Dry Eye
Conditions
Brief summary
Protocol AXR201701 is a multicenter, double-masked, vehicle-controlled, randomized, parallel group study carried out in 2 stages (Stage 1: AXR-159 Ophthalmic Solution (30 mg/mL or 50 mg/mL); Stage 2: AXR-159 Ophthalmic Solution (3 mg/mL, 30 mg/mL or 50 mg/mL) in approximately 430 patients diagnosed with dry eye disease (DED).
Detailed description
Protocol AXR201701 is designed with 2 stages. For both Stages 1 and 2, patients with signs and symptoms of DED will be randomly assigned to receive either a single concentration of AXR-159 Ophthalmic Solution or AXR-159 Ophthalmic Solution Vehicle. A screening visit will be followed by a baseline period where subjects will dose with AXR-159 Ophthalmic Solution Vehicle for 14 days. At the end of the baseline period patients who still exhibit signs and symptoms of DED will be enrolled into a 3-month double-masked treatment period.
Interventions
DRUGAXR-159
AXR-159 Ophthalmic Solution
DRUGVehicle
AXR-159 Ophthalmic Solution Vehicle
Sponsors
ORA, Inc.
AxeroVision, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female, 18 years of age or older at screening visit * Best-corrected visual acuity (BCVA) of 20/100 or better (Snellen equivalent), using the logarithm of the minimum angle of resolution (LogMAR) in each eye * Reported history of dry eye for at least 6 months * Corneal fluorescein staining score ≥ 2 * Eye dryness score ≥ 40 * Total Ocular Surface Disease Index (OSDI) score \> 18
Exclusion criteria
* Uncontrolled ocular disease (except for dry eye disease/keratoconjunctivitis sicca) or uncontrolled systemic disease * Patient has glaucoma, ocular hypertension, on IOP-lowering medications or have previously undergone any glaucoma laser or surgical procedure. * Corneal abnormality or disorder that impacts normal spreading of the tear film (keratoconus, pterygia, scarring) or compromised corneal integrity * BCVA worse than 20/100 in either eye * Current use of punctal plugs, anticipated insertion during the study, or a history of punctal cautery in either eye * Keratoconjunctivitis sicca secondary to destruction of conjunctival goblet cells * Patients with clinically significant inflammation of the lid margin such as anterior blepharitis or ocular rosacea * Recent (within the past 3 months) ocular surgery, trauma or herpes * Use of contact lenses in either eye within one month prior to the screening visit or anticipated use during the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Inferior Corneal Staining Score | Month 3 | Change from Baseline in Ora Calibra® Corneal and Conjunctival Staining Scale with a range from 0 to 4 (0=None, 1=Trace, 2=Mild, 3=Moderate, 4=Severe) in the study eye. Higher negative scores mean a better outcome. |
| Eye Dryness | Month 3 | Change from baseline in Eye Dryness score on a subject level across both eyes. Using the visual analogue scale (VAS) subjects rated eye dryness by placing a vertical mark on the horizontal line to indicate the level of discomfort with a range of 0 to 100. 0% corresponds to no dryness (no discomfort) and 100% corresponds to maximal dryness indicating maximal discomfort. A greater negative change from baseline score means a better outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tear Film Break-up Time (TBUT) | Month 3 | Change from baseline in the study eye with a greater positive increase indicating a better outcome. Following the instillation of a sodium fluorescein solution into the inferior conjunctival cul-de-sac of each eye and several blinks over 30 seconds, the examiner monitored the integrity of the tear film with the aid of a slit lamp, noting the time it takes to form micelles from the time that the eye is opened. TBUT was measured in seconds using a stopwatch and a digital image recording system for the right eye followed by the left eye. Values reported are for the study eye. |
| Total Ocular Surface and Disease Index (OSDI) © for Dry Eye | Month 3 | Change from baseline in OSDI © score on a subject level. The 12-question OSDI © is assessed on a total scale from 0 to 100, where higher scores represent greater disability. A greater negative change from baseline indicates a better outcome. |
| Total Lissamine Green Conjunctival Staining | Month 3 | Change from baseline of Oxford Grading Scale measuring staining within a range from 0-5 (0=None, 1=Trace, 2=Mild, 3=Moderate, 4=Severe, 5=Confluent) for each panel (temporal and nasal) and 0-10 as the sum of both panel scores for the total exposed inter-palpebral conjunctiva. Larger negative numbers indicate reduced staining and a better outcome. Values reported are for the study eye. |
| Conjunctival Redness Score | Month 3 | Change from baseline of Ora Calibra® Conjunctival Redness Scale for Dry Eye. Scores range from 0 to 4 with 0=None, 1=Trace, 2=Mild, 3=Moderate, 4=Severe; with higher numbers indicating more conjunctival redness. Greater negative numbers indicate a better outcome. Values reported are for the study eye. |
| Schirmer's Test | Month 3 | Change from baseline in Schirmer's Test score in the study eye. Unanesthetized Schirmer's Test measures the length of the moistened area of a test strip, placed in the lower temporal lid margin of each eye, in mm following a 5-minute exposure period. Greater positive numbers indicate a better outcome. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited based on prespecified inclusion and exclusion criteria between June 2018 and September 2018. Of 265 subjects initially screened, 102 subjects were randomized. The first subject's screening visit was on June 26; the last subject's exit visit was on December 28.
