Clinical trial NCT04314362
Conditions: Meibomian Gland Dysfunction
Sponsor: Azura Ophthalmics
Start date: 2020-07-14; Completion date: 2021-01-06
Enrollment: 32 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Single-center, single-masked (the individual(s) performing efficacy and safety measures will be masked to treatment assignment for the patient(s) they are assessing), vehicle-controlled, randomized study.

Detailed description:
Randomized study with 6 visits. For all dose groups a screening visit will be followed by a baseline visit 14 days later (qualification period). At the end of the qualification period patients who still exhibit signs of Meibomian Gland Dysfunction (MGD) at the baseline visit will be enrolled into a 3-month treatment period. At the baseline (Day 0) visit, patients will be randomly assigned to receive either AZR-MD-001 ointment/semi-solid drug or AZR-MD-001 vehicle twice-weekly.

Arms: arm 1: AZR-MD-001 ointment/semi-solid drug (1.0%) arm 2: AZR-MD-001 ointment/semi-solid drug (1.0%) plus Hylo-Forte® arm 3: AZR-MD-001 vehicle control
Interventions: intervention 1: AZR-MD-001 ointment/semi-solid drug
Intervention descriptions: intervention 1: AZR-MD-001 (1.0%) and suitable excipient

Protocol documents:
Prot_SAP_000.pdf: 
A Single-centre, Vehicle-controlled Study to Evaluate 
Methods to Enhance the Safety and Tolerability of AZR-
MD-001 for Meibomian Gland Dysfunction (MGD). 
Short Title: 
Methods to enhance AZR-MD-001 for 
Meibomian Gland Dysfunction (MGD)  
Protocol Number: 
SOVS2020-080 
National Clinical Trial (NCT) 
Identified Number: 
TBD 
Principal Investigator: 
Prof. Fiona Stapleton 
School of Optometry and Vision 
Science; UNSW Sydney;  
Sydney NSW 2052 Australia 
Institution: 
School of Optometry and Vision 
Science; UNSW Sydney;  
Sydney NSW 2052 Australia 
Tel: + 61 2 9385 6551 
E-mail: jacqueline@unsw.edu.au 
Funded by: 
 
 
 
 
Azura Ophthalmics, Level 9,  
31 Queens Street  
Melbourne, VIC 300 Australia 
 
Version and Version Number: 
Final, 2.0 
Date: 14Apr2020 
 
 
 
 
 
 


 
 
ii 
Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
1.2 and 5.2  
Added exclusion criteria “Known carrier of 
infectious disease” 
As per UNSW HREC’s recommendation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
 
iii 
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. v 
1 
PROTOCOL SUMMARY .............................................................................................................................. vi 
1.1 
Synopsis ............................................................................................................................................... vi 
1.2 
Schema ................................................................................................................................................ vi 
1.3 
Schedule of Activities (SoA) ............................................................................................................. xii 
2 
INTRODUCTION ............................................................................................................................................ 1 
2.1 
Background MGD ................................................................................................................................ 1 
2.2 
Study RationalE & Known Potential Benefits .................................................................................. 2 
2.3 
Risk/Benefit Assessment .................................................................................................................... 6 
2.3.1 
Known Potential Risks ..................................................................................................... 6 
2.3.2 
Assessment of Potential Risks and Benefits ................................................................ 7 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................................ 7 
4 
STUDY DESIGN ............................................................................................................................................. 8 
4.1 
Overall Design ...................................................................................................................................... 8 
4.2 
Scientific Rationale for Study Design................................................................................................ 8 
4.3 
End of Study Definition ....................................................................................................................... 9 
5 
STUDY POPULATION .................................................................................................................................. 9 
5.1 
Inclusion Criteria ................................................................................................................................ 10 
5.2 
Exclusion Criteria ............................................................................................................................... 11 
5.3 
Lifestyle Considerations .................................................................................................................... 13 
5.4 
Screen Failures .................................................................................................................................. 13 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 14 
6 
STUDY INTERVENTION ............................................................................................................................ 14 
6.1 
Study Intervention(s) Administration ............................................................................................... 14 
6.1.1 
Study Treatment(s)/ Formulation(s)/ Medical Device Composition or Design ...... 14 
6.1.2 
Selection of Doses in the Study ................................................................................... 15 
6.1.3 
Dosing and Administration ............................................................................................ 16 
Preparation/Handling/Storage/ Accountability .................................................................................................. 16 
6.1.4 
Acquisition and accountability ...................................................................................... 16 
6.1.5 
Formulation, Appearance, Packaging, and Labeling ................................................ 16 
6.1.6 
Product Storage and Stability ....................................................................................... 17 
6.1.7 
Preparation ...................................................................................................................... 17 
6.2 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 17 
6.3 
Concomitant Therapy ........................................................................................................................ 18 
6.3.1 
Rescue Medicine ............................................................................................................ 18 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 18 
7.1 
Discontinuation of Study Intervention ............................................................................................. 18 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 18 
7.3 
Lost to Follow-Up ............................................................................................................................... 19 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 20 
8.1 
Safety and Other Assessments ....................................................................................................... 20 
8.1.1 
Safety Measures ............................................................................................................ 20 
8.2 
Adverse Events and Serious Adverse Events ............................................................................... 20 
8.2.1 
Definition of Adverse Events (AE) ............................................................................... 20 
8.2.2 
Definition of Serious Adverse Events (SAE) .............................................................. 22 


  
 
iv 
8.2.3 
Classification of an Adverse Event .............................................................................. 24 
8.2.4 
Time Period & Frequency for Event Assessment and Follow-Up ........................... 26 
8.2.5 
Reporting Events to Participants ................................................................................. 26 
8.2.6 
Events of Special Interest ............................................................................................. 27 
8.2.7 
Reporting of Pregnancy ................................................................................................ 27 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 27 
9.1 
Sample Size Determination .............................................................................................................. 27 
9.2 
Populations for Analyses .................................................................................................................. 27 
9.3 
Protocol Deviations............................................................................................................................ 28 
9.4 
Statistical Analyses............................................................................................................................ 29 
9.4.1 
General Approach .......................................................................................................... 29 
9.4.2 
Analysis of the Primary SAFETY Endpoint(s) ............................................................ 29 
9.4.3 
Baseline Descriptive Statistics ..................................................................................... 29 
9.4.4 
Planned Interim Analyses ............................................................................................. 29 
9.4.5 
Sub-Group Analyses ..................................................................................................... 29 
9.4.6 
Tabulation of Individual participant Data .................................................................... 31 
9.4.7 
Exploratory Analyses ..................................................................................................... 31 
10 
Regulatory, ethical, and study oversight considerations ........................................................................ 31 
10.1 
Independent Ethics Committee ....................................................................................................... 31 
10.2 
Regulatory authorities ....................................................................................................................... 31 
10.3 
Ethical conduct of the study ............................................................................................................. 31 
10.4 
Informed consent process ................................................................................................................ 31 
10.5 
Subject confidentiality ....................................................................................................................... 32 
11 
Quality Assurance ........................................................................................................................................ 33 
11.1 
Audit and Inspection .......................................................................................................................... 33 
11.2 
Monitoring ........................................................................................................................................... 33 
11.3 
Data Management and Coding ........................................................................................................ 33 
12 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 33 
12.1 
Study Discontinuation and Closure ................................................................................................. 33 
12.2 
Future Use of Stored Specimens and Data ................................................................................... 34 
12.2.1 
Handling of Biological Specimens ............................................................................... 34 
12.3 
Retention of Documentation............................................................................................................. 34 
12.4 
Source Documents ............................................................................................................................ 35 
12.5 
Study Summary ................................................................................................................................. 35 
12.6 
Institutional Review Board /Independent Ethics Committee (IEC) Records Retention ........... 36 
12.7 
Publication and Data Sharing Policy ............................................................................................... 36 
12.8 
Conflict of Interest Policy .................................................................................................................. 36 
12.9 Additional Considerations ........................................................................................................................... 36 
12.10 Abbreviations .............................................................................................................................................. 37 
12.11 Protocol Amendment History ................................................................................................................... 38 
13 
REFERENCES ............................................................................................................................................. 39 
14 
Approval(s) .................................................................................................................................................... 42 
 


STATEMENT OF COMPLIANCE 
 
 
 
INVESTIGATOR: 
 
STUDY LOCATION: 
 
 
I agree to:  
 
• Implement and conduct this study diligently and in strict compliance 
with the protocol, International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and all applicable state, local and federal 
regulatory requirements.  
 
• The protocol, informed consent form(s), recruitment materials, and all 
participant materials will be submitted to the Institutional Review 
Board (IRB)/ Independent Ethics Committee (IEC) for review and 
approval.  Approval of both the protocol and the consent form will be 
obtained before any participant is enrolled. 
 
• Maintain all information supplied by Azura Ophthalmics in 
confidence and, when this information is submitted to an Institutional 
Review Board (IRB), Independent Ethics Committee (IEC) or another 
group, it will be submitted with a designation that the material is 
confidential. 
 
• I have read this protocol in its entirety and I agree to all aspects.  
 
 
 
 
 
 
  
Investigator Printed Name 
 
Signature 
 
Date 
 


 
 
vi 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
 
Study Compound(s):  
 
AZR-MD-001 (Selenium Disulfide) 
 
Phase: 
 
2 
 
Objectives: 
 
 
To determine the safety and tolerability of AZR-MD-001 1.0% following 
evening only dosing for Meibomian Gland Dysfunction (MGD).   
 
To determine if dosing Hylo-Forte® approximately 5 minutes before study 
ointment will enhance either the safety or tolerability of AZR-MD-001 1.0% 
following evening only dosing.   
 
 
Clinical Hypotheses: 
 
AZR-MD-001 1.0% ointment/semi-solid drug has an acceptable safety and 
tolerability profile following twice-weekly evening ocular administration 
for the duration of the study.   
 
Dosing Hylo-Forte® approximately 5 minutes before study ointment will 
enhance the safety or tolerability of AZR-MD-001 1.0% following evening 
only dosing.  
 
 
1.2 
SCHEMA 
 
Study Design: 
Structure:  Single-center, single-masked (the individual(s) performing efficacy 
and safety measures will be masked to treatment assignment for the patient(s) they 
are assessing), vehicle-controlled, randomized study.  For all dose groups a 
screening visit will be followed by a baseline visit 14 days later (qualification 
period). At the end of the qualification period patients who still exhibit signs of 
MGD and who can comply with dosing instructions at the baseline visit will be 
enrolled into a 3-month treatment period. At the baseline (Day 0) visit , patients 
will be randomly assigned in a 2:2:1:1 ratio to receive either AZR-MD-001 1.0% 
ointment/semi-solid drug or AZR-MD-001 1.0% ointment/semi-solid drug plus 
Hylo-Forte® or AZR-MD-001 vehicle or AZR-MD-001 vehicle plus Hylo-
Forte® for twice-weekly evening administration for 3 months.  The study flow is 
shown in Figure 1. 
 
