Conditions: Meibomian Gland Dysfunction
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 31
Healthy volunteers: no

Brief summary:
AZ202001 is a multicenter study of AZR-MD-001 ointment and AZR-MD-001 vehicle in patients with Meibomian Gland Dysfunction (MGD)

Detailed description:
AZ202001 is a multicenter, double-masked, vehicle-controlled, randomized, parallel group study evaluating the safety, efficacy and tolerability of AZR-MD-001 ointment and AZR-MD-001 vehicle in patients with Meibomian Gland Dysfunction (MGD)

Arms:
arm 1: AZR-MD-001 Vehicle will be dosed up to twice weekly. arm 2: AZR-MD-001 Active will be dosed up to twice weekly.

Interventions: intervention 1: AZR-MD-001 Active intervention 2: AZR-MD-001 Vehicle
Intervention descriptions: intervention 1: AZR-MD-001 is an active ophthalmic ointment intervention 2: AZR-MD-001 is a vehicle ophthalmic ointment

Protocol document:
Prot_000.pdf: 
AZR-MD-001 (Selenium disulfide Agonist) 
Protocol AZ202001 
Version 1.0 
12-Mar-2020 
 
 
 
A Multicenter, Vehicle-controlled, Randomized Study to 
Evaluate the Safety, Tolerability and Pharmacodynamics of 
AZR-MD-001 in Patients with Meibomian Gland 
Dysfunction (MGD)  
 
Protocol Number: 
AZ202001 
National Clinical Trial (NCT) 
Identified Number: 
TBD 
Sponsor: 
Azura Ophthalmics, Level 9, 
31 Queen Street 
Melbourne, VIC 3000 Australia 
 
Tel: +1 714-559-8435 
E-mail: 
Charles.Bosworth@azuraophthalmics.com 
Funded by: 
Azura Ophthalmics 
 
 
 
Version and Version Number: 
 
 
 
Final, 1.0 
Date: 12Mar2020 


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Summary of Changes from Previous Version: 
 
Affected 
Section(s) 
 
Summary of Revisions Made 
 
Rationale 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
 
1 
PROTOCOL SUMMARY ........................................................................................................................... viii 
1.1 
SYNOPSIS ........................................................................................................................................ viii 
1.2 
SCHEMA ......................................................................................................................................... viii 
1.3 
SCHEDULE OF ACTIVITIES (SOA) COHORT 1 AND EXPANSION COHORT ........................................ xvi 
2 
INTRODUCTION ......................................................................................................................................... 1 
2.1 
BACKGROUND ................................................................................................................................... 1 
2.2 
STUDY RATIONAL & 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 BENIFITS ................................................................... 8 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................................... 9 
4 
STUDY DESIGN ........................................................................................................................................ 10 
4.1 
OVERALL DESIGN ................................................................................................................................ 10 
4.2 
PROCEDURES ...................................................................................................................................... 10 
4.2.1 Screening ....................................................................................................................................... 10 
4.2.2 Baseline (Day 0) ............................................................................................................................. 11 
4.2.3 Day 14/Month 1/Month 1.5/Month 3 (plus follow up call) .......................................................... 11 
4.3. SCIENTIFIC RATIONALE FOR STUDY DESIGN ............................................................................................ 12 
4.4  DATA REVIEW COMMITTEE (DRC) ........................................................................................................... 13 
4.5  END OF STUDY DEFINITION ...................................................................................................................... 13 
5 
STUDY POPULATION ............................................................................................................................... 13 
5.1 
INCLUSION CRITERIA ....................................................................................................................... 13 
5.2 
EXCLUSION CRITERIA ...................................................................................................................... 16 
5.3 
LIFESTYLE CONSIDERATIONS ........................................................................................................... 17 
5.4 
SCREEN FAILURES............................................................................................................................ 18 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION ......................................................................... 19 
6 
STUDY INTERVENTION ............................................................................................................................ 19 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION .................................................................................. 19 
6.1.1 
STUDY TREATMENT(S)/ FORMULATION(S)/ MEDICAL DEVICE COMPOSITION OR DESIGN ... 19 
6.1.2 
SELECTION OF DOSES IN THE STUDY ...................................................................................... 20 
6.1.3 
DOSING AND ADMINISTRATION ............................................................................................. 21 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY ............................................................... 21 
6.2.1 
ACQUISITION AND ACCOUNTABILITY ..................................................................................... 21 
6.2.2 
FORMULATION, APPEARANCE, PACKAGING, AND LABELING ................................................. 22 


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6.2.3 
PRODUCT STORAGE AND STABILITY ....................................................................................... 22 
6.2.4 
PREPARATION ......................................................................................................................... 22 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ................................................ 23 
6.4 
CONCOMITANT THERAPY ............................................................................................................... 24 
6.4.1 
RESCUE MEDICINE .................................................................................................................. 24 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL .... 24 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ............................................................................... 24 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY ............................................ 25 
7.3 
LOST TO FOLLOW-UP ...................................................................................................................... 25 
8 
STUDY ASSESSMENTS AND PROCEDURES .............................................................................................. 26 
8.1 
EFFICACY ASSESSMENTS ................................................................................................................. 26 
8.1.1 
PRIMARY EFFICACY MEASURES .............................................................................................. 26 
8.1.2 
SECONDARY EFFICACY MEASURES ......................................................................................... 26 
8.1.3 
DATA REVIEW COMMITTEE (DRC) .......................................................................................... 27 
8.2 
SAFETY AND OTHER ASSESSMENTS ................................................................................................ 27 
8.2.1 
SAFETY MEASURES .................................................................................................................. 27 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................................ 28 
8.3.1 
DEFINITION OF ADVERSE EVENTS (AE) ................................................................................... 28 
8.3.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)................................................................... 30 
8.3.2.1 
REPORTING OF SERIOUS ADVERSE EVENTS ............................................................................ 30 
8.3.3 
CLASSIFICATION OF AN ADVERSE EVENT ................................................................................ 32 
8.3.3.1 
SEVERITY OF EVENT ................................................................................................................ 32 
8.3.3.2 
RELATIONSHIP TO STUDY INTERVENTION .............................................................................. 32 
8.3.3.3 
ACTION TAKEN ........................................................................................................................ 33 
8.3.4 
TIME PERIOD & FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP ............................ 33 
8.3.4.1 
DOCUMENTATION AND REPORTING OF ADVERSE EVENTS.................................................... 33 
8.3.5 
REPORTING EVENTS TO PARTICIPANTS........................................................................... 34 
8.3.6 
EVENTS OF SPECIAL INTEREST ................................................................................................ 34 
8.3.6.1 
UNEXPECTED ADVERSE REACTION DEFINITION ..................................................................... 34 
8.3.7 
REPORTING OF PREGNANCY ................................................................................................... 34 
9 
STATISTICAL CONSIDERATIONS .............................................................................................................. 35 
9.1 
SAMPLE SIZE DETERMINATION ....................................................................................................... 35 
9.2 
POPULATIONS FOR ANALYSES ........................................................................................................ 35 
9.3 
PROTOCOL DEVIATIONS .................................................................................................................. 36 
9.4 
STATISITICAL ANALYSES .................................................................................................................. 36 
9.4.1 
GENERAL APPROACH .............................................................................................................. 36 
9.4.2 
ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) .............................................................. 38 


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9.4.3 
ANALYSIS OF THE SECONDARY ENDPOINT(S) ......................................................................... 39 
9.4.4 
SAFETY ANALYSES ................................................................................................................... 39 
9.4.5 
BASELINE DESCRIPTIVE STATISTICS ......................................................................................... 40 
9.4.6 
PLANNED INTERIM ANALYSES................................................................................................. 40 
9.4.7 
SUB-GROUP ANALYSES ........................................................................................................... 40 
9.4.8 
TABULATION OF INDIVIDUAL PARTICIPANT DATA ................................................................. 40 
9.4.9 
EXPLORATORY ANALYSES ....................................................................................................... 40 
10 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ................................................. 41 
10.1 
INDEPENDENT ETHICS COMMITTEE ............................................................................................... 41 
10.2 
REGULATORY AUTHORITIES ............................................................................................................ 41 
10.3 
ETHICAL CONDUCT OF THE STUDY ................................................................................................. 41 
10.4 
INFORMED CONSENT PROCESS ...................................................................................................... 41 
10.5 
SUBJECT CONFIDENTIALITY ............................................................................................................. 42 
11 
QUALITY ASSURANCE .......................................................................................................................... 42 
11.1 
AUDIT AND INSPECTION ................................................................................................................. 42 
11.2 
MONITORING .................................................................................................................................. 42 
11.3 
DATA MANAGEMENT AND CODING ............................................................................................... 43 
12 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .......................................... 43 
12.1 
STUDY DISCONTINUATION AND CLOSURE ..................................................................................... 43 
12.2 
FUTURE USE OF STORED SPECIMENS AND DATA ........................................................................... 44 
12.2.1 
HANDLING OF BIOLOGICAL SPECIMENS ................................................................................. 44 
12.3 
KEY ROLES AND STUDY GOVERNANCE ........................................................................................... 44 
12.4 
RETENTION OF DOCUMENTATION ................................................................................................. 45 
12.5 
SOURCE DOCUMENTS ..................................................................................................................... 45 
12.6 
STUDY SUMMARY ........................................................................................................................... 46 
12.7 
INSTITUTIONAL REVIEW BOARD /INDEPENDENT ETHICS COMMITTEE (IEC) RECORDS RETENTION
 
46 
12.8 
PUBLICATION AND DATA SHARING POLICY .................................................................................... 46 
12.9 
CONFLICT OF INTEREST POLICY ...................................................................................................... 46 
12.10 
ADDITIONAL CONSIDERATIONS .................................................................................................. 47 
12.11 
ABBREVIATIONS .......................................................................................................................... 48 
12.12 
PROTOCOL AMENDMENT HISTORY ............................................................................................ 49 
13 
REFERENCES ........................................................................................................................................ 50 
14 
SUBJECTIVE STUDY SCALES ................................................................................................................. 52 
14.1 
VISUAL ANALOG SCALE (VAS) ......................................................................................................... 52 
14.2 
OCULAR SURFACE DISEASE INDEX (OSDI) ....................................................................................... 53 
14.3 
STANDARD PATIENT EVALUATION OF EYE DRYNESS (SPEED) ........................................................ 55 


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14.4 
STUDY MEDICATION TOLERABILITY/COMFORT QUESTIONAIRE .................................................... 56 
15 
SPONSOR APPROVAL(S) ...................................................................................................................... 57 
 


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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 
STATEMENT OF COMPLIANCE 


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1 
PROTOCOL SUMMARY 
 
1.1 
SYNOPSIS 
 
 
Study Compound(s): 
AZR-MD-001 (Selenium Disulfide) 
 
Phase: 
 
2b 
 
Objectives: 
 
To evaluate the safety, tolerability and pharmacodynamics of AZR-MD-001 
ointment/semi-solid drug applied to the lower lid twice-weekly for up to 3 
months compared to its vehicle in patients with meibomian gland 
dysfunction (MGD). 
Clinical Hypotheses: 
AZR-MD-001 ointment/semi-solid drug has an acceptable safety and 
tolerability 
profile 
following 
twice-weekly, 
evening 
peri-ocular 
administration for the study treatment duration. 
 
AZR-MD-001 ointment/semi-solid drug is more effective than vehicle for 
treating MGD as measured by the meibum gland secretion score (MGS). 
 
AZR-MD-001 ointment/semi-solid drug is more effective than vehicle for 
treating symptoms associated with MGD as measured by Total Ocular Surface 
Disease Index (OSDI) score. 
 
1.2 
SCHEMA 
 
Study Design: 
Structure: Multicenter, investigator-masked, vehicle-controlled, randomized, 
parallel group study comparing AZR-MD-001 (0.5%) ointment/semi-solid drug 
and AZR-MD-001 vehicle dosed twice-weekly in the evening. 
 
Patients with MGD will be randomly assigned in a 1:1 ratio to receive either a 
single concentration of AZR-MD-001 ointment/semi-solid drug (i.e., 0.5%) or AZR-
MD-001 vehicle. 
 
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. 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 (i.e., 0.5%). 
 
Active Period Control:  AZR-MD-001 Vehicle 
 


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Baseline Visit: “Vaseline” (AZR-MD-001 Vehicle) 
 
 
Dosage/Dose Regimen: Upon meeting inclusion/exclusion criteria patients will 
be randomized to AZR-MD-001 ointment/semi-solid drug (0.5%) or AZR-MD-
001 vehicle administered twice-weekly, in the evening at bed time for three 
months. 
 
Randomization/Stratification: Patients will be randomized to receive AZR-MD- 
001 ointment/semi-solid drug (0.5%) or AZR-MD-001 vehicle in a 1:1 treatment 
allocation ratio at the baseline visit. 
 
Patients will be stratified by duration of MGD diagnosis (i.e., < 5 years or ≥ 5 
years) and baseline MGS score (MGS score of < 6 or MGS score ≥6 and ≤ 12) for 
the qualified eye (i.e., the eye meeting the inclusion/exclusion criteria). If the 
patient has 2 qualified eyes, the stratification will be based on the eye with the 
lower numerical MGS score. If the eyes have the same MGS score, then the right 
eye will be selected as the study eye. 
 
Visit Schedule: Up to 6 scheduled visits: screening, randomization, day 14, month 
1, month 1.5, and month 3 (exit).  For patients who discontinue the study early, 
  
the month 3 visit procedures should be completed.  
 
 
Study Population Characteristics 
Number of Patients: The total number of randomized patients for the study will 
be up to approximately 30. Approximately 15 patients should have a baseline 
MGS score of < 6 and approximately 15 patients should have a baseline MGS 
score ≥6 and ≤ 12. Based upon data from ongoing study AZ201801 and the 
simplified inclusion/exclusion criteria for this study a screen failure rate of ~ 
40% is expected. Thus, ~42 patients will need to be screened to achieve ~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 and baseline 
visits 
 
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 and baseline visits 
 
Reported dry eye signs and symptoms within the past 3 months 


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 
Prior to starting screening visit procedures, patients are required to have 
discontinued: 
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 All other topical ophthalmic preparations (including artificial 
tear substitutes) other than the study drops: 72 hours prior to 
screening visit.  If artificial tear substitutes were used within 
72 hours of the screening visit the visit should be rescheduled 
 
Evidence of active MGD associated signs and symptoms at the 
screening and baseline visits: 
o Score ≥6 on the Standard Patient Evaluation of Eye Dryness 
questionnaire (SPEED) 
o Ocular Surface Disease Index (OSDI) questionnaire score ≥13 
And 
o TBUT < 10 seconds in both eyes 
 
Demonstrated ability to follow dosing instructions at the baseline visit 
 
A negative pregnancy test result for all women at the screening visit 
 
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 not considered a reliable method of birth control. If 
these methods of birth control do not apply, woman 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 and dry eye 
disease/keratoconjunctivitis sicca associated with MGD) or 
uncontrolled systemic disease 
 
Patient has glaucoma, ocular hypertension, or intraocular pressure 
(IOP) in either eye at screening ≥24 mm Hg as 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 or baseline visit 


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 
Current use of punctal plugs, anticipated insertion during the study, or 
a history of punctal cautery in either eye at any time prior to the 
screening visit or anticipate such a procedure during the study 
 
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 or 
baseline visits 
 
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 screening visit) ocular 
surgery, trauma, herpes, or recurrent inflammation 
 
Contact lens use anticipated during the study 
 
Periocular application of makeup likely to impact meibomian gland 
function 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 baseline 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) 
 
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 
 
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 
 
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 


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 
Schirmer's tear test without anesthesia ≤ 5 mm in either eye at 
the baseline visit 
 
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.  Woman of childbearing 
potential may have a monogamous partner who has had a vasectomy 
at least 3 months before the screening visit or who is of the same 
gender.  
 
