Conditions: Dry Eye
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 102
Healthy volunteers: no

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.

Arms:
arm 1: AXR-159 Low Dose arm 2: AXR-159 Mid Dose arm 3: AXR-159 High Dose arm 4: Control Group

Interventions: intervention 1: AXR-159 intervention 2: Vehicle
Intervention descriptions: intervention 1: AXR-159 Ophthalmic Solution intervention 2: AXR-159 Ophthalmic Solution Vehicle

Protocol document:
Prot_000.pdf: 
Clinical Trial Protocol: AXR201701 
Protocol Title: 
A Multicenter, Vehicle-controlled, Randomized 
Study to Evaluate the Safety, Tolerability, 
Systemic Pharmacokinetics, and 
Pharmacodynamics of AXR-159 Ophthalmic 
Solution 3 mg/mL, 30 mg/mL, and 50 mg/mL in 
Patients with Dry Eye Disease (DED) 
Protocol Number: 
AXR201701 
Study Phase: 
2 
Investigational Product 
Name: 
AXR-159 (α4β1 and α4β7 Antagonist) 
IND/IDE/PMA Number: 
IND123799 
Indication: 
Dry Eye Disease 
Investigators: 
Multi-center 
Sponsor: 
AxeroVision, Inc. 
5857 Owens Ave., Suite 300 
Carlsbad, CA 92008 
Tel: 484-238-6255 
Contract Research 
Organization: 
Ora, Inc. 
300 Brickstone Square, 3rd Floor 
Andover, MA 01810 
IRB/IEC: 
Alpha IRB 
1001 Avenida Pico 
Suite C, #497 
San Clemente, CA 92673 
Original Protocol: 
February 17, 2018 
Amendment 1: 
N/A 
NCT03598699


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Clinical Trial Protocol: AXR201701/17-110-0016 
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Confidentiality Statement 
This protocol contains confidential, proprietary information of Ora, Inc. and/or 
AxeroVision, Inc.  Further dissemination, distribution or copying of this protocol or its 
contents is strictly prohibited. 
SPONSOR PERSONNEL 
Sponsor: 
Charles Bosworth 
Tel: 714-559-7209 
charles@axerovision.com 
ORA PERSONNEL 
Department Vice President: 
George Ousler 
Tel: (978) 685-8900 x 9481 
Fax: (978) 689-0020 
gousler@oraclinical.com 
Department Senior Manager: 
Michael Watson 
Tel: (978) 685-8900 x 9446 
Fax: (978) 849-7371 
mwatson@oraclinical.com 
Project Manager: 
Brian Orrick 
Tel: (978) 685-8900 x 9584 
Fax: (978) 689-0020 
borrick@oraclinical.com 
MEDICAL MONITOR 
Medical Monitor: 
Joseph B. Ciolino, MD 
Tel: (617) 573-5575 
Cell: (401) 935-9662 
Fax: (617) 573- 4324 
joseph_ciolino@meei.harvard.edu 


AXR-159 ophthalmic solution 
AxeroVision, Inc. 
Clinical Trial Protocol: AXR201701/17-110-0016 
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SYNOPSIS 
Protocol Title: 
A Multicenter, Vehicle-controlled, Randomized 
Study to Evaluate the Safety, Tolerability, Systemic 
Pharmacokinetics, and Pharmacodynamics of AXR-
159 Ophthalmic Solution 3 mg/mL, 30 mg/mL, and 
50 mg/mL in Patients with Dry Eye Disease (DED) 
Protocol Number: 
AXR201701 
Investigational Product: 
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)   
Controls:  AXR-159 Ophthalmic Solution Vehicle 
(Stages 1 and 2) 
Study Phase: 
2 
Primary Objective(s): 
Stage 1:   
To evaluate the safety, tolerability, and exploratory 
pharmacodynamics of up to 2 different 
concentrations of AXR-159 Ophthalmic Solution 
(30 mg/mL or 50 mg/mL) dosed three-times daily 
(TID) or twice-daily (BID) for up to 12 weeks 
compared to its vehicle in patients with Dry Eye 
Disease (DED). 
Stage 2:   
To evaluate the safety, tolerability, and 
pharmacodynamics of up to 3 different 
concentrations of AXR-159 Ophthalmic Solution (3 
mg/mL, 30 mg/mL or 50 mg/mL) dosed three-times 
daily (TID) or twice-daily (BID) for up to 12 weeks 
compared to its vehicle in patients with Dry Eye 
Disease (DED). 


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Secondary Endpoints(s): 
 
Stage 1 and 2:   
• Schirmer’s test w/o anesthesia 
• Tear film break-up time (TBUT)  
• Conjunctival redness score 
• Sodium fluorescein corneal staining  
• Lissamine green conjunctival staining  
• Ocular Discomfort Score 
• Patient symptoms (visual analog scale 
[VAS]) 
• OSDI (subscales and items) 
• Symptom Assessment iN Dry Eye (SANDE) 
• 
Tear collection (for exploratory analyses) 
(selected sites)  
 
Overall Study Design: 
Structure: 
Multi-center, double-masked, vehicle-controlled, 
randomized, parallel group study 
Duration: 
An individual subject’s participation is estimated to 
be approximately 14 weeks in stage 1 and 14 weeks 
in stage 2. 
Controls: 
AXR-159 Ophthalmic Solution Vehicle (Stages 1 
and 2) 
Dosage/Dose Regimen/ 
Instillation/Application/Use: 
Stage 1:   
Study patients will receive a 2-week run-in on AXR-
159 Ophthalmic Solution Vehicle to be administered 
either TID (Stage 1, Cohort 1; Stage 1, Cohort 2) or 
BID (Stage 1, Cohort 3).  The assigned randomized 
study medication will be instilled into the eye TID 
for 3 months in Stage 1, Cohort 1; or Stage 1, 
Cohort 2 and BID in Cohort 3. 
 
Stage 2:   
Study patients will receive a 2-week run-in on AXR-
159 Ophthalmic Solution Vehicle to be administered 
either TID or BID corresponding to the frequency of 
treatment dosing to be assigned post-randomization.  
The assigned randomized study medication will be 
instilled into the eye either TID or BID for 3 months 
in Stage 2 depending upon the groups selected for 
evaluation by the DRC.  


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Summary of Visit Schedule: 
5 visits over the course of approximately 14 weeks 
•
Visit 1 = Screening (Day -14 ± 2)
•
Visit 2 = Baseline & Randomization, Day 1
•
Visit 3 = 2-Week Follow-Up (Day 15 ± 2)
•
Visit 4 = 1.5 Month Follow-up (Day 43 ± 2)
•
Visit 5 = 3 Month Follow-up (Day 85 ± 2)
Measures Taken to Reduce 
Bias: 
This is a randomized treatment assignment, double-
masked study 
Study Population Characteristics: 
Number of Subjects: 
Stage 1:  
The total number of randomized patients for Stage 1 
of the study will be approximately 100 at up to 2 
sites.  Approximately 50% of patients should have a 
baseline eye dryness score of ≥ 60 and 
approximately 50% of patients should have a 
baseline inferior corneal staining score (ICCS) > 1.5 
according to the Ora Calibra® staining scale.   Based 
upon data from Xiidra®, OPUS 2 a screen failure 
rate of ~ 50% is expected.   Thus, ~200 patients will 
need to be screened to achieve ~100 patients 
randomized to treatment.   
Stage 2:  
The total number of randomized patients for Stage 2 
of the study will be approximately 330 (see Figure 
6.1-1, Stage 2) at up to 7 sites.  Approximately 50% 
of patients should have a baseline eye dryness score 
of ≥ 60 and approximately 50% of patients should 
have a baseline inferior corneal staining score 
(ICCS) > 1.5.   Based upon data from Xiidra®, 
OPUS 2 a screen failure rate of ~ 50% is expected.   
Thus, ~660 patients will need to be screened to 
achieve ~330 patients randomized to treatment.   
Note: patients can be reallocated from discontinued 
groups to increase the power in groups that are 
continued at the discretion of the DRC.   


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Condition/Disease: 
Dry Eye Disease (DED) 
Inclusion Criteria: 
1. Male or female, 18 years of age or older at 
screening visit  
2. Provide written informed consent 
3. Be willing and able to follow instructions 
and participate in all study assessments and 
visits 
4. 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 at Visits 1 
and 2 
5. Must have patient reported history of dry eye 
for at least 6 months prior to Visit 1  
6. Use of non-prescription artificial tears for the 
symptoms of DED within the 30 days 
preceding the screening visit and willing to 
suspend use of artificial tears for the study 
duration 
7. Corneal fluorescein staining score ≥ 2  
according to the Ora Calibra® scale in at least 
one region in at least one eye at the screening 
Visit 1 (Pre-CAE®) and Visit 2 
8. Conjunctival redness score ≥ 1 according to 
the Ora Calibra® Conjunctival Redness for 
Dry Eye Scale in at least one eye at Visit 1 
(Pre-CAE®) and Visit 2 
9. Eye dryness score ≥ 40 (0-100 VAS scale in 
both eyes) at Visit 1 (Pre-CAE®) and Visit 2 
10. Total Ocular Surface Disease Index (OSDI) 
score > 18 at Visit 1 (Pre-CAE®) and Visit 2 
11. In the same eye at Visits 1 and 2, subjects 
must have: 
a.  Inferior corneal fluorescein staining score 
≥ 0.5 according to the Ora Calibra® Corneal 
and Conjunctival Staining Scale for Grading 
of Fluorescein Staining, Pre-CAE® at Visit 1   
b. Schirmer’s Tear Test without anesthesia ≥ 
1 and ≤ 10 mm  
 
 
 
 


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Exclusion Criteria: 
1. Uncontrolled ocular disease (except for dry
eye disease/keratoconjunctivitis sicca) or
uncontrolled systemic disease
2. Patient has glaucoma, ocular hypertension,
on IOP-lowering medications or have
previously undergone any glaucoma laser or
surgical procedure.
3. Corneal abnormality or disorder that impacts
normal spreading of the tear film
(keratoconus, pterygia, scarring) or
compromised corneal integrity
4. BCVA worse than 20/100 in either eye
5. Current use of punctal plugs, anticipated
insertion during the study, or a history of
punctal cautery in either eye at any time
prior to the screening visit or anticipate such
a procedure during the study
6. Keratoconjunctivitis sicca secondary to
destruction of conjunctival goblet cells as
occurs with vitamin A deficiency or scarring,
such as that with cicatricial pemphigoid,
alkali burns, Stevens-Johnson syndrome,
trachoma, or irradiation
7. Active ocular infection or inflammation
other than that caused by DED (including
allergic, vernal, or giant papillary
conjunctivitis and severe eyelid
inflammation)
8. Patients with clinically significant
inflammation of the lid margin such as
anterior blepharitis or ocular rosacea
9. Recent (within the past 3 months) ocular
surgery, trauma or herpes
10. Use of contact lenses in either eye within one
month prior to the screening visit or
anticipated use during the study
11. Use of any type of scleral lenses or sealed
compartment ocular frames within 2 months
of the screening visit, or planned use during
the study


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12. Use prohibited medication within the 
prescribed washout window or anticipated 
use during the study: 
a. Topical cyclosporine (e.g., Restasis) 
or integrins (i.e., Xiidra): 12 weeks 
prior to Visit 1 
b. Corticosteroids or mast cell 
stabilizers: 2 weeks prior to Visit 1 
c. Antihistamines (including ocular): 72 
hours prior to Visit 1 
d. Oral aspirin or aspirin containing 
products only if a stable dosing 
regimen has been established for at 
least 30 days before Visit 1 
e. Medications known to impact ocular 
dryness must be on a stable dosing 
regimen for at least 30 days before 
Visit 1 
f. All other ophthalmic preparations 
including artificial tears: 72 hours 
prior to Visit 1 
13. Eyelid abnormalities that affect lid function 
or impact lid closure 
14. Systemic disease condition that causes dry 
eye 
15. Diagnosis of hepatitis C infection, human 
immunodeficiency virus (HIV) infection, 
sarcoidosis, amyloidosis, active tuberculosis, 
or graft versus host disease  
16. History of anterior segment surgery or 
trauma that could affect corneal sensitivity 
(e.g., cataract surgery, refractive surgery or 
any surgery involving a limbal or corneal 
incision) in either eye within the 12 months 
prior to Visit 1 
17. Planned anterior segment surgery (e.g., 
cataract surgery or any surgery involving a 
limbal or corneal incision) in either eye 
during the study 


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18. Known allergy or sensitivity to fluorescein,
lissamine green, or the study medication or
its components
19. Patient is unlikely to follow study
instructions or to complete all required study
visits or has a condition or situation that in
the investigator's opinion, may put the
patient at significant risk, may confound the
study results, or may interfere significantly
with the patient's participation in the study
20. Patient is an employee at the investigational
site or is related to any member of the study
staff
21. Patient cannot tolerate multiple blood draws
22. Pregnant, nursing, or females of childbearing
potential and not utilizing adequate birth
control measures
23. Participation in another ophthalmic clinical
trial involving a therapeutic drug or device
within the past 30 days
24. Previous exposure to AXR-159 Ophthalmic
Solution or Ophthalmic Solution Vehicle.
Study Formulations and 
Formulation Numbers: 
Stage 1:  
•
30 mg/mL AXR-159 Ophthalmic Solution
•
50 mg/mL AXR-159 Ophthalmic Solution
•
AXR-159 Ophthalmic Solution Vehicle
Stage 2:  
•
3 mg/mL AXR-159 Ophthalmic Solution
•
30 mg/mL AXR-159 Ophthalmic Solution
•
50 mg/mL AXR-159 Ophthalmic Solution
•
AXR-159 Ophthalmic Solution Vehicle


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Evaluation Criteria: 
Efficacy Measures and 
Endpoints: 
Primary Efficacy (pre-CAE) 
• Change from Baseline to Month 3 in inferior 
corneal staining score (Ora Calibra® scale) in 
the study eye 
• Change from Baseline to Month 3 in total 
corneal staining score (Oxford and Ora 
Calibra® scales) in the study eye 
• Change from Baseline to Month 3 in eye 
dryness measured using a visual analogue 
scale (VAS) 
• Change from Baseline to Month 3 in Total 
Ocular Surface Disease Index (OSDI) score 
 
Secondary Efficacy Measures 
• Schirmer’s test w/o anesthesia 
• Tear film break-up time (TBUT)  
• Conjunctival redness score 
• Sodium fluorescein corneal staining  
• Lissamine green conjunctival staining  
• Ocular Discomfort Score 
• Patient symptoms (visual analog scale 
[VAS]) 
• OSDI (subscales and items) 
• Symptom Assessment iN Dry Eye (SANDE) 
• Proportion of patients with a TBUT ≥ 10 
seconds at each visit  
• Proportion of patients with a Schirmer’s test 
≥ 10 mm at each visit  
• Proportion of patients with a Total OSDI < 
18 at each visit 
• Proportion of patients with an Ocular 
Discomfort Score = 0 at each visit 
• Tear collection (for exploratory analyses) 
(selected sites)  
 
 
 


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Safety Measures: 
•
Adverse events
•
Vital signs
•
Study medication tolerability as measured by
the Ocular Comfort Questionnaire
•
Urine pregnancy test
•
Best-corrected visual acuity (BCVA;
Logarithmic visual acuity chart)
•
Biomicroscopy
•
Ophthalmoscopy
•
Intraocular pressure (IOP)
•
Lab analysis of blood and urine (including
hematology, chemistry, and urinalysis)
Other: 
Pharmacokinetics (Stage 1 Only)   
•
Systemic pharmacokinetics
General Statistical Methods and Types of Analyses 
The safety population will include all randomized subjects who have received at least 
one dose of the investigational product. The safety population will be analyzed for all 
safety assessments. Subjects in the Safety population will be analyzed as treated.  The 
modified intent-to-treat (mITT) population will be comprised of all randomized 
subjects that have baseline and at least 1 post-baseline assessment for 1 or more of the 
efficacy measurements.  All patients in the mITT population will be analyzed by the 
treatment as randomized with last observation carried forward (LOCF) for missing 
data.  This population will be used for the primary and the secondary efficacy analyses. 
The modified intent-to-treat 2 (mITT2) population will be comprised of patients who 
are included in the mITT and have baseline inferior corneal staining score (Ora 
Calibra® scale) in the study eye > 1.5.  The mITT2 population will be analyzed as 
randomized.    
In general, continuous data will be summarized with descriptive statistics (number of 
subjects, mean, standard deviation, median, minimum, and maximum) and will be 
analyzed using analysis of variance (ANOVA), analysis of covariance (ANCOVA) 
techniques, two-sample t-tests, or Wilcoxon rank sum tests for between-group 
comparisons, and paired t-tests or sign-rank tests for within-group analyses.  
Categorical variables will be summarized by number of subjects (n), frequency counts, 
and percentages, and they will be analyzed using Pearson’s chi-square test or Fisher’s 
exact test (if the expected cell count is less than 5 in 25% or more of the cells).  Ordinal 
variables will be analyzed using the Cochran-Mantel-Haenszel (CMH) or the Wilcoxon 
rank-sum test for between-treatment comparisons and the sign-rank test for within-
treatment comparisons.  


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The primary efficacy variables are: 
• Change from Baseline to Month 3 in inferior corneal staining score (Ora 
Calibra® scale) in the study eye 
• Change from Baseline to Month 3 in total corneal staining score (Oxford 
and Ora Calibra® scales) in the study eye 
• Change from Baseline to Month 3 in eye dryness measured using a visual 
analogue scale (VAS) 
And 
• Change from Baseline to Month 3 in Total Ocular Surface Disease Index 
(OSDI) score.   
A patient will be considered a responder if a cure is reached for TFBUT (i.e., ≥ 10 sec), 
a Schirmer’s test (i,e., ≥ 10 mm), Total OSDI (< 18), or Ocular Discomfort Score 
(Score = 0) at a post-randomization visit.  The visit for the primary variable is month 3 
and the primary analysis population is mITT with last observation carried forward 
(LOCF).  Statistical tests will be performed for each AXR-159 Ophthalmic Solution 
group versus vehicle group.  Pairwise comparisons of the proportion of responders will 
be performed using the CMH method stratifying by baseline eye dryness score and 
baseline inferior corneal staining score.  There will be no alpha adjustment for the 
multiple tests for the pairwise comparisons or multiple endpoints.   
An interim analysis will be performed when the last enrolled patient in Stage 1 
completes Month 3 of the Expansion Cohort.  There is no plan to stop the study for 
efficacy on the basis of the interim analysis.  However, termination of individual dose 
groups due to safety, tolerability and/or futility may occur.  Statistical significance will 
not be declared at the time of the interim analysis.   
A final database lock will occur at the completion of Stage 2 and the safety, 
tolerability, and efficacy data from both Stage 1 and 2 will be analyzed separately and 
in a combined fashion to fully leverage the advantage of this two-stage study design.  
At the final analysis, statistical significance will be declared for two-sided p-values < 
0.05.   
Safety: Safety measures will be analyzed using the safety population.  Medical 
Dictionary for Regulatory Activities (MedDRA) nomenclature will be used to code 
adverse events.  Incidence rates of each treatment-emergent adverse event will be 
summarized by primary system organ class and preferred term.  Summary tables will 
be generated for all treatment-emergent adverse events regardless of causality as well 
as for those considered to be treatment-related.   
 
 


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Sample Size Calculation:    The sample size is determined empirically.  Xiidra 
achieved a 0.25 unit difference between lifitegrast ophthalmic solution and vehicle in 
mean change from baseline to day 84 in inferior cornel staining and a standard 
deviation of approximately 0.75 in Phase 2. Sample sizes for this study are based on 
detecting a 0.35 unit difference between the active and vehicle groups, assuming a 
standard deviation of 0.75.  In Stage 1 the number of expected enrolled subjects varies 
between 43 and 53 subjects in the active group and between 37 and 47 subjects in the 
vehicle group.  In Stage 2 the number of expected enrolled subjects is 60 in the active 
group and 30 to 60 subjects in the vehicle group. Thus, the combined sample provides 
between 103 and 113 subjects in the active group and between 67 and 77 subjects in 
the matching vehicle group or between 97 and 107 subjects in the combined vehicle 
group.  Under these assumptions and allowing a dropout rate of 10%, sample sizes of 
93 in the active treatment group and 60 in the vehicle group will yield 80% power to 
show a significant difference at the α = 0.05 level using a two-sample t-test. 
Summary of Known and Potential Risks and Benefits to Human Subjects 
AXR-159X has previously been well tolerated clinically when administered via oral 
inhalation or intranasal routes to healthy volunteers, asthma and allergic rhinitis 
patients. This is the first time that a competitive antagonist of the α4 subunit, α4β1 and 
α4β7 integrins, (AXR-159 Ophthalmic Solution) is being administered as an eye drop 
in humans. The eye drop formulation was very well tolerated in preclinical species 
(i.e., rabbits, dogs) when administered at 50 mg/mL up to 12 times per day for up to 3 
months.  Eye drop administration can be expected to produce negligible systemic 
levels of drug.  
Most reported adverse events from AXR-159 were considered mild to moderate in 
intensity and there have been no serious adverse events associated with the 
administration of AXR-159. Findings from pre-clinical studies support the 
administration of AXR-159 Ophthalmic Solution (3 mg/mL, 30 mg/mL or 50 mg/mL) 
BID or TID in patients with DED.  While it is hoped that topical ocular dosing with 
AXR-159 Ophthalmic Solution will impart some degree of relief from dry eye signs or 
symptoms including redness, itching, foreign body sensation or blurred vision while on 
study, this is a first in patient study and these benefits cannot be predicted from 
preclinical models of DED with certainty. 


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1 TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ..........................................................................................14 
2 
LIST OF ABBREVIATIONS ...................................................................................17 
3 
INTRODUCTION ....................................................................................................19 
4 
STUDY OBJECTIVES .............................................................................................21 
5 
CLINICAL HYPOTHESES .....................................................................................23 
6 
OVERALL STUDY DESIGN ..................................................................................23 
 
Overall Design ................................................................................................23 
 
Scientific Rationale for Study Design ............................................................25 
 
Data Review Committee (DRC) .....................................................................26 
 
End of Study Definition .................................................................................26 
7 
STUDY POPULATION ...........................................................................................26 
 
Number of Subjects (approximate) ................................................................26 
 
Study Population Characteristics ....................................................................27 
 
Inclusion Criteria ............................................................................................27 
 
Exclusion Criteria ...........................................................................................27 
 
Withdrawal Criteria (if applicable) ................................................................29 
8 
STUDY PARAMETERS ..........................................................................................30 
 
Efficacy Measures and Endpoints ..................................................................30 
8.1.1 
Primary Efficacy Measure(s) ............................................................30 
8.1.2 
Secondary Efficacy Measure(s) ........................................................30 
 
Safety Measures .............................................................................................30 
 
Other Measures ...............................................................................................31 
9 
STUDY MATERIALS .............................................................................................31 
 
Study Treatment(s) .........................................................................................31 
9.1.1 
Study Treatment(s)/ Formulation(s)/ Medical Device 
Composition or Design .....................................................................31 
9.1.2 
Dosing and Administration ...............................................................32 
 
Other Study Supplies ......................................................................................33 
10 
STUDY METHODS AND PROCEDURES ............................................................33 
  Subject Entry Procedures ...............................................................................33 
10.1.1  Overview ...........................................................................................33 
10.1.2  Informed Consent..............................................................................33 
10.1.3  Washout Intervals .............................................................................33 
10.1.4  Procedures for Final Study Entry ......................................................34 
10.1.5  Methods for Assignment to Treatment Groups: ...............................34 
  Concurrent Therapies .....................................................................................35 
10.2.1  Prohibited Medications/Treatments ..................................................35 
10.2.2  Rescue Medications ..........................................................................35 
10.2.3  Special Diet or Activities ..................................................................35 
  Examination Procedures .................................................................................35 
10.3.1  Procedures to be Performed at Each Study Visit with Regard to 
Study Objective(s) ............................................................................35 
  Schedule of Visits, Measurements and Dosing ..............................................43 
10.4.1  Scheduled Visits................................................................................43 


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10.4.2  Unscheduled Visits ...........................................................................43 
  Compliance with Protocol ..............................................................................43 
  Subject Disposition .........................................................................................44 
10.6.1  Completed Subjects ..........................................................................44 
10.6.2  Discontinued Subjects .......................................................................44 
  Study Termination ..........................................................................................44 
  Study Duration ...............................................................................................44 
  Monitoring and Quality Assurance ................................................................44 
11 
ADVERSE EVENTS ................................................................................................45 
  Adverse Event ................................................................................................45 
11.1.1  Severity .............................................................................................45 
11.1.2  Relationship to Investigational Product ............................................45 
11.1.3  Expectedness .....................................................................................46 
  Serious Adverse Events ..................................................................................47 
  Procedures for Reporting Adverse Events .....................................................48 
11.3.1  Reporting a Suspected Unexpected Adverse Reaction .....................48 
11.3.2  Reporting a Serious Adverse Event ..................................................48 
  Procedures for Unmasking (if applicable) ......................................................48 
  Type and Duration of the Follow-up of Subjects after Adverse Events ........49 
12 
STATISTICAL HYPOTHESES AND METHODS OF ANALYSES .....................50 
  Sample Size Determination ............................................................................50 
  Analysis Populations ......................................................................................50 
  Statistical Hypotheses .....................................................................................51 
  Statistical Analyses .........................................................................................52 
12.4.1  General Approach .............................................................................52 
12.4.2  Unit of Analysis ................................................................................52 
12.4.3  Missing Data .....................................................................................53 
12.4.4  Multiplicity Consideration ................................................................53 
12.4.5  Primary Efficacy Analyses ...............................................................53 
12.4.6  Secondary Efficacy Analyses ...........................................................54 
12.4.7  Safety Variables ................................................................................54 
12.4.8  Planned Interim Analyses .................................................................55 
12.4.9  Sub-Group Analyses .........................................................................55 
12.4.10  Tabulation of Individual Participant Data .........................................55 
12.4.11  Exploratory Analyses ........................................................................55 
12.4.12  Pharmacokinetics Analyses ..............................................................55 
13 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES ....................................56 
  Protection of Human Subjects ........................................................................56 
13.1.1  Subject Informed Consent.................................................................56 
13.1.2  Institutional Review Board (IRB) Approval .....................................56 
  Ethical Conduct of the Study ..........................................................................57 
  Subject Confidentiality ...................................................................................57 
  Documentation ...............................................................................................57 
13.4.1  Retention of Documentation .............................................................57 


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Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Investigational Product ...................................................................................58 
13.5.1  Labeling/Packaging ...........................................................................58 
13.5.2  Storage of Investigational Product ....................................................58 
13.5.3  Accountability of Investigational Product ........................................58 
13.5.4  Return or Disposal of Investigational Product ..................................58 
Recording of Data on Source Documents and Case Reports Forms (CRFs) .58 
Handling of Biological Specimens .................................................................59 
13.7.1  Handling of Biological Specimens ...................................................59 
13.7.2  Blood and Urine Samples for Safety Analysis .................................59 
13.7.3  Blood Samples for Pharmacokinetic Analysis ..................................59 
13.7.4  Tear Samples .....................................................................................59 
13.7.5  Key Roles and Study Governance ....................................................59 
13.7.6  Safety Oversight................................................................................60 
13.7.7  Clinical Monitoring ...........................................................................60 
13.7.8  Quality Assurance and Quality Control ............................................60 
Publications ....................................................................................................61 
14 
REFERENCES .........................................................................................................62 
15 
APPENDICES ..........................................................................................................63 
Appendix 1: Schedule of Visits and Measurements ..........................................................63 
Appendix 2: Examination Procedures, Tests, Equipment, and Techniques ......................65 
Appendix 3: Handling of Biological Specimens ...............................................................80 
Appendix 4: Protocol Amendment Summary ....................................................................82 
Appendix 5: Sponsor and Ora Approvals ..........................................................................83 
Appendix 6: Investigator’s Signature ................................................................................84 
List of Tables 
Table 4–1 Table of Objectives, Endpoint, and Endpoint Justification ..............................21 
Table 9.1.1–1 Investigational Product and Packaging Characteristics  .............................32 
List of Figures 
Figure 6.1-1 Study Design .................................................................................................25 


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2 LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
ANCOVA 
Analysis of Covariance 
AXR-159 
GW559090 
AXR-159A 
GW559090A, potassium salt of GW559090 
AXR-159X 
GW559090X, free acid of GW559090 
BCVA 
Best-Corrected Visual Acuity 
BID 
Twice Daily 
CAE 
Controlled Adverse Environment 
CFR 
Code of Federal Regulations 
Cmax 
Maximum Concentration 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case Report Form 
DED 
Dry Eye Disease 
DHHS 
Department of Health and Human Services 
DRC 
Data Review Committee 
ESOE 
Early Signal of Efficacy 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICCS 
Inferior Corneal Staining Score 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug Application 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent To Treat 
LASIK 
Laser In Situ Keratomileusis 
LOCF 
Last Observation Carried Forward 
logMAR 
Logarithm of the Minimum Angle of Resolution 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 


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NCS 
Not Clinically Significant 
OD 
Right Eye 
OS 
Left Eye 
OSDI 
Ocular Surface Disease Index 
OU 
Both Eyes 
PK 
Pharmacokinetics 
PI 
Principal Investigator 
PP 
Per Protocol 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SDC 
Statistics and Data Corporation 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
TID 
Three Times Daily 
TF 
Tear Film 
TBUT/TFBUT 
Tear Film Break-up Time 
US 
United States 
VA 
Visual Acuity 
VAS 
Visual Analog Scale 
 
 


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3 INTRODUCTION 
Dry eye disease (DED) is a multifactorial disease of the ocular surface characterized by a 
loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear 
film instability and hyperosmolarity, ocular surface inflammation and damage, and 
neuronal sensory abnormalities play etiological roles (Craig et al, 2017).  DEWS II 
hypothesizes that dry eye disease (DED) is ”…initiated by desiccating stress and 
perpetuated by a Vicious Circle of ocular surface inflammation (Bron et al, 2017).”  
Thus, no matter what initiates a patient’s dry eye disease (e.g., allergic eye disease, 
topical preservative toxicity, or xerophthalmia) all patients eventually enter a chain of 
inflammatory events that perpetuate the disease.   
Experimentally, the expression of IL-1, TNF-α, and IL-6 by ocular surface epithelia are 
critical to the ocular surface dry eye inflammatory response.  A key step in the 
amplification process for inflammation is the generation of signals that recruit 
inflammatory cells to the site of inflammation: 1) chemokines and 2) integrin adhesion 
molecules.  Chemokines produced at the ocular surface (e.g., CCL3, CCL4, CCL5, 
CXCL9, CXCL10, and CX3CL1) can bind macrophages, dendritic cells, neutrophils, and 
activated T cells.  The other key step in homing inflammatory cells to the ocular surface 
is the expression of endothelial integrin adhesion molecules (e.g., ICAM-1, VCAM-1).  
ICAM-1 and VCAM-1 are adhesion molecules that bind to inflammatory cells expressing 
the ligand, integrated leukocyte function antigen 1 (LFA-1; integrin αLβ2) and very late 
antigen 4 (VLA-4; integrin α4β1), respectively.  Integrins facilitate cell-cell and cell-
extracellular matrix (ECM) adhesion and include the β1, β2, β4, immunoglobulin, and 
selectin super families.  Known targets for treating ocular inflammation include αLβ2 and 
α4β1 (Bron et al, 2017). 
Lifitegrast ophthalmic solution (Xiidra®) 5% was approved by the US FDA for the 
treatment of DED in 2016.  Lifitegrast is an antagonist of LFA-1 (also known as 
CD11a/CD18 or αLβ2).  Lifitegrast demonstrated a statistically significant treatment 
response in the objective endpoint, change from baseline to Day 84 in inferior corneal 
staining score in the Phase 2 and OPUS 1 studies and a statically significant treatment 
response in the subjective endpoint, change from baseline to Day 84 in eye dryness score 
(VAS) in the OPUS 2 and 3 studies (Semba & Gadek, 2016). 
Natalizumab, an antibody directed against the α4- integrin subunit, has been shown to 
profoundly inhibit inflammation and improve clinical outcomes in both multiple sclerosis 
and Crohn’s disease.  Topical, ocular application of BIO-8809 (Anti-VLA-4 small 
molecule) decreased corneal fluorescein staining, conjunctival T-cell infiltrates, and 
TNFα expression in cornea and conjunctiva in a murine dry eye model (Ecoiffier et al, 
2008).
AXR-159 (GW559090) is potent and selective antagonist for the α4 subunit, α4β1 and 
α4β7 integrins, which has been formulated as an eye drop and has been shown to be safe 
and well tolerated in the eye with no target organ toxicity identified at doses up to 30 
mg/kg/day in animal models. It lacks significant systemic exposure following topical 
ocular administration due to low systemic exposure and its high clearance rate from the 
circulation. 


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In preclinical murine models of DED, AXR-159A improved corneal staining with similar 
efficacy and onset of action, as the topical steroid dexamethasone. Topical steroids are an 
unapproved, but effective treatment for DED and often serve as positive controls in 
preclinical models of DED.  Topical ophthalmic corticosteroids are commonly used for 
the treatment of dry eye disease (DED) (Holland et al, 2007; DEWS, 2007; Avunduk et 
al, 2003; Pflugfelder et al, 1999; Pflugfelder et al, 2004; Yang et al, 2006).  Topical 
AXR-159A also significantly reduced corneal uptake of Oregon Green Dextran (OGD) 
compared to vehicle-treated disease controls, murine model of dry eye, in a dose-
dependent manner (1, 3, 10, and 30 mg/mL) with 30 mg/mL showing the greatest 
reduction in OGD staining. When administered topically, corneal expression of IL-1α, 
matrix metalloproteinase (MMP)–9, chemokine ligand 9 (CXCL9), and TGF-β1 were 
reduced in AXR-159A -treated eyes. Topical treatment with AXR-159A decreased 
dendritic cell activation in lymph nodes. The effects on corneal staining and cellular 
composition in draining cervical lymph nodes (CLN) were not reproduced by systemic 
administration of AXR-159A, suggestive of a local role for integrin antagonism in the 
treatment of dry eye (Krauss et al, 2015).  
The presence of CD4+ T cells at the ocular surface in DED and the successful treatment 
of ocular surface inflammation with cyclosporine (i.e., Restasis® and Ikervis®) suggest 
that adaptive immunity is important in the pathophysiology of DED.  Initiation of an 
adaptive immune response requires that antigens at the site of inflammation are presented 
by professional antigen presenting cells that migrate to regional lymphoid tissue to 
activate and expand antigen-specific T cells.  The ability of AXR-159A to decreased 
dendritic cell activation in lymph nodes suggests it has the ability to block adaptive 
immunity associated with DED.    
Given the above clinical experience in man with an antibody directed against the α4- 
integrin subunit and preclinical work with novel α4 integrin antagonists, i.e., AXR-159A 
and BIO-8809, in pre-clinical models of DED, AxeroVision Inc. believes that AXR-159 
has potential as a novel agent for the treatment of dry eye disease. 