Duration:  The total duration of study is approximately 3.5 months (from 
screening to study completion).  
  
Study Treatment Groups:  AZR-MD-001 ointment/semi-solid drug (1.0%) and 
AZR-MD-001 ointment/semi-solid drug (1.0%) plus Hylo-Forte®.     
 
Controls:  AZR-MD-001 vehicle and AZR-MD-001 vehicle plus Hylo-Forte®.  
 
Baseline Visit: “Vaseline” (AZR-MD-001 Vehicle) 


 
 
vii 
 
Dosage/Dose Regimen:  All study treatments are to be self-administered by the 
patient twice-weekly in the evening. Where applicable, Hylo-Forte® will be dosed 
approximately 5 minutes before study ointment.  
 
Randomization/Stratification:  At Day 0, patients will be randomly assigned in a 
2:2:1:1 ratio to receive either AZR-MD-001 1.0% ointment/semi-solid drug or 
AZR-MD-001 1.0% ointment/semi-solid drug plus Hylo-Forte® or AZR-MD-
001 vehicle or AZR-MD-001 vehicle plus Hylo-Forte® for twice-weekly evening 
administration for 3 months.  
 
Patients will be stratified by average (i.e., across both eyes) baseline MGS score 
(MGS score of < 6 or MGS score ≥6 and ≤ 12). Both eyes should qualify for the 
study (i.e., meet the inclusion/exclusion criteria).   
 
Visit Schedule:  Six scheduled visits:  screening (-2 weeks), baseline (day 0), 2 
weeks, 4 weeks, 6 weeks and 3 months.  For patients who discontinue the study 
early, the month 3 visit procedures should be completed. 
 
Study Population 
Characteristics 
 
Number of Patients:  Approximately thirty (30) patients with MGD will be 
randomized to the study. Based upon data from the LipiFlow® development 
program a screen failure rate of ~ 40% is expected for new patients.  Thus, ~up to 
42 patients will need to be screened to achieve ~up to 30 patients randomized to 
treatment. 
  
Condition/Disease:  Meibomian Gland Dysfunction (MGD)  
 
Key Inclusion Criteria:    
 
• 
Male or female, 18 years of age or older at screening visit  
• 
Capable of understanding and willing to provide written informed consent 
and likely to complete the entire course of study according to instructions 
• 
Written authorization for use and release of health and research study 
information has been obtained 
• 
Best-corrected visual acuity (BCVA) of 20/40 or better (Snellen 
equivalent), using the logarithm of the minimum angle of resolution 
(LogMAR) in each eye at the screening visit 
• 
Evidence of meibomian gland obstruction (based on a meibomian gland 
secretion (MGS) score of ≤12 for 15 glands of the lower lid) in both eyes 
at the screening visit 
• 
Reported dry eye signs and symptoms within the past 3 months: Ocular 
Surface Disease Index (OSDI) score ≥ 13; TBUT < 10 seconds in both 
eyes  
• 
Demonstrated ability to follow dosing instructions at the baseline visit 
• 
Prior to the screening visit patients are required to discontinue:  
o Use of systemic antihistamines or isotretinoin for at least 1 month  


 
 
viii 
o Anti-inflammatory treatments for DED (e.g., cyclosporine 
ophthalmic emulsion [Restasis® or Ikervis®] or lifitegrast 
ophthalmic solution [Xiidra®]) for at least 3 months 
o All other prescription medications used for dry eye or MGD (e.g., 
antibiotics, corticosteroids, and non-steroidal anti-inflammatory 
drugs) for at least 2 weeks 
o LipiFlow® or other lid-heating therapy, meibomian gland 
probing, or therapeutic gland expression in either eye within 6 
months prior to the screening visit 
o All other MGD treatments (e.g., at-home warm compress 
therapy, eyelid hygiene, eyelid massage, and manual lid 
expression) for at least 2 weeks   
And 
o Women of childbearing potential must have a history of bilateral 
tubal ligation or use oral contraceptives, implants, injectables, 
transdermal patch, or intrauterine device for birth control during 
the study.  Abstinence is considered a reliable method of birth 
control.  If these methods of birth control do not apply, women of 
childbearing potential must have a monogamous partner who has 
had a vasectomy at least 3 months before the screening visit or 
who is of the same gender. 
 
Exclusion Criteria:    
 
• 
Uncontrolled ocular disease (except for MGD) or uncontrolled systemic 
disease 
• 
Patient has glaucoma or ocular hypertension as demonstrated by an 
intraocular pressure (IOP) in either eye at screening of ≥24 mm Hg 
determined by Goldman applanation tonometry or has planned 
insertion/removal of glaucoma filtration shunts/devices during the study  
• 
Corneal abnormality or disorder that impacts normal spreading of the tear 
film (keratoconus, pterygia, scarring) or corneal integrity 
• 
BCVA worse than 20/40 in either eye at the screening visit 
• 
Current use of punctal plugs, anticipated insertion during the study, or a 
history of punctal cautery in either eye at any time prior to the baseline 
visit or anticipate such a procedure during the study 
• 
Keratoconjunctivitis sicca secondary to destruction of conjunctival goblet 
cells as occurs with vitamin A deficiency or scarring, such as that with 
cicatricial pemphigoid, alkali burns, Stevens-Johnson syndrome, 
trachoma, or irradiation 
• 
Keratoconjunctivitis sicca secondary to aqueous deficient DED 
• 
Active ocular infection (bacterial, viral, or fungal) at the screening visit 
• 
Corneal, conjunctival, or eyelid inflammation (including allergic, vernal, 
or giant papillary conjunctivitis and mucous membrane pemphigoid) that 


 
 
ix 
in the judgment of the investigator may interfere with the study results or 
the ability of subjects to complete the treatment period 
• 
Recent (within the past 3 months of the baseline visit) ocular surgery, 
trauma, herpes, or recurrent inflammation 
• 
Contact lens use anticipated during the study 
• 
Periocular application of makeup during the study or tattooing of the lids  
• 
Use of any type of scleral lenses or sealed compartment ocular frames 
within 2 months of the screening visit, or planned use during the study 
• 
Use prohibited medications (topical, topical ophthalmic, systemic and/or 
injectable) during the appropriate pre-study wash-out period and during 
the study  
• 
Unwilling to abstain from the use of systemic medications known to cause 
dryness for the study duration that is not used on a stable dosing regimen 
for at least 30 days prior to the screening visit 
• 
Unwilling to abstain from the use of systemic or topical treatments for 
MGD or dry eye for the study duration (Including over-the-counter [OTC] 
artificial tears, ocular lubricants, or dietary supplements known to impact 
ocular surface health [e.g., Omega 3 supplements] except those prescribed 
for use as part of the study) 
• 
Eyelid abnormalities that affect normal lid function in either eye other 
than those caused by meibomian gland dysfunction 
• 
Diagnosis of hepatitis C infection, human immunodeficiency virus (HIV) 
infection, sarcoidosis, amyloidosis, active tuberculosis, or graft versus 
host disease  
• 
Known carrier of infectious disease 
• 
History of anterior segment surgery or trauma that could affect corneal 
sensitivity (e.g., cataract surgery or any surgery involving a limbal or 
corneal incision) in either eye within the 12 months prior to the screening 
visit  
• 
Planned anterior segment surgery (e.g., cataract surgery or any surgery 
involving a limbal or corneal incision) in either eye during the study 
period  
• 
Known allergy or sensitivity to fluorescein, lissamine green, or the study 
medication or its components  
• 
Use of medicated shampoos containing selenium (e.g., Selsun Blue, 
Exsel, Selsum, and Seleen) following the screening visit  
• 
Patient is unlikely to follow study instructions or to complete all required 
study visits or has a condition or situation that in the investigator’s 
opinion, may put the patient at significant risk, may confound the study 
results, or may interfere significantly with the patient’s participation in 
the study 
• 
Patient is an employee at the investigational site or is related to any 
member of the study staff  
• 
Pregnant, nursing, or females of childbearing potential and not utilizing 
adequate birth control measures, or planning pregnancy 
• 
Participation in another clinical trial involving a therapeutic drug or 
device within the past 30 days (except for AZR-MD-001) 
• 
Epilepsy or history of migraines exacerbated by flashing, strobe-like 
lights 


 
 
x 
• 
Meibography score at the screening visit of 4 (greater than 75% partial 
glands using the gestalt grading system) 
• 
Corneal staining ≥ 3 (between 33 and 100 dots) using the Oxford Scheme 
• 
Schirmer’s tear test without anesthesia ≤ 5 seconds in either eye at the 
screening visit 
 
 
 
Response 
Measures 
Evidence for safety and tolerability of AZR-MD-001 1.0%: 
 
• 
Adverse events  
• 
Study medication tolerability as measured by the Ocular Comfort 
Questionnaire 
• 
Best-corrected visual acuity (BCVA) 
• 
Biomicroscopy 
• 
Ophthalmoscopy 
 
General Statistical 
Methods and 
Types of Analyses:   
The safety population will include all treated patients.  For safety variables, 
patients in the safety population will be analyzed by the treatment actually 
received.  
 
Safety: Safety measures will be analyzed using the safety population.  Medical 
Dictionary for Regulatory Activities (MedDRA) nomenclature will be used to 
code adverse events. Treatment-emergent adverse events will be summarized.  
The adverse events will be classified into ocular and nonocular types and will be 
summarized separately.   
 
In general, continuous data will be summarized with descriptive statistics (number 
of patients, mean, standard deviation, median, minimum, and maximum) and will 
be analyzed using analysis of variance (ANOVA) techniques or 2-sample t-tests 
for between-group comparisons, and paired t-tests for within-group analyses.  
Categorical variables will be summarized by sample size (N), frequency count, 
and percent, and they will be analyzed using Pearson’s chi-square test or Fisher’s 
exact test (if the expected cell count is less than 5 in 25% or more of the cells).  
Ordinal variables will be analyzed using the Cochran-Mantel-Haenszel (CMH) or 
the Wilcoxon rank-sum test for between-treatment comparisons and the sign-rank 
test for within-treatment comparisons.  
 
Sample Size Calculation:   The sample size is determined empirically.   
 