Pre-assignment details
All subjects who met the enrollment criteria at the initial screening visit were assigned to a 2-week run-in period on thrice daily topical vehicle. At the conclusion of the run-in period, 102 subjects again met the enrollment criteria and were randomized to either active or vehicle groups.
Participants by arm
| Arm | Count |
|---|---|
| AXR-159 Ophthalmic Solution 50 mg/mL AXR-159 High Dose
AXR-159: AXR-159 Ophthalmic Solution | 54 |
| AXR-159 Ophthalmic Solution Vehicle Control Group
AXR-159: AXR-159 Ophthalmic Solution Vehicle | 48 |
| Total | 102 |
Baseline characteristics
| Characteristic | AXR-159 Ophthalmic Solution Vehicle | AXR-159 Ophthalmic Solution 50 mg/mL | Total |
|---|---|---|---|
| Age, Continuous | 65.3 years STANDARD_DEVIATION 10.18 | 62.5 years STANDARD_DEVIATION 10.72 | 63.8 years STANDARD_DEVIATION 10.51 |
| Conjunctival Redness Score | 1.61 units on a scale | 1.72 units on a scale | 1.67 units on a scale |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 47 Participants | 51 Participants | 98 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Eye Dryness | 76.9 units on a scale | 76.8 units on a scale | 76.9 units on a scale |
| Inferior Corneal Staining Score | 2.29 units on a scale | 2.16 units on a scale | 2.22 units on a scale |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 6 Participants | 14 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 39 Participants | 47 Participants | 86 Participants |
| Region of Enrollment United States | 48 participants | 54 participants | 102 participants |
| Schirmer's Test | 6.4 millimeters | 5.7 millimeters | 6.0 millimeters |
| Sex: Female, Male Female | 33 Participants | 42 Participants | 75 Participants |
| Sex: Female, Male Male | 15 Participants | 12 Participants | 27 Participants |
| Tear Film Break-up Time (TBUT) | 2.388 seconds | 2.239 seconds | 2.311 seconds |
| Total Lissamine Green Conjunctival Staining | 2.96 units on a scale | 3.28 units on a scale | 3.12 units on a scale |
| Total Ocular Surface and Disease Index (OSDI) © for Dry Eye | 44.1 units on a scale | 50.9 units on a scale | 47.6 units on a scale |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 54 | 0 / 48 |
| other Total, other adverse events | 34 / 54 | 7 / 48 |
| serious Total, serious adverse events | 0 / 54 | 1 / 48 |
Outcome results
Primary
Eye Dryness
Change from baseline in Eye Dryness score on a subject level across both eyes. Using the visual analogue scale (VAS) subjects rated eye dryness by placing a vertical mark on the horizontal line to indicate the level of discomfort with a range of 0 to 100. 0% corresponds to no dryness (no discomfort) and 100% corresponds to maximal dryness indicating maximal discomfort. A greater negative change from baseline score means a better outcome.
Time frame: Month 3
Population: Modified Intent-to-Treat population with last observation carried forward
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AXR-159 Ophthalmic Solution 50 mg/mL | Eye Dryness | -12.5 units on a scale | Standard Deviation 22.62 |
| AXR-159 Ophthalmic Solution Vehicle | Eye Dryness | -14.9 units on a scale | Standard Deviation 21.79 |
Primary
Inferior Corneal Staining Score
Change from Baseline in Ora Calibra® Corneal and Conjunctival Staining Scale with a range from 0 to 4 (0=None, 1=Trace, 2=Mild, 3=Moderate, 4=Severe) in the study eye. Higher negative scores mean a better outcome.