Positive urine pregnancy test at the screening visit 
 
Participation in another clinical trial involving a therapeutic drug or 
device within the past 30 days 
 
Response 
Measures 
 
Primary Sign for MGD: 
 
Change from Baseline to month 3 in meibum gland secretion score 
(MGS) (0 to 45 scale) 
 
Primary Symptom for MGD: 
 
Change from Baseline to month 3 in Total OSDI 
 
Other Efficacy Measures: 
 
Change from Baseline to day14, month 1 and month 1.5 in MGS (0 to 
45 scale) 
 
MGS score (0 to 45 scale) at each visit 
 
Proportion of patients with a MGS score > 12 at each visit 
 
Change from Baseline to day14, month 1, month 1.5 and month 3 in 
the number of Meibomian Glands Yielding Liquid Secretion (MGYLS) 
(0 to 15 scale) 
 
MGYLS (0 to 15 scale) at each visit  
 
Change from Baseline to day 14, month 1, month 1.5, and month 3 in TBUT 
 
TBUT at each visit 
 
Proportion of patients with a TBUT score > 5 at each visit 
 
Change from Baseline to day 14, month 1, month 1.5 and month 3 
in Standard Patient Evaluation of Eye Dryness (SPEED) 
 
SPEED at each visit 
 
Proportion of patients with a SPEED < 6 at each visit 
 
Change from Baseline to day 14, month 1, month 1.5 and month 3 


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in average visual analogue scale (VAS) 
 
Average VAS at each visit 
 
Change from Baseline to day 14, month 1, month 1.5 and month 3 
in worst VAS 
 
Worst VAS at each visit 
 
Change from Baseline to day 14, month 1 and month 1.5 in Total OSDI 
 
Total OSDI, OSDI sub-scales, and individual items from the OSDI across visits 
 
Proportion of patients with a Total OSDI change from baseline > 4.5, the 
known minimally important clinical difference (MICD) for early to moderate 
disease, at month 3 
 
Proportion of patients with a Total OSDI < 13 at each visit 
 
Number of expressible glands yielding clear meibum at day14, month 1, 
month 1.5, and month 3 
 
Eyelid margin erythema/telangiectasias at day14, month 1, month 1.5, 
and month 3 
 
Corneal and conjunctival staining (0 to 5 scale) at each visit 
 
Safety: 
 
Adverse events 
 
Vital signs 
 
Study medication tolerability as measured by the Ocular Comfort 
Questionnaire 
 
Urine pregnancy test 
 
Best-corrected visual acuity (BCVA; Logarithmic visual acuity chart) 
 
Biomicroscopy 
 
Ophthalmoscopy 
 
Intraocular pressure (IOP) 
 
 
 
 
 
 
 
 
 
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. The 
modified intent-to-treat (mITT) population will be comprised of all patients 
randomized and, who have values at randomization, and at least 1 post- 
randomization value for MGS at a regularly scheduled visit (i.e., Day 14 or Month 
1). 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 modified intent-to-treat 2 (mITT2) population will be comprised of patients 
who are included in the mITT and have the randomization MGS score in the study 
eye ≥6 and ≤ 12. The mITT2 population will be analyzed by the treatment received. 
 
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, 


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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. 
 
Primary Efficacy (MGD):  
 
The primary efficacy sign for MGD is change from baseline in MGS. The visit 
for the primary variable is month 3 and the primary analysis population is mITT. 
Statistical testing will be performed for the AZR-MD-001 group versus vehicle 
group.  
 
The primary efficacy symptom for MGD is change from baseline in Total OSDI. 
The visit for the primary variable is month 3 and the primary analysis 
population is mITT. Statistical testing will be performed for the AZR-MD-001 
group versus vehicle group.  
 
Safety: Safety measures will be analyzed using the safety population. Medical 
Dictionary for Regulatory Activities (MedDRA) nomenclature will be used to 
code adverse events. Incidence rates of each treatment-emergent adverse 
event will be summarized by primary system organ class and preferred term. 
Summary tables will be generated for all treatment-emergent adverse events 
regardless of causality as well as for those considered to be treatment-related. 
 
Sample Size Calculation:  Estimates for sample size calculations are from the first 
interim analysis from Azura Clinical Protocol AZ201801.  The standard deviation for 
MGS was 3.35 units for an ineffective dose and 9.48 units for the high dose.  A 
sample size of 12 subjects per group will have 90% power to detect a difference of 
10.4 units between the active treatment group and the vehicle group using a two-
sample t-test at a significance level of 0.05.   The standard deviation for Total OSDI 
was 13.01 units for an ineffective dose and 6.79 units for the high dose.  A sample 
size of 11 subjects per group will have 90% power to detect a difference of 15.9 
units between the active treatment group and the vehicle group using a two-
sample t-test at a significance level of 0.05.   
 
Multiplicity Consideration: To address the multiple primary endpoints defined in this 
study, the primary endpoints have been prioritized into a hierarchical structure.  In 
order to test the primary symptom endpoint of Total OSDI, the primary sign 
endpoint of MGS must be statistically significantly higher in the 0.5% AZR-MD-001 
treatment group compared to the vehicle treatment group using a two-sided 
significance level of 0.05.  Using this strategy, the family-wise Type I error rate will 
be maintained at the 0.05 significance level for the two primary endpoints. 
 
Interim Analysis:  None Planned 
 
 


 
xv 
 
Figure 1 
Study Flow – Multicenter, investigator-masked, vehicle-controlled, randomized, parallel group 
study  
 
 
 


 
xvi 
 
 
 
1.3 
SCHEDULE OF ACTIVITIES (SOA) COHORT 1 AND EXPANSION COHORT 
 
Table 1 Schedule of Visits and Procedures 
 
Study Period 
Qualification Period 
Investigator-Masked Period 
 
Screeninga 
(Day -14) 
Baseline 
Day 0 
Randomization 
Day 14 
Month 1 
Month 1.5 
Month 3 
(Exit) 
Visit Window 
± 2 Days 
N/A 
± 2 Days 
± 7 Days 
± 7 Days 
± 7 Days 
Informed consent/authorization 
X 
 
 
 
 
 
Contact IVRS/IWRS for patient number assignment 
(screening number) 
X 
 
 
 
 
 
Demographics (including height and weight) 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
Medical and ophthalmic history 
X 
X 
 
 
 
 
Medication history 
X 
 
 
 
 
 
Washout medications 
X 
 
 
 
 
 
Vital signs (pulse rate, blood pressure) f 
X 
X 
 
X 
 
X 
Pregnancy test (urine) for female patients b, f 
X 
 
 
 
 
X 
OSDI f 
X 
X 
X 
X 
X 
X 
SPEED f 
X 
X 
X 
X 
X 
X 
Patient Ocular Symptoms (VAS) f 
X 
X 
X 
X 
X 
X 
Best-corrected visual acuity (BCVA) f 
X c 
X 
X 
X 
X 
X 
Slit-lamp biomicroscopy (includes eyelid margin 
erythema/telangiectasias and do not touch the lids)f 
X 
X 
X 
X 
X 
X 
Tear Break Up Time (TBUT) e, f 
X 
X 
X 
X 
X 
X 
Sodium fluorescein corneal staining, Oxford scale f 
X 
X 
X 
X 
X 
X 
Lissamine green conjunctival staining, Oxford scale f 
X 
X 
X 
X 
X 
X 


 
xvii 
 
 
Study Period 
Qualification Period 
Double-Masked Period 
 
Screeninga 
(Day -14) 
Baseline 
Day 0 
Randomization 
Day 14 
Month 1 
Month 1.5 
Month 3 
(Exit) 
Visit Window 
± 2 Days 
N/A 
± 2 Days 
± 7 Days 
± 7 Days 
± 7 Days 
Meibomian gland evaluation (MGE) e, f 
X 
X 
X 
X 
X 
X 
Schirmer without anesthesia f 
X 
X 
 
X 
 
X 
Intraocular pressure (IOP) f 
X 
 
 
 
 
X 
Ophthalmoscopy exam d 
X 
 
 
 
 
X 
Meibography f 
X 
 
 
 
 
X 
Study medication Tolerability/Comfort Questionnaire f 
 
Xg 
X 
X 
X 
X 
Adverse events/medications/procedures f 
X 
X 
X 
X 
X 
Xh 
Discontinue concomitant medication(s) impacting 
inclusion/exclusion 
X 
 
 
 
 
 
Contact IVRS/IWRS for patient randomization number 
 
X 
 
 
 
 
Medication dispensing/return 
 
X 
X 
X 
X 
X 
Physician Observation of Drug Application Methods 
 
X 
 
 
 
 
BCVA = Best Corrected Visual Acuity; OSDI = Ocular Surface Disease Index; SPEED = Standard Patient Evaluation of Eye Dryness; TBUT = tear break up time; 
VAS = Visual Analogue Scale; PM = Evening 
a Screening diagnostic procedures are not required to be performed on the same day, and can be performed across multiple days from days -14 to -2. At screening, patients will be 
asked to report use of artificial tears and all other treatments for MGD and/or associated DED. Patients should wash out from all medication listed in the inclusion/exclusion 
criteria.  
b For females of childbearing potential. 
c Manifest refraction performed at screening will be used at each visit to obtain BCVA. 
d Ophthalmoscopy examination will be dilated at screening and undilated for month 3 visit unless dilation is necessary 
e TBUT and MGE should be performed by the same individual for a given patient. 
f The individual performing the measurement will not be involved in drug dispensing or accountability and should remain masked to the treatment received by the patient. 
g The tolerability questionnaire at BSL is completed based on participants experience with the “practice dose” using Vaseline. At other visits, participants are to complete it referring 
back to their last evening dose 
h A follow up telephone call will occur 1 week (+/- 2 days) after the participant has attended the final on site 3 Month visit.  This is a safety follow up call.


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2 
INTRODUCTION 
 
2.1 
BACKGROUND 
 
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 


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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, 
and forms a barrier to protect the eye from microbial agents and organic matter (e.g., dust 
and pollen) (Green-Church et al, 2011). 
 
Conventional treatments of obstructive MGD entail eyelid hygiene (e.g., lid washing and use of 
preservative-free artificial tears), omega-3 dietary supplementation (e.g., eicosapentaenoic acid 
and docosahexaenoic acid), topical antibiotics (e.g., bacitracin and erythromycin), topical 
corticosteroids, topical cyclosporine, oral antibiotics (e.g., doxycycline, minocycline, and 
tetracycline), oral omega-6 fatty acids (e.g., linoleic acid and gamma-linolenic acid), as well as 
unclogging of glands that are blocked, which can be achieved by applying warm compresses to 
the eyelid or gentle lid massaging (Olson et al, 2003; Romero et al, 2004; Yoo et al, 2005; Perry et 
al, 2006; Pinna et al, 2007; Souchier et al, 2008; and Foster et al, 2009). Moreover, eyelid-warming 
devices have also been employed in the treatment of patients with MGD (Goto et al, 2002; Mitra 
et al, 2005; Matsumoto et al, 2006; Geerling et al, 2011; Lane et al, 2012). 
 
2.2 
STUDY RATIONAL & KNOWN POTENTIAL BENEFITS 
 
The recognition that terminal duct obstruction from hyperkeratinization of the ductal epithelium 
on meibomian glands is a core mechanism behind meibomian gland dysfunction (MGD) is 
consistent with clinical experience demonstrating that effective treatments for MGD require 
resolution of ductal obstruction and evacuation of glandular contents (Nichols et al, 2011; Lane et 
al, 2012; Blackie et al, 2015). Warm compresses and thermal/mechanical devises (e.g., LipiFlow) 
are used in an attempt to raise the internal temperature of the meibomian glands over the 
normal melting point for meibum (i.e., 32°C to 40°C) resolving the terminal duct obstruction 
(Lane et al, 2012). Unfortunately, warm compresses are unable to achieve this benefit for 
severely obstructed glands which can having a melting point > 40°C. 
 
Finis and colleagues (2014), conducted a prospective, randomized, observer-masked trial in 40 
patients with MGD: 19 patients were randomized to LipiFlow and 16 patients were randomized to 
standard of care (i.e., twice-daily lid warming, massage, and cleaning of the lid margin) for 3 
months. LipiFlow and standard of care demonstrated significant improvements from baseline in 
symptoms, measured by SPEED, and in the number of expressible glands by 1 month. 
Consistently observed benefits for devices designed to treat glandular obstruction include: 
 
1) Improvement in the meibum gland score (MGS) (0 to 45 scale); 
2) Increases in the number of meibomian glands yielding liquid secretion (MGYLS) (0 
to 15 scale); 


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3) Increased Tear Break-up Time (TBUT); and 


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4)   Improved Total OSDI, SPEED and eye dryness scores (measured using a visual 
analogue scale [VAS]) (Blackie et al, 2015). 
 
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 
(Bahn, 1954). 
 
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 disulfide 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 disulfide 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 disulfide 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 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 


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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. 
 
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 safety, tolerability and effectiveness of 
AZR-MD-001 (0.5%) 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 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. 
 
To further evaluate the ocular tolerability and ocular toxicity of selenium disulfide, Azura 
Ophthalmics evaluated AZR-MD-001 ointment/semi-solid drug in a preclinical study at three 
concentrations (i.e., 0.5%, 1.0%, and 2.5%) over  three dosing frequencies (i.e., twice weekly 
once daily and twice daily) with a standard clinical dosing volume (i.e 5 μL) and with an 
exaggerated dosing volume (i.e., 25 μL) for the highest concentration of 2.5%. Thirty-nine female 
albino rabbits (New Zealand White strain) were included across 10 groups (see Table 2–1). All 
groups were treated for 7 days. During the study, eyes were evaluated macroscopically (Draize’s 
scale) and under the slit-


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lamp (McDonald-Shadduck’s scale). At the end of the study, eye globes were histopathologically 
examined. 
 
Table 2–1 
Dose Groups Included in the Pre-Clinical Evaluation of AZR-MD-001 Ointment/semi- 
solid Drug 
 
 
Group n° 
 
Treatment 
(concentration) 
 
Dose Regimen (Right eye) 
Number of animals 
Series 1 
Series 2 
Series 3 
4 
AZR149 (0.5% - 5 µL) 
 
 
Twice weekly (q3.5d ± 1d) ocular topical 
application from Day 1 to Day 7 onto the 
lower lid margin 
-- 
3 
-- 
3 
AZR150 (1% - 5 µL) 
-- 
3 
-- 
 
1 
AZR141 (2.5% - 25 
µL) 
 
3 
 
-- 
 
-- 
 
2 
AZR140 (Placebo - 25 
µL) 
 
3 
 
-- 
 
-- 
8 
AZR149 (0.5% - 5 µL) 
 
 
Once daily ocular topical application from 
Day 1 to Day 7 onto the lower lid margin 
-- 
6 
-- 
7 
AZR150 (1% - 5 µL) 
-- 
3 
-- 
 
5 
AZR141 (2.5% - 25 
µL) 
 
6 
 
-- 
 
-- 
 
6 
AZR140 (Placebo - 25 
µL) 
 
6 
 
-- 
 
-- 
 
 
 
9 
 
AZR149 (0.5% - 5 µL) 
Twice daily (7h ± 1h) ocular topical 
application from Day 1 to Day 7 onto the 
lower lid margin 
 
-- 
 
6 
 
-- 
 
10 
AZR141 (2.5% - 5 µL) 
Once daily ocular topical application from 
Day 1 to Day 7 onto the lower lid margin 
-- 
-- 
3* 
*Note 1: These 3 animals were already treated once daily with AZR149 0.5% during 7 days before joining the series 3 
(without wash-out period). 
 