 
 


 
 
xi 
 
Figure 1 
Single-center, single-masked, vehicle-controlled, randomized, parallel group study 
 
 
 
 
 
 
 
 
 
 
 
 
 


1.3 
SCHEDULE OF ACTIVITIES (SOA)  
Table 1 Schedule of Visits and Procedures 
 
Screening/-2 weeks 
Day 0 
2, 4 and 6 weeks 
Month 3 (Exit) 
Visit Window 
N/A 
± 3 Days 
± 7 Days 
± 7 Days 
Informed consent/authorization 
X 
 
 
 
Demographics  
X 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
Medical and ophthalmic history 
X 
 
 
 
Medication history 
X 
 
 
 
Washout medications 
X 
 
 
 
Best-corrected visual acuity (BCVA) 
X 
X 
X 
X 
Subjective questionnaires including visual analogue scales (VAS) and ocular 
surface disease index (OSDI) 
X 
X 
X 
X 
Tear evaporation rate 
X 
X 
X 
X 
Non-Invasive Tear Break Up Time (TearScope) 
X 
X 
X 
X 
Lipid layer thickness (LipiView II) 
X 
X 
X 
X 
Tear meniscus height (Oculus Keratograph 5M) 
X 
X 
X 
X 
Tear Break Up Time (TBUT)  
X 
X 
X 
X 
Sodium fluorescein corneal staining, Oxford scale 
X 
X 
X 
X 
Sodium fluorescein staining (Eyelid margin and mucocutaneous junction 
evaluation) 
X 
X 
X 
X 
Meibomian gland evaluation  
X 
X 
X 
X 
Slit-lamp biomicroscopy (includes eyelid margin) a 
X 
X 
X 
X 
Lissamine green conjunctival staining, Oxford scale 
X 
 
X 
X 
Lissamine green staining (Eyelid margin and mucocutaneous junction evaluation)  
X 
X 
X 
X 
Schirmer without Anesthesia 
X 
X 
X 
X 
Intraocular pressure (IOP) 
X 
 
 
X 
Ophthalmoscopy exam  
X 
 
 
X 
Meibography 
X 
 
 
X 
Adverse events/medications/tolerability  
X 
X 
X 
X 
Medication dispensing/return 
X 
X 
X 
X 
Physician Observation of Drug Application Methods 
 
X 
 
 
a a photograph of each eye will be obtained at least once for each patient, and photographs and video recording of any interesting/unusual findings may also be 
made for documentation and/or follow-up purposes 


AZR-MD-001 (Selenium disulfide Agonist) 
Version 2.0 
Protocol SOVS2020-080 
14Apr-2020 
 
 
1 
 
2 
 
INTRODUCTION 
 
2.1 
BACKGROUND MGD 
Meibomian gland dysfunction (MGD) is a chronic, diffuse abnormality of the meibomian glands, 
commonly characterized by terminal duct obstruction and/or qualitative/quantitative changes in 
the glandular secretion.  Terminal duct obstruction is caused by hyperkeratinization of the ductal 
epithelium (Nichols et al, 2011).  This may result in alteration of the tear film, symptoms of eye 
irritation, and ocular surface disease such as evaporative dry eye.  The principal clinical 
consequence of obstructive MGD is evaporative dry eye syndrome and large population based 
studies (i.e., Bankok Study and the Shihpai Eye Study) estimate that over 60% of patients with dry 
eye symptoms also have MGD (Schaumberg et al, 2011).     
MGD may be diagnosed by meibomian gland expression alone, with demonstration of an altered 
quality of expressed secretions, and/or by a loss of gland functionality (Nelson et al, 
2011).   Population based studies have estimated the prevalence of MGD to vary between 3.5% 
and 70% of the general population.  The prevalence of MGD appears higher in Asian populations 
(i.e., 46.5% to 69.3%) and increases with age (Schaumberg et al, 2011).  Risk factors in the 
pathogenesis of obstructive MGD include age, hormonal disturbances and environmental 
influences (e.g., contact lenses).  
Meibomian glands are large sebaceous glands that are located as separate gland strands in parallel 
arrangement within the tarsal plates of the eyelids.  Meibomian glands produce meibum via a 
holocrine mechanism during which meibocytes are transformed into the meibum.  Following 
production in the gland acini, meibum is transported through the ductal system via the connecting 
duct and the central duct towards the orifice at the free eyelid margin close to the inner eyelid 
border (Knop et al, 2011).   
Meibum is a complex mixture of various polar and nonpolar lipids containing cholesteryl esters, 
triacylglycerol, free cholesterol, free fatty acids, phospholipids, wax esters, diesters, and minor 
protein components.  Normal meibum is a clear liquid at body temperature (Green-Church et al, 
2011).  It is transported within the gland by the force of secretory pressure from continuous 
secretion and by muscular action of the orbicularis muscle and riolans muscles during 
blinking.  After it is delivered onto the posterior eyelid margin, meibum moves from the posterior 
eyelid margin reservoir onto the tear meniscus and is pulled as a thin layer onto the pre-ocular tear 
film every time the eyelid opens.  During closure of the eyelid, it is compressed and a small part 
is continuously renewed.  Meibum forms the outer lipid layer of the tear film which functions to 
slow evaporation of the aqueous component of the tear film, preserves the clear optical surface, 


AZR-MD-001 (Selenium disulfide Agonist) 
Version 2.0 
Protocol SOVS2020-080 
14Apr-2020 
 
 
2 
and forms a barrier to protect the eye from microbial agents and organic matter (e.g., dust and 
pollen) (Green-Church et al, 2011).   
 
2.2 
STUDY RATIONALE & KNOWN POTENTIAL BENEFITS 
While there are no approved pharmacological treatments for terminal duct obstruction from 
hyperkeratinization associated with MGD, compounds that reduce disulfide bonds (S-S) have 
shown promise. Akyol-Salman and colleagues (2010) used N-acetyl-cysteine (NAC) in 20 patients 
with MGD and demonstrated a statistically significant improvement in TBUT and symptoms (e.g., 
itching) by 1 month (Akyol-Salman et al, 2010; Akyol-Salman et al, 2012).  Selenium sulfide as a 
0.5% ointment has also been applied to the lid margin as a treatment for seborrheic blepharitis (see 
Table 2). 
 
 


AZR-MD-001 (Selenium disulfide Agonist) 
Version 2.0 
Protocol SOVS2020-080 
14Apr-2020 
 
 
3 
 
Table 2: Topical ophthalmic use of selenium disulfide as a treatment for seborrheic blepharitis 
 
Study 
No. of 
Subjects 
Selenium 
Disulfide 
Concentration  
Exposure 
Efficacy 
Outcome 
Bahn (1954) 
100 
0.50% 
Twice-weekly for 2 
weeks then once-
weekly for 6 weeks. 
Resolution of 
signs and 
symptoms in 
97% of subjects. 
Thygeson and Vaughan 
(1954) 
89 
0.50% 
Twice-weekly for a 
period of between 2 
months and 1 year. 
Improvement in 
all eyes and a 
cure in 75% of 
subjects. 
Cohen (1954) 
40 
0.63% 
Every other night 
for 4 applications 
then repeated 
whenever disease 
flared. 
Resolution of 
signs and 
symptoms in 
92% of subjects. 
Wong et al. (1956) 
76 
(eyes) 
0.50% 
Twice-daily for 4 
weeks + daily eyelid 
cleaning. 
Improvement of 
signs and 
symptoms in 
80% of subjects. 
 
Azura Ophthalmics is evaluating AZR-MD-001 ointment/semi-solid drug (selenium sulfide) as a 
potential treatment for MGD and associated evaporative DED.  Selenium sulfide exists as a 
mixture of selenium monosulfide and selenium disulfide.  AZR-MD-001 uses the same API as 
commercially available marketed products (i.e., Selsun Blue, Exsel, Selsum. And Seleen).  In these 
shampoos selenium sulfide is used as an anti-fungal and anti-dandruff ingredient.  It is marketed 
at a 1% concentration in non-prescription products and at a 2.5% concentration in prescription 
products.  Selenium sulfide works as a keratolytic agent by softening keratinized material.   
Clinical study MGSS1 was a prospective, interventional, non-randomized, contra-lateral eye 
controlled pilot study of selenium sulfide shampoo (2.5%) in 18 MGD patients.  Patients were 
treated under additional safety measures, twice-weekly for 34 weeks and then had a single 
treatment on day 44.  Selenium sulfide shampoo (2.5%) was safe and well tolerated with controlled 
dosing.  One patient (FHT,002) developed conjunctivitis and superficial punctate keratitis and one 
patient (MCG,006) developed superficial punctate keratitis.  The adverse events could be 
attributed to the surfactant in the shampoo (Sodium Lauryl Sulphate).  Both patient’s symptoms 


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resolved upon cessation of treatment.  Significant improvements in TBUT (p = 0.0008), meibum 
quality (p = 0.002), and patency (p=0.02) for the drug treated eye over the contra-lateral eye were 
observed by day 22.   
Clinical Protocol AZ201801 was a multicenter, double-masked, vehicle-controlled, randomized, 
parallel group study carried out in 2 sequentially overlapping cohorts (Cohort 1: sequential rising 
concentrations of AZR-MD-001 ointment/semi-solid drug (i.e., 0.1%, 0.5%, 1.0%, or a top dose 
up to 2.5%) and AZR-MD-001 vehicle dosed twice-weekly and/or once daily in the evening; 
Expansion Cohort: parallel doses of up to two concentrations of AZR-MD-001 ointment/semi-
solid drug (i.e., two of four available concentrations: 0.1%, 0.5%, 1.0%, or 2.5%) and AZR-MD-
001 vehicle dosed either twice-weekly or once daily in the evening.  The first pre-planned Interim 
Analysis covered all patients up to the 10th enrolled patient in Cohort 1, Group 3 completing the 
Month 3 Visit and who met all protocol inclusion and exclusion criteria and had at least one post-
baseline visit. 
Eleven patients were randomized to Cohort 1, Group 1 (0.1%, twice-weekly) between September 
10th, 2018 and October 19th, 2018 in ongoing clinical study AZ201801.  Twelve patients were 
randomized to Cohort 1, Group 2 (0.5%, twice-weekly) between October 19th, 2018 and February 
20th, 2019.  Ten patients were randomized to Cohort 1, Group 3 (1.0%, twice-weekly) between 
April 22nd, 2019 and June 19th, 2019.   
As specified in Protocol Amendment # 2 dated January 2019, the primary efficacy variables for 
MGD included change from baseline to month 3 in Meibomian Gland Score (MGS) and measures 
of Total Ocular Surface Disease Index (OSDI).  Least Square (LS) mean changes from baseline 
(larger scores signal improvement) for MGS at month 3 were 4.5 ± 2.0 (p = 0.025) for the Vehicle 
Group; 1.2 ± 2.0 (p = 0.56) for the AZR-MD-001 0.1% Group (sub-therapeutic dose); 4.9 ± 2.1 (p 
= 0.02) for the AZR-MD-001 0.5% Group; and 12.2 ± 2.4 (p = < 0.0001) for the AZR-MD-001 
1.0% Group.  Total OSDI showed the same pattern of results.  Least square (LS) mean changes 
from baseline (smaller scores signal improvement) for Total OSDI at month 3 were 0.0 ± 3.4 (p = 
0.99) for the Vehicle Group; 9.5 ± 3.8 (p = 0.01) for the AZR-MD-001 0.1% Group; -6.9 ± 4.0 (p 
= 0.08) for the AZR-MD-001 0.5% Group; and -12 ± 5.1 (p = < 0.01) for the AZR-MD-001 1.0% 
Group.  The difference of 12 between the Vehicle and AZR-MD-001 1.0% Groups was statistically 
significant (p = 0.03) and the results appear dose responsive. 
Ocular irritation, conjunctivitis, and epithelial keratitis were observed in clinical protocol 
AZ201801. Data review from study AZ201801, up to the Interim Analysis, did not identify any 
significant and/or unexpected safety or tolerability findings for AZR-MD-001 0.1%, 0.5% or 1.0% 
(see the Investigator’s Brochure for more detail). Some patients did anecdotally report that they 


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preferred nighttime application over daytime application in the clinic as they experienced better 
study drug tolerability. Investigators also noted that tolerability was improved for some patients 
with pre-dosing of an artificial tear.  
Based upon positive efficacy and safety results from clinical study MGSS1 for the ocular 
application of selenium disulfide shampoo (2.5%) and from Clinical Protocol AZ201801 for AZR-
MD-001 (0.5% and 1.0%), Azura Ophthalmics is further evaluating the best dosing regimen for 
AZR-MD-001 (1.0%) ointment/semi-solid drug, surfactant free, in patients with MGD. 
 
