of water. Minimal change from the start of the study indicates a better outcome.

40. Mean Change From Baseline in Urinalysis by Visit - pH Level

    Time frame: Baseline (Day 1 pretreatment), Day 180, Day 365

    A small volume of urine was collected and sent to a laboratory for analysis. The pH scale ranges from 0 (most acidic) to 14 (most alkaline), with 7 as neutral. Minimal change from the start of the study indicates a better outcome.

41. Mean Best Corrected Visual Acuity (BCVA) Letter Score by Visit

    Time frame: Baseline (Day 1 pretreatment), Day 365

    Visual acuity with correction in place (spectacles or a trial frame with lenses) was measured using Early Treatment Diabetic Retinopathy Study (ETDRS) letter charts (original or modified) at a distance of 10 feet. Each line on the ETDRS chart typically has five letters, and each letter correctly identified adds to the overall score. ETDRS letter scores range from 0 to 100, with each letter correctly identified representing a score of 1. A perfect score of 100 is achieved when all 70 letters on the chart are correctly identified. 85 letters correctly identified corresponds to normal distance eyesight.

42. Mean Corrected Visual Acuity in LogMar by Visit

    Time frame: Baseline (Day 1 pretreatment), Day 14, Day 90, Day 180, Day 270, Day 365

    Visual acuity with correction in place (spectacles or a trial frame with lenses) was measured using Early Treatment Diabetic Retinopathy Study (ETDRS) letter charts (original or modified) at a distance of 10 feet. Each line on the ETDRS chart typically has five letters, and each letter correctly identified adds to the overall score. The overall letter score was converted to Logarithmic minimum angle of resolution (LogMAR). LogMAR scores typically range from -0.3 to 1.0, where zero represents normal vision, negative values indicate better than normal vision, and positive values indicate poorer than normal vision.

43. Number of Subjects With Clinically Significant Biomicroscopy Findings as Determined by the Investigator at Each Study Visit - Lid Erythema

    Time frame: Baseline (Day 1 pretreatment), Day 14, Day 90, Day 180, Day 270, Day 365

    An eye exam (slit lamp biomicroscopy) was performed by the investigator at each study visit. Findings related to lid erythema (redness of the eyelid) were graded as Normal or Abnormal. Abnormal findings were categorized as clinically significant (CS) or not clinically significant (NCS). CS findings were defined at those that may interfere with study parameters or otherwise confound the data as determined by the investigator.

44. Number of Subjects With Clinically Significant Biomicroscopy Findings as Determined by the Investigator at Each Study Visit - Lid Edema

    Time frame: Baseline (Day 1 pretreatment), Day 14, Day 90, Day 180, Day 270, Day 365

    An eye exam (slit lamp biomicroscopy) was performed by the investigator at each study visit. Findings related to lid edema (swelling of the eyelid) were graded as Normal or Abnormal. Abnormal findings were categorized as clinically significant (CS) or not clinically significant (NCS). CS findings were defined at those that may interfere with study parameters or otherwise confound the data as determined by the investigator.

45. Number of Subjects With Clinically Significant Biomicroscopy Findings as Determined by the Investigator at Each Study Visit - Conjunctiva Hyperemia

    Time frame: Baseline (Day 1 pretreatment), Day 14, Day 90, Day 180, Day 270, Day 365

    An eye exam (slit lamp biomicroscopy) was performed by the investigator at each study visit. Findings related to conjunctiva hyperemia (increased amount of blood in the conjunctiva) were graded as Normal or Abnormal. Abnormal findings were categorized as clinically significant (CS) or not clinically significant (NCS). CS findings were defined at those that may interfere with study parameters or otherwise confound the data as determined by the investigator.

46. Number of Subjects With Clinically Significant Biomicroscopy Findings as Determined by the Investigator at Each Study Visit - Conjunctiva Edema

    Time frame: Baseline (Day 1 pretreatment), Day 14, Day 90, Day 180, Day 270, Day 365

    An eye exam (slit lamp biomicroscopy) was performed by the investigator at each study visit. Findings related to conjunctiva edema (swelling of the conjunctiva) were graded as Normal or Abnormal. Abnormal findings were categorized as clinically significant (CS) or not clinically significant (NCS). CS findings were defined at those that may interfere with study parameters or otherwise confound the data as determined by the investigator.

47. Number of Subjects With Clinically Significant Biomicroscopy Findings as Determined by the Investigator at Each Study Visit - Cornea Staining/Erosion

    Time frame: Baseline (Day 1 pretreatment), Day 14, Day 90, Day 180, Day 270, Day 365

    An eye exam (slit lamp biomicroscopy) was performed by the investigator at each study visit. Findings related to cornea staining/erosion were graded as Normal or Abnormal. Abnormal findings were categorized as clinically significant (CS) or not clinically significant (NCS). CS findings were defined at those that may interfere with study parameters or otherwise confound the data as determined by the investigator.

48. Number of Subjects With Clinically Significant Biomicroscopy Findings as Determined by the Investigator at Each Study Visit - Cornea Edema

    Time frame: Baseline (Day 1 pretreatment), Day 14, Day 90, Day 180, Day 270, Day 365

    An eye exam (slit lamp biomicroscopy) was performed by the investigator at each study visit. Findings related to cornea edema (swelling of the cornea) were graded as Normal or Abnormal. Abnormal findings were categorized as clinically significant (CS) or not clinically significant (NCS). CS findings were defined at those that may interfere with study parameters or otherwise confound the data as determined by the investigator.