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4 STUDY OBJECTIVES 
TABLE 4–1 
TABLE OF OBJECTIVES, ENDPOINT, AND ENDPOINT JUSTIFICATION 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
Stage 1:  
To evaluate the safety, 
tolerability, and exploratory 
pharmacodynamics of up to 2 
different concentrations of 
AXR-159 Ophthalmic Solution 
(30 mg/mL or 50 mg/mL) 
dosed three-times daily (TID) 
or twice-daily (BID) for up to 
12 weeks compared to its 
vehicle in patients with Dry 
Eye Disease (DED). 
Adverse Events: 
•
Incidence rates of each
treatment-emergent adverse
event summarized by
primary system organ class
and preferred term.
•
Tables for all treatment-
emergent adverse events
regardless of causality.
•
Tables for all treatment-
emergent adverse events
considered to be treatment-
related.
•
Shift tables for safety
variables (e.g., IOP,
biomicroscopy, and
ophthalmoscopy).
Signal of Efficacy: 
•
Change from Baseline in
inferior corneal staining
score in the study eye
•
Change from Baseline in
total corneal staining score
in the study eye
•
Change from Baseline in
eye dryness measured using
a visual analogue scale
(VAS)
•
Change from Baseline in
Total Ocular Surface
Disease Index (OSDI) score
The endpoints for safety and 
tolerability are all commonly 
used in drug trials.   
The efficacy endpoints match 
those captured in the Xiidra 
clinical development program 
and are listed on the U.S. Food 
& Drug Administration 
webpage 
(https://www.accessdata.fda.go
v/drugsatfda_docs/nda/2016/ 
208073Orig1s000TOC.cfm). 
Stage 2:  
To evaluate the safety, 
tolerability, and 
pharmacodynamics of up to 3 
different concentrations of 
See Above for Stage 1 
See Above for Stage 1 


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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
AXR-159 Ophthalmic Solution 
(3 mg/mL, 30 mg/mL or 50 
mg/mL) dosed three-times 
daily (TID) or twice-daily 
(BID) for up to 12 weeks 
compared to its vehicle in 
patients with Dry Eye Disease 
(DED). 
Secondary 
 
 
 
 
 
See Above for Stages 1 & 2 
• Schirmer’s test w/o 
anesthesia 
• Tear film break-up time 
(TBUT)  
• Conjunctival redness score 
• Sodium fluorescein corneal 
staining  
• Lissamine green 
conjunctival staining  
• Ocular Discomfort Score 
• Patient symptoms (visual 
analog scale [VAS]) 
• OSDI (subscales and items) 
• Symptom Assessment 
iN Dry Eye (SANDE) 
• Proportion of patients with a 
TBUT ≥ 10 seconds at each 
visit  
• Proportion of patients with a 
Schirmer’s test ≥ 10 mm at 
each visit  
• Proportion of patients with a 
Total OSDI < 18 at each 
visit 
• Proportion of patients with 
an Ocular Discomfort Score 
= 0 at each visit 
• Tear collection (for 
exploratory analyses) 
(selected sites)  
 
 
 
See Above for Stages 1 & 2 
 


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5 CLINICAL HYPOTHESES 
Stage 1:   
 
AXR-159 Ophthalmic Solution (50 mg/mL or 30 mg/mL) has an acceptable safety and 
tolerability profile following TID or BID administration for the study treatment duration.  
 
AXR-159 Ophthalmic Solution (50 mg/mL or 30 mg/mL) demonstrates an Early Signal 
of Efficacy (ESOE) for either a sign (e.g., Inferior Corneal Staining) or Symptom (e.g., 
eye dryness measured by VAS or Total OSDI) of DED.  
 
Stage 2:   
 
At least 1 concentration of AXR-159 Ophthalmic Solution (3 mg/mL, 30 mg/mL or 50 
mg/mL) has an acceptable safety and tolerability profile following TID or BID 
administration for the study treatment duration.  
 
At least 1 concentration of AXR-159 Ophthalmic Solution (3 mg/mL, 30 mg/mL or 50 
mg/mL) is more effective than vehicle for treating DED as measured by either a sign 
(e.g., Inferior Corneal Staining) or Symptom (e.g., eye dryness measured by VAS or 
Total OSDI) of DED. 
6 OVERALL STUDY DESIGN 
 
Overall Design 
This 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) dosed three-times daily (TID) or twice-daily (BID); Stage 2: AXR-159 
Ophthalmic Solution (3 mg/mL, 30 mg/mL or 50 mg/mL) dosed three-times daily (TID) 
or twice-daily (BID).  
For both Stages 1 and 2, patients with signs and symptoms of DED will be randomly 
assigned in a 1:1 (Stage 1) or up to a 2:2:2:2:1:1:1 (Stage 2) ratio 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 treatment period (See Appendix 1 for study visit structure across Stages 1 and  
2 and Figure 6.1-1 for the study flow diagram).  If only a single dosing regimen is 
selected for Stage 2 a 1:1:1:1 regime may be selected: AXR-159 Ophthalmic Solutions 
and AXR-159 Ophthalmic Solution Vehicle. 
When the 10th patient enrolled in Stage 1, Cohort 1 (8 patients on AXR-159 Ophthalmic 
Solution 50 mg/mL TID and 2 patients on vehicle TID) completes the Week 2 visit, a 
Data Review Committee (DRC) will evaluate all available safety data.  If AXR-159 
Ophthalmic Solution 50 mg/mL TID is safe and well tolerated the DRC will recommend 


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expansion of the AXR-159 Ophthalmic Solution 50 mg/mL and vehicle TID groups  
(N = 45 per group) and to halt the initiation of Stage 1, Cohorts 2 and 3.  If AXR-159 
Ophthalmic Solution 50 mg/mL TID is NOT safe and well tolerated the DRC will 
recommend Stage 1, Cohort 2 (8 patients on AXR-159 Ophthalmic Solution 30 mg/mL 
TID and 2 patients on vehicle TID) and to halt the Cohort 1 Expansion Cohort.  Patients 
already enrolled in Stage 1, Cohort 1 will continue at the investigator’s discretion.  Any 
patients that discontinue during the study will be followed through the resolution of their 
adverse event(s) or end of study.  When the 10th patient enrolled in Stage 1, Cohort 2 
completes the Week 2 visit, a DRC will evaluate all available safety data.  If AXR-159 
Ophthalmic Solution 30 mg/mL TID is safe and well tolerated the DRC will recommend 
expansion of the AXR-159 Ophthalmic Solution 30 mg/mL and vehicle TID Expansion 
Cohort (N = 40 per group) and to halt Cohort 3.  If AXR-159 Ophthalmic Solution 30 
mg/mL TID is NOT safe and well tolerated the DRC will recommend Stage 1, Cohort 3 
(8 patients on AXR-159 Ophthalmic Solution 30 mg/mL BID and 2 patients on vehicle 
BID) and to halt the Cohort 2 Expansion Cohort.  Patients already enrolled in Stage 1, 
Cohort 2 will continue at the investigator’s discretion.  When the 10th patient enrolled in 
Stage 1, Cohort 3 completes the Week 2 visit, a DRC will evaluate all available safety 
data.  If AXR-159 Ophthalmic Solution 30 mg/mL BID is safe and well tolerated the 
DRC will recommend expansion of the AXR-159 Ophthalmic Solution 30 mg/mL and 
vehicle BID Expansion Cohort (N = 35 per group).  If AXR-159 Ophthalmic Solution 30 
mg/mL BID is NOT safe and well tolerated the DRC will recommend stopping the study.  
Thus, in stage 1 a successive cohort will only be started if the previous cohort is felt to be 
either unsafe or poorly tolerated by the DRC.    
When the last patient enrolled in Stage 1 completes the Month 3 visit in the Expansion 
Cohort, a formal Interim Analysis will be completed and the DRC will evaluate all 
available safety and efficacy data from Stage 1 before recommending initiation of Stage 
2.  Stage 2 is a parallel group design and the DRC may recommend up to a maximum of 
7 groups as depicted in Figure 6.1-1.  Groups that are either unsafe, poorly tolerated, or 
likely futile may be discontinued by the DRC.  The DRC may reallocate patients to the 
surviving AXR-159 Ophthalmic Solution dose groups. 
A final database lock will occur at the completion of Stage 2 and the safety, tolerability, 
and efficacy data from both Stage 1 and 2 will be analyzed separately and in a combined 
fashion to fully leverage the advantage of this two-stage study design. 


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FIGURE 6.1-1 STUDY DESIGN 
 
 
Scientific Rationale for Study Design 
Prior studies in dry eye have been marked by poor reproducibility. This is due partly to 
the heterogeneity of the population, inadequate assessment methods, and poor correlation 
between signs and symptoms.  
Xiidra (lifitegrast ophthalmic solution) which was approved by the US FDA on July 11th, 
2016 addressed these challenges through a variety of design considerations which are 
incorporated into the current study design: 
1. 
The registration studies used a vehicle which was not palliative 
2. 
Subjects showing active signs and symptoms of DED after a 2 week run-in on 
the vehicle either switched to lifitegrast ophthalmic solution 5% or stayed on 
vehicle 
3. 
The studies were enriched for both inferior corneal staining and/or eye 
dryness 
Thus, clinical study AXR201701 incorporates the learnings from the recently successful 
clinical program for Xiidra. 


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Data Review Committee (DRC) 
A DRC consisting of physicians and trained study personnel, in addition to ad hoc 
internal/external experts, will assess study treatment effects.  The composition and 
activities of the committee are described in the DRC charter.  The DRC will review 
available data to determine the appropriateness of continuing dosing and enrollment in 
Stage 1.  Based on review of data from all executed Stage 1 cohorts, the DRC will 
recommend whether to proceed to Stage 2 and the dose levels to be employed.  The DRC 
may recommend at any time during Stage 1 to de-escalate, delay, or to stop patient 
recruitment.  The number of treatment groups, doses, and number of subjects per-group 
in Stage 2 will be based on recommendations by the DRC following review of available 
Stage 1 data.  Details of the planned analyses will be provided in the DRC analysis plan.  
The DRC may also request ad-hoc review of masked or unmasked data at any time 
throughout the course of the study to evaluate new findings or recommend changes to 
study progression. 
 
End of Study Definition 
A participant is considered to have completed the study if he or she has completed all 
phases of the study including the last visit or the last scheduled procedure shown in the 
Schedule of Activities (SoA), Appendix 1. 
7 STUDY POPULATION 
 
Number of Subjects (approximate) 
Stage 1:   
The total number of randomized patients for Stage 1 of the study will be approximately 
100 at up to 2 sites.  Approximately 50% of patients should have a baseline eye dryness 
score of ≥ 60 and approximately 50% of patients should have a baseline inferior corneal 
staining score (ICCS) > 1.5 according to the Ora Calibra® staining scale.   Based upon 
data from Xiidra®, OPUS 2 a screen failure rate of ~ 50% is expected.   Thus, ~200 
patients will need to be screened to achieve ~100 patients randomized to treatment.   
Stage 2:   
The total number of randomized patients for Stage 2 of the study will be approximately 
330 (see Figure 6.1-1, Stage 2) at up to 7 sites.  Approximately 50% of patients should 
have a baseline eye dryness score of ≥ 60 and approximately 50% of patients should have 
a baseline inferior corneal staining score (ICCS) > 1.5 according to the Ora Calibra® 
staining scale.   Based upon data from Xiidra®, OPUS 2 a screen failure rate of ~ 50% is 
expected.   Thus, ~660 patients will need to be screened to achieve ~330 patients 
randomized to treatment.   
Note: patients can be reallocated from discontinued groups to increase the power in 
groups that are continued at the discretion of the DRC. 


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Study Population Characteristics 
The study will consist of patients with DED, who at the screening visit (day -14) are 
administering a conventional artificial tear for the symptoms of DED within the 30 days 
preceding the screening visit and are willing to suspend use of artificial tears for the study 
duration.   
Patients with systemic autoimmune disorders (including, but not limited to, primary and 
secondary Sjögren’s Syndrome, systemic lupus erythematosus, rheumatoid arthritis, 
chronic osteoarthritis, eczema, ankylosing spondylitis, scleroderma, and atopic 
dermatitis) may be included in the study. 
 
Inclusion Criteria 
1. Male or female, 18 years of age or older at screening visit  
2. Provide written informed consent 
3. Be willing and able to follow instructions and participate in all study assessments 
and visits 
4. 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 at 
Visits 1 and 2 
5. Must have patient reported history of dry eye for at least 6 months prior to Visit 1  
6. Use of non-prescription artificial tears for the symptoms of DED within the 30 
days preceding the screening visit and willing to suspend use of artificial tears for 
the study duration 
7. Corneal fluorescein staining score ≥ 2 according to the Ora Calibra® scale in at 
least one region in at least one eye at the screening Visit 1 (Pre-CAE®) and Visit 2 
8. Conjunctival redness score ≥ 1 according to the Ora Calibra® Conjunctival 
Redness for Dry Eye Scale in at least one eye at Visit 1 (Pre-CAE®) and Visit 2 
9. Eye dryness score ≥ 40 (0-100 VAS scale in both eyes) at Visit 1 (Pre-CAE®) and 
Visit 2 
10. Total Ocular Surface Disease Index (OSDI) score > 18 at Visit 1 (Pre-CAE®) and 
Visit 2 
11. In the same eye at Visits 1 and 2, subjects must have: 
a. Inferior corneal fluorescein staining score ≥ 0.5 according to the Ora 
Calibra® Corneal and Conjunctival Staining Scale for Grading of 
Fluorescein Staining, Pre-CAE® at Visit 1   
b. Schirmer’s Tear Test without anesthesia ≥ 1 and ≤ 10 mm 
 
 
Exclusion Criteria 
1. Uncontrolled ocular disease (except for dry eye disease/keratoconjunctivitis sicca) 
or uncontrolled systemic disease 
2. Patient has glaucoma, ocular hypertension, on IOP-lowering medications or have 
previously undergone any glaucoma laser or surgical procedure  


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3. Corneal abnormality or disorder that impacts normal spreading of the tear film 
(keratoconus, pterygia, scarring) or compromised corneal integrity 
4. BCVA worse than 20/100 in either eye 
5. Current use of punctal plugs, anticipated insertion during the study, or a history of 
punctal cautery in either eye at any time prior to the screening visit or anticipate 
such a procedure during the study 
6. Keratoconjunctivitis sicca secondary to destruction of conjunctival goblet cells as 
occurs with vitamin A deficiency or scarring, such as that with cicatricial 
pemphigoid, alkali burns, Stevens-Johnson syndrome, trachoma, or irradiation 
7. Active ocular infection or inflammation other than that caused by DED (including 
allergic, vernal, or giant papillary conjunctivitis and severe eyelid inflammation) 
8. Patients with clinically significant inflammation of the lid margin such as anterior 
blepharitis or ocular rosacea 
9. Recent (within the past 3 months) ocular surgery, trauma or herpes 
10. Use of contact lenses in either eye within one month prior to the screening visit or 
anticipated use during the study 
11. Use of any type of scleral lenses or sealed compartment ocular frames within 2 
months of the screening visit, or planned use during the study 
12. Use prohibited medication within the prescribed washout window or anticipated 
use during the study: 
a. Topical cyclosporine (e.g., Restasis) or integrins (i.e., Xiidra): 12 weeks 
prior to Visit 1 
b. Corticosteroids or mast cell stabilizers: 2 weeks prior to Visit 1 
c. Antihistamines (including ocular): 72 hours prior to Visit 1 
d. Oral aspirin or aspirin containing products only if a stable dosing regimen 
has been established for at least 30 days before Visit 1 
e. Medications known to impact ocular dryness must be on a stable dosing 
regimen for at least 30 days before Visit 1 
f. All other ophthalmic preparations including artificial tears: 72 hours prior 
to Visit 1 
13. Eyelid abnormalities that affect lid function or impact lid closure 
14. Systemic disease condition that causes dry eye 
15. Diagnosis of hepatitis C infection, human immunodeficiency virus (HIV) 
infection, sarcoidosis, amyloidosis, active tuberculosis, or graft versus host 
disease  
16. History of anterior segment surgery or trauma that could affect corneal sensitivity 
(e.g., cataract surgery, refractive surgery or any surgery involving a limbal or 
corneal incision) in either eye within the 12 months prior to Visit 1 
17. Planned anterior segment surgery (e.g., cataract surgery or any surgery involving 
a limbal or corneal incision) in either eye during the study 


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18. Known allergy or sensitivity to fluorescein, lissamine green, or the study 
medication or its components  
19. Patient is unlikely to follow study instructions or to complete all required study 
visits or has a condition or situation that in the investigator's opinion, may put the 
patient at significant risk, may confound the study results, or may interfere 
significantly with the patient's participation in the study 
20. Patient is an employee at the investigational site or is related to any member of 
the study staff  
21. Patient cannot tolerate multiple blood draws 
22. Pregnant, nursing, or females of childbearing potential and not utilizing adequate 
birth control measures 
23. Participation in another ophthalmic clinical trial involving a therapeutic drug or 
device within the past 30 days 
24. Previous exposure to AXR-159 Ophthalmic Solution or Ophthalmic Solution 
Vehicle. 
 
 
Withdrawal Criteria (if applicable) 
Patients can voluntarily withdraw from the study at any time. The investigator and 
AxeroVision Inc. can withdraw a patient from the study at any time for any reason. 
Additionally, patients can be discontinued from the study by an investigator if any of the 
following criteria are met: 
• 
Patient develops (or had an exacerbation of) any medical condition that, in 
the opinion of the investigator, would put the patient at an unacceptable 
medical risk or compromised the patient’s ability to participate in the study 
• 
Patient is unwilling or unable to continue to comply with study procedures 
• 
Patient becomes pregnant 
The study can be stopped at the study site(s) at any time by the site investigator(s). 
AxeroVision Inc. can stop the study (and/or the study site[s]) with appropriate 
notification. 
If a patient discontinued participation in the study early, every attempt will be made to 
complete the exit procedures. Notification of early patient discontinuation from the study 
and the reason for discontinuation should be made to AxeroVision Inc. and clearly 
documented on the appropriate eCRF. 


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8 STUDY PARAMETERS 
 
Efficacy Measures and Endpoints 
8.1.1 Primary Efficacy Measure(s) 
Primary efficacy measures for Stage 1 and Stage 2 include total sodium fluorescein 
corneal staining (Oxford and Ora Calibra® scales), sodium fluorescein corneal staining in 
the inferior cornea (Ora scale), patient symptoms of dryness (visual analog scale [VAS]), 
and total OSDI.  For specific timings of efficacy measures see Appendix 1.   
• Change from Baseline to Month 3 in inferior corneal staining score (Ora 
Calibra® scale) in the study eye 
• Change from Baseline to Month 3 in total corneal staining score (Oxford 
and Ora Calibra® scales) in the study eye 
• Change from Baseline to Month 3 in eye dryness measured using a visual 
analogue scale (VAS) 
• Change from Baseline to Month 3 in Total Ocular Surface Disease Index 
(OSDI) score 
8.1.2 Secondary Efficacy Measure(s) 
Secondary efficacy measures for Stage 1 and Stage 2 include Schirmer’s test without 
anesthesia, TBUT, conjunctival redness score, sodium fluorescein corneal staining 
(Oxford and Ora Calibra® scales), lissamine green conjunctival staining (Oxford and Ora 
Calibra® scales), ocular discomfort score, patient symptoms (VAS), OSDI (total and 
subscales), Symptom Assessment iN Dry Eye (SANDE), and tear sampling for 
mechanism of action biomarkers.  Refer to Appendix 1 for specific timings of exploratory 
efficacy measures. 
• Schirmer’s test w/o anesthesia 
• Tear film break-up time (TBUT)  
• Conjunctival redness score 
• Sodium fluorescein corneal staining  
• Lissamine green conjunctival staining  
• Ocular Discomfort Score 
• Patient symptoms (visual analog scale [VAS]) 
• OSDI (subscales and items) 
• Symptom Assessment iN Dry Eye (SANDE) 
• Tear collection (for exploratory analyses) (selected sites)  
 
Safety Measures 
For stages 1 and 2, the following safety measures will be examined: 


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• Adverse events (ocular and non-ocular) 
• Ora Calibra® Drop Comfort Assessment 
• Best-corrected visual acuity (BCVA) 
• Slit-lamp biomicroscopy  
• Intraocular pressure (IOP) 
• Ophthalmoscopy   
• Ora Calibra® Conjunctival Redness for Dry Eye Scale  
• Vital signs 
• Laboratory tests (chemistry, hematology, urinalysis) 
• Urine pregnancy test 
Laboratory test results will be forwarded from the central laboratory to the study site and 
to AxeroVision Inc. or its designee.  The laboratory results from screening will be 
reviewed prior to randomization.  Laboratory tests at screening may be repeated once at 
the discretion of the investigator and pending discussion with AxeroVision Inc., to 
confirm exclusionary status.  Study treatment will be performed only if the investigator 
deems the laboratory results to be acceptable.  The most current specimen results will be 
reviewed prior to randomization.  The investigator will review all laboratory results for 
the clinical significance of any abnormalities.  Evaluation and management of abnormal 
laboratory results should be conducted according to local site practice.  Clinically 
significant abnormalities are to be recorded on an adverse event electronic case report 
form (eCRF) page. 
 
Other Measures 
Stage 1:   
Systemic pharmacokinetic samples will be collected in a subset of patients.  For 
determination of drug concentration in the circulation, blood samples will be collected at 
baseline (prior to treatment) and month 1.5.  (see Appendix 1). 
• Systemic pharmacokinetics 
9 STUDY MATERIALS 
 
Study Treatment(s) 
9.1.1 Study Treatment(s)/ Formulation(s)/ Medical Device Composition or Design 
All concentrations of AXR-159 Ophthalmic Solution are preservative-free and contain 
the drug product, AXR-159 (GW559090) (3 mg/mL, 30 mg/mL or 50 mg/mL), and 
suitable excipients.  Excipients in the formulation include phosphate buffer and sodium 
chloride.  The formulations will be supplied in identical unit dose containers (see Table 
9.1.1-1). 


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TABLE 9.1.1–1 INVESTIGATIONAL PRODUCT AND PACKAGING CHARACTERISTICS 
 
 
Investigational Product 
Product name: 
AXR-159 
Vehicle (Placebo) 
Formulation 
description: 
AXR-159 solutions contain 
3 mg/mL, 30 mg/mL or 50 
mg/mL AXR-159 as 
parent.  
Placebo solution matches 
30 mg/mL or 50 mg/mL 
AXR-159 as parent 
solutions. 
Dosage form: 
Ophthalmic Sterile 
Solution 
Ophthalmic Sterile 
Solution 
Unit dose 
strength(s)/Dosage 
level(s): 
3 mg/mL 
30 mg/mL 
50 mg/mL 
Placebo - phosphate buffer 
+ sodium chloride 
Route of 
Administration  
Topical 
Topical 
Dosing instructions : 
 
Single use vial - one drop 
in the same selected eye 
three times a day (or twice 
a day).  Each container will 
be used to dose both eyes 
and should then be 
discarded.  Thus, a patient 
dosing TID will use 3 units 
in one day and a patient 
dosing BID will use 2 units 
in one day. 
Single use vial - one drop 
in the same selected eye 
three times a day (or twice 
a day). Each container will 
be used to dose both eyes 
and should then be 
discarded.  Thus, a patient 
dosing TID will use 3 units 
in one day and a patient 
dosing BID will use 2 units 
in one day. 
Physical description: 
A clear, colourless solution 
packaged in a single use 
container. 
A clear, colourless solution 
packaged in a single use 
container. 
Device: 
 
Single use blow fill seal 
vial, tear-off cap 
Single use blow fill seal 
vial, tear-off cap 
Method for 
individualizing 
dosage: 
Five single use containers 
are placed in an individual 
foil wrap and appropriately 
labelled. 
Five single use containers 
are placed in an individual 
foil wrap and appropriately 
labelled. 
 
9.1.2 Dosing and Administration 
The study medication will be self-administer by the patient (or administered by site staff 
or a caregiver) at the study site after all procedures have been completed for the run-in 
and post-randomization visits.  At these visits, each patient will be asked to stay at the 
site for 30 minutes after study drug administration.   
 
 


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Patients will be instructed to twist-off the tips of the unit of use containers.  They should 
not pull them off. Patients (or site staff or a caregiver) will then make a pouch with the 
lower lid and instil the study medication.   
Each patient (or caregiver) must instil 1 drop of the vehicle either tree times daily (TID) 
(once in the morning, once around mid-day, and once in the evening) or twice daily 
(BID) (once in the morning and once in the evening) to both eyes during the 2 week run-
in period.  During the double-masked treatment period, each patient (or caregiver) must 
instil 1 drop of the study medication either tree times daily (TID) (once in the morning, 
once around mid-day, and once in the evening) or twice daily (BID) (once in the morning 
and once in the evening) to both eyes for 3 months.  For both the dosing regimens the 
morning and evening study medication doses should be instilled about 12 hours apart.  
For the TID dosing regimen the mid-day medication doses should be instilled about 6 
hours after the morning dose.   
One unit dose vial of the masked study medication is to be used for only 1 application to 
both eyes. The patient should be instructed to place the used vial in the used vial bag after 
use and should return used and unused vials at the next study visit.  
 
Other Study Supplies 
Urine pregnancy tests, Schirmer’s test strips, sodium fluorescein, lissamine green, 
Fluress, tear collection supplies, phlebotomy supplies, urinalysis supplies. 
10 STUDY METHODS AND PROCEDURES 
 Subject Entry Procedures 
10.1.1 Overview 
Subjects as defined by the criteria in sections 7.2, 7.3, and 7.4 will be considered for 
entry into this study. 
10.1.2 Informed Consent 
Prior to a subject’s participation in the trial (i.e., prior to changes in a subject’s medical 
treatment and/or prior to study related procedures), the study will be discussed with each 
subject, and subjects wishing to participate must give written informed consent using an 
informed consent form (ICF).  The informed consent form must be the most recent version 
that has received approval/favorable review by a properly constituted Institutional Review 
Board (IRB) 
 
10.1.3 Washout Intervals 
Prohibited medications, treatments, and activities are outlined in the Exclusion Criteria 
(Section 7.4).  
 
 


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10.1.4 Procedures for Final Study Entry 
Subjects must meet all inclusion and none of the exclusion criteria.  
10.1.5 Methods for Assignment to Treatment Groups: 
Prior to initiation of study run-in (at Visit 1), each subject who qualifies for entry will be 
assigned a screening number. All screening numbers will be assigned in strict numerical 
sequence at a site and no numbers will be skipped or omitted. If all inclusion and exclusion 
criteria are met at Visits 1 and 2, each qualifying subject will then be assigned a 
randomization number at the end of Visit 2.  
A randomization schedule will be provided to each investigational site. The 
randomization schedule will use block randomization stratified by site, such that there 
will be an approximate equal number of subjects assigned to each of the two treatment 
arms at each site for the Stage 1, Expansion Cohort. For Stage 1, Cohorts 1-3 patients 
with signs and symptoms of DED will be randomly assigned in a 4:1 ratio to receive 
either a single concentration of AXR-159 Ophthalmic Solution or AXR-159 Ophthalmic 
Solution Vehicle. The site staff will dispense to the patient the study kit labelled with the 
corresponding randomization number. The randomization number will be recorded on the 
patient’s source document and eCRF. New kits will be dispensed at Visits 2, 3, and 4 
based on the subject’s randomization. The Sponsor, Investigators, and study staff will be 
masked during the randomization process and throughout the study. 
During the run-in period, the patients will all be supplied with AXR-159 Ophthalmic 
Solution Vehicle.  Patients will be informed that they will receive only vehicle during the 
2-week run-in period.  Following the run-in period the patient, site personnel, the sponsor 
and patients will be masked to the treatment assignment for the 3 month treatment period.  
All study medication will be provided in identical unit of dose vials and cartons to 
maintain masking of the study.   
For both Stages 1 and 2, patients with signs and symptoms of DED will be randomly 
assigned in a 4:1 (Stage 1, Cohorts 1-3) ratio, a 1:1 (Stage 1, Expansion Cohort) ratio, or 
to a 2:2:2:2:1:1:1 (Stage 2) ratio to receive either a single concentration of AXR-159 
Ophthalmic Solution or AXR-159 Ophthalmic Solution Vehicle.   
For the expansion cohort in Stage 1 and Stage 2, subjects will be randomized by strata as 
follows: 
• Site 
• Baseline eye dryness score ≥ 60, < 60 
• Baseline inferior corneal staining > 1.5, ≤ 1.5 
Subjects will not be stratified in Cohorts 1, 2 and 3 in Stage 1. 
 


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 Concurrent Therapies 
The use of any concurrent medication, prescription or over-the-counter, is to be recorded 
on the subject’s source document and corresponding case report form (CRF) along with 
the reason the medication was taken. 
Concurrent enrollment in another investigational drug or medical device study is not 
permitted. 
10.2.1 Prohibited Medications/Treatments 
Prohibited medications, treatments, and activities are outlined in the Exclusion Criteria 
(Section 7.4).  
10.2.2 Rescue Medications 
In the event that rescue medication is required for worsening signs or symptoms of dry 
eye disease during the course of the study, patients will be provided an appropriate rescue 
regimen by the investigator/treating clinician, and will be exited from the study. 
10.2.3 Special Diet or Activities 
No special diets or activities are required for this study. 
 Examination Procedures 
10.3.1 Procedures to be Performed at Each Study Visit with Regard to Study 
Objective(s) 
10.3.1.1 Visit 1: Screening (Day -14 ± 2) 
Pre–CAE®  
• Written informed consent form 
• Demographic information 
• Medical, ophthalmic, and dry eye disease history 
• Concomitant medications and procedures 
• Inclusion and exclusion criteria 
• Urine pregnancy test (for females of childbearing potential) 
• Patient symptoms using the Visual Analog Scale 
• Ocular Discomfort Score 
• OSDI® 


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• SANDE 
• Best-corrected visual acuity 
• Vital signs 
• Bulbar conjunctival hyperemia scores (Ora Calibra® Conjunctival Redness for 
Dry Eye Scale) 
• Slit-lamp biomicroscopy 
• Oculus Keratograph 5® procedures: TBUT and tear meniscus height (selected 
sites) 
• TFBUT  
• Sodium fluorescein corneal staining, using the Oxford scale and Ora Calibra® 
scales 
• Lissamine green conjunctival staining, using the Oxford scale 
• 15+ minute wait from end of Lissamine staining to start of Schirmer’s Test 
• Schirmer’s without anesthesia  
• 90-minute CAE® exposure; 
o Ora Calibra® Ocular Discomfort Scale upon entering the CAE® and every 5 
minutes thereafter; 
Post–CAE®  
• Inclusion and exclusion criteria 
• Patient symptoms using the Visual Analog Scale 
• Ocular Discomfort Score 
• Bulbar conjunctival hyperemia scores (Ora Calibra® Conjunctival Redness for 
Dry Eye Scale) 
• Slit-lamp biomicroscopy 
• TFBUT  
• Sodium fluorescein corneal staining, using the Oxford scale and Ora Calibra® 
scales 


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• Lissamine green conjunctival staining, using the Oxford scale 
• Intraocular pressure (IOP) 
• Ophthalmoscopy (the dilating drug should not be given until the time of 
ophthalmoscopy)  
• Blood sample collection for Hematology and Chemistry 
• Urine sample collection for Urinalysis 
• Dispense AXR-159 Ophthalmic Solution Vehicle 
• Adverse event query 
10.3.1.2 Visit 2: Baseline & Randomization (Day 1) 
• Study drug collection  
• Medical/medication history update 
• Inclusion and exclusion criteria 
• Patient symptoms using the Visual Analog Scale 
• Ocular Discomfort Score 
• OSDI 
• SANDE 
• BCVA with manifest refraction  
• Vital signs 
• Bulbar conjunctival hyperemia scores (Ora Calibra® Conjunctival Redness for 
Dry Eye Scale) 
• Slit-lamp biomicroscopy 
• Tear Collection (selected sites) 


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• Oculus Keratograph 5® procedures: TBUT and tear meniscus height (selected 
sites) 
• TFBUT  
• Sodium fluorescein corneal staining, using the Oxford scale and Ora Calibra® 
scales 
• Lissamine green conjunctival staining, using the Oxford scale 
• 15+ minute wait from end of Lissamine staining to start of Schirmer’s Test 
• Schirmer without anesthesia  
• Intraocular pressure (IOP) 
• Randomization 
• Blood sample collection for systemic pharmacokinetics (in selected Stage 1 
patients) 
• Administer AXR-159 Ophthalmic Solution or vehicle in both eyes (must NOT be 
done before blood and tear sample collection) 
• Ora Calibra® Drop Comfort Assessment 
• Collect and dispense study drug 
• Adverse event query 
10.3.1.3 Visit 3: 2-Week Follow-up (Day 15 ± 2 Days) 
• Study drug collection  
• Medical/medication history update 
• Patient symptoms using the visual analog scale 
• Ocular Discomfort Score 
• OSDI 
• SANDE 


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• BCVA with manifest refraction  
• Bulbar conjunctival hyperemia scores (Ora Calibra® Conjunctival Redness for 
Dry Eye Scale) 
• Slit-lamp biomicroscopy 
• Oculus Keratograph 5® procedures: TBUT and tear meniscus height (selected 
sites) 
• TFBUT  
• Sodium fluorescein corneal staining, using the Oxford scale and Ora Calibra® 
scales 
• Lissamine green conjunctival staining, using the Oxford scale 
• 15+ minute wait from end of Lissamine staining to start of Schirmer’s Test 
• Schirmer without anesthesia 
• Intraocular pressure (IOP) 
• Dispense study drug 
• Administer AXR-159 Ophthalmic Solution or vehicle in both eyes ) 
• Adverse event query 
10.3.1.4 Visit 4: Month 1.5 Follow-up (Day 43 ± 2 Days) 
• Study drug collection  
• Medical/medication history update 
• Patient symptoms using the visual analog scale 
• Ocular Discomfort Score 
• OSDI 
• SANDE 
• BCVA with manifest refraction  


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• Bulbar conjunctival hyperemia scores (Ora Calibra® Conjunctival Redness for 
Dry Eye Scale) 
• Slit-lamp biomicroscopy 
• Oculus Keratograph 5® procedures: TBUT and tear meniscus height (selected 
sites) 
• TFBUT  
• Sodium fluorescein corneal staining, using the Oxford scale and Ora Calibra® 
scales 
• Lissamine green conjunctival staining, using the Oxford scale 
• 15+ minute wait from end of Lissamine staining to start of Schirmer’s Test 
• Schirmer without anesthesia 
• Intraocular pressure (IOP) 
• Dispense study drug 
• Blood sample collection for systemic pharmacokinetics (in selected Stage 1 
patients) 
o Collected pre-dose, and at 15, 30, 60, 90, 180, 360 minutes post-dose 
• Administer AXR-159 Ophthalmic Solution or vehicle in both eyes (must NOT be 
done before blood and tear sample collection) 
• Ora Calibra® Drop Comfort Assessment 
• Adverse event query 
10.3.1.5 Visit 5: 3 Month Follow-up (Day 85 ± 2 Days) 
Pre–CAE®  
• Study drug collection  
• Medical/medication history update 
• Urine pregnancy test (for females of childbearing potential) 


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• Patient symptoms using the visual analog scale 
• Ocular Discomfort Score 
• OSDI 
• SANDE 
• BCVA with manifest refraction  
• Vital signs 
• Bulbar conjunctival hyperemia scores (Ora Calibra® Conjunctival Redness for 
Dry Eye Scale) 
• Slit-lamp biomicroscopy 
• Tear Collection (selected sites) 
• Oculus Keratograph 5® procedures: TBUT and tear meniscus height (selected 
sites) 
• TFBUT  
• Sodium fluorescein corneal staining, using the Oxford scale and Ora Calibra® 
scales 
• Lissamine green conjunctival staining, using the Oxford scale 
• 15+ minute wait from end of Lissamine staining to start of Schirmer’s Test 
• Schirmer without anesthesia 
• 90-minute CAE® exposure; 
o Ora Calibra® Ocular Discomfort Scale upon entering the CAE® and every 5 
minutes thereafter; 
Post–CAE®  
• Patient symptoms using the Visual Analog Scale 
• Ocular Discomfort Score 


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• Bulbar conjunctival hyperemia scores (Ora Calibra® Conjunctival Redness for 
Dry Eye Scale) 
• Slit-lamp biomicroscopy 
• TFBUT  
• Sodium fluorescein corneal staining, using the Oxford scale and Ora Calibra® 
scales 
• Lissamine green conjunctival staining, using the Oxford scale 
• Intraocular pressure (IOP) 
• Ophthalmoscopy  
• Blood sample collection for Hematology and Chemistry 
• Urine sample collection for Urinalysis 
• Administer AXR-159 Ophthalmic Solution or vehicle in both eyes (must NOT be 
done before blood and tear sample collection) 
• Ora Calibra® Drop Comfort Assessment 
• Adverse event query 
• Study Exit 
Adverse Events (AEs) (both elicited and observed) will be monitored throughout the 
study. All AEs (both elicited and observed) will be promptly reviewed by the investigator 
for accuracy and completeness. All AEs will be documented on the appropriate CRF. 
If a female becomes pregnant during the study, the investigator will notify AxeroVision 
Inc. immediately after the pregnancy is confirmed and the patient will be exited from the 
study after appropriate safety follow-up.  The investigator will (1) notify the patient’s 
physician that the patient was being treated with an investigational drug (AXR-159 
Ophthalmic Solution), and (2) follow the progress of the pregnancy.  The investigator 
must document the outcome of the pregnancy and provide a copy of the documentation to 
AxeroVision Inc. 