 


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2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
 
Selenium sulfide: 
Selenium sulfide is used as an anti-fungal and anti-dandruff ingredient in commercially available 
shampoo (i.e., Selsun Blue, Exsel, Selsum. And Seleen).  Selenium sulfide is not absorbed through 
the skin following topical use and is considered safe for topical use.  In 15 people who applied 
2.5% selenium sulfide to the torso overnight no appreciable levels of selenium sulfide were 
measured in the serum or in the urine (Kalivas, 1993).  Additionally, in a 1-year exposure study, 
16 people who washed their hair weekly with 1% shampoo monthly did not demonstrate urine 
selenium levels that were different from 8 control subjects (Cummins and Kimura, 1971).  These 
data support the conclusion that selenium is not absorbed through intact skin.  Systemic absorption 
of selenium has been reported with open lesions on the scalp (Sternberg et al, 1964).  Based upon 
these findings, systemic exposure to selenium disulfide following topical, ocular dosing of AZR-
MD-001 ointment/semi-solid drug is considered a minimal risk. 
Selenium can have inhibitory effects on proteins and enzymes by reacting with thiol or sulfhydryl 
groups in proteins.  Specifically, selenium sulfide, in vitro, was shown to inactivate the free 
sulfhydryl groups on human epidermis and mouse liver (Flesch, 1953). 
Ocular toxicity studies with selenium sulfide have been completed in rabbits.  Selenium sulfide 
was administered to the conjunctival sac of rabbits to compare the toxicity of 0.5% selenium 
disulfide ophthalmic ointment to that of 2.5% selenium sulfide shampoo (Rosenthal and Adler, 
1962).  Administration of the 0.5% selenium disulfide ophthalmic ointment was not associated 
with any ocular toxicity while 2.5% selenium sulfide shampoo was associated with chemosis, 
redness, corneal clouding, edema, and “total staining” in all eyes within 2 hours of administration.  
It is unclear if 2.5% selenium sulfide or if another ingredient of the shampoo is bothersome to the 
ocular surface.  Ocular irritation, conjunctivitis, and epithelial keratitis have been reported in 
humans dosed with selenium sulfide as a 0.5% ophthalmic ointment and Sodium Lauryl Sulphate 
applied to the lid margin (Bahn, 1954).  In clinical study MGSS1, selenium sulfide shampoo 
(2.5%) was safe and well tolerated with controlled dosing.  One patient (FHT,002) developed 
conjunctivitis and superficial punctate keratitis and one patient (MCG,006) developed superficial 
punctate keratitis.  Both patient’s symptoms resolved upon cessation of drug treatment.  The 
observed ocular signs could be attributed to the surfactant, Sodium Lauryl Sulphate, in the 
shampoo. 


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To date ongoing study AZ201801 has evaluated AZR-MD-001 ointment/semi-solid drug (0.1% 
and 0.5%) either twice weekly or once daily without any obvious, significant ocular safety or 
tolerability findings (see the AZR-MD-001 Investigator’s Brochure for a more detailed description 
of the AZR-MD-001 safety profile).   
2.3.2 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
The predominate conventional treatments for obstructive MGD are relatively invasive, time 
consuming and uncomfortable for patients.  There are currently no approved pharmacologic 
treatments for MGD.  Thus, there is a medical need for pharmacologic treatments for MGD.  
resulting in an improved safety profile.  
Given that the tolerability findings associated with AZR-MD-001 1.0% in protocols SOVS-2019-
070 and AZ201801 appear to be improved by both nighttime drug application and artificial tear 
use, it is desirable to determine the safety and tolerability of AZR-MD-001 1.0% following evening 
administration only, and whether dosing Hylo-Forte® approximately 5 minutes before study 
ointment will enhance either the safety or tolerability of AZR-MD-001 1.0% following evening 
dosing. 
3 
OBJECTIVES AND ENDPOINTS 
Table 3–1 
Table of Objectives, Endpoint, and Endpoint Justification 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
 
 
 
 
To evaluate the safety and 
tolerability of AZR-MD-001 
1.0% ointment/semi-solid drug 
applied to the lower lid twice-
weekly following evening only 
dosing for up to 3 months in 
MGD.   
 
To evaluate whether dosing 
Hylo-Forte® approximately 5 
minutes before study ointment 
will enhance either the safety 
or tolerability of AZR-MD-001 
1.0% following evening only 
dosing. 
 
  
Safety/Adverse Events: 
• Incidence rates of each 
treatment-emergent adverse 
events.   
• Tables for all treatment-
emergent adverse events 
regardless of causality. 
• Tables for all treatment-
emergent adverse events 
considered to be treatment-
related. 
• Shift tables for safety 
variables (e.g., IOP, 
biomicroscopy, and 
ophthalmoscopy). 
 
 
The endpoints for safety and 
tolerability are all commonly 
used in ophthalmic drug and 
device trials.   
 
 
 
 
 
 
 
 
 
 
 
 
 


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4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
Single-center, single-masked (the individual(s) performing efficacy and safety measures will be 
masked to treatment assignment for the patient(s) they are assessing), vehicle-controlled, 
randomized, parallel group study.  For all dose groups a screening visit will be followed by a 
baseline visit 14 days later (qualification period). At the end of the qualification period patients 
who still exhibit signs of MGD and who can comply with dosing instructions at the baseline visit 
will be enrolled into a 3-month treatment period.. At the baseline (Day 0) visit, patients will be 
randomly assigned in a 2:2:1:1 ratio to receive either AZR-MD-001 1.0% ointment/semi-solid 
drug or AZR-MD-001 1.0% ointment/semi-solid drug plus Hylo-Forte® or AZR-MD-001 vehicle 
or AZR-MD-001 vehicle plus Hylo-Forte® for twice-weekly evening administration for 3 months. 
Where applicable, Hylo-Forte® will be dosed approximately 5 minutes before study ointment. The 
study flow is shown in Figure 1. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
While there are no approved pharmacological treatments for terminal duct obstruction from 
hyperkeratinization associated with MGD, compounds that reduce disulfide bonds (S-S) have 
shown promise. Akyol-Salman and colleagues (2010) used N-acetyl-cysteine (NAC) in 20 patients 
with MGD and demonstrated a statistically significant improvement in TBUT and symptoms (e.g., 
itching) by 1 month (Akyol-Salman et al, 2010; Akyol-Salman et al, 2012).  Selenium sulfide as a 
0.5% ointment has also been applied to the lid margin as a treatment for seborrheic blepharitis (see 
Table 2). 
Azura Ophthalmics is evaluating AZR-MD-001 ointment/semi-solid drug (selenium disulfide) as 
a potential treatment for MGD and associated evaporative DED.  Selenium sulfide exists as a 
mixture of selenium monosulfide and selenium disulfide.  AZR-MD-001 uses the same API as 
commercially available marketed products (i.e., Selsun Blue, Exsel, Selsum. And Seleen).  In these 
shampoos selenium sulfide is used as an anti-fungal and anti-dandruff ingredient.  It is marketed 
at a 1% concentration in non-prescription products and at a 2.5% concentration in prescription 
products.   
Clinical study MGSS1 was a prospective, interventional, non-randomized, contra-lateral eye 
controlled pilot study of selenium sulfide shampoo (2.5%) in 18 MGD patients.  Patients were 
treated under additional safety measures, twice-weekly for 34 weeks and then had a single 
treatment on day 44.  Selenium sulfide shampoo (2.5%) was safe and well tolerated with controlled 
dosing.  One patient (FHT,002) developed conjunctivitis and superficial punctate keratitis and one 


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patient (MCG,006) developed superficial punctate keratitis.  The adverse events could be 
attributed to the surfactant in the shampoo (Sodium Lauryl Sulphate).  Both patient’s symptoms 
resolved upon cessation of drug treatment.  Significant improvements in TBUT (p = 0.0008), 
meibum quality (p = 0.002), and patency (p=0.02) for the drug treated eye over the contra-lateral 
eye were observed by day 22.   
Clinical study AZ201801, Amendment 3 is an ongoing multicenter, double-masked, vehicle-
controlled, randomized, parallel group study carried out in 2 sequentially overlapping cohorts 
(Cohort 1:  sequential rising concentrations of AZR-MD-001 ointment/semi-solid drug (i.e., 
Cohort 1, Group 1-0.1%, Cohort 1, Group 2-0.5%, Cohort 1, Group 3-1.0%, and Group 4-0.1%, 
0.5%, 1.0%, or 2.5%) and AZR-MD-001 vehicle dosed twice-weekly and/or once daily in the 
evening; Expansion Cohort: parallel doses of up to two concentrations of AZR-MD-001 
ointment/semi-solid drug (i.e., two of four available concentrations: 0.1%, 0.5%, 1.0%, or 2.5%) 
and AZR-MD-001 vehicle dosed either twice-weekly or once daily in the evening.  For Cohort 1 
patients will be randomized in a 4:1 ratio (AZR-MD-001: Vehicle) and in the Expansion Cohort 
patients will be randomized in a 1:1:1 ratio (see Section 2.2 for more detail on the study). 
  