 
No clinical or microscopic findings were observed for any tested concentration, (i.e., 0.5%, 1.0% 
or 2.5%) or dosing regimen (i.e., twice weekly or once daily) with the intended clinical dose 
volume of 5 μL. Animals treated with 2.5% at an exaggerated dosing volume (i.e., 25 μL), 
presented with signs of conjunctival redness from Day 5 in 6/6 animals through Day 7 in 5/6 
animals, conjunctival chemosis from Day 6 in 6/6 animals through Day 7 in 3/6 animals, slight 
corneal opacity for 5/6 animals on Day 3 through day 7 in 3/6 animals (1 slight, 2 moderate), and 
red and swollen eyelids. All signs self-resolved within 14 days of treatment cessation with no 
particular management. On ocular histopathology examinations, no microscopic changes were 
observed for any dosing group including the 2.5% exaggerated dosing volume. Thus, AZR-MD- 
001 ointment/semi-solid drug up to a concentration of 2.5% using the intended clinical dosing 
volume of 5 μL is both macroscopically and microscopically well tolerated in these experimental 
conditions. 


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Clinically, ocular irritation, conjunctivitis, and epithelial keratitis have been reported in humans 
dosed with selenium sulfide as a 0.5% ophthalmic ointment with Sodium Lauryl Sulphate applied 
to the lid margin (Bahn, 1954). The most severe AE reported in all prior topical ophthalmic studies 
using selenium sulfide was self-limiting keratitis which resolved upon cessation of treatment. Thus, 
published literature has established the ocular safety and tolerability of selenium sulfide up to 
a maximal daily exposure of 0.5% dosed twice-daily (BID) for 1 month (see the Investigator’s 
Brochure for more detail). In clinical study MGSS1, selenium disulfide 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.   
 
Ocular irritation, conjunctivitis, and epithelial keratitis were observed in clinical protocol 
AZ201801. Data review from study AZ201801, up to the Interim Analysis, did not identified 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). 
 
2.3.2 
ASSESSMENT OF POTENTIAL RISKS AND BENIFITS 
 
The predominate conventional treatments for obstructive MGD entail eyelid hygiene (e.g., lid 
washing and use of preservative-free artificial tears), applying warm compresses to the eyelid, and 
gentle lid massaging (Olson et al, 2003; Romero et al, 2004; Yoo et al, 2005; Perry et al, 2006; 
Pinna et al, 2007; Souchier et al, 2008; and Foster et al, 2009). Eyelid-warming devices have also 
been employed in the treatment of patients with MGD (Goto et al, 2002; Mitra et al, 2005; 
Matsumoto et al, 2006; Geerling et al, 2011; Lane et al, 2012). Unfortunately, these treatments 
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 a less 
invasive, pharmacologic treatment for MGD and associated evaporative DED. 
 
Given the high unmet medical need, the reversibility of ocular findings with selenium disulfide 
shampoo (2.5%) in clinical study MGSS1, and the observed safety and efficacy for both MGD 
and evaporative DED in clinical protocol AZ201801, the risk/benefit profile of AZR-MD-001 
ointment/semi-solid drug supports continued development in the proposed study design. 


AZR-MD-001 (Selenium disulfide Agonist) 
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9 
 
 
 
 
3 
OBJECTIVES AND ENDPOINTS 
Table 3–1 
Table of Objectives, Endpoint, and Endpoint Justification 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Cohort 1 and Expansion Cohort 
To evaluate the safety, tolerability 
and pharmacodynamics of AZR-
MD-001 ointment/semi-solid drug 
applied to the lower lid twice-
weekly for up to 3 months 
compared to its vehicle in patients 
with meibomian gland 
dysfunction (MGD). 
Safety/Adverse Events: 
 
Incidence rates of each treatment-
emergent adverse event 
summarized by primary system 
organ class and preferred term. 
 
Tables 
for 
all 
treatment- 
emergent 
adverse 
events 
regardless of causality. 
 
Tables for all treatment- 
emergent adverse events 
considered to be treatment- 
related. 
 
Shift tables for safety 
variables (e.g., IOP, 
biomicroscopy, and 
ophthalmoscopy). 
 
Signal of Efficacy: 
Primary Efficacy for MGD: 
 Change from Baseline to Month 3 
in meibum gland secretion score 
(MGS) (0 to 45 scale) 
 Change from Baseline to Month 3 
in Total OSDI
The endpoints for safety and 
tolerability are all commonly used 
in ophthalmic drug trials. 
 
Consistently observed benefits for 
devices designed to treat glandular 
obstruction and for AZR-MD-001 
ointment/semi-solid drug include: 
 
Improvement in the 
meibum gland secretion 
score (MGS) (0 to 45 
scale); 
 
Improved Total OSDI 
(Blackie et al, 2015). 


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4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
 
This is a multicenter, investigator-masked, vehicle-controlled, randomized, parallel group study 
comparing AZR-MD-001 (0.5%) ointment/semi-solid drug and AZR-MD-001 vehicle dosed twice-
weekly in the evening. 
 
Patients with MGD will be randomly assigned in a 1:1 ratio to receive either a single 
concentration of AZR-MD-001 ointment/semi-solid drug (i.e., 0.5%) or AZR-MD-001 vehicle. 
 
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 will be enrolled into a 3-month treatment 
period. The study flow is shown in Figure 1. 
4.2 
PROCEDURES 
4.2.1 Screening 
 
Participants will be identified by the sites and brought in for screening visits. Participants may be provided 
with the Participant information sheet in advance, though will only sign consent during the visit with the 
study team. Written informed consent will be obtained from each participant prior to commencing any 
study related activities. Written and verbal versions of the Participant Information and Informed Consent 
will be presented to the participants detailing: the exact nature of the trial; what it will involve for the 
participant; the implications and constraints of the protocol; the known side effects and any risks involved 
in taking part. The participant must personally sign and date the latest approved version of the Informed 
Consent form. 
 
It will be clearly stated that the participant is free to withdraw from the trial at any time for any reason 
without prejudice to future care, without affecting their legal rights and with no obligation to give the 
reason for withdrawal. 
 
The following data will be collected at the screening visit – which may be conducted over one day, or 
multiple days in the window before the baseline visit: 
- 
Medical History (including opthalmic) 
- 
Demographics (date of birth, gender, race, ethnicity) 
- 
Vital Signs – height, weight, pulse rate and blood pressure  
- 
Urine pregnancy test for women of childbearing potential 
- 
Current medications (including any washout required) 
- 
Questionnaires completed by the participant: OSDI, SPEED, VAS 
- 
Slit -lamp Biomicroscopy  
- 
Tear Break up Time 


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- 
Sodium Fluorescein corneal staining  
- 
Lissamine green conjunctival staining 
- 
Meibomian gland evaluation 
- 
Schirmer’s test – without anesthesia 
- 
Intraocular Pressure 
- 
Opthalmoscopy Examination (dilated) 
- 
Meibography 
 
4.2.2 Baseline (Day 0) 
 
Participants will return to the clinical site up to 14 days from screening visit.  Assessments will be 
conducted as per the Schedule of Assessment table. If the participant is still eligible based upon results of 
BCVA, TBUT and meibomian gland score, the participant will be asked to “practice dose” with Vaseline in 
order for the study doctor to confirm their suitability and compliance with being able to self-dose. The 
tolerability questionnaire will be provided to participants to complete based upon this “practice dose”. 
 
The study doctor observing the participants application of dose is required to confirm that they will be able 
to consistently administer the mediation themselves at home by answering some specific questions about 
the self-dosing.  If the participant is confirmed as eligible at this stage, they will be randomized into one of 
the 2 arms, and provided with the appropriate medication to take home, with instruction for storage and 
the requirement to keep and return all used and unused containers.  
 
In order to main the blind, the person performing the Randomization and dispensing the mediation must 
not be involved in performing any assessments with the participants.  
 
Participants will be required to dose twice per week at bedtime. Patients will take their first at-home dose 
in the evening of the Baseline Visit and then 2 or 3 days of “rest” before taking the next dose (i.e., twice 
weekly dosing).  
 
For example, if a patient is dosed for the first time on Monday evening, then they can dose again on 
Thursday or Friday.  It is recommended they keep dosing on the same two days of each week. If the 
participant misses a dose on their “scheduled” day, they should dose the next day and then go back to the 
same schedule for the following weeks. 
 
4.2.3 Day 14/Month 1/Month 1.5/Month 3 (plus follow up call) 
 
Participants will return to site at Day 14 (+/- 2 days), Month 1 (+/- 7 days), Month 1.5 (+/- 7 days) and 
Month 3 (+/- 2 days). 
 
Assessments will be conducted as per the Schedule of Assessment table. Note the Ophthalmoscopy 
examination will be conducted undilated, unless dilation is necessary. 
 
Participants are expected to return all used and unused containers for compliance check at each visit, with 
new medication dispensed.  
 
Month 3 is the final on site study visit for participants.  For any participant that withdraws early, the Month 
3 assessments should be conducted at the next study visit. 
 
The participants will be called one week (+/- 2 days) after their month 3 visit, to assess adverse events and 
address any issues noted since ceasing the study medication.  


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4.3. 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 dosed up to a total daily dose of 1.0% has also been applied 
to the lid margin as a treatment for seborrheic blepharitis (Bahn, 1954, see the Investigator’s 
Brochure for more detail). 
 
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 disulfide 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. 
 
Four clinical studies of topical ocular formulations of selenium sulfide have been completed in 
seborrheic blepharitis (Bhan GC, 1954; Thygeson P & Vaughan DG, 1954; Cohen LB, 1954; Wong AS, 
Fasanella RM, Haley LD et al, 1956). Bhan GC (1954) evaluated selenium sulfide 0.5% applied 
twice-weekly for 2 weeks followed by once-weekly administration for 6 weeks in 100 subjects. 
He reported resolution of signs and symptoms of seborrheic blepharitis in 97% of treated patients. 
Thygeson P & Vaughan DG (1954) evaluated selenium sulfide 0.5% applied twice- weekly for 
a period of between 2 months to 1 year in 89 seborrheic blepharitis patients and reported 
improvement in all eyes and a cure in 75%. Cohen LB (1954) evaluated selenium sulfide 0.625% 
ointment (assuming 25% of 2.5% shampoo) applied every other night for four applications then 
repeated whenever the seborrheic blepharitis flared in 40 seborrheic blepharitis patients. He 
reported resolution of signs and symptoms in 92% of patients. Finally, Wong AS et al (1956) 
evaluated selenium sulfide 0.5% vs Ammoniated Mercury (control) applied twice-daily (BID) for 
4 weeks in combination with daily eyelid cleaning in 76 seborrheic blepharitis eyes. They reported 
improvement of sign and symptoms in 80% of seborrheic blepharitis patients. Across all studies 
topical ocular application of selenium sulfide up to maximal daily exposure of 0.5% BID was safe 
and well tolerated. The most severe AE reported across studies was self-limiting keratitis which 
resolved upon cessation of treatment. 
 


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Clinical study MGSS1 was a prospective, interventional, non-randomized, contra-lateral eye 
controlled pilot study of selenium disulfide 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 disulfide 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 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 Protocol AZ201801 was a multicenter, double-masked, vehicle-controlled, randomized, 
parallel group study carried out in 2 sequentially overlapping cohorts.  Significant, dose responsive 
improvements for both MGS and total OSDI were observed. 
 
Based upon positive efficacy and safety results from both clinical study MGSS1 and Clinical 
Protocol AZ201801, Azura Ophthalmics is further evaluating the safety, tolerability and 
effectiveness of AZR-MD-001 (0.5%) ointment/semi-solid drug, surfactant free, in patients with 
MGD. 
 
4.4  DATA REVIEW COMMITTEE (DRC) 
 
This study does not use a DRC. 
 
4.5  END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed all phases 
of the study including the last visit or the last scheduled procedure shown in the Schedule of 
Activities (SoA), Section 1.3. 
 
5 
STUDY POPULATION 
 
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 


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 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 and 
baseline visits 
 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 and baseline 
visits 
 Reported dry eye signs and symptoms within the past 3 months 
 Prior to starting screening visit procedures, patients are required to have discontinued: 
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 All other topical ophthalmic preparations (including artificial tear substitutes) 
other than the study drops: 72 hours prior to screening visit.  If artificial tear 
substitutes were used within 72 hours of the screening visit the visit should be 
rescheduled 
 Evidence of active MGD associated signs and symptoms at the screening and baseline 
visits: 
o Score ≥6 on the Standard Patient Evaluation of Eye Dryness questionnaire 
(SPEED) 
o Ocular Surface Disease Index (OSDI) questionnaire score ≥13 
And 
o TBUT < 10 seconds in both eyes 
 Demonstrated ability to follow dosing instructions at the baseline visit 
 A negative pregnancy test result for all women at the screening visit 
 Women of childbearing potential must have a history of bilateral tubal ligation or use 
oral contraceptives, implants, injectables, transdermal patch, or intrauterine device for 


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birth control during the study. Abstinence is not considered a reliable method of birth 
control. If these methods of birth control do not apply, woman 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. 


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5.2 
EXCLUSION CRITERIA 
 
 
 Uncontrolled ocular disease (except for MGD and dry eye disease/keratoconjunctivitis sicca 
associated with MGD) or uncontrolled systemic disease 
 Patient has glaucoma, ocular hypertension, or intraocular pressure (IOP) in either eye at 
screening ≥24 mm Hg as 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 or baseline 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 screening 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 or baseline visits 
 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 screening visit) ocular surgery, trauma, herpes, or 
recurrent inflammation 
 Contact lens use anticipated during the study 
 Periocular application of makeup likely to impact meibomian gland function 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 
baseline 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) 
 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 
 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 


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 Planned anterior segment surgery (e.g., cataract surgery or any surgery involving a limbal or 
corneal incision) in either eye during the study period 
 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 mm in either eye at the baseline visit 
 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.  Woman of childbearing potential may have a monogamous partner who 
has had a vasectomy at least 3 months before the screening visit or who is of the same 
gender.  
 Positive urine pregnancy test at the screening visit 
 
Participation in another clinical trial involving a therapeutic drug or device within the past 30 
days 
 
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 
screening visit or during the study. 
 Patients must have discontinued (2 weeks before screening) 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. 
 Patients should not have punctal plugs or plan to have punctal plugs inserted during 
the study. 
 Patients must have discontinued (1 month before screening) and be willing to remain 
off antihistamines or isotretinoin during the study. 
 Patients must have discontinued (3 months before screening) 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 screening visit. 
 Patients must have discontinued (2 weeks before screening) 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. 