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 Schedule of Visits, Measurements and Dosing 
10.4.1 Scheduled Visits 
Refer to Appendix 1 for a schedule of visits and measurements. 
10.4.2 Unscheduled Visits 
These visits may be performed in order to ensure subject safety. All procedures 
performed at an unscheduled visit will be recorded in the source documents and on the 
Unscheduled Visit eCRF pages. Any procedure indicated in the eCRF that is not 
performed should be indicated as “Not done.” 
Evaluations that may be conducted at an Unscheduled Visit include: 
• Vital Signs 
• Labs 
• Slit-lamp Biomicroscopy 
• Visual Acuity 
• Intraocular Pressure 
• Urine Pregnancy Test 
• Ophthalmoscopy 
• Assessment of Adverse Events 
• Assessment of concomitant medications and/or treatments 
• Any other assessments needed in the judgment of the investigator. 
 Compliance with Protocol 
Whilst subjects are dosed at site, they will receive their study treatment directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents.  The dose of study 
treatment and study subject identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study treatment. 
Subjects will be instructed on proper instillation and storage of study drug at the end of 
Visits 1, 2, 3, and 4, and given written instructions. The used and unused study drug vials 
will be collected at each visit from Visit 2 up to and including Visit 5 to assess dosing 
and symptom assessment compliance. Dosing compliance will be based off of the used 
and unused vial count. If the subject is less than 80% or more than 125% compliant with 
dosing based on the expected number of used vials, then the subject will be deemed non-
compliant and a deviation should be recorded.  


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 Subject Disposition 
10.6.1 Completed Subjects 
A completed subject is one who has not been discontinued from the study. 
10.6.2 Discontinued Subjects 
Subjects may be discontinued prior to their completion of the study due to: 
• 
subject request/withdrawal 
• 
AEs 
• 
protocol violations 
• 
administrative reasons (e.g., inability to continue, lost to follow up) 
• 
sponsor termination of study 
• 
other 
Note: In addition, any subject may be discontinued for any sound medical reason. 
Notification of a subject discontinuation and the reason for discontinuation will be made 
to Ora and/or sponsor and will be clearly documented on the CRF. 
 Study Termination 
The study may be stopped at any time by the investigator, the sponsor, and/or Ora with 
appropriate notification. 
 Study Duration 
The total duration of study is approximately 3.5 months (from screening to study 
completion).  
 Monitoring and Quality Assurance 
During the course of the study a monitor, or designee, will make routine site visits to 
review protocol compliance, assess Investigational Product (IP)/device accountability, 
and ensure the study is being conducted according to the pertinent regulatory 
requirements. The review of the subjects’ medical records will be performed in a manner 
that adequately maintains subject confidentiality. Further details of the study monitoring 
will be outlined in a monitoring plan. 
Regulatory authorities of domestic and foreign agencies, Ora, Inc. quality assurance and 
or its designees may carry out on-site inspections and/or audits which may include source 
data checks. Therefore, direct access to the original source data will be required for 
inspections and/or audits. All inspections and audits will be carried out giving 
consideration to data protection as well as subject confidentiality to the extent that local, 
state, and federal laws apply. 


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11 ADVERSE EVENTS 
 Adverse Event 
An AE is defined as any untoward medical occurrence associated with the use of an IP in 
humans, whether or not considered IP-related. An AE can be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an IP, without any judgment about causality. An AE can arise 
from any use of the IP (e.g., off-label use, use in combination with another drug or 
medical device) and from any route of administration, formulation, or dose, including an 
overdose. An AE can arise from any delivery, implantation, or use of a medical device, 
including medical device failure, subject characteristics that may impact medical device 
performance (e.g., anatomical limitations), and therapeutic parameters (e.g., energy 
applied, sizing, dose release, and anatomic fit) associated with medical device use. 
All AEs spontaneously reported by the subject and/or in response to an open question 
from study personnel or revealed by observation, physical examination or other 
diagnostic procedures will be recorded in the source document and on the appropriate 
pages of the CRF. Any clinically relevant deterioration in clinical finding is considered 
an AE and must be recorded. When possible, signs and symptoms indicating a common 
underlying pathology should be noted as one comprehensive event. 
Documentation regarding the AE should be made as to the nature, date of onset, end date, 
severity, and relationship to IP, action(s) taken, seriousness, and outcome of any sign or 
symptom observed by the physician or reported by the subject upon indirect questioning.  
11.1.1 Severity 
Severity of an AE is defined as a qualitative assessment of the degree of intensity of an 
AE as determined by the investigator or reported to him/her by the subject. The 
assessment of severity is made irrespective of relationship to IP or seriousness of the 
event and should be evaluated according to the following scale: 
• 
Mild: Event is noticeable to the subject, but is easily tolerated and does not 
interfere with the subject’s daily activities. 
• 
Moderate: Event is bothersome, possibly requiring additional therapy, and may 
interfere with the subject’s daily activities. 
• 
Severe: Event is intolerable, necessitates additional therapy or alteration of 
therapy, and interferes with the subject’s daily activities. 
11.1.2 Relationship to Investigational Product 
A determination will be made of the relationship (if any) between an adverse event and 
the study drug or study procedure, as applicable.  A causal relationship is present if a 
determination is made that there is a reasonable possibility that the adverse event may 
have been caused by the drug or study procedure.   
 
 


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The relationship of each AE to the IP should be determined by the investigator using 
these explanations: 
• Suspected: A reasonable possibility exists that the IP caused the AE. A suspected 
AE can be further defined as: 
 Definite: Relationship exists when the AE follows a reasonable sequence from 
the time of IP administration, follows a known response pattern of the drug 
class, is confirmed by improvement on stopping the IP and no other 
reasonable cause exists. 
 Probable: Relationship exists when the AE follows a reasonable sequence 
from the time of IP administration, follows a known response pattern of the 
drug class, is confirmed by improvement on stopping the IP and the suspect IP 
is the most likely of all causes. 
 Possible: Relationship exists when the AE follows a reasonable sequence 
from the time of IP administration, but could also have been produced by the 
subject’s clinical state or by other drugs administered to the subject. 
• Not Suspected: A reasonable possibility does not exist that the IP caused the AE. 
• Not Related: Concurrent illness, concurrent medication, or other known cause 
is clearly responsible for the AE, the administration of the IP and the 
occurrence of the AE are not reasonably related in time, OR exposure to IP 
has not occurred. 
Suspected adverse reaction means any AE for which there is a reasonable possibility that 
the IP caused the AE. “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the IP and the AE. Types of evidence that would suggest a 
causal relationship between the IP and the AE event include: a single occurrence of an 
event that is uncommon and known to be strongly associated with IP exposure (e.g., 
angioedema, hepatic injury, Stevens-Johnson Syndrome); one or more occurrences of an 
event that is not commonly associated with IP exposure, but is otherwise uncommon in 
the population exposed to the IP (e.g., tendon rupture); an aggregate analysis of specific 
events observed in a clinical trial (such as known consequences of the underlying disease 
or condition under investigation or other events that commonly occur in the study 
population independent of drug therapy) that indicates those events occur more 
frequently in the IP-treatment group than in a concurrent or historical control group. 
11.1.3 Expectedness 
The expectedness of an AE should be determined based upon existing safety information 
about the IP using these explanations: 
• Unexpected: An AE that is not listed in the Investigator’s Brochure (IB) or is not 
listed at the specificity or severity that has been observed. 
• Expected:  An AE that is listed in the IB at the specificity and severity that has been 
observed. 
• Not applicable: An AE unrelated to the IP. 


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AE events that are mentioned in the IB as occurring with a class of products or as 
anticipated from the pharmacological/mechanical (or other) properties of the product, but 
are not specifically mentioned as occurring with the particular product under 
investigation are to be considered unexpected. 
The investigator should initially classify the expectedness of an AE, but the final 
classification is subject to the Medical Monitor’s determination. 
 Serious Adverse Events 
An AE is considered serious if, in the view of either the investigator or sponsor, it results 
in any of the following outcomes: 
• Death; 
• A life-threatening AE; 
Note: An AE is considered “life-threatening” if, in the view of either the investigator or 
sponsor, its occurrence places the subject at immediate risk of death. It does not include 
an AE that, had it occurred in a more severe form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization; 
Note: The term “inpatient hospitalization” refers to any inpatient admission (even if less 
than 24 hours). For chronic or long-term inpatients, inpatient admission includes transfer 
within the hospital to an acute/intensive care inpatient unit. Inpatient hospitalization does 
not include: emergency room visits; outpatient/same-day/ambulatory procedures; 
observation/short stay units; rehabilitation facilities; hospice facilities; nursing homes; or 
clinical research/phase 1 units. 
Note: The term “prolongation of existing hospitalization” refers to any extension of an 
inpatient hospitalization beyond the stay anticipated or required for the reason for the 
initial admission as determined by the investigator or treating physician. 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions; 
Note: A serious adverse event (SAE) specifically related to visual threat would be 
interpreted as any potential impairment or damage to the subject’s eyes (e.g., 
hemorrhage, retinal detachment, central corneal ulcer or damage to the optic nerve). 
• A congenital anomaly/birth defect. 
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 


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 Procedures for Reporting Adverse Events 
All AEs and their outcomes must be reported to Ora, the sponsor, and the IRB/IEC as 
required by the IRB/IEC, federal, state, or local regulations and governing health 
authorities and recorded on the appropriate CRF.  
11.3.1 Reporting a Suspected Unexpected Adverse Reaction 
All AEs that are ‘suspected’ and ‘unexpected’ are to be reported to Ora, the sponsor and 
the IRB/IEC as required by the IRB/IEC, federal, state, or local regulations and 
governing health authorities. 
11.3.2 Reporting a Serious Adverse Event 
To ensure subject safety, all SAEs, regardless of relationship to the IP, must be 
immediately reported. All information relevant to the SAE must be recorded on the 
appropriate CRFs. The investigator is obligated to pursue and obtain information 
requested by Ora and/or the sponsor in addition to that information reported on the CRF. 
All subjects experiencing a SAE must be followed up and the outcome reported. 
In the event of a SAE, the investigator must notify Ora and the sponsor immediately; 
obtain and maintain in his/her files all pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and follow-up of the 
subject; provide Ora and the sponsor with a complete case history, which includes a 
statement as to whether the event was or was not suspected to be related to the use of the 
IP; and inform the IRB of the SAE within their guidelines for reporting SAEs. 
Contact information for reporting SAEs and ADEs: 
Name: 
Title: 
Company: 
Office Telephone: 
Brian Orrick 
Clinical Project Manager, Dry Eye 
Ora, Inc. 
978-685-8900 x9584 
Mobile Telephone: 
978-409-0138 
Office Facsimile: 
 
Name: 
Title: 
Office Telephone: 
Mobile Phone: 
Office Facsimile: 
978-849-7371 
 
Joseph B. Ciolino, MD 
Medical Monitor 
617-573-5575 
401-935-9662 
617-573- 4324 
 
 Procedures for Unmasking (if applicable) 
When necessary for the safety and proper treatment of the patient, the investigator can 
unmask the patient’s treatment assignment to determine which treatment has been 
assigned and institute appropriate follow-up care.  When possible, the sponsor 


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(AxeroVision Inc.) should be notified prior to unmasking study medication.  The 
investigator should inform the sponsor (AxeroVision Inc.) of the unmasking if there is no 
notification prior to the unmasking.   
A report of the results of this study may be published, sent to the appropriate health 
authorities in any country in which the study drug may ultimately be marketed, and 
published in part as required by appropriate health authorities (e.g., Clinical Trials 
posting and disclosure), but the patient’s name will not be disclosed in these documents.   
Patients will be informed that the study is posted and the results eventually disclosed by 
appropriate health authorities (e.g., Clinical Trials posting or freedom of information by 
the FDA). 
 Type and Duration of the Follow-up of Subjects after Adverse Events 
Any serious adverse event occurring during the study period (beginning with informed 
consent) and for at least 12 weeks after the last dose of study drug must be immediately 
reported, but no later than 24 hours after learning of a serious adverse event.  Serious 
adverse events must be reported to AxeroVision Inc. (or Agent of AxeroVision Inc.) as 
listed on the AxeroVision Inc. Study Contacts Sheet and recorded on the serious adverse 
event form.  All patients with a serious adverse event must be followed up and the 
outcomes reported.  The investigator must supply AxeroVision Inc. and the IRB/IEC with 
any additional requested information (e.g., autopsy reports and discharge summaries).  
In the event of a serious adverse event, the investigator must: 
1. Notify AxeroVision Inc. immediately by fax or email using the serious adverse 
event form (contact details can be found on page 1 of the serious adverse event 
form); phone numbers and relevant AxeroVision Inc. personnel contacts are also 
on the front page of the protocol. 
2. Obtain and maintain in his/her files all pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and follow-up 
of the patient. 
3. Provide AxeroVision Inc. with a complete, written description of the adverse 
event(s) on the serious adverse event form describing the event chronologically, 
including any treatment given (e.g., medications administered, procedures 
performed) for the adverse event(s).  Summarize relevant clinical information 
about the event:  signs, symptoms, diagnosis, clinical course and relevant clinical 
laboratory tests, etc.  Include any additional or alternative explanation(s) for the 
causality which includes a statement as to whether the event was or was not 
related to the use of the investigational drug. 


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4. Promptly inform the governing IRB/IEC of the serious adverse event as required 
by the IRB/IEC, local regulations, and the governing health authorities. 
12 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
The statistical analysis plan (SAP) will provide a detailed description of the planned 
statistical analysis. 
 Sample Size Determination 
The sample size is determined empirically.  Xiidra achieved a 0.25 unit difference 
between lifitegrast ophthalmic solution and vehicle in mean change from baseline to day 
84 in inferior cornel staining and a standard deviation of approximately 0.75 in Phase 2. 
Sample sizes for this study are based on detecting a 0.35 unit difference between the 
active and vehicle groups, assuming a standard deviation of 0.75.  In Stage 1 the number 
of expected enrolled subjects varies between 43 and 53 subjects in the active group and  
between 37 and 47 subjects in the vehicle group.  In Stage 2 the number of expected 
enrolled subjects is 60 in the active group and 30 to 60 subjects in the vehicle group. 
Thus, the combined sample provides between 103 and 113 subjects in the active group 
and between 67 and 77 subjects in the matching vehicle group or between 97 and 107 
subjects in the combined vehicle group.  Under these assumptions and allowing a dropout 
rate of 10%, sample sizes of 93 in the active treatment group and 60 in the vehicle group 
will yield 80% power to show a significant difference at the α = 0.05 level using a two-
sample t-test. 
 Analysis Populations 
The following analysis populations will be considered: 
• Modified Intent-to-Treat Population – The modified intent-to-treat (mITT) 
population includes all randomized subjects that have baseline and at least 1 post-
baseline assessment for 1 or more of the efficacy measurements (see Section 8.1).  
The primary analysis will be performed on the mITT population with the Last 
Observation Carried Forward (LOCF) imputation method for missing values. The 
mITT population may also be analyzed with observed data only (i.e., without 
LOCF) and using multiple imputation methods to assess sensitivity. Subjects in the 
mITT population will be analyzed as randomized. 
• Modified Intent-to-Treat 2 Population – The modified intent-to-treat 2 (mITT2) 
population includes all subjects in the mITT population that have baseline inferior 
corneal staining score in the study eye > 1.5.  The mITT2 population will be 
analyzed using LOCF.  The mITT2 population may also be analyzed using 
observed data only to assess sensitivity.  Subjects in the mITT2 population will be 
analyzed as randomized. 
• Per Protocol Population – The per protocol (PP) population includes subjects in the 
mITT population who do not have significant protocol deviations and who 


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complete the study. Protocol deviations will be assessed prior to database lock and 
unmasking. The PP population will be analyzed using observed data only for 
primary efficacy variables. Subjects in the PP population will be analyzed as 
treated. 
• Safety Population – The safety population includes all randomized subjects who 
have received at least one dose of the investigational product. The safety population 
will be analyzed for all safety assessments. Subjects in the Safety population will be 
analyzed as treated.  
The statistical analysis of safety data will be performed for the safety population.  The 
analysis of baseline and efficacy data will be performed for the mITT population.  The 
primary efficacy analysis will also be performed on the mITT2 and PP populations as 
sensitivity analyses. 
 Statistical Hypotheses 
The statistical hypotheses are stated in terms of one-sided hypotheses, although statistical 
testing will be two-sided. All hypotheses are Pre-CAE®. 
H01:  There is no difference between AXR-159 Ophthalmic Solution (50 mg/ml, 30 
mg/ml or 3 mg/ml, TID or BID) and vehicle (TID or BID) in the change from 
baseline to Month 3 in inferior corneal staining score in the study eye. 
H11:  The change from baseline to Month 3 in inferior corneal staining score in the 
study eye is less with AXR-159 Ophthalmic Solution (50 mg/ml, 30 mg/ml or 3 
mg/ml, TID or BID) than with vehicle (TID or BID). 
H02:  There is no difference between AXR-159 Ophthalmic Solution (50 mg/ml, 30 
mg/ml or 3 mg/ml, TID or BID) and vehicle (TID or BID) in the change from 
baseline to Month 3 in total corneal staining score in the study eye. 
H12:  The change from baseline to Month 3 in total corneal staining score in the study 
eye is less with AXR-159 Ophthalmic Solution (50 mg/ml, 30 mg/ml or 3 mg/ml, 
TID or BID) than with vehicle (TID or BID). 
H03:  There is no difference between AXR-159 Ophthalmic Solution (50 mg/ml, 30 
mg/ml or 3 mg/ml, TID or BID) and vehicle (TID or BID) in the change from 
baseline to Month 3 in eye dryness. 
H13:  The change from baseline to Month 3 in eye dryness is less with AXR-159 
Ophthalmic Solution (50 mg/ml, 30 mg/ml or 3 mg/ml, TID or BID) than with 
vehicle (TID or BID). 
H04:  There is no difference between AXR-159 Ophthalmic Solution (50 mg/ml, 30 
mg/ml or 3 mg/ml, TID or BID) and vehicle (TID or BID) in the change from 
baseline to Month 3 in total OSDI score. 


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H14:  The change from baseline to Month 3 in total OSDI score is less with AXR-159 
Ophthalmic Solution (50 mg/ml, 30 mg/ml or 3 mg/ml, TID or BID) than with 
vehicle (TID or BID). 
In the hypotheses above, dosing (TID or BID) of the vehicle will match the dosing of the 
active treatment.   
 Statistical Analyses 
12.4.1 General Approach 
In general, continuous data will be summarized with descriptive statistics (number of 
subjects, mean, standard deviation, median, minimum, and maximum) and will be 
analyzed using analysis of variance (ANOVA), analysis of covariance (ANCOVA) 
techniques, two-sample t-tests or Wilcoxon rank sum tests for between-group 
comparisons, and paired t-tests or sign-rank tests for within-group analyses.  Categorical 
variables will be summarized by number of subjects (n), frequency counts, and 
percentages, and they will be analyzed using Pearson’s chi-square test or Fisher’s exact 
test (if the expected cell count is less than 5 in 25% or more of the cells).  Ordinal 
variables will be analyzed using the Cochran-Mantel-Haenszel (CMH) or the Wilcoxon 
rank-sum test for between-treatment comparisons and the sign-rank test for within-
treatment comparisons. 
All summaries will be presented by treatment group and visit.  Summaries will be 
provided for demographics, baseline medical history, concurrent therapies, and subject 
disposition. 
For the purpose of summarization, medical history, concurrent therapies, and adverse 
events will be coded to MedDRA and WHO Drug dictionaries, as appropriate. 
Baseline measures are defined as the last measure prior to the initiation of study 
treatment, usually at Day 1.  If a measure is taken both pre-CAE® and post-CAE®, the 
baseline will be the last time point matched value prior to the initiation of study 
treatment.  For post-CAE® measures, this will be at Day -14.  For changes from pre-
CAE® to post-CAE® post first treatment, the change from pre-CAE® to post-CAE® at 
Day -14 will be considered the baseline value. 
Changes from baseline will be calculated as visit – baseline and summarized by treatment 
and visit as described above.  Treatment comparisons between an active treatment and 
vehicle will be calculated as active – vehicle.   
All primary and secondary analyses will be two-sided at a significance level of 0.05.  
95% confidence intervals will be provided where appropriate. 
12.4.2 Unit of Analysis 
Safety endpoints will be analyzed for both eyes.  For efficacy endpoints, the unit of 
analysis will be the study eye, or the “worst eye,” as defined by the following: 


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Study Eye/Worst Eye: Eyes are eligible for analysis if they meet all of the inclusion 
criteria.  In the case that both eyes are eligible for analysis, the study eye will be the eye 
with worse (higher) inferior corneal staining score (Ora Calibra® scale) on Day 1.  If the 
inferior corneal staining score is the same in both eyes, then the right eye will be selected 
as the study eye. 
12.4.3 Missing Data 
The primary efficacy analyses will be performed using Last Observation Carried Forward 
(LOCF) methodology.  For the LOCF analyses of the primary efficacy variables at Month 
3, the last value from the previous visits will be carried forward, matching pre-CAE® or 
post-CAE® time points.  A pre-CAE® time point will never be imputed for a post-CAE® 
value, and vice versa.     
An analysis using observed data only will also be performed for the primary efficacy 
variables.  As additional sensitivity analyses, Markov Chain Monte Carlo (MCMC) 
multiple imputation methodology may be used to impute missing data for the analyses of 
the primary efficacy variables. 
No secondary efficacy endpoints or safety endpoints will be imputed. 
12.4.4 Multiplicity Consideration 
This is a Phase 2 study to evaluate the safety, tolerability, systemic pharmacokinetics, and 
pharmacodynamics of AXR-159 Ophthalmic Solution in patients with dry eye disease.  
There will be no multiplicity adjustments for the multiple treatment groups or multiple 
primary endpoints.   
12.4.5 Primary Efficacy Analyses 
The primary efficacy variables (Pre-CAE®) are: 
• Change from Baseline to Month 3 in inferior corneal staining score (Ora Calibra® 
scale) in the study eye 
• Change from Baseline to Month 3 in total corneal staining score (Oxford and Ora 
Calibra® scales) in the study eye 
• Change from Baseline to Month 3 in eye dryness measured using a visual 
analogue scale (VAS) 
• Change from Baseline to Month 3 in Total Ocular Surface Disease Index (OSDI) 
score, and 
The primary variables will be summarized as described in Section 12.4.1.  The primary 
efficacy analysis will use the mITT population with LOCF.   
 
 


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Statistical tests will be performed for each AXR-159 Ophthalmic Solution group versus 
vehicle group at matched dosing frequency (TID or BID).  ANCOVA models will be 
used to compare the change from baseline primary efficacy variables.  The ANCOVA 
models will include terms for baseline value, baseline inferior corneal staining score 
(ICCS) and baseline eye dryness score as covariates and treatment (AXR-159 or vehicle) 
as a factor in the model.  Pairwise comparisons will be performed for each AXR-159 
treatment group versus vehicle using t-tests of the least square means from this model.  
Two-sided confidence intervals (95%) will be provided for the differences between 
treatments.  As supportive analyses, two-sample t-tests and Wilcoxon rank sum tests will 
also be conducted.   
Details of additional supportive primary efficacy analyses will be provided in the 
statistical analysis plan. 
12.4.6 Secondary Efficacy Analyses 
Continuous secondary efficacy variables (see Section 8.1.2) and changes from baseline in 
these measures will be summarized as described in Section 12.4.1, and analyzed by visit 
using ANCOVA as described for the primary efficacy analyses.   
Binary clinical cure variables representing clinical cure will be defined by visit for TBUT 
≥ 10, Schirmer’s test ≥ 10 mm, Total OSDI < 18, and Ocular Discomfort Score = 0.  
These binary variables will be summarized as described in Section 12.4.1.  Additionally, 
within each treatment group, shift tables for complete treatment response (yes/no) in the 
study eye relative to baseline will be presented for each variable.   
The Cochran-Mantel-Haenszel test, stratified by baseline inferior corneal staining score 
(ICCS, > 1.5 and ≤ 1.5) and eye dryness score (≥ 60 and < 60) will be used to compare 
treatments with respect to the proportion of cured patients.  Pairwise comparisons will be 
performed for each AXR-159 treatment group versus vehicle.  Two-sided confidence 
intervals (95%) will be provided for the differences between treatments.  The confidence 
intervals will be constructed using the normal approximation to the binomial distribution. 
The secondary efficacy analysis will use the mITT population with observed data only. 
Details of additional secondary efficacy analyses will be provided in the statistical 
analysis plan. 
12.4.7 Safety Variables 
Safety measures will be analyzed using the safety population.  Medical Dictionary for 
Regulatory Activities (MedDRA) nomenclature will be used to code adverse events.  
Incidence rates of each treatment-emergent adverse event will be summarized by primary 
system organ class and preferred term.  Summary tables will be generated for all 
treatment-emergent adverse events regardless of causality as well as for those considered 
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12.4.8 Planned Interim Analyses 
An interim analysis will be performed when the last enrolled patient in Stage 1 completes 
Month 3 of the Expansion Cohort.  There is no plan to stop the study for efficacy on the 
basis of the interim analysis.  However, termination in individual dose groups due to 
safety, tolerability and/or futility may occur.  Statistical significance will not be declared 
at the time of the interim analysis.   
A final database lock will occur at the completion of Stage 2 and the safety, tolerability, 
and efficacy data from both Stage 1 and 2 will be analyzed separately and in a combined 
fashion to fully leverage the advantage of this two-stage study design.  At the final 
analysis, statistical significance will be declared for two-sided p-values < 0.05.   
Given the exploratory nature of the study no adjustments for multiplicity will be applied 
across the primary or secondary endpoints. 
12.4.9 Sub-Group Analyses 
Patients will be stratified by the Pre-CAE® inferior corneal staining score (ICCS) (i.e., ≤ 
1.5 or > 1.5) according to the Ora Calibra® staining scale and eye dryness score (i.e., < 60 
or ≥ 60) in the study eye.       
Subgroup analyses are planned for the 4 groups defined by the 2 stratification factors 
(Pre-CAE®): 
1. inferior corneal staining score (ICCS) ≤ 1.5 according to the Ora Calibra® staining 
scale and eye dryness score < 60 
2. inferior corneal staining score (ICCS) ≤ 1.5 according to the Ora Calibra® staining 
scale and eye dryness score ≥ 60 
3. inferior corneal staining score (ICCS) > 1.5 according to the Ora Calibra® staining 
scale and eye dryness score < 60 
4. inferior corneal staining score (ICCS) > 1.5 according to the Ora Calibra® staining 
scale and eye dryness score ≥ 60. 
12.4.10Tabulation of Individual Participant Data 
Individual participant data will be listed by measure and time point. 
12.4.11Exploratory Analyses 
The statistical analysis plan (SAP) will provide a detailed description of the planned 
exploratory statistical analysis. 
12.4.12 Pharmacokinetics Analyses 
A model independent approach will be used to calculate the pharmacokinetic parameters 
of AXR-159 in blood.  Pharmacokinetic parameters for blood will only be calculated for 
samples collected from patients who receive study treatment (Stage 1, the first 40 patients 
in the expansion cohort).  To enable only bioanalysis of samples from patients who 
receive active AXR-159 treatment, the randomization codes will be made available based 


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on AxeroVision Inc. internal procedures.  Pharmacokinetic parameters including area 
under the curve from time 0 to t (AUC0-t), AUC from time 0 to infinity (AUC0-∞), Cmax, 
time to highest observed concentration (Tmax), and half-life (T1/2) will be calculated when 
possible. 
The concentration of AXR-159 in blood and tear samples will be summarized by dose 
and timepoint using descriptive statistics, if applicable. 
13 COMPLIANCE WITH GOOD CLINICAL PRACTICES, 
ETHICAL CONSIDERATIONS, AND ADMINISTRATIVE 
ISSUES 
This study will be conducted in compliance with the protocol, current Good Clinical 
Practices (GCPs), including the International Conference on Harmonisation (ICH) 
Guidelines, and in general, consistent with the Declaration of Helsinki. In addition, all 
applicable local, state, and federal requirements relevant to the use of IP in the countries 
involved will be adhered to. 
 Protection of Human Subjects 
13.1.1 Subject Informed Consent 
Informed consent/assent must take place before any study specific procedures are 
initiated. Signed and dated written informed consent must be obtained from each subject 
and/or from the subject’s parent or legal guardian prior to enrollment into the study. If the 
subject is under the legal age of consent, the consent form must be signed by a legal 
guardian or as required by state and/or local laws and regulations. 
All informed consent/assent forms must be approved for use by the sponsor and receive 
approval/favorable opinion from an IRB/IEC prior to their use. If the consent form 
requires revision (e.g., due to a protocol amendment or significant new safety 
information), it is the investigator’s responsibility to ensure that the amended informed 
consent is reviewed and approved by Ora prior to submission to the governing IRB/IEC 
and that it is read, signed and dated by all subjects subsequently enrolled in the study as 
well as those currently enrolled in the study. 
If informed consent is taken under special circumstances (oral informed consent), then 
the procedures to be followed must be determined by Ora and/or sponsor and provided in 
writing by Ora and/or sponsor prior to the consent process. 
13.1.2 Institutional Review Board (IRB) Approval 
This study is to be conducted in accordance with IRB regulations (U.S. 21 CFR Part 
56.103). The investigator must obtain appropriate IRB approval before initiating the 
study and re-approval at least annually. 
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 Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles that originated 
with the Declaration of Helsinki. 
 Subject Confidentiality 
All personal study subject data collected and processed for the purposes of this study 
should be maintained by the investigator and his/her staff with adequate precautions as to 
ensure that the confidentiality of the data is in accordance with local, state, and federal 
laws and regulations. 
Monitors, auditors and other authorized representatives of Ora, the sponsor, the IRB/IEC 
approving this study, the FDA, the DHHS, other domestic government agencies, and 
other foreign regulatory agencies will be granted direct access to the subject’s original 
medical and study records for verification of the data and/or clinical trial procedures. 
Access to this information will be permitted to the aforementioned individuals to the 
extent permitted by law. 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the IP may ultimately be marketed, but the subject’s 
identity will not be disclosed in these documents. 
 Documentation 
Source documents may include a subject’s medical records, hospital charts, clinic charts, 
the investigator’s study subject files, as well as the results of diagnostic tests such as X-
rays, laboratory tests, and EKGs. The investigator’s copy of the CRFs serves as the 
investigator’s record of a subject’s study-related data. 
13.4.1 Retention of Documentation 
All study related correspondence, subject records, consent forms, record of the 
distribution and use of all IP, and copies of CRFs should be maintained on file for at least 
two years after the last approval of a marketing application in an ICH region and until 
there are no pending or contemplated marketing applications in an ICH region; or until at 
least two years have elapsed since the formal discontinuation of clinical development of 
the IP. These documents will be retained for a longer period if required by the applicable 
regulatory requirements or by an agreement with the sponsor. It is the responsibility of 
the sponsor to inform the investigator/institution as to when these documents no longer 
need to be retained. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address 
of the new custodian. 