Clinical study SOVS2019-070 is an ongoing single-center, double-masked, vehicle-controlled, 
randomized study to evaluate the efficacy, safety and tolerability of AZR-MD-001 1.0% in 
participants with contact lens discomfort (CLD). During this study, some tolerability issues were 
observed, with three participants experiencing adverse events which led to discontinuation from 
the study. All findings were consistent with prior reported adverse events for AZR-MD-001 and 
selenium sulfide and were reversable upon discontinuation of treatment.   
Based upon these findings, patient’s antidotal reports of improved tolerability with nighttime 
application, and the successful use of artificial tears before dosing to improve tolerability, it is 
desirable to investigate different methods to improve the safety and tolerability of AZR-MD-001 
1.0% in patients with MGD, who are the target population for this treatment.   
 
4.3 
END OF STUDY DEFINITION 
A participant is considered to have completed the study if he or she has completed all scheduled 
visits including the last visit or the last scheduled procedure shown in the Schedule of Activities 
(SoA), Section 1.3. 
5 
STUDY POPULATION 


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The study will consist of patients with Meibomian Gland Dysfunction (MGD).   
5.1 
INCLUSION CRITERIA 
 
• Male or female, 18 years of age or older at screening visit  
• Capable of understanding and willing to provide written informed consent and likely to 
complete the entire course of study according to instructions 
• Written authorization for use and release of health and research study information has been 
obtained 
• Best-corrected visual acuity (BCVA) of 20/40 or better (Snellen equivalent), using the 
logarithm of the minimum angle of resolution (LogMAR) in each eye at the screening visit 
• Evidence of meibomian gland obstruction (based on a meibomian gland secretion (MGS) 
score of ≤12 for 15 glands of the lower lid) in both eyes at the baseline visit 
• Reported dry eye signs and symptoms within the past 3 months: Ocular Surface Disease 
Index (OSDI) score ≥ 13; TBUT < 10 seconds in both eyes  
• Demonstrated ability to follow dosing instructions at the baseline visit 
• Prior to the screening visit patients are required to discontinue:  
o Use of systemic antihistamines or isotretinoin for at least 1 month  
o Anti-inflammatory treatments for DED (e.g., cyclosporine ophthalmic emulsion 
[Restasis® or Ikervis®] or lifitegrast ophthalmic solution [Xiidra®]) for at least 3 
months 
o All other prescription medications used for dry eye or MGD (e.g., antibiotics, 
corticosteroids, and non-steroidal anti-inflammatory drugs) for at least 2 weeks 
o LipiFlow® or other lid-heating therapy, meibomian gland probing, or therapeutic 
gland expression in either eye within 6 months prior to the screening visit 
o All other MGD treatments (e.g., at-home warm compress therapy, eyelid hygiene, 
eyelid massage, and manual lid expression) for at least 2 weeks   
And 
o Women of childbearing potential must have a history of bilateral tubal ligation or 
use oral contraceptives, implants, injectables, transdermal patch, or intrauterine 


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device for birth control during the study.  Abstinence is considered a reliable 
method of birth control.  If these methods of birth control do not apply, women of 
childbearing potential must have a monogamous partner who has had a vasectomy 
at least 3 months before the screening visit or who is of the same gender. 
 
5.2 
EXCLUSION CRITERIA 
 
• Uncontrolled ocular disease (except for MGD) or uncontrolled systemic disease 
• Patient has glaucoma or ocular hypertension as demonstrated by an intraocular pressure 
(IOP) in either eye at screening of ≥24 mm Hg determined by Goldman applanation 
tonometry or has planned insertion/removal of glaucoma filtration shunts/devices during 
the study  
• Corneal abnormality or disorder that impacts normal spreading of the tear film 
(keratoconus, pterygia, scarring) or corneal integrity 
• BCVA worse than 20/40 in either eye at the screening visit 
• Current use of punctal plugs, anticipated insertion during the study, or a history of punctal 
cautery in either eye at any time prior to the baseline visit or anticipate such a procedure 
during the study 
• Keratoconjunctivitis sicca secondary to destruction of conjunctival goblet cells as occurs 
with vitamin A deficiency or scarring, such as that with cicatricial pemphigoid, alkali burns, 
Stevens-Johnson syndrome, trachoma, or irradiation 
• Keratoconjunctivitis sicca secondary to aqueous deficient DED 
• Active ocular infection (bacterial, viral, or fungal) at the screening visit 
• Corneal, conjunctival, or eyelid inflammation (including allergic, vernal, or giant papillary 
conjunctivitis and mucous membrane pemphigoid) that in the judgment of the investigator 
may interfere with the study results or the ability of subjects to complete the treatment 
period 
• Recent (within the past 3 months of the baseline visit) ocular surgery, trauma, herpes, or 
recurrent inflammation 
• Contact lens use anticipated during the study 
• Periocular application of makeup during the study or tattooing of the lids  
• Use of any type of scleral lenses or sealed compartment ocular frames within 2 months of 
the screening visit, or planned use during the study 
• Use prohibited medications (topical, topical ophthalmic, systemic and/or injectable) during 
the appropriate pre-study wash-out period and during the study  


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• Unwilling to abstain from the use of systemic medications known to cause dryness for the 
study duration that is not used on a stable dosing regimen for at least 30 days prior to the 
screening visit 
• Unwilling to abstain from the use of systemic or topical treatments for MGD or dry eye for 
the study duration (Including over-the-counter [OTC] artificial tears, ocular lubricants, or 
dietary supplements known to impact ocular surface health [e.g., Omega 3 supplements] 
except those prescribed for use as part of the study) 
• Eyelid abnormalities that affect normal lid function in either eye other than those caused 
by meibomian gland dysfunction 
• Diagnosis of hepatitis C infection, human immunodeficiency virus (HIV) infection, 
sarcoidosis, amyloidosis, active tuberculosis, or graft versus host disease  
• Known carrier of infectious disease 
• History of anterior segment surgery or trauma that could affect corneal sensitivity (e.g., 
cataract surgery or any surgery involving a limbal or corneal incision) in either eye within 
the 12 months prior to the screening visit  
• Planned anterior segment surgery (e.g., cataract surgery or any surgery involving a limbal 
or corneal incision) in either eye during the study period  
• Known allergy or sensitivity to fluorescein, lissamine green, or the study medication or its 
components  
• Use of medicated shampoos containing selenium (e.g., Selsun Blue, Exsel, Selsum, and 
Seleen) following the screening visit  
• Patient is unlikely to follow study instructions or to complete all required study visits or 
has a condition or situation that in the investigator’s opinion, may put the patient at 
significant risk, may confound the study results, or may interfere significantly with the 
patient’s participation in the study 
• Patient is an employee at the investigational site or is related to any member of the study 
staff  
• Pregnant, nursing, or females of childbearing potential and not utilizing adequate birth 
control measures, or planning pregnancy 
• Participation in another clinical trial involving a therapeutic drug or device within the past 
30 days (except for AZR-MD-001) 
• Epilepsy or history of migraines exacerbated by flashing, strobe-like lights 
• Meibography score at the screening visit of 4 (greater than 75% partial glands using the 
gestalt grading system) 
• Corneal staining ≥ 3 (between 33 and 100 dots) using the Oxford Scheme 
• Schirmer’s tear test without anesthesia ≤ 5 seconds in either eye at the screening visit 
 


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5.3 
LIFESTYLE CONSIDERATIONS 
To be eligible for this study patient must comply with the following: 
• Patients should not have LipiFlow® or other lid-heating therapy, meibomian gland 
probing, or therapeutic gland expression in either eye within 6 months of the baseline visit 
or during the study. 
• Patients must have discontinued (2 weeks before baseline) and be willing to remain off 
other MGD treatments (e.g., at-home warm compress therapy, eyelid hygiene, eyelid 
massage, and manual lid expression) during the study (except those prescribed for use as 
part of the study). 
• Patients should not have punctal plugs or plan to have punctal plugs inserted during the 
study. 
• Patients must have discontinued (1 month before baseline) and be willing to remain off 
antihistamines or isotretinoin during the study. 
• Patients must have discontinued (3 months before baseline) and be willing to remain off 
Anti-inflammatory treatments for DED (e.g., cyclosporine ophthalmic emulsion 
[Restasis® or Ikervis®] or lifitegrast ophthalmic solution [Xiidra®]). 
• Patients should avoid the use of medicated shampoos containing selenium (e.g., Selsun 
Blue, Exsel, Selsum, and Seleen) following the baseline visit. 
• Patients must have discontinued (2 weeks before baseline) and be willing to remain off all 
other prescription medications used for dry eye or MGD (e.g., antibiotics, corticosteroids, 
and non-steroidal anti-inflammatory drugs) during the study. 
• Patients must avoid periocular application of makeup during the study  
 
Patients should be instructed to strictly follow the visit schedule and to report any changes in 
condition to the investigative site personnel.  
The patients should be instructed to maintain a stable dose of any concomitant medication used 
chronically, or any new medication initiated during the study if possible.  Patients should be 
instructed to communicate any changes to their medication at their next study visit.  Patients should 
also be reminded to contact the study site if they experience difficulties during their study 
participation. 
Patients should refrain from using any ophthalmic preparations other than study treatment in order 
to obtain an accurate assessment of their signs and symptoms.  Patients should be instructed to 
communicate any changes to their ophthalmic preparations other than study treatment at their next 
study visit.   
5.4 
SCREEN FAILURES 


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Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently randomly assigned to the study intervention or entered in the study. A minimal 
set of screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of 
normal variability in safety measures may be rescreened one additional time. Rescreened 
participants should be assigned the same participant number as for the initial screening. 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Approximately thirty (30) patients with MGD will be randomized to the study. Based upon data 
from the LipiFlow® development program a screen failure rate of ~ 40% is expected for new 
patients.  Thus, ~up to 42 patients will need to be screened to achieve ~up to 30 patients 
randomized to treatment. 
All advertisements, if required for subject recruitment, will be submitted to the IEC and approved 
by the IEC before they are used.   
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY TREATMENT(S)/ FORMULATION(S)/ MEDICAL DEVICE 
COMPOSITION OR DESIGN 
AZR-MD-001 Ophthalmic Ointment contains the drug product, AZR-MD-001 (1.0%), and 
suitable excipient.  The only excipient in the formulation is White Soft Paraffin (Petrolatum 
white).  The AZR-MD-001 vehicle and product labelled “Vaseline” for use at the baseline visit 
contain only Petrolatum white. The formulations will be supplied in unit dose containers (see  


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Table 6.1.1–1).  
 
