A Phase I/II, Randomized, Double-Masked, Vehicle-Controlled Study of the Safety, Tolerability, and Efficacy of AXR-270 Topical Eyelid Cream in Treating Posterior Blepharitis Associated With Meibomian Gland Dysfunction
Phase: PHASE2
Conditions: Posterior Blepharitis, Meibomian Gland Dysfunction
Sponsor: AxeroVision, Inc.

AXEROVISION, INC.
Clinical Protocol AXFUZ01901
CLINICAL PROTOCOL INCORPORATING AMENDMENT 02
Protocol Number:
Protocol Title:
AXR20l901
A Phase I/II, Randomized, Double-Masked, Vehicle-
Controlled Study of the Safety, Tolerability, and Efficacy
of AXR-270 Topical Eyelid Cream in Treating Posterior
Blepharitis Associated with Meibomian Gland
Dysfunction.
AxeroVision" Inc.
Kenneth Sall, MD
Lexitas Pharma Services, Inc.
313 Foster St. Durham. NC 27701
Original: 16January2020
l't Amendment: 28April2020
2nd Amendment: 03Jun2020
06032020
Date
3 June 2020
Date
Sponsor:
Medical Monitor:
Issue Date:
Houman Hemmati, MD, PhD
Director of Clinical Development
lchtnr,(tancr
Achim Krauss {Jun 3,2020 15:23 PDTI
Achim Krauss, PhD
Chief Executive Officer
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL
CONFIDENTIAL
Houman Ddtid Henfiati {Jun 3,2020 15:OG PDT)
Page I of80
NCT Number 04469998

 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 1 of 80                                      
CONFIDENTIAL 
  
AXEROVISION, INC. 
Clinical Protocol AXR201901 
CLINICAL PROTOCOL INCORPORATING AMENDMENT 02 
 
 
Protocol Number: 
AXR201901 
Protocol Title: 
A Phase I/II, Randomized, Double-Masked, Vehicle-
Controlled Study of the Safety, Tolerability, and Efficacy 
of AXR-270 Topical Eyelid Cream in Treating Posterior 
Blepharitis Associated with Meibomian Gland 
Dysfunction. 
Sponsor: 
AxeroVision, Inc. 
 
Medical Monitor: 
Kenneth Sall, MD 
 Lexitas Pharma Services, Inc.  
 313 Foster St. Durham, NC 27701 
 
Issue Date: 
Original:  16January2020 
                                                           1st Amendment: 28April2020 
                                                           2nd Amendment: 03Jun2020 
 
 
 
 
Approved:   
 
 
 
________________________________________________ 
 
 
______________  
Houman Hemmati, MD, PhD 
 
Date 
Director of Clinical Development 
 
 
________________________________________________ 
 
 
______________  
Achim Krauss, PhD 
 
Date 
Chief Executive Officer 
 
 
 
 

 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 2 of 80                                      
CONFIDENTIAL 
  
AXEROVISION, INC. 
Clinical Protocol AXR201901 
Incorporating Amendment 02 
 Investigator Signature Page 
 
 
Protocol Number: 
AXR201901  
 
Protocol Title: 
A Phase I/II, Randomized, Double-Masked, Vehicle-
Controlled Study of the Safety, Tolerability, and 
Efficacy of AXR-270 Topical Eyelid Cream in Treating 
Posterior Blepharitis Associated with Meibomian Gland 
Dysfunction. 
 
Sponsor: 
AxeroVision, Inc. 
 
 
 
Issue Date: 
Original:  16January2020 
 
1st Amendment: 28April2020 
                                                           2nd Amendment: 03Jun2020 
 
Contact for Serious Adverse Events: Kenneth Sall, MD 
 
  
Lexitas Pharma Services, Inc. 
  
313 Foster St. Durham, NC 27701 
  
562-754-2947  
 
Investigator Name (printed or typed): 
 
________________________________________________ 
 
Investigator's Signature: 
 
________________________________________________ 
 
 
______________  
 
                     Date  

 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 3 of 80                                      
CONFIDENTIAL 
  
SYNOPSIS  
Study Title: 
A Phase I/II, Randomized, Double-Masked, Vehicle-Controlled Study of the 
Safety, Tolerability, and Efficacy of AXR-270 Topical Eyelid Cream in 
Treating Posterior Blepharitis Associated with Meibomian Gland Dysfunction. 
Study Objectives: 
The primary objective of this study is to evaluate the safety and tolerability of 
two concentrations of AXR-270 Cream (0.2% AXR-270 Cream; 2.0% AXR-
270 Cream) in treating posterior blepharitis associated with Meibomian Gland 
Disease (MGD).   
The secondary objective is to evaluate the efficacy of AXR-270 Cream in 
treating signs and symptoms of posterior blepharitis associated with MGD. 
Study Population:  Subjects with a diagnosis of symptomatic posterior blepharitis associated with 
MGD will be included in this trial. 
Number of 
Subjects: 
Approximately one hundred and twenty-six (126) subjects across 10-16 sites.  
Investigational 
Products: 
 
• 
0.2% AXR-270 Topical eyelid Cream 
• 
2.0% AXR-270 Topical eyelid Cream 
• 
AXR-270 Vehicle  
Route and 
Duration of 
Administration: 
AXR-270 Cream will be administered as a topical ophthalmic cream. Subjects 
will receive Investigational Product (IP) administered in the clinic at Day 
1/Visit 2 and will self-administer either AXR-270 Cream or Vehicle once a day 
(QD) applied to upper and lower eyelid skin bilaterally for approximately 21 
days. 
Study Design:   
This is a multi-center, double-masked, randomized, vehicle-controlled, two 
cohort study. Subjects will be randomized into either 0.2% AXR-270 Cream, 
2.0% AXR-270 Cream or Vehicle administered in both eyes. 
Cohort 1: 
Approximately sixty-three (63) subjects with a diagnosis of symptomatic 
posterior blepharitis associated with MGD meeting all inclusion/exclusion 
criteria at the Screening visit (Visit 1) will be asked to discontinue their eyelid 
hygiene regimen and use only Sponsor supplied commercial sterile eyelid 
wipes between Visit 1 and Visit 2 daily (Equalization Period). Subjects will 
then be evaluated at Baseline/Randomization (Visit 2; Week 0/Day 1) to 
confirm they continue to meet all inclusion/exclusion and are eligible for 
randomization. Note: The daily use of sponsor-supplied sterile eyelid wipes is 
to be discontinued after randomization at Visit 2. All subjects within this 
Cohort will be assessed for safety and exploratory efficacy. Both Investigator 
and subjects will be masked as to the IP. Subjects will be shown an 
instructional video on applying the investigational product to help ensure 
consistency in application across subjects. Further, the site should reinforce to 
the subject how to self-administer the IP to the eyelids and avoid ocular 

 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 4 of 80                                      
CONFIDENTIAL 
  
instillation. Subjects will self-administer a pre-specified volume 
(approximately 50 milligrams per eyelid) of 0.2% AXR-270 Cream or its 
Vehicle across the epidermis corresponding to the external surface overlying 
the tarsal plate of the upper and lower eyelids of both eyes. Refer to more 
detailed instructions in the Subject Dosing Instructions document. Blood draws 
for safety labs for all subjects will be performed prior to IP dosing in the clinic 
at Visit 2/Day 1. Following the in-clinic dose administration, subjects will be 
supplied with sufficient IP (2 tubes) to apply once daily at home in the evening 
during the treatment period. Subjects will self-administer IP QD in the 
evenings beginning on Day 2.  
 
On the following week (Visit 3; Week 1/Day 8), the Investigators will examine 
the subject and perform all safety and efficacy assessments (excluding safety 
labs and dilated Ophthalmoscopy).  
 
Subjects will return for a Week 2 (Visit 4; Day 15) visit, wherein the 
Investigators will examine the subject and perform all safety and efficacy 
assessments (excluding safety labs and dilated Ophthalmoscopy). Subjects will 
return the used IP and will be instructed to use the 2nd IP tube dispensed at 
Visit 2 to apply once daily at home in the evening for the remaining 1 week of 
treatment duration. 
 
Following the completion of the fifteenth (15th) subject from Visit 4 of Cohort 
1, the Data Safety Review Committee (DSRC) will meet to review safety data 
and will make a recommendation about whether to allow escalation to the 
higher (2.0%) dose of AXR-270 Cream for Cohort 2, which if recommended, 
will begin immediately upon the completion of enrollment in Cohort 1 (See 
Appendix 2). 
 
Subjects will return for a Week 3 (Visit 5; Day 22) visit, wherein the 
Investigators will examine the subject and perform all safety and efficacy 
assessments (including safety labs). Subjects should not dose at Visit 5/Day 22 
and following the visit, subjects will exit the study. Remaining IP will be 
collected from every subject. (See Appendix 1 for procedures planned for this 
study). 
 
Cohort 2: 
Following the completion of the fifteenth subject from Visit 4 of Cohort 1, the 
DSRC will meet to review safety data and will make a recommendation about 
whether to escalate to the higher (2.0%) dose of AXR-270 Cream for Cohort 2, 
which if recommended, will begin upon completion of enrollment in Cohort 1. 
 
The Screening and study visits will be conducted in the same fashion as 
described above for Cohort 1. Approximately sixty-three (63) subjects will be 
randomized to 2.0% AXR-270 Cream or its Vehicle.    
 

 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 5 of 80                                      
CONFIDENTIAL 
  
Study Schematic (Cohort 1): 
  
 
Note: Cohort 2 (AXR-270 Cream 2.0% or vehicle) follows the same visit 
schedule as above and will start enrolling once enrollment of Cohort 1 is 
complete.  
 
Safety Endpoints: 
• 
Adverse event (AE)  
• 
Best corrected visual acuity (BCVA) 
• 
Slit-lamp biomicroscopy and external eye exam 
• 
Intraocular pressure (IOP)  
• 
Dilated ophthalmoscopy 
• 
Safety labs (Hematology, clinical chemistry, and urinalysis)  
Efficacy 
Endpoints: 
 
All efficacy endpoints are exploratory in nature. The following endpoints will 
be considered to assess the efficacy of AXR-270 Cream. 
1. Change from baseline (Visit 2/Day 1) in the following individual 
subject-reported symptoms using Visual Analog Scale (VAS, 0-100 
point scale) score in the AXR-270 Cream (0.2% or 2.0%) arms 
compared to Vehicle at Day 22: 
o Eye Discomfort  
o Eye Dryness 
2. Change from baseline in Investigator-rated signs of MGD using 
individual severity scores in AXR-270 Cream arm compared to 
Vehicle at Day 22:  
o Total MGD Score: the sum of secretion in 5 central glands on 
each individual eyelid will be evaluated, each will be scored 
from 0-3; 0 = clear/slightly yellow, 1 = opaque/yellow, 
whitish, particulate, 2 = paste, 3 = none/occluded; total score 
will range from 0-15 

 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 6 of 80                                      
CONFIDENTIAL 
  
o Vascularity of the eyelid margin (Grade 0-4; 0 = normal, 1 = 
mild, 2 = moderate, 3 = severe, 4 = very severe vascular 
engorgement) 
3. Change from baseline in Tear Break-up Time (TBUT) in AXR-270 
Cream arm compared to Vehicle at Day 22. (Tear Break-up Time is the 
number of seconds that elapse between the last blink and the 
appearance of the first dry spot in the tear film). 
4. Change from baseline in Lissamine Green Staining (LGS) grade of the 
eyelid margin in AXR-270 Cream arm compared to Vehicle at Day 22. 
5. Change from baseline in Total Fluorescein Corneal Staining (tFCS) 
score using the National Eye Institute (NEI) Industry Workshop (0-15 
scale) in the AXR-270 Cream arm compared to Vehicle at Day 22. 
6. Change from baseline in FCS by individual region in AXR-270 arm 
compared to Vehicle at Day 22 (0-3 scale). 
7. Change from baseline in bulbar conjunctival hyperemia in AXR-270 
Cream arm compared to Vehicle at Day 22. 
8. Change from baseline in Ocular Surface Disease Index (OSDI) score 
(0-100) in AXR-270 Cream arm compared to Vehicle at Day 22. 
9. Change from baseline in the modified BLepharItIS Symptom (BLISS) 
score in AXR-270 Cream arm compared to Vehicle at Day 22. 
10. Change from baseline in the Schirmer in AXR-270 Cream arm 
compared to Vehicle at Day 22. 
Inclusion Criteria: 
 
At Visit 1 (and Visit 2 where applicable), individuals of any gender or any race 
will be eligible for study participation if they: 
1. Have provided written informed consent prior to any study procedures. 
2. Are 18 years of age or above. 
3. Have a clinical diagnosis of moderate to severe MGD and who meet 
both of the following criteria, in at least one qualifying eyelid (upper 
and lower eyelid for each eye will be evaluated independently), at both 
Visit 1 (Screening) and again in the same eye/eyelid at Visit 2 
(Randomization) examinations: 
a) Total MGD score ≥5 and ≤14 (the sum of secretion 5 central 
glands on the upper and lower eyelids will be evaluated, each 
will be scored from 0-3; 0 = clear/slightly yellow, 1 = 
opaque/yellow, whitish, particulate, 2 = paste, 3 = 
none/occluded; total score will range from 0-15). 
b) Clinical sign severity score of at least 2 (moderate) on 
vascularity of the eyelid margin  
4. Have a score of ≥35 using on Eye Discomfort VAS (0-100 point scale) 
at both Visit 1 and Visit 2. 

 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 7 of 80                                      
CONFIDENTIAL 
  
5. Meet the following criteria, in both or the same qualifying eye as in 
Inclusion #3, at both Visit 1 (Screening) and Visit 2 (Randomization) 
examinations: 
a) tFCS score ≥3 and ≤14 in the NEI/Industry Workshop scale 
(0-15 scale) 
b) Schirmer score of >7 mm without topical anesthesia 
6. OSDI score >30 at both Visit 1 and Visit 2. 
7. Required use of non-prescription over the counter (OTC) artificial tear 
substitute for symptoms of dry eye more than 3 times per day for 3 
consecutive days within 30 days prior to the Screening Visit (Visit 1) 
and willingness to suspend use of tear substitutes at Visit 1 and for the 
duration of study participation. 
8. Are willing and able to follow instructions and willing to be present for 
the required study visits for the duration of the study.  
9. Have a Logarithm of the Minimum Angle of Resolution (LogMAR) 
BCVA equal to or better than +0.7 using corrective lenses if necessary, 
in both eyes at both Visit 1 and Visit 2, by Early Treatment of Diabetic 
Retinopathy Study (ETDRS) or modified ETDRS.  
10. If female, are non-pregnant, non-lactating and women of childbearing 
potential (WOCBP) must be using an acceptable method of birth 
control [e.g., an Intrauterine Contraceptive Device (IUCD) with a 
failure rate of <1%, hormonal contraceptives, or a barrier method] for 
the duration of the study.  If a female subject is currently abstinent, 
they must agree to use one of the acceptable methods of birth control 
before they become sexually active.   
• 
Non-childbearing potential is defined as a woman who is 
postmenopausal for 12 consecutive months or a woman who is 
post hysterectomy, bilateral oophorectomy or 3 months status 
post bilateral tubal ligation. 
 