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 Patients must have discontinued all other topical ophthalmic preparations (including 
artificial tear substitutes) other than the study drops 72 hours prior to the screening 
visit. If artificial tear substitutes were used within 72 hours of the screening visit the 
visit should be rescheduled. 
 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 
 
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 


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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 or efficacy measures (e.g., minimally important clinical difference 
for OSDI) may be rescreened one additional time. Rescreened participants should be assigned 
a new screening number and the original number should not be reused.  
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
The total number of randomized patients for the study will be up to approximately 30. 
Approximately 15 patients should have a baseline MGS score of < 6 and approximately 15 
patients should have a baseline MGS score ≥6 and ≤ 12. Based upon data from ongoing study 
AZ201801 and the simplified inclusion/exclusion criteria for this study a screen failure rate of ~ 
40% is expected. Thus, ~42 patients will need to be screened to achieve ~30 patients 
randomized to treatment. 
 
Individual study sites may choose to advertise the study in order to facilitate patient 
recruitment. All advertisements will be approved by the sponsor Azura Ophthalmics, submitted 
to their IEC, and approved by the IEC before they are used by the site. 
 
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 (0.5%), and 
suitable excipient. The only excipient in the formulation is 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 identical unit dose containers (see Table 6.1.1–1). 
 
 


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Table 6.1.1–1  Investigational Product and Packaging / Labelling Characteristics 
 
 
Product name: 
AZR-MD-001 
(Selenium disulfide API in 
ointment/semi-solid 
Petrolatum white) 
 
Vaseline 
 
Vehicle 
Formulation 
description: 
AZR-MD-001 is an 
orange opaque dispersion 
ointment with an odor 
faintly of hydrogen 
sulfide 
Ointment will match 
AZR-MD-001’s 
texture 
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): 
0.5%/5mg 
 
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. Discard 4 weeks 
(30 days) after opening. 
Protect from light 
Store between 2 – 
8°C until opened. 
Refrigerate. Do not 
freeze. Discard 4 
weeks (30 days) 
after opening. 
Protect from light 
Store between 2 – 8°C 
until opened. 
Refrigerate. Do not 
freeze. Discard 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 
 
Azura Ophthalmics is further evaluating the safety, tolerability and effectiveness of AZR-MD-001 


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ointment/semi-solid drug, surfactant free, at an effective concentration of 0.5% based upon 
positive results from clinical studies MGSS1 and AZ201801 (see the Investigators’ Brochure 
for more detail) that demonstrated the safe and effective treatment of MGD with selenium 
sulfide exposures up to 1.0% twice-weekly, pre-clinical safety data with exaggerated dosing up to 
2.5% with the clinical formulation and concentrations up to 2.5% fulfil the criteria for a low risk 
Schedule 2 (Pharmacy medicine) classification as specified in the Australian Poisons Standard 
October 2017 (Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP), No. 
18) (see Table 6.1.2-1). 
 
Table 6.1.2-1: Australian Poisons Standard for Selenium 
 
Australian Poisons Standard Dated 26th September 2017 
Schedule 
Description 
Topical 
Oral 
1 
Schedule is intentionally blank. 
2 
Pharmacy Medicine-Safe use may require advice from a 
pharmacist or licensed person. 
For human topical use of 3.5% or less 
For human oral use with a recommended dose of 150 
micrograms or less 
3 
Pharmacist Only Medicine-Safe use requires advice from a 
pharmacist without a prescription. 
 
 
 
4 
Prescription Only Medicine-Use should be ordered by persons 
permitted by State or Territory legislation to prescribe and 
should be available from a pharmacists on prescription. 
 
For human oral use with a recommended dose of 300 
micrograms or more 
 
6 
Poison-Substances with a moderate potential for causing harm, 
the extent of which can be handled through distinctive packaging 
and strong safety labeling. 
 
In this schedule if it occurs with an "arsenic" (i.e., selenium arsenide) 
 
Azura Ophthalmics believes that the use of AZR-MD-001 ointment/semi-solid drug with selenium 
disulfide at a concentration of 0.5% is likely to safely and effectively treat MGD. 
 
6.1.3 
DOSING AND ADMINISTRATION 
 
Patients (or a caregiver) will dispense 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 apply the thin drug film and 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). 
 
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. 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 
ACQUISITION AND ACCOUNTABILITY 
 
Subjects will be instructed on proper instillation and storage of study drug at the end of the 
baseline, day 14, month 1, and month 1.5 visits, will be given written instructions and may also 


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watch an instructional video. The used and unused study drug tubes will be collected at each 
visit from day 14 up to and including month 3 to assess dosing and symptom assessment 
compliance. Dosing compliance will be based off of the used and unused tube count. 
 
6.2.2 
FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
The study packaging will be performed by PCI Pharma Services. 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. 
 
6.2.3 
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) or a pharmacist, 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 the sponsor 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 sites. 
 
6.2.4 
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. 


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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 discarded. 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
Patients (or a caregiver) will apply approximately 3.5mm (0.14inch, 4mg) using a dosing aid 
supplied by Azura Ophthalmics. Patients will 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. The patient will then 
blink several times to transfer a portion of the drug from the lower eyelid to the upper eyelid. 
 
To minimize the risk for noncompliance with the dosing instructions patients enrolled into the 
clinical study will be given dosing instructions and will have access to instructional dosing videos. 
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.  
 
Only patients demonstrating an understanding with the provided dosing instructions can be 
enrolled into the clinical study. 
 
Following the qualification period, the patient, staff members performing all safety and efficacy 
assessments, site personnel (with the exception of designated personnel who are responsible for 
drug accountability) and the sponsor study team will be masked to the treatment assignment for 
the 3 month treatment period. All study medication will be provided in identical tubes and cartons 
to maintain masking of the study. Due to the difference in color between the active and control 
treatments, which are in opaque tubes, designated personnel who are responsible for drug 
accountability will not perform any safety or efficacy assessments and will not discuss assigned 
treatment(s) with staff members who are performing safety or efficacy assessments.  
 
To obtain a screening number at the screening visit the site will access an electronic data capture 
(EDC) system and complete the appropriate electronic Case Report Form (eCRF). The numbers will 
be assigned sequentially by site. 
 
The automated IWRS system will provide the site with the specific medication kit number(s) to 
use for each qualified patient at the baseline visit. At the baseline/randomization visit, patients 
meeting all inclusion/exclusion criteria, will be placed in one of the strata. A randomization 
number will be assigned to each patient corresponding to the treatment arm they are assigned 
to. The numbers will be assigned sequentially in order of enrollment within the patient’s stratum. 
The IWRS system will report a medication kit number to use for each patient corresponding to the 
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The site will dispense the study medication kit assigned by the IWRS system. Sites will log onto the 
IWRS system at all subsequent study visits to obtain medication kit number for dispensing study 
medication. Sites will receive an IWRS confirmation notice for each transaction. All notifications 
are to be maintained with the study source documents. 
 
6.4 
CONCOMITANT THERAPY 
 
Not-applicable: Patients must have discontinued and be willing to remain off all other ophthalmic 
preparations including artificial tears during the study. 
 
6.4.1 
RESCUE MEDICINE 
 
In the event that rescue medication is required for clinically relevant worsening of keratitis, 
patients will be provided a concomitant regimen the investigator/treating clinician can initiate: 
 Flarex® 0.1% dosed four times a day for up to 10 days as recommended by the 
prescribing physician. 
and 
 Instillation of Hylo-Forte® in each eye 5 minutes prior to applying the study ointment.  
This can be maintained for the duration of the study as recommended by the 
prescribing physician. 
Patients responding to treatment may remain in the study.  Patients not-responding to treatment 
and who are still demonstrating clinically significant keratitis may be temporally discontinued 
from treatment or discontinued from the study at the investigator/treating clinician’s discretion. 
 
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 and Azura 
Ophthalmics 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 
 


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 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. Notification of early patient discontinuation from the study and the reason 
for discontinuation should be made to Azura Ophthalmics and should be clearly documented 
on the appropriate eCRF. 
 
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 discussed with Azura Ophthalmics. 
 
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 
EFFICACY ASSESSMENTS 
 
8.1.1 
PRIMARY EFFICACY MEASURES 
 
 
Primary Sign for MGD: 
 
Change from Baseline to month 3 in meibum gland secretion score 
(MGS) (0 to 45 scale) 
 
Primary Symptom for MGD: 
 
Change from Baseline to month 3 in Total OSDI 
 
8.1.2 
SECONDARY EFFICACY MEASURES 
 
Secondary efficacy measures include: 
 
Change from Baseline to day14, month 1 and month 1.5 in MGS (0 to 
45 scale) 
 
MGS score (0 to 45 scale) at each visit 
 
Proportion of patients with a MGS score > 12 at each visit 
 
Change from Baseline to day14, month 1, month 1.5 and month 3 in 
the number of Meibomian Glands Yielding Liquid Secretion (MGYLS) (0 
to 15 scale) 
 
MGYLS (0 to 15 scale) at each visit  
 
Change from Baseline to day 14, month 1, month 1.5, and month 3 in TBUT 
 
TBUT at each visit 
 
Proportion of patients with a TBUT score > 5 at each visit 
 
Change from Baseline to day 14, month 1, month 1.5 and month 3 
in Standard Patient Evaluation of Eye Dryness (SPEED) 
 
SPEED at each visit 
 
Proportion of patients with a SPEED < 6 at each visit 
 
Change from Baseline to day 14, month 1, month 1.5 and month 3 
in average visual analogue scale (VAS) 
 
Average VAS at each visit 
 
Change from Baseline to day 14, month 1, month 1.5 and month 3 
in worst VAS 
 
Worst VAS at each visit 
 
Change from Baseline to day 14, month 1 and month 1.5 in Total OSDI 
 
Total OSDI, OSDI sub-scales, and individual items from the OSDI across visits 
 
Proportion of patients with a Total OSDI change from baseline > 4.5, the 
known minimally important clinical difference (MICD) for early to moderate 
disease, at month 3 
 
Proportion of patients with a Total OSDI < 13 at each visit 
 
Number of expressible glands yielding clear meibum at day14, month 1, 
month 1.5, and month 3 
 
Eyelid margin erythema/telangiectasias at day14, month 1, month 1.5, 
and month 3 
 
Corneal and conjunctival staining (0 to 5 scale) at each visit 


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8.1.3 
DATA REVIEW COMMITTEE (DRC) 
 
 
                                       Not applicable.  
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
 
8.2.1 
SAFETY MEASURES 
 
The following safety measures will be examined: 
 
 
Adverse events 
 
Vital signs 
 
Study medication tolerability as measured by the Ocular Comfort 
Questionnaire 
 
Urine pregnancy test 
 
Best-corrected visual acuity (BCVA; Logarithmic visual acuity chart) 
 
Biomicroscopy 
 
Ophthalmoscopy 
 
Intraocular pressure (IOP) 
 
 


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8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
Adverse events occurring during the study will be recorded on an adverse event case report form 
(CRF). 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. 
8.3.1 
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 
significant worsening of the indication under investigation that is not recorded elsewhere in the 
CRF 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 page of the CRF. 
 
Some illustrate examples follow to help understand the difference between events meeting 
the definition of an AE and those that don’t. 


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Events meeting AE definition include: 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), 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. 

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. 


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8.3.2 
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 CRF). 
 
 
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 suggest any significant hazard, contraindication, side effect, or 
precaution that may be associated with the use of the investigational product. 
8.3.2.1 
REPORTING OF SERIOUS ADVERSE EVENTS 
 
Any SAE must be reported by the investigator if it occurs during the clinical study or within 30 
days of receiving the study drug, 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. A copy of these forms must be faxed or e-mailed within 24 
hours for the attention of the CRO. The appropriate pages in the eCRF must be completed as soon 
as possible. The CRO will handle the SAE as per the Safety Management Plan and ensure 


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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: 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 the study monitor. 
 
The sponsor and/or CRO 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. In addition, CRO, on behalf of the sponsor, will expedite 
the reporting to all concerned investigators, to the IECs/IRBs, where required, and to the 
regulatory authorities of all adverse reactions that are both serious and unexpected. 
 
Details of the procedures to be followed if a pregnancy occurs are provided in Section 8.3.7. 


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8.3.3 
CLASSIFICATION OF AN ADVERSE EVENT 
 
8.3.3.1 
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 
 
 
8.3.3.2 
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 


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or chemicals. 
 
 
8.3.3.3 
ACTION TAKEN 
 
The investigator will describe the action taken in the appropriate section of the CRF, as 
follows: 
 
 
None 
 
Study drug stopped 
 
Study drug temporarily interrupted 
 
Concomitant medication 
 
Other, specify. 
 
8.3.4 
TIME PERIOD & FREQUENCY FOR EVENT ASSESSMENT AND 
FOLLOW-UP 
 
 
All investigators should follow up subjects with AEs 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 CRF. 
 
Subjects should be followed up for 30 days (check time limit with sponsor) 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. 
8.3.4.1 
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 CRF 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]) 
 


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8.3.5 
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 determine which treatment has been assigned and 
institute appropriate follow-up care. The Randomization and Unblinding Plan should be followed 
in any instance of request for unblinding. When possible, the sponsor (Azura Ophthalmics) should 
be notified prior to unmasking study medication. The investigator should inform the sponsor 
(Azura Ophthalmics) of the unmasking if there is no notification prior to the unmasking. 
 
The reason for breaking the code 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). 
 
8.3.6 
EVENTS OF SPECIAL INTEREST 
8.3.6.1 
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 sponsor and/or CRO 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 sponsor 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 sponsor 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 sponsor. 
 
8.3.7 
REPORTING OF PREGNANCY 
 
If a female becomes pregnant during the study, the investigator will notify Azura Ophthalmics 


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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 Ophthalmics. 
 
 
9 
STATISTICAL CONSIDERATIONS 
 
The statistical analysis plan (SAP) will provide a detailed description of the planned statistical 
analysis. 
 
9.1 
SAMPLE SIZE DETERMINATION 
 
Sample Size Calculation:  Estimates for sample size calculations are from the first interim analysis 
from Azura Clinical Protocol AZ201801.  The standard deviation for MGS was 3.35 units for an 
ineffective dose and 9.48 units for the high dose.  A sample size of 12 subjects per group will have 
90% power to detect a difference of 10.4 units between the active treatment group and the vehicle 
group using a two-sample t-test at a significance level of 0.05.   The standard deviation for Total 
OSDI was 13.01 units for an ineffective dose and 6.79 units for the high dose.  A sample size of 11 
subjects per group will have 90% power to detect a difference of 15.9 units between the active 
treatment group and the vehicle group using a two-sample t-test at a significance level of 0.05.   
 
Multiplicity Consideration: To address the multiple primary endpoints defined in this study, the 
primary endpoints have been prioritized into a hierarchical structure.  In order to test the primary 
symptom endpoint of Total OSDI, the primary sign endpoint of MGS must be statistically 
significantly higher in the 0.5% AZR-MD-001 treatment group compared to the vehicle treatment 
group using a two-sided significance level of 0.05.  Using this strategy, the family-wise Type I error 
rate will be maintained at the 0.05 significance level for the two primary endpoints. 
 
