Safety, PK and Efficacy Study of SJP-0132 in Subjects With Dry Eye Disease

Study Overview
=================
Brief Summary
-----------------
This is the first study in humans to evaluate the effectiveness of SJP-0132 in the treatment of dry eye disease. This study will evaluate the safety, tolerability, efficacy, and pharmacokinetics of single- and multiple-dose regimens of SJP-0132 in subjects with dry eye disease

Official Title
-----------------
A Randomized, Double-Masked, Single-Center, Placebo-Controlled Single and Multiple Ascending Dose Study to Assess Safety, Tolerability, Pharmacokinetics, and Efficacy of SJP-0132 in Subjects With Dry Eye Disease

Conditions
-----------------
Dry Eye Disease, Dry Eye Syndrome

Intervention / Treatment
-----------------
* Drug: SJP-0132
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Body mass index (BMI) within 18.5 to 30.0 kg/m2 (inclusive) and body weight between 45 kg and 100 kg Generally healthy as determined by medical history, physical examinations, clinical laboratory examination, and ophthalmologic examinations performed at Screening Have a subject reported history of Dry Eye Disease in both eyes for at least 6 months prior to Screening Non-smoker or ex-smoker for >12 months Exclusion Criteria: Have clinically significant systemic or ophthalmic disease Has a positive serum pregnancy test at Screening or urine pregnancy test Have had significant blood loss or have donated or received one or more units (450 mL) of blood or plasma within 30 days before randomization Have used or anticipates use of any prescription or over-the-counter medication, including topical medications such as ophthalmic solutions, nasal drops or spray, vitamins, alternative and complementary medicines (including herbal formulations) within 14 days or 5 half-lives (whichever is longer) before randomization or at any time during the study Use or anticipates use of prescribed dry eye medications within 28 days prior to randomization or at any time during the study Have used or anticipates use CYP3A4 inducers, such as St. John's Wort, within 14 days before randomization or at any time during the study. Have consumed red wine, grapefruit or grapefruit juice, Seville oranges, star fruit, or any products containing these items, or any foods that may inhibit CYP3A4, within 48 hours before randomization and throughout the duration of the study Have a positive urine alcohol or urine drug test at Screening or Day -1 Contact lens wearers who cannot discontinue the wear over the trial period Have undergone eye surgery (including laser surgery) within the last 12 months or whom the Investigator considers unsuitable Have a best corrected visual acuity (BCVA) worse than 20/100 in either eye History of permanent punctal occlusion (cautery or laser) or current use of punctal plugs Any corneal abnormality or disease which might impact normal tear film spreading Active or history of significant corneal disease Known allergy or sensitivity to fluorescein, lissamine green or any of the study medications Other protocol-defined Inclusion/Exclusion Criteria may apply