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 Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Investigational Product 
13.5.1 Labeling/Packaging 
Each vial is embossed with lot-specific information on the vial tab. The vials are 
produced as a card of five (5) vials with each card being packaged in hermetically sealed 
aluminum foil pouches containing an identifying label on the pouch exterior. Ten (10) 
pouched cards are further packaged into a paper board carton comprising a two week 
supply of drug product. The carton has an identifying label with lot-specific information 
on its exterior.  
13.5.2 Storage of Investigational Product 
The IP must be stored at refrigerated temperature (2-8 ⁰C) in its original packaged kit 
until dispensed to the patient in a secure area accessible only to the investigator and 
his/her designees. The IP will be administered only to subjects entered into the clinical 
study, in accordance with the conditions specified in this protocol. 
13.5.3 Accountability of Investigational Product 
The IP is to only be prescribed by the principal investigator or his/her named sub-
investigator(s), and is to only be used in accordance with this protocol. The IP must only 
be distributed to subjects properly qualified under this protocol to receive IP. 
The investigator must keep an accurate accounting of the IP received from the supplier. 
This includes the amount of IP dispensed to subjects, amount of IP returned to the 
investigator by the subjects, and the amount returned or disposed upon the completion of 
the study. A detailed inventory must be completed for the IP. 
13.5.4 Return or Disposal of Investigational Product 
All IP will be returned to the sponsor or their designee or destroyed at the study site. The 
return or disposal of IP will be specified in writing. 
 Recording of Data on Source Documents and Case Reports Forms 
(CRFs) 
The investigator is responsible for ensuring that study data is completely and accurately 
recorded on each subject’s CRF, source document, and all study-related material. All 
study data should also be attributable, legible, contemporaneous, and original. Recorded 
datum should only be corrected in a manner that does not obliterate, destroy, or render 
illegible the previous entry (e.g., by drawing a single line through the incorrect entry and 
writing the revision next to the corrected data). An individual who has corrected a data 
entry should make clear who made the correction and when, by adding to the correction 
his/her initials as well as the date of the correction. 
Data entry of all enrolled and randomized subjects will use software that conforms to 21 
CFR Part 11 requirements, and will be performed only by staff who have been trained on 
the system and have access to the system.  Data will not be entered for screen failure 
subjects. An audit trail will be maintained within the electronic system to capture all 


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changes made within the eCRF database. After the end of the study and database lock, 
compact discs (CDs) containing copies of all applicable subjects’ eCRFs will be provided 
to each Investigator Site to be maintained on file by the Investigator. 
 Handling of Biological Specimens 
13.7.1 Handling of Biological Specimens 
All samples will be returned to AxeroVision Inc. or AxeroVision Inc. designee at the 
completion of the study.  Axer0Vision Inc. shall have full ownership rights to any 
biological specimens/samples derived from the study. 
13.7.2 Blood and Urine Samples for Safety Analysis 
Samples of blood (non-fasting) will be evaluated for blood chemistry, and hematology 
[including complete blood count with differential and HbA1c] at a centralized clinical 
laboratory (ie, ICON Central Laboratory Services, Whitesboro, New York, USA) with 
certification from a recognized accreditation agency.  Details of sample collection are 
found in the procedure manual. 
13.7.3 Blood Samples for Pharmacokinetic Analysis 
Blood samples obtained at the study sites will be analyzed for AXR-159 concentrations 
by an AxeroVision Inc. qualified laboratory (i.e., Intertek Pharmaceutical Services, El 
Dorado Hills, California, USA) using a validated method.  This laboratory has been 
qualified by AxeroVision Inc.’s Bioanalytical Sciences department to conduct analysis of 
clinical samples. Details of sample collection and handling are found in the procedure 
manual. 
13.7.4 Tear Samples 
Details of sample collection and handling are found in the procedure manual. 
All samples will be stored at the clinical site or at ICON until shipment to the 
bioanalytical laboratory. 
13.7.5 Key Roles and Study Governance 
The name and contact information of the Principal Investigator and the DRC Chair 
follow: 
Principal Investigator 
DRC Chair 
Gail L. Torkildsen, M.D. 
Achim Krauss, Ph.D. 
Andover Eye Associates  
AxeroVision Inc.  
138 Haverhill St, Suite 104 
Andover, MA 01810 
5857 Owens Ave., Suite 300 
Carlsbad, CA 92008 
978-475-0705 
484-238-6255 
mdlasik@comcast.net 
Achim@axerovision.com 


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13.7.6 Safety Oversight 
Safety oversight will be under the direction of a DRC composed of individuals with the 
appropriate expertise (see Section 6.3). Members of the DRC should be independent 
from the study conduct and free of conflict of interest, or measures should be in place to 
minimize perceived conflict of interest.  The DRC will meet at least monthly to assess 
safety and efficacy data on each arm of the study. The DRC will operate under the rules 
of an approved charter that will be written and reviewed at the organizational meeting of 
the DRC. At this time, each data element that the DRC needs to assess will be clearly 
defined. The DRC will provide its input to AxeroVision Inc., the IRB and regulatory 
authorities as necessary. 
13.7.7 Clinical Monitoring 
A representative of Ora, Inc. will monitor the study on a periodic basis.  The 
determination of the extent and nature of monitoring will be based on considerations such 
as the objective, purpose, design, complexity, blinding, size, and endpoints of the study.   
Authorized representatives of AxeroVision Inc., Ora, Inc., or regulatory authority 
representatives will conduct onsite visits to review, audit, and copy study-related 
documents.  These representatives will meet with the investigator(s) and appropriate staff 
at mutually convenient times to discuss study-related data and questions. 
13.7.8 Quality Assurance and Quality Control 
Each clinical site will perform internal quality management of study conduct, data and 
biological specimen collection, documentation and completion.  An individualized 
quality management plan will be developed to describe a site’s quality management. 
Quality control (QC) procedures will be implemented beginning with the data entry 
system and data QC checks that will be run on the database will be generated. Any 
missing data or data anomalies will be communicated to the site(s) for 
clarification/resolution. 
Following written Standard Operating Procedures (SOPs), the monitors will verify that 
the clinical trial is conducted and data are generated and biological specimens are 
collected, documented (recorded), and reported in compliance with the protocol, 
International Conference on Harmonisation Good Clinical Practice (ICH GCP), and 
applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP)).  
The investigational site will provide direct access to all trial related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the sponsor, 
and inspection by local and regulatory authorities. 


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 Publications 
AxeroVision Inc. as the sponsor, has proprietary interest in this study.  Authorship and 
manuscript composition will reflect joint cooperation between multiple investigators and 
sites and AxeroVision Inc. personnel.  Authorship will be established prior to the writing 
of the manuscript.  As this study involves multiple centers, no individual publications 
will be allowed prior to completion of the final report of the multicenter study except as 
agreed with AxeroVision Inc.  
 
 


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14 REFERENCES 
1. Avunduk AM, Avunduk MC, Varnell ED, Kaufman HE. The comparison of 
efficacies of topical corticosteroids and nonsteroidal anti-inflammatory drops on 
dry eye patients:  A clinical and immunocytochemical study. Am J Ophthalmol. 
2003;136:593-602. 
2. Bron AJ, dePaiva CS, Chauhan SK, Donini S, Gabison EE, Jain S, Knop E, 
Markoulli M, Ogawa Y, Perez V, Uchino Y, Yokoi N, Zoukhri D, Sullivan DA. 
TFOS DEWS II pathophysiology report.  The Ocular Surface. 2017;15:438-510. 
3. Craig JP, Nichols KK, Akpek EK, Caffery B, Dua HS, Joo C, Liu Z, Nelson JD, 
Nichols JJ, Tsubota K, Stapleton F. TFOS DEWS II definition and classification 
report. The Ocular Surface. 2017;17:276-283. 
4. DEWS. Report of the international dry eye workshop. Ocul Surf. 2007;5(2):65-
204. 
5. Ecoiffier T, Al Annan J, Rashid S, Schaumberg D, Dana R. Modulation of 
integrin alpha4beta1 (VLA-4) in dry eye disease. Arc Ophthalmol. 
2008;126:1695-1699. 
6. Holland EJ, Donnenfeld ED, Lindstrom RL, et al.  Expert consensus in the 
treatment of dry eye inflammation.  Ophthalmol Times 2007;32:S3–11. 
7. Krauss AH, Corrales RM, Pelegrino FSA, Tukler-Henriksson J, Pflugfelder SC, 
dePaiva CS. Improvement of outome measures of dry eye by a novel interin 
antagonist in the murine desiccating stress model. Cornea, 2015;56:5888-5895. 
8. Pflugfelder SC, Jones D, Ji Z, Afonso A, Monroy D. Altered cytokine balance in 
the tear fluid and conjunctiva of patients with Sjögren’s syndrome 
keratoconjunctivitis sicca. Curr Eye Res. 1999;19(3):201-211.  
9. Pflugfelder SC, Maskin SL, Anderson B, Chodosh J, Holland EJ, De Paiva CS, et 
al.  A randomized, double-masked, placebo-controlled, multicenter comparison of 
loteprednol etabonate ophthalmic suspension, 0.5%, and placebo for treatment of 
keratoconjunctivitis sicca in patients with delayed tear clearance.  Am J 
Ophthalmol.  2004;138(3):444-457. 
10. Semba CP and Gadek TR. Development of lifitegrast: a novel T-cell inhibitor for 
the treatment of dry eye disease. Clinical Ophthalmology 2016:10 1083–1094. 
11. Yang C-Q, Sun W, Gu Y-S.  A clinical study of the efficacy of topical 
corticosteroids on dry eye.  J Zhejiang Univ Sci B.  2006;7(8):675-678. 
 
 


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15  APPENDICES 
APPENDIX 1: SCHEDULE OF VISITS AND MEASUREMENTS 
Procedure 
Visit 1 
Day -14±2 
Visit 2 
Day 1 
Visit 3 
Day 15± 2 
Visit 4 
Day 43± 2 
Visit 5 
Day 85 ± 2 
 
Pre  
CAE® 
Post  
CAE® 
Non 
CAE® 
Non CAE® 
Non 
CAE® 
Pre 
CAE® 
Post  
CAE® 
Informed Consent / HIPAA 
X 
 
 
 
 
 
 
Medical / Medication History and 
Demographics 
X 
 
 
 
 
 
 
Medical / Medication Update 
 
 
X 
X 
X 
X 
 
Vehicle Run-in Collection 
 
 
X 
 
 
 
 
Study Drug Collection 
 
 
X 
X 
X 
X 
 
Review of Qualification Criteria 
X 
X 
X 
 
 
 
 
Adverse Event Query 
 
X 
X 
X 
X 
X 
X 
Pregnancy Test 
Xa 
 
 
 
 
Xa 
 
Visual Analog Scale 
X 
X 
X 
X 
X 
X 
X 
Ora Calibra® Ocular Discomfort 
Scale 
X 
X 
X 
X 
X 
X 
X 
SANDE Questionnaire 
X 
 
X 
X 
X 
X 
 
OSDI© Questionnaire 
X 
 
X 
X 
X 
X 
 
Visual Acuity (ETDRS) 
X 
 
X 
X 
X 
X 
 
Vital Signs 
X 
 
X 
 
 
X 
 
Bulbar Conjunctival Hyperemia  
X 
X 
X 
X 
X 
X 
X 
Slit-lamp Biomicroscopy 
X 
X 
X 
X 
X 
X 
X 
Tear Collection (Selected Sites) 
 
 
X 
 
 
X 
 
Oculus Keratograph 5® 
Xb 
 
Xb 
Xb 
Xb 
Xb 
 
TFBUT 
X 
X 
X 
X 
X 
X 
X 
Fluorescein Staining (Ora & 
Oxford Scales) 
X 
X 
X 
X 
X 
X 
X 
Lissamine Green Staining 
(Oxford Scale) 
X 
X 
X 
X 
X 
X 
X 
15 Minute Wait Period 
X 
 
X 
X 
X 
X 
 
Schirmer’s Test 
X 
 
X 
X 
X 
X 
 
CAE® Exposure 
X 
 
 
 
X 
Discomfort Grading during CAE® 
Exposure 
X 
 
 
 
X 
Intraocular Pressure 
 
X 
X 
X 
X 
 
X 
Ophthalmoscopy Exam 
 
Xc 
 
 
 
 
Xc 
CBC and Differential Blood Draw 
 
X 
 
 
 
 
X 
Pharmacokinetic Blood Draw 
 
 
Xd 
 
Xd 
 
 
Randomization 
 
 
X 
 
 
 
 
Vehicle Run-In Dispensation 
 
X 
 
 
 
 
 
Vehicle Run-In Instillation 
 
X 
 
 
 
 
 
Study Drug Dispensation 
 
 
X 
X 
X 
 
 
Study Drug Instillation 
 
 
X 
X 
X 
 
X 


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Procedure 
Visit 1 
Day -14±2 
Visit 2 
Day 1 
Visit 3 
Day 15± 2 
Visit 4 
Day 43± 2 
Visit 5 
Day 85 ± 2 
 
Pre  
CAE® 
Post  
CAE® 
Non 
CAE® 
Non CAE® 
Non 
CAE® 
Pre 
CAE® 
Post  
CAE® 
Ora Calibra® Drop Comfort 
Assessment 
 
 
X 
 
X 
 
X 
Exit Subject from Study 
 
 
 
 
 
 
X 
a To women of child-bearing potential, as defined. 
b TFBUT and Tear meniscus height only; only at selected sites 
 
c Ophthalmoscopy examination will be dilated at randomization and undilated for Visit 5 unless dilation is 
necessary 
d Blood samples for pharmacokinetic analysis will only be collected for Stage 1, the first 40 patients in the 
expansion cohort as follows: Visit 2: pre-dose, Visit 4: pre-dose, 15 min, 30 min, 60 min, 90 min, and 3 hr, 
& 6 hr post dose. 
 
 
 
 


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APPENDIX 2: EXAMINATION PROCEDURES, TESTS, 
EQUIPMENT, AND TECHNIQUES 
Visual Acuity Procedures (ETDRS Chart) 
LogMAR visual acuity (VA) must be assessed using an Early Treatment Diabetic 
Retinopathy Study (ETDRS) chart. The procedure used will be consistent with the 
recommendations provided for using the ETDRS eye chart. VA should be evaluated at 
the beginning of each visit in the study (i.e., prior to slit-lamp examination). VA testing 
should be done with most recent correction. 
Equipment 
The VA chart to be used is the ETDRS chart. If smaller reproduction (18" by 18", e.g., 
from Prevent Blindness) wall charts are used, the subject viewing distance should be 
exactly 10 feet (or as specified by the manufacturer). In ALL cases, for purposes of 
standardizing the testing conditions during the study, all sites must use only the 'R' charts, 
and the right eye should be tested first. For reflectance (wall) charts, the chart should be 
placed frontally and well-illuminated. 
Measurement Technique 
The chart should be at a comfortable viewing angle. The right eye should be tested first. 
The subject should attempt to read each letter, line-by-line, left to right, beginning with 
line 1 at the top of the chart. The subject should be told that the chart has letters only, no 
numbers. If the subject reads a number, he or she should be reminded that the chart 
contains no numbers, and the examiner should then request a letter in lieu of the number. 
The subject should be asked to read slowly, so as to achieve the best identification of 
each letter. He/she is not to proceed to the next letter until he/she has given a definite 
response. 
If the subject changes a response (e.g., that was a "C" not an "O") before he has read 
aloud the next letter, then the change must be accepted. If the subject changes a response 
having read the next letter, then the change is not to be accepted. The examiner should 
never point to the chart or to specific letters on the chart during the test. 
A maximum effort should be made to identify each letter on the chart. When the subject 
says he or she cannot read a letter, he or she should be encouraged to guess. If the subject 
identifies a letter as 1 of 2 letters, he or she should be asked to choose 1 letter and, if 
necessary, to guess. When it becomes evident that no further meaningful readings can be 
made, despite encouragement to read or guess, the examiner should stop the test for that 
eye. However, all letters on the last line should be attempted as letter difficulties vary and 
the last may be the only one read correctly. The number of letters missed or read 
incorrectly should be noted. 
 
 


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LogMAR Visual Acuity Calculations 
The last line in which a letter is read correctly will be taken as the base logMAR reading. 
To this value will be added the number "N x 0.02" where 'N' represents the total number 
of letters missed up to and included in the last line read. This total sum represents the 
logMAR VA for that eye. 
For example: Subject correctly reads 4 of 5 letters on the 0.2 line, and 2 of 5 letters on the 
0.1 line. 
Base logMAR 
= 0.1 
N (total number of letters incorrect on line 0.2 as 
well as 0.1) 
= 4 
N x T (T=0.02) 
= 0.08 
Base logMAR + (N x T) 
= 0.1 + 0.08 
logMAR VA 
= 0.18 
Repeat the procedure for the left eye. 
In order to provide standardized and well-controlled assessments of VA during the study, 
all VA assessments at a single site must be consistently done using the same lighting 
conditions and same correction if possible during the entire study. If the same correction 
cannot be used (i.e., a subject forgets his glasses), the reason for the change in correction 
should be documented. 
Slit Lamp Biomicroscopy Procedures 
Slit lamp biomicroscopic observations will be graded as Normal or Abnormal. Abnormal 
findings will be categorized as clinically significant (findings that may interfere with 
study parameters or otherwise confound the data as determined by the investigator) or not 
clinically significant (NCS). The following will be examined:  
• Cornea  
• Conjunctiva 
• Anterior Chamber 
• Iris 
• Lens 
• Eyelid 


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External magnification and biomicroscopy will be performed using a slit-lamp. 
Magnification will be consistent with standard clinical practice. The subject will be 
seated. 
Fundus Exams 
Dilated fundus exams will be performed at Visit 1 using indirect ophthalmoscopy. At 
visit 5, undilated fundus exams will be performed unless dilation is necessary. The 
investigator will make observations of the vitreous, retina, macula, choroid and optic 
nerve.   
Observations will be graded as Normal or Abnormal. Abnormal findings that are 
clinically significant (as determined by the investigator that may interfere with study 
parameters or otherwise confound the data) and those that are not clinically significant 
will be described. An indirect Fundoscopy examination should be performed if retinal 
disease is detected.  
• Vitreous: Examination should emphasize the visual axis.  
• Retina, Macula, Choroid: Include an observation of the retina and its blood 
vessels. Eyes should be excluded from the study if active inflammation is present.  
• Optic Nerve: Significant damage or cupping to the optic nerve should be noted. 
 
It is recommended that tropicamide 1% ophthalmic solution be used to dilate subjects.   
Vital Signs 
Each subject will have vital signs assessments (resting blood pressure and pulse) 
conducted at Visits 1, 2, and 5. Vital signs are to be conducted by a qualified staff 
member who may be any of the following: a board-certified investigator or sub-
investigator, nurse practitioner, registered nurse, or physician assistant.  
Systolic/Diastolic Blood Pressure (mmHg) 
Systolic and diastolic blood pressure should be measured in the same arm each time using 
a sphygmomanometer with the subjects who have been in a resting state (seated upright) 
at least 5 minutes. Blood pressure will be recorded in mmHg. 
Pulse (bpm) 
Pulse will be measured with the subjects who have been in a resting state (seated) for at 
least 5 minutes. Pulse will be counted for 30 seconds and multiplied by 2, and recorded in 
beats per minute (bpm). 


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Intraocular Pressure 
Intraocular pressure (IOP) will be measured in each eye by contact tonometry by the 
examiner and the results will be recorded in mmHg.  A single measurement is made to 
obtain a determination of IOP.  The same tonometer employing the investigator’s 
standard technique will be used throughout the study.  In addition, all reasonable efforts 
will be made to have the same examiner obtain all IOP measurements for a given subject. 


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Ora proprietary scales – Not for distribution without permission 
Ora Calibra® Conjunctival Redness Scale for Dry Eye 
This procedure will be performed according to Ora, Inc. SOPs and/or guidance 
documents. 
None  
0 = Normal, without vasodilation 
Trace  
1 = Trace ciliary or conjunctival vasodilation 
Mild  
2 = Broad ciliary vasodilation; 
Moderate  
3 = Broad ciliary and slight, horizontal conjunctival vasodilation 
Severe  
4 = Broad ciliary and prominent, horizontal conjunctival 
vasodilation 
Half (0.5) unit increments are allowed. 
Ora Calibra® Ocular Discomfort Scale for Dry Eye 
This procedure will be performed according to Ora, Inc. SOPs and/or guidance 
documents. 
Ocular discomfort scores will be subjectively graded by the subjects according to the 
following scale, rating each eye separately.   
0 
No discomfort 
1 
Intermittent awareness 
2 
Constant awareness 
3 
Intermittent discomfort 
4 
Constant discomfort 
 


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Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire for Dry Eye 
This procedure will be performed according to Ora, Inc. SOPs and/or guidance 
documents. 
Subjects will rate the severity of each of the following symptoms, with regard to how 
both their eyes feel, in general – overall ocular discomfort, burning, dryness, grittiness 
and stinging according to the following 6-point (0 to 5) scale where 0 = none and 5 = 
worst. 
0 
1 
2 
3 
4 
5 
(None) 
      (Worst) 


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Ocular Surface and Disease Index (OSDI) © for Dry Eye 


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Tear Film Break-Up Time (TFBUT) © 
The examiner will instill 5 µL of 2% preservative-free sodium fluorescein solution into 
the inferior conjunctival cul-de-sac of each eye.  To thoroughly mix the fluorescein with 
the tear film, the subject will be instructed to blink several times.  In order to achieve 
maximum fluorescence, the examiner should wait approximately 30 seconds after 
instillation before evaluating TFBUT.    
With the aid of a slit-lamp, the examiner will monitor the integrity of the tear film, noting 
the time it takes to form micelles from the time that the eye is opened.  TFBUT will be 
measured in seconds using a stopwatch and a digital image recording system for the right 
eye followed by the left eye.  A Wratten #12 yellow filter will be used to enhance the 
ability to grade TFBUT.   
For each eye, 2 measurements will be taken and averaged unless the 2 measurements are 
> 2 seconds apart and are each < 10 seconds, in which case, a third measurement would
be taken and the 2 closest of the 3 would be averaged.
Fluorescein Staining 
The examiner will instill 5 µL of 2% preservative-free sodium fluorescein solution into 
the inferior conjunctival cul-de-sac of each eye. In order to achieve maximum 
fluorescence, the examiner should wait approximately 3-5 minutes after instillation 
before evaluating fluorescein staining. A Wratten #12 yellow filter will be used to 
enhance the ability to grade fluorescein staining. The staining will be graded with the 
Oxford Scale and Ora Calibra® Scale. 
Oxford Grading Scale 
Fluorescein staining is represented by punctate dots on a series of panels (A-E). Staining 
ranges from 0-5 for each panel and 0-10 for the total exposed inter-palpebral conjunctiva. 
Inferior, superior, and Central regions will be graded separately. The dots are ordered on 
a log scale. Conjunctiva: temporal zone grading performed when the subject looks 
nasally; grading nasally by looking temporally.  


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Ora proprietary scale – Not for distribution without permission 
Ora Calibra® Corneal and Conjunctival Staining Scale for Grading of 
Fluorescein Staining 
This procedure will be performed according to Ora, Inc. SOPs and/or guidance 
documents. 
The following scale will be used to grade staining of the ocular surface (areas A, B, C, D, 
and E). Half (0.5) grade increments may be used.  
None 
0 = no staining 
Trace 
1 = occasional 
Mild 
2 = countable 
Moderate 
3 = uncountable, but not confluent 
Severe 
4 = confluent 
Staining areas: 


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Staining Areas 
Ocular Structure 
Position 
A – Inferior 
Cornea 
4-8 o’clock, extending 2 mm onto the
conjunctiva
Limbus/Conjunctiva 
4-8 o’clock, extending 2 mm towards the
center
B – Superior 
Cornea 
8-4 o’clock, extending 3 mm onto the
conjunctiva
Limbus/Conjunctiva 
8-10 o’clock and 2-4 o’clock, extending 1
mm onto the conjunctiva;
10-2 o’clock, extending 2 mm onto the
conjunctiva
C – Central 
Cornea 
Central cornea 
D – Temporal 
Conjunctiva 
Triangular wedge of temporal conjunctiva 
E – Nasal 
Conjunctiva 
Triangular wedge of nasal conjunctiva 
Lissamine Green Staining 
The Investigator will instill 10 µL of lissamine green solution into the inferior 
conjunctival cul-de-sac or insert lissamine strips and wait approximately 30 seconds 
before evaluating staining. The subject will be instructed to blink several times to 
distribute the lissamine green. The staining will be graded with Oxford Scale. 
Oxford Grading Scale 
Lissamine staining is represented by punctate dots on a series of panels (A-E). Staining 
ranges from 0-5 for each panel and 0-10 for the total exposed inter-palpebral conjunctiva. 
Both nasal and temporal regions will be graded separately. The dots are ordered on a log 
scale. Conjunctiva: temporal zone grading performed when the subject looks nasally; 
grading nasally by looking temporally.  


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Unanesthetized Schirmer’s Test 
Schirmer Tear Test will be performed according to the following procedure: 
•
Using a sterile Tear Flo Schirmer test strip (Rose Enterprises), a bend in the strip
will be made in line with the notch in the strip.
•
The subject will be instructed to gaze up and in.
•
The Schirmer test strip will be placed in the lower temporal lid margin of each
eye such that the strip fits tightly. Subjects will be instructed to close their eyes.
•
After 5 minutes have elapsed, the Schirmer strip will be removed. The length of
the moistened area will be recorded (mm) for each eye.


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Visual Analog Scale (VAS) 
Subjects will be asked the following questions regarding ocular discomfort 
(unrelated to study drug instillation) at all visits. The assessment period will include 
the previous week as well as Post-CAE. 
The subject will be asked to rate each ocular symptom due to ocular dryness by 
placing a vertical mark on the horizontal line to indicate the level of discomfort. 
0% corresponds to “no discomfort” and 100% corresponds to “maximal 
discomfort”. 


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Clinical Trial Protocol: AXR201701/17-110-0016 
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Symptom Assessment in Dry Eye (SANDE) 
Subjects will be asked to: 
PLEASE COMPLETE THE FOLLOWING QUESTIONS RELATED TO YOUR DRY 
EYE SYMPTOMES: 
Place a vertical line to indicate how often, on average, your eyes feel dry and/or irritated. 
Place a vertical line to indicate how severe, on average, you feel your symptoms of 
dryness and/or irritation. 
The assessment line length of the scale will be 100 mm and will be similar to the 
following depiction: 
1. Frequency
Rarely 
All the time 
2. Severity
Very Mild 
Very Severe 


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Clinical Trial Protocol: AXR201701/17-110-0016 
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APPENDIX 3: HANDLING OF BIOLOGICAL SPECIMENS 
Blood sample will be collected for hematology (3 mL per draw), serum chemistry (4 mL per 
draw), pharmacokinetics (6 mL per draw + 5mL for heparin/saline flush for post-dose draws, 
6 mL per draw for the pre-dose V2 and V4 draw. The approximate collection amounts per 
visit are described below: 
 
 
 


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Approximate Blood Collection Amounts per Visit 
 
Visit 1 
Visit 2 
Visit 4 
Visit 5 
Hematology 
3mL 
N/A 
N/A 
3mL 
Serum 
Chemistry 
4mL 
N/A 
N/A 
4mL 
PK 
N/A 
6mL 
71mL 
N/A 
Total 
7mL 
6mL 
71mL 
7mL 
 
• 
Hematology includes leucocytes, erythrocytes, Hgb, Hematocrit (Hct), Mean Cell 
Volume (MCV), Mean Cell Hemoglobin (MCH), Mean Cell Hemoglobin 
Concentration (MCHC), thrombocytes, and partial automated differentiation: 
lymphocytes, neutrophils, monocytes, eosinophils, and basophils.  
• 
Serum Chemistry includes sodium (Na), potassium (K), chloride (Cl), bicarbonate 
(CO2), calcium (Ca), phosphorus (P), blood urea nitrogen (BUN), creatinine, 
albumin, globulin, glucose, cholesterol, low density lipoprotein (LDL), high 
density lipoprotein (HDL), triglycerides, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), lactate dehydrogenase (LDH), alkaline 
phosphatase (Alk Phos), gamma GT, and total bilirubin (any total bilirubin > ULN 
should be fractionated for direct bilirubin).  
• 
Urinalysis includes appearance, glucose, ketones, Hgb, protein, nitrate, bilirubin, 
specific gravity, hydrogen ion concentration (pH), urobilinogen, and leucocytes. If 
positive for blood or protein trace, then microscopy will be included.  
• 
Pharmacokinetics testing for AXR-159. 
 


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APPENDIX 4: PROTOCOL AMENDMENT SUMMARY 
Not applicable. 




Page 84
APPENDIX 6: INVESTIGATOR'S SIGNATURE 
Protocol Title: 
A Multicenter, Vehicle-controlled, Randomized Study to 
Evaluate the Safety, Tolerability, Systemic Pharmacokinetics, 
and Pharmacodynamics of AXR-159 Ophthalmic Solution 3 
mglmL, 30 mglmL, and 50 mg/mL in Patimts with Dry Eye 
Disease (DED) 
Protocol Number: 
AXR201701 
Final Date: 
February 17, 2018 
I agree to implement and conduct the study diligently and in strict compliance with the 
protocol, good clinical practices and all applicable laws and regulations. I agree to 
maintain all information supplied by Ora and the sponsor in confidence and, when this 
information is submitted to an Institutional Review Board (IRB), Ethical Review 
Committee (ERC) or another group, it will be submitted with a designation that the 
material is confidential. 
I have read this protocol in its entirety, including the above statement, and I agree to all 
aspects. 
Signed: 
- .,,.1/ t.-----
OaivToririldscn, M.D 
Principal Investigator 
Andover Eye Associates 
138 Haverhill Street 
Doctor's Parle. II Suite 104 
Andover, MA. 01810 
978-409-6117 
Date: I :> 11-i A-.,· 1 

SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS PLAN  
A Multicenter, Vehicle-controlled, Randomized Study to Evaluate 
the Safety, Tolerability, Systemic Pharmacokinetics, and 
Pharmacodynamics of AXR-159 Ophthalmic Solution 3 mg/mL, 30 
mg/mL, and 50 mg/mL in Patients with Dry Eye Disease (DED) 
 
 
Sponsor:   
 
AxeroVision, Inc. 
 
 
 
 
 
 
Protocol Number: 
AXR201701 
 
 
Author:   
 
Garrick Wallstrom 
 
 
 
Principal Research Biostatistician 
Statistics & Data Corporation 
 
Date:    
 
25-January-2019 
Version:  
 
2.0 
 






 
 
 
Page 2 of 57 
A Multicenter, Vehicle-controlled, Randomized Study to Evaluate 
the Safety, Tolerability, Systemic Pharmacokinetics, and 
Pharmacodynamics of AXR-159 Ophthalmic Solution 3 mg/mL, 30 
mg/mL, and 50 mg/mL in Patients with Dry Eye Disease (DED) 
 
Protocol Number: 
AXR201701 
Version:  
 
2.0  
Date:    
 
25-January-2019 
 
Statistical Analysis Plan Approval 
 
Prepared by: 
 
 
 
 
 
 
 
 
 
 
 
Garrick Wallstrom, PhD  
 
 
Date 
 
 
Principal Research Biostatistician 
 
 
Statistics & Data Corporation 
 
 
Reviewed by:  
 
 
 
 
          
___________ 
 
 
Kirk Bateman, MS 
 
 
 
Date 
 
 
Senior Director, Biostatistics and SAS Programming 
 
 
Statistics & Data Corporation 
 
 
Approved by:  
 
 
 
 
 
 
 
 
 
 
George Ousler  
 
 
  
Date 
Vice President, Dry Eye 
 
 
Ora, Inc. 
 
 
Approved by:  
 
 
 
 
 
 
 
 
 
 
Charles Bosworth, PhD  
 
 
 Date 
Vice President, Head of Clinical Development 
 
 
AxeroVision, Inc.


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Table of Contents 
1. 
Introduction .............................................................................................................................. 8 
2. 
Study Objectives ...................................................................................................................... 8 
2.1 Primary Variables ..................................................................................................................... 8 
2.2 Secondary Variables ................................................................................................................ 8 
2.3 Exploratory Variables ............................................................................................................... 9 
2.4 Safety Variables ....................................................................................................................... 9 
2.5 Statistical Hypotheses .............................................................................................................. 9 
3. 
Study Design and Procedures ............................................................................................... 10 
3.1 General Study Design ............................................................................................................ 10 
3.2 Schedule of Visits and Assessments ..................................................................................... 11 
4. 
Study Treatments ................................................................................................................... 12 
4.1 Method of Assigning Subjects to Treatment Groups ............................................................. 12 
4.2 Masking and Unmasking ........................................................................................................ 13 
5. 
Sample Size and Power Considerations ............................................................................... 13 
6. 
Data Preparation .................................................................................................................... 14 
7. 
Analysis Populations .............................................................................................................. 14 
7.1 Modified Intent-to-Treat .......................................................................................................... 15 
7.2 Modified Intent-to-Treat 2 ....................................................................................................... 15 
7.3 Per Protocol ........................................................................................................................... 15 
7.4 Safety ..................................................................................................................................... 15 
8. 
General Statistical Considerations ......................................................................................... 15 
8.1 Unit of Analysis ...................................................................................................................... 15 
8.2 Missing or Inconclusive Data Handling .................................................................................. 15 
8.3 Definition of Baseline ............................................................................................................. 16 
8.4 Data Analysis Conventions .................................................................................................... 16 
8.5 Adjustments for Multiplicity .................................................................................................... 17 
9. 
Disposition of Subjects ........................................................................................................... 17 
10. 
Demographic Variables .......................................................................................................... 18 
11. 
Medical History and Concomitant Medications ...................................................................... 18 
11.1 Medical History ...................................................................................................................... 18 
11.2 Concomitant Medications ....................................................................................................... 18 
12. 
Dosing Compliance and Treatment Exposure ....................................................................... 19 
12.1 Dosing Compliance ................................................................................................................ 19 
12.2 Treatment Exposure .............................................................................................................. 19 


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13. 
Efficacy Analyses ................................................................................................................... 20 
13.1 Primary Analysis .................................................................................................................... 20 
13.1.1 
Pre-CAE® Inferior Fluorescein Staining (Ora Calibra® scale) .................................... 20 
13.1.2 
Pre-CAE® Total Corneal Fluorescein Staining (Ora Calibra® scale).......................... 23 
13.1.3 
Pre-CAE® Total Corneal Fluorescein Staining (Oxford scale) ................................... 23 
13.1.4 
Pre-CAE® Eye Dryness (Visual Analog Scale) .......................................................... 24 
13.1.5 
Pre-CAE® Total OSDI ................................................................................................ 24 
13.2 Secondary Analyses .............................................................................................................. 25 
13.2.1 
Unanesthetized Schirmer’s Test ................................................................................ 26 
13.2.2 
Tear Film Break-up Time (TFBUT) ............................................................................ 27 
13.2.3 
Oculus Keratograph ................................................................................................... 27 
13.2.4 
Conjunctival Redness Score ...................................................................................... 28 
13.2.5 
Fluorescein Corneal Staining (Ora Calibra® scale) .................................................... 29 
13.2.6 
Fluorescein Corneal Staining (Oxford scale) ............................................................. 30 
13.2.7 
Lissamine Green Conjunctival Staining (Oxford scale) ............................................. 30 
13.2.8 
Ocular Discomfort Score ............................................................................................ 31 
13.2.8.1 
Ora Calibra® Ocular Discomfort Scale Pre-, Post-, and Non-CAE® ................... 31 
13.2.8.2 
Ora Calibra® Ocular Discomfort Scale During CAE® Exposure ......................... 32 
13.2.9 
Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire................................... 32 
13.2.10 
Visual Analog Scale ................................................................................................... 33 
13.2.11 
Ocular Surface Disease Index (OSDI) ....................................................................... 33 
13.2.12 
Symptom Assessment in Dry Eye (SANDE) .............................................................. 34 
14. 
Exploratory Analyses ............................................................................................................. 35 
15. 
Subgroup Analyses ................................................................................................................ 35 
16. 
Safety Analyses ..................................................................................................................... 36 
16.1 Adverse Events ...................................................................................................................... 36 
16.2 Ora Calibra Drop Comfort Assessment ................................................................................. 39 
16.3 Best-corrected Visual Acuity (BCVA) ..................................................................................... 39 
16.4 Slit-lamp Biomicroscopy ......................................................................................................... 40 
16.5 Intraocular Pressure (IOP) ..................................................................................................... 40 
16.6 Ophthalmoscopy .................................................................................................................... 40 
16.7 Conjunctival Redness Score .................................................................................................. 41 
16.8 Vital Signs .............................................................................................................................. 41 
16.9 Laboratory Tests .................................................................................................................... 42 
16.10 
Urine Pregnancy Test .................................................................................................... 42 
17. 
Interim Analyses .................................................................................................................... 42 


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18. 
Changes from Protocol-Stated Analyses ............................................................................... 42 
19. 
Revision History ..................................................................................................................... 42 
20. 
Tables .................................................................................................................................... 43 
21. 
Listings ................................................................................................................................... 54 
22. 
Figures ................................................................................................................................... 56 
 
 
 


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List of Abbreviations 
 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
ATC 
Anatomical Therapeutic Chemical Classification 
BCVA 
Best-Corrected Visual Acuity 
BID 
Bis in die (twice daily) 
CAE 
Controlled Adverse Environment 
CI 
Confidence Interval 
CRF 
Case Report Form 
CS 
Clinically Significant 
DED 
Dry Eye Disease 
eCRF 
Electronic Case Report Form 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
HIPAA 
Health Information Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICCS 
Inferior Corneal Staining Score 
ICH 
International Conference on Harmonisation 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
LOCF 
Last Observation Carried Forward 
logMAR 
Logarithm of the Minimum Angle of Resolution 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
mITT2 
Modified Intent-to-Treat 2 
NCS 
Not clinically significant 
OD 
Oculus Dextrus (Right Eye) 
OS 
Oculus Sinister (Left Eye) 
OSDI 
Ocular Surface Disease Index 
PDF 
Portable Document Format 
PP 
Per Protocol 
PT 
Preferred Term 
RDC 
Remote Data Capture 
RTF 
Rich Text Format 
SAAS 
Software-as-a-Service 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SANDE 
Symptom Assessment in Dry Eye 
SD 
Standard Deviation 
SDC 
Statistics and Data Corporation, Incorporated 
SOC 
System Organ Class 


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TEAE 
Treatment-Emergent Adverse Event 
TE-SAE 
Treatment-Emergent Serious Adverse Event 
TFBUT 
Tear Film Break-Up Time 
TID 
Ter in die (three times daily) 
VA 
Visual Acuity 
VAS 
Visual Analog Scale 
WHO DDE 
World Health Organization Drug Dictionary Enhanced 
 
 


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1. Introduction 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and reporting for 
protocol AXR201701, version 1 dated 17Feb2018. 
This SAP is being written with due consideration of the recommendations outlined in the most recent 
International Conference on Harmonization (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials and the most recent ICH E3 Guideline, entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports. 
This SAP describes the data that will be analyzed and the subject characteristics, efficacy, and safety 
assessments that will be evaluated. This SAP provides details of the specific statistical methods that will 
be used. The statistical analysis methods presented in this document will supersede the statistical 
analysis methods described in the clinical protocol. If additional analyses are required to supplement 
the planned analyses described in this SAP they may be completed and will be identified in the CSR. 
2. Study Objectives 
The primary objectives for Stage 1 are to evaluate the safety, tolerability, and exploratory 
pharmacodynamics of up to 2 different concentrations of AXR-159 Ophthalmic Solution (30 mg/mL or 
50 mg/mL) dosed three-times daily (TID) or twice-daily (BID) for up to 12 weeks compared to its vehicle 
in patients with Dry Eye Disease (DED).  The primary objectives for Stage 2 are to evaluate the safety, 
tolerability, and pharmacodynamics of up to 3 different concentrations of AXR-159 Ophthalmic Solution 
(3 mg/mL, 30 mg/mL or 50 mg/mL) dosed TID or BID for up to 12 weeks compared to its vehicle in 
patients with DED. 
2.1 
Primary Variables 
Primary efficacy measures for Stage 1 and Stage 2 include changes from baseline to Month 3 in total 
sodium fluorescein corneal staining (Oxford and Ora Calibra® scales), sodium fluorescein corneal 
staining in the inferior cornea (Ora scale), patient symptoms of dryness (visual analog scale [VAS]), and 
total Ocular Surface Disease Index (OSDI). 
2.2 
Secondary Variables 
Secondary efficacy measures for Stage 1 and Stage 2 include Schirmer’s test without anesthesia, tear 
film break-up time (TFBUT), conjunctival redness score, sodium fluorescein corneal staining (Oxford 
and Ora Calibra® scales), lissamine green conjunctival staining (Oxford and Ora Calibra® scales), 
ocular discomfort score, Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire, patient 
symptoms (VAS), OSDI (total and subscales), Symptom Assessment iN Dry Eye (SANDE), and tear 
sampling for mechanism of action biomarkers.   