49. Number of Subjects With Clinically Significant Biomicroscopy Findings as Determined by the Investigator at Each Study Visit - Anterior Chamber Cells

    Time frame: Baseline (Day 1 pretreatment), Day 14, Day 90, Day 180, Day 270, Day 365

    An eye exam (slit lamp biomicroscopy) was performed by the investigator at each study visit. Findings related to cells in the anterior chamber (the fluid-filled space located in the front of the eye between the cornea and the iris) were graded as Normal or Abnormal. Abnormal findings were categorized as clinically significant (CS) or not clinically significant (NCS). CS findings were defined at those that may interfere with study parameters or otherwise confound the data as determined by the investigator.

50. Number of Subjects With Clinically Significant Biomicroscopy Findings as Determined by the Investigator at Each Study Visit - Anterior Chamber Flare

    Time frame: Baseline (Day 1 pretreatment), Day 14, Day 90, Day 180, Day 270, Day 365

    An eye exam (slit lamp biomicroscopy) was performed by the investigator at each study visit. Findings related to anterior chamber flare (a visible clouding of the the fluid-filled space located in the front of the eye between the cornea and the iris) were graded as Normal or Abnormal. Abnormal findings were categorized as clinically significant (CS) or not clinically significant (NCS). CS findings were defined at those that may interfere with study parameters or otherwise confound the data as determined by the investigator.

51. Number of Subjects With Clinically Significant Biomicroscopy Findings as Determined by the Investigator at Each Study Visit - Lens Opacity

    Time frame: Baseline (Day 1 pretreatment), Day 14, Day 90, Day 180, Day 270, Day 365

    An eye exam (slit lamp biomicroscopy) was performed by the investigator at each study visit. Findings related to lens opacity (a clouding of the eye's natural lens) were graded as Normal or Abnormal. Abnormal findings were categorized as clinically significant (CS) or not clinically significant (NCS). CS findings were defined at those that may interfere with study parameters or otherwise confound the data as determined by the investigator.

52. Mean Total Ocular Staining Score by Visit

    Time frame: Baseline (Day 1 pretreatment), Day 14, Day 90, Day 180, Day 270, Day 365

    Total corneal (fluorescein) staining score ranges between 0 and 5. Total conjunctival staining score is collected as the sum of lissamine green staining nasal and temporal scores and ranges between 0 and 10 per eye. Total ocular staining score is collected as the sum of total corneal and conjunctival scores (0 to 15) with a maximum possible score of 15 per eye. A higher total score indicates greater staining (or worse condition).

53. Mean Intraocular Pressure by Visit

    Time frame: Baseline (Day 1 pretreatment), Day 14, Day 90, Day 180, Day 270, Day 365

    Intraocular pressure was measured using Goldmann applanation tonometry and measured in millimeters mercury (mmHg). Values between 10mmHg and 20mmHg are considered normal eye pressure.

54. Number of Subjects With Clinically Significant Change From Baseline in Dilated Fundus Exam Results by Visit - Vitreous

    Time frame: Baseline (Day 1 pretreatment), Day 14, Day 90, Day 180, Day 270, Day 365

    An examination of the back of the eye (dilated fundus exam) was performed by the investigator. Findings related to the vitreous (the clear gel that fills the space between the lens and the retina of the eyeball) were graded as Normal or Abnormal. Abnormal findings were categorized as clinically significant (CS) or not clinically significant (NCS). CS findings were defined at those that may interfere with study parameters or otherwise confound the data as determined by the investigator.

55. Number of Subjects With Clinically Significant Change From Baseline in Dilated Fundus Exam Results by Visit - Retina

    Time frame: Baseline (Day 1 pretreatment), Day 14, Day 90, Day 180, Day 270, Day 365

    An examination of the back of the eye (dilated fundus exam) was performed by the investigator. Findings related to the retina (the light-sensitive tissue lining the back of the eye that converts light into electrical signals the brain then interprets as images) were graded as Normal or Abnormal. Abnormal findings were categorized as clinically significant (CS) or not clinically significant (NCS). CS findings were defined at those that may interfere with study parameters or otherwise confound the data as determined by the investigator.

56. Number of Subjects With Clinically Significant Change From Baseline in Dilated Fundus Exam Results by Visit - Macula

    Time frame: Baseline (Day 1 pretreatment), Day 14, Day 90, Day 180, Day 270, Day 365

    An examination of the back of the eye (dilated fundus exam) was performed by the investigator. Findings related to the macula (the round area at the center of the retina that provides central vision) were graded as Normal or Abnormal. Abnormal findings were categorized as clinically significant (CS) or not clinically significant (NCS). CS findings were defined at those that may interfere with study parameters or otherwise confound the data as determined by the investigator.

57. Number of Subjects With Clinically Significant Change From Baseline in Dilated Fundus Exam Results by Visit - Optic Nerve

    Time frame: Baseline (Day 1 pretreatment), Day 14, Day 90, Day 180, Day 270, Day 365

    An examination of the back of the eye (dilated fundus exam) was performed by the investigator. Findings related to the optic nerve (the nerve that transmits visual information from the retina to the brain) were graded as Normal or Abnormal. Abnormal findings were categorized as clinically significant (CS) or not clinically significant (NCS). CS findings were defined at those that may interfere with study parameters or otherwise confound the data as determined by the investigator.

58. Number of Subjects With Clinically Significant Change From Baseline in Dilated Fundus Exam Results by Visit - Choroid

    Time frame: Baseline (Day 1 pretreatment), Day 14, Day 90, Day 180, Day 270, Day 365

    An examination of the back of the eye (dilated fundus exam) was performed by the investigator. Findings related to the choroid (the layer of blood vessels and connective tissue between the white of the eye and retina) were graded as Normal or Abnormal. Abnormal findings were categorized as clinically significant (CS) or not clinically significant (NCS). CS findings were defined at those that may interfere with study parameters or otherwise confound the data as determined by the investigator.