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1-4: SJP-0132<br>Each cohort will receive a single dose of 1 of 4 strengths of SJP-0132 | Drug: SJP-0132<br>* SJP-0132 is administered as an eye drop<br>|
| Placebo Comparator: Cohort 1-4: Placebo<br>Single dose of placebo | Drug: Placebo<br>* Placebo is administered as an eye drop<br>|
| Experimental: Cohort 5-6: SJP-0132<br>Cohort 5 SJP-0132 will receive the second maximum acceptable dose from Cohorts 1-4 for 4 weeks. Cohort 6 SJP-0132 will receive the maximum acceptable dose from Cohorts 1-4 for 4 weeks | Drug: SJP-0132<br>* SJP-0132 is administered as an eye drop<br>|
| Placebo Comparator: Cohort 5-6: Placebo<br>Multiple dose placebo for 4 weeks | Drug: Placebo<br>* Placebo is administered as an eye drop<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events by Severity in Each Cohort | Number of participants with adverse events by severity are summarize in each cohort. Adverse events are reported as Treatment-Emergent Adverse Events (TEAEs), which are defined as any event not present before exposure to the study drug or any event already presented that worsened in either intensity or frequency after exposure to the study drug. | Day 2 for cohort 1-4, Day 29 for cohort 5-6 | 
| Number of Subjects With Abnormal Changes in Laboratory Parameters, Vital Signs, and/or Physical and Ophthalmologic Observations in Each Cohort | Clinical laboratory parameters include hematology, clinical chemistry, urinalysis, and serology. Vital signs include diastolic blood pressure, systolic blood pressure, heart rate, respiratory rate, and body temperature. Ophthalmologic observations include examination of visual acuity, slit lamp biomicroscopy, Schirmer I, intraocular pressure, and ophthalmoscopy. | Day 2 for cohort 1-4, Day 29 for cohort 5-6 | 
| Maximum Plasma Concentration (Cmax) | The results are from the maximum plasma concentration (Cmax) on Day 1. The blood for pharmacokinetics assessment was collected at 0, 0.25, 0.5, 1, 2, 4, 8, and 12 hours after dosing on Day 1 for Cohorts 1 to 4. The blood for pharmacokinetics assessment was collected at 0, 0.25, 0.5, 1, 2, and 4 hours after dosing on Day 1 for Cohorts 5 and 6. | Day 1 | 
| Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration (AUC0-last) | Area under the plasma concentration-time curves (AUCs) for Cohorts 1 to 4 were calculated using the plasma collected at 0, 0.25, 0.5, 1, 2, 4, 8, and 12 hours after dosing on Day 1, and those for Cohorts 5 and 6 were calculated using the plasma collected at 0, 0.25, 0.5, 1, 2, and 4 hours after dosing on Day 1. | Day 1 | 
| Accumulation Ratio (Rac) After Multiple Dosing | Plasma were collected at 0, 0.25, 0.5, 1, 2, and 4 hours after dosing on Day 1, pre-dose on Day 2, Day 4 and Day 8. Accumulation ratios calculated as (predose plasma concentration [Ctrough] on Day 4) / (Ctrough on Day 2) and (Ctrough on Day 8) / (Ctrough on Day 2) | Day 2, 4, 8 | 
| Change From Baseline in Eye Dryness Symptom (VAS) at 4hour on Day 29 | Visual analog scale (VAS): 0 mean none, and 100 mean the worst imaginable for the symptom question. | Day 29 | 
| Change From Baseline in Corneal Fluorescein Staining (CFS) Score at the Central Zone on Day 29 | Change from baseline of central zone CFS score at the central zone on Day 29. CFS score at the central zone ranged from 0 to 5, where '0' represents no fluorescein staining, and '5' represents severe staining on the cornea. The higher scores mean worse outcomes. Results from the study eye are reported. | Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Eye Dryness Symptom by Visual Analog Scale (VAS) in Each Timepoints | Visual analog scale (VAS): 0 mean none, and 100 mean the worst imaginable for the symptom question. Results from pre-dose are reported. | Day 29 | 
| Change From Baseline in Corneal Fluorescein Staining (CFS) Score at Total Zone in Each Timepoints | Change from baseline of CFS score at the total zone of pre-dose in each time point. Total zone means a summary of central, superior, inferior, nasal, and temporal zones. The range of the score in each zone is 0 to 5 points, and the total score is 25 points. The higher scores mean worse outcomes. | Day 8, 15, 22, 29 | 
| Change From Baseline in Conjunctival Lissamine Green Staining (CLGS) Score at Total Zone in Each Timepoints | The score in each zone is 0 to 5 points, and the maximum total score is 30 points. The higher scores mean worse outcomes. Results from the study eye are reported. | Day 8, 15, 22, 29 | 
| Change From Baseline in Lid Wiper Epitheliopathy Score in Each Timepoints | Lissamine green staining of the lid wiper was graded from 0 to 3. The higher scores mean worse outcomes. Results from the study eye are reported. | Day 8, 15, 22, 29 | 
| Change From Baseline in Tear Film Break-up Time (TFBUT) in Each Timepoints | Tear film break-up time is the time taken for the first dry spot to appear on the cornea after a complete blink. | Day 8, 15, 22, 29 | 
| Change From Baseline in Ocular Surface Disease Index (OSDI) | The OSDI questionnaire consists of 12 questions regarding ocular symptoms, environmental triggers, and vision-related functioning. The participant was asked to rate each question using a 5-point scale (0 to 4), where 0 = none of the time; 1 = some of the time; 2 = half of the time; 3 = most of the time; and 4 = all of the time. The total OSDI was calculated from the raw scores of each of the 12 questions based on the formula: ([sum of scores for all questions answered] X 25)/([total number of questions answered]). The OSDI can range from 0 (normal) to 100 (abnormal). | Day 8, 15, 22, 29 | 
| Change From Baseline in Dry Eye Questionnaire 5 (DEQ-5) Scores | The participants rated the frequency on a scale of 0 (never) to 4 (constant) with which they have experienced 3 symptoms (watery eyes, discomfort and dryness). The participant was also asked to rate the intensity of discomfort and dryness on a scale of 0 (never have it) to 5 (very intense). Total DEQ-5 score was the sum of scores for frequency and intensity of dryness and discomfort plus frequency of watery eyes. Maximum score is 22. Higher scores mean a worse outcome. | Day 29 | 
| Change in Matrix Metalloproteinase-9 (MMP-9) | Levels of the inflammatory marker Matrix Metalloproteinase-9 (MMP-9) were measured in each eye using InflammaDry. The test was recorded as either positive or negative. Results from the study eye are reported. | Day 29 |