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2.3 
Exploratory Variables 
There are no exploratory variables. 
2.4 
Safety Variables 
The safety variables include the following: 
• 
Adverse events (AE) (ocular and non-ocular) 
• 
Ora Calibra® Drop Comfort Assessment 
• 
Best-corrected visual acuity (BCVA) 
• 
Slit-lamp biomicroscopy 
• 
Intraocular pressure (IOP) 
• 
Ophthalmoscopy 
• 
Ora Calibra® Conjunctival Redness for Dry Eye Scale 
• 
Vital signs 
• 
Laboratory tests (chemistry, hematology, urinalysis) 
• 
Urine pregnancy test 
2.5 
Statistical Hypotheses 
The statistical hypotheses are stated in terms of one-sided hypotheses, although statistical testing will 
be two-sided. All hypotheses are Pre-Controlled Adverse Environment (CAE)®. The null and alternative 
hypotheses, based on the primary variables, are as follows: 
H01:  There is no difference between AXR-159 Ophthalmic Solution (50 mg/ml, 30 mg/ml or 3 mg/ml, 
TID or BID) and vehicle (TID or BID) in the change from baseline to Month 3 in inferior corneal 
staining score in the study eye. 
H11:  The change from baseline to Month 3 in inferior corneal staining score in the study eye is less 
with AXR-159 Ophthalmic Solution (50 mg/ml, 30 mg/ml or 3 mg/ml, TID or BID) than with vehicle 
(TID or BID). 
H02:  There is no difference between AXR-159 Ophthalmic Solution (50 mg/ml, 30 mg/ml or 3 mg/ml, 
TID or BID) and vehicle (TID or BID) in the change from baseline to Month 3 in total corneal staining 
score in the study eye. 
H12:  The change from baseline to Month 3 in total corneal staining score in the study eye is less 
with AXR-159 Ophthalmic Solution (50 mg/ml, 30 mg/ml or 3 mg/ml, TID or BID) than with vehicle 
(TID or BID). 
H03:  There is no difference between AXR-159 Ophthalmic Solution (50 mg/ml, 30 mg/ml or 3 mg/ml, 
TID or BID) and vehicle (TID or BID) in the change from baseline to Month 3 in eye dryness. 


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H13:  The change from baseline to Month 3 in eye dryness is less with AXR-159 Ophthalmic Solution 
(50 mg/ml, 30 mg/ml or 3 mg/ml, TID or BID) than with vehicle (TID or BID). 
H04:  There is no difference between AXR-159 Ophthalmic Solution (50 mg/ml, 30 mg/ml or 3 mg/ml, 
TID or BID) and vehicle (TID or BID) in the change from baseline to Month 3 in total OSDI score. 
H14:  The change from baseline to Month 3 in total OSDI score is less with AXR-159 Ophthalmic 
Solution (50 mg/ml, 30 mg/ml or 3 mg/ml, TID or BID) than with vehicle (TID or BID). 
In the hypotheses above, dosing (TID or BID) of the vehicle will match the dosing of the active treatment.   
3. Study Design and Procedures 
3.1 
General Study Design 
This 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) dosed TID or BID; Stage 
2: AXR-159 Ophthalmic Solution (3 mg/mL, 30 mg/mL or 50 mg/mL) TID or BID.  
Subjects with signs and symptoms of DED will be randomly assigned in a 4:1 (Cohorts 1-3 in Stage 1), 
1:1 (Expansion Cohort in Stage 1) or up to a 2:2:2:2:1:1:1 (Stage 2; AXR-159 50 mg/mL TID : AXR-159 
50 mg/mL BID : AXR-159 30 mg/mL TID : AXR-159 3 mg/mL TID : Vehicle TID : Vehicle BID : AXR-159 
50 mg/ML + Artificial Tear TID or BID) ratio 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, TID 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 treatment period (See Protocol Appendix 1 for study visit structure across Stages 1 and 
2 and Protocol Figure 6.1-1 for the study flow diagram).  
Study visits will be referred to in all tables and listings as the expected study day corresponding to the 
visit to enable reviewers to understand the assessment timing without referring to the protocol visit 
schedule.  The following table shows the scheduled study visits, their planned study day, and the 
acceptable visit window for each study visit: 
Scheduled Visit 
Planned Study Day 
Visit Window 
Visit 1 
Day -14 
+/- 2 Days 
Visit 2 
Day 1 
N/A 
Visit 3 
Day 15 
+/- 2 Days 
Visit 4 
Day 43 
+/- 2 Days 
Visit 5 
Day 85 (Month 3) 
+/- 2 Days 


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3.2 
Schedule of Visits and Assessments 
The schedule of visits and assessments is provided below. 
Procedure 
Visit 1 
Day -14 ± 2 
Visit 2 
Day 1 
Visit 3 
Day 15 ± 2 
Visit 4 
Day 43 ± 2 
Visit 5 
Day 85 ± 2 
Pre  
CAE® 
Post  
CAE® 
Non- 
CAE® 
Non-CAE® Non-CAE® 
Pre- 
CAE® 
Post-  
CAE® 
Informed Consent / HIPAA 
X 
 
 
 
 
 
 
Medical / Medication History and 
Demographics 
X 
 
 
 
 
 
 
Medical / Medication Update 
 
 
X 
X 
X 
X 
 
Vehicle Run-in Collection 
 
 
X 
 
 
 
 
Study Drug Collection 
 
 
X 
X 
X 
X 
 
Review of Qualification Criteria 
X 
X 
X 
 
 
 
 
Adverse Event Query 
 
X 
X 
X 
X 
X 
X 
Pregnancy Test 
Xa 
 
 
 
 
Xa 
 
Visual Analog Scale 
X 
X 
X 
X 
X 
X 
X 
Ora Calibra® Ocular Discomfort Scale 
X 
X 
X 
X 
X 
X 
X 
Ora Calibra® Ocular Discomfort & 4-
Symptom Questionnaire 
X 
X 
X 
X 
X 
X 
X 
SANDE Questionnaire 
X 
 
X 
X 
X 
X 
 
OSDI© Questionnaire 
X 
 
X 
X 
X 
X 
 
Visual Acuity (ETDRS) 
X 
 
X 
X 
X 
X 
 
Vital Signs 
X 
 
X 
 
 
X 
 
Bulbar Conjunctival Hyperemia  
X 
X 
X 
X 
X 
X 
X 
Slit-lamp Biomicroscopy 
X 
X 
X 
X 
X 
X 
X 
Tear Collection (Selected Sites) 
 
 
X 
 
 
X 
 
Oculus Keratograph 5® 
Xb 
 
Xb 
Xb 
Xb 
Xb 
 
TFBUT 
X 
X 
X 
X 
X 
X 
X 
Fluorescein Staining (Ora & Oxford 
Scales) 
X 
X 
X 
X 
X 
X 
X 
Lissamine Green Staining (Oxford 
Scale) 
X 
X 
X 
X 
X 
X 
X 
15 Minute Wait Period 
X 
 
X 
X 
X 
X 
 
Schirmer’s Test 
X 
 
X 
X 
X 
X 
 
CAE® Exposure 
X 
 
 
 
X 
Discomfort 
Grading 
during 
CAE® 
Exposure 
X 
 
 
 
X 
Intraocular Pressure 
 
X 
X 
X 
X 
 
X 
Ophthalmoscopy Exam 
 
Xc 
 
 
 
 
Xc 
CBC and Differential Blood Draw 
 
X 
 
 
 
 
X 
Pharmacokinetic Blood Draw 
 
Xd 
 
 
Xd 
 
 
Randomization 
 
 
X 
 
 
 
 
Vehicle Run-In Dispensation 
 
X 
 
 
 
 
 


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Procedure 
Visit 1 
Day -14 ± 2 
Visit 2 
Day 1 
Visit 3 
Day 15 ± 2 
Visit 4 
Day 43 ± 2 
Visit 5 
Day 85 ± 2 
Pre  
CAE® 
Post  
CAE® 
Non- 
CAE® 
Non-CAE® Non-CAE® 
Pre- 
CAE® 
Post-  
CAE® 
Vehicle Run-In Instillation 
 
X 
 
 
 
 
 
Study Drug Dispensation 
 
 
X 
X 
X 
 
 
Study Drug Instillation 
 
 
X 
X 
X 
 
X 
Ora 
Calibra® 
Drop 
Comfort 
Assessment 
 
 
X 
 
X 
 
X 
Exit Subject from Study 
 
 
 
 
 
 
X 
a To women of child-bearing potential, as defined. 
b TFBUT and Tear meniscus height only; only at selected sites 
 
c Ophthalmoscopy examination will be dilated at randomization and undilated for Visit 5 unless dilation is 
necessary 
d Blood samples for pharmacokinetic analysis will only be collected for Stage 1, the first 40 patients in the 
expansion cohort as follows: Visit 2: pre-dose, Visit 4: pre-dose, 15 min, 30 min, 60 min, 90 min, and 3 hr, & 6 hr 
post dose. 
 
4. Study Treatments 
4.1 
Method of Assigning Subjects to Treatment Groups 
Prior to initiation of study run-in (at Visit 1), each subject who qualifies for entry will be assigned a 
screening number. All screening numbers will be assigned in strict numerical sequence at a site and 
no numbers will be skipped or omitted. If all inclusion and exclusion criteria are met at Visits 1 and 2, 
each qualifying subject will then be assigned a randomization number at the end of Visit 2. 
 
A randomization schedule will be provided to each investigational site. The randomization schedule 
will use block randomization stratified by site, such that there will be an approximate equal number of 
subjects assigned to each of the two treatment arms at each site for the Stage 1, Expansion Cohort. 
For Stage 1, Cohorts 1-3 patients with signs and symptoms of DED will be randomly assigned in a 4:1 
ratio to receive either a single concentration of AXR-159 Ophthalmic Solution or AXR-159 Ophthalmic 
Solution Vehicle. The site staff will dispense to the patient the study kit labelled with the corresponding 
randomization number. The randomization number will be recorded on the patient’s source document 
and eCRF. New kits will be dispensed at Visits 2, 3, and 4 based on the subject’s randomization. The 
Sponsor, Investigators, and study staff will be masked during the randomization process and 
throughout the study. 
 
During the run-in period, the patients will all be supplied with AXR-159 Ophthalmic Solution Vehicle. 
Patients will be informed that they will receive only vehicle during the 2-week run-in period. Following 
the run-in period the patient, site personnel, the sponsor and patients will be masked to the treatment 


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assignment for the 3 month treatment period. All study medication will be provided in identical unit of 
dose vials and cartons to maintain masking of the study. 
 
For both Stages 1 and 2, patients with signs and symptoms of DED will be randomly assigned in a 4:1 
(Stage 1, Cohorts 1-3) ratio, a 1:1 (Stage 1, Expansion Cohort) ratio, or to a 2:2:2:2:1:1:1 (Stage 2) 
ratio to receive either a single concentration of AXR-159 Ophthalmic Solution or AXR-159 Ophthalmic 
Solution Vehicle. For the expansion cohort in Stage 1 and Stage 2, subjects will be randomized by 
strata as follows: 
• 
Site 
• 
Baseline eye dryness score ≥ 60, < 60 
• 
Baseline inferior corneal staining > 1.5, ≤ 1.5 
Subjects will not be stratified in Cohorts 1, 2 and 3 in Stage 1.  
The Subject ID that will be used to identify subjects in all datasets and listings for this study will be of 
the form xx-yyy, where xx is a two-digit site number and yyy is a three-digit screening number. 
4.2 
Masking and Unmasking 
An independent biostatistician who is not otherwise involved in the trial will generate the complete 
randomized study drug kit list.  The subject, Sponsor, Investigators and study staff will be masked during 
the randomization process and throughout the study. All study medication will be provided in identical 
unit of dose vials and cartons to maintain masking of the study. 
When necessary for the safety and proper treatment of the patient, the investigator can unmask the 
patient’s treatment assignment to determine which treatment has been assigned and institute 
appropriate follow-up care.  When possible, the sponsor (AxeroVision Inc.) should be notified prior to 
unmasking study medication.  The investigator should inform the sponsor (AxeroVision Inc.) of the 
unmasking if there is no notification prior to the unmasking.   
A report of the results of this study may be published, sent to the appropriate health authorities in any 
country in which the study drug may ultimately be marketed, and published in part as required by 
appropriate health authorities (e.g., Clinical Trials posting and disclosure), but the patient’s name will 
not be disclosed in these documents.   
Patients will be informed that the study is posted and the results eventually disclosed by appropriate 
health authorities (e.g., Clinical Trials posting or freedom of information by the FDA). 
5. Sample Size and Power Considerations 
The sample size is determined empirically.  Xiidra achieved a 0.25 unit difference between lifitegrast 
ophthalmic solution and vehicle in mean change from baseline to day 84 in inferior corneal staining and 


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a standard deviation of approximately 0.75 in Phase 2. Sample sizes for this study are based on 
detecting a 0.35 unit difference between the active and vehicle groups, assuming a standard deviation 
of 0.75.  In Stage 1 the number of expected enrolled subjects varies between 43 and 53 subjects in the 
active group and  between 37 and 47 subjects in the vehicle group.  In Stage 2 the number of expected 
enrolled subjects is 60 in the active group and 30 to 60 subjects in the vehicle group. Thus, the combined 
sample provides between 103 and 113 subjects in the active group and between 67 and 77 subjects in 
the matching vehicle group or between 97 and 107 subjects in the combined vehicle group.  Under these 
assumptions and allowing a dropout rate of 10%, sample sizes of 93 in the active treatment group and 
60 in the vehicle group will yield 80% power to show a significant difference at the α = 0.05 level using 
a two-sample t-test. 
6. Data Preparation 
The clinical study database for AXR201701 will be developed and tested in iMedNet™ v1.174.2 or 
higher.  iMedNet™ is delivered as a single-instance multi-tenant Software-as-a-Service (SaaS) EDC 
system and is developed, maintained, and hosted by MedNet Solutions located in Minnetonka, 
Minnesota.  Therefore, over the duration of the study, MedNet Solutions may apply system updates to 
the EDC system as part of their continuous improvement efforts.  The version of the system at the time 
of the study completion will be recorded on the Study Lock CheckList. 
Data from source documents will be entered into the eCRF by site personnel.  After data are entered 
into the clinical study database, electronic edit checks and data review will be performed.  All data 
validation specifications and procedures are detailed in the Data Validation Manual as a separate 
document.  When the database has been declared to be complete and accurate, the database will be 
locked.  Any changes to the database after data have been locked can only be made with the approval 
Ora, Inc. and AxeroVision, Inc. in consultation with SDC.  
All analyses outlined in this document will be carried out after the following have occurred: 
• 
All data management requirements are met according to SDC standard operating procedures, 
including data entry, performance of edit and validation checks, documentation and resolution 
of data queries, and database lock with written authorization provided by appropriate SDC and 
Sponsor personnel; 
• 
Protocol deviations have been identified and status defined (major/minor deviations);  
• 
Analysis populations have been determined; and 
• 
Randomized treatment codes have been unmasked 
7. Analysis Populations 
The statistical analysis of safety data will be performed for the safety population.  The analysis of 
baseline and efficacy data will be performed for the modified intent-to-treat (mITT) population.  The 


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primary efficacy analysis will also be performed on the modified intent-to-treat 2 (mITT2) and the per 
protocol (PP)  populations as sensitivity analyses. 
7.1 
Modified Intent-to-Treat 
The mITT population includes all randomized subjects that have baseline and at least 1 post-baseline 
assessment for 1 or more of the efficacy measurements. Subjects in the mITT population will be 
analyzed as randomized. 
7.2 
Modified Intent-to-Treat 2 
The mITT2 population includes all subjects in the mITT population that have baseline inferior corneal 
staining score in the study eye > 1.5.  Subjects in the mITT2 population will be analyzed as randomized. 
7.3 
Per Protocol 
The per protocol (PP) population includes subjects in the mITT population who do not have significant 
protocol deviations and who complete the study. Protocol deviations will be assessed prior to database 
lock and unmasking. The PP population will be analyzed using observed data only for primary efficacy 
variables. Subjects in the PP population will be analyzed as treated. 
7.4 
Safety 
The Safety population includes all randomized subjects who have received at least one dose of the 
investigational product. The Safety population will be analyzed for all safety assessments. Subjects in 
the Safety population will be analyzed as treated.  
8. General Statistical Considerations 
8.1 
Unit of Analysis 
Safety endpoints will be analyzed for both eyes.  For efficacy endpoints, the unit of analysis will be the 
study eye, or the “worst eye,” as defined by the following: 
Study Eye/Worst Eye: Eyes are eligible for analysis if they meet all of the inclusion criteria.  In the case 
that both eyes are eligible for analysis, the study eye will be the eye with worse (higher) inferior corneal 
staining score (Ora Calibra® scale) on Day 1.  If the inferior corneal staining score is the same in both 
eyes, then the right eye will be selected as the study eye. 
8.2 
Missing or Inconclusive Data Handling 
The primary efficacy analyses will be performed using LOCF methodology.  For the LOCF analyses of 
the pre-CAE® primary efficacy variables at Month 3 (Visit 5 [Day 85 ± 2]), the last value from the previous 
visits will be carried forward.  Only pre-CAE® or non-CAE® time points will be used to impute a missing 
pre-CAE® value.   


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An analysis using observed data only will also be performed for the primary efficacy variables.  As 
additional sensitivity analyses, Markov Chain Monte Carlo (MCMC) multiple imputation methodology will 
be used to impute missing data for the analyses of the primary efficacy variables. 
No secondary efficacy endpoints or safety endpoints will be imputed. 
8.3 
Definition of Baseline 
Baseline measures are defined as the last measure prior to the initiation of study treatment, usually at 
Day 1.  If a measure is taken both pre-CAE® and post-CAE®, the baseline will be the last time point 
matched value prior to the initiation of study treatment.  For post-CAE® measures, this will be at Day -
14.  For changes from pre-CAE® to post-CAE® post first treatment, the change from pre-CAE® to post-
CAE® at Day -14 will be considered the baseline value. 
Changes from baseline will be calculated as visit minus baseline and summarized by treatment and visit 
as described above.  Treatment comparisons between an active treatment and vehicle will be calculated 
as active minus vehicle.   
8.4 
Data Analysis Conventions 
All data analysis will be performed by Statistics & Data Corporation (SDC) after the study is completed 
and the database has been locked and released for unmasking.  Statistical programming and analyses 
will be performed using SAS® Version 9.4 or higher.  Output will be provided in rich text format (RTF) 
for tables and portable document format (PDF) for tables, listings, and figures using landscape 
orientation.  All study data will be listed by subject, treatment, and visit (as applicable) based on all 
randomized subjects unless otherwise specified. 
Summaries for continuous and ordinal variables will include the number of observations (n), arithmetic 
mean, standard deviation (SD), median, minimum, and maximum).  Minima and maxima will be reported 
with the same precision as the raw values; means and medians will be presented to one additional 
decimal place than reported in the raw values.  SDs will be presented to two additional decimal places 
than reported in the raw values.  Summaries for discrete variables will include frequency counts and 
percentages.  All percentages will be rounded to one decimal place (i.e., XX.X%).  Differences between 
active treatment groups and vehicle will be calculated as Active minus Vehicle and change from baseline 
will be calculated as follow-up visit minus baseline.  The baseline measure will be defined as the last 
non-missing measure prior to initiation of investigational treatment.   
Statistical comparisons between each AXR-159 Ophthalmic Solution group will be to the vehicle group 
at matched dosing frequency (TID or BID).  AXR-159 Ophthalmic Solution plus Artificial Tear group will 
be compared to both AXR-159 Ophthalmic Solution and to the vehicle group at matched dosing 
frequency.   


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A final database lock will occur at the completion of Stage 2 and the safety, tolerability, and efficacy data 
from both Stage 1 and 2 will be analyzed separately and in a combined fashion to fully leverage the 
advantage of this two-stage study design.   
All statistical tests will be two-sided with a significance level of 0.05 (α = 0.05) unless otherwise specified.  
Confidence intervals (CI) for differences between treatment groups will be two-sided at 95% confidence.  
All p-values will be rounded to four decimal places; p-values less than 0.0001 will be presented as 
“<0.0001”; p-values greater than 0.9999 will be presented as “>0.9999”. 
Unless otherwise specified, summaries will be presented by treatment group and, where appropriate, 
visit. 
8.5 
Adjustments for Multiplicity 
This is a Phase 2 study to evaluate safety, tolerability, systemic pharmacokinetics, and 
pharmacodynamics.  All efficacy analyses will be exploratory.  There will be no multiplicity adjustments 
for the multiple treatment groups or multiple primary endpoints.   
9. Disposition of Subjects 
Subject disposition will be presented in terms of the numbers and percentages of subjects who were 
randomized, completed the study, and discontinued from the study.  Subjects who are not discontinued 
from the study will be considered study completers.  Disposition will be summarized by treatment group 
and for all subjects. 
The number of subjects in each of the analysis populations (mITT, mITT2, PP and Safety) will be 
displayed by treatment and percentages will be calculated using randomized subjects as the 
denominator. 
The number and percentage of subjects prematurely discontinued from the study and the reasons for 
study discontinuation will be summarized by treatment group for all randomized subjects.  The reasons 
for study discontinuation that will be summarized include: subject choice, AE, protocol violations, 
administrative reasons, sponsor termination of study, and other.  A subject listing will be provided that 
includes the date of and reason for premature study discontinuation. 
The number and percentage of subjects with major protocol deviations will be summarized by treatment 
group for all randomized subjects.  The protocol deviations that will be summarized include: informed 
consent, inclusion / exclusion and randomization, test article / study drug instillation and assignment at 
site, improper protocol procedures at site, site’s failure to report SAE / AE, visit out of window, subject’s 
non-compliance with test article / study drug, subject’s use of prohibited concomitant medication, 
subject’s failure to follow instructions, and other. A subject listing will be provided that includes the date 


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of the deviation, the deviation description and the classification of whether the deviation was judged to 
be major or minor. 
In addition, subject listings will be provided that include informed consent date, inclusion and exclusion 
criteria violations, and exclusions from the PP population. 
10. Demographic Variables 
The demographic variables collected in this study include age, sex, race, ethnicity and iris color.  
Subjects who record more than one race will be grouped into a single category denoted as  “Multiple 
Races”. Demographic variables will be summarized for the mITT, mITT2 and Safety populations, 
separately. 
Age (years) will be summarized, overall and by treatment, using continuous descriptive statistics.  Age 
will also be categorized as follows:  <65 years and ≥65 years.  Age will be reported in years and 
calculated using the following formula: 
Age = (informed consent date – date of birth) / 365.25 truncated as an integer 
The number and percentage of subjects will be presented, overall and by treatment, for age category, 
sex, race, ethnicity and iris color.  Iris color will be summarized for the right eye (OD), left eye (OS), and 
study eye separately. 
A subject listing that includes all demographic variables will be provided. 
11. Medical History and Concomitant Medications 
11.1 
Medical History 
Medical history will be coded using MedDRA Version 21.0. 
Non-ocular medical history will be summarized using discrete summary statistics and presented by 
treatment group at the subject and event level by System Organ Class (SOC) and Preferred Term (PT) 
using the mITT population.  Ocular medical history will be similarly summarized at the subject level.  If 
a subject reports the same PT multiple times within the same SOC, that PT will only be reported once 
within that SOC.  As with the PT, if a subject reports multiple conditions within the same SOC, that SOC 
will only be reported once.   
Listings of medical history will be generated separately for ocular and non-ocular data. 
11.2 
Concomitant Medications 
Concomitant medications will be coded using World Health Organization (WHO) Drug Global B3 
Dictionary March 2018 and summarized to the therapeutic drug class (Anatomical Therapeutic Chemical 
[ATC] 4 classification) and preferred name.   


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Concomitant medications are defined as those medications listed as having been taken 1) prior to 
initiation of study drug administration and continuing for any period of time following the first 
administration of study drug or 2) at any time following the first administration of study drug. 
Concomitant medications will be summarized using the mITT population.  Medications will be tabulated 
for each treatment group using frequencies and percentages. Subjects may have more than 1 
medication per ATC text.  At each level of subject summarization, a subject will be counted once if he/she 
reports 1 or more medications.  Percentages will be based on the number of subjects in each treatment 
group.  Listings of concomitant medications will be generated separately for ocular and non-ocular data. 
12. Dosing Compliance and Treatment Exposure 
12.1 
Dosing Compliance 
Dosing compliance (% compliance) will be assessed by calculating the number of actual doses received 
and comparing that to the number of expected doses as follows: 
Compliance (%) = 
Number of Actual Doses Received 
x 100% 
Number of Expected Doses 
The number of actual doses received will be calculated from the number of used vials recorded in the 
CRF after Visit 2 (Day 1).  The number of expected doses that will be used for calculating compliance 
will be calculated as 2x[(date of completion/discontinuation – date of Visit 2 [Day 1]) +1] for all subjects 
with BID dosing.  For subjects with TID dosing, the number of expected doses will be calculated as 
3x[(date of completion/discontinuation – date of Visit 2 [Day 1]) +1].   
A categorical dosing compliance variable will also be derived as non-compliant (<80% or >125%) and 
compliant (≥80% and ≤125%). 
Dosing compliance (%) will be summarized with continuous descriptive statistics for each treatment 
group, using the mITT and mITT2 populations.  The compliance category defined above will be 
summarized with discrete summary statistics. 
A subject listing of dosing compliance will also be produced. 
12.2 
Treatment Exposure 
Extent of treatment exposure for all subjects will be calculated in days using the following: 
Extent of Exposure (days) = (Date of completion/discontinuation – date of Visit 2 [Day 1]) + 1 
Extent of treatment exposure (days) for each subject exposed to study drug will be summarized with 
continuous descriptive statistics for each treatment group, using the Safety population.  A subject listing 
of treatment exposure will also be produced. 


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13. Efficacy Analyses 
13.1 
Primary Analysis 
The primary efficacy variables (Pre-CAE®) are: 
• 
Change from Baseline to Visit 5 (Day 85 ± 2) in inferior corneal staining score (Ora Calibra® 
scale) in the study eye 
• 
Change from Baseline to Visit 5 (Day 85 ± 2) in total corneal staining score (Ora Calibra® 
scale) in the study eye 
• 
Change from Baseline to Visit 5 (Day 85 ± 2) in total corneal staining score (Oxford scale) in 
the study eye 
• 
Change from Baseline to Visit 5 (Day 85 ± 2) in eye dryness measured using VAS, and 
• 
Change from Baseline to Visit 5 (Day 85 ± 2) in Total OSDI score 
For each endpoint, change from baseline will be calculated as visit minus baseline such that a positive 
difference indicates a worsening of dry eye signs or symptoms.  In addition, treatment comparisons 
between active and vehicle will be calculated as active minus vehicle, such that a negative result 
indicates a better score for the active treatment (i.e., the active treatment had a smaller increase in dry 
eye signs or symptoms than the placebo group). For comparisons between active and vehicle, dosing 
(TID or BID) of the vehicle will match the dosing of the active treatment.   
13.1.1 PRE-CAE® INFERIOR FLUORESCEIN STAINING (ORA CALIBRA® SCALE) 
Pre-CAE® fluorescein staining in the inferior region of the cornea will be graded using the Ora Calibra® 
Corneal and Conjunctival Staining Scale.  The Ora Calibra® Corneal and Conjunctival Staining Scale 
ranges from 0 to 4 (half grade increments may be used), where grade 0 = none, 1 = trace, 2 = mild, 3 = 
moderate, and 4 = severe.   
Changes from baseline in the pre-CAE® inferior fluorescein staining scores will be summarized at Visit 
5 (Day 85 ± 2) by treatment group for the study eye using quantitative summary statistics.  Changes 
from baseline will be compared between each AXR-159 Ophthalmic Solution group versus vehicle group 
at matched dosing frequency (TID or BID) using an ANCOVA model that adjusts for baseline.  
Specifically, the ANCOVA model will include terms for baseline inferior corneal staining score (ICCS) 
and baseline eye dryness score as covariates and treatment group as a factor in the model. The 
differences in means, two-sided 95% CIs for the difference in means and p-values will be reported.  
Pairwise t-tests from the ANCOVA model will be used to compare treatment and vehicle groups.  
The following SAS code will be used to run the ANCOVA analysis for each of Stage 1 and Stage 2: 
 
PROC MIXED DATA = INDATA; 


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CLASS TREATMENT; 
MODEL CHANGE_ICSS = BASELINE_ICSS BASELINE_EDS TREATMENT  
/ SOLUTION COVB; 
LSMEANS TREATMENT / CL PDIFF; 
ODS OUTPUT LSMEANS = OUTLS DIFFS = OUTDIFFS; 
RUN; 
 
where 
- TREATMENT is the name of the treatment group variable  
- BASELINE_ICSS  is the baseline pre-CAE® inferior fluorescein staining score in the study 
eye 
- BASELINE_EDS  is the baseline pre-CAE® eye dryness score 
- CHANGE_ICSS is the pre-CAE® inferior fluorescein staining in the study eye at Visit 5 (Day 
85 ± 2) – BASELINE_ICSS 
- OUTLS is the name of the output dataset that contains the statistical results for the treatment 
means from the ANCOVA model 
- OUTDIFFS is the name of the output dataset that contains the statistical results for the 
differences in treatment means from the ANCOVA model  
 
T-tests and Wilcoxon rank sum tests will also be conducted as sensitivity analyses to assess robustness 
of the results.   
The primary analysis will be performed on the mITT population with the LOCF imputation method for 
missing values.  For the LOCF analysis, the last value from the previous visits will be carried forward.  
Only pre-CAE® or non-CAE® time points will be used to impute a missing pre-CAE® value.     
As sensitivity analyses, the primary analysis will also be performed on the mITT2 population with LOCF, 
the PP population with LOCF, the mITT population with observed data only, and the mITT population 
with MCMC imputation.   
The MCMC method will be performed using the SAS procedure PROC MI. The SAS code for obtaining 
multiple imputation data is: 
PROC MI DATA = INDATA SEED = SEED_VALUE OUT = OUTDATA NIMPUTE = 20 
MINIMUM = 0 MAXIMUM = 4 ROUND = 0.5; 
BY TREATMENT 
MCMC INITIAL = EM; 
VAR BASELINE_ICSS ICSS; 
RUN; 
where 
- INDATA is the name of the input dataset 
- OUTDATA is the name of the output dataset 


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- TREATMENT is the name of the treatment group variable  
- BASELINE_ICSS is the baseline pre-CAE® inferior fluorescein staining score in the study eye 
- ICSS  is the pre-CAE® inferior fluorescein staining in the study eye at Visit 5 (Day 85 ± 2) 
In the above, the random number seed SEED_VALUE will be set to 62521 + S, where S = 1 for Stage 
1 data analysis, S = 2 for Stage 2 data analysis, and S = 3 for analysis of the combined Stage 1 and 
Stage 2 data. 
After obtaining twenty complete data sets and calculating changes from baseline, the following SAS 
code will be used to run the ANCOVA model on each data set and combine the results from the twenty 
analyses: 
 
PROC MIXED DATA = OUTDATA; 
BY _IMPUTATION_; 
CLASS TREATMENT; 
MODEL CHANGE_ICSS = BASELINE_ICSS BASELINE_EDS TREATMENT  
/ SOLUTION COVB; 
LSMEANS TREATMENT / CL PDIFF; 
ODS OUTPUT LSMEANS = OUTLS DIFFS = OUTDIFFS; 
RUN; 
 
PROC SORT DATA=OUTLS; BY TREATMENT _IMPUTATION_; RUN; 
PROC MIANALYZE DATA=OUTLS; 
BY TREATMENT; 
MODELEFFECTS ESTIMATE; 
STDERR STDERR; 
RUN; 
 
DATA OUTDIFFS; 
SET OUTDIFFS; 
COMPARISON = TREATMENT||’ – ‘||LEFT(_TREATMENT); 
RUN; 
PROC SORT DATA=OUTDIFFS; BY COMPARISON _IMPUTATION_; RUN; 
PROC MIANALYZE DATA=OUTDIFFS; 
BY COMPARISON; 
MODELEFFECTS ESTIMATE; 
STDERR STDERR; 
RUN; 
 
where 
- TREATMENT is the name of the treatment group variable  
- BASELINE_ICSS  is the baseline pre-CAE® inferior fluorescein staining score in the study 
eye 
- BASELINE_EDS  is the baseline pre-CAE® eye dryness score 
- CHANGE_ICSS is the pre-CAE® inferior fluorescein staining in the study eye at Visit 5 (Day 
85 ± 2) – BASELINE_ICSS 


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- OUTLS is the name of the output dataset that contains the statistical results for the treatment 
means from the ANCOVA model that is run on each of the twenty imputation datasets 
- OUTDIFFS is the name of the output dataset that contains the statistical results for the 
differences in treatment means from the ANCOVA model that is run on each of the twenty 
imputation datasets 
 
Similar SAS code will be used to conduct MCMC multiple imputation analysis for t-tests using the same 
imputation data sets generated above. 
Pre-CAE® inferior fluorescein staining changes from baseline in the study eye will be displayed 
graphically in a bar chart with standard error bars by visit and treatment group based on the ANCOVA 
analysis. 
13.1.2 PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (ORA CALIBRA® SCALE) 
Pre-CAE® fluorescein staining will be graded using the Ora Calibra® Corneal and Conjunctival Staining 
Scale.  The Ora Calibra® Corneal and Conjunctival Staining Scale ranges from 0 to 4 (half grade 
increments may be used), where grade 0 = none, 1 = trace, 2 = mild, 3 = moderate, and 4 = severe.  
Staining will be graded in the inferior, superior, corneal, temporal and nasal regions.  The total corneal 
fluorescein staining score is the sum of the scores from the inferior, corneal and superior regions.   
Pre-CAE® total corneal fluorescein staining will be analyzed similarly to pre-CAE® inferior fluorescein 
staining.  Pre-CAE® total corneal fluorescein staining changes from baseline in the study eye will be 
displayed graphically in a bar chart with standard error bars by visit and treatment group based on the 
ANCOVA analysis.  The ANCOVA models, including the ANCOVA model used in the MCMC analysis, 
will include terms for baseline total corneal staining score, baseline ICCS and baseline eye dryness 
score as covariates and treatment group as a factor in the model.   
LOCF and MCMC imputation will be performed for each region separately, prior to calculating the total 
corneal fluorescein staining score.  The following random number seed values will be used for the 
MCMC imputations:  62521 + S for inferior region, 38751 + S for central region, 91121 + S for superior 
region, 22252 + S for temporal region, and 83620 + S for nasal region, where S = 1 for Stage 1 data 
analysis, S = 2 for Stage 2 data analysis, and S = 3 for analysis of the combined Stage 1 and Stage 2 
data. 
13.1.3 PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (OXFORD SCALE) 
The Oxford scale ranges from 0 to 5 for the corneal region with higher scores indicating greater staining.   
Pre-CAE® total corneal fluorescein staining (Oxford scale) will be analyzed similarly to pre-CAE® inferior 
fluorescein staining (Ora Calibra® scale).  The ANCOVA models, including the ANCOVA model used in 


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the MCMC analysis, will include terms for baseline total corneal staining score (Oxford scale), baseline 
inferior corneal staining score (Ora Calibra® scale) and baseline eye dryness score as covariates and 
treatment group as a factor in the model.  Pre-CAE® total corneal fluorescein staining changes from 
baseline in the study eye will be displayed graphically in a bar chart with standard error bars by visit and 
treatment group based on the ANCOVA analysis.   
The random number seed values that will be used for the MCMC imputations are given by 61521 + S, 
where S = 1 for Stage 1 data analysis, S = 2 for Stage 2 data analysis, and S = 3 for analysis of the 
combined Stage 1 and Stage 2 data. 
13.1.4 PRE-CAE® EYE DRYNESS (VISUAL ANALOG SCALE) 
In the VAS assessment, the subject will be asked to rate each of several ocular symptoms due to ocular 
dryness by placing a vertical mark on a 100 mm horizontal line to indicate the level of discomfort.  A 
score of 0 corresponds to “no discomfort” and 100 corresponds to “maximal discomfort”.   
Eye dryness will be assessed by VAS and analyzed similarly to pre-CAE® inferior fluorescein staining 
(Ora Calibra® scale).  The ANCOVA models, including the ANCOVA model used in the MCMC analysis, 
will include terms for baseline eye dryness (VAS) and baseline inferior corneal staining score (Ora 
Calibra® scale) as covariates and treatment group as a factor in the model.  Eye dryness changes from 
baseline will be displayed graphically in a bar chart with standard error bars by visit and treatment group 
based on the ANCOVA analysis.   
The random number seed values that will be used for the MCMC imputations are given by 65521 + S, 
where S = 1 for Stage 1 data analysis, S = 2 for Stage 2 data analysis, and S = 3 for analysis of the 
combined Stage 1 and Stage 2 data. 
13.1.5 PRE-CAE® TOTAL OSDI 
The OSDI© is assessed on a scale of 0 to 100, with higher scores representing greater disability.  The 
OSDI© asks the following 12 questions at the subject level: 
Have you experienced any of the following during the last week: 
1) Eyes that are sensitive to light? 
2) Eyes that feel gritty? 
3) Painful or sore eyes? 
4) Blurred vision? 
5) Poor vision? 
Have problems with your eyes limited you in performing any of the following during the last week: 
6) Reading? 
7) Driving at night? 
8) Working with a computer or bank machine (ATM)? 