 


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Table 6.1.1–1 Investigational Product and Packaging / Labelling Characteristics 
 
Investigational Product 
 
Product name: 
AZR-MD-001 sterile 
ophthalmic ointment 
(Selenium disulfide 
API in suspension) 
Vehicle 
“Vaseline” 
Formulation 
description: 
AZR-MD-001 is an 
orange opaque 
dispersion ointment 
with an odor faintly of 
hydrogen sulfide 
Placebo ointment will 
match AZR-MD-001’s 
texture  
Placebo ointment will 
match AZR-MD-
001’s texture  
Dosage form: 
Ophthalmic 
ointment/semi-solid 
drug 
Ophthalmic 
ointment/semi-solid 
drug 
Ophthalmic 
ointment/semi-solid 
drug 
Unit dose 
strength(s)/Dosage 
level(s): 
1.0%10mg 
 
Placebo  
Petrolatum, white  
Placebo  
Petrolatum, white  
Route of 
Administration  
Topical 
Topical 
Topical 
Dosing 
instructions: 
 
Store between 2 – 8°C 
until opened. 
Refrigerate. Do not 
freeze. Stop use 4 
weeks (30 days) after 
opening. Protect from 
light 
Store between 2 – 8°C 
until opened. 
Refrigerate. Do not 
freeze. Stop use 4 
weeks (30 days) after 
opening. Protect from 
light. 
Store between 2 – 8°C 
until opened. 
Refrigerate. Do not 
freeze. Stop use 4 
weeks (30 days) after 
opening. Protect from 
light. 
Physical 
description: 
An orange opaque 
ointment packaged in 
a multi-use tube 
A white opaque 
ointment packaged in 
a multi-use tube 
A white opaque 
ointment packaged in 
a multi-use tube 
Device: 
 
Multi -use white tube 
with cap 
Multi -use white tube 
with cap 
Multi -use white tube 
with cap 
Method for 
individualizing 
dosage: 
Each container/tube is 
placed in an 
individual package 
and appropriately 
labelled. 
Each container/tube is 
placed in an individual 
package and 
appropriately labelled. 
Each container/tube is 
placed in an individual 
package and 
appropriately labelled 
API = Active pharmaceutical ingredient 
6.1.2 SELECTION OF DOSES IN THE STUDY 
AZR-MD-001 1.0% ointment/semi-solid drug has been selected for evaluation in this study.  


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6.1.3 DOSING AND ADMINISTRATION 
The study medication will be self-administered by the patient (or administered by a caregiver) at 
home in the evening.   
Patients (or a caregiver) will apply a dose of approximately 3.5mm (0.14inch, 4mg)using a dosing 
aid supplied by Azura Ophthalmics. Patients will then use their washed index finger to apply the 
drug to the tarsus of the lower lid of both eyes in the evening just before bedtime. They will be 
instructed to press the ointment strip against their index finger to leave a thin and uniform ointment layer 
over the finger. The patient will then blink several times to transfer a portion of the drug from the 
lower eyelid to the upper eyelid (see the Dosing Instruction Sheet for more detail). 
During the double-masked treatment period, each patient (or caregiver) must apply 1 application 
of the vehicle or active drug twice weekly in the evening to the tarsus of the lower lid of both eyes.   
Multi-dose tubes of the masked study medication are each to be used for only 30 days to both eyes. 
The patient should be instructed to place the used tube in the used tube bag after use and should 
return used and unused tubes at the next study visit. 
 
PREPARATION/HANDLING/STORAGE/ 
ACCOUNTABILITY 
6.1.4 ACQUISITION AND ACCOUNTABILITY 
Subjects will be instructed on proper instillation and storage of study drug at the end of the baseline 
(day 0), 2 weeks, 4 weeks and 6 weeks visits, will be given written instructions and may also watch 
an instructional video. The used and unused study drug tubes will be collected at each visit from 
baseline up to and including month 3 to assess dosing. Dosing compliance will be based off of the 
used and unused tube count. If the subject is less than 80% or more than 125% compliant with 
dosing based on the expected number of used tubes, then the subject will be deemed non-compliant 
and a deviation should be recorded. 
6.1.5 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
The study packaging will be performed by PCI Pharma Services (PCI). All packaging 
and labeling operations will be performed according to Good Manufacturing Practice for 
Medicinal Products and the relevant regulatory requirements. 
Details of packaging and labeling are in final study documentation provided by PCI Pharma 
Services.  


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6.1.6 PRODUCT STORAGE AND STABILITY 
The study medication must be stored in a secure area accessible only to the investigator and his/her 
designees. The study medication will be administered only to patients entered into the clinical 
study, in accordance with the conditions specified in this protocol.   
The study medication is to only be prescribed by the principal investigator or his/her named sub-
investigator(s), and is to only be used in accordance with this protocol. The study medication must 
only be distributed to patients properly qualified under this protocol to receive study medication. 
The investigator must keep an accurate accounting of the study medication received from the 
supplier. This includes the amount of study medication dispensed to patients, amount of study 
medication returned to the investigator by the patients, and the amount returned or disposed upon 
the completion of the study. A detailed inventory must be completed for the study medication. 
All study medication will be returned to Azura Ophthalmics or their designee or destroyed at the 
study site. The return or disposal of study medication will be specified in writing. AZR-MD-001 
is to be refrigerated between 2 – 8°C until opened and protected from light. Maintenance of a 
temperature log (manual or automated) is required at the clinical site. 
6.1.7 PREPARATION 
Patients should let the study tube equilibrate at room temperature below 25°C for up to 15 minutes 
before dosing. Patients will use the study medication directly from the dose container in 
accordance with the protocol and should return the dose container to refrigeration between 2 – 8°C 
following successful dosing. For the next day of dosing, this process should be repeated. This in 
use pattern should continue for 30 days at which time the dose container should be used for a final 
day of dosing and then set aside for return to study investigator.   
6.2 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND 
BLINDING 
 
Site personnel conducting efficacy and safety measures will be masked to the treatment assignment 
for the 3 month treatment period.  
Screening numbers will be assigned sequentially by site.  At the end of the baseline visit, patients 
will be given a sequential randomization number which corresponds to a specific medication kit 
number(s) and type in the randomization log. Designated site personnel will report a medication 
kit number to use for each patient corresponding to the randomization number and will be 
responsible for monitoring and documenting patient compliance with dosing at each visit. The 
individual dispensing drug and monitoring compliance will not be the same person who conducts 
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Additionally, site personnel will observe patients applying ointment from a tube labelled “Vaseline” 
at the baseline visit, and will have access to instructional dosing videos.  
 
6.3 
CONCOMITANT THERAPY 
Patients must have discontinued and be willing to remain off all other ophthalmic preparations 
including artificial tears during the study (except those prescribed for use as part of the study).   
  
6.3.1 RESCUE MEDICINE 
In the event that rescue medication is required for worsening signs or symptoms of MGD or dry 
eye disease during the course of the study, patients will be provided an appropriate rescue regimen 
by the investigator/treating clinician, which may include ophthalmic corticosteroid preparations.  
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION   
Patients can voluntarily withdraw from the study at any time. The investigator can withdraw a 
patient from the study at any time for any reason. Additionally, patients can be discontinued from 
the study by an investigator if any of the following criteria are met: 
• patient develops (or had an exacerbation of) any medical condition that, in the opinion of 
the investigator, would have put the patient at an unacceptable medical risk or 
compromised the patient’s ability to participate in the study 
• patient is unwilling or unable to continue to comply with study procedures 
• patient becomes pregnant 
The study can be stopped at the study site(s) at any time by the site investigator(s). Azura 
Ophthalmics can also stop the study (and/or the study site[s]) with appropriate notification. 
If a patient discontinues participation in the study early, every attempt must be made to complete 
the exit procedures.  
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
FROM THE STUDY 
The investigator and Azura Ophthalmics have the right to withdraw a patient from the study at any 
time for any reason. When possible, the decision to withdraw a patient from the study should be 
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Azura Ophthalmics may recommend the site withdraw a participant for the following reasons: 
i. 
Patient Safety: New data/findings plus a DRC decision from ongoing study AZ201801 
indicates it is unsafe to continue patients in that study at a dose and frequency being used 
in the current study; 
ii. 
Manufacturing:  Any problem identified with clinical supplies that may require stopping 
of dosing; 
iii. 
Negligence: A general right to stop a study in the event of overt negligence by either party.  
Patients who are withdrawn early from the study should have early exit visit procedures completed 
at the time of withdrawal, or at their next scheduled visit, whenever possible. 
7.3 
LOST TO FOLLOW-UP 
A patient will be considered lost to follow-up if he or she fails to return for 2 consecutive scheduled 
visits and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site will attempt to contact the participant and reschedule the missed visit within the 
specified visit window (see Table 1.3) and counsel the patient on the importance of 
maintaining the assigned visit schedule and ascertain if the participant wishes to and/or 
should continue in the study. 
• Before a patient is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the patient’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the patient’s medical record or 
study file.  
• Should the patient continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
 


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8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
SAFETY AND OTHER ASSESSMENTS 
 
8.1.1 
SAFETY MEASURES 
The following safety measures will be examined: 
• adverse events (ocular and nonocular) 
• study medication tolerability as measured by the Ocular Comfort Questionnaire 
• best-corrected visual acuity (BCVA) 
• slit-lamp biomicroscopy  
• intraocular pressure (IOP) 
• ophthalmoscopy   
 
8.2 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
 
Adverse events occurring during the study will be recorded on an adverse event form.  If adverse 
events occur, the first concern will be the safety of the study participants.  
All adverse events that are drug-related and unexpected (not listed as treatment-related in the 
current Investigator's Brochure) must be reported to the governing Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) as required by the IRB/IEC, local regulations, 
and the governing health authorities.  Any adverse event that is marked ‘ongoing’ at the exit visit 
must be followed-up as appropriate. 
8.2.1 DEFINITION OF ADVERSE EVENTS (AE) 
An AE is defined as any untoward medical occurrence in a clinical study subject administered a 
medicinal product which does not necessarily have a causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not it is related to the medicinal (investigational) product. This includes an 
exacerbation of pre-existing conditions or events, intercurrent illnesses, drug interaction or the 
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source under specific efficacy assessments. Anticipated fluctuations of pre-existing conditions, 
including the disease under study that do not represent a clinically significant exacerbation or 
worsening need not be considered AEs. 
It is the responsibility of the investigator to document all AEs that occur during the study. AEs will 
be elicited by asking the subject a nonleading question, for example, “Have you experienced any 
new or changed symptoms since we last asked/since your last visit?”. AEs should be reported on 
the appropriate source page. 
Some illustrate examples follow to help understand the difference between events meeting the 
definition of an AE and those that don’t. 
Events meeting AE definition include: 
• 
Any abnormal safety assessments (e.g., vital signs), including those that worsen 
from baseline, and felt to be clinically significant in the medical and scientific 
judgement of the investigator. 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae). 
• 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not 
be reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE. 
 
Events NOT meeting definition of an AE include: 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition. 