Exclusion 
Criteria: 
 
In order for subjects to be eligible at Visit 1 they may not: 
1. Have presence or history of iritis/uveitis in either eye. 
2. Have lid structural abnormalities including but not limited to entropion 
or ectropion that in the opinion of the Investigator may confound the 
study data.  
3. In the study eyelid, have greater than 4 glands that are not expressible 
from the 5 upper and/or 5 lower eyelid meibomian glands at both Visit 
1 and Visit 2. 
4. Subjects with ocular inflammatory conditions (e.g., conjunctivitis, 
keratitis, severe anterior blepharitis, etc.) not related to MGD. 
5. Subjects who in the study eye have tFCS score = 15 or a FCS score = 3 
in either eye in the superior region NEI/Industry Workshop scale or 

 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 8 of 80                                      
CONFIDENTIAL 
  
subjects who have FCS with diffuse confluent staining, filaments or 
frank epithelial defects at either Visit 1 or Visit 2. 
6. Have suspected ocular fungal, viral or bacterial infection.  
7. Subjects who within the past 6 months have had cauterization of the 
punctum.  Non-dissolvable plugs must not be inserted within 2 weeks 
of Screening (Visit 1) and current non-dissolvable plugs in position 
must be stable in the Investigator's opinion. 
8. Use of any of the prohibited medications (see Table 2: List of 
Prohibited Medications and/or procedures) within a time period prior 
to or upon Screening (Visit 1). NOTE:  These medications may not be 
used after Visit 1 through the end of the study. 
9. Use short-term dissolvable plugs for 3 months prior to Screening (Visit 
1) and long-term dissolvable plugs within 6 months prior to Screening 
(Visit 1). 
10. Any prior use of isotretinoin. 
11. Are unwilling to discontinue use of cosmetic makeup applied to the 
eyelids or eyelashes on the day of a study visit after Visit 1. 
12. Have a known hypersensitivity to active ingredient or to any of the 
other ingredients in the IP. 
13. Are unable or unwilling to withhold the use of eyelid scrubs or use of 
mechanical eyelid cleaning therapy during the study, other than the 
Sponsor supplied commercial sterile eyelid wipes from Visit 1 through 
Visit 2. After Visit 2, subjects are also permitted to follow their usual 
routine to remove eyelid or eyelash makeup (including eyelid wipes if 
applicable), ensuring that no new products/techniques are introduced 
during the study.   
14. Have been diagnosed with glaucoma, are currently using any glaucoma 
medication or known to have elevated IOP related to steroid use. 
15. Have a history of herpetic keratitis. 
16. Have a concomitant ocular pathology other than condition under study 
assessed as potentially confounding by the Investigator. 
17. Have a serious systemic disease or uncontrolled medical condition that 
in the judgment of the Investigator could confound study assessments 
or limit compliance. 
18. Have been exposed to any investigational drug or investigational 
device within the preceding 30 days. 

 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 9 of 80                                      
CONFIDENTIAL 
  
19. Are an employee of the site that is directly involved in the 
management, administration, or support of this study or be an 
immediate family member of the same. 
20. Have trigger factors that in the opinion of the Investigator may 
confound the data, including but not limited to conjunctivochalasis, 
allergic conjunctivitis, contact lens intolerance, trichiasis, epithelial 
basement membrane dystrophy, infectious keratitis or conjunctivitis. 
21. Have a documented history of ocular allergies, which, in the judgment 
of the Investigator, are likely to have an acute increase in severity due 
to the expected timing of the exposure to the allergen to which the 
subject is sensitive. Subjects sensitive to seasonal allergens that are not 
expected to be present during the study are permitted. 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 10 of 80                                         
CONFIDENTIAL 
  
Contents 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..............................15 
1. 
INTRODUCTION ....................................................................................17 
1.1. 
DESCRIPTION OF INVESTIGATIONAL PRODUCT...........................................18 
1.2. 
JUSTIFICATION FOR ROUTE OF ADMINISTRATION AND DOSE SELECTION ...19 
1.3. 
GCP COMPLIANCE .....................................................................................19 
1.4. 
POPULATION TO BE STUDIED .....................................................................19 
2. 
TRIAL OBJECTIVES AND PURPOSE ..................................................20 
2.1. 
OBJECTIVE .................................................................................................20 
3. 
TRIAL DESIGN .......................................................................................21 
3.1. 
STUDY ENDPOINTS ....................................................................................21 
3.1.1. 
Safety Endpoints .......................................................................................21 
3.1.2. 
Efficacy Endpoints ....................................................................................21 
3.2. 
DESCRIPTION OF TRIAL DESIGN .................................................................22 
3.2.1. 
Investigational Product .............................................................................24 
3.2.2. 
Methods to Minimize Bias........................................................................25 
4. 
SELECTION OF SUBJECTS ..................................................................26 
4.1. 
SUBJECT INCLUSION CRITERIA ..................................................................26 
4.2. 
SUBJECT EXCLUSION CRITERIA .................................................................27 
4.3. 
STUDY EYE/EYELID ...................................................................................29 
4.4. 
RANDOMIZATION .......................................................................................29 
5. 
PROCEDURES ........................................................................................30 
5.1. 
VISIT DESCRIPTIONS ..................................................................................30 
5.1.1. 
Visit 1 (Screening):  Day minus 14 (±2 days) prior to Visit 2 .................30 
5.1.2. 
Visit 2 (Randomization):  Day 1 ...............................................................31 
5.1.3. 
Visit 3: Day 8 (±2 days) ............................................................................33 
5.1.4. 
Visit 4: Day 15 (±3 days) ..........................................................................34 
5.1.5. 
Visit 5:  Day 22 (±3 days) .........................................................................35 
5.1.6. 
Unscheduled Visit .....................................................................................36 
5.1.7. 
Early Termination Visit ............................................................................36 
5.2. 
SUBJECT WITHDRAWAL AND/OR DISCONTINUATION .................................37 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 11 of 80                                         
CONFIDENTIAL 
  
5.3. 
COLLECTION OF DATA ...............................................................................38 
6. 
TREATMENT OF SUBJECTS ................................................................39 
6.1. 
INVESTIGATIONAL PRODUCTS TO BE ADMINISTERED .................................39 
6.2. 
CONCOMITANT MEDICATIONS ...................................................................39 
6.2.1. 
Permitted Medications and Therapies ......................................................39 
6.2.2. 
Medications and Procedures Not Permitted .............................................40 
6.3. 
INVESTIGATIONAL PRODUCT USE COMPLIANCE ........................................40 
6.4. 
DRUG ACCOUNTABILITY ...........................................................................41 
6.5. 
MAINTENANCE OF RANDOMIZATION AND PROCEDURE FOR BREAKING THE 
CODE .........................................................................................................41 
7. 
ASSESSMENT OF EFFICACY ..............................................................42 
8. 
ASSESSMENT OF SAFETY ...................................................................43 
8.1. 
SAFETY PARAMETERS ................................................................................43 
8.2. 
ADVERSE EVENT DEFINITIONS ..................................................................43 
8.3. 
PROCEDURES FOR AE REPORTING BY THE INVESTIGATOR .........................45 
8.4. 
SERIOUS ADVERSE EVENT REPORTING BY THE INVESTIGATOR .................45 
9. 
STATISTICS ............................................................................................48 
9.1. 
STATISTICAL METHODS .............................................................................48 
9.2. 
ANALYSIS POPULATIONS ...........................................................................48 
9.3. 
SUBJECT DISPOSITION, DEMOGRAPHIC AND BACKGROUND 
CHARACTERISTICS .....................................................................................48 
9.4. 
ANALYSIS OF EFFICACY .............................................................................48 
9.5. 
ANALYSIS OF SAFETY ................................................................................49 
9.6. 
SAMPLE SIZE ESTIMATION .........................................................................49 
9.7. 
LEVEL OF SIGNIFICANCE ............................................................................49 
9.8. 
PROCEDURE FOR ACCOUNTING FOR MISSING, UNUSED, OR SPURIOUS DATA
 ..................................................................................................................50 
9.9. 
PROCEDURE FOR REPORTING DEVIATIONS FROM THE STATISTICAL PLAN .50 
10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .......................51 
11. 
QUALITY CONTROL .............................................................................52 
12. 
ETHICS ....................................................................................................53 
12.1. 
Institutional Review Board .......................................................................53 
12.2. 
Informed Consent Requirements ..............................................................53 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 12 of 80                                         
CONFIDENTIAL 
  
13. 
DATA HANDLING AND RECORDKEEPING .....................................54 
13.1. 
Data Quality Control and Reporting .........................................................54 
13.2. 
Records Retention .....................................................................................54 
14. 
PUBLICATION POLICY ........................................................................55 
15. 
REFERENCES .........................................................................................56 
16. 
APPENDICES ..........................................................................................58 
 
 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 13 of 80                                         
CONFIDENTIAL 
  
LIST OF TABLES 
 
Table 1: 
Composition of AXR-270 Investigational Product (0.2% and 2.0% 
Concentrations, Vehicle) ..........................................................................24 
Table 2:      List of Prohibited Medications and/or Procedures ...................................27 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 14 of 80                                         
CONFIDENTIAL 
  
LIST OF FIGURES 
FIGURE 1: STUDY SCHEMATIC (COHORT 1) ................................................................23 
 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 15 of 80                                         
CONFIDENTIAL 
  
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse Event 
AR 
Adverse Reaction 
API 
Active Pharmaceutical Ingredient 
BCVA 
Best Corrected Visual Acuity 
BLISS 
BLepharITIS Symptom 
CDC 
Centers for Disease Control 
CMS 
Centers for Medicare & Medicaid Services 
COPD 
Chronic Obstructive Pulmonary Disease 
COVID-19 
Coronavirus Disease 2019 
CRO 
Contract Research Organization 
CS 
Clinically Significant 
CCLRU 
Cornea and Contact Lens Research Unit 
DED 
Dry Eye Disease 
DEWS 
Dry Eye Workshop 
DSRC 
Data Safety Review Committee 
eCRF 
Electronic Case Report Form 
EDE 
Evaporative Dry Eye 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
EU 
European Union 
FAS 
Full Analysis Set 
FCS 
Fluorescein Corneal Staining 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HHS 
Health and Human Services 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation  
ID 
Identification 
IMPD 
Investigational Medicinal Product Dossier 
IOP 
Intraocular Pressure 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 16 of 80                                         
CONFIDENTIAL 
  
IP 
Investigational Product 
IRB 
Institutional Review Board 
IUCD 
Intrauterine Contraceptive Device 
IWRS 
Interactive Web Response System 
LASIK 
Laser-Assisted In Situ Keratomileusis 
LGS 
Lissamine Green Staining 
LogMAR 
Logarithm of the Minimum Angle of Resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGD 
Meibomian Gland Dysfunction 
mm 
Millimeter 
NCS 
Non-Clinically Significant 
NEI 
National Eye Institute 
NSAID 
Non-steroidal anti-inflammatory drug 
OSDI 
Ocular Surface Disease Index 
OTC 
Over the Counter 
OU 
Oculus Uterque (both eyes) 
PDF 
Portable Document Format 
PPS 
Per Protocol Set 
PK 
Pharmacokinetics 
QD 
Once Daily 
SAE 
Serious Adverse Event 
SAF 
Safety Set 
SAR 
Suspected Adverse Reaction 
SOP 
Standard Operating Procedure 
TBUT 
Tear Break-Up Time 
tFCS 
Total Fluorescein Corneal Staining 
UPT 
Urine Pregnancy Test 
VA 
Visual Acuity  
VAS 
Visual Analog Scale 
WOCBP 
Women of Child Bearing Potential 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 17 of 80                                         
CONFIDENTIAL 
  