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, have values at randomization, 
and at least 1 post-randomization value for MGS at a regularly scheduled visit (i.e., Day 14 or Month 
1). 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 


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population. In these analyses, non-missing values recorded at visit 3 (i.e., Day 14) or later will be used 
to replace missing data at visits where data are not recorded. 
Additional imputation methods will be used for sensitivity analysis and will be outlined in the 
Statistical Analysis Plan (SAP). 
 
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, reported to the sponsor or their designee. 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. 
 
9.4 
STATISITICAL 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 Wilcoxon rank-sum test for between-treatment comparisons and the 
sign-rank test for within-treatment comparisons. 
Efficacy (MGD): 


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Primary Sign for MGD: 
 
Change from Baseline to month 3 in meibum gland secretion score 
(MGS) (0 to 45 scale) 
 
Primary Symptom for MGD: 
 
Change from Baseline to month 3 in Total OSDI 
 
Other Efficacy Measures: 
 
Change from Baseline to day14, month 1 and month 1.5 in MGS (0 to 
45 scale) 
 
MGS score (0 to 45 scale) at each visit 
 
Proportion of patients with a MGS score > 12 at each visit 
 
Change from Baseline to day14, month 1, month 1.5 and month 3 in the 
number of Meibomian Glands Yielding Liquid Secretion (MGYLS) (0 to 15 
scale) 
 
MGYLS (0 to 15 scale) at each visit  
 
Change from Baseline to day 14, month 1, month 1.5, and month 3 in TBUT 
 
TBUT at each visit 
 
Proportion of patients with a TBUT score > 5 at each visit 
 
Change from Baseline to day 14, month 1, month 1.5 and month 3 in 
Standard Patient Evaluation of Eye Dryness (SPEED) 
 
SPEED at each visit 
 
Proportion of patients with a SPEED < 6 at each visit 
 
Change from Baseline to day 14, month 1, month 1.5 and month 3 in 
average visual analogue scale (VAS) 
 
Average VAS at each visit 
 
Change from Baseline to day 14, month 1, month 1.5 and month 3 in 
worst VAS 
 
Worst VAS at each visit 
 
Change from Baseline to day 14, month 1 and month 1.5 in Total OSDI 
 
Total OSDI, OSDI sub-scales, and individual items from the OSDI across visits 
 
Proportion of patients with a Total OSDI change from baseline > 4.5, the 
known minimally important clinical difference (MICD) for early to moderate 
disease, at month 3 
 
Proportion of patients with a Total OSDI < 13 at each visit 
 
Number of expressible glands yielding clear meibum at day14, month 1, 
month 1.5, and month 3 
 
Eyelid margin erythema/telangiectasias at day14, month 1, month 1.5, and 
month 3 
 
Corneal and conjunctival staining (0 to 5 scale) at each visit 
Safety: Safety measures will be analyzed using the safety population. Medical Dictionary for 
Regulatory Activities (MedDRA) nomenclature will be used to code adverse events. Incidence 
rates of each treatment-emergent adverse event will be summarized by primary system organ  
class and preferred term. Summary tables will be generated for all treatment-emergent 
adverse events regardless of causality as well as for those considered to be treatment-related. 
 


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9.4.2 
ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
The primary efficacy variables (see Section 8.1.1) will be analyzed at month 3 using an analysis of 
covariance [ANCOVA] model with baseline MGS score and duration of disease as covariates and 
treatment (AZR-MD-001 ointment/semi-solid drug or vehicle) as factors in the model. Pairwise 
comparisons will be performed for each AZR-MD-001 ointment/semi-solid drug treatment group 
versus vehicle using t-tests of the least square means from this model. Two-sided confidence 
intervals (95%) will be provided for the differences between treatments. 
 
Details of other efficacy analyses will be provided in the statistical analysis plan. 
 
 


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9.4.3 
ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
 
The secondary efficacy variables (see Section 8.1.2) will be analyzed using an analysis of 
covariance [ANCOVA] model with baseline MGS score and duration of disease as covariates and 
treatment (AZR-MD-001 ointment/semi-solid drug or vehicle) as factors in the model. Pairwise 
comparisons will be performed for each AZR-MD-001 ointment/semi-solid drug treatment group 
versus vehicle using t-tests of the least square means from this model. Two-sided confidence 
intervals (95%) will be provided for the differences between treatments. 
 
Descriptive statistics (change from baseline variables) will be tabulated for the following within 
treatment group changes in the mITT population: 
 
 Patients in the AZR-MD-001 ointment/semi-solid drug treatment group:  changes from 
baseline to days 14, month 1, month 1.5 and month 3 
 Patients in the AZR-MD-001 vehicle group:  changes from baseline to days 14, month 1, 
month 1.5 and month 3 
Within each treatment group, shift tables for complete treatment response (yes/no) in the study eye 
will be presented for patients in the mITT population for endpoint signifying a “clinical cure” 
(Proportion of patients with a MGS score > 12; Proportion of patients with a MGYLS score of >2; 
Proportion of patients with a MGYLOS score of >2; Proportion of patients with a TBUT > 5 seconds 
at each visit; Proportion of patients with a Schirmer’s test ≥ 10 mm at each visit; Proportion of 
patients with a Total OSDI < 13 at each visit; and Proportion of patients with a SPEED Score < 6. 
 
 Patients in the AZR-MD-001 ointment/semi-solid drug treatment group:  changes from 
baseline to days 14, month 1, month 1.5 and month 3. 
 
 Patients in the AZR-MD-001 vehicle group:  changes from baseline to days 14, month 1, 
month 1.5 and month 3. 
The Logistic Regression method for general association, stratified by baseline MGS score and 
duration of disease will be used to compare treatments with respect to the proportion of patients 
achieving a “clinical cure” in the study eye. Odds ratio along with 95% CI will be obtained by 
pairwise comparisons will be performed for each AZR-MD-001 treatment groups versus vehicle.. 
 
9.4.4 
SAFETY ANALYSES 
 
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 


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adverse events will be summarized. The adverse events will be classified into ocular and nonocular 
types and will be summarized separately. Detailed methods for the analyses of adverse events and 
other safety variables will be described in the analysis plan. 
 
9.4.5 
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. 
 
9.4.6 
PLANNED INTERIM ANALYSES 
 
 
None planned. 
 
9.4.7 
SUB-GROUP ANALYSES 
 
 
Patients will be stratified by duration of MGD diagnosis (i.e., < 5 years or ≥ 5 years) and baseline 
MGS score for the qualified eye (i.e., the eye meeting the inclusion/exclusion criteria). If the eyes 
have the same MGS score the right eye will be selected as the study eye. 
Thus, subgroup analyses are planned for the 4 groups defined by the 2 stratification factors: 
 
1. MGD diagnosis < 5 years and MGS score for the qualified eye < 6 
2. MGD diagnosis < 5 years and MGS score for the qualified eye ≥ 6 and ≤ 12 
3. MGD diagnosis ≥ 5 years and MGS score for the qualified eye < 6 
4. MGD diagnosis ≥ 5 years and MGS score for the qualified eye ≥ 6 and ≤ 12. 
 
 
9.4.8 
TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
Individual participant data will be listed by measure and time point. 
 
9.4.9 
EXPLORATORY ANALYSES 
 
 
The statistical analysis plan (SAP) will provide a detailed description of the planned exploratory 
statistical analysis. 
 
 


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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. 
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 


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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, and other authorized agents of the sponsor and/or its designee, 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 
 
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 the sponsor or its nominated representative. In addition, inspections may 
be conducted by regulatory authorities at their discretion. 
 
11.2 
MONITORING 
 
 
Data for each subject will be recorded on a CRF. Data collection must be completed for each 
subject who signs an informed consent form (ICF) and is administered study drug. 


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In accordance with GCP and ICH guidelines, the study monitor will carry out source document 
verification at regular intervals to ensure that the data collected in the CRF are accurate and 
reliable. 
The investigator must permit the monitor, the IEC, the sponsor’s internal auditors, and 
representatives from regulatory authorities direct access to all study-related documents and 
pertinent hospital or medical records for confirmation of data contained within the CRFs. 
 
11.3 
DATA MANAGEMENT AND CODING 
 
 
Study centers will enter data directly into an electronic data capture (EDC) system by completing 
the CRF via a secure internet connection. Data entered into the eCRF must be verifiable against 
source documents at the study center. Data to be recorded directly on the eCRF will be identified 
and the eCRF will be considered the source document. Any changes to the data entered into 
the EDC system will be recorded in the audit trail and will be FDA CFR 21 Part 11 compliant. 
 
Medical coding will use Medical Dictionary for Regulatory Activities (MedDRA) for concomitant 
diseases and AEs and WHO Drug for medications. Missing or inconsistent data will be queried in 
writing to the investigator for clarification. Subsequent modifications to the database will be 
documented. 
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 sponsor and will provide the reason(s) for the 
termination or suspension. 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 


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 Data that are not sufficiently complete and/or evaluable 
 Determination that the primary endpoint has been met 
 Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and/or applicable regulatory agencies. 
 
12.2 
 FUTURE USE OF STORED SPECIMENS AND DATA 
 
12.2.1 HANDLING OF BIOLOGICAL SPECIMENS 
 
None are planned for collection during the study. 
 
12.3 
KEY ROLES AND STUDY GOVERNANCE 
 
 
 
 
 
Medical Monitor 
DRC Chair 
Peter McCluskey 
N/A 
Phone: 02 9382 7300 
N/A 
E-mail: 
peter.mccluskey@sydney.edu.au 
N/A 
 
 
 


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12.4 
RETENTION OF DOCUMENTATION 
 
 
 
For countries falling within the scope of the ICH guidelines, Azura Ophthalmics-specific essential 
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 CRFs 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 the sponsor 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. 
 
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 
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 CRFs 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. 
 
 


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12.6 
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. 
 
12.7 
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 or Azura Ophthalmics requests the SOPs and membership lists, the IRB should 
comply with the request. 
 
12.8 
PUBLICATION AND DATA SHARING POLICY 
 
Azura  Ophthalmics  as  the  sponsor,  has  proprietary  interest  in  this  study. Authorship and 
manuscript composition will reflect joint cooperation between multiple investigators and sites and 
Azura Ophthalmics personnel. Authorship will be established prior to the writing of the manuscript. 
As this study involves multiple centers, no individual publications will be allowed prior to 
completion of the final report of the multicenter study except as agreed with Azura Ophthalmics. 
 
12.9 
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. The study leadership in conjunction with the DRC has established policies and 


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procedures for all study group members to disclose all conflicts of interest and will establish a 
mechanism for the management of all reported dualities of interest. 
 
12.10 ADDITIONAL CONSIDERATIONS 
 
None 
 
 


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12.11 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 
CRF 
Case Report Form 
DED 
Dry Eye Disease 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
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 evaluation 
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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12.12 PROTOCOL AMENDMENT HISTORY 
 
 
Version 
Date 
Description of Change 
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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13 
REFERENCES 
 
 
1. Akyol-Salman I, Azizi S, Murncu UY, and Baykal O. Efficacy of topical N- acetylcysteine 
in the treatment of Meibomian gland dysfunction. J Ocular Pharm & Ther. 
2010;26(4):329-333. 
2. Akyol-Salman I, Azizi S, Murncu UY, Ates O, and Baykal O.  Comparison of the 
efficacy of topical N-acetylcysteine and a topical steroid-antibiotic combination 
therapy in the treatment of Meibomian gland dysfunction.  J Ocular Pharm & Ther. 
2012;28(1):49-52. 
3. Bahn GC. 1954. The treatment of seborrheic blepharitis. Southern Medical Journal, 
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4. Blackie CA, Carlson AN, and Korb DR. Treatment for Meibomian gland dysfunction and 
dry eye symptoms with a single-dose vectored thermal pulsation: a review.  Curr Opin 
Ophthalmol. 2015;26(4):306-313. 
5. Cohen LB. Use of selsun in blepharitis marginalis.  Am J Ophthalmol. 
1954 Oct;38(4):560-2. 
6. Cummins LM & Kimura ET. Safety evaluation of selenium sulfide 
antidandruff shampoos. 1971;20:89-96 
7. Finis D, Hayajneh J, Konig C, Borrelli M, Schrader S, Greerling G. Evaluation of an 
automated thermodynamic treatment (LipiFlow) system for Meibomian gland 
dysfunction: a prospective, randomized, observer-masked trial. The Ocular 
Surface. 2014;12:146-154. 
8. Flesch P. On the mode of action of selenium sulfide. The J Inves Derm. 
1953;21:233- 235. 
9. Foster CS, Yuksel C, Anzaar F, Ekong AS. Dry eye syndrome: Treatment & medication. 
emedicine, 
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http://emedicine.medscape.com/article/1210417-   treatment. Accessed January 11, 
2010. 
10. Geerling G, Tauber J, Baudouin C, Goto E, Matsumoto Y, O’Brien T, Rolando M, 
Tsubota K, and Nichols KK. The international workshop on Meibomian gland 
dysfunction: report of the subcommittee on management and treatment of 
meibomian gland dysfunction.  Investigative Ophthalmology and Visual Science. 
2011;52(4):2050- 2064. 
11. Goto E, Monden Y, Takano Y, etal. Treatment of non-inflamed obstructive 
meibomian gland dysfunction by an infrared warm compression device. Br J 
Ophthalmol. 2002;86(12):1403-1407. 
12. Green-Church KB, Butovich I, Willcox M, Borchman D, Paulsen F, Barabino S, 
Glasgow BJ.  . The international workshop on meibomian gland dysfunction:  report 
of the subcommittee on tear film lipids and lipid-protein interactions in health and 
disease. Investigative Ophthalmology and Visual Science. 2011;52(4):1979-1993. 
13. Kalivas J. 1993. Lack of serum selenium rise after overnight application of 
selenium sulfide. Arch Dermatol. 19:646-648. Abstract Only. 
14. Knop E, Knop N, Millar T, Obata H, Sullivan DA. The international workshop on 
meibomian gland dysfunction:  report of the subcommittee on anatomy, physiology, 