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• 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
subject’s condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE. 
• 
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
 
8.2.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
If an event is not an AE per the definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease, etc). 
An SAE is any untoward medical occurrence or effect that, at any dose, 
• 
Results in death. 
• 
Is life-threatening (an AE is life-threatening if the subject was at immediate risk of death from 
the event as it occurred, i.e., it does not include a reaction that might have caused death if it 
had occurred in a more serious form). 
• 
Requires or prolongs inpatient hospitalization. (Complications occurring during 
hospitalization are AEs and are SAEs if they cause prolongation of the current hospitalization. 
Hospitalization for elective treatment of a pre-existing non-worsening condition is not, 
however, considered an AE. The details of such hospitalizations must be recorded on the 
medical history or physical examination page of the source). 
• 
Results in persistent or significant disability/incapacity. (An AE is incapacitating or disabling 
if it results in a substantial and/or permanent disruption of the subject’s ability to carry out 
normal life functions). 
• 
Results in a congenital anomaly/birth defect. 
In addition, medical and scientific judgement is required to decide if prompt notification is required 
in situations other than those defined for SAEs above. This may include any event that the 
investigator regards as serious that did not strictly meet the criteria above but may have jeopardized 
the subject or required intervention to prevent one of the outcomes listed above, or that would 


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suggest any significant hazard, contraindication, side effect, or precaution that may be associated 
with the use of the investigational product. 
8.2.2.1 
REPORTING OF SERIOUS ADVERSE EVENTS 
Any SAE must be reported by the investigator if it occurs during the clinical study within 24 hours 
of the investigator’s or site’s knowledge of the event, whether or not the SAE is considered to be 
related to the investigational product. An SAE report consists of the SAE form, the AE form 
medical history and the concomitant medication form. SAEs will be reported to Azura 
Ophthalmics, the Human Research Ethics Committee and any other relevant approving authorities.  
The site investigator will handle the SAE and ensure appropriate review and onward reporting to 
the Sponsor, with oversight of reporting to the ethics committees and competent authority as per 
local regulatory requirements:  
 
For medical emergencies contact the medical monitor: Peter McCluskey 
Phone: 02 9382 7300 
E-Mail: peter.mccluskey@sydney.edu.au 
 
The investigator should not wait to receive additional information to document fully the event 
before notification of a SAE, though additional information may be requested. Where applicable, 
information from relevant laboratory results, hospital case records, and autopsy reports should be 
obtained. 
Instances of death, congenital abnormality, or an event that is of such clinical concern as to 
influence the overall assessment of safety, if brought to the attention of the investigator at any time 
after cessation of study drug administration and linked by the investigator to this study, should be 
reported to Azura Ophthalmics. 
UNSW will promptly notify all relevant investigators and the regulatory authorities of findings 
that could adversely affect the safety of subjects, impact on the conduct of the study or alter the 
independent ethics committee (IEC)/institutional review board (IRB) approval/favorable opinion 
of the study.  
Details of the procedures to be followed if a pregnancy occurs are provided in Section 8.3.7. 


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8.2.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
8.2.3.1 
SEVERITY OF EVENT 
A clinical determination will be made of the intensity of an adverse event.  The severity assessment 
for a clinical adverse event must be completed using the following definitions as guidelines: 
Mild 
Awareness of sign or symptom, but easily tolerated 
Moderate 
Discomfort enough to cause interference with usual activity 
Severe 
Incapacitating with inability to work or do usual activity 
 
 
 


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8.2.3.2 
RELATIONSHIP TO STUDY INTERVENTION 
A determination will be made of the relationship (if any) between an adverse event and the study 
drug or study procedure, as applicable.  A causal relationship is present if a determination is made 
that there is a reasonable possibility that the adverse event may have been caused by the drug or 
study procedure.  Causality should be assessed using the following categories: 
• 
Unrelated: 
Clinical event with an incompatible time relationship to study drug 
administration, and that could be explained by underlying disease or other drugs or 
chemicals or is incontrovertibly not related to the study drug. 
• 
Unlikely: 
Clinical event whose time relationship to study drug administration makes 
a causal connection improbable, but that could plausibly be explained by underlying 
disease or other drugs or chemicals. 
• 
Possible: 
Clinical event with a reasonable time relationship to study drug 
administration, but that could also be explained by concurrent disease or other drugs or 
chemicals. 
• 
Probable: 
Clinical event with a reasonable time relationship to study drug 
administration, and is unlikely to be attributed to concurrent disease or other drugs or 
chemicals. 
• 
Very Likely/Certain: Clinical event with plausible time relationship to study drug 
administration, and that cannot be explained by concurrent disease or other drugs or 
chemicals. 
8.2.3.3 
ACTION TAKEN 
The investigator will describe the action taken in the appropriate source document, as follows: 
• 
None 
• 
Study drug stopped 
• 
Study drug temporarily interrupted 
• 
Concomitant medication 
• 
Other, specify. 
 
 


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8.2.4 TIME PERIOD & FREQUENCY FOR EVENT ASSESSMENT AND 
FOLLOW-UP 
Subjects with AEs will be followed-up until the event is resolved or until, in the opinion of the 
investigator, the event is stabilized or determined to be chronic. Details of AE resolution must be 
documented in the source documents.  
Subjects should be followed up for 30 days after receiving the last dose of study drug, and any 
AEs that occur during this time should be reported according to the procedures outlined above. 
8.2.4.1 
DOCUMENTATION AND REPORTING OF ADVERSE EVENTS 
AEs should be reported and documented in accordance with the procedures outlined below. All 
AEs occurring during the study must be documented on the relevant source pages. The following 
data should be documented for each AE: 
• 
Description of the symptom event 
• 
Classification of ‘serious’ or ‘not serious’ 
• 
Severity 
• 
Date of first occurrence and date of resolution (if applicable) 
• 
Action taken 
• 
Causal relationship 
• 
Outcome of event (unknown, recovered, not yet recovered, recovered with sequelae, 
death [with date and cause reported]) 
 
8.2.5 REPORTING EVENTS TO PARTICIPANTS  
When necessary for the safety and proper treatment of the patient, the investigator can unmask the 
patient’s treatment assignment to all site personnel to determine which treatment has been assigned 
and institute appropriate follow-up care.   
The reason for unmasking the patient must be recorded in the patient’s source documents. 
A report of the results of this study may be published, sent to the appropriate health authorities in 
any country in which the study drug may ultimately be marketed, and published in part as required 
by appropriate health authorities (e.g., Clinical Trials posting and disclosure), but the patient’s 
name will not be disclosed in these documents.   
Patients will be informed that the study is posted and the results eventually disclosed by 
appropriate health authorities (e.g., Clinical Trials posting or freedom of information by the FDA). 


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8.2.6 EVENTS OF SPECIAL INTEREST  
8.2.6.1 UNEXPECTED ADVERSE REACTION DEFINITION 
An unexpected adverse reaction is any untoward and unintended response that is related to the 
administration of the study drug at any dose that is not consistent with the applicable product 
information (e.g., investigators brochure for an unauthorized investigational medicinal product or 
summary of product characteristics for an authorized product). 
All suspected unexpected serious adverse reactions (SUSARs) will be the subject of expedited 
reporting. The UNSW shall ensure that all relevant information about a SUSAR that is fatal or life-
threatening is reported to the relevant competent authorities and IEC/IRB within 7 days after 
knowledge by the UNSW of such a case and that relevant follow up information is communicated 
within an additional 8 days. All other SUSARs will be reported to the relevant competent 
authorities and IEC/IRB within 15 days after knowledge by the UNSW of such a case. All 
investigators should follow up SUSARs until the event is resolved or until, in the opinion of the 
investigator, the event is stabilized or determined to be chronic. Post study SUSARs that occur 
after the subject has completed the clinical study must be reported by the investigator to the UNSW. 
 
8.2.7 REPORTING OF PREGNANCY  
If a female becomes pregnant during the study, the investigator will notify Azura Ophthalmics 
immediately after the pregnancy is confirmed and the patient will be exited from the study after 
appropriate safety follow-up.  The investigator will (1) notify the patient’s physician that the 
patient was being treated with an investigational drug, and (2) follow the progress of the pregnancy.  
The investigator must document the outcome of the pregnancy and provide a copy of the 
documentation to Azura Opththalmics. 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
SAMPLE SIZE DETERMINATION 
The sample size is determined empirically.    
 
9.2 
POPULATIONS FOR ANALYSES 
The safety population will include all treated patients.  For safety variables, patients in the safety 
population will be analyzed by the treatment actually received. The modified intent-to-treat 
(mITT) population will be comprised of all patients randomized and who have values at 


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randomization, and at least 1 post-randomization for MGE.  All patients in the mITT population 
will be analyzed by the treatment received.   This population will be used for the primary and the 
secondary efficacy analyses. 
The method of Last Observation Carried Forward (LOCF) will be used for efficacy on the mITT 
population. In these analyses, non-missing values recorded at visit 3 or later will be used to replace 
missing data at visits where data are not recorded.   
 
9.3 
PROTOCOL DEVIATIONS 
A protocol deviation is any noncompliance with the clinical trial protocol, International 
Conference on Harmonization Good Clinical Practice (ICH GCP), or Manual of Procedures 
(MOP) requirements. The noncompliance may be either on the part of the participant, the 
investigator, or the study site staff.  As a result of deviations, corrective actions are to be developed 
by the site and implemented promptly.  
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within 10 working days of identification of the protocol deviation, or within 5 working 
days of the scheduled protocol-required activity.  All deviations must be addressed in study source 
documents.  Protocol deviations must be sent to the reviewing IEC per their policies. The site 
investigator is responsible for knowing and adhering to the reviewing IEC requirements.  
 
 


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9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
In general, continuous data will be summarized with descriptive statistics (number of patients, 
mean, standard deviation, median, minimum, and maximum) and will be analyzed using analysis 
of variance (ANOVA) techniques or 2-sample t-tests for between-group comparisons, and paired 
t-tests for within-group analyses.  Categorical variables will be summarized by sample size (N), 
frequency count, and percent, and they will be analyzed using Pearson’s chi-square test or Fisher’s 
exact test (if the expected cell count is less than 5 in 25% or more of the cells).  Ordinal variables 
will be analyzed using the Cochran-Mantel-Haenszel (CMH) or the Wilcoxon rank-sum test for 
between-treatment comparisons and the sign-rank test for within-treatment comparisons.  
9.4.2 ANALYSIS OF THE PRIMARY SAFETY ENDPOINT(S) 
Safety measures will be analyzed using the safety population.  Medical Dictionary for Regulatory 
Activities (MedDRA) nomenclature will be used to code adverse events. Treatment-emergent 
adverse events will be summarized.  The adverse events will be classified into ocular and nonocular 
types and will be summarized separately.  
 