1. 
INTRODUCTION  
 
Posterior blepharitis is a condition characterized by inflammation of the posterior lid margin.  
The condition may be inclusive of MGD in which there is an alteration in the quality and 
expression of gland secretions (Nelson, 2011). Meibomian gland dysfunction is associated 
with posterior blepharitis, plays an essential role in the health and stability of the tear film and 
in maintaining optimal ocular surface condition. It is recognized as one of the most common 
pathologies seen by Ophthalmologist and is a significant contributor to Evaporative Dry Eye 
(EDE) is further considered the leading cause of Dry Eye Disease (DED) (Nelson, 2011; 
DEWS II Report 2017). Meibomian gland dysfunction is commonly treated on a chronic basis 
(DEWS II Report 2017) via either mechanical therapy (lid hygiene, lid massage and lid 
compression/expression) alone or in combination with topical or systemic antibiotics or 
topical cyclosporine.   
Dry Eye Disease is a widespread dysfunction of the tears and ocular surface and is 
characterized by ocular signs such as inflammation of the ocular surface (Pflugfelder, 1999) 
and tear film instability (Holly, 1973; Bron, 2001; Goto, 2003) resulting in corneal and 
conjunctival epithelial changes. Dry Eye Disease is a dysfunction with etiologies inclusive of 
aqueous deficient and evaporative DED (DEWS II Report 2017). These changes are 
understood to be the underlying basis for EDE in human subjects (Foulks, 2003; DEWS II 
Report 2017).  
A number of studies and reports support the short-term use of topical corticosteroids known to 
be potent anti-inflammatory agents in the treatment of patients with DED (Avunduk et al, 
2003; DEWS II Report 2017; Pflugfelder et al, 1999; Yang et al, 2006).  While topical 
ophthalmic corticosteroids are approved by the Food and Drug Administration (FDA) for 
corticosteroid-responsive inflammatory conditions of the conjunctiva, cornea, and anterior 
globe, they are generally only recommended for short-term use, as prolonged use may result 
in adverse ocular events, including elevated Intraocular Pressure (IOP), cataracts, and ocular 
infection (Becker, 1964; Bowling and Russell, 2011; Dinning, 1976). Short-term 
corticosteroid therapy can serve as both an important adjunct to existing chronic therapies 
(e.g., artificial tears) and can also be used to address environmental and iatrogenic induced 
breakthrough periods of increased ocular surface inflammation (Becker, 1964; Behrens et al, 
2006). 
Pflugfelder and colleagues (Pflugfelder, 2004) demonstrated that a topical corticosteroid may 
achieve the objective of a short-term treatment of acute exacerbations of DED signs or 
symptoms. They evaluated loteprednol etabonate ophthalmic suspension (0.5%) dosed 4 times 
daily versus placebo for the treatment of DED in patients with delayed tear clearance. In 
patients with at least moderate clinical inflammation, significant differences in clinical signs 
(nasal and tarsal hyperemia) between groups were observed as early as Week 2 and persisted 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 18 of 80                                         
CONFIDENTIAL 
  
through Week 4 of the study. In addition, the improvement in the redness Visual Analog Scale 
(VAS) score was consistently 20% better in the loteprednol-treated patients compared with 
the Vehicle-treated patients. 
AxeroVision, Inc. intends to develop AXR-270 Cream, for the treatment of MGD secondary 
to posterior blepharitis. Study AXR201901 will evaluate the safety and tolerability of AXR-
270 Cream in subjects with lid margin inflammation (as characterized by eyelid margin 
hyperemia) due to Meibomian Gland Dysfunction. Additional information about AXR-270 
Cream, including nonclinical pharmacology study results, and potential risks and benefits to 
human subjects, is found in the Investigator’s Brochure. 
AXR-270 was initially in clinical development for asthma, chronic obstructive pulmonary 
disease (COPD) and atopic dermatitis. Early testing was conducted in the European Union 
(EU), under an Investigational Medicinal Product Dossier (IMPD), and consisted of 
evaluation in 24 healthy male volunteers administered via topical administration with the goal 
of identifying any blanching response in the skin at doses up to 4000ng using a method 
described by McKenzie and Stoughton (McKenzie and Stoughton, 1962).  It was later 
delivered via inhalation to 36 healthy male subjects in a dose escalation safety study with both 
single and repeat doses. Additionally, a repeat dose study in 24 male steroid naive asthmatics 
and 36 mild to moderate subjects with mild asthma for one (1) month. AXR-270 was then 
evaluated in 12 healthy adult male subjects for 14 days of oral inhalation and as a dermal 
cream for 42 days in 20 healthy volunteers and for 21 days in 25 patients with moderate or 
severe atopic dermatitis.  
Based on the physicochemical characteristics of AxeroVision’s topical cream formulation, 
reported anti-inflammatory properties of AXR-270 Cream and rationale described above, 
development of AXR-270 Cream is proposed for ophthalmic conditions, such as MGD, in 
which ocular inflammation is thought to be the source of pathology. 
 
1.1. 
DESCRIPTION OF INVESTIGATIONAL PRODUCT 
 
AXR-270 Cream (0.2% and 2.0%) contain AXR-270 as an active pharmaceutical ingredient 
(API).  
The AXR-270 Vehicle control has the same composition as AXR-270 Cream except that it 
does not contain AXR-270.  
 
 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 19 of 80                                         
CONFIDENTIAL 
  
1.2. 
JUSTIFICATION FOR ROUTE OF ADMINISTRATION AND DOSE SELECTION 
 
AXR-270 will be administered as a topical ophthalmic cream. Subjects will receive IP 
administered in the clinic at Day 1/Visit 2 and will then self-administer either AXR-270 
Cream or Vehicle once a day (QD) applied to upper and lower eyelid skin bilaterally for 
approximately 21 days. The concentrations of AXR-270 Cream and dosing schedule were 
chosen based on nonclinical pharmacokinetic and toxicology studies and data reflecting 
relative safety multiples. For details on the pharmacokinetic and toxicology studies and the 
respective safety multiples, see the Investigator’s Brochure.  
 
The purpose of using lid wipes during the Equalization Period (between Visit 1 and Visit 2) is 
to normalize baseline conditions between subjects as much as possible. 
 
For subjects wearing eyelid or eyelash makeup, remove makeup before IP application. (Use of 
eyelid or eyelash makeup may be resumed between clinic visits with the exception of the day 
of study visits). Subjects should be instructed to follow their usual routine to remove eyelid or 
eyelash makeup between Visits 2 and 5 (including eyelid wipes, if applicable), ensuring that 
no new products/techniques are introduced during the treatment period. Each dose of IP 
should be applied onto the upper and lower eyelids (refer to detailed instructions in the 
Subject Dosing Instructions document).  Subjects will also view an instructional video at Visit 
2 demonstrating the proper dosing technique.  
 
Subjects should not wipe away excess cream unless there is a concern of the cream running 
onto the ocular surface. For subjects who wish to apply eyelid makeup, they should wait until 
the next morning before cleaning the eyelids and applying makeup.  
 
1.3. 
GCP COMPLIANCE  
 
This clinical trial will be conducted in compliance with the protocol, International Council on 
Harmonisation (ICH) guidelines, Good Clinical Practice (GCP) guidelines, and other 
applicable regulatory requirements. 
 
1.4. 
POPULATION TO BE STUDIED 
 
Approximately one hundred and twenty-six (126) subjects with a diagnosis of symptomatic 
posterior blepharitis associated with MGD will be enrolled in the trial. 
 
 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 20 of 80                                         
CONFIDENTIAL 
  
2. 
TRIAL OBJECTIVES AND PURPOSE 
2.1. 
OBJECTIVE 
 
The primary objective of this study is to evaluate the safety and tolerability of two 
concentrations (0.2% and 2.0%) of AXR-270 Cream in treating posterior blepharitis 
associated with MGD.   
The secondary objective is to evaluate the efficacy of AXR-270 Cream in treating signs and 
symptoms of posterior blepharitis associated with MGD. 
 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 21 of 80                                         
CONFIDENTIAL 
  
3. 
TRIAL DESIGN 
3.1. 
STUDY ENDPOINTS 
3.1.1. 
Safety Endpoints 
• Adverse events (AE)  
• Best corrected visual acuity (BCVA) 
• Slit-lamp biomicroscopy and external eye exam 
• Intraocular pressure (IOP)  
• Dilated ophthalmoscopy 
• Safety Labs (Hematology, clinical chemistry, and urinalysis)   
3.1.2. 
Efficacy Endpoints 
All efficacy endpoints are exploratory in nature. The following endpoints will be considered 
to assess the efficacy of AXR-270 Cream. 
1. Change from baseline in the following individual subject-reported symptoms using 
VAS (0-100 point scale) in the AXR-270 Cream (0.2% or 2.0%) arms compared to 
Vehicle at Day 22: 
o Eye Discomfort  
o Eye Dryness 
2. Change from baseline in Investigator-rated signs of MGD using individual severity 
scores in AXR-270 Cream arm compared to Vehicle at Day 22:  
o Total MGD Score: the sum of secretion in 5 central glands on each individual 
eyelid will be evaluated, each will be scored from 0-3; 0 = clear/slightly 
yellow, 1 = opaque/yellow, whitish, particulate, 2 = paste; 3 = none/occluded; 
total score will range from 0-15 
o Vascularity of the eyelid margin (Grade 0-4) 
3. Change from baseline in TBUT in AXR-270 Cream arm compared to Vehicle at Day 
22. (Tear Break-up Time is the number of seconds that elapse between the last blink 
and the appearance of the first dry spot in the tear film). 
4. Change from baseline in LGS grade of the eyelid margin in AXR-270 Cream arm 
compared to Vehicle at Day 22. 
5. Change from baseline in tFCS score (NEI/Industry Workshop; 0-15 scale) in the 
AXR-270 Cream arm compared to Vehicle at Day 22. 
6. Change from baseline in FCS by individual region in AXR-270 Cream arm compared 
to Vehicle at Day 22 (0-3 scale). 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 22 of 80                                         
CONFIDENTIAL 
  
7. Change from baseline in bulbar conjunctival hyperemia in AXR-270 Cream arm 
compared to Vehicle at Day 22. 
8. Change from baseline in OSDI score (0-100) in AXR-270 Cream arm compared to 
Vehicle at Day 22. 
9. Change from baseline in the modified BLepharItIS Symptom (BLISS) score in AXR-
270 Cream arm compared to Vehicle at Day 22. 
10. Change from baseline in the Schirmer in AXR-270 Cream arm compared to Vehicle at Day 
22. 
3.2. 
DESCRIPTION OF TRIAL DESIGN 
 
Design and Investigational Plan:   
This is a multi-center, double-masked, randomized, vehicle-controlled, two cohort study. 
Subjects will be randomized into either 0.2% AXR-270 Cream (approximately 42 subjects in 
Cohort 1), 2.0% AXR-270 Cream (approximately 42 subjects in Cohort 2) or Vehicle 
(approximately 42 subjects) administered in both eyes. 
 
Cohort 1: 
Approximately sixty-three (63) subjects with a diagnosis of symptomatic posterior blepharitis 
associated with MGD meeting all inclusion/exclusion criteria at the Screening visit (Visit 1) 
will be asked to discontinue their eyelid hygiene regimen and use only Sponsor supplied 
commercial sterile eyelid wipes between Visit 1 and Visit 2 daily (Equalization Period).  
Subjects will then be evaluated at Baseline/Randomization (Visit 2; Week 0/Day 1) to  
confirm they continue to meet all inclusion/exclusion and are eligible for randomization. 
Note: The use of sponsor-supplied sterile eyelid wipes is to be discontinued after 
randomization at Visit 2. All subjects within this Cohort will be assessed for safety and 
exploratory efficacy. Both Investigator and subjects will be masked as to the IP. Subjects will 
be shown an instructional video on applying the investigational product to help ensure 
consistency in application across subjects. Further, the site should reinforce to the subject how 
to self-administer the IP to the eyelids and avoid ocular instillation. Subjects will self-
administer a pre-specified volume (approximately 50 milligrams per eyelid) of 0.2% AXR-
270 Cream or its Vehicle across the epidermis corresponding to the external surface overlying 
the tarsal plate of the upper and lower eyelids of both eyes. Refer to more detailed instructions 
in the Subject Dosing Instructions document. Blood draws for safety labs for all subjects will 
be performed prior to IP dosing in the clinic at Visit 2/Day 1. Following the in-clinic dose 
administration, subjects will be supplied with sufficient IP (2 tubes) to apply once daily at 
home in the evening during the treatment period. Subjects will self-administer IP QD in the 
evenings beginning on Day 2.  
 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 23 of 80                                         
CONFIDENTIAL 
  
On the following week (Visit 3; Week 1/Day 8), the Investigators will examine the subject 
and perform all safety and efficacy assessments (excluding safety labs and dilated 
Ophthalmoscopy).  
 
Subjects will return for a Week 2 (Visit 4; Day 15) visit, wherein the Investigators will 
examine the subject and perform all safety and efficacy assessments (excluding safety labs 
and dilated Ophthalmoscopy). Subjects will return the used IP and will be instructed to use the 
2nd IP tube dispensed at Visit 2 to apply once daily at home in the evening for the remaining 1 
week of treatment duration. 
 
Following the completion of the fifteenth (15th) subject from Visit 4 of Cohort 1, the Data 
Safety Review Committee (DSRC) will meet to review safety data and will make a 
recommendation about whether to escalate to the higher (2.0%) dose of AXR-270 Cream for 
Cohort 2, which if recommended, will begin immediately upon completion of enrollment in 
Cohort 1. 
 
Subjects will return for a Week 3 (Visit 5; Day 22) visit, wherein the Investigators will 
examine the subject and perform all safety and efficacy assessments (including safety labs). 
Subjects should not dose at Visit 5/Day 22 and following the visit, subjects and will exit the 
study. Remaining IP will be collected from every subject. (See Appendix 1 for procedures 
planned for this study). 
 
FIGURE 1: STUDY SCHEMATIC (COHORT 1) 
 
 
 
Note: Cohort 2 (AXR-270 2.0% Cream or vehicle) follows the same visit schedule as above and will 
start enrolling once enrollment of Cohort 1 is complete.  
 
Cohort 2: 
Following the completion of the fifteenth subject from Visit 4 of Cohort 1, the DSRC will 
meet to review safety data and will make a recommendation about whether to escalate to the 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 24 of 80                                         
CONFIDENTIAL 
  
higher (2.0%) dose of AXR-270 Cream for Cohort 2, which if recommended, will begin 
immediately upon completion of enrollment in Cohort 1. 
 
The Screening and study visits will be conducted in the same fashion as described above for 
Cohort 1. Approximately sixty-three (63) subjects will be randomized to 2.0% AXR-270 
Cream or its Vehicle.  A study schematic follows (Figure 1). 
 
3.2.1. 
Investigational Product 
The AXR-270 Cream IP is a sterile, water in oil, cream formulation in which micronized 
AXR-270 Active Pharmaceutical Ingredient (API) is suspended uniformly for topical 
application to the upper and lower eyelids at either 0.2% or 2.0% concentrations. 
 
The IP is packaged in laminated polyfoil tubes. Each tube will contain 5g of sterile AXR-270 
topical cream. Subjects randomized to the Vehicle control arm will receive the same 
containers containing all components at the concentrations used in the AXR-270 Cream 
except for the active component. 
 
The product composition is presented in Table 1.  
 