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and pthophysiology of the meibomian glands.  Investigative Ophthalmology and 
Visual Science. 2011;52(4):1938-1978. 
15. Lane SS, DuBiner HB, Epstein RJ, et al.  A new system, the LipiFlow, for the treatment 
of meibomian gland dysfunction (MGD). Cornea. 2012; 31(4): 396-404. 
16. Matsumoto Y, Dogru M, Goto E, et al. Efficacy of a new warm moist air device on tear 
functions of patients with simple meibomian gland dysfunction. Cornea. 
2006;25(6):644- 650. 
17. Mitra M, Menon GJ, Casini A, et al. Tear film lipid layer thickness and ocular comfort 
after meibomian therapy via latent heat with a novel device in normal subjects. Eye. 
2005;19(6):657-660. 
18. Nelson DJ, Shimazaki J, Benitez-del-Castillo JM, Craig JP, McCulley JP, Den S, Faulks 
GN. The international workshop on meibomian gland dysfunction:  report of the 
definition and classification sucommittee.  Investigative Ophthalmology and Visual 
Science. 2011;52(4):1930-1937. 
19. Nichols KK, Foulks GN, Bron AJ, Glasgow BJ, Dogru M, Tsubota K, Lemp MA, Sullivan 
DA. The international workshop on Meibomian gland dysfunction: executive 
summary. Inv Oph & Vis Sci. 2011;52(4):1922-1929. 
20. Olson MC, Korb DR, Greiner JV. Increase in tear film lipid layer thickness following 
treatment with warm compresses in patients with meibomian gland dysfunction. Eye 
Contact Lens. 2003;29(2):96-99. 
21. Perry HD, Doshi-Carnevale S, Donnenfeld ED, et al. Efficacy of commercially available 
topical cyclosporine A 0.05% in the treatment of meibomian gland dysfunction. Cornea. 
2006;25(2):171-175. 
22. Romero JM, Biser SA, Perry HD, et al. Conservative treatment of meibomian gland 
dysfunction. Eye Contact Lens. 2004;30(1):14-19. 
23. Pinna A, Piccinini P, Carta F. Effect of oral linoleic and gamma-linolenic acid on 
meibomian gland dysfunction. Cornea. 2007;26(3):260-264. 
24. Rosenthal JW and Adler H. Effect of selenium sulfide on rabbit eyes. Southern Medical 
Journal. 1962; March, p 318. 
25. Schaumberg DA, Nichols JJ, Papas EB, Tong L, Uchino M, Nicholes KK. The international 
workshop on meibomian gland dysfunction: report of the subcommittee on the 
epidemiology of, and associated risk factors for, MGD. Investigative Ophthalmology 
and Visual Science. 2011;52(4):1994-2005. 
26. Sternberg TH, Newcomer VD, Calnan CD, Rostenberg A, and Rothman S, eds. 1964. 
Percutaneous toxicity. In: The evaluation of therapeutic agents and cosmetics, 
McGraw- Hill Book Co., N.Y., p. 178. 
27. Souchier M, Joffre C, Grégoire S, et al. Changes in meibomian fatty acids and clinical 
signs in patients with meibomian gland dysfunction after minocycline treatment. Br J 
Ophthalmol. 2008;92(6):819-822. 
28. Thygeson P, Vaughan DG Jr. Seborrheic blepharitis. Trans Am Ophthalmol Soc 1954; 
52: 173–188 
29. Wong AS, Fasanella RM, Haley LD, Marshall CL, Krehl WA. Selenium (Selsun) in the 
treatment of marginal blepharitis. AMA Arch Ophthalmol. 1956;55(2):246-253. 
30. Yoo SE, Lee DC, Chang MH. The effect of low-dose doxycycline therapy in chronic 
meibomian gland dysfunction. Korean J Ophthalmol. 2005;19(4):258-263. 


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14 
SUBJECTIVE STUDY SCALES 
 
 
 
14.1 
VISUAL ANALOG SCALE (VAS) 
Patients will be asked the following questions regarding their ocular discomfort (unrelated to 
study drug instillation). 
 
The patient will be asked to subjectively rate each symptom (OU) by placing a vertical mark on 
the horizontal line to indicate the level of discomfort. 0% corresponds to “no discomfort” and 
100% corresponds to “maximal discomfort.” 
 
 


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14.2 
OCULAR SURFACE DISEASE INDEX (OSDI) 
The OSDI questionnaire consists of 12 questions regarding ocular symptoms, environmental 
triggers, and vision-related functioning in patients with DED. The patient will be asked to rate 
each symptom using a 5-point scale (0 to 4), where 0 = none of the time; 1 = some of the time; 
2 
= half of the time; 3 = most of the time; and 4 = all of the time. Seven questions related to 
visual functioning allow a response of “N/A” (not applicable). The total OSDI will be calculated 
by EDC from the raw scores of each of the 12 questions based on the formula: ([sum of scores 
for all questions answereda] X 100)/([total number of questions answereda] X 4). 
a Questions answered with N/A will be excluded in the calculation of total OSDI. 


AZR-MD-001 (Selenium disulfide Agonist) 
Protocol AZ202001 
Version 1.0 
12-Mar-2020 
 
54 
 
 
 


AZR-MD-001 (Selenium disulfide Agonist) 
Protocol AZ202001 
Version 1.0 
12-Mar-2020 
55 
 
 
 
 
 
14.3 
STANDARD PATIENT EVALUATION OF EYE DRYNESS (SPEED) 
 
 


56 
AZR-MD-001 (Selenium disulfide Agonist) 
Protocol AZ202001 
Version 1.0 
12-Mar-2020 
 
 
 
14.4 
STUDY MEDICATION TOLERABILITY/COMFORT QUESTIONAIRE 
 
 
Patients will use a visual analog scale ranging from 0 to 100 to answer 8 questions assessing the 
acute overall comfort of the study drug (in both eyes together). Questions 1 through 4 assess 
to what degree the drops felt comfortable, felt soothing, were moistening/lubricating, and 
enhanced clear vision, respectively. Questions 5 through 8 assess to what degree the drops 
caused stickiness, blur, burning/stinging, and discomfort, respectively. Higher scores 
represented greater comfort for questions 1 to 4 (i.e., 100% corresponds to “comfortable” 
and 0% corresponds to “not comfortable”), while lower scores represented greater comfort 
for questions 5 to 8. (i.e., 0% corresponds to “no discomfort” and 100% corresponds to 
“maximal discomfort”). 
 
Ratings should commence ~5 ± 1 minutes after eye drop administration. 
 
 


57 
AZR-MD-001 (Selenium disulfide Agonist) 
Protocol AZ202001 
Version 1.0 
12-Mar-2020 
 
 
 
15 
SPONSOR APPROVAL(S) 
 
 
 
 
Protocol Title: 
A Multicenter, Vehicle-controlled, Randomized Study to Evaluate 
the Safety, Tolerability and Pharmacodynamics of AZR-MD-001 in 
Patients with Meibomian Gland Dysfunction (MGD) 
Protocol Number: 
AZ202001 
Final Date: 
12Mar2020 
 
This clinical study protocol was subject to critical review and has been approved by the sponsor. The following 
personnel contributed to writing and/or approving this protocol. 
 
 
 
 
 
 
 
 
 
Signed: 
Date:   Charles Bosworth Ph.D. 
Chief Medical Officer Azura 
Ophthalmics 

SAP_001.pdf: 
 
 
 
 
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Statistical Analysis Plan 
for 
 
AZ202001 
Azura Ophthalmics  
 
 
A Multicenter, Vehicle-controlled, Randomized Study to 
Evaluate the Safety, Tolerability and Pharmacodynamics of 
AZR-MD-001 in Patients with Meibomian Gland Dysfunction (MGD) 
 
AZ202001 
 
Version 1.0, dated 25JAN2021  
 
 
Author 
Name 
Function 
Signature 
Date 
dd 
mmm 
yy 
Allie Ferreira  
Lead Biostatistician 
 
 
 
 
 
21
Jan 
26


 
 
 
 
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SIGNATURE PAGE  
The undersigned hereby jointly declare that they have reviewed the Statistical Analysis Plan, and agree 
to its form and content. 
Approval by  
Name 
Function 
Signature 
Date 
dd 
mmm 
yy 
Charles Bosworth  
Sponsor 
Representative 
 
 
 
 
 Audra Wilson 
Project Manager 
 
 
 
 
Elizabeth Kane  
Director, Analytical 
Services 
 
 
 
 
Venita DePuy  
Independent 
Biostatistician 
 
 
 
 
Allie Ferreira 
Lead Biostatistician  
 
 
 
 
 
 
 
 
26
21
Jan
21
01
21
26
01
21
JAN
26
21
26
21
JAN


 
 
 
 
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TABLE OF CONTENTS 
Document History ......................................................................................................................................... 6 
1 
Abbreviations ........................................................................................................................................ 7 
2 
Summary ............................................................................................................................................... 8 
3 
Study Objectives and Endpoints ......................................................................................................... 10 
3.1 
Study Objective ........................................................................................................................... 10 
3.2 
Study Endpoints .......................................................................................................................... 10 
3.2.1 
Primary Efficacy Endpoints ................................................................................................. 10 
3.2.2 
Other Efficacy Endpoints ..................................................................................................... 10 
3.2.3 
Safety Endpoints ................................................................................................................. 11 
4 
Sample Size ......................................................................................................................................... 11 
5 
Sequence of Planned Analyses ........................................................................................................... 12 
5.1 
Interim Analyses.......................................................................................................................... 12 
5.2 
Final Analyses and Reporting ...................................................................................................... 12 
6 
Analysis Populations ........................................................................................................................... 12 
6.1 
Intent to Treat Population (ITT) .................................................................................................. 12 
6.2 
Modified Intent to Treat Population (mITT) ............................................................................... 12 
6.3 
Modified Intent to Treat 2 Population (mITT2) .......................................................................... 12 
6.4 
Safety Population ........................................................................................................................ 12 
7 
General Issues for Statistical Analysis ................................................................................................. 13 
7.1 
Analysis Software ........................................................................................................................ 13 
7.2 
Disposition of Subjects and Withdrawals ................................................................................... 13 
7.3 
Methods for Withdrawals and Missing Data .............................................................................. 13 
7.4 
Protocol Deviations ..................................................................................................................... 14 
7.5 
Multiple Comparisons and Multiplicity ....................................................................................... 14 
7.6 
Assessment of Homogeneity ...................................................................................................... 14 


 
 
 
 
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8 
Demographics and Other Baseline Characteristics ............................................................................. 15 
8.1 
Demographics and Vital Signs ..................................................................................................... 15 
8.2 
Baseline Non-Ophthalmic Medical History ................................................................................. 15 
8.3 
Baseline Ophthalmic History ....................................................................................................... 15 
8.4 
Prior and Concurrent Medications.............................................................................................. 16 
9 
Efficacy Analyses ................................................................................................................................. 16 
9.1 
Primary Efficacy Sign for MGD .................................................................................................... 16 
9.2 
Primary Efficacy Symptom for MGD ........................................................................................... 16 
9.3 
Other Efficacy Analyses ............................................................................................................... 17 
9.3.1 
Score.................................................................................................................................... 17 
9.3.2 
MGS Score at Each Visit ...................................................................................................... 17 
9.3.3 
Proportion of Patients with MGS Score > 12 at Each Visit .................................................. 18 
9.3.4 
Change from Baseline in Number of MGYLS ....................................................................... 18 
9.3.5 
MGYLS at Each Visit ............................................................................................................. 19 
9.3.6 
Change from Baseline in TBUT ............................................................................................ 19 
9.3.7 
TBUT at Each Visit ............................................................................................................... 19 
9.3.8 
Proportion of Patients with TBUT > 5 ................................................................................. 19 
9.3.9 
Change from Baseline in SPEED .......................................................................................... 20 
9.3.10 
SPEED at Each Visit .............................................................................................................. 20 
9.3.11 
Proportion of Patients with SPEED < 6 ................................................................................ 20 
9.3.12 
Change from Baseline in Average VAS ................................................................................ 20 
9.3.13 
Average VAS at Each Visit ................................................................................................... 20 
9.3.14 
Change from Baseline in Worst VAS ................................................................................... 20 
9.3.15 
Worst VAS at Each Visit ....................................................................................................... 20 
9.3.16 
Change from Baseline in Total OSDI ................................................................................... 20 
9.3.17 
OSDI Across Visits ................................................................................................................ 20 


 
 
 
 
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9.3.18 
Proportion of Patients with Total OSDI Change from Baseline > 4.5 at Month 3 ............... 21 
9.3.19 
Proportion of Patients with Total OSDI < 13 ....................................................................... 21 
9.3.20 
Number of Expressible Glands Yielding Clear Meibum....................................................... 21 
9.3.21 
Eyelid Margin Erythema and Telangiectasias ..................................................................... 21 
9.3.22 
Corneal and Conjunctival Staining at Each Visit .................................................................. 21 
10 
Safety Analyses ............................................................................................................................... 21 
10.1 
Ocular Comfort Questionnaire / Study Medication Tolerability ................................................. 22 
10.2 
Best-Corrected Visual Acuity (BCVA) .......................................................................................... 22 
10.3 
Biomicroscopy ............................................................................................................................. 22 
10.4 
Ophthalmoscopy ......................................................................................................................... 22 
10.5 
Intraocular Pressure (IOP) ........................................................................................................... 22 
11 
Adverse Events ................................................................................................................................ 23 
11.1 
All Adverse Events ....................................................................................................................... 23 
11.2 
Adverse Events Leading to Withdrawal ...................................................................................... 23 
11.3 
Serious Adverse Events ............................................................................................................... 23 
11.4 
Drug or Procedure Related Adverse Events ................................................................................ 24 
11.5 
Deaths ......................................................................................................................................... 24 
12 
Other Planned Analyses .................................................................................................................. 24 
12.1 
Planned Subgroup Analyses ........................................................................................................ 24 
12.1.1 
Sex ....................................................................................................................................... 24 
12.1.2 
MGD diagnosis and MGS score ........................................................................................... 24 
13 
Summary of Changes from the Protocol ......................................................................................... 25 
14 
Reporting Conventions ................................................................................................................... 25 
 
 
 


 
 
 
 
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DOCUMENT HISTORY 
 
Revision Date 
Author 
Version 
Reason for Change 
25JAN2021 
Allie Ferreira 
1.0 
NA – Initial Version 
 
 
 


 
 
 
 
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1 ABBREVIATIONS 
Abbreviation 
Definition 
AE  
Adverse Event 
ANCOVA  
Analysis of Covariance 
ANOVA 
Analysis of Variance  
BCVA  
Best-Corrected Visual Acuity 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CMH  
Cochran-Mantel-Haenszel 
CRF 
Case Report Forms 
CSR 
Clinical Study Report 
DBP 
Diastolic Blood Pressure 
FDA  
Food and Drug Administration 
IOP  
Intraocular Pressure 
ITT 
Intent-To-Treat Population 
LOCF  
Last Observation Carried Forward 
MedDRA  
Medical Dictionary for Regulatory Activities 
MGD  
Meibomian Gland Dysfunction 
MGS  
Meibum Gland Secretion Score 
MGYLS 
Meibomian Glands Yielding Liquid Secretion 
MICD 
Most Important Clinical Difference  
MITT 
Modified Intent-To-Treat Population 
MITT2 
Modified Intent-To-Treat 2 Population 
OSDI  
Ocular Surface Disease Index 
PT 
Preferred Term 
SAE  
Serious Adverse Event 
SAP 
Statistical Analysis Plan  
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP  
 Standard Operating Procedure 
SPEED  
Standard Patient Evaluation of Eye 
TBUT 
Tear Break-Up Time  
TEAE 
Treatment Emergent Adverse Event 
VAS 
Visual Analogue Scale 
 
 


 
 
 
 
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2 SUMMARY 
TITLE 
A Multicenter, Vehicle-controlled, Randomized Study to Evaluate the Safety, 
Tolerability and Pharmacodynamics of AZR-MD-001 in Patients with 
Meibomian Gland Dysfunction (MGD) 
PREFACE 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting 
for Azura protocol AZ202001 (Multicenter, Vehicle-controlled, Randomized 
Study to Evaluate the Safety, Tolerability and Pharmacodynamics of AZR-MD-
001 (Selenium disulfide Agonist) in Patients with Meibomian Gland 
Dysfunction (MGD). This study is being completed to assess the safety, 
tolerability, and pharmacodynamics of AZR-MD-001 in patients with 
meibomian gland dysfunction (MGD). 
 