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9) Watching TV? 
Have your eyes felt uncomfortable in any of the following situations during the last week: 
10) Windy conditions? 
11) Places or areas with low humidity (very dry)? 
12) Areas that are air conditioned? 
OSDI© will be collected for both eyes pre-CAE® at each visit.  The 5-unit scale for responses to the 
OSDI© is given by the following:  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© score is calculated by the following: 
OSDI© = 
(sum of scores) x 25 
# of questions answered 
Note that the number of questions answered in the denominator should exclude those questions with a 
response of “N/A”.   
Pre-CAE® Total OSDI© will be analyzed similarly to pre-CAE® inferior fluorescein staining (Ora Calibra® 
scale).  The ANCOVA models, including the ANCOVA model used in the MCMC analysis, will include 
terms for baseline Total OSDI©, baseline inferior corneal staining score (Ora Calibra® scale) and 
baseline eye dryness score as covariates and treatment group as a factor in the model.  Pre-CAE® Total 
OSDI© changes from baseline will be displayed graphically in a bar chart with standard error bars by 
visit and treatment group based on the ANCOVA analysis.   
LOCF and MCMC imputation will be performed for total OSDI score; separate imputations will not be 
created for each individual question score. The random number seed values that will be used for the 
MCMC imputations are given by 67521 + S, where S = 1 for Stage 1 data analysis, S = 2 for Stage 2 
data analysis, and S = 3 for analysis of the combined Stage 1 and Stage 2 data. 
13.2 
Secondary Analyses 
The continuous and ordinal secondary efficacy variables collected at each visit will be summarized 
descriptively (n, mean, SD, median, min and max) by visit and treatment group.  Change scores from 
pre- to post-CAE® will be calculated as post-CAE® score minus pre-CAE® score.  Changes from baseline 
will also be summarized descriptively by visit and treatment group.  No imputation will be performed for 
secondary efficacy variables.  Analyses will be performed on the mITT population with observed data 
only.  All secondary measures will also be presented in subject listings. 
The following secondary efficacy endpoints will be tested: 
• 
Unanesthetized Schirmer’s Test 
• 
TFBUT 


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• 
Conjunctival Redness Score 
• 
Fluorescein Corneal Staining (Ora Calibra® scale) 
• 
Fluorescein Corneal Staining (Oxford scale) 
• 
Lissamine Green Conjunctival Staining (Oxford scale) 
• 
Ocular Discomfort Score 
• 
Ocular Discomfort & 4-Symptom Questionnaire 
• 
VAS 
• 
OSDI 
• 
SANDE 
 
13.2.1 UNANESTHETIZED SCHIRMER’S TEST 
Unanesthetized Schirmer’s Test will be assessed on both eyes at all visits.  Visit 1 and 5 assessments 
will be pre-CAE®.  The Schirmer’s test strip will be placed in the lower temporal lid margin of each eye.  
After 5 minutes, the test strip will be removed and the length of the moistened area will be recorded in 
millimeters (mm) for each eye.  Lower values indicate less tears produced in the eye.   
Unanesthetized Schirmer’s Test will be summarized by treatment group and visit using quantitative 
summary statistics.  Change from baseline will be also summarized.   
Pairwise two-sample t-tests will be employed to compare treatment and vehicle means at each visit and 
time point.  The differences in means, two-sided 95% CIs for the difference in means and p-values will 
be reported.  Wilcoxon rank sum tests will also be conducted.  Analyses will be performed on the mITT 
population with observed data only. 
Changes from baseline will be compared between treatment groups using ANCOVA models that adjust 
for baseline value, baseline inferior corneal staining (Ora Calibra® scale) and baseline eye dryness 
(VAS).  The differences in means, two-sided 95% CIs for the difference in means and p-values will be 
reported.  T-tests and Wilcoxon rank sum tests will also be conducted.  Analyses will be performed on 
the mITT population with observed data only. 
Binary clinical cure variables will be defined by visit for Schirmer’s test ≥ 5 mm, Schirmer’s test ≥ 10 mm 
and Schirmer’s change from baseline ≥ 5 mm, and will summarized by visit using number of subjects, 
frequency counts and percentages.  Treatment groups will be compared pairwise with vehicle using 
Pearson’s chi-square test or Fisher’s exact test if the expected cell count is less than 5 in 25% or more 
of the cells.  In addition, the proportion of responders will be compared between treatment groups using 
the Cochran-Mantel-Haenszel method stratifying by baseline ICSS (≤ 1.5, > 1.5) and baseline eye 
dryness (< 60, ≥ 60).  For the Cochran-Mantel-Haenszel analysis of the combined Stage 1 and Stage 2 
data, the study Stage will also be included as a stratification factor.   


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13.2.2 TEAR FILM BREAK-UP TIME (TFBUT) 
TFBUT will be measured at all scheduled visits on both eyes.  Both pre- and post-CAE® assessments 
will be made at Visits 1 and 5.  For each eye, two measurements will be recorded in seconds and 
averaged unless the two measurements are >2 seconds apart and are each <10 seconds, in which 
case, a third measurement will be taken and the two closest of the three will be averaged and used for 
analyses.  If the differences between two sequential pairs of measurements are the same, e.g., 3, 6, 9 
seconds, then the median of the three readings will be used for analysis.   
TFBUT will be summarized by treatment group, visit and time point (pre- and post-CAE®) using 
quantitative summary statistics.  Change from baseline will be also summarized.   
Pairwise two-sample t-tests will be employed to compare treatment and vehicle means at each visit and 
time point.  The differences in means, two-sided 95% CIs for the difference in means and p-values will 
be reported.  Wilcoxon rank sum tests will also be conducted.  Analyses will be performed on the mITT 
population with observed data only. 
Changes from baseline will be compared between treatment groups using ANCOVA models that adjust 
for baseline value, baseline inferior corneal staining (Ora Calibra® scale) and baseline eye dryness 
(VAS).  The differences in means, two-sided 95% CIs for the difference in means and p-values will be 
reported.  T-tests and Wilcoxon rank sum tests will also be conducted.  Analyses will be performed on 
the mITT population with observed data only. 
Binary clinical cure variables will be defined by visit for TFBUT ≥ 5 s, TFBUT ≥ 10 s, and TFBUT change 
from baseline ≥ 5 s, and will be summarized by visit using number of subjects, frequency counts and 
percentages.  Treatment groups will be compared pairwise with vehicle using Pearson’s chi-square test 
or Fisher’s exact test if the expected cell count is less than 5 in 25% or more of the cells.  In addition, 
the proportion of responders will be compared between treatment groups using the Cochran-Mantel-
Haenszel method stratifying by baseline ICSS (≤ 1.5, > 1.5) and baseline eye dryness (< 60, ≥ 60).  For 
the Cochran-Mantel-Haenszel analysis of the combined Stage 1 and Stage 2 data, the study Stage will 
also be included as a stratification factor.   
13.2.3 OCULUS KERATOGRAPH 
Oculus keratography will be assessed at all visits at selected sites only.  Only pre-CAE® assessments 
will be made at Visits 1 and 5.  First break (seconds), average time (seconds) and tear meniscus height 
(mm) will be recorded.   
Oculus keratography measurements will be summarized by treatment group and visit using quantitative 
summary statistics.  Change from baseline will be also summarized.   


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Pairwise two-sample t-tests will be employed to compare treatment and vehicle means at each visit and 
time point.  The differences in means, two-sided 95% CIs for the difference in means and p-values will 
be reported.  Wilcoxon rank sum tests will also be conducted.  Analyses will be performed on the mITT 
population with observed data only. 
Changes from baseline will be compared between treatment groups using ANCOVA models that adjust 
for baseline value, baseline inferior corneal staining (Ora Calibra® scale) and baseline eye dryness 
(VAS).  The differences in means, two-sided 95% CIs for the difference in means and p-values will be 
reported.  T-tests and Wilcoxon rank sum tests will also be conducted.  Analyses will be performed on 
the mITT population with observed data only. 
13.2.4 CONJUNCTIVAL REDNESS SCORE 
The Ora Calibra® Conjunctival Redness Scale for Dry Eye will be performed on all scheduled visits.  
Both pre- and post-CAE® assessments will be made at Visits 1 and 5.  The conjunctival redness scale 
ranges from 0 to 4 where 0 = normal, without vasodilation, 1 = trace ciliary or conjunctival vasodilation, 
2 = broad ciliary vasodilation, 3 = broad ciliary and slight, horizontal conjunctival vasodilation, and 4 = 
broad ciliary and prominent, horizontal conjunctival vasodilation. Half unit increments are allowed. 
Conjunctival redness will be summarized by treatment group, visit and time point (pre- and post-CAE®) 
using quantitative summary statistics.  Change from baseline will be also summarized.   
Pairwise two-sample t-tests will be employed to compare treatment and vehicle means at each visit and 
time point.  The differences in means, two-sided 95% CIs for the difference in means and p-values will 
be reported.  Wilcoxon rank sum tests will also be conducted.  Analyses will be performed on the mITT 
population with observed data only. 
Changes from baseline will be compared between treatment groups using ANCOVA models that adjust 
for baseline value, baseline inferior corneal staining (Ora Calibra® scale) and baseline eye dryness 
(VAS).  The differences in means, two-sided 95% CIs for the difference in means and p-values will be 
reported.  T-tests and Wilcoxon rank sum tests will also be conducted.  Analyses will be performed on 
the mITT population with observed data only. 
A binary clinical cure variable will be defined by visit for conjunctival redness = 0, and will be summarized 
by visit using number of subjects, frequency counts and percentages.  Treatment groups will be 
compared pairwise with vehicle using Pearson’s chi-square test or Fisher’s exact test if the expected 
cell count is less than 5 in 25% or more of the cells.  In addition, the proportion of responders will be 
compared between treatment groups using the Cochran-Mantel-Haenszel method stratifying by 
baseline ICSS (≤ 1.5, > 1.5) and baseline eye dryness (< 60, ≥ 60).  For the Cochran-Mantel-Haenszel 


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analysis of the combined Stage 1 and Stage 2 data, the study Stage will also be included as a 
stratification factor.   
13.2.5 FLUORESCEIN CORNEAL STAINING (ORA CALIBRA® SCALE) 
Corneal and conjunctival fluorescein staining will be performed at all scheduled visits, on both eyes and 
graded using the Ora Calibra® Corneal and Conjunctival Staining Scale.  Both pre- and post-CAE® 
assessments will be made at Visits 1 and 5.  The scale will grade the cornea and conjunctiva by five 
regions: inferior, superior, central, temporal, and nasal. The Ora Calibra® Corneal and Conjunctival 
Staining Scale ranges from 0 to 4 (half grade increments may be used), where grade 0 = none, 1 = 
trace, 2 = mild, 3 = moderate, and 4 = severe.   
Fluorescein staining scores will be summarized by treatment group, visit, time point (pre- and post-
CAE®), and region (5 regions, plus corneal sum, conjunctival sum, and total scores) for the study eye 
using quantitative summary statistics. The corneal sum score will be the sum of scores from the inferior, 
superior, and central regions. The conjunctival sum score will be the sum of scores from the nasal and 
temporal regions.  The total score will be the sum of scores from all five regions.   
Pairwise two-sample t-tests will be employed to compare treatment and vehicle means at each visit and 
time point.  The differences in means, two-sided 95% CIs for the difference in means and p-values will 
be reported.  Wilcoxon rank sum tests will also be conducted.  Analyses will be performed on the mITT 
population with observed data only. 
Changes from baseline will be compared between treatment groups using ANCOVA models that adjust 
for baseline value, baseline inferior corneal staining (Ora Calibra® scale) and baseline eye dryness 
(VAS).  The differences in means, two-sided 95% CIs for the difference in means and p-values will be 
reported.  T-tests and Wilcoxon rank sum tests will also be conducted.  Analyses will be performed on 
the mITT population with observed data only. 
Binary clinical cure variables will be defined by visit and region for clearing (score = 0) and 1-unit 
improvement (change from baseline <= -1), and will be summarized by visit and region using number of 
subjects, frequency counts and percentages.  Treatment groups will be compared pairwise with vehicle 
using Pearson’s chi-square test or Fisher’s exact test if the expected cell count is less than 5 in 25% or 
more of the cells.  In addition, the proportion of responders will be compared between treatment groups 
using the Cochran-Mantel-Haenszel method stratifying by baseline ICSS (≤ 1.5, > 1.5) and baseline eye 
dryness (< 60, ≥ 60).  For the Cochran-Mantel-Haenszel analysis of the combined Stage 1 and Stage 2 
data, the study Stage will also be included as a stratification factor.   
 


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13.2.6 FLUORESCEIN CORNEAL STAINING (OXFORD SCALE) 
Corneal fluorescein staining will be performed at all scheduled visits and graded using the Oxford Scale.  
Both pre- and post-CAE® assessments will be made at Visits 1 and 5.  The Oxford scale for corneal 
staining ranges from 0 to 5 for the corneal region. with higher scores indicating greater staining. 
Staining scores will be summarized by treatment group, visit and time point (pre- and post-CAE®) using 
quantitative summary statistics.  Change from baseline will be also summarized.  Each region and total 
score will be summarized separately. 
Pairwise two-sample t-tests will be employed to compare treatment and vehicle means at each visit and 
time point.  The differences in means, two-sided 95% CIs for the difference in means and p-values will 
be reported.  Wilcoxon rank sum tests will also be conducted.  Analyses will be performed on the mITT 
population with observed data only. 
Changes from baseline will be compared between treatment groups using ANCOVA models that adjust 
for baseline value, baseline inferior corneal staining (Ora Calibra® scale) and baseline eye dryness 
(VAS).  The differences in means, two-sided 95% CIs for the difference in means and p-values will be 
reported.  T-tests and Wilcoxon rank sum tests will also be conducted.  Analyses will be performed on 
the mITT population with observed data only. 
Binary clinical cure variables will be defined by visit and region for clearing (score = 0) and 1-unit 
improvement (change from baseline <= -1), and will be summarized by visit and region using number of 
subjects, frequency counts and percentages.  Treatment groups will be compared pairwise with vehicle 
using Pearson’s chi-square test or Fisher’s exact test if the expected cell count is less than 5 in 25% or 
more of the cells.  In addition, the proportion of responders will be compared between treatment groups 
using the Cochran-Mantel-Haenszel method stratifying by baseline ICSS (≤ 1.5, > 1.5) and baseline eye 
dryness (< 60, ≥ 60).  For the Cochran-Mantel-Haenszel analysis of the combined Stage 1 and Stage 2 
data, the study Stage will also be included as a stratification factor.   
13.2.7 LISSAMINE GREEN CONJUNCTIVAL STAINING (OXFORD SCALE) 
Lissamine green conjunctival staining will be performed at all scheduled visits and graded using the 
Oxford Scale. The Oxford scale for conjunctival staining ranges from 0 to 5 for each of the nasal and 
temporal regions, with higher scores indicating greater staining.  The total conjunctival score is the sum 
of the two regions and ranges from 0 to 10. 
Staining scores will be summarized by treatment group, visit and time point (pre- and post-CAE®) using 
quantitative summary statistics.  Change from baseline will be also summarized.  Each region and total 
score will be summarized separately. 


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Pairwise two-sample t-tests will be employed to compare treatment and vehicle means at each visit and 
time point.  The differences in means, two-sided 95% CIs for the difference in means and p-values will 
be reported.  Wilcoxon rank sum tests will also be conducted.  Analyses will be performed on the mITT 
population with observed data only. 
Changes from baseline will be compared between treatment groups using ANCOVA models that adjust 
for baseline value, baseline inferior corneal staining (Ora Calibra® scale) and baseline eye dryness 
(VAS).  The differences in means, two-sided 95% CIs for the difference in means and p-values will be 
reported.  T-tests and Wilcoxon rank sum tests will also be conducted.  Analyses will be performed on 
the mITT population with observed data only. 
Binary clinical cure variables will be defined by visit and region for clearing (score = 0) and 1-unit 
improvement (change from baseline <= -1), and will be summarized by visit and region using number of 
subjects, frequency counts and percentages.  Treatment groups will be compared pairwise with vehicle 
using Pearson’s chi-square test or Fisher’s exact test if the expected cell count is less than 5 in 25% or 
more of the cells.  In addition, the proportion of responders will be compared between treatment groups 
using the Cochran-Mantel-Haenszel method stratifying by baseline ICSS (≤ 1.5, > 1.5) and baseline eye 
dryness (< 60, ≥ 60).  For the Cochran-Mantel-Haenszel analysis of the combined Stage 1 and Stage 2 
data, the study Stage will also be included as a stratification factor.   
13.2.8 OCULAR DISCOMFORT SCORE 
Ocular discomfort scores will be subjectively graded by the subjects using the Ora Calibra® Ocular 
Discomfort Scale at all scheduled visits.  Both pre- and post-CAE® assessments will be made at Visits 
1 and 5.  Ocular discomfort scores will also be assessed during the CAE® exposure, immediately upon 
entering the chamber and every 5 minutes thereafter for the duration of the 90 minute exposure.  The 
ocular discomfort scale ranges from 0 to 4 where 0 = no discomfort, 1 = intermittent awareness, 2 = 
constant awareness, 3 = intermittent discomfort, and 4 = constant discomfort.   
13.2.8.1 
ORA CALIBRA® OCULAR DISCOMFORT SCALE PRE-, POST-, AND NON-CAE® 
Pre- and post-CAE® assessments of ocular discomfort will be made at Visits 1 and 5.  Ocular discomfort 
will also be assessed during the non-CAE Visits 2, 3, and 4.  Ocular discomfort will be summarized by 
treatment group, visit and time point (pre- and post-CAE®) using quantitative summary statistics.  
Change from baseline will be also summarized.   
Pairwise two-sample t-tests will be employed to compare treatment and vehicle means at each visit and 
time point.  The differences in means, two-sided 95% CIs for the difference in means and p-values will 
be reported.  Wilcoxon rank sum tests will also be conducted.  Analyses will be performed on the mITT 
population with observed data only. 


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Changes from baseline will be compared between treatment groups using ANCOVA models that adjust 
for baseline value, baseline inferior corneal staining (Ora Calibra® scale) and baseline eye dryness 
(VAS).  The differences in means, two-sided 95% CIs for the difference in means and p-values will be 
reported.  T-tests and Wilcoxon rank sum tests will also be conducted.  Analyses will be performed on 
the mITT population with observed data only. 
A binary clinical cure variable will be defined by visit for pre-CAE® ocular discomfort score = 0, and 
summarized by visit using number of subjects, frequency counts and percentages.  Treatment groups 
will be compared pairwise with vehicle using Pearson’s chi-square test or Fisher’s exact test if the 
expected cell count is less than 5 in 25% or more of the cells.  In addition, the proportion of responders 
will be compared between treatment groups using the Cochran-Mantel-Haenszel method stratifying by 
baseline ICSS (≤ 1.5, > 1.5) and baseline eye dryness (< 60, ≥ 60).  For the Cochran-Mantel-Haenszel 
analysis of the combined Stage 1 and Stage 2 data, the study Stage will also be included as a 
stratification factor.   
13.2.8.2 
ORA CALIBRA® OCULAR DISCOMFORT SCALE DURING CAE® EXPOSURE 
Ocular discomfort scores will be assessed every 5 minutes during the CAE® exposure.  Continuous 
descriptive statistics, including 95% CIs, as well as changes from baseline will be summarized by 
treatment group, visit, and time point.  The change from the 0 minutes assessment within the same visit 
and changes from baseline will also be summarized by treatment group, visit, and time point.   
For both the ocular discomfort score and the change from 0 minutes, pairwise two-sample t-tests will be 
employed to compare treatment and vehicle means at each visit and time point.  The differences in 
means, two-sided 95% CIs for the difference in means and p-values will be reported.  Wilcoxon rank 
sum tests will also be conducted.  Analyses will be performed on the mITT population with observed 
data only. 
Changes from baseline will be compared between treatment groups using ANCOVA models that adjust 
for baseline value, baseline inferior corneal staining (Ora Calibra® scale) and baseline eye dryness 
(VAS).  The differences in means, two-sided 95% CIs for the difference in means and p-values will be 
reported.  T-tests and Wilcoxon rank sum tests will also be conducted.  Analyses will be performed on 
the mITT population with observed data only. 
13.2.9 ORA CALIBRA® OCULAR DISCOMFORT & 4-SYMPTOM QUESTIONNAIRE 
Ocular discomfort and dry eye symptoms will be assessed at all scheduled visits at the subject level in 
regard to how both eyes feel.  Both pre- and post-CAE® assessments will be made at Visits 1 and 5.  
The Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire will be used, which includes rating of 
the severity of 5 symptoms: ocular discomfort, burning, dryness, grittiness, and stinging.  Each symptom 
rating ranges from 0 to 5, where 0 = none and 5 = worst. 


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Symptom scores will be summarized by visit, time point, and treatment group using quantitative 
summary statistics, including 95% CIs.  Change from baseline will also be summarized.   
Pairwise two-sample t-tests will be employed to compare treatment and vehicle means at each visit and 
time point.  The differences in means, two-sided 95% CIs for the difference in means and p-values will 
be reported.  Wilcoxon rank sum tests will also be conducted.  Analyses will be performed on the mITT 
population with observed data only. 
Changes from baseline will be compared between treatment groups using ANCOVA models that adjust 
for baseline value, baseline inferior corneal staining (Ora Calibra® scale) and baseline eye dryness 
(VAS).  The differences in means, two-sided 95% CIs for the difference in means and p-values will be 
reported.  T-tests and Wilcoxon rank sum tests will also be conducted.  Analyses will be performed on 
the mITT population with observed data only. 
13.2.10 VISUAL ANALOG SCALE 
At every visit, subjects will be asked to rate each ocular symptom due to ocular dryness by placing a 
vertical mark on a horizontal line of length 100 mm to indicate the level of discomfort. 0 mm corresponds 
to “no discomfort” and 100 mm corresponds to “maximal discomfort.” Both pre- and post-CAE® 
assessments will be made at Visits 1, 2, 4, and 5.  Symptoms assessed are burning/stinging, itching, 
foreign body sensation, blurred vision, eye dryness, photophobia, and pain. 
Symptom scores and the average symptom score will be summarized by visit, time point, and treatment 
group using quantitative summary statistics, including 95% CIs.  Change from baseline will also be 
summarized.   
Pairwise two-sample t-tests will be employed to compare treatment and vehicle means at each visit and 
time point.  The differences in means, two-sided 95% CI for the difference in means and p-values will 
be reported.  Wilcoxon rank sum tests will also be conducted.  Analyses will be performed on the mITT 
population with observed data only. 
Changes from baseline will be compared between treatment groups using ANCOVA models that adjust 
for baseline value, baseline inferior corneal staining (Ora Calibra® scale) and baseline eye dryness 
(VAS).  The differences in means, two-sided 95% CIs for the difference in means and p-values will be 
reported.  T-tests and Wilcoxon rank sum tests will also be conducted.  Analyses will be performed on 
the mITT population with observed data only. 
13.2.11 OCULAR SURFACE DISEASE INDEX (OSDI) 
The OSDI is described in Section 13.1.5.  OSDI will be assessed on both eyes at all visits.  Visit 1 and 
5 assessments will be pre-CAE®.  OSDI will be summarized by treatment group and visit using 


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quantitative summary statistics.  Change from baseline will be also summarized.  Each individual 
response, subtotal scores, and total OSDI score will be presented separately. 
Pairwise two-sample t-tests will be employed to compare treatment and vehicle means at each visit and 
time point.  The differences in means, two-sided 95% CIs for the difference in means and p-values will 
be reported.  Wilcoxon rank sum tests will also be conducted.  Analyses will be performed on the mITT 
population with observed data only. 
Changes from baseline will be compared between treatment groups using ANCOVA models that adjust 
for baseline value, baseline inferior corneal staining (Ora Calibra® scale) and baseline eye dryness 
(VAS).  The differences in means, two-sided 95% CIs for the difference in means and p-values will be 
reported.  T-tests and Wilcoxon rank sum tests will also be conducted.  Analyses will be performed on 
the mITT population with observed data only. 
A binary clinical cure variable will be defined by visit for Total OSDI < 18, and summarized by visit using 
number of subjects, frequency counts and percentages.  Treatment groups will be compared pairwise 
with vehicle using Pearson’s chi-square test or Fisher’s exact test if the expected cell count is less than 
5 in 25% or more of the cells.  In addition, the proportion of responders will be compared between 
treatment groups using the Cochran-Mantel-Haenszel method stratifying by baseline ICSS (≤ 1.5, > 1.5) 
and baseline eye dryness (< 60, ≥ 60).  For the Cochran-Mantel-Haenszel analysis of the combined 
Stage 1 and Stage 2 data, the study Stage will also be included as a stratification factor.   
13.2.12 SYMPTOM ASSESSMENT IN DRY EYE (SANDE) 
The SANDE Questionnaire will be assessed on both eyes at all visits.  Visit 1 and 5 assessments will 
be pre-CAE®.  In this questionnaire, subjects indicate the frequency that their eyes feel dry and/or 
irritated and the severity of their symptoms.  Frequency is measured on a 0-100 mm scale with 0 
indicating rarely and 100 indicating all the time.  Severity is also measured on a 0-100 mm scale with 0 
indicating very mild and 100 indicating very severe.  The SANDE Score is calculated as the product of 
the square root of the Frequency Score and the square root of the Severity Score. 
The Frequency, Severity and combined SANDE Scores will be summarized by treatment group and visit 
using quantitative summary statistics.  Change from baseline will be also summarized.   
Pairwise two-sample t-tests will be employed to compare treatment and vehicle means at each visit and 
time point.  The differences in means, two-sided 95% CIs for the difference in means and p-values will 
be reported.  Wilcoxon rank sum tests will also be conducted.  Analyses will be performed on the mITT 
population with observed data only. 
Changes from baseline will be compared between treatment groups using ANCOVA models that adjust 
for baseline value, baseline inferior corneal staining (Ora Calibra® scale) and baseline eye dryness 


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(VAS).  The differences in means, two-sided 95% CIs for the difference in means and p-values will be 
reported.  T-tests and Wilcoxon rank sum tests will also be conducted.  Analyses will be performed on 
the mITT population with observed data only. 
14. Exploratory Analyses 
No exploratory analyses are planned. 
15. Subgroup Analyses 
Patients will be stratified by the Pre-CAE® ICCS (i.e., ≤ 1.5 or > 1.5) according to the Ora Calibra® 
staining scale and eye dryness score (i.e., < 60 or ≥ 60) in the study eye.       
Subgroup analyses are planned for the 4 groups defined by the 2 stratification factors (Pre-CAE®): 
1. ICCS ≤ 1.5 according to the Ora Calibra® staining scale and eye dryness score < 60 
2. ICCS ≤ 1.5 according to the Ora Calibra® staining scale and eye dryness score ≥ 60 
3. ICCS > 1.5 according to the Ora Calibra® staining scale and eye dryness score < 60 
4. ICCS > 1.5 according to the Ora Calibra® staining scale and eye dryness score ≥ 60. 
Subgroup analyses will be conducted for corneal fluorescein staining (Ora Calibra® scale), corneal 
fluorescein staining (Oxford scale), VAS, and Total OSDI.  Each endpoint will be summarized by 
subgroup, treatment group, visit and time point (where appropriate).   
Additional subgroup analyses will be conducted based upon strata defined by median baseline values 
in pre-CAE assessments.  For each endpoint, separate analyses will be conducted for patients with pre-
CAE baseline scores ≤ the pre-CAE baseline median, and for patients with pre-CAE baseline scores > 
the pre-CAE baseline median.  These subgroup analyses will be conducted for all efficacy endpoints. 
Subgroup analyses of symptom endpoints will also be conducted for the following two groups: 
1. Patients with time to CAE qualification ≤ 20 minutes 
2. Patients with time to CAE qualification > 20 minutes 
For each subgroup, pairwise two-sample t-tests will be employed to compare treatment and vehicle 
means at each visit and time point.  The differences in means, two-sided 95% CIs for the difference in 
means and p-values will be reported.  Wilcoxon rank sum tests will also be conducted.  Analyses will be 
performed on the mITT population with observed data only. 
Changes from baseline will be compared between treatment groups using ANCOVA models that adjust 
for baseline value.  The differences in means, two-sided 95% CIs for the difference in means and p-
values will be reported.  T-tests and Wilcoxon rank sum tests will also be conducted.  Analyses will be 
performed on the mITT population with observed data only. 


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16. Safety Analyses 
All safety analyses will be conducted using the Safety Population. 
16.1 
Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of an IP in humans, 
whether or not considered IP-related. An AE can be any unfavorable and unintended sign (e.g., an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an IP, without 
any judgment about causality. An AE can arise from any use of the IP (e.g., off-label use, use in 
combination with another drug or medical device) and from any route of administration, formulation, or 
dose, including an overdose. An AE can arise from any delivery, implantation, or use of a medical device, 
including medical device failure, subject characteristics that may impact medical device performance 
(e.g., anatomical limitations), and therapeutic parameters (e.g., energy applied, sizing, dose release, 
and anatomic fit) associated with medical device use. 
All AEs spontaneously reported by the subject and/or in response to an open question from study 
personnel or revealed by observation, physical examination or other diagnostic procedures will be 
recorded in the source document and on the appropriate pages of the case report form. Any clinically 
relevant deterioration in clinical finding is considered an AE and must be recorded. When possible, signs 
and symptoms indicating a common underlying pathology should be noted as one comprehensive event. 
Documentation regarding the AE should be made as to the nature, date of onset, end date, severity, 
and relationship to IP, action(s) taken, seriousness, and outcome of any sign or symptom observed by 
the physician or reported by the subject upon indirect questioning. 
Severity of an AE is defined as a qualitative assessment of the degree of intensity of an AE as 
determined by the investigator or reported to him/her by the subject. The assessment of severity is made 
irrespective of relationship to IP or seriousness of the event and should be evaluated according to the 
following scale: 
• 
Mild: Event is noticeable to the subject, but is easily tolerated and does not interfere with the 
subject’s daily activities. 
• 
Moderate: Event is bothersome, possibly requiring additional therapy, and may interfere with 
the subject’s daily activities. 
• 
Severe: Event is intolerable, necessitates additional therapy or alteration of therapy, and 
interferes with the subject’s daily activities. 
A determination will be made of the relationship (if any) between an adverse event and the study drug 
or study procedure, as applicable.  A causal relationship is present if a determination is made that 


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there is a reasonable possibility that the adverse event may have been caused by the drug or study 
procedure.   
The relationship of each AE to the IP should be determined by the investigator using these 
explanations: 
• 
Suspected: A reasonable possibility exists that the IP caused the AE. A suspected AE can be 
further defined as: 
 
Definite: Relationship exists when the AE follows a reasonable sequence from the time of 
IP administration, follows a known response pattern of the drug class, is confirmed by 
improvement on stopping the IP and no other reasonable cause exists. 
 