Table 1: Composition of AXR-270 Investigational Product (0.2% and 2.0% 
Concentrations, Vehicle) 
Material 
Grade 
Function 
Vehicle 
Formula 
(% w/w) 
0.2% AXR-
270 Cream 
Formula 
(% w/w) 
2.0% AXR-
270 Cream 
Formula 
(% w/w) 
White 
Petrolatum 
USP 
Vehicle 
47.89 
47.69 
45.89 
Emulsifier 10 
N/A 
Emulsifier 
3.30 
3.30 
3.30 
ST- Elastomer 
10 
N/A 
Emulsifier 
2.00 
2.00 
2.00 
Mineral Oil 
USP 
Vehicle 
8.00 
8.00 
8.00 
ST- 
Cyclomethicone 
5-NF 
NF 
Emollient 
6.60 
6.60 
6.60 
Propylene 
Glycol 
USP 
Solvent 
8.00 
8.00 
8.00 
Methylparaben 
NF 
Preservative 
0.08 
0.08 
0.08 
Propylparaben 
NF 
Preservative 
0.02 
0.02 
0.02 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 25 of 80                                         
CONFIDENTIAL 
  
Sterile Water for 
Irrigation 
USP 
Vehicle 
24.00 
24.00 
24.00 
Anhydrous Citric 
Acid 
USP 
Buffer 
0.05 
0.05 
0.05 
Dibasic Sodium 
Phosphate 
USP 
Buffer 
0.06 
0.06 
0.06 
 
Each randomized, double-masked IP kit contains 3 tubes of IP, each tube sufficient for 2 
weeks of dosing.   
IP Dispensation Instructions 
At Visit 2, randomized subjects will be assigned to an IP Kit which contains three tubes of 
Double-Masked IP (AXR-270 Cream or Vehicle). The first dose of Double-Masked IP (AXR-
270 Cream or Vehicle) will be self-administered by the subject at Visit 2 under supervision of 
the site staff. 
AXR-270 Cream should be stored at 2° to 8°C (36° to 46°F); excursions permitted between 0° 
and 15°C (32° and 59°F). Transient spikes up to 25°C (77°F) and not to exceed 24 hours are 
permitted. IP should be protected from light and moisture. The refrigerator will be 
temperature monitored. IP will be supplied to subjects in coolers with gel packs to maintain 
refrigerated temperature while in transit. 
 
Timing of Self-Administration 
At Visit 2, sufficient training will be provided to the subjects to self-administer their once-
daily dose of double-masked IP. Subjects will then self-administer additional doses of IP at 
home for the remainder of the study. Two tubes of randomized double-masked IP will be 
dispensed to each subject at Visit 2 for self-administration. The first tube will be used from 
the time of Visit 2 to the time of Visit 4. The second IP tube will be used from Visit 4 to Visit 
5 (note: if a subject is unable to come in to the clinic for Visit 4, they should begin dosing 
with the second tube on Day 15).  One tube from the kit will be kept in reserve at the clinic. 
Refer to more detailed instructions in the Subject Dosing Instructions document. 
 
3.2.2. 
Methods to Minimize Bias 
To minimize bias, the following measures will be taken: 
• IP allocation (AXR-270 Cream versus Vehicle) will be randomized and masked to the 
Sponsor, subjects, and investigative staff. 
• The randomization schedule will be generated by an independent unmasked 
statistician (who is not on the project team) or designee and maintained in a secure and 
limited-access location separate from the study Investigator and members of the 
project team. 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 26 of 80                                         
CONFIDENTIAL 
  
4. 
SELECTION OF SUBJECTS 
4.1. 
SUBJECT INCLUSION CRITERIA 
 
At Visit 1 (and Visit 2 where applicable), individuals of any gender or any race will be 
eligible for study participation if they: 
1. Have provided written informed consent prior to any study procedures. 
2. Are 18 years of age or above. 
3. Have a clinical diagnosis of moderate to severe MGD and who meet both of the 
following criteria, in at least one qualifying eyelid (upper and lower eyelid for each 
eye that will be evaluated independently), at both Visit 1 (Screening) and again in the 
same eye/eyelid Visit 2 (Randomization) examinations: 
a) Total MGD score ≥5 and ≤14 (the sum of secretion 5 central glands on the 
upper and lower eyelids will be evaluated, each will be scored from 0-3; 0 = 
clear/slightly yellow, 1 = opaque/yellow, whitish, particulate, 2 = paste, 3 = 
none/occluded; total score will range from 0-15) and  
b) Clinical sign severity score of at least 2 (moderate) on vascularity of the eyelid 
margin  
4. Have a score of ≥35 in Eye Discomfort VAS (0-100 point scale) at both Visit 1 and 
Visit 2. 
5. Meet the following criteria, in both or the same qualifying eye as in Inclusion #3, at 
both Visit 1 (Screening) and Visit 2 (Randomization) examinations: 
1. tFCS score ≥3 and ≤14 (NEI/Industry Workshop scale; 0-15 scale) 
2. Schirmer score of >7 mm without topical anesthesia 
6. OSDI score >30 at both Visit 1 and Visit 2. 
7. Required use of non-prescription (OTC) artificial tear substitute for symptoms of dry 
eye more than 3 times per day for 3 consecutive days within 30 days prior to the 
Screening Visit (Visit 1) and willingness to suspend use of tear substitutes at Visit 1 
and for the duration of study participation. 
8. Are willing and able to follow instructions and willing to be present for the required 
study visits for the duration of the study.  
9. Have a LogMAR BCVA equal to or better than +0.7 using corrective lenses if 
necessary, in both eyes at both Visit 1 and Visit 2, by Early Treatment of Diabetic 
Retinopathy Study (ETDRS) or modified ETDRS. 
10. If female, are non-pregnant, non-lactating and women of childbearing potential 
(WOCBP) must be using an acceptable method of birth control [e.g., an Intrauterine 
Contraceptive Device (IUCD) with a failure rate of <1%, hormonal contraceptives, or 
a barrier method] for the duration of the study. If a female subject is currently 
abstinent, they must agree to use one of the acceptable methods of birth control before 
they become sexually active. 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 27 of 80                                         
CONFIDENTIAL 
  
• A non-childbearing potential is defined as a woman who is postmenopausal for 
12 consecutive months or a woman who is post hysterectomy, bilateral 
oophorectomy or 3 months status post bilateral tubal ligation. 
 
4.2. 
SUBJECT EXCLUSION CRITERIA 
 
In order for subjects to be eligible at Visit 1 they may not: 
 
1. Have presence or history of iritis/uveitis in either eye. 
2. Have lid structural abnormalities including but not limited to entropion or ectropion 
that in the opinion of the Investigator may confound the study data.  
3. In the study eyelid, have greater than 4 glands that are not expressible from the 5 
upper and/or 5 lower eyelid meibomian glands at both Visit 1 and Visit 2. 
4. Subjects with ocular inflammatory conditions (e.g., conjunctivitis, keratitis, severe 
anterior blepharitis, etc.) not related to MGD. 
5. Subjects who in the study eye have tFCS total score = 15 or a FCS score = 3 in either 
eye in the superior region NEI/Industry Workshop scale or subjects who have FCS 
with diffuse confluent staining, filaments or frank epithelial defects at either Visit 1 or 
Visit 2. 
6. Have suspected ocular fungal, viral or bacterial infection.  
7. Subjects who within the past 6 months have had cauterization of the punctum. Non-
dissolvable plugs must not be inserted within 2 weeks of Screening (Visit 1) and 
current non-dissolvable plugs in position must be stable in the Investigator's opinion. 
8. Use of any of the prohibited medications (see Table 2: List of Prohibited Medications 
and/or procedures) within a time period prior to or upon Screening (Visit 1). NOTE: 
These medications may not be used after Visit 1 through the end of the study. 
Table 2:  List of Prohibited Medications and/or Procedures  
Medication 
Minimum 
Washout 
Period Prior 
to Screening 
(Visit 1) 
Have had incisional ocular surface surgery (e.g., LASIK, 
refractive, pterygium removal) 
12 months 
Penetrating intraocular surgery 
90 days 
Topical ocular or systemic antibiotics for the treatment of an 
ocular condition 
30 days 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 28 of 80                                         
CONFIDENTIAL 
  
Topical cyclosporine 
30 days 
Lifitegrast 
30 days 
Systemic corticosteroids (oral, injectable, inhaled, and nasal) 
30 days 
Topical ocular corticosteroids, ocular non-steroidal anti-
inflammatory drugs (NSAIDs), and topical dermatologic 
corticosteroids on the face within 30 days prior to Visit 1 
and during study participation.  Topical dermatologic 
corticosteroids not used on the face are allowed if applied to 
less than 3 areas for less than 3 consecutive days 
30 days 
Topical ocular antihistamine and/or mast cell stabilizers 
within 30 days prior to Visit 1 or during study participation.  
Have used topical ocular vasoconstrictors for the purpose of 
eye whitening within 30 days prior to Visit 1 (phenylephrine 
used to dilate the eyes is allowed) 
30 days 
Treatments for MGD including but not limited to thermal 
pulsation (Lipiflow), debridement of lid margin 
(BlephEx), thermal application (MeiBoFlo, Tear Care), or 
meibomian gland probing 
30 days 
All topical ophthalmic gels, ointments or drops (including 
artificial tears) and the TrueTear® Stimulator 
2 days 
Contact Lenses 
At Screening 
 
9. Use short-term dissolvable plugs for 3 months prior to Screening (Visit 1) and long-
term dissolvable plugs within 6 months prior to Screening (Visit 1). 
10. Any prior use of isotretinoin. 
11. Are unwilling to discontinue use of cosmetic makeup applied to the eyelids or 
eyelashes on the day of a study visit after Visit 1. 
12. Have a known hypersensitivity to active ingredient or to any of the other ingredients in 
the IP. 
13. Are unable or unwilling to withhold the use of eyelid scrubs or use of mechanical 
eyelid cleaning therapy during the study, other than the Sponsor supplied commercial 
sterile eyelid wipes from Visit 1 through Visit 2. After Visit 2, subjects are also 
permitted to follow their usual routine to remove eyelid or eyelash makeup (including 
eyelid wipes), ensuring that no new products/techniques are introduced during the 
study.   
14. Have been diagnosed with glaucoma, are currently using any glaucoma medication or 
known to have elevated IOP related to steroid use. 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 29 of 80                                         
CONFIDENTIAL 
  
15. Have a history of herpetic keratitis. 
16. Have a concomitant ocular pathology other than condition under study assessed as 
potentially confounding by the Investigator. 
17. Have a serious systemic disease or uncontrolled medical condition that in the 
judgment of the Investigator could confound study assessments or limit compliance. 
18. Have been exposed to any investigational drug or investigational device within the 
preceding 30 days. 
19. Are an employee of the site that is directly involved in the management, 
administration, or support of this study or be an immediate family member of the 
same. 
20. Have trigger factors that in the opinion of the Investigator may confound the data, 
including but not limited to conjunctivochalasis, allergic conjunctivitis, contact lens 
intolerance, trichiasis, epithelial basement membrane dystrophy, infectious keratitis or 
conjunctivitis. 
21. Have a documented history of ocular allergies, which, in the judgment of the 
Investigator, are likely to have an acute increase in severity due to the expected timing 
of the exposure to the allergen to which the subject is sensitive. Subjects sensitive to 
seasonal allergens that are not expected to be present during the study are permitted. 
 
4.3. 
STUDY EYE/EYELID 
The study eye/eyelid is the eye with the eyelid having the worst (higher) score defined as 
the sum of the following two severity scores for the clinical signs of MGD:   
1. Vascularity of eyelid margin  
2. Total MGD Score 
If both eyes, and eyelids, have the same score, then select the right eye and upper eyelid. 
 
4.4. 
RANDOMIZATION 
At the Randomization Visit (Visit 2), an eligible subject must continue to meet all 
clinical inclusion/exclusion criteria as defined in Sections 4.1 and 4.2. Note: Subjects 
must meet all criteria from Visit 2 eye/eyelid specific criteria in the same qualifying 
eye and/or qualifying eyelid as in Visit 1. 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 30 of 80                                         
CONFIDENTIAL 
  
5. 
PROCEDURES 
 
Written Informed Consent and Health Insurance Portability and Accountability Act (HIPAA) 
authorization will be obtained from all subjects prior to any study procedures being 
performed. Visit assessments will be performed in the order suggested in both eyes. 
 
5.1. 
VISIT DESCRIPTIONS  
 
NOTE: In light of the Coronavirus Disease 2019 (COVID-19) pandemic, the site should 
utilize risk mitigation techniques for all in-clinic visits as described by the American 
Academy of Ophthalmology (Appendix 17). 
 
5.1.1. 
Visit 1 (Screening):  Day minus 14 (±2 days) prior to Visit 2 
The following will be performed/assessed in the order suggested below and in both eyes:  
• Explain the purpose and conduct of the study to the subject, answer the subject’s 
questions, and obtain written informed consent. 
• Obtain information including demographics, concomitant medications, ocular and 
systemic medical and medication history and surgical history.*  
• Evaluate eligibility 
• A Screening Identification (ID) should be assigned to the Subject once any Visit 1 
procedures (other than ICF) are performed. The Subject ID format will be XXX-
001 where XXX represents the site number and the last three digits represent the 
unique subject number. 
• Subject-rated symptom assessments (in this order):   
o 
Individual Symptom Assessment via VAS  
o 
OSDI 
o 
Modified BLISS  
• Urine Pregnancy Test (UPT) for all eligible women of childbearing potential. * 
• For subjects presenting at Visit 1 or Visit 2 with makeup applied to the eyelids or 
eyelashes, subjects should use a Sponsor provided lid scrub to remove the makeup. 
(Subjects may resume using makeup between study visits but not on the day of a 
study visit). Study specific testing related to the evaluation of the eye and eyelids 
should start 15 minutes after makeup removal. 
• For subjects presenting at any post-randomization visit with makeup applied to the 
eyelids or eyelashes, the site staff should use the Sponsor provided lid scrub to 
remove the eyelid makeup. Care should be taken not to aggressively clean the lid 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 31 of 80                                         
CONFIDENTIAL 
  
margin with the lid scrub and only to gently remove any remaining makeup from 
the skin surface. 
• BCVA 
• Slit-lamp biomicroscopy and external eye exam 
• TBUT 
• FCS 
• Investigator-rated assessment of MGD (in both eyes for upper and lower lids)  
o 
See Appendix 3. Assessment of Efficacy for full description of 
Investigator-rated assessments for objective signs of change from baseline  
• LGS (at a subset of sites) 
• Wait 15-20 minutes after LGS before proceeding 
• Unanesthetized Schirmer test 
• IOP 
• Dilated Ophthalmoscopy 
• Determine if the subject is eligible to continue in the study. Do not continue 
screening any subject who does not meet eligibility requirements. Any subject who 
does not meet eligibility requirements will be designated as a Screen Failure.  
• Instruct the subject to discontinue using all prohibited medications for the 
remainder of the study. 
• If the subject is qualified, a four-week supply of commercial lid wipes will be 
provided. 
• Schedule the subject to return for Visit 2 (Day 1) and remind subjects to bring the 
remaining lid wipes to Visit 2. 
* May be performed at any time during the visit in order to facilitate subject and site 
schedules. 
 