Time frame: Month 3
Population: Modified Intent-to-Treat population with last observation carried forward (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AXR-159 Ophthalmic Solution 50 mg/mL | Inferior Corneal Staining Score | -0.08 units on a scale | Standard Deviation 0.65 |
| AXR-159 Ophthalmic Solution Vehicle | Inferior Corneal Staining Score | -0.03 units on a scale | Standard Deviation 0.447 |
Secondary
Conjunctival Redness Score
Change from baseline of Ora Calibra® Conjunctival Redness Scale for Dry Eye. Scores range from 0 to 4 with 0=None, 1=Trace, 2=Mild, 3=Moderate, 4=Severe; with higher numbers indicating more conjunctival redness. Greater negative numbers indicate a better outcome. Values reported are for the study eye.
Time frame: Month 3
Population: Modified Intent-to-Treat population with observed data only
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AXR-159 Ophthalmic Solution 50 mg/mL | Conjunctival Redness Score | 0.04 units on a scale | Standard Deviation 0.673 |
| AXR-159 Ophthalmic Solution Vehicle | Conjunctival Redness Score | 0.26 units on a scale | Standard Deviation 0.518 |
Secondary
Schirmer's Test
Change from baseline in Schirmer's Test score in the study eye. Unanesthetized Schirmer's Test measures the length of the moistened area of a test strip, placed in the lower temporal lid margin of each eye, in mm following a 5-minute exposure period. Greater positive numbers indicate a better outcome.
Time frame: Month 3
Population: Modified Intent-to-Treat population with observed data only
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AXR-159 Ophthalmic Solution 50 mg/mL | Schirmer's Test | 0.8 millimeters | Standard Deviation 5.13 |
| AXR-159 Ophthalmic Solution Vehicle | Schirmer's Test | 1.9 millimeters | Standard Deviation 6.77 |
Secondary
Tear Film Break-up Time (TBUT)
Change from baseline in the study eye with a greater positive increase indicating a better outcome. Following the instillation of a sodium fluorescein solution into the inferior conjunctival cul-de-sac of each eye and several blinks over 30 seconds, the examiner monitored the integrity of the tear film with the aid of a slit lamp, noting the time it takes to form micelles from the time that the eye is opened. TBUT was measured in seconds using a stopwatch and a digital image recording system for the right eye followed by the left eye. Values reported are for the study eye.
Time frame: Month 3
Population: Modified Intent-to-Treat with observed data only
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AXR-159 Ophthalmic Solution 50 mg/mL | Tear Film Break-up Time (TBUT) | -0.143 seconds | Standard Deviation 1.093 |
| AXR-159 Ophthalmic Solution Vehicle | Tear Film Break-up Time (TBUT) | -0.178 seconds | Standard Deviation 1.105 |
Secondary
Total Lissamine Green Conjunctival Staining
Change from baseline of Oxford Grading Scale measuring staining within a range from 0-5 (0=None, 1=Trace, 2=Mild, 3=Moderate, 4=Severe, 5=Confluent) for each panel (temporal and nasal) and 0-10 as the sum of both panel scores for the total exposed inter-palpebral conjunctiva. Larger negative numbers indicate reduced staining and a better outcome. Values reported are for the study eye.
Time frame: Month 3
Population: Modified Intent-to-Treat population with observed data only
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AXR-159 Ophthalmic Solution 50 mg/mL | Total Lissamine Green Conjunctival Staining | 0.40 units on a scale | Standard Deviation 1.912 |
| AXR-159 Ophthalmic Solution Vehicle | Total Lissamine Green Conjunctival Staining | 0.59 units on a scale | Standard Deviation 1.758 |
Secondary
Total Ocular Surface and Disease Index (OSDI) © for Dry Eye
Change from baseline in OSDI © score on a subject level. The 12-question OSDI © is assessed on a total scale from 0 to 100, where higher scores represent greater disability. A greater negative change from baseline indicates a better outcome.
Time frame: Month 3
Population: Modified Intent-to-Treat with observed data only
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AXR-159 Ophthalmic Solution 50 mg/mL | Total Ocular Surface and Disease Index (OSDI) © for Dry Eye | -8.8 units on a scale | Standard Deviation 9.3 |
| AXR-159 Ophthalmic Solution Vehicle | Total Ocular Surface and Disease Index (OSDI) © for Dry Eye | -5.0 units on a scale | Standard Deviation 16.93 |