The following documents were reviewed in preparation of this SAP: 
 
Clinical Research Protocol AZ202001 issued 12MAR2020 
 
Case report forms (CRFs) issued 25JUN2020 for AZ202001 
PURPOSE 
The purpose of this SAP is to outline the planned analyses in 
support of the Clinical Study Report (CSR) for protocol AZ202001. Exploratory 
analyses not necessarily identified in this SAP may be performed to support 
the clinical development program. Any post-hoc, or unplanned, analyses not 
identified in this SAP will be clearly identified in the respective CSR. 
STUDY OBJECTIVES  
To evaluate the safety, tolerability, and pharmacodynamics of AZR-MD-001 
ointment/semi-solid drug applied to the lower lid twice weekly for up to 3 
months compared to its vehicle in patients with meibomian gland 
dysfunction (MGD). 
STUDY DESIGN 
Multicenter, investigator-masked, vehicle-controlled, randomized, parallel 
group study comparing AZR-MD-001 (0.5%) ointment/semi-solid drug and 
AZR-MD-001 vehicle dosed twice-weekly in the evening. 
ENDPOINTS 
The study’s primary efficacy sign for MGD is change from baseline to month 3 
in meibum gland secretion score (MGS) (0 to 45 scale). The study’s primary 
efficacy symptom for MGD is change from baseline to month 3 in total OSDI.  
 
Other Efficacy Measures: 
 
Change from Baseline to day 14, month 1 and month 1.5 in MGS (0 to 
45 scale) 
 
MGS score (0 to 45 scale) at each visit 
 
Proportion of patients with an MGS score > 12 at each visit 
 
Change from Baseline to day 14, month 1, month 1.5 and month 3 in 
the number of Meibomian Glands Yielding Liquid Secretion (MGYLS) 


 
 
 
 
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(0 to 15 scale) 
 
MGYLS (0 to 15 scale) at each visit 
 
Change from Baseline to day 14, month 1, month 1.5, and month 3 in 
TBUT 
 
TBUT at each visit 
 
Proportion of patients with a TBUT score > 5 at each visit 
 
Change from Baseline to day 14, month 1, month 1.5 and month 3 in 
Standard Patient Evaluation of Eye Dryness (SPEED) 
 
SPEED at each visit 
 
Proportion of patients with a SPEED < 6 at each visit 
 
Change from Baseline to day 14, month 1, month 1.5 and month 3 in 
average visual analogue scale (VAS) 
 
Average VAS at each visit 
 
Change from Baseline to day 14, month 1, month 1.5 and month 3 in 
worst VAS 
 
Worst VAS at each visit 
 
Change from Baseline to day 14, month 1 and month 1.5 in Total OSDI 
 
Total OSDI, OSDI sub-scales, and individual items from the OSDI across 
visits 
 
Proportion of patients with a Total OSDI change from baseline > 4.5, 
the known minimally important clinical difference (MICD) for early to 
moderate disease, at month 3 
 
Proportion of patients with a Total OSDI < 13 at each visit 
 
Number of expressible glands yielding clear meibum at day 14, month 
1, 
month 1.5, and month 3 
 
Eyelid margin erythema/telangiectasias at day 14, month 1, month 
1.5, 
and month 3 
 
Corneal and conjunctival staining (0 to 5 scale) at each visit 
 
Safety Endpoints: 
 
Adverse events 
 
Vital signs 
 
Study medication tolerability as measured by the Ocular Comfort 
Questionnaire 
 
Urine pregnancy test 
 
Best-corrected visual acuity (BCVA; Logarithmic visual acuity chart) 
 
Biomicroscopy 


 
 
 
 
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 
Ophthalmoscopy 
 
Intraocular pressure (IOP) 
INTERIM ANALYSES 
No interim analyses are planned for this study. 
FINAL ANALYSES 
All final planned analyses identified in this SAP will be completed after the last 
participant has completed 3-months follow up. 
3 STUDY OBJECTIVES AND ENDPOINTS 
3.1 STUDY OBJECTIVE 
To evaluate the safety, tolerability, and pharmacodynamics of AZR-MD-001 ointment/semi-solid drug 
applied to the lower lid twice-weekly for up to 3 months compared to its vehicle in patients with 
meibomian gland dysfunction (MGD). 
3.2 STUDY ENDPOINTS  
3.2.1 PRIMARY EFFICACY ENDPOINTS 
The study’s primary efficacy sign for MGD is change from baseline to month 3 in meibum gland 
secretion score (MGS) (0 to 45 scale).  
 
The study’s primary efficacy symptom for MGD is change from baseline to month 3 in total OSDI.  
3.2.2 OTHER EFFICACY ENDPOINTS 
 
Change from Baseline to day 14, month 1 and month 1.5 in MGS (0 to 45 scale) 
 
MGS score (0 to 45 scale) at each visit 
 
Proportion of patients with an MGS score > 12 at each visit 
 
Change from Baseline to day 14, month 1, month 1.5 and month 3 in the number of Meibomian 
Glands Yielding Liquid Secretion (MGYLS) (0 to 15 scale) 
 
MGYLS (0 to 15 scale) at each visit 
 
Change from Baseline to day 14, month 1, month 1.5, and month 3 in TBUT 
 
TBUT at each visit 
 
Proportion of patients with a TBUT score > 5 at each visit 
 
Change from Baseline to day 14, month 1, month 1.5 and month 3 in Standard Patient 
Evaluation of Eye Dryness (SPEED) 
 
SPEED at each visit 
 
Proportion of patients with a SPEED < 6 at each visit 
 
Change from Baseline to day 14, month 1, month 1.5 and month 3 in average visual analogue 
scale (VAS) 


 
 
 
 
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 
Average VAS at each visit 
 
Change from Baseline to day 14, month 1, month 1.5 and month 3 in worst VAS 
 
Worst VAS at each visit 
 
Change from Baseline to day 14, month 1 and month 1.5 in Total OSDI 
 
Total OSDI, OSDI sub-scales, and individual items from the OSDI across visits 
 
Proportion of patients with a Total OSDI change from baseline > 4.5, the known minimally 
important clinical difference (MICD) for early to moderate disease, at month 3 
 
Proportion of patients with a Total OSDI < 13 at each visit 
 
Number of expressible glands yielding clear meibum at day 14, month 1, month 1.5, and month 
3 
 
Eyelid margin erythema/telangiectasias at day 14, month 1, month 1.5, and month 3 
 
Corneal and conjunctival staining (0 to 5 scale) at each visit 
3.2.3 SAFETY ENDPOINTS 
 
Adverse events 
 
Vital signs 
 
Study medication tolerability as measured by the Ocular Comfort Questionnaire 
 
Urine pregnancy test 
 
Best-corrected visual acuity (BCVA; Logarithmic visual acuity chart) 
 
Biomicroscopy 
 
Ophthalmoscopy 
 
Intraocular pressure (IOP) 
4 SAMPLE SIZE 
Estimates for sample size calculations are from the first interim analysis from Azura Clinical Protocol 
AZ201801. The standard deviation for MGS was 3.35 units for an ineffective dose and 9.48 units for the 
high dose. A sample size of 12 subjects per group will have 90% power to detect a difference of 10.4 
units between the active treatment group and the vehicle group using a two-sample t-test at a 
significance level of 0.05. The standard deviation for Total OSDI was 13.01 units for an ineffective dose 
and 6.79 units for the high dose. A sample size of 11 subjects per group will have 90% power to detect a 
difference of 15.9 units between the active treatment group and the vehicle group using a two-sample t-
test at a significance level of 0.05. 
 
The total number of randomized patients for the study will be up to approximately 30. Approximately 15 
patients should have a baseline MGS score of < 6 and approximately 15 patients should have a baseline 


 
 
 
 
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MGS score ≥6 and ≤ 12. Based upon data from ongoing study AZ201801 and the simplified 
inclusion/exclusion criteria for this study a screen failure rate of ~ 40% is expected. Thus, ~42 patients 
will need to be screened to achieve ~30 patients randomized to treatment. 
5 SEQUENCE OF PLANNED ANALYSES 
5.1 INTERIM ANALYSES 
There are no planned Interim Analyses for this study. 
5.2 FINAL ANALYSES AND REPORTING 
All final planned analyses identified in this SAP will be completed after the last participant has 
completed month 3 follow up. Any post-hoc, exploratory analyses completed to support planned study 
analyses, which were not identified in this SAP, will be documented and reported as necessary. Any 
results from these unplanned analyses will also be clearly identified in the final study report. 
6 ANALYSIS POPULATIONS 
6.1 INTENT TO TREAT POPULATION (ITT) 
The intent-to-treat (ITT) population for this study includes all enrolled and randomized patients.  
6.2 MODIFIED INTENT TO TREAT POPULATION (MITT) 
The modified intent-to-treat (ITT) population for this study includes all patients randomized and, who 
have values at randomization, and at least 1 post-randomization value for MGS at a regularly scheduled 
visit (i.e., Day 14 or Month 1). All patients in the mITT population will be analyzed by the treatment 
received. This population will be used for the primary and secondary efficacy analyses. 
6.3 MODIFIED INTENT TO TREAT 2 POPULATION (MITT2) 
The modified intent-to-treat 2 (mITT2) population will be comprised of patients who are included in the mITT 
and have the randomization MGS score in the study eye ≥6 and ≤ 12. The mITT2 population will be analyzed 
by the treatment received. The primary efficacy endpoints related to MGD will be repeated using this mITT2 
population as sensitivity analyses. 
6.4 SAFETY POPULATION 


 
 
 
 
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The safety population includes all treated patients. This is the primary analysis population for safety 
variables; subjects are analyzed under the treatment received. 
7 GENERAL ISSUES FOR STATISTICAL ANALYSIS 
Descriptive statistics for continuous variables will include the sample size, mean, standard deviation 
(SD), median, minimum, and maximum. Percent and frequencies will be provided for categorical 
variables. Results will be generated by treatment group.  
7.1 ANALYSIS SOFTWARE 
Analysis data sets, statistical analyses and associated output generated by Avania will be generated 
using SAS® Software version 9.4 or later, or R version 3.3.2 or later. 
7.2 DISPOSITION OF SUBJECTS AND WITHDRAWALS 
The number and percent of subjects in each analysis population will be presented, with percentages 
based on the ITT Population All subjects who provide written informed consent will be accounted for. A 
summary of the reasons for screen failure among subjects who signed an Informed Consent will be 
provided.  
The frequency and percent of enrolled subjects who completed each scheduled assessment will be 
presented for the ITT, mITT and mITT2 populations. The number and percentage of patients exposed 
(i.e. initiated procedure), prematurely terminated (overall and by reason of premature termination) and 
completed patients will be summarized.  
7.3 METHODS FOR WITHDRAWALS AND MISSING DATA 
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 (i.e., Day 14) or later will be used to 
replace missing data at visits where data are not recorded. 
 
If more than 5% of patients are missing data for MGS score or OSDI at 3 months prior to LOCF, then 
multiple imputation will be used for a sensitivity analysis for these endpoints. Missing MGS score at 3 
months (prior to LOCF) will be imputed using a monotone linear regression multiple imputation 
approach for continuous outcome data. However, assuming the missing data pattern will not be 
completely monotone at first, then a Markov Chain Monte Carlo (MCMC) imputation will first be carried 
out using MGS scores at all time points where it is collected (prior to 3 months) to make a monotone 
missing data pattern. There will be 50 datasets generated in this manner to create 50 datasets with a 


 
 
 
 
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monotone missing data pattern. For each of these 50 data sets, missing MGS score at 3 months will then 
be imputed once from a monotone multiple imputation linear regression model with independent 
variables: age, gender, duration of disease, and TBUT at month 3. Also included will be baseline and 
post-baseline non-missing MGS scores. The ANCOVA model will then be carried out on each of the 
resulting 50 complete datasets, with the ANCOVA results being combined across the 50 complete 
datasets using standard multiple imputation theory to obtain one overall p-value assessing the 
treatment on reduction in MGS score after accounting for missing data. 
The same analysis will be conducted for missing OSDI data at 3 months if more than 5% of subjects are 
missing this assessment, using baseline and post-baseline non-missing OSDI in the imputation model. 
7.4 PROTOCOL DEVIATIONS 
Protocol deviations will be summarized in the CSR for the ITT population. This summary will include the 
number and percent of participants (overall and by site) with each deviation type. A listing of protocol 
deviations will be presented and will include deviation number, date deviation occurred, visit, type of 
deviation, description of deviation, and action taken. 
7.5 MULTIPLE COMPARISONS AND MULTIPLICITY 
To address the multiple primary endpoints defined in this study, the primary endpoints have been 
prioritized into a hierarchical structure. In order to test the primary symptom endpoint of Total OSDI, 
the primary sign endpoint of MGS must be statistically significantly higher in the 0.5% AZR-MD-001 
treatment group compared to the vehicle treatment group using a two-sided significance level of 0.05. 
Using this strategy, the family-wise Type I error rate will be maintained at the 0.05 significance level for 
the two primary endpoints. 
There will be no statistical adjustment of the significance level for multiple testing for the other efficacy 
endpoints as these comparisons will be descriptive in nature. 
7.6 ASSESSMENT OF HOMOGENEITY 
Tests of homogeneity across sites will be done to determine if the sites have reasonably homogenous 
responses. An analysis of covariance (ANCOVA) model will be performed for both the primary efficacy 
sign for MGD and primary efficacy symptom for MGD. For the primary efficacy sign for MGD, change in 
MGS score will be the dependent variable, baseline MGS score and duration of disease will be 
covariates, and the independent variables will consist of treatment group, site and a site*treatment 
group interaction term. For the primary efficacy symptom for MGD, change in OSDI will be the 
dependent variable, and baseline OSDI and duration of disease will be the covariates. A site*treatment 


 
 
 
 
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group interaction that is significant at a 0.15 level will require further investigation of results by site to 
assess if sites are still poolable despite being significant at the liberal 0.15 level of significance.  
In study sites with small numbers of subjects, it will be difficult to evaluate a site by treatment 
interaction. For this reason, study sites with fewer than 5 subjects may be combined into pseudosites. 
Pseudosites will be used for all multivariate analyses including the analysis to determine a site by 
treatment interaction for pooling. All pseudosite categorizations will be determined before the database 
is locked. 
8 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS  
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 comparisons. 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.  
8.1 DEMOGRAPHICS AND VITAL SIGNS 
Participant demographics for the ITT, mITT, mITT2, and safety population will be summarized in a table. 
Sex, race, duration of MGD, and ethnicity will be summarized with frequency and percent. Age, height, 
weight, BMI, SBP, DBP and heart rate will be summarized with number of observations, mean, median, 
minimum, maximum and standard deviation. 
8.2 BASELINE NON-OPHTHALMIC MEDICAL HISTORY 
The frequency and percent of patients with relevant medical and surgical history for each body system 
(e.g. General, Respiratory, Cardiovascular) will be presented for the mITT population. A listing of medical 
history information will be presented with information regarding body system, relevant medical 
condition/surgery, and start and end date. The listing will also include information regarding if a urine 
pregnancy test was performed and the result.  
8.3 BASELINE OPHTHALMIC HISTORY  


 
 
 
 
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The frequency and percent of patients with relevant ophthalmic and surgical history by ocular disease / 
condition / procedure by will be presented for the mITT population. A listing of ophthalmic history will 
be presented with information regarding the eye/eyelid, the ocular disease / condition / procedure, any 
related current medication for the condition, and start and end date. 
8.4 PRIOR AND CONCURRENT MEDICATIONS 
All relevant prior and concomitant medications will be presented in a listing for the mITT population. 
Patients must have discontinued and be willing to remain off all other ophthalmic preparations including 
artificial tears during the study. In the event that rescue medication is required for clinically relevant 
worsening of keratitis, patients will be provided a concomitant regimen the investigator/treating 
clinician. 
9 EFFICACY ANALYSES 
9.1 PRIMARY EFFICACY SIGN FOR MGD 
The primary sign for MGD is based on change from baseline in meibum gland secretion (MGS) score (0 
to 45 scale) at the 3-month follow-up between AZR-MD-001 group versus vehicle group. The primary 
efficacy sign will be evaluated in the mITT and mITT2 populations and will be analyzed at month 3 using 
an analysis of covariance (ANCOVA) model with baseline MGS score and duration of disease stratum (< 5 
years or ≥ 5 years) as covariates and treatment (AZR-MD-001 ointment/semi-solid drug or vehicle) as 
factors in the model. The difference between treatment groups will be evaluated using t-tests of the 
least square means from this model. The two-sided confidence interval (95%) will be provided for the 
difference between treatments. 
The following pseudocode will be used:  
PROC GENMOD data=xxx;  
BY visit;  
CLASS treatment (ref = ‘AZR-MD-001 VEHICLE’) duration;  
MODEL chg = treatment base duration;  
LSMEANS treatment;  
run; 
9.2 PRIMARY EFFICACY SYMPTOM FOR MGD 
The primary symptom for MGD is based on change from baseline in total OSDI at the 3-month follow-up 
between AZR-MD-001 group versus vehicle group. The primary efficacy symptom will be evaluated in 


 
 
 
 
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the mITT and mITT2 populations and will be analyzed at month 3 using an analysis of covariance 
(ANCOVA) model with baseline OSDI, baseline MGS score stratum (<6 or ≥6) and duration of disease 
stratum (< 5 years or ≥ 5 years) as covariates and treatment group as factors in the model. The 
difference between treatment groups will be evaluated using t-tests of the least square means from this 
model.  The two-sided confidence interval (95%) will be provided for the difference between 
treatments. 
 