5.1.2. 
Visit 2 (Randomization):  Day 1  
Visit 2 will occur 14 (±2 days) after Visit 1 (Screening). The following will be 
performed/assessed in both eyes:  
• Evaluate continued eligibility 
• Subject-rated symptom assessments (in this order):   
o Individual symptom assessment via VAS 
o OSDI 
o Modified BLISS 
• Use of any concomitant medications since the last visit 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 32 of 80                                         
CONFIDENTIAL 
  
• Occurrence of any AEs since the last visit  
• BCVA 
• Slit-lamp biomicroscopy and external eye exam 
• TBUT 
• FCS 
• Investigator-rated assessment of signs of MGD  
o  See Appendix 3. Assessment of Efficacy for full description of 
Investigator-rated assessments for objective signs of change from baseline  
• LGS (at a subset of sites) 
• Wait 15-20 minutes after LGS before proceeding 
• Unanesthetized Schirmer test 
• IOP 
• Safety laboratory blood draw 
• Determine if subject is eligible for randomization 
For eligible subjects, the following is the process regarding administration of Double-Masked 
IP whereby the trained site staff will conduct the following procedures: 
• Enter subject information into IWRS to determine randomization code and Kit 
Number. Cohort 1 versus Cohort 2 will be part of the Interactive Web Response 
System (IWRS) input 
• Show the subjects an instructional video on applying the investigational product. 
Review Subject Dosing Instructions document, reiterating that the subject should 
administer IP across the entire surface (corresponding to the tarsal plate) of the 
upper and lower eyelids of both eyes 
• Subject will self-administer first dose of double-masked IP in clinic under the 
supervision of site staff. The site staff will record the Day 1 dosing time in the 
source document.  
• Assess for occurrence of any IP related AEs 
• The subject will complete the IP Comfort Assessment in the clinic approximately 
2 minutes following administration. Site will document in the source document.  
• Dispense three Daily Dosing Diaries (including IP Comfort Assessment) to the 
subject. Note: each diary will contain sufficient entries for approximately one 
week of dosing 
• Instruct subject to bring completed diaries, cooler/gel packs and used/unused IP to 
each subsequent clinic visit 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 33 of 80                                         
CONFIDENTIAL 
  
• Dispense two tubes of IP to the subject and instruct the subject to open only one 
tube initially and apply once daily at home in the evening beginning on Day 2  
• Dispense a cooler and gel packs to the subject for the purpose of transporting IP.  
Remind the subject to store the IP and the gel packs in the refrigerator at home and 
to use the cooler/refrigerated gel packs any time IP is transported including 
to/from study visits 
• Reinforce the subject instructions to administer IP across the entire surface of the 
upper and lower eyelids of both eyes QD and to record each administration and IP 
Comfort Assessment on the daily dosing diary 
• Remind subjects to discontinue the use of eyelid wipes for the remainder of 
the study except if used for routine makeup removal. Collect Sponsor-provided 
eyelid wipes from the subject   
• Schedule the subject to return for Visit 3 (Day 8 ±2 days) 
 
5.1.3. 
Visit 3: Day 8 (±2 days) 
This visit will occur on Day 8 as calculated from Visit 2: Day 1, and the following will be 
performed in both eyes:  
• Subject-rated symptom assessments (in this order):   
o Individual Symptom Assessment via VAS 
o OSDI 
o Modified BLISS 
• Use of any concomitant medications since the last visit 
• Occurrence of any AEs since the last visit  
• Review/collect Daily Dosing Diary #1 (including IP Comfort assessment) to assess 
compliance  
• BCVA 
• Slit-lamp biomicroscopy and external eye exam 
• TBUT 
• FCS 
• Investigator-rated assessment of signs of MGD  
o  See Appendix 3. Assessment of Efficacy for full description of 
Investigator-rated assessments for objective signs of change from baseline  
• LGS (at a subset of sites) 
• Wait 15-20 minutes after LGS before proceeding 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 34 of 80                                         
CONFIDENTIAL 
  
• Unanesthetized Schirmer test 
• IOP 
• Reinforce the subject instructions to administer IP across the entire surface of the 
upper and lower eyelids of both eyes QD and to record each administration and IP 
comfort assessment on the daily dosing diary. 
• Schedule the subject to return for Visit 4 (Day 15 ±3 days). 
 
5.1.4. 
Visit 4: Day 15 (±3 days) 
This visit will occur on Day 15 as calculated from Visit 2: Day 1, and the following will be 
performed in both eyes:  
• Subject-rated symptom assessments (in this order):   
o Individual Symptom Assessment via VAS 
o OSDI 
o Modified BLISS 
• Use of any concomitant medications since the last visit 
• Occurrence of any AEs since the last visit  
• Review/collect Daily Dosing Diary #2 (including IP Comfort assessment) to assess 
compliance  
• Collect used tube of double-masked IP and remind subject to begin dosing with 
second tube 
• BCVA 
• Slit-lamp biomicroscopy and external eye exam 
• TBUT 
• FCS 
• Investigator-rated assessment of signs of MGD  
o See Appendix 3. Assessment of Efficacy for full description of 
Investigator-rated assessments for objective signs of change from baseline  
• LGS (at a subset of sites) 
• Wait 15-20 minutes after LGS before proceeding 
• Unanesthetized Schirmer test 
• IOP 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 35 of 80                                         
CONFIDENTIAL 
  
• Reinforce the subject instructions to administer IP across the entire surface of the 
upper and lower eyelids of both eyes QD and to record each administration and IP 
comfort assessment on the daily dosing diary. 
• Schedule the subject to return for Visit 5 (Day 22 ±3 days). 
• NOTE:  For Cohort 1, when the first 15 subjects across all study sites have 
completed Visit 4, the DSRC will convene to review data and make 
recommendation regarding escalation to Cohort 2. 
 
5.1.5. 
Visit 5:  Day 22 (±3 days) 
This visit will occur on Day 22 as calculated from Visit 2: Day 1, and the following will be 
performed in both eyes:  
• Subject-rated symptom assessments (in this order):   
o Individual Symptom Assessment via VAS 
o OSDI 
o Modified BLISS 
• UPT (women of childbearing potential) 
• Use of any concomitant medications since the last visit 
• Occurrence of any AEs since the last visit  
• Review/collect Daily Dosing Diary #3 (including IP Comfort assessment) to assess 
compliance  
• BCVA  
• Slit-lamp biomicroscopy and external eye exam 
• TBUT 
• FCS 
• Investigator-rated assessment of signs of MGD  
o  See Appendix 3. Assessment of Efficacy for full description of 
Investigator-rated assessments for objective signs of change from baseline  
• LGS (at a subset of sites) 
• Wait 15-20 minutes after LGS before proceeding 
• Unanesthetized Schirmer test 
• IOP 
• Dilated Ophthalmoscopy 
• Safety Laboratory blood draw 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 36 of 80                                         
CONFIDENTIAL 
  
• Collect tube of double-masked IP and coolers/gel packs from the subject  
• All subjects will be discharged from the study at this visit  
 
5.1.6. 
Unscheduled Visit 
 
Any visits or procedures performed beyond those specified within the protocol must be 
documented in the Unscheduled Visit pages of the electronic case report form (eCRF). 
Unscheduled visits may include but are not limited to reporting AEs, changes in concomitant 
medications, or ophthalmic assessments as deemed appropriate by an appropriately qualified 
physician.   
 
5.1.7. 
Early Termination Visit 
 
In the event of termination prior to Visit 5, every attempt will be made to ensure that all the 
following Visit 5 assessments are performed in both eyes at the Early Termination Visit prior 
to discharge from the study:  
 
• Subject-rated symptom assessments (in this order): 
o Individual symptom assessments via VAS 
o OSDI 
o Modified BLISS 
• Use of any concomitant medications since the last visit 
• Occurrence of any AEs since the last visit 
• Collect all used/unused IP and review/collect Daily Dosing Diaries (including IP 
Comfort assessment) to assess compliance  
• UPT 
• BCVA 
• Slit-lamp biomicroscopy and external eye exam 
• TBUT 
• FCS 
• Investigator-rated assessment of MGD 
o  See Appendix 3. Assessment of Efficacy for full description of 
Investigator-rated assessments for objective signs of change from baseline  
• LGS (at a subset of sites) 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 37 of 80                                         
CONFIDENTIAL 
  
• Wait 15-20 minutes after LGS before proceeding 
• Unanesthetized Schirmer test  
• IOP measurement 
• Dilated Ophthalmoscopy 
• Safety Laboratory blood draw 
Include subject withdrawal criteria (i.e., terminating IP treatment/trial treatment).  
5.2. 
SUBJECT WITHDRAWAL AND/OR DISCONTINUATION  
 
Any subject who wishes to discontinue IP use or withdraw from participation in the study for 
any reason is entitled to do so without obligation. The Investigator may also discontinue any 
subject from IP use or from study participation, if deemed necessary.  
 
Investigational product use may be discontinued, and any subject may be discontinued from 
study participation at any time during the study at the discretion of the Investigator or the 
Sponsor for any reason including but not limited to: 
 
1. Occurrence of any medical condition or circumstance that exposes the subject to 
substantial risk and/or does not allow the subject to adhere to the requirements of the 
protocol. 
2. Any Serious Adverse Event (SAE), clinically significant AE, severe laboratory 
abnormality, intercurrent illness, or other medical condition that indicates to the 
Investigator that continued participation is not in the best interest of the subject. 
3. Subject's decision to withdraw. 
4. Any woman who becomes pregnant while participating in the study. Information on 
the pregnancy and outcome will be requested. 
5. Subject’s failure to comply with protocol requirements or study related procedures. 
6. Termination of the study by the Sponsor, FDA, or other regulatory authorities. 
 
In the event study discontinuation of a randomized subject is necessary, the Investigator 
should make every attempt to have the subject complete Visit 5 assessments. If a non-serious 
AE is unresolved at the time of the subject’s final study visit, an effort will be made to follow 
up until the AE is resolved or stabilized, the subject is lost to follow-up, or there is some other 
resolution of the event. The Investigator should make every attempt to follow all SAEs to 
resolution. The reason for premature discontinuation should be entered into the eCRF and 
recorded in the subject chart. 
 
Subjects who withdraw from the study will not be replaced. 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 38 of 80                                         
CONFIDENTIAL 
  
 
Additionally, the trial or parts of the trial may be discontinued by the Sponsor or at the 
recommendation of the Investigator after consultation with AxeroVision, Inc. This may be 
based on a significant number of AEs of a similar nature that warrant such action.    
 
 
 
5.3. 
COLLECTION OF DATA 
 
Source documentation for data collected in this study will be maintained at the investigative 
site. In cases where no source will be used (e.g., dosing diary), it will be noted in the 
Investigator files. The CRF will be electronic (eCRF) and data will be entered from source 
documentation into the eCRF. After study completion, an archival copy [e.g., Portable 
Document Format (PDF)] of the eCRF data will be retained by the site. 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 39 of 80                                         
CONFIDENTIAL 
  
6. 
TREATMENT OF SUBJECTS 
6.1. 
INVESTIGATIONAL PRODUCTS TO BE ADMINISTERED 
 
All subjects meeting Randomization criteria at Visit 2 will be randomized to either AXR-270 
Cream (0.2% or 2.0%) or Vehicle. Two tubes of randomized double-masked IP will be 
dispensed to each subject at Visit 2 for self-administration (with one tube from each kit 
remaining at the site to serve as a back-up). The first tube will be used from the time of Visit 2 
to the time of Visit 4. The second IP tube will be used from Visit 4 to Visit 5 (note: if a 
subject is unable to come to the clinic for Visit 4, they should begin dosing with the second 
tube on Day 15). The first used tube of IP will be returned to the site at Visit 4. The second 
used tube of IP will be returned at Visit 5. The IP will be stored at the site in a secure area 
with limited access at controlled refrigerated temperature 2° to 8°C [36° to 46°F] with 
excursions permitted between 0° and 15°C [32° and 59°F]. Transient spikes up to 25°C (77 
°F) and not to exceed 24 hours are permitted. The refrigerator will be temperature monitored. 
IP will be supplied to subjects in coolers with gel packs to maintain refrigerated temperature 
while in transit.  
Subjects will be asked to administer IP QD in the evening (except on Day 1 when IP will be 
administered during the office visit). It is important that IP is applied to the full eyelid as per 
detailed instructions in the Subject Dosing Instructions document. Subjects should be 
instructed to wash hands thoroughly prior to and after administration of IP. 
The subjects will record the date and time of administration of each dose of IP at the time of 
instillation in a dosing diary. Compliance with application of IP will be reviewed and assessed 
at Visit 3 through Visit 5. 
 
6.2. 
CONCOMITANT MEDICATIONS 
 
All medications that the subject has taken 1 month prior to Visit 1 and through Visit 5 or 
discontinuation from the study will be recorded in the eCRF and the subject chart. The 
generic name of the drug, dose, route of administration, duration of treatment (including start 
and stop dates), frequency, indication, and whether or not the medication was taken due to an 
AE will be recorded for each medication. 
 
6.2.1. 
Permitted Medications and Therapies 
 
Medications and therapies not specifically excluded in Section 6.2.2 may be taken as 
necessary.   
 
Omega-3 supplements are permitted if the dose is stable within 3 months of Visit 1 and 
expected to remain stable for the duration of the study. 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 40 of 80                                         
CONFIDENTIAL 
  
 
6.2.2. 
Medications and Procedures Not Permitted 
Medication 
Minimum Washout 
Period Prior to 
Screening (Visit 1) 
Have had incisional ocular surface surgery (e.g., LASIK, refractive, 
pterygium removal) 
12 months 
Penetrating intraocular surgery 
90 days 
Topical ocular or systemic antibiotics for the treatment of an ocular 
condition 
30 days 
Topical cyclosporine 
30 days 
Lifitegrast 
30 days 
Systemic corticosteroids (oral, injectable, inhaled, and nasal) 
30 days 
Topical ocular corticosteroids, ocular non-steroidal anti-inflammatory 
drugs (NSAIDs), and topical dermatologic corticosteroids on the face 
within 30 days prior to Visit 1 and during study participation. Topical 
dermatologic corticosteroids not used on the face are allowed if applied to 
less than 3 areas for less than 3 consecutive days 
30 days 
Topical ocular antihistamine and/or mast cell stabilizers within 30 days 
prior to Visit 1 or during study participation. Have used topical ocular 
vasoconstrictors for the purpose of eye whitening within 30 days prior to 
Visit 1 (phenylephrine used to dilate the eyes is allowed) 
30 days 
Treatments for MGD including but not limited to thermal pulsation 
(Lipiflow), debridement of lid margin (BlephEx), thermal application 
(MeiBoFlo, Tear Care), or meibomian gland probing 
30 days 
All topical ophthalmic gels, ointments or drops (including artificial tears) 
and the TrueTear® Stimulator 
2 days 
Contact Lenses 
At Screening 
 
From Visit 2: 
• Eyelid scrubs (unless used as part of subject’s routine eye make-up removal practice) 
or use of mechanical therapy. 
 