Probable: Relationship exists when the AE follows a reasonable sequence from the time 
of IP administration, follows a known response pattern of the drug class, is confirmed by 
improvement on stopping the IP and the suspect IP is the most likely of all causes. 
 
Possible: Relationship exists when the AE follows a reasonable sequence from the time of 
IP administration, but could also have been produced by the subject’s clinical state or by 
other drugs administered to the subject. 
• 
Not Suspected: A reasonable possibility does not exist that the IP caused the AE. 
• 
Not Related: Concurrent illness, concurrent medication, or other known cause is clearly 
responsible for the AE, the administration of the IP and the occurrence of the AE are not 
reasonably related in time, OR exposure to IP has not occurred. 
The expectedness of an AE should be determined based upon existing safety information about the IP 
using these explanations: 
• 
Unexpected: An AE that is not listed in the Investigator’s Brochure (IB) or is not listed at the 
specificity or severity that has been observed. 
• 
Expected:  An AE that is listed in the IB at the specificity and severity that has been observed. 
• 
Not applicable: An AE unrelated to the IP. 
AE events that are mentioned in the IB as occurring with a class of products or as anticipated from the 
pharmacological/mechanical (or other) properties of the product, but are not specifically mentioned as 
occurring with the particular product under investigation are to be considered unexpected. 
The investigator should initially classify the expectedness of an AE, but the final classification is subject 
to the Medical Monitor’s determination. 


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An AE is considered serious if, in the view of either the investigator or sponsor, it results in any of the 
following outcomes: 
• 
Death; 
• 
A life-threatening AE; 
Note: An AE is considered “life-threatening” if, in the view of either the investigator or sponsor, its 
occurrence places the subject at immediate risk of death. It does not include an AE that, had it occurred 
in a more severe form, might have caused death. 
The AE reporting period ends upon study exit.  Study drug includes the investigational drug under 
evaluation and vehicle given during any stage of the study.  All AEs will be coded using the MedDRA 
21.0.   
Treatment-emergent adverse events (TEAEs) are defined as any adverse event that occurs or worsens 
after the first dose of study treatment.  AEs recorded in the eCRF which began prior to treatment will not 
be included in the summary tables but will be included in the AE data listings. 
An overall summary will be presented that includes the number of AEs, TEAEs, serious AEs (SAE), and 
serious TEAEs (TE-SAE).  The summary will also include the number and percentage of subjects 
withdrawn due to an AE, the number and percentage of subjects with an AE resulting in death, and the 
number and percentage of subjects who experienced at least one AE, TEAE, SAE and TE-SAE, by 
treatment group and for all subjects.  This summary will include breakdowns of AEs further categorized 
as ocular or non-ocular.  The summary will also include the number and percentage of resolved ocular 
AEs, and the mean number of days until AE resolution for resolved ocular AEs. 
Additional summaries of TEAEs will be provided showing the number and percentage of subjects who 
experienced at least one TEAE.  These summaries will be presented by SOC and PT.  Non-ocular 
TEAEs will be summarized using discrete summary statistics and presented by treatment group at the 
subject and event level by SOC and PT.  Ocular TEAEs will be similarly summarized at the subject and 
event level as well as for study and fellow eyes separately.  If a subject reports the same PT multiple 
times within the same SOC, that PT will only be reported once within that SOC.  As with the PT, if a 
subject reports multiple conditions within the same SOC, that SOC will only be reported once.  In the 
summary, SOC will be listed in order of descending frequency for all subjects; PTs will be listed in order 
of descending frequency for all subjects within each SOC.  The occurrence of non-ocular and ocular 
TEAEs will also be tabulated by SOC, PT, and maximal severity, as well as by study day of onset (prior 
to Day 15, Day 15 to Day 43, After Day 43). 
Separate summaries will be provided for the following categories of AEs:  


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• 
Ocular TEAEs 
• 
Non-ocular TEAEs  
• 
Treatment-related ocular TEAEs 
• 
Treatment-related non-ocular TEAEs 
• 
SAEs 
Summaries of TEAEs by maximal severity will be presented for ocular AEs and non-ocular AEs 
separately.  The number of subjects with any TEAEs (along with percentages) will be tabulated by SOC 
and PT within each SOC by treatment group.  To count the number of subjects with any TEAEs, if a 
subject has multiple TEAEs coded to the same PT within the same SOC, the subject will be counted 
once under the maximal severity. 
All TEAEs with possible, probable, and definite relationship to IP are considered as treatment-related 
TEAEs.  
All AEs will be presented in a subject listing that classifies each AE as ocular or non-ocular and indicates 
whether it is a TEAE.  Separate listings will be produced for AEs leading to study discontinuation,  AEs 
leading to death and SAEs. 
16.2 
Ora Calibra Drop Comfort Assessment 
Ora Calibra® Drop Comfort Scale will be used at Visits 2, 4 and 5 to assess drop comfort for each eye 
separately upon instillation, and at 1 and 2 minutes post-instillation.  The scale ranges from 0 to 10, with 
0 indicating very comfortable and 10 indicating very uncomfortable. The scale will be summarized using 
continuous descriptive statistics by visit, time point and eye (study eye and fellow eye) for each treatment 
group.   
Ora Calibra® Drop Comfort Questionnaire will be used to assess drop comfort 3 minutes post-instillation.  
Subjects will be asked to choose three words (among 12) that best describe how the eye drops feel in 
both eyes.  The positive responses are comfortable, cool, refreshing, smooth, and soothing. The 
negative responses include burning, irritating, filmy, gritty, sticky, stinging, and thick.  Subjects may also 
select “other” and write in a response of their choosing, which may be either a positive or a negative 
response.  The results will be summarized for each response individually and for positive and negative 
responses using counts and percentages for each treatment group at each visit for each eye (study eye 
and fellow eye).  Percentages will be based on the number of subjects in each treatment group with 
responses.  A subject listing of the drop comfort assessment parameters will also be produced. 
16.3 
Best-corrected Visual Acuity (BCVA) 
The visual acuity procedure will be performed at each visit pre-CAE®.  The logarithm of the minimum 
angle of resolution (logMAR) VA must be assessed using an ETDRS chart. The procedure used will be 


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consistent with the recommendations provided for using the ETDRS eye chart. Visual Acuity should be 
evaluated at the beginning of each visit in the study (i.e., prior to slit-lamp examination). Subjects should 
use their most recent correction to attain their BCVA. 
The observed and change from baseline visual acuity will be summarized for each eye (study eye and 
fellow eye) using continuous descriptive statistics by visit for each treatment group.  A subject listing of 
visual acuity will also be produced.   
16.4 
Slit-lamp Biomicroscopy 
A slit-lamp biomicroscopy examination of the cornea, conjunctiva, anterior chamber, iris, lens, and eyelid 
will be performed at each visit, and potentially at an Early Termination Visit.  Both pre- and post-CAE® 
examinations will be made at Visits 1 and 5.  The results will be graded as normal, Abnormal Not 
Clinically Significant (NCS) or Abnormal Clinically Significant (CS).  Abnormal findings will be described. 
The results will be summarized using counts and percentages for each treatment group at each visit for 
each eye (study eye and fellow eye).  Percentages will be based on the number of subjects in each 
treatment group with responses.  Shift tables for the slit-lamp biomicroscopy parameters will also be 
provided comparing each follow-up visit to Visit 1, Pre-CAE.  A subject listing of the slit-lamp 
biomicroscopy parameters will also be produced. 
16.5 
Intraocular Pressure (IOP) 
IOP will be measured in each eye by contact tonometry by the examiner and the results will be recorded 
in mmHg at all scheduled visits, and potentially at an Early Termination Visit.  Assessments at Visits 1 
and 5 will be post-CAE®. A single measurement is made to obtain a determination of IOP. The same 
tonometer employing the investigator’s standard technique will be used throughout the study. In addition, 
all reasonable efforts will be made to have the same examiner obtain all IOP measurements for a given 
subject. 
The IOP values and changes from baseline for each eye (study eye and fellow eye) will be summarized 
using continuous descriptive statistics by visit and eye for each treatment group and for all actively 
treated subjects.  A subject listing of IOP will also be produced.   
16.6 
Ophthalmoscopy 
Dilated fundus exams will be performed at Visit 1 using indirect ophthalmoscopy. At Visit 5, undilated 
fundus exams will be performed unless dilation is necessary. The investigator will make observations of 
the vitreous, retina, macula, choroid and optic nerve.   
Observations will be graded as Normal or Abnormal. Abnormal findings that are clinically significant (as 
determined by the investigator that may interfere with study parameters or otherwise confound the data) 


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and those that are not clinically significant will be described. An indirect Fundoscopy examination should 
be performed if retinal disease is detected.  
The results will be summarized using counts and percentages for each treatment group at each visit for 
each eye (study eye and fellow eye).  Percentages will be based on the number of subjects in each 
treatment group with responses.  Shift tables for the fundoscopy parameters will also be provided 
comparing Visit 5 to baseline (Visit 1).  A subject listing of the fundoscopy parameters will also be 
produced. 
16.7 
Conjunctival Redness Score 
The Ora Calibra® Conjunctival Redness Scale for Dry Eye will be performed on all scheduled visits.  
Both pre- and post-CAE® assessments will be made at Visits 1 and 5.  The conjunctival redness scale 
ranges from 0 to 4 where 0 = normal, without vasodilation, 1 = trace ciliary or conjunctival vasodilation, 
2 = broad ciliary vasodilation, 3 = broad ciliary and slight, horizontal conjunctival vasodilation, and 4 = 
broad ciliary and prominent, horizontal conjunctival vasodilation. Half unit increments are allowed. 
Conjunctival redness will be summarized by treatment group, visit and time point (pre- and post-CAE®) 
using quantitative summary statistics.  Change from baseline will be also summarized.   
16.8 
Vital Signs 
Each subject will have vital signs assessments (resting blood pressure and pulse) conducted at Visits 
1, 2, and 5. Vital signs are to be conducted by a qualified staff member who may be any of the following: 
a board-certified investigator or sub-investigator, nurse practitioner, registered nurse, or physician 
assistant.  
Systolic and diastolic blood pressure should be measured in the same arm each time using a 
sphygmomanometer with the subjects who have been in a resting state (seated upright) at least 5 
minutes. Blood pressure will be recorded in mmHg.  
Pulse will be measured with the subjects who have been in a resting state (seated) for at least 5 minutes. 
Pulse will be counted for 30 seconds and multiplied by 2, and recorded in beats per minute (bpm). 
The vital signs and changes from baseline will be summarized using continuous descriptive statistics by 
visit for each treatment group and for all actively treated subjects.  A subject listing of vital signs will also 
be produced.   
Vital signs will also be presented categorically for the number of subjects with low, normal, or high values 
as defined by the table below: 
Vital Signs 
Low 
Normal 
High 
Systolic Blood Pressure (mmHg) 
<90 
90-180 
>180 


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Vital Signs 
Low 
Normal 
High 
Diastolic Blood Pressure (mmHg) 
<50 
50-100 
>100 
Pulse Rate (bpm) 
<50 
50-110 
>110 
 
16.9 
Laboratory Tests 
Samples of blood (non-fasting) and urine will be collected at Visits 1 and 5 and evaluated for blood 
chemistry, hematology, and urinalysis.  Parameters will be summarized using continuous descriptive 
statistics by visit for each treatment group and for all actively treated subjects.  A subject listing will also 
be produced.   
16.10 
Urine Pregnancy Test 
A urine pregnancy test will be conducted for females of childbearing potential at Visit 1 (Day -14 ± 2), 
Visit 5 (Day 85 ± 2), and may be conducted at an Unscheduled Visit.   A listing of urine pregnancy test 
results will be generated. 
17. Interim Analyses 
An interim analysis will be performed when the last enrolled patient in Stage 1 completes Month 3 of the 
Expansion Cohort.  There is no plan to stop the study for efficacy on the basis of the interim analysis.  
However, termination in individual dose groups due to safety, tolerability and/or futility may occur.  
Statistical significance will not be declared at the time of the interim analysis.   
Given the exploratory nature of the study no Type I error adjustments will be made for the interim 
analysis including the Stage 1 data only. 
18. Changes from Protocol-Stated Analyses 
There are no changes from the protocol-stated analyses. 
19. Revision History 
The following revisions were made to SAP Version 2.0. 
SAP Section 
Revision 
Rationale 
12.1 
Revised compliance calculation 
to use date of 
completion/discontinuation 
rather than date of last in-office 
instillation 
Conservative estimation of 
compliance for discontinued 
subjects 


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12.2 
Revised exposure calculation 
to use date of 
completion/discontinuation 
rather than date of last in-office 
instillation 
Conservative estimation of 
exposure for discontinued 
subjects 
13.1.1 
Revised specification of 
random number seeds for 
MCMC 
Consistency with 13.1.2 
13.1.3, 13.1.4, 13.1.5 
Revised specification of 
random number seeds for 
MCMC 
Correction of seed specification 
 
20. Tables 
Tables that will be included in the topline delivery are shown in boldface font.  Tables that will be included 
in the interim analysis are qualified as “Stage 1”.   
 
Table Number 
Title 
Population 
TABLE 14.1.1.1 
SUBJECT DISPOSITION – STAGE 1  
ALL RANDOMIZED SUBJECTS 
TABLE 14.1.1.2 
SUBJECT DISPOSITION – STAGE 2  
ALL RANDOMIZED SUBJECTS 
TABLE 14.1.1.3 
SUBJECT DISPOSITION – COMBINED STAGE 1 AND STAGE 2  
ALL RANDOMIZED SUBJECTS 
TABLE 14.1.2.1.1 
DEMOGRAPHICS – STAGE 1  
MITT POPULATION 
TABLE 14.1.2.1.2 
DEMOGRAPHICS – STAGE 1  
MITT2 POPULATION 
TABLE 14.1.2.1.3 
DEMOGRAPHICS – STAGE 1  
SAFETY POPULATION 
TABLE 14.1.2.2.1 
DEMOGRAPHICS – STAGE 2  
MITT POPULATION 
TABLE 14.1.2.2.2 
DEMOGRAPHICS – STAGE 2  
MITT2 POPULATION 
TABLE 14.1.2.2.3 
DEMOGRAPHICS – STAGE 2  
SAFETY POPULATION 
TABLE 14.1.2.3.1 
DEMOGRAPHICS – COMBINED STAGE 1 AND STAGE 2  
MITT POPULATION 
TABLE 14.1.2.3.2 
DEMOGRAPHICS – COMBINED STAGE 1 AND STAGE 2  
MITT2 POPULATION 
TABLE 14.1.2.3.3 
DEMOGRAPHICS – COMBINED STAGE 1 AND STAGE 2  
SAFETY POPULATION 
TABLE 14.1.3.1.1 
OCULAR MEDICAL HISTORY – STAGE 1  
MITT POPULATION 
TABLE 14.1.3.1.2 
OCULAR MEDICAL HISTORY – STAGE 2  
MITT POPULATION 
TABLE 14.1.3.1.3 
OCULAR MEDICAL HISTORY – COMBINED STAGE 1 AND STAGE 
2  
MITT POPULATION 
TABLE 14.1.3.2.1 
NON-OCULAR MEDICAL HISTORY – STAGE 1  
MITT POPULATION 
TABLE 14.1.3.2.2 
NON-OCULAR MEDICAL HISTORY – STAGE 2  
MITT POPULATION 
TABLE 14.1.3.2.3 
NON-OCULAR MEDICAL HISTORY – COMBINED STAGE 1 AND 
STAGE 2  
MITT POPULATION 


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Table Number 
Title 
Population 
TABLE 14.1.4.1.1 
CONCOMITANT OCULAR MEDICATIONS BY TREATMENT 
GROUP, DRUG CLASS AND PREFERRED NAME – STAGE 1  
MITT POPULATION 
TABLE 14.1.4.1.2 
CONCOMITANT OCULAR MEDICATIONS BY TREATMENT 
GROUP, DRUG CLASS AND PREFERRED NAME – STAGE 2  
MITT POPULATION 
TABLE 14.1.4.1.3 
CONCOMITANT OCULAR MEDICATIONS BY TREATMENT 
GROUP, DRUG CLASS AND PREFERRED NAME – COMBINED 
STAGE 1 AND STAGE 2  
MITT POPULATION 
TABLE 14.1.4.2.1 
CONCOMITANT NON-OCULAR MEDICATIONS BY TREATMENT 
GROUP, DRUG CLASS AND PREFERRED NAME – STAGE 1  
MITT POPULATION 
TABLE 14.1.4.2.2 
CONCOMITANT NON-OCULAR MEDICATIONS BY TREATMENT 
GROUP, DRUG CLASS AND PREFERRED NAME – STAGE 2  
MITT POPULATION 
TABLE 14.1.4.2.3 
CONCOMITANT NON-OCULAR MEDICATIONS BY TREATMENT 
GROUP, DRUG CLASS AND PREFERRED NAME – COMBINED 
STAGE 1 AND STAGE 2  
MITT POPULATION 
TABLE 14.2.1.1.1 
PRE-CAE® INFERIOR CORNEAL FLUORESCEIN STAINING (ORA 
CALIBRA® SCALE) – STAGE 1  
MITT POPULATION WITH LOCF 
TABLE 14.2.1.1.2 
PRE-CAE® INFERIOR CORNEAL FLUORESCEIN STAINING (ORA 
CALIBRA® SCALE) – STAGE 2  
MITT POPULATION WITH LOCF 
TABLE 14.2.1.1.3 
PRE-CAE® INFERIOR CORNEAL FLUORESCEIN STAINING (ORA 
CALIBRA® SCALE) – COMBINED STAGE 1 AND STAGE 2  
MITT POPULATION WITH LOCF 
TABLE 14.2.1.2.1 
PRE-CAE® INFERIOR CORNEAL FLUORESCEIN STAINING (ORA 
CALIBRA® SCALE) – STAGE 1  
MITT2 POPULATION WITH LOCF 
TABLE 14.2.1.2.2 
PRE-CAE® INFERIOR CORNEAL FLUORESCEIN STAINING (ORA 
CALIBRA® SCALE) – STAGE 2  
MITT2 POPULATION WITH LOCF 
TABLE 14.2.1.2.3 
PRE-CAE® INFERIOR CORNEAL FLUORESCEIN STAINING (ORA 
CALIBRA® SCALE) – COMBINED STAGE 1 AND STAGE 2  
MITT2 POPULATION WITH LOCF 
TABLE 14.2.1.3.1 
PRE-CAE® INFERIOR CORNEAL FLUORESCEIN STAINING (ORA 
CALIBRA® SCALE) – STAGE 1  
PP POPULATION WITH LOCF 
TABLE 14.2.1.3.2 
PRE-CAE® INFERIOR CORNEAL FLUORESCEIN STAINING (ORA 
CALIBRA® SCALE) – STAGE 2  
PP POPULATION WITH LOCF 
TABLE 14.2.1.3.3 
PRE-CAE® INFERIOR CORNEAL FLUORESCEIN STAINING (ORA 
CALIBRA® SCALE) – COMBINED STAGE 1 AND STAGE 2  
PP POPULATION WITH LOCF 
TABLE 14.2.1.4.1 
PRE-CAE® INFERIOR CORNEAL FLUORESCEIN STAINING (ORA 
CALIBRA® SCALE) – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.1.4.2 
PRE-CAE® INFERIOR CORNEAL FLUORESCEIN STAINING (ORA 
CALIBRA® SCALE) – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.1.4.3 
PRE-CAE® INFERIOR CORNEAL FLUORESCEIN STAINING (ORA 
CALIBRA® SCALE) – COMBINED STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.1.5.1 
PRE-CAE® INFERIOR CORNEAL FLUORESCEIN STAINING (ORA 
CALIBRA® SCALE) – STAGE 1  
MITT POPULATION WITH MCMC 
TABLE 14.2.1.5.2 
PRE-CAE® INFERIOR CORNEAL FLUORESCEIN STAINING (ORA 
CALIBRA® SCALE) – STAGE 2  
MITT POPULATION WITH MCMC 
TABLE 14.2.1.5.3 
PRE-CAE® INFERIOR CORNEAL FLUORESCEIN STAINING (ORA 
CALIBRA® SCALE) – COMBINED STAGE 1 AND STAGE 2  
MITT POPULATION WITH MCMC 
TABLE 14.2.2.1.1 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (ORA 
CALIBRA® SCALE) – STAGE 1  
MITT POPULATION WITH LOCF 
TABLE 14.2.2.1.2 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (ORA 
CALIBRA® SCALE) – STAGE 2  
MITT POPULATION WITH LOCF 


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Table Number 
Title 
Population 
TABLE 14.2.2.1.3 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (ORA 
CALIBRA® SCALE) – COMBINED STAGE 1 AND STAGE 2  
MITT POPULATION WITH LOCF 
TABLE 14.2.2.2.1 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (ORA 
CALIBRA® SCALE) – STAGE 1  
MITT2 POPULATION WITH LOCF 
TABLE 14.2.2.2.2 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (ORA 
CALIBRA® SCALE) – STAGE 2  
MITT2 POPULATION WITH LOCF 
TABLE 14.2.2.2.3 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (ORA 
CALIBRA® SCALE) – COMBINED STAGE 1 AND STAGE 2  
MITT2 POPULATION WITH LOCF 
TABLE 14.2.2.3.1 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (ORA 
CALIBRA® SCALE) – STAGE 1  
PP POPULATION WITH LOCF 
TABLE 14.2.2.3.2 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (ORA 
CALIBRA® SCALE) – STAGE 2  
PP POPULATION WITH LOCF 
TABLE 14.2.2.3.3 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (ORA 
CALIBRA® SCALE) – COMBINED STAGE 1 AND STAGE 2  
PP POPULATION WITH LOCF 
TABLE 14.2.2.4.1 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (ORA 
CALIBRA® SCALE) – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.2.4.2 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (ORA 
CALIBRA® SCALE) – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.2.4.3 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (ORA 
CALIBRA® SCALE) – COMBINED STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.2.5.1 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (ORA 
CALIBRA® SCALE) – STAGE 1  
MITT POPULATION WITH MCMC 
TABLE 14.2.2.5.2 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (ORA 
CALIBRA® SCALE) – STAGE 2  
MITT POPULATION WITH MCMC 
TABLE 14.2.2.5.3 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (ORA 
CALIBRA® SCALE) – COMBINED STAGE 1 AND STAGE 2  
MITT POPULATION WITH MCMC 
TABLE 14.2.3.1.1 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (OXFORD 
SCALE) – STAGE 1  
MITT POPULATION WITH LOCF 
TABLE 14.2.3.1.2 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (OXFORD 
SCALE) – STAGE 2  
MITT POPULATION WITH LOCF 
TABLE 14.2.3.1.3 
PRE-CAE® 
TOTAL 
CORNEAL 
FLUORESCEIN 
STAINING 
(OXFORD SCALE) – COMBINED STAGE 1 AND STAGE 2  
MITT POPULATION WITH LOCF 
TABLE 14.2.3.2.1 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (OXFORD 
SCALE) – STAGE 1  
MITT2 POPULATION WITH LOCF 
TABLE 14.2.3.2.2 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (OXFORD 
SCALE) – STAGE 2  
MITT2 POPULATION WITH LOCF 
TABLE 14.2.3.2.3 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (OXFORD 
SCALE) – COMBINED STAGE 1 AND STAGE 2  
MITT2 POPULATION WITH LOCF 
TABLE 14.2.3.3.1 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (OXFORD 
SCALE) – STAGE 1  
PP POPULATION WITH LOCF 
TABLE 14.2.3.3.2 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (OXFORD 
SCALE) – STAGE 2  
PP POPULATION WITH LOCF 
TABLE 14.2.3.3.3 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (OXFORD 
SCALE) – COMBINED STAGE 1 AND STAGE 2  
PP POPULATION WITH LOCF 
TABLE 14.2.3.4.1 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (OXFORD 
SCALE) – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.3.4.2 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (OXFORD 
SCALE) – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 


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Table Number 
Title 
Population 
TABLE 14.2.3.4.3 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (OXFORD 
SCALE) – COMBINED STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.3.5.1 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (OXFORD 
SCALE) – STAGE 1  
MITT POPULATION WITH MCMC 
TABLE 14.2.3.5.2 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (OXFORD 
SCALE) – STAGE 2  
MITT POPULATION WITH MCMC 
TABLE 14.2.3.5.3 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (OXFORD 
SCALE) - COMBINED STAGE 1 AND STAGE 2  
MITT POPULATION WITH MCMC 
TABLE 14.2.4.1.1 
PRE-CAE® EYE DRYNESS (VISUAL ANALOG SCALE) – STAGE 1  
MITT POPULATION WITH LOCF 
TABLE 14.2.4.1.2 
PRE-CAE® EYE DRYNESS (VISUAL ANALOG SCALE) – STAGE 2  
MITT POPULATION WITH LOCF 
TABLE 14.2.4.1.3 
PRE-CAE® EYE DRYNESS (VISUAL ANALOG SCALE) – 
COMBINED STAGE 1 AND STAGE 2  
MITT POPULATION WITH LOCF 
TABLE 14.2.4.2.1 
PRE-CAE® EYE DRYNESS (VISUAL ANALOG SCALE) – STAGE 1  
MITT2 POPULATION WITH LOCF 
TABLE 14.2.4.2.2 
PRE-CAE® EYE DRYNESS (VISUAL ANALOG SCALE) – STAGE 2  
MITT2 POPULATION WITH LOCF 
TABLE 14.2.4.2.3 
PRE-CAE® EYE DRYNESS (VISUAL ANALOG SCALE) – COMBINED 
STAGE 1 AND STAGE 2  
MITT2 POPULATION WITH LOCF 
TABLE 14.2.4.3.1 
PRE-CAE® EYE DRYNESS (VISUAL ANALOG SCALE) – STAGE 1  
PP POPULATION WITH LOCF 
TABLE 14.2.4.3.2 
PRE-CAE® EYE DRYNESS (VISUAL ANALOG SCALE) – STAGE 2  
PP POPULATION WITH LOCF 
TABLE 14.2.4.3.3 
PRE-CAE® EYE DRYNESS (VISUAL ANALOG SCALE) – COMBINED 
STAGE 1 AND STAGE 2  
PP POPULATION WITH LOCF 
TABLE 14.2.4.4.1 
PRE-CAE® EYE DRYNESS (VISUAL ANALOG SCALE) – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.4.4.2 
PRE-CAE® EYE DRYNESS (VISUAL ANALOG SCALE) – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.4.4.3 
PRE-CAE® EYE DRYNESS (VISUAL ANALOG SCALE) - COMBINED 
STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.4.5.1 
PRE-CAE® EYE DRYNESS (VISUAL ANALOG SCALE) – STAGE 1  
MITT POPULATION WITH MCMC 
TABLE 14.2.4.5.2 
PRE-CAE® EYE DRYNESS (VISUAL ANALOG SCALE) – STAGE 2  
MITT POPULATION WITH MCMC 
TABLE 14.2.4.5.3 
PRE-CAE® EYE DRYNESS (VISUAL ANALOG SCALE) – COMBINED 
STAGE 1 AND STAGE 2  
MITT POPULATION WITH MCMC 
TABLE 14.2.5.1.1 
PRE-CAE® TOTAL OSDI© SCORE – STAGE 1  
MITT POPULATION WITH LOCF 
TABLE 14.2.5.1.2 
PRE-CAE® TOTAL OSDI© SCORE – STAGE 2  
MITT POPULATION WITH LOCF 
TABLE 14.2.5.1.3 
PRE-CAE® TOTAL OSDI© SCORE – COMBINED STAGE 1 AND 
STAGE 2  
MITT POPULATION WITH LOCF 
TABLE 14.2.5.2.1 
PRE-CAE® TOTAL OSDI© SCORE – STAGE 1  
MITT2 POPULATION WITH LOCF 
TABLE 14.2.5.2.2 
PRE-CAE® TOTAL OSDI© SCORE – STAGE 2  
MITT2 POPULATION WITH LOCF 
TABLE 14.2.5.2.3 
PRE-CAE® TOTAL OSDI© SCORE – COMBINED STAGE 1 AND 
STAGE 2  
MITT2 POPULATION WITH LOCF 
TABLE 14.2.5.3.1 
PRE-CAE® TOTAL OSDI© SCORE – STAGE 1  
PP POPULATION WITH LOCF 
TABLE 14.2.5.3.2 
PRE-CAE® TOTAL OSDI© SCORE – STAGE 2  
PP POPULATION WITH LOCF 
TABLE 14.2.5.3.3 
PRE-CAE® TOTAL OSDI© SCORE – COMBINED STAGE 1 AND 
STAGE 2  
PP POPULATION WITH LOCF 
TABLE 14.2.5.4.1 
PRE-CAE® TOTAL OSDI© SCORE – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.5.4.2 
PRE-CAE® TOTAL OSDI© SCORE – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 


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Table Number 
Title 
Population 
TABLE 14.2.5.4.3 
PRE-CAE® TOTAL OSDI© SCORE – COMBINED STAGE 1 AND 
STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.5.5.1 
PRE-CAE® TOTAL OSDI© SCORE – STAGE 1  
MITT POPULATION WITH MCMC 
TABLE 14.2.5.5.2 
PRE-CAE® TOTAL OSDI© SCORE – STAGE 2  
MITT POPULATION WITH MCMC 
TABLE 14.2.5.5.3 
PRE-CAE® TOTAL OSDI© SCORE – COMBINED STAGE 1 AND 
STAGE 2  
MITT POPULATION WITH MCMC 
TABLE 14.2.6.1.1 
FLUORESCEIN CORNEAL AND CONJUNCTIVAL STAINING (ORA 
CALIBRA® SCALE) – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.6.1.2 
FLUORESCEIN CORNEAL AND CONJUNCTIVAL STAINING (ORA 
CALIBRA® SCALE) – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.6.1.3 
FLUORESCEIN CORNEAL AND CONJUNCTIVAL STAINING (ORA 
CALIBRA® SCALE) – COMBINED STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.6.2.1 
FLUORESCEIN CORNEAL AND CONJUNCTIVAL STAINING (ORA 
CALIBRA® SCALE) BY SUBGROUP – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.6.2.2 
FLUORESCEIN CORNEAL AND CONJUNCTIVAL STAINING (ORA 
CALIBRA® SCALE) BY SUBGROUP – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.6.2.3 
FLUORESCEIN CORNEAL AND CONJUNCTIVAL STAINING (ORA 
CALIBRA® SCALE) BY SUBGROUP – COMBINED STAGE 1 AND 
STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.6.3.1 
FLUORESCEIN CORNEAL AND CONJUNCTIVAL STAINING (ORA 
CALIBRA® SCALE) BY BASELINE MEDIAN – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.6.3.2 
FLUORESCEIN CORNEAL AND CONJUNCTIVAL STAINING (ORA 
CALIBRA® SCALE) BY BASELINE MEDIAN – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.6.3.3 
FLUORESCEIN CORNEAL AND CONJUNCTIVAL STAINING (ORA 
CALIBRA® SCALE) BY BASELINE MEDIAN – COMBINED STAGE 1 
AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.7.1.1 
FLUORESCEIN CORNEAL STAINING (OXFORD SCALE) – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.7.1.2 
FLUORESCEIN CORNEAL STAINING (OXFORD SCALE) – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.7.1.3 
FLUORESCEIN CORNEAL STAINING (OXFORD SCALE) – 
COMBINED STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.7.2.1 
FLUORESCEIN CORNEAL STAINING (OXFORD SCALE) BY 
SUBGROUP – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.7.2.2 
FLUORESCEIN CORNEAL STAINING (OXFORD SCALE) BY 
SUBGROUP – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.7.2.3 
FLUORESCEIN CORNEAL STAINING (OXFORD SCALE) BY 
SUBGROUP – COMBINED STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.7.3.1 
FLUORESCEIN CORNEAL STAINING (OXFORD SCALE) BY 
BASELINE MEDIAN – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.7.3.2 
FLUORESCEIN CORNEAL STAINING (OXFORD SCALE) BY 
BASELINE MEDIAN – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.7.3.3 
FLUORESCEIN CORNEAL STAINING (OXFORD SCALE) BY 
BASELINE MEDIAN – COMBINED STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.8.1.1 
VISUAL ANALOG SCALE – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.8.1.2 
VISUAL ANALOG SCALE – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 


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Table Number 
Title 
Population 
TABLE 14.2.8.1.3 
VISUAL ANALOG SCALE – COMBINED STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.8.2.1 
VISUAL ANALOG SCALE BY SUBGROUP – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.8.2.2 
VISUAL ANALOG SCALE BY SUBGROUP – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.8.2.3 
VISUAL ANALOG SCALE BY SUBGROUP – COMBINED STAGE 1 
AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.8.3.1 
VISUAL ANALOG SCALE BY BASELINE MEDIAN – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.8.3.2 
VISUAL ANALOG SCALE BY BASELINE MEDIAN – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.8.3.3 
VISUAL ANALOG SCALE BY BASELINE MEDIAN – COMBINED 
STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.8.4.1 
VISUAL ANALOG SCALE BY TIME TO CAE QUALIFICATION – 
STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.8.4.2 
VISUAL ANALOG SCALE BY TIME TO CAE QUALIFICATION – 
STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.8.4.3 
VISUAL ANALOG SCALE BY TIME TO CAE QUALIFICATION – 
COMBINED STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.9.1.1 
OCULAR SURFACE DISEASE INDEX (OSDI) – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.9.1.2 
OCULAR SURFACE DISEASE INDEX (OSDI) – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.9.1.3 
OCULAR SURFACE DISEASE INDEX (OSDI) – COMBINED STAGE 
1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.9.2.1 
OCULAR SURFACE DISEASE INDEX (OSDI) BY SUBGROUP – 
STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.9.2.2 
OCULAR SURFACE DISEASE INDEX (OSDI) BY SUBGROUP – 
STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.9.2.3 
OCULAR SURFACE DISEASE INDEX (OSDI) BY SUBGROUP – 
COMBINED STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.9.3.1 
OCULAR SURFACE DISEASE INDEX (OSDI) BY BASELINE 
MEDIAN – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.9.3.2 
OCULAR SURFACE DISEASE INDEX (OSDI) BY BASELINE 
MEDIAN – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.9.3.3 
OCULAR SURFACE DISEASE INDEX (OSDI) BY BASELINE 
MEDIAN – COMBINED STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.9.4.1 
OCULAR SURFACE DISEASE INDEX (OSDI) BY TIME TO CAE 
QUALIFICATION – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.9.4.2 
OCULAR SURFACE DISEASE INDEX (OSDI) BY TIME TO CAE 
QUALIFICATION – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.9.4.3 
OCULAR SURFACE DISEASE INDEX (OSDI) BY TIME TO CAE 
QUALIFICATION – COMBINED STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.10.1.1 
UNANESTHETIZED SCHIRMER’S TEST (MM) – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.10.1.2 
UNANESTHETIZED SCHIRMER’S TEST (MM) – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 