9.4.3 BASELINE DESCRIPTIVE STATISTICS 
In general, continuous data will be summarized with descriptive statistics (number of patients, 
mean, standard deviation, median, minimum, and maximum) and will be analyzed using analysis 
of variance (ANOVA) techniques or 2-sample t-tests for between-group comparisons, and paired 
t-tests for within-group analyses.  Categorical variables will be summarized by sample size (N), 
frequency count, and percent, and they will be analyzed using Pearson’s chi-square test or 
Fisher’s exact test (if the expected cell count is less than 5 in 25% or more of the cells).  Ordinal 
variables will be analyzed using the Cochran-Mantel-Haenszel (CMH) or the Wilcoxon rank-
sum test for between-treatment comparisons and the sign-rank test for within-treatment 
comparisons. 
9.4.4 PLANNED INTERIM ANALYSES  
No interim analysis is planned for this study.  
 
9.4.5 SUB-GROUP ANALYSES  
Patients will be stratified by average baseline MGS score (i.e., both eyes should meet the 
inclusion/exclusion criteria).   


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Thus, subgroup analyses are planned for the 2 groups defined by the 2 stratification factors: 
1. Average MGS score < 6 
2. Average MGS score ≥ 6 and ≤ 12 
 
 
 


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9.4.6 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
Individual participant data will be listed by measure and time point. 
 
9.4.7 EXPLORATORY ANALYSES 
Additional exploratory statistical analysis may be performed at the UNSW’s or Azura Ophthalmics 
discretion. 
 
10 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1  INDEPENDENT ETHICS COMMITTEE 
Before initiation of the study at each study center, the protocol, the ICF, other written material 
given to the subjects, and any other relevant study documentation will be submitted to the 
appropriate IEC/IRB. Written approval of the study and all relevant study information must be 
obtained before the study center can be initiated or the study drug is released to the investigator. 
Any necessary extensions or renewals of IEC/IRB approval must be obtained for changes to the 
study such as amendments to the protocol, the ICF or other study documentation. The written 
approval of the IEC/IRB together with the approved ICF must be filed in the study files. The 
investigator will report promptly to the IEC/IRB any new information that may adversely affect 
the safety of the subjects or the conduct of the study. The investigator will submit written 
summaries of the study status to the IEC/IRB as required. On completion of the study, the IEC 
will be notified that the study has ended.  
 
10.2  REGULATORY AUTHORITIES 
Relevant study documentation will be submitted to the regulatory authority according to 
local/national requirements, for review and approval before the beginning of the study. On 
completion of the study, the regulatory authority will be notified that the study has ended. 
10.3 ETHICAL CONDUCT OF THE STUDY 
The investigator(s) and all parties involved in this study should conduct the study in adherence to 
the ethical principles based on the Declaration of Helsinki, GCP, ICH guidelines, and the 
applicable national and local laws and regulatory requirements. 
10.4 INFORMED CONSENT PROCESS 
The process of obtaining informed consent must be in accordance with applicable regulatory 
requirement(s) and must adhere to GCP. 


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The investigator is responsible for ensuring that no subject undergoes any study related 
examination or activity before that subject has given written informed consent to participate in the 
study. 
The investigator or designated personnel will inform the subject of the objectives, methods, 
anticipated benefits and potential risks and inconveniences of the study. The subject should be 
given every opportunity to ask for clarification of any points s/he does not understand and, if 
necessary, ask for more information. At the end of the interview, the subject will be given ample 
time to consider the study. Subjects will be required to sign and date the ICF. After signatures are 
obtained, the ICF will be kept and archived by the investigator in the investigator’s study file. A 
signed and dated copy of the subject ICF will be provided to the subject or their authorized 
representative. 
It should be emphasized that the subject may refuse to enter the study or to withdraw from the 
study at any time, without consequences for their further care or penalty or loss of benefits to which 
the subject is otherwise entitled. Subjects who refuse to give or who withdraw written informed 
consent should not be included or continue in the study. 
If new information becomes available that may be relevant to the subject’s willingness to continue 
participation in the study, a new ICF will be approved by the IRB/IEC(s) (and regulatory 
authorities, if required). The study subjects will be informed about this new information and 
reconsent will be obtained. 
 
10.5 SUBJECT CONFIDENTIALITY 
Monitors, auditors,  the IEC(s) approving this research, and the United States (US) FDA, as well 
as that of any other applicable agency(ies), will be granted direct access to the study subjects’ 
original medical records for verification of clinical study procedures and/or data, without violating 
the confidentiality of the subjects to the extent permitted by the law and regulations. In any 
presentations of the results of this study or in publications, the subjects’ identity will remain 
confidential. 
 
 


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11 QUALITY ASSURANCE 
 
11.1 AUDIT AND INSPECTION 
Study centers and study documentation may be subject to Quality Assurance audit during the 
course of the study by UNSW Sydney. In addition, inspections may be conducted by regulatory 
authorities at their discretion. 
 
11.2 MONITORING 
Data for each subject will be recorded on a source document. Data collection must be completed 
for each subject who signs an informed consent form (ICF) and is administered study drug. 
11.3 DATA MANAGEMENT AND CODING 
Missing or inconsistent data will be queried to the investigator for clarification. Subsequent 
modifications to the database will be documented. 
12 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
12.1 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to the investigator, IRB, and 
regulatory authorities.  If the study is prematurely terminated or suspended, the Principal 
Investigator (PI) will promptly inform study participants, the Institutional Review Board (IRB)/ 
Independent Ethics Committee (IEC) and reason(s) for the termination or suspension will be 
provided.  Study participants will be contacted, as applicable, and be informed of changes to study 
visit schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping    
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 


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• Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy Azura Ophthalmics, IRB and/or applicable regulatory agencies. 
 
12.2 FUTURE USE OF STORED SPECIMENS AND DATA  
12.2.1 HANDLING OF BIOLOGICAL SPECIMENS  
Not applicable. 
12.2.1.1 TEAR SAMPLES 
Not applicable. 
 
12.3 RETENTION OF DOCUMENTATION 
 
For countries falling within the scope of the ICH guidelines, all study related correspondence, 
patient records, consent forms, patient privacy documentation, records of the distribution and use 
of all investigational products, and copies of source should be retained until at least 2 years after 
the last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product or as per local 
regulation if longer.  These documents should be retained for a longer period, however, if required 
by the applicable regulatory requirement(s) or if needed by Azura Ophthalmics. 
In addition, for countries not falling within the scope of the ICH guidelines, local regulatory 
requirements should be followed regarding the retention of clinical study documentation. 
It is the responsibility of Azura Ophthalmics to inform the study center when these documents no 
longer need to be retained. The investigator must contact Azura Ophthalmics before destroying 
any study related documentation. In addition, all subject medical records and other source 
documentation will be kept for the maximum time permitted by the hospital, institution, or medical 
practice. 


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Azura Ophthalmics requires that it be notified in writing if the investigator wishes to relinquish 
ownership of the data so that mutually agreed-upon arrangements can be made for transfer of 
ownership to a suitably qualified, responsible person. 
 
12.4 SOURCE DOCUMENTS 
All study related correspondence, patient records, consent forms, patient privacy documentation, 
records of the distribution and use of all investigational products, and copies of source should be 
maintained on file. 
In addition, for countries not falling within the scope of the ICH guidelines, local regulatory 
requirements should be followed regarding the retention of clinical study documentation. 
Azura Ophthalmics requires that it be notified in writing if the investigator wishes to relinquish 
ownership of the data so that mutually agreed-upon arrangements can be made for transfer of 
ownership to a suitably qualified, responsible person. 
12.5 STUDY SUMMARY 
An investigator's summary will be provided to Azura Ophthalmics within a short time after the 
completion of the study, or as designated by Azura Ophthalmics. A summary is also to be provided 
to the responsible IRB/IEC. 
 
 
 


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12.6 INSTITUTIONAL REVIEW BOARD /INDEPENDENT 
ETHICS COMMITTEE (IEC) RECORDS RETENTION  
The IRB should retain all relevant records such as standard operating procedures (SOPs), 
membership lists (including qualifications of the members), submitted documents, minutes of 
meetings, and correspondence until either item 1 or 2 listed below, whichever is later.   
1. The date of approval for manufacturing and marketing applications of the relevant 
investigational products (in case of discontinuing its development, until at least 3 years 
after the date of development discontinuation) 
2. The day at least 3 years after the date of the termination or completion of the clinical study 
When the study site requests the SOPs and membership lists, the IRB should comply with the 
request. 
 
12.7 PUBLICATION AND DATA SHARING POLICY 
See Clinical Trials Research Agreement for Publication and Data sharing policy. 
12.8 CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial.   
12.9 ADDITIONAL CONSIDERATIONS 
None 
 
 


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12.10 ABBREVIATIONS 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
BCVA 
Best-corrected visual acuity 
CFR 
Code of Federal Regulations 
CMH 
Cochran-Mantel-Haenszel 
CONSORT 
Consolidated Standards of Reporting Trials 
DED 
Dry Eye Disease 
EC 
Ethics Committee 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
ICH GCP 
International Conference on Harmonisation Good Clinical Practice 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug Application 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
LOCF 
Last Observation Carried Forward 
LogMAR 
Logarithm of the minimum angle of resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGD 
Meibomian gland dysfunction 
MGE 
Meibum gland secretion score 
MGS 
Meibum gland secretion score 
MGYLS 
Meibomian Glands Yielding Liquid Secretion 
mITT 
The modified intent-to-treat 
MOP 
Manual of Procedures 
NAC 
N-acetyl-cysteine 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OSDI 
Ocular Surface Disease Index 
PI 
Principal Investigator 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
SPEED 
Eye Dryness questionnaire 
TBUT 
Tear Break-up Time 
US 
United States 
VAS 
Visual analogue scale  
 
 
 


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12.11 PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Description of Change  
Brief Rationale 
2.0 
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Addition of exclusion criteria 
“Known carrier of infectious disease” 
As per UNSW HREC’s 
recommendation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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14 APPROVAL(S) 
 
Protocol Title: 
A Single-center, Vehicle-controlled, Study to Evaluate Methods to 
Enhance the Safety and Tolerability of AZR-MD-001 for 
Meibomian Gland Dysfunction (MGD) 
Protocol Number: 
SOVS2020-080 
Final Date: 
14Apr2020 
This clinical study protocol was subject to critical review and has been approved by UNSW and Azura Ophthalmics. 
The following personnel contributed to writing and/or approving this protocol. 
 
 
Signed: 
 
 
Date:  
 
Jacqueline Tan 
School of Optometry and Vision Science; UNSW Sydney;  
Sydney NSW 2052 Australia 
Tel: + 61 2 9385 6551 
E-mail: jacqueline@unsw.edu.au