6.3. 
INVESTIGATIONAL PRODUCT USE COMPLIANCE 
 
Compliance will be assessed by comparing IP accountability records with the dosing 
information recorded daily in the daily dosing diary by the subject. Trained Site Coordinator 
will document this comparison along with verification of returned used and unused IP tubes. 
The number of missed doses as assessed at each clinic visit should be documented in the 
eCRF. 
 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 41 of 80                                         
CONFIDENTIAL 
  
6.4. 
DRUG ACCOUNTABILITY 
 
Sponsor study monitors or designees will conduct accountability of IP (AXR-270 Cream or 
Vehicle). Accountability will be ascertained by performing reconciliation between the number 
of kits/tubes sent to the site, accounted for at the time of reconciliation during routine 
monitoring and at the end of the study. 
 
Clinical trial materials will be shipped to the investigational sites under sealed conditions. 
Shipment records will be verified by comparing the shipment inventory sheet to the actual 
quantity of drug received at the site. Accurate records of receipt and disposition of the IP 
(e.g., dates, quantity, subject number, dose dispensed, returned) must be maintained by the 
Investigator or his/her designee. The Subject ID format will be XXX-001, where XXX 
represents the site number and the last three digits represent the unique subject number.  
 
At the end of the study, all study materials, including any used and unused IP (AXR-270 
Cream or Vehicle kits), as well as original tube containers (even if empty), will be destroyed 
or returned to the Sponsor (or designee) in accordance with Sponsor or designee’s Standard 
Operating Procedures (SOPs), following approval by the Sponsor. All returns of IP will be 
documented. The study monitor or designee will verify drug accountability. All drug 
accounting procedures must be completed before the study is considered complete. 
 
6.5. 
MAINTENANCE OF RANDOMIZATION AND PROCEDURE FOR BREAKING THE CODE 
 
The Sponsor, the project teams at the designated Contract Research Organizations (CROs), 
and investigative staff responsible for assessments of study endpoints will be masked to IP 
assignments. In the absence of medical need, the randomization code will not be available to 
the above individuals until after the study is completed and the database is locked. 
 
In the event of a medical need, the Investigator will treat each subject as needed. Since there 
is no specific antidote to AXR-270 Cream, immediate emergency unmasking is not necessary. 
If the Investigator feels it is necessary to unmask a subject’s assignment after an emergency 
situation, the Investigator may call the Medical Monitor and notify the Sponsor. The IP 
assignment will be revealed on a subject-by-subject basis with the approval of the Medical 
Monitor and Sponsor, thus leaving the masking of the remaining subjects intact. 
 
A randomization code will be computer-generated by AxeroVision, Inc. or designee. 
Randomization team members will work independently of other team members at the CRO. 
Study personnel, study subjects, the Sponsor, and project teams at the CROs involved in the 
study will be masked to IP assignments. 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 42 of 80                                         
CONFIDENTIAL 
  
7. 
ASSESSMENT OF EFFICACY 
 
Efficacy assessments include the following: 
• OSDI 
• Modified BLISS 
• Individual Symptom Assessments via VAS: 
o Eye Discomfort 
o Eye Dryness 
• LGS (at a subset of sites) 
• FCS  
• Unanesthetized Schirmer Test 
• TBUT  
• Bulbar conjunctiva hyperemia grading 
• Investigator-rated assessment of objective signs including change from baseline (Visit 
2/Day 1) for: 
1. Total MGD Score 
2. Vascularity of the eyelid margin 
 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 43 of 80                                         
CONFIDENTIAL 
  
8. 
ASSESSMENT OF SAFETY 
8.1. 
SAFETY PARAMETERS 
 
Safety parameters include: 
• AE Monitoring 
• BCVA  
• Slit-lamp biomicroscopy and external eye exam  
• IOP  
• Dilated Ophthalmoscopy  
• Safety lab draw 
 
8.2. 
ADVERSE EVENT DEFINITIONS 
 
Adverse Event (AE):  Any untoward medical occurrence associated with the use of an IP in 
humans, whether or not considered drug related.  
 
Adverse Reaction (AR): Any AE caused by a drug. Adverse reactions are a subset of all 
suspected adverse reactions where there is reason to conclude that the drug caused the event.  
 
Suspected Adverse Reaction (SAR): Any AE for which there is a reasonable possibility that 
the drug caused the AE. For the purposes of IND safety reporting, “reasonable possibility” 
means there is evidence to suggest a causal relationship between the drug and the AE. A SAR 
implies a lesser degree of certainty about causality than adverse reaction, which means any 
AE caused by a drug.  
 
Unexpected:  An AE or SAR is considered “unexpected” if it is not listed in the 
Investigator’s Brochure or is not listed at the specificity or severity that has been observed; or, 
if an Investigator’s Brochure is not required or available, is not consistent with the risk 
information described in the general investigational plan or elsewhere in the current 
application.   
 
Life-threatening: An AE or SAR 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 or suspected adverse reaction that, had it occurred in a more severe form, 
might have caused death.  
 
 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 44 of 80                                         
CONFIDENTIAL 
  
A SERIOUS ADVERSE EVENT (SAE) is any AE or suspected adverse reaction occurring 
at any dose that:  
 
• Results in death. 
• Is life-threatening. 
• Results in a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions. 
• Requires inpatient hospitalization. 
• Prolongs inpatient hospitalization. 
• Is a congenital anomaly/birth defect. 
• Is a significant medical event (i.e., one that may jeopardize the subject or may 
require intervention to prevent one or more of the other outcomes listed above). 
 
A NON-SERIOUS ADVERSE EVENT is any AE that does not meet the definitions for 
SAEs as described above.  
 
Each AE will be classified as SERIOUS or NON-SERIOUS using the definitions provided 
above. 
 
The SEVERITY of each AE will be classified as MILD, MODERATE, or SEVERE.   
The Investigator will review each event and assess its RELATIONSHIP to use of IP 
(unrelated, unlikely, possibly, probably, definitely). The AE will be assessed using the 
following definitions: 
 
Unrelated: 
 
• Event occurring before dosing. 
• Event or intercurrent illness due wholly to factors other than IP use. 
 
Unlikely:  
• Poor temporal relationship with IP use. 
• Event easily explained by subject’s clinical state or other factors. 
 
Possible: 
 Reasonable temporal relationship with IP use. 
 Event could be explained by subject’s clinical state or other factors.  
 
Probable: 
 Reasonable temporal relationship with IP use. 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 45 of 80                                         
CONFIDENTIAL 
  
 Likely to be known reaction to agent or chemical group, or predicted by known 
pharmacology. 
 Event cannot easily be explained by subject’s clinical state or other factors. 
 
Definite:  
• Distinct temporal relationship with IP use. 
• Known reaction to agent or chemical group, or predicted by known pharmacology. 
• Event cannot be explained by subject’s clinical state or other factors.  
 
8.3. 
PROCEDURES FOR AE REPORTING BY THE INVESTIGATOR 
 
AEs will be monitored throughout the study and will be recorded on the eCRF with the date 
and time of onset, date and time of resolution, severity, seriousness, causality (relationship to 
use of IP), treatment required, and the outcome.   
 
To elicit AEs, simple questions with minimal suggestions or implications should be used as 
the initial questions at all evaluation points during the trial. For example: 
 
• How have you felt since your last assessment? 
• Have you had any health problems since your last assessment? 
 
The severity of each AE should be categorized as mild, moderate, or severe. 
 
The causality of use of IP in relation to the AE will be assessed by the Principal Investigator 
after careful medical consideration and categorized as unrelated, unlikely, possible, probable, 
or definite. 
 
If an AE occurs, the Investigator will institute support and/or treat as deemed appropriate.   
If a non-SAE is unresolved at the time of the last day of the study, an effort will be made to 
follow up until the AE is resolved or stabilized, the subject is lost to follow-up, or there is 
some other resolution of the event. The Investigator should make every attempt to follow 
SAEs to resolution. 
 
8.4. 
SERIOUS ADVERSE EVENT REPORTING BY THE INVESTIGATOR 
 
Serious Adverse Event Reporting 
It is the responsibility of the Investigators or their designees to report any event of this nature 
to the Sponsor or a designee within 24 hours of the event being brought to the Investigators’ 
or their staffs’ attention. It is also the responsibility of the Investigator to report all SAEs 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 46 of 80                                         
CONFIDENTIAL 
  
reported at their site to their Institutional Review Board (IRB), as required. The Investigator 
should make every attempt to follow all SAEs to resolution.   
 
The following information should be provided when an SAE is reported to the Sponsor or 
designee: 
1. Protocol Number 
2. Site Number 
3. Subject Number 
4. Subject Demographic information, including: 
• Date of Birth 
• Sex 
• Race 
5. IP start date 
6. Date of last dose of IP  
7. Date investigational product reinitiated (if investigational product interrupted)  
8. SAE information, including: 
• SAE term (diagnosis only; if known or serious signs/symptoms) 
• Description of SAE/narrative 
• Date/time of onset 
• Severity 
• Outcome 
• Date/time of resolution or death (if duration < 24 hours) 
• Relationship to IP 
• Action taken with IP 
9. Criteria for classifying the event as serious, including whether the SAE:   
• Resulted in death 
• Was life-threatening 
• Required inpatient hospitalization 
• Prolonged inpatient hospitalization 
• Resulted in a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions 
• Was a congenital anomaly/birth defect 
• Important medical events that may not result in death, were not life-threatening, or 
did not require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the subject or subject may 
require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 47 of 80                                         
CONFIDENTIAL 
  
or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse  
10. Concomitant medications 
11. Relevant history 
12. Possible causes of SAE other than IP 
13. Copy of AE page from the eCRF 
 
NOTE: If a SAE occurs in any study involving AXR-270 Cream or Vehicle that is 
unexpected and is determined to be definitely related, probably related or possibly related to 
IP, all sites will be notified by the Sponsor and each site should report it to its IRB.   
 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 48 of 80                                         
CONFIDENTIAL 
  
9. 
STATISTICS 
9.1. 
STATISTICAL METHODS 
Continuous measures (e.g., age) will be summarized descriptively by the mean, standard 
deviation, median, minimum and maximum values. Categorical measures will be summarized 
by the number and percent of subjects. The statistical analyses will be performed in 
accordance with a formal Statistical Analysis Plan (provided as a separate document). All 
study data will be listed by treatment, subject and visit (as applicable). 
9.2. 
ANALYSIS POPULATIONS 
The following analysis populations will be considered: 
Full Analysis Set (FAS) – The FAS includes all randomized subjects. The efficacy analysis 
will be performed on the FAS. Subjects in the FAS will be analyzed as randomized. 
Per Protocol Set (PPS) – The PPS includes subjects in the FAS who do not have significant 
protocol deviations and who complete the study. Protocol deviations will be assessed prior to 
database lock and unmasking. The PPS will be analyzed using observed data only for efficacy 
variables. Subjects in the PPS will be analyzed as treated. 
Safety Set (SAF) – The SAF includes all randomized subjects who have received at least one 
dose of the IP. The SAF will be analyzed for all safety assessments. Subjects in the SAF will 
be analyzed as treated.  
The statistical analysis of safety data will be performed for the SAF. The analysis of baseline 
and efficacy data will be performed for the FAS. Sensitivity analyses may be performed on 
the PPS. 
9.3. 
SUBJECT DISPOSITION, DEMOGRAPHIC AND BACKGROUND CHARACTERISTICS 
Subject disposition, demographic characteristics, and background variables will be 
summarized by treatment group. 
9.4. 
ANALYSIS OF EFFICACY 
To assess whether AXR-270 Cream is more effective than Vehicle, exploratory efficacy will 
be performed. The unit of analysis for ophthalmic efficacy measures depends on the measure 
itself. Some endpoints will be analyzed by eye whereas others will be analyzed by study 
eyelid, where study eye/eyelid are defined in Section 4.3.  
The following parameters will be assessed by eyelid: 
• Vascularity of eyelid margin 
• Total MGD Score 
• LGS grade 
The following parameters will be assessed by eye: 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 49 of 80                                         
CONFIDENTIAL 
  
• VAS for Eye Discomfort (one score for both eyes) 
• VAS for Eye Dryness (one score for both eyes) 
• TBUT  
• Total and Individual FCS score 
• OSDI (subject level) 
• Modified BLISS (one score for both eyes) 
• Bulbar Conjunctival Hyperemia 
• Unanesthetized Schirmer score 
VAS scores, Total MGD score, eyelid margin vascularity, LGS grade, conjunctival 
hyperemia, Schirmer score, TBUT, FCS, and OSDI will be analyzed as continuous data. 
Analysis will be performed at each timepoint using summary statistics as well as a 
longitudinal model. 
All other parameters will be analyzed as categorical or discrete measures.  Frequencies and 
percentages of each category as well as a shift from baseline (Visit 2/Day 1) to each timepoint 
will be summarized. 
Analyses of all efficacy endpoints will be done using the FAS. Analyses on the study 
eye/eyelid will be repeated for all non-study eye/eyelids as supportive analyses. Analyses may 
also be repeated on the PPS. 
9.5. 
 ANALYSIS OF SAFETY 
Analysis of safety data will be presented for all subjects in the Safety Population. AEs will be 
coded using Medical Dictionary for Regulatory Activities (MedDRA, most current version) 
and categorized by system organ class using preferred terms. AEs will be tabulated by 
treatment group with respect to their Severity and relationship to the IP. Ophthalmoscopy 
findings will be summarized descriptively. IOP measurements, BCVA, dilated 
ophthalmoscopy, and slit-lamp biomicroscopy (including external eye exam) will be 
summarized as safety outcomes.   
9.6. 
SAMPLE SIZE ESTIMATION 
As this study is exploratory in nature, no formal sample size calculation was performed. 
9.7. 
LEVEL OF SIGNIFICANCE 
P-values will be descriptive in nature. 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 50 of 80                                         
CONFIDENTIAL 
  