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Table Number 
Title 
Population 
TABLE 14.2.10.1.3 
UNANESTHETIZED SCHIRMER’S TEST (MM) – COMBINED 
STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.10.2.1 
UNANESTHETIZED SCHIRMER’S TEST (MM) STRATIFIED BY 
BASELINE MEDIAN – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.10.2.2 
UNANESTHETIZED SCHIRMER’S TEST (MM) STRATIFIED BY 
BASELINE MEDIAN – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.10.2.3 
UNANESTHETIZED SCHIRMER’S TEST (MM) STRATIFIED BY 
BASELINE MEDIAN – COMBINED STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.11.1.1 
TEAR FILM BREAK-UP TIME (TFBUT) – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.11.1.2 
TEAR FILM BREAK-UP TIME (TFBUT) – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.11.1.3 
TEAR FILM BREAK-UP TIME (TFBUT) – COMBINED STAGE 1 
AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.11.2.1 
TEAR FILM BREAK-UP TIME (TFBUT) STRATIFIED BY BASELINE 
MEDIAN – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.11.2.2 
TEAR FILM BREAK-UP TIME (TFBUT) STRATIFIED BY BASELINE 
MEDIAN – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.11.2.3 
TEAR FILM BREAK-UP TIME (TFBUT) STRATIFIED BY BASELINE 
MEDIAN – COMBINED STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.12.1.1 
OCULUS KERATOGRAPH – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.12.1.2 
OCULUS KERATOGRAPH – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.12.1.3 
OCULUS KERATOGRAPH – COMBINED STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.12.2.1 
OCULUS KERATOGRAPH STRATIFIED BY BASELINE MEDIAN – 
STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.12.2.2 
OCULUS KERATOGRAPH STRATIFIED BY BASELINE MEDIAN – 
STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.12.2.3 
OCULUS KERATOGRAPH STRATIFIED BY BASELINE MEDIAN – 
COMBINED STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.13.1.1 
ORA CALIBRA® CONJUNCTIVAL REDNESS SCALE – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.13.1.2 
ORA CALIBRA® CONJUNCTIVAL REDNESS SCALE – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.13.1.3 
ORA CALIBRA® CONJUNCTIVAL REDNESS SCALE – COMBINED 
STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.13.2.1 
ORA CALIBRA® CONJUNCTIVAL REDNESS SCALE STRATIFIED BY 
BASELINE MEDIAN – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.13.2.2 
ORA CALIBRA® CONJUNCTIVAL REDNESS SCALE STRATIFIED BY 
BASELINE MEDIAN – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.13.2.3 
ORA CALIBRA® CONJUNCTIVAL REDNESS SCALE STRATIFIED BY 
BASELINE MEDIAN – COMBINED STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.14.1.1 
LISSAMINE GREEN CONJUNCTIVAL STAINING (OXFORD SCALE) 
– STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.14.1.2 
LISSAMINE GREEN CONJUNCTIVAL STAINING (OXFORD SCALE) 
– STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 


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Table Number 
Title 
Population 
TABLE 14.2.14.1.3 
LISSAMINE GREEN CONJUNCTIVAL STAINING (OXFORD SCALE) 
– COMBINED STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.14.2.1 
LISSAMINE GREEN CONJUNCTIVAL STAINING (OXFORD SCALE) 
STRATIFIED BY BASELINE MEDIAN – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.14.2.2 
LISSAMINE GREEN CONJUNCTIVAL STAINING (OXFORD SCALE) 
STRATIFIED BY BASELINE MEDIAN – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.14.2.3 
LISSAMINE GREEN CONJUNCTIVAL STAINING (OXFORD SCALE) 
STRATIFIED BY BASELINE MEDIAN – COMBINED STAGE 1 AND 
STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.15.1.1 
ORA CALIBRA® OCULAR DISCOMFORT SCALE – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.15.1.2 
ORA CALIBRA® OCULAR DISCOMFORT SCALE – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.15.1.3 
ORA CALIBRA® OCULAR DISCOMFORT SCALE – COMBINED 
STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.15.2.1 
ORA CALIBRA® OCULAR DISCOMFORT SCALE STRATIFIED BY 
BASELINE MEDIAN – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.15.2.2 
ORA CALIBRA® OCULAR DISCOMFORT SCALE STRATIFIED BY 
BASELINE MEDIAN – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.15.2.3 
ORA CALIBRA® OCULAR DISCOMFORT SCALE STRATIFIED BY 
BASELINE MEDIAN – COMBINED STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.15.3.1 
ORA CALIBRA® OCULAR DISCOMFORT SCALE  
STRATIFIED BY TIME TO CAE QUALIFICATION – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.15.3.2 
ORA CALIBRA® OCULAR DISCOMFORT SCALE  
STRATIFIED BY TIME TO CAE QUALIFICATION – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.15.3.3 
ORA CALIBRA® OCULAR DISCOMFORT SCALE  
STRATIFIED BY TIME TO CAE QUALIFICATION – COMBINED 
STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.16.1.1 
ORA CALIBRA® OCULAR DISCOMFORT SCALE (DURING CAE®) – 
STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.16.1.2 
ORA CALIBRA® OCULAR DISCOMFORT SCALE (DURING CAE®) – 
STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.16.1.3 
ORA CALIBRA® OCULAR DISCOMFORT SCALE (DURING CAE®) – 
COMBINED STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.16.2.1 
ORA CALIBRA® OCULAR DISCOMFORT SCALE (DURING CAE®) 
STRATIFIED BY BASELINE MEDIAN – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.16.2.2 
ORA CALIBRA® OCULAR DISCOMFORT SCALE (DURING CAE®) 
STRATIFIED BY BASELINE MEDIAN – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.16.2.3 
ORA CALIBRA® OCULAR DISCOMFORT SCALE (DURING CAE®) 
STRATIFIED BY BASELINE MEDIAN – COMBINED STAGE 1 AND 
STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.16.3.1 
ORA CALIBRA® OCULAR DISCOMFORT SCALE (DURING CAE®)  
STRATIFIED BY TIME TO CAE QUALIFICATION – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.16.3.2 
ORA CALIBRA® OCULAR DISCOMFORT SCALE (DURING CAE®)  
STRATIFIED BY TIME TO CAE QUALIFICATION – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.16.3.3 
ORA CALIBRA® OCULAR DISCOMFORT SCALE (DURING CAE®)  
STRATIFIED BY TIME TO CAE QUALIFICATION – COMBINED 
STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 


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Table Number 
Title 
Population 
TABLE 14.2.17.1.1 
ORA CALIBRA® OCULAR DISCOMFORT AND 4-SYMPTOM 
QUESTIONNAIRE – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.17.1.2 
ORA CALIBRA® OCULAR DISCOMFORT AND 4-SYMPTOM 
QUESTIONNAIRE – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.17.1.3 
ORA CALIBRA® OCULAR DISCOMFORT AND 4-SYMPTOM 
QUESTIONNAIRE – COMBINED STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.17.2.1 
ORA CALIBRA® OCULAR DISCOMFORT AND 4-SYMPTOM 
QUESTIONNAIRE STRATIFIED BY BASELINE MEDIAN – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.17.2.2 
ORA CALIBRA® OCULAR DISCOMFORT AND 4-SYMPTOM 
QUESTIONNAIRE STRATIFIED BY BASELINE MEDIAN – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.17.2.3 
ORA CALIBRA® OCULAR DISCOMFORT AND 4-SYMPTOM 
QUESTIONNAIRE STRATIFIED BY BASELINE MEDIAN – 
COMBINED STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.17.3.1 
ORA CALIBRA® OCULAR DISCOMFORT AND 4-SYMPTOM 
QUESTIONNAIRE STRATIFIED BY TIME TO CAE QUALIFICATION 
– STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.17.3.2 
ORA CALIBRA® OCULAR DISCOMFORT AND 4-SYMPTOM 
QUESTIONNAIRE STRATIFIED BY TIME TO CAE QUALIFICATION 
– STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.17.3.3 
ORA CALIBRA® OCULAR DISCOMFORT AND 4-SYMPTOM 
QUESTIONNAIRE STRATIFIED BY TIME TO CAE QUALIFICATION 
– COMBINED STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.18.1.1 
SYMPTOM ASSESSMENT IN DRY EYE (SANDE) – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.18.1.2 
SYMPTOM ASSESSMENT IN DRY EYE (SANDE) – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.18.1.3 
SYMPTOM ASSESSMENT IN DRY EYE (SANDE) – COMBINED 
STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.18.2.1 
SYMPTOM ASSESSMENT IN DRY EYE (SANDE) STRATIFIED BY 
BASELINE MEDIAN – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.18.2.2 
SYMPTOM ASSESSMENT IN DRY EYE (SANDE) STRATIFIED BY 
BASELINE MEDIAN – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.18.2.3 
SYMPTOM ASSESSMENT IN DRY EYE (SANDE) STRATIFIED BY 
BASELINE MEDIAN – COMBINED STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.18.3.1 
SYMPTOM ASSESSMENT IN DRY EYE (SANDE) STRATIFIED BY 
TIME TO CAE QUALIFICATION – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.18.3.2 
SYMPTOM ASSESSMENT IN DRY EYE (SANDE) STRATIFIED BY 
TIME TO CAE QUALIFICATION – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.18.3.3 
SYMPTOM ASSESSMENT IN DRY EYE (SANDE) STRATIFIED BY 
TIME TO CAE QUALIFICATION – COMBINED STAGE 1 AND 
STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.19.1.1 
RESPONDER ANALYSIS – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.19.1.2 
RESPONDER ANALYSIS – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.19.1.3 
RESPONDER ANALYSIS – COMBINED STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 


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Table Number 
Title 
Population 
TABLE 14.2.20.1.1 
RESPONDER SHIFT FROM BASELINE – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.20.1.2 
RESPONDER SHIFT FROM BASELINE – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.20.1.3 
RESPONDER SHIFT FROM BASELINE – COMBINED STAGE 1 
AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.21.1.1 
P-VALUE SUMMARY – STAGE 1  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.21.1.2 
P-VALUE SUMMARY – STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.2.21.1.3 
P-VALUE SUMMARY – COMBINED STAGE 1 AND STAGE 2  
MITT 
POPULATION 
WITH 
OBSERVED DATA ONLY 
TABLE 14.3.1.1.1 
ADVERSE EVENT SUMMARY – STAGE 1  
SAFETY POPULATION 
TABLE 14.3.1.1.2 
ADVERSE EVENT SUMMARY – STAGE 2  
SAFETY POPULATION 
TABLE 14.3.1.1.3 
ADVERSE EVENT SUMMARY – COMBINED STAGE 1 AND 
STAGE 2  
SAFETY POPULATION 
TABLE 14.3.1.2.1 
ALL OCULAR ADVERSE EVENTS  
SAFETY POPULATION 
TABLE 14.3.1.2.2 
ALL OCULAR ADVERSE EVENTS – STAGE 2  
SAFETY POPULATION 
TABLE 14.3.1.2.3 
ALL OCULAR ADVERSE EVENTS – COMBINED STAGE 1 AND 
STAGE 2  
SAFETY POPULATION 
TABLE 14.3.1.3.1 
ALL NON-OCULAR ADVERSE EVENTS – STAGE 1  
SAFETY POPULATION 
TABLE 14.3.1.3.2 
ALL NON-OCULAR ADVERSE EVENTS – STAGE 2  
SAFETY POPULATION 
TABLE 14.3.1.3.3 
ALL NON-OCULAR ADVERSE EVENTS – COMBINED STAGE 1 
AND STAGE 2  
SAFETY POPULATION 
TABLE 14.3.1.4.1 
ALL OCULAR TREATMENT-EMERGENT ADVERSE EVENTS – 
STAGE 1  
SAFETY POPULATION 
TABLE 14.3.1.4.2 
ALL OCULAR TREATMENT-EMERGENT ADVERSE EVENTS – 
STAGE 2  
SAFETY POPULATION 
TABLE 14.3.1.4.3 
ALL OCULAR TREATMENT-EMERGENT ADVERSE EVENTS – 
COMBINED STAGE 1 AND STAGE 2  
SAFETY POPULATION 
TABLE 14.3.1.5.1 
ALL NON-OCULAR TREATMENT-EMERGENT ADVERSE EVENTS 
– STAGE 1  
SAFETY POPULATION 
TABLE 14.3.1.5.2 
ALL NON-OCULAR TREATMENT-EMERGENT ADVERSE EVENTS 
– STAGE 2  
SAFETY POPULATION 
TABLE 14.3.1.5.3 
ALL NON-OCULAR TREATMENT-EMERGENT ADVERSE EVENTS 
– COMBINED STAGE 1 AND STAGE 2  
SAFETY POPULATION 
TABLE 14.3.1.6.1 
ALL OCULAR TREATMENT-RELATED TREATMENT-EMERGENT 
ADVERSE EVENTS – STAGE 1  
SAFETY POPULATION 
TABLE 14.3.1.6.2 
ALL OCULAR TREATMENT-RELATED TREATMENT-EMERGENT 
ADVERSE EVENTS – STAGE 2  
SAFETY POPULATION 
TABLE 14.3.1.6.3 
ALL OCULAR TREATMENT-RELATED TREATMENT-EMERGENT 
ADVERSE EVENTS – COMBINED STAGE 1 AND STAGE 2  
SAFETY POPULATION 
TABLE 14.3.1.7.1 
ALL 
NON-OCULAR 
TREATMENT-RELATED 
TREATMENT-
EMERGENT ADVERSE EVENTS – STAGE 1  
SAFETY POPULATION 
TABLE 14.3.1.7.2 
ALL 
NON-OCULAR 
TREATMENT-RELATED 
TREATMENT-
EMERGENT ADVERSE EVENTS – STAGE 2  
SAFETY POPULATION 


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Table Number 
Title 
Population 
TABLE 14.3.1.7.3 
ALL 
NON-OCULAR 
TREATMENT-RELATED 
TREATMENT-
EMERGENT ADVERSE EVENTS – COMBINED STAGE 1 AND 
STAGE 2  
SAFETY POPULATION 
TABLE 14.3.1.8.1 
ALL SERIOUS ADVERSE EVENTS – STAGE 1  
SAFETY POPULATION 
TABLE 14.3.1.8.2 
ALL SERIOUS ADVERSE EVENTS – STAGE 2  
SAFETY POPULATION 
TABLE 14.3.1.8.3 
ALL SERIOUS ADVERSE EVENTS – COMBINED STAGE 1 AND 
STAGE 2  
SAFETY POPULATION 
TABLE 14.3.1.9.1 
ALL OCULAR TREATMENT-EMERGENT ADVERSE EVENTS BY 
MAXIMAL SEVERITY – STAGE 1  
SAFETY POPULATION 
TABLE 14.3.1.9.2 
ALL OCULAR TREATMENT-EMERGENT ADVERSE EVENTS BY 
MAXIMAL SEVERITY – STAGE 2  
SAFETY POPULATION 
TABLE 14.3.1.9.3 
ALL OCULAR TREATMENT-EMERGENT ADVERSE EVENTS BY 
MAXIMAL SEVERITY – COMBINED STAGE 1 AND STAGE 2  
SAFETY POPULATION 
TABLE 14.3.1.10.1 
ALL NON-OCULAR TREATMENT-EMERGENT ADVERSE EVENTS 
BY MAXIMAL SEVERITY – STAGE 1  
SAFETY POPULATION 
TABLE 14.3.1.10.2 
ALL NON-OCULAR TREATMENT-EMERGENT ADVERSE EVENTS 
BY MAXIMAL SEVERITY – STAGE 2  
SAFETY POPULATION 
TABLE 14.3.1.10.3 
ALL NON-OCULAR TREATMENT-EMERGENT ADVERSE EVENTS 
BY MAXIMAL SEVERITY – COMBINED STAGE 1 AND STAGE 2  
SAFETY POPULATION 
TABLE 14.3.1.11.1 
ALL OCULAR TREATMENT-EMERGENT ADVERSE EVENTS BY 
STUDY DAY OF ONSET – STAGE 1  
SAFETY POPULATION 
TABLE 14.3.1.11.2 
ALL OCULAR TREATMENT-EMERGENT ADVERSE EVENTS BY 
STUDY DAY OF ONSET – STAGE 2  
SAFETY POPULATION 
TABLE 14.3.11.3 
ALL OCULAR TREATMENT-EMERGENT ADVERSE EVENTS BY 
STUDY DAY OF ONSET – COMBINED STAGE 1 AND STAGE 2  
SAFETY POPULATION 
TABLE 14.3.1.12.1 
ALL NON-OCULAR TREATMENT-EMERGENT ADVERSE EVENTS 
BY STUDY DAY OF ONSET – STAGE 2  
SAFETY POPULATION 
TABLE 14.3.1.12.2 
ALL NON-OCULAR TREATMENT-EMERGENT ADVERSE EVENTS 
BY STUDY DAY OF ONSET – STAGE 2  
SAFETY POPULATION 
TABLE 14.3.1.12.3 
ALL NON-OCULAR TREATMENT-EMERGENT ADVERSE EVENTS 
BY STUDY DAY OF ONSET – COMBINED STAGE 1 AND STAGE 2  SAFETY POPULATION 
TABLE 14.3.2.1 
ORA CALIBRA® DROP COMFORT SCALE – STAGE 1  
SAFETY POPULATION 
TABLE 14.3.2.2 
ORA CALIBRA® DROP COMFORT SCALE – STAGE 2  
SAFETY POPULATION 
TABLE 14.3.2.3 
ORA CALIBRA® DROP COMFORT SCALE – COMBINED STAGE 1 
AND STAGE 2  
SAFETY POPULATION 
TABLE 14.3.3.1 
ORA CALIBRA® DROP COMFORT QUESTIONNAIRE – STAGE 1  
SAFETY POPULATION 
TABLE 14.3.3.2 
ORA CALIBRA® DROP COMFORT QUESTIONNAIRE – STAGE 2  
SAFETY POPULATION 
TABLE 14.3.3.3 
ORA 
CALIBRA® 
DROP 
COMFORT 
QUESTIONNAIRE 
– 
COMBINED STAGE 1 AND STAGE 2  
SAFETY POPULATION 
TABLE 14.3.4.1 
BEST-CORRECTED VISUAL ACUITY (BCVA; LOGMAR) – STAGE 1  SAFETY POPULATION 
TABLE 14.3.4.2 
BEST-CORRECTED VISUAL ACUITY (BCVA; LOGMAR) – STAGE 2  SAFETY POPULATION 
TABLE 14.3.4.3 
BEST-CORRECTED VISUAL ACUITY (BCVA; LOGMAR) – 
COMBINED STAGE 1 AND STAGE 2  
SAFETY POPULATION 
TABLE 14.3.5.1.1 
SLIT-LAMP BIOMICROSCOPY – STAGE 1  
SAFETY POPULATION 
TABLE 14.3.5.1.2 
SLIT-LAMP BIOMICROSCOPY – STAGE 2  
SAFETY POPULATION 
TABLE 14.3.5.1.3 
SLIT-LAMP BIOMICROSCOPY – COMBINED STAGE 1 AND 
STAGE 2  
SAFETY POPULATION 


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Table Number 
Title 
Population 
TABLE 14.3.5.2.1 
SHIFT IN SLIT-LAMP BIOMICROSCOPY – STAGE 1  
SAFETY POPULATION 
TABLE 14.3.5.2.2 
SHIFT IN SLIT-LAMP BIOMICROSCOPY – STAGE 2  
SAFETY POPULATION 
TABLE 14.3.5.2.3 
SHIFT IN SLIT-LAMP BIOMICROSCOPY – COMBINED STAGE 1 
AND STAGE 2  
SAFETY POPULATION 
TABLE 14.3.6.1 
INTRAOCULAR PRESSURE (IOP; MMHG) – STAGE 1  
SAFETY POPULATION 
TABLE 14.3.6.2 
INTRAOCULAR PRESSURE (IOP; MMHG)  – STAGE 2  
SAFETY POPULATION 
TABLE 14.3.6.3 
INTRAOCULAR PRESSURE (IOP; MMHG) – COMBINED STAGE 1 
AND STAGE 2  
SAFETY POPULATION 
TABLE 14.3.7.1.1 
OPHTHALMOSCOPY – STAGE 1  
SAFETY POPULATION 
TABLE 14.3.7.1.2 
OPHTHALMOSCOPY – STAGE 2  
SAFETY POPULATION 
TABLE 14.3.7.1.3 
OPHTHALMOSCOPY – COMBINED STAGE 1 AND STAGE 2  
SAFETY POPULATION 
TABLE 14.3.7.2.1 
SHIFT IN OPHTHALMOSCOPY – STAGE 1  
SAFETY POPULATION 
TABLE 14.3.7.2.2 
SHIFT IN OPHTHALMOSCOPY – STAGE 2  
SAFETY POPULATION 
TABLE 14.3.7.2.3 
SHIFT IN OPHTHALMOSCOPY – COMBINED STAGE 1 AND 
STAGE 2  
SAFETY POPULATION 
TABLE 14.3.8.1 
VITAL SIGNS – STAGE 1  
SAFETY POPULATION 
TABLE 14.3.8.2 
VITAL SIGNS – STAGE 2  
SAFETY POPULATION 
TABLE 14.3.8.3 
VITAL SIGNS – COMBINED STAGE 1 AND STAGE 2  
SAFETY POPULATION 
TABLE 14.3.9.1 
LABORATORY TESTS – STAGE 1  
SAFETY POPULATION 
TABLE 14.3.9.2 
LABORATORY TESTS – STAGE 2  
SAFETY POPULATION 
TABLE 14.3.9.3 
LABORATORY TESTS – COMBINED STAGE 1 AND STAGE 2  
SAFETY POPULATION 
TABLE 14.3.10.1 
COMPLIANCE WITH STUDY DRUG – STAGE 1  
SAFETY POPULATION 
TABLE 14.3.10.2 
COMPLIANCE WITH STUDY DRUG – STAGE 2  
SAFETY POPULATION 
TABLE 14.3.10.3 
COMPLIANCE WITH STUDY DRUG – COMBINED STAGE 1 AND 
STAGE 2  
SAFETY POPULATION 
TABLE 14.3.11.1 
EXPOSURE TO STUDY DRUG – STAGE 1  
SAFETY POPULATION 
TABLE 14.3.11.2 
EXPOSURE TO STUDY DRUG – STAGE 2  
SAFETY POPULATION 
TABLE 14.3.11.3 
EXPOSURE TO STUDY DRUG – COMBINED STAGE 1 AND STAGE 
2  
SAFETY POPULATION 
 
21. Listings 
 
Listing Number 
Title 
LISTING 16.1.7.1 
RANDOMIZATION – STAGE 1 
LISTING 16.1.7.2 
RANDOMIZATION – STAGE 2 
LISTING 16.2.1.1 
SUBJECT DISPOSITION – STAGE 1 
LISTING 16.2.1.2 
SUBJECT DISPOSITION – STAGE 2 
LISTING 16.2.2.1 
PROTOCOL DEVIATIONS – STAGE 1 
LISTING 16.2.2.2 
PROTOCOL DEVIATIONS – STAGE 2 
LISTING 16.2.3.1 
STUDY POPULATION INCLUSION – STAGE 1 
LISTING 16.2.3.2 
STUDY POPULATION INCLUSION – STAGE 2 
LISTING 16.2.4.1.1 
DEMOGRAPHICS – STAGE 1 
LISTING 16.2.4.1.2 
DEMOGRAPHICS – STAGE 2 
LISTING 16.2.4.2.1 
OCULAR MEDICAL HISTORY – STAGE 1 


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Listing Number 
Title 
LISTING 16.2.4.2.2 
OCULAR MEDICAL HISTORY – STAGE 2 
LISTING 16.2.4.3.1 
NON-OCULAR MEDICAL HISTORY – STAGE 1 
LISTING 16.2.4.3.2 
NON-OCULAR MEDICAL HISTORY – STAGE 2 
LISTING 16.2.5.1.1 
PRIOR AND CONCOMITANT OCULAR MEDICATIONS – STAGE 1 
LISTING 16.2.5.1.2 
PRIOR AND CONCOMITANT OCULAR MEDICATIONS – STAGE 2 
LISTING 16.2.5.2.1 
PRIOR AND CONCOMITANT NON-OCULAR MEDICATIONS – STAGE 1 
LISTING 16.2.5.2.1 
PRIOR AND CONCOMITANT NON-OCULAR MEDICATIONS – STAGE 2 
LISTING 16.2.5.3.1 
IN-OFFICE STUDY MEDICATION INSTILLATION – STAGE 1 
LISTING 16.2.5.3.2 
IN-OFFICE STUDY MEDICATION INSTILLATION – STAGE 2 
LISTING 16.2.5.4.1 
STUDY DRUG EXPOSURE AND DOSING COMPLIANCE – STAGE 1 
LISTING 16.2.5.4.2 
STUDY DRUG EXPOSURE AND DOSING COMPLIANCE – STAGE 2 
LISTING 16.2.5.5.1 
STUDY DRUG ACCOUNTABILITY – STAGE 1 
LISTING 16.2.5.5.2 
STUDY DRUG ACCOUNTABILITY – STAGE 2 
LISTING 16.2.6.1.1 
CORNEAL AND CONJUNCTIVAL FLUORESCEIN STAINING (ORA CALIBRA® AND 
OXFORD SCALES) – STAGE 1 
LISTING 16.2.6.1.2 
CORNEAL AND CONJUNCTIVAL FLUORESCEIN STAINING (ORA CALIBRA® AND 
OXFORD SCALES) – STAGE 2 
LISTING 16.2.6.2.1 
VISUAL ANALOGUE SCALE (VAS) – STAGE 1 
LISTING 16.2.6.2.2 
VISUAL ANALOGUE SCALE (VAS) – STAGE 2 
LISTING 16.2.6.3.1 
OCULAR SURFACE DISEASE INDEX (OSDI; PRE-CAE) – STAGE 1 
LISTING 16.2.6.3.2 
OCULAR SURFACE DISEASE INDEX (OSDI; PRE-CAE) – STAGE 2 
LISTING 16.2.6.4.1 
UNANESTHETIZED SCHIRMER’S TEST (PRE-CAE) – STAGE 1 
LISTING 16.2.6.4.2 
UNANESTHETIZED SCHIRMER’S TEST (PRE-CAE) – STAGE 2 
LISTING 16.2.6.5.1 
TEAR FILM BREAK-UP TIME (TFBUT) – STAGE 1 
LISTING 16.2.6.5.2 
TEAR FILM BREAK-UP TIME (TFBUT) – STAGE 2 
LISTING 16.2.6.5.3 
OCULUS KERATOGRAPH (PRE-CAE) - STAGE 1 
LISTING 16.2.6.5.4 
OCULUS KERATOGRAPH (PRE-CAE) – STAGE 2 
LISTING 16.2.6.6.1 
ORA CALIBRA® CONJUNCTIVAL REDNESS SCALE FOR BULBAR CONJUNCTIVAL 
HYPEREMIA – STAGE 1 
LISTING 16.2.6.6.2 
ORA CALIBRA® CONJUNCTIVAL REDNESS SCALE FOR BULBAR CONJUNCTIVAL 
HYPEREMIA – STAGE 2 
LISTING 16.2.6.7.1 
LISSAMINE GREEN CONJUNCTIVAL STAINING (OXFORD SCALE) – STAGE 1 
LISTING 16.2.6.7.2 
LISSAMINE GREEN CONJUNCTIVAL STAINING (OXFORD SCALE) – STAGE 2 
LISTING 16.2.6.8.1 
ORA CALIBRA® OCULAR DISCOMFORT SCALE PRE-, POST-, AND NON-CAE – 
STAGE 1 
LISTING 16.2.6.8.2 
ORA CALIBRA® OCULAR DISCOMFORT SCALE PRE-, POST-, AND NON-CAE – 
STAGE 2 
LISTING 16.2.6.9.1 
ORA CALIBRA® OCULAR DISCOMFORT SCALE DURING CAE EXPOSURE – 
STAGE 1 
LISTING 16.2.6.9.2 
ORA CALIBRA® OCULAR DISCOMFORT SCALE DURING CAE EXPOSURE – 
STAGE 2 
LISTING 16.2.6.10.1 
ORA CALIBRA® OCULAR DISCOMFORT AND 4-SYMPTOM QUESTIONNAIRE – 
STAGE 1 
LISTING 16.2.6.10.2 
ORA CALIBRA® OCULAR DISCOMFORT AND 4-SYMPTOM QUESTIONNAIRE – 
STAGE 2 
LISTING 16.2.6.11.1 
SYMPTOM ASSESSMENT IN DRY EYE (SANDE; PRE-CAE) – STAGE 1 


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Listing Number 
Title 
LISTING 16.2.6.11.2 
SYMPTOM ASSESSMENT IN DRY EYE (SANDE; PRE-CAE) – STAGE 2 
LISTING 16.2.6.12.1 
TEAR COLLECTION (PRE-CAE) – STAGE 1 
LISTING 16.2.6.12.2 
TEAR COLLECTION (PRE-CAE) – STAGE 2 
LISTING 16.2.7.1.1.1 
ALL ADVERSE EVENTS – STAGE 1 
LISTING 16.2.7.1.1.2 
ALL ADVERSE EVENTS – STAGE 2 
LISTING 16.2.7.1.2.1 
ADVERSE EVENTS LEADING TO TREATMENT DISCONTINUATION – STAGE 1 
LISTING 16.2.7.1.2.2 
ADVERSE EVENTS LEADING TO TREATMENT DISCONTINUATION – STAGE 2 
LISTING 16.2.7.1.3.1 
ADVERSE EVENTS LEADING TO DEATH – STAGE 1 
LISTING 16.2.7.1.3.2 
ADVERSE EVENTS LEADING TO DEATH – STAGE 2 
LISTING 16.2.7.1.4.1 
ALL SERIOUS ADVERSE EVENTS – STAGE 1 
LISTING 16.2.7.1.4.2 
ALL SERIOUS ADVERSE EVENTS – STAGE 2 
LISTING 16.2.7.2.1 
ORA CALIBRA® DROP COMFORT SCALE – STAGE 1 
LISTING 16.2.7.2.2 
ORA CALIBRA® DROP COMFORT SCALE – STAGE 2 
LISTING 16.2.7.2.3 
ORA CALIBRA® DROP COMFORT QUESTIONNAIRE 3 MINUTES POST-
INSTALLATION – STAGE 1 
LISTING 16.2.7.2.4 
ORA CALIBRA® DROP COMFORT QUESTIONNAIRE 3 MINUTES POST-
INSTALLATION – STAGE 2 
LISTING 16.2.7.3.1.1 
BEST-CORRECTED VISUAL ACUITY (BCVA; LOGMAR) (PRE-CAE) – STAGE 1 
LISTING 16.2.7.3.1.2 
BEST-CORRECTED VISUAL ACUITY (BCVA; LOGMAR) (PRE-CAE) – STAGE 2 
LISTING 16.2.7.3.2.1 
SLIT LAMP BIOMICROSCOPY – STAGE 1 
LISTING 16.2.7.3.2.2 
SLIT LAMP BIOMICROSCOPY – STAGE 2 
LISTING 16.2.7.3.3.1 
OPHTHALMOSCOPY (POST-CAE) – STAGE 1 
LISTING 16.2.7.3.3.2 
OPHTHALMOSCOPY (POST-CAE) – STAGE 2 
LISTING 16.2.7.3.4.1 
INTRAOCULAR PRESSURE (IOP; POST-CAE) – STAGE 1 
LISTING 16.2.7.3.4.2 
INTRAOCULAR PRESSURE (IOP; POST-CAE) – STAGE 2 
LISTING 16.2.8.1.1 
BLOOD CHEMISTRY – STAGE 1 
LISTING 16.2.8.1.2 
BLOOD CHEMISTRY – STAGE 2 
LISTING 16.2.8.2.1 
HEMATOLOGY – STAGE 1 
LISTING 16.2.8.2.2 
HEMATOLOGY – STAGE 2 
LISTING 16.2.8.3.1 
URINALYSIS – STAGE 1 
LISTING 16.2.8.3.2 
URINALYSIS – STAGE 2 
LISTING 16.2.8.4 
PHARMACOKINETICS SAMPLES 
LISTING 16.2.9.1.1 
VITAL SIGNS (PRE-CAE) – STAGE 1 
LISTING 16.2.9.1.2 
VITAL SIGNS (PRE-CAE) – STAGE 2 
LISTING 16.2.9.2.1 
CHILDBEARING POTENTIAL AND URINE PREGNANCY TEST – STAGE 1 
LISTING 16.2.9.2.2 
CHILDBEARING POTENTIAL AND URINE PREGNANCY TEST – STAGE 2 
 
22. Figures 
 
Figure Number 
Title 
Population 
FIGURE 14.2.1.1 
PRE-CAE® INFERIOR FLUORESCEIN STAINING (ORA CALIBRA® SCALE) CHANGE 
FROM BASELINE – STAGE 1 
MITT 
POPULATION 
WITH LOCF 


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Figure Number 
Title 
Population 
FIGURE 14.2.1.2 
PRE-CAE® INFERIOR FLUORESCEIN STAINING (ORA CALIBRA® SCALE) CHANGE 
FROM BASELINE – STAGE 2 
MITT 
POPULATION 
WITH LOCF 
FIGURE 14.2.1.3 
PRE-CAE® INFERIOR FLUORESCEIN STAINING (ORA CALIBRA® SCALE) 
CHANGE FROM BASELINE – COMBINED STAGE 1 AND STAGE 2 
MITT 
POPULATION 
WITH LOCF 
FIGURE 14.2.2.1 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (ORA CALIBRA® SCALE) 
CHANGE FROM BASELINE – STAGE 1 
MITT 
POPULATION 
WITH LOCF 
FIGURE 14.2.2.2 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (ORA CALIBRA® SCALE) 
CHANGE FROM BASELINE – STAGE 2 
MITT 
POPULATION 
WITH LOCF 
FIGURE 14.2.2.3 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (ORA CALIBRA® SCALE) 
CHANGE FROM BASELINE – COMBINED STAGE 1 AND STAGE 2 
MITT 
POPULATION 
WITH LOCF 
FIGURE 14.2.3.1 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (OXFORD SCALE) 
CHANGE FROM BASELINE – STAGE 1 
MITT 
POPULATION 
WITH LOCF 
FIGURE 14.2.3.2 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (OXFORD SCALE) 
CHANGE FROM BASELINE – STAGE 2 
MITT 
POPULATION 
WITH LOCF 
FIGURE 14.2.3.3 
PRE-CAE® TOTAL CORNEAL FLUORESCEIN STAINING (OXFORD SCALE) 
CHANGE FROM BASELINE – COMBINED STAGE 1 AND STAGE 2 
MITT 
POPULATION 
WITH LOCF 
FIGURE 14.2.4.1 
PRE-CAE® EYE DRYNESS (VISUAL ANALOG SCALE) CHANGE FROM BASELINE – 
STAGE 1 
MITT 
POPULATION 
WITH LOCF 
FIGURE 14.2.4.2 
PRE-CAE® EYE DRYNESS (VISUAL ANALOG SCALE)  CHANGE FROM BASELINE 
– STAGE 2 
MITT 
POPULATION 
WITH LOCF 
FIGURE 14.2.4.3 
PRE-CAE® EYE DRYNESS (VISUAL ANALOG SCALE) CHANGE FROM BASELINE 
– COMBINED STAGE 1 AND STAGE 2 
MITT 
POPULATION 
WITH LOCF 
FIGURE 14.2.5.1 
PRE-CAE® TOTAL OSDI© SCORE CHANGE FROM BASELINE – STAGE 1 
MITT 
POPULATION 
WITH LOCF 
FIGURE 14.2.5.2 
PRE-CAE® TOTAL OSDI© SCORE CHANGE FROM BASELINE – STAGE 2 
MITT 
POPULATION 
WITH LOCF 
FIGURE 14.2.5.3 
PRE-CAE® TOTAL OSDI© SCORE CHANGE FROM BASELINE – COMBINED 
STAGE 1 AND STAGE 2 
MITT 
POPULATION 
WITH LOCF