9.8. 
PROCEDURE FOR ACCOUNTING FOR MISSING, UNUSED, OR SPURIOUS DATA 
Any missing, unused, or spurious data will be noted in the final clinical study report. The data 
will be analyzed as reported. The last observation carried forward approach will be used to 
analyze incomplete datasets. 
9.9. 
PROCEDURE FOR REPORTING DEVIATIONS FROM THE STATISTICAL PLAN 
Any deviations from the statistical analysis plan will be described and a justification given in 
the final clinical study report. 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 51 of 80                                         
CONFIDENTIAL 
  
10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
 
The Investigator will permit trial-related monitoring, audits, IRB review, and regulatory 
inspection(s) by providing direct access to source data and documents (such as tests 
performed as a requirement for participation in the study and other medical records required 
to confirm information contained in the eCRF such as medical history) to the monitor or 
appropriate designee. 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 52 of 80                                         
CONFIDENTIAL 
  
11. 
QUALITY CONTROL 
 
The progress of the study will be monitored by on-site, written, e-mail, and telephone 
communications between personnel at the study center and the Sponsor (or designated 
monitor). The Investigator will allow AxeroVision, Inc. monitors or designees to inspect all 
eCRFs; subject records (source documents); signed informed consent forms; HIPAA 
authorizations; records of IP receipt, storage, and disposition; and regulatory files related to 
the study. 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 53 of 80                                         
CONFIDENTIAL 
  
12. 
ETHICS 
12.1. 
Institutional Review Board 
 
This protocol and the informed consent form must be approved by an appropriately 
constituted and qualified IRB and the approvals made available to the Sponsor or designee 
prior to the start of enrollment into the study. Materials used to recruit subjects will be 
approved by the appropriate IRB and the approvals made available to the Sponsor or designee 
prior to their use. In addition, the Investigator’s Brochure should be submitted to the IRB.  
Written IRB approval must adequately identify the protocol and ICF. Copies of all approved 
materials, all correspondence with the IRB, and written approval from the IRB must be made 
available to the Sponsor (or designated monitor). 
 
Any modification of study procedures or amendments to the protocol must be approved by the 
IRB prior to implementation. In the event that a modification or amendment is considered by 
the Investigator to be immediately necessary to ensure subject safety, the Investigator will 
promptly notify his or her IRB and the Sponsor. 
 
Investigators will report all SAEs reported at their site to their IRB, as appropriate.   
 
12.2. 
Informed Consent Requirements 
 
Written informed consent will be obtained from each participant prior to any study-related 
procedures being performed (prior to or upon Visit 1/Screening). A copy of the signed and 
dated informed consent document will be given to each subject. The original signed and dated 
informed consent document must be maintained in the study files at the investigative site and 
be available for Sponsor or designee review. 
 
Each informed consent will contain Investigator contact information with a telephone number 
the subject or the subject’s authorized representative can call 24 hours a day if they have 
medical concerns.  

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 54 of 80                                         
CONFIDENTIAL 
  
13. 
DATA HANDLING AND RECORDKEEPING 
 
All procedures for the handling and analysis of data will be conducted using GCP and will 
meet ICH guidelines and FDA regulations for the handling and analysis of data for clinical 
trials. 
 
13.1. 
Data Quality Control and Reporting 
 
After data have been entered into the study database, a system of computerized data validation 
checks will be implemented and applied to the database. Query reports pertaining to data 
omissions and discrepancies will be forwarded to the clinical Investigator and monitor(s) for 
resolution. The study database will be updated in accordance with the resolved query reports.  
All changes to the study database will be documented. 
 
13.2. 
Records Retention 
 
The study center will retain all records related to the study in accordance with local and ICH 
GCP guidelines. 
 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 55 of 80                                         
CONFIDENTIAL 
  
14. 
PUBLICATION POLICY 
 
The institution and Investigators participating in this trial shall have no right to publish or 
present the results of this study without the prior written consent of the Sponsor. 
 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 56 of 80                                         
CONFIDENTIAL 
  
15. 
REFERENCES  
 
1. Bron AJ. Diagnosis of dry eye. Surv Ophthalmol. 2001 Mar;45 Suppl 2:S221-6. 
2. DEWS II Definition and Classification Report. 2017:276-283. Available at 
https://www.theocularsurfacejournal.com/article/S1542-0124(17)30119-2/pdf.  
3. Dougherty JM, McCulley JP. Comparative bacteriology of chronic blepharitis. Br J 
Ophthalmol. 1984;68(8):524-528. 
4. Foulks GN. The evolving treatment of dry eye. Ophthalmol Clin North Am. 2003 
Mar;16(1):29-35 
5. Nelson JD, Shimazaki J, Benitez-del-Castillo JM, Craig JP, McCulley JP, Den S, and Foulks 
GN. The International Workshop on Meibomian Gland Dysfunction: Report of the Deﬁnition 
and Classiﬁcation Subcommittee. Investigative Ophthalmology & Visual Science, Special 
Issue. 2011; 52, (4): 1930-1937. 
6. Pflugfelder S, 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.   
7. Pflugfelder SC. Antiinflammatory therapy for dry eye. Am J Ophthalmol. 2004;137(2):337–
342. doi: 10.1016/j.ajo.2003.10.036. 
8. Holly FJ. Formation and rupture of the tear film. Exp Eye Res. 1973;15:515–525. 
9. Goto E, Tseng SC. Kinetic analysis of tear interference images in aqueous tear 
deficiency dry eye before and after punctal occlusion. Invest Ophthalmol Vis Sci. 
2003;44:1897–1905. 
10. Avunduk AM, Avunduk MC, Varnell ED, Kaufman HE. The comparison of efficacies of 
topical corticosteroids and nonsteroidal antiinflammatory drops on dry eye patients:  A clinical 
and immunocytochemical study. Am J Ophthalmol. 2003;136:593-602.  
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. 
12. Becker B. The side effects of corticosteroids. Invest Ophthalmol. 1964;3(5):492-497.  
13. Behrens A, Doyle JJ, Stern L, Chuck RS, McDonnell PJ, Azar DT, et al. Dysfunctional tear 
syndrome study group. Dysfunctional tear syndrome: a Delphi approach to treatment 
recommendations. Cornea. 2006;25(8):900-907.  
14. Bowling E, Russell G. Topical steroids and the treatment of dry eye:  with dry eye linked to 
ocular surface inflammation, short-term corticosteroids and long-term soft steroids are the 
most effective treatment to prescribe. Review of Cornea and Contact Lenses. Cited 17 Mar 
2011. Available at: http://www.reviewofcontactlenses.com/content/d/dry_eye/c/27245/  
15. Dinning WJ. Steroids and the eye—indications and complications. Postgrad Med J. 
1976;52:634-638. 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 57 of 80                                         
CONFIDENTIAL 
  
16. McKenzie AW, Stoughton RB. Method for comparing percutaneous absorption of steroids. 
Arch Derm. 1962;86:608-610. 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 58 of 80                                         
CONFIDENTIAL 
  
16. 
APPENDICES 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL   Page 59 of 80                                          CONFIDENTIAL 
  
APPENDIX 1: SCHEDULE OF EVENTS 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Procedures 
Day minus 14  
(±2 days) 
Day 1 
 
Day 8 
(±2 days) 
Day 15 
(±3 days) 
Day 22 
(±3 days) 
 
Screening 
Randomization 
Week 1 
Week 2 
Week 3 
 
Equalization 
Period 
Treatment Period 
Study Termination 
Informed Consent  
X 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
Randomization Criteria 
 
X 
 
 
 
Demographics, Systemic and Ocular Medical History 
X 
 
 
 
 
Subject-rated Symptom Assessments 
      VAS (Eye Discomfort and Eye Dryness) 
X 
X 
X 
X 
X 
      OSDI 
X 
X 
X 
X 
X 
      Modified BLISS 
X 
X 
X 
X 
X 
Concomitant Medication Query 
X 
X 
X 
X 
X 
Adverse Event Query 
 
X 
X 
X 
X 
UPT  
X 
 
 
 
X 
BCVA 
X 
X 
X 
X 
X 
Slit-lamp Biomicroscopy (including External Eye Exam) 
X 
X 
X 
X 
X 
TBUT 
X 
X 
X 
X 
X 
FCS 
X 
X 
X 
X 
X 
Investigator-rated assessment of signs of MGD:   
    Total MGD Score 
    Eyelid margin vascularity 
    Bulbar conjunctival hyperemia 
X 
X 
X 
X 
X 
LGSa  
X 
X 
X 
X 
X 
Unanesthetized Schirmer Test 
X 
X 
X 
X 
X 
IOP 
X 
X 
X 
X 
X 
Dilated Ophthalmoscopy  
X 
 
 
 
X 
Safety Lab Draw 
 
X 
 
 
X 
Dispense Investigational Product for Home Administration 
 
X  
 
 
 
Dispense Daily Dosing Diaries / IP Comfort Assessment Questionnaire 
 
X 
 
 
 
In Clinic Administration of Investigational Product, IP Comfort 
Assessment Questionnaire and Instruction on Proper Administrationb 
 
X 
 
 
 
Collect/Review Daily Dosing Diary, IP Comfort Assessment 
Questionnaire and Investigational Product  
 
 
Xc 
X 
X 
Study Termination 
 
 
 
 
X 
Key: OSDI=Ocular Surface Disease Index; TBUT=Tear Break up Time; BLISS= BLepharItIS Symptom; AE=Adverse Event; UPT=Urine Pregnancy Test; IOP=Intraocular 
Pressure; VAS=Visual Analog Scale; BCVA=Best Corrected Visual Acuity; FCS=Fluorescein Corneal Staining; LGS=Lissamine Green Staining; IP=Investigational Product. 
aOnly to be performed at a subset of sites  
bIncludes dosing video on proper administration of IP  
cIP will not be collected at Visit 3 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 60 of 80                                      
CONFIDENTIAL 
  
APPENDIX 2:  DATA SAFETY REVIEW COMMITTEE (DSRC) 
A description of the function and membership of the masked DSRC will be detailed in 
a separate charter describing the agreed upon standard operating procedures. The 
general plan for the review and description of the committee is outlined here:  
• A review of safety will be conducted by the DSRC after the last of those 15 
subjects has completed Visit 4.  
• The DSRC will be minimally comprised of an independent Ophthalmologist and a 
Statistician who are otherwise not involved in the conduct of the study. 
• The DSRC may request the participation of an independent Statistician to assist in 
the assessment of the safety of the IP and the decision to continue enrolling 
subjects after the first 15 have been treated and have completed study procedures 
through Visit 4. 
• In order to maintain the integrity of the trial, unless it is absolutely necessary, the 
safety evaluation should be conducted using masked subject-specific information.  
• Upon review of the safety data obtained in the first 15 subjects in Cohort 1, the 
DSRC will issue a memorandum to AxeroVision, Inc. recommending one of the 
following:   
1. Continue with the low-dose Cohort 1 and expand study to high-dose Cohort 2 
upon completion of enrollment in Cohort 1. 
2. Continue with enrollment in the low-dose Cohort 1 but conduct an additional 
review of safety information from the next 15 subjects reaching the 2-week 
mid-point of the study before deciding to recommend escalation to Cohort 2. 
3. Stop study due to safety concerns. 
• If, upon the review of the masked safety information, the DSRC requires 
unmasked information in order to ensure the safeguard of the interests of the study 
subjects, the unmasked information will be provided per the details outlined in the 
charter.  
• The DSRC will make every effort to arrive to a decision by consensus.  
 
 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 61 of 80                                      
CONFIDENTIAL 
  
APPENDIX 3:   INVESTIGATOR-RATED ASSESSMENT OF SIGNS OF MEIBOMIAN GLAND 
DYSFUNCTION 
 
The investigator will rate the bilateral severity of the subject’s MGD signs according to the 
following classification and for each eyelid:  
1. Total MGD Score 
A digital expression by applying pressure with thumb or forefinger will be used to express the 
meibomian gland of the UPPER eyelids. A cotton tip applicator is preferred but not required 
to evaluate the LOWER eyelids meibomian glands. 
The character of the secretion of 5 central glands on both the upper and lower eyelids will be 
evaluated for each eye. Each of the glands will be scored from 0-3:  
0 = clear/slightly yellow 
1 = opaque/yellow, whitish, particulate 
2 = paste 
3 = none/occluded.  
The total score will thus range from 0-15 for each eyelid. 
 
2. Eyelid Margin Vascularity 
0 = Normal – Typical vascularity for subject age 
1 = Mild vascular engorgement – Slightly dilated and pink blood vessels  
2 = Moderate vascular engorgement – Slightly more dilated pink/red blood vessels  
3 = Severe vascular engorgement – Multiple significantly dilated red blood vessels  
4 = Very Severe vascular engorgement – Multiple significantly dilated deep red blood vessels  
 
3.  Bulbar Conjunctival Hyperemia 
Investigator-Rated Assessment of Bulbar conjunctival hyperemia 
Investigators will rate overall bulbar conjunctival hyperemia using the Cornea and Contact 
Lens Research Unit (CCLRU) Grading Scale. 
 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 62 of 80                                      
CONFIDENTIAL 
  
 
0 = None 
1 = Very Slight 
2 = Slight 
3 = Moderate 
4 = Severe 
 
 
 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 63 of 80                                      
CONFIDENTIAL 
  
APPENDIX 4:  ETDRS BEST CORRECTED VISUAL ACUITY 
 
Visual acuity testing should precede any examination requiring contact with the eye or 
instillation of study dyes, as is detailed in the order of assessments for each Visit in Section 
5.1. Logarithm of the Minimal Angle of Resolution (LogMAR) visual acuity must be assessed 
using an ETDRS or modified ETDRS chart. Visual acuity testing should be performed with 
best correction using subject’s own corrective lenses (spectacles only) or pinhole refraction. 
An ETDRS or modified ETDRS chart may be used. If a Lighthouse chart is used (24.5” by 
25”; either reflectance or retro-illuminated), the subject must view the chart from a distance of 
exactly 4 meters (13.1 feet). If smaller reproductions (18” by 18”, e.g., Prevent Blindness) are 
used, the subject viewing distance should be exactly 10 feet. Reflectance wall charts should 
be frontally illuminated (60 watt bulb or a well-lit room). 
The subject should be positioned according to the elevation of the chart (either seated or 
standing) so that the chart is 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 instead of the number. The subject 
should be asked to read slowly, about 1 letter per second, 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 before he has read aloud the next letter, then the 
change must be accepted. 
Maximum effort should be made to identify each letter on the chart; the subject should be 
encouraged to guess. When it becomes evident that no further meaningful readings can be 
made, the examiner should stop the test. The number of letters missed or read incorrectly 
should be noted. 
In order to provide standardized and well-controlled assessments of visual acuity during the 
study, the same lighting conditions must be used consistently throughout the study. 
 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 64 of 80                                      
CONFIDENTIAL 
  
Calculations: LogMAR VA = Baseline value + (n X 0.02)  
where:  
the baseline value is the LogMAR number of the last line read (at least 1 letter read 
correctly in this line), and “n” is the total number of letters missed up to and including 
the last line read, and “0.02” is the value for each letter. 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 65 of 80                                      
CONFIDENTIAL 
  
APPENDIX 5:  SLIT LAMP BIOMICROSCOPY  
The biomicroscopy exam should be performed with the slit-lamp using a beam width and 
intensity that provide optimal evaluation of the anterior segment. 
This procedure will be the performed in the same manner for all subjects observed at the 
Investigator’s site. The site will record all ABNORMAL findings in the source document and 
the investigator will evaluate the ABNORMAL findings as Non-Clinically Significant (NCS) 
or Clinically Significant (CS). CS and NCS ABNORMAL findings will be recorded in the 
source documentation. However, only ABNORMAL CS descriptions will be captured in the 
eCRF.  
Lashes  
             0 = Normal 
 
 
 1 = Abnormal 
 
Eyelid 
Edema  
 
     
 0 = Normal, no swelling of the lid tissue 
 
 
 1 = Abnormal 
     
     Skin 
            0 = Normal, including but not limited to thinning, pigment changes, dermatitis 
            1 = Abnormal 
 
Conjunctiva 
Edema   
    
  0 = Normal, no swelling of the conjunctiva 
 
 
  1 = Abnormal 
 
Palpebral Conjunctival Erythema 
 
0 = Normal, no redness of the conjunctiva 
 
1 = Abnormal 
 
Cornea 
Infiltrates 
 
 
 0 = Absent 
 
 
 1 = Present 
Endothelial Changes 
 
 
 0 = Normal, None 
 
 
 1 = Abnormal, pigment, keratoprecipitates, guttata 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 66 of 80                                      
CONFIDENTIAL 
  
 
Edema 
    
 0 = Normal, None, transparent and clear 
 
 
 1 = Abnormal 
 
Anterior Chamber 
 
Cells 
 
  
 0 = Normal, No cells seen 
 
  
 1 = Abnormal (+ to +++ cells) 
 
Flare 
 
  
 0 = Normal, No Tyndall effect 
     
 1 = Abnormal, Tyndall beam in the anterior chamber 
 
Lens Pathology  
 0 = Normal, no opacity in the lens 
 1 = Abnormal, existing opacity in the lens; aphakic or pseudophakic eyes or other  
 
 
 
abnormal findings 
 
Sclera 
 
 
0 = Normal  
 
 
1 = Abnormal 
 
 
 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 67 of 80                                      
CONFIDENTIAL 
  
APPENDIX 6:  IOP MEASUREMENT 
 
IOP measurements will be performed utilizing Goldmann applanation tonometry according to 
the Investigator’s standard procedure. All pressures will be recorded in mmHg. 
 
 
 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 68 of 80                                      
CONFIDENTIAL 
  
APPENDIX 7:  DILATED OPHTHALMOSCOPY 
 
Dilated Ophthalmoscopy will include assessment of the retina for any abnormal findings, 
optic nerve head for pallor and cupping (cup to disc ratio). After the Ophthalmoscopy 
procedure, the Investigator will determine if findings are within normal limits or are 
abnormal. For abnormal findings at Visit 1, the Investigator will determine whether or not the 
abnormality would exclude subject from study participation.  
 
 
 
 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 69 of 80                                      
CONFIDENTIAL 
  
APPENDIX 8:  EYE DISCOMFORT, EYE DRYNESS SYMPTOM ASSESSMENT  
 
Symptom Assessment Visual Analog Scale (VAS) 
Subjects will be asked the following questions regarding their current symptoms (unrelated to 
Investigational Product instillation) at each visit. 
The subject will be asked to subjectively rate each ocular symptom (OU) by placing a vertical 
mark on the horizontal line to indicate the level of eye discomfort and dryness. 0 corresponds 
to “No Symptoms” and 100 corresponds to “Severe Symptoms”  
__________________________________________________________________________ 
Subject Instructions:  Please review the symptoms below. After your review, please rate how 
your eyes feel for each of the following symptoms by placing a single vertical mark that 
represents how your symptom feels at this moment.  
 
 0 = No Symptoms and 100 = Severe Symptoms 
 
Eye Discomfort 
 
  0                                                                                                  100 
|                                                                                                     |        
 
Eye Dryness 
 
  0                                                                                                  100 
|                                                                                                     |        
 
 
 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 70 of 80                                      
CONFIDENTIAL 
  
APPENDIX 9:  MODIFIED BLISS 
Check each box which most reflects the frequency of each symptom. 
Symptoms 
None of 
the time 
 Occasionally   Frequently   All of the time 
Eyes that itch 
 
 
 
 
Eyes that burn 
Eyelids feel heavy or 
puffy 
 
 
 
 
Feel like something in 
your eye 
Dry eyes 
 
 
 
 
Gritty eyes 
Irritated eyes 
Eyes that tear or water 
Crusty eyes 
Eyelids that are stuck 
together 
 
 
 
 
Red eyes or eyelids 
https://www.nei.nih.gov/learn-about-eye-health/eye-conditions-and-diseases/blepharitis 
 
 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 71 of 80                                      
CONFIDENTIAL 
  
APPENDIX 10:  TEAR BREAK-UP TIME (TBUT) 
TBUT will be measured at each visit. To measure TBUT, fluorescein is instilled into the 
subject’s tear film, the subject is allowed to blink once or twice to disperse the fluorescein, 
after approximately 30 seconds  the subject is then asked not to blink while the tear film is 
observed under a broad beam of cobalt blue illumination using a slit-lamp.   
Using a stopwatch the TBUT is recorded as the number of seconds that elapse between the 
last blink and the appearance of the first dry spot in the tear film. The time is measured to 
hundredth and using normal rounding rules, rounded to tenths. A TBUT under 10 seconds is 
considered abnormal.  
A total of 2 measurements are obtained and entered into the record. If the 2 measurements are 
> 2 seconds apart then a third measurement is obtained and the closest 2 measurements are 
recorded. 
NOTE:  The TBUT and the FCS may be performed right eye then left eye or staggered with 
the TBUT for the left eye being done during the waiting period before completing the FCS for 
the right eye. 
 
 
 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 72 of 80                                      
CONFIDENTIAL 
  
APPENDIX 11:  FLUORESCEIN CORNEAL STAINING (FCS) / NATIONAL EYE INSTITUTE / 
INDUSTRY WORKSHOP SCALE  
The 5 areas of the cornea will be scored by the investigator according to the following scoring 
system and the total score will also be calculated. NOTE: The TBUT and the FCS may be 
performed right eye then left eye or staggered with the TBUT for the left eye being done 
during the waiting period before completing the FCS for the right eye. 
 
 
 
 
 
 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 73 of 80                                      
CONFIDENTIAL 
  
APPENDIX 12:  UNANESTHETIZED SCHIRMER TEST 
The Schirmer test will be conducted on unanesthetized eyes. A 35 mm x 5 mm filter paper 
strip is used to measure the amount of tears that are produced over 5 minutes. The strip is 
placed in the lower eyelid margin without the use of a preplaced ophthalmic anesthetic drop. 
After 5 minutes, the strip is removed and the amount of wetting is measured in millimeters. 
The wetting margin on the Schirmer strip is marked with a pen and the strip is placed in the 
subject’s source document.  
 
 
 
 
 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 74 of 80                                      
CONFIDENTIAL 
  
APPENDIX 13:  OCULAR SURFACE DISEASE INDEX (OSDI) 
 
 
 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 75 of 80                                      
CONFIDENTIAL 
  
 
 
 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 76 of 80                                      
CONFIDENTIAL 
  
APPENDIX 14: DAILY DOSING DIARY  
Subjects will be asked to record each day the following information related to administration 
of IP: 
• Date 
• Time of Administration 
• IP Comfort Assessment (Below) 
 
Each evening, the subject will be asked to respond to the following questions: 
Investigational Product Comfort Assessment 
Overall tolerance of Investigational 
Product 
1-Exellent   
2-Good 
3-Fair 
4-Poor 
Concern about the following immediately after application: 
Eyelid Redness  
1-No Concern 
2-Slightly Concerned 
3-Moderately Concerned 
4-Very Concerned 
Eyelid Stinging 
1-No Concern 
2-Slightly Concerned 
3-Moderately Concerned 
4-Very Concerned 
Eyelid Burning 
1-No Concern 
2-Slightly Concerned 
3-Moderately Concerned 
4-Very Concerned 
Heavy Eyelid Sensation 
 
1-No Concern 
2-Slightly Concerned 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 77 of 80                                      
CONFIDENTIAL 
  
3-Moderately Concerned 
4-Very Concerned 
Sticky Feeling in Eye 
 
1-No Concern 
2-Slightly Concerned 
3-Moderately Concerned 
4-Very Concerned 
Spreading into Eye  
 
1-No Concern 
2-Slightly Concerned 
3-Moderately Concerned 
4-Very Concerned 
Oily Feeling in Eye 
 
1-No Concern 
2-Slightly Concerned 
3-Moderately Concerned 
4-Very Concerned 
 
 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 78 of 80                                      
CONFIDENTIAL 
  
 
APPENDIX 15:  EYELID WIPE INSTRUCTIONS 
 
Use 1 wipe to clean the eyelids of both eyes.  
The desired area to clean is the skin of the eyelids at the area of the eyelashes. 
Wash hands with soap and water, then dry hands. 
Open the packet containing the moistened wipe and place over the index finger of either hand. 
Gently close your eyelids. Forced, hard closure of the eyelids will prevent the wipe from 
cleaning the eyelash area of your eyelid.  
Using a back and forth motion gently wipe the skin of the eyelid and eyelash area for 
approximately 30 seconds. 
Use the underside of the wipe (portion of the wipe that was against the index finger) to clean 
the other eye. 
You may use the same hand or other hand to clean the other eye. 
 
 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 79 of 80                                      
CONFIDENTIAL 
  
 
APPENDIX 16: LID MARGIN LISSAMINE GREEN STAINING 
Note: This procedure will only be performed at a subset of sites. 
Set the slit-lamp to moderate illumination and low magnification. 
• Apply Lissamine green dye to the inferior cul-de-sac of the right eye and wait at least 
1 minute. 
• With the subject’s chin in the chinrest and the forehead against the forehead strap and 
evert the upper lid.  
•  Evaluate the lid margin anatomy starting with the Line of Marx. This should appear 
as a thin green line. 
• The width of Lid Wiper area does not have exact landmarks to identify its width on 
the palpebral conjunctival surface and the Investigator judgment is required to 
approximate the width. 
• The distal lid has rigidity due to the tarsal plate. 
• The Lid Wiper area extends proximally from the Line of Marx to the first curve in the 
conjunctival surface. 
LID WIPER GRADING 
 
 
HORIZONTAL 
LENGTH  
STAINING 
 
GRADE 0 
< 2 mm 
 
GRADE 1 
2 mm to 4 mm 
 
GRADE 2 
5 mm to 9 mm 
 
GRADE 3 
     >9 mm 
 
LONGEST 
SAGITTAL 
WIDTH OF 
STAINING 
 
GRADE 0 
< 25 % 
 
GRADE 1 
25% to 50% 
 
GRADE 2 
51% to 75% 
 
GRADE 3 
>75% 
 
Grade the length and sagittal width of the Lissamine staining and record the Grade score for 
the length and sagittal width. 
Repeat the same procedure for the left eye. 
 

 
 
AXR201901 Protocol Incorporating Amendment 02_03Jun2020_FINAL    
Page 80 of 80                                      
CONFIDENTIAL 
  
APPENDIX 17: 
 
American Academy of Ophthalmology Recommended protocols when scheduling or 
seeing patients 
• 
If the office setup permits, patients who come to an appointment should be asked prior 
to entering the waiting room about fever and respiratory illness and whether they or a 
family member have had contact with another person with confirmed COVID-19 in 
the past 2 to 14 days. If they answer yes to either question, they should be sent home 
and told to speak to their primary care physician. 
• 
Keep the waiting room as empty as possible, advise seated patients to remain at least 6 
feet from one another. As much as prudent, reduce the visits of the most vulnerable 
patients. 
• 
The use of commercially available slit-lamp barriers or breath shields is encouraged, 
as they may provide a measure of added protection against the virus. These barriers do 
not, however, prevent contamination of equipment and surfaces on the patient's side of 
the barrier, which may then be touched by staff and other patients and lead to 
transmission. Homemade barriers may be more difficult to sterilize and could be a 
source of contamination. In general, barriers are not a substitute for careful cleaning 
of equipment between patients and asking those patients who cough, sneeze, or have 
flu-like symptoms to wear masks during examination. 
• 
To further decrease the risk of any virus transmission, ophthalmologists should inform 
their patients that they will speak as little as possible during the slit-lamp examination, 
and request that the patient also refrain from talking. 
• 
For in-office procedures that require close physical proximity to the patient (e.g., 
intravitreal injection, lateral tarsorrhaphy), we recommend the patient wear a surgical 
mask or a cloth face covering if surgical masks are in short supply, and that the 
surgeon wear a surgical mask and eye protection. In regions with high prevalence of 
COVID-19, an N95 mask for the surgeon can be considered when available. The 
CDC’s recommendations on N95 extended use and/or reuse should be followed.  
• 
The CMS and HHS have allowed for the expanded use of telehealth services during 
the COVID-19 public health crisis. For more information on telephone services, 
internet-based consultation or telemedicine exam, visit the Academy’s Coding for 
Phone Calls, Internet and Telehealth Consultations.