The following pseudocode will be used:  
PROC GENMOD data=xxx;  
BY visit;  
CLASS treatment (ref = ‘AZR-MD-001 VEHICLE’) duration baseMGS;  
MODEL chg = treatment base duration baseMGS;  
LSMEANS treatment;  
run; 
9.3 OTHER EFFICACY ANALYSES 
All other efficacy endpoints will be summarized and analyzed in the mITT population unless otherwise 
stated. 
9.3.1 MGS SCORE  
The change from baseline to day 14, month 1, and month 1.5 in MGS score (0 to 45 scale) will be 
summarized using N, mean, standard deviation, median, minimum, and maximum. 
 
The change from baseline will be analyzed at each visit in the same manner as described in Section 9.1.  
9.3.2 MGS SCORE AT EACH VISIT 
MGS score (0 to 45 scale) at each visit will be summarized in the mITT population using N, mean, 
standard deviation, median, minimum, and maximum. 
 
The MGS score will be analyzed at each visit using an ANCOVA model with baseline MGS score and 
duration of disease stratum (< 5 years or ≥ 5 years) as covariates and treatment (AZR-MD-001 
ointment/semi-solid drug or vehicle) as factors in the model. The difference between treatment groups 
will be evaluated using t-tests of the least square means from this model. The two-sided confidence 
interval (95%) will be provided for the difference between treatments. 
 
The following pseudocode will be used:  


 
 
 
 
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PROC GENMOD data=xxx;  
BY visit;  
CLASS treatment (ref = ‘AZR-MD-001 VEHICLE’) duration;  
MODEL score =treatment base duration;  
LSMEANS treatment;  
run; 
9.3.3 PROPORTION OF PATIENTS WITH MGS SCORE > 12 AT EACH VISIT  
The proportion of patients with an MGS score > 12 at each visit will be summarized using shift tables 
displaying the frequency and percent of patients in each category (yes/no) by treatment group.  
 
Logistic regression will be performed to compare treatments with respect to the proportion of patients 
achieving MGS score >12 at each visit, adjusting for baseline MGS score stratum and duration of disease 
stratum. The odds ratio, along with the 95% CI, for the treatment effect will be presented. 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), 
will also be performed. 
 
The following pseudocode will be used: 
PROC LOGISTIC data=xxx;  
BY visit;  
CLASS treatment (ref = ‘AZR-MD-001 VEHICLE’) duration baseMGS;  
MODEL response =treatment base duration baseMGS;  
LSMEANS treatment; 
run;  
 
PROC FREQ data=xxx;  
BY visit;  
TABLE treatment * response/EXACT;  
ODS OUTPUT CHISQ = outc (where=(STATISTIC=’Chi-Square’))  
FISHERSEXACT=outf (where=(NAME1=’XP2_FISH’));  
Run; 
9.3.4 CHANGE FROM BASELINE IN NUMBER OF MGYLS 
The change from baseline to day 14, month 1, month 1.5, and month 3 in the number of Meibomian 
Glands Yielding Liquid Secretion (MGYLS) (0 to 15 scale) will be summarized using N, mean, standard 
deviation, median, minimum, and maximum. 
 
An ANCOVA test will be performed to assess the difference of change from baseline in number of 
MGYLS between treatment groups with baseline MGYLS, baseline MGS score stratum and duration of 
disease stratum as covariates. The difference between treatment groups will be evaluated using t-tests 


 
 
 
 
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of the least square means from this model. The two-sided confidence interval (95%) will be provided for 
the difference between treatments. 
The following pseudocode will be used:  
PROC GENMOD data=xxx;  
BY visit;  
CLASS treatment (ref = ‘AZR-MD-001 VEHICLE’) duration baseMGS;  
MODEL chg =treatment base duration baseMGS;  
LSMEANS treatment;  
run; 
9.3.5 MGYLS AT EACH VISIT 
MGYLS (0 to 15 scale) at each visit will be summarized using N, mean, standard deviation, median, 
minimum, and maximum. 
 
An ANCOVA test will be performed to assess the difference of MGYLS between treatment groups with 
baseline MGYLS, baseline MGS score stratum and duration of disease stratum as covariates. The 
difference between treatment groups will be evaluated using t-tests of the least square means from this 
model. The two-sided confidence interval (95%) will be provided for the difference between treatments. 
 
The following pseudocode will be used:  
PROC GENMOD data=xxx;  
BY visit;  
CLASS treatment (ref = ‘AZR-MD-001 VEHICLE’) duration baseMGS;  
MODEL score =treatment base duration baseMGS;  
LSMEANS treatment;  
run; 
9.3.6 CHANGE FROM BASELINE IN TBUT 
The change from baseline to day 14, month 1, month 1.5, and month 3 in TBUT will be summarized and 
analyzed using the same methods as described in Section 9.3.4. 
9.3.7 TBUT AT EACH VISIT  
TBUT at each visit will be summarized and analyzed using the same methods as described in Section 
9.3.5. 
9.3.8 PROPORTION OF PATIENTS WITH TBUT > 5 


 
 
 
 
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The proportion of patients with a TBUT score > 5 at each visit will be summarized and analyzed using the 
same methods as described in Section 9.3.3. 
9.3.9 CHANGE FROM BASELINE IN SPEED 
The change from baseline to day 14, month 1, month 1.5, and month 3 in SPEED will be summarized and 
analyzed using the same methods as described in Section 9.3.4. 
9.3.10 SPEED AT EACH VISIT  
SPEED at each visit will be summarized and analyzed using the same methods as described in Section 
9.3.5. 
9.3.11 PROPORTION OF PATIENTS WITH SPEED < 6 
The proportion of patients with a SPEED < 6 at each visit will be summarized and analyzed using the 
same methods as described in Section 9.3.3. 
9.3.12 CHANGE FROM BASELINE IN AVERAGE VAS 
The change from baseline to day 14, month 1, month 1.5, and month 3 in average VAS will be 
summarized and analyzed using the same methods as described in Section 9.3.4. 
9.3.13 AVERAGE VAS AT EACH VISIT  
Average VAS at each visit will be summarized and analyzed using the same methods as described in 
section 9.3.5.  
9.3.14 CHANGE FROM BASELINE IN WORST VAS 
The change from baseline to day 14, month 1, month 1.5, and month 3 in worst VAS will be summarized 
and analyzed using the same methods as described in Section 9.3.4. 
9.3.15 WORST VAS AT EACH VISIT  
Worst VAS at each visit will be summarized will be summarized and analyzed using the same methods as 
described in section 9.3.5.  
9.3.16 CHANGE FROM BASELINE IN TOTAL OSDI 
The change from baseline to day 14, month 1 and month 1.5, in total OSDI will be summarized and 
analyzed using the same methods as described in Section 9.3.4. 
9.3.17 OSDI ACROSS VISITS 


 
 
 
 
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Total OSDI, OSDI sub-scales, and individual items from the OSDI across visits will be summarized and 
analyzed using the same methods as described in section 9.3.5.  
9.3.18 PROPORTION OF PATIENTS WITH TOTAL OSDI CHANGE FROM BASELINE > 4.5 AT MONTH 3 
The proportion of patients with a total OSDI change from baseline > 4.5, the known minimally important 
clinical difference (MICD) for early to moderate disease, at month 3 will be summarized and analyzed 
using the same methods as described in Section 9.3.3. 
9.3.19 PROPORTION OF PATIENTS WITH TOTAL OSDI < 13 
The proportion of patients with a total OSDI < 13 at each visit will be summarized and analyzed using the 
same methods as described in Section 9.3.3. 
9.3.20 NUMBER OF EXPRESSIBLE GLANDS YIELDING CLEAR MEIBUM 
The number of expressible glands yielding clear meibum at day 14, month 1, month 1.5, and month 3 
will be summarized and analyzed using the same methods as described in section 9.3.5.  
9.3.21 EYELID MARGIN ERYTHEMA AND TELANGIECTASIAS  
Eyelid margin erythema and telangiectasias scores at day 14, month 1, month 1.5, and month 3 will be 
summarized using N, mean, standard deviation, median, minimum, and maximum. Actual values and 
shifts from baseline will be summarized by parameter and time point. Changes from baseline will be 
analyzed at each time point using Cochran-Mantel-Haenszel (CMH) statistics to test for a treatment 
effect.  
The following pseudocode will be used: 
PROC FREQ data=xxx;  
BY visit;  
TABLE treatment * base * result / CMH;  
ODS output CMH=outcmh (where=(ALTHYPOTHESIS=’General Association’));  
run; 
9.3.22 CORNEAL AND CONJUNCTIVAL STAINING AT EACH VISIT  
Corneal and conjunctival staining scores (0 to 5 scale) at each visit will be summarized by frequency of 
each score and shift from baseline. Changes from baseline will be analyzed at each time point using 
Cochran-Mantel-Haenszel (CMH) statistics as described in section 9.3.21.  
10 SAFETY ANALYSES 


 
 
 
 
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Safety measures will be analyzed using the safety population and shift tables will be presented for 
change from baseline variables. 
10.1 OCULAR COMFORT QUESTIONNAIRE / STUDY MEDICATION TOLERABILITY 
Ocular comfort questionnaire measures (drug felt comfortable, drug felt soothing, drug felt 
moistening/lubricating, drug enhanced clear vision, drug stickiness, drug blur, drug burning/stinging, and 
drug discomfort), will be summarized by treatment group for screening, baseline (Day 0), Day 14, Month 
1, Month 1.5, Month 3. Summary will include N, mean, standard deviation, median, minimum, and 
maximum response (measured in %) at each visit, as well as change from baseline. 
10.2 BEST-CORRECTED VISUAL ACUITY (BCVA) 
A summary of raw visual acuity (number of letters read) by eye (study eye and non-study eye), 
treatment group, and visit will be provided in tables for screening, Baseline (Day 0), Day 14, Month 1, 
Month 1.5, and Month 3. Summary will include N, mean, standard deviation, median, minimum, and 
maximum response (measured in %) at each visit, as well as change from baseline. 
  
The proportion of patients with a change from baseline BCVA ≤5 and >5 and a change from baseline ≤10 
and >10 at each visit will be summarized by study eye and non-study eye using shift tables displaying the 
frequency and percent of patients in each category (≤5 and >5 / ≤10 and >10) by treatment group and 
eye.  
10.3 BIOMICROSCOPY 
Biomicroscopy will be summarized by treatment group, eye (study eye and non-study eye), and visit for 
screening, Baseline (Day 0), Day 14, Month 1, Month 1.5, and Month 3 by treatment group. The 
summary will include frequency and percent of each response. A shift table (shift form baseline) will be 
provided by treatment. 
10.4  OPHTHALMOSCOPY 
Ophthalmoscopy results (lens status, cataract, vitreous and fundus) will be summarized by treatment 
group, eye (study eye and non-study eye), and visit for screening (dilated) and month 3 (not dilated) 
using a shift table (shift form baseline). 
10.5 INTRAOCULAR PRESSURE (IOP) 


 
 
 
 
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A summary of raw IOP will be provided by treatment group and eye (study eye and non-study eye) at 
baseline and Month 3. Summary will include N, mean, standard deviation, median, minimum, and 
maximum response (measured in %) at each visit, as well as change from baseline. 
11 ADVERSE EVENTS 
All adverse events (AEs) will be coded using the standardized Medical Dictionary for Regulatory Activities 
(MedDRA) central coding dictionary, version 23.1 or greater. 
11.1 ALL ADVERSE EVENTS 
Summaries of incidence rates of individual TEAEs by System Organ Class (SOC) and Preferred Term (PT) 
will be prepared. Because a subject may experience more than one AE, summaries will provide both the 
number of subjects experiencing at least one event and the number of events within a reporting period. 
Percentages provided will be the percent of subjects experiencing one or more adverse events. In 
addition, incidence of TEAEs will be presented by severity (mild, moderate, severe) and by relationship 
(unrelated, unlikely, possible, probable, very likely/certain) to investigational treatment. Subjects 
experiencing an event within a given PT and SOC more than once will be counted under the maximum 
severity/relationship experienced.  
 
A TEAE is any AE that is new in onset or was aggravated in severity or frequency following the 
application of first study drug, up to 30 days of receiving the last study drug. If the start date of any AE is 
incomplete or missing, the event will be assumed to be a TEAE, unless the incomplete start date (month 
and/or year) or the stop date (complete or incomplete) clearly indicates that the event started prior to 
the study drug. 
 
A listing of all adverse events will include the subject number, AE number, the AE SOC and PT, the 
severity of AE, whether or not the AE is classified as serious (SAE), the relationship of the AE to the study 
intervention, the action taken, the outcome, and the adjudication status.  
11.2 ADVERSE EVENTS LEADING TO WITHDRAWAL 
A summary of incidence rates (frequencies and percentages) of AEs leading to study withdrawal, by SOC 
will be prepared for the safety population. A data listing of AEs leading to withdrawal will also be 
provided, displaying details of the event(s) captured on the CRF. 
11.3 SERIOUS ADVERSE EVENTS 


 
 
 
 
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Summaries of incidence rates and relationship to the investigational drug/procedure of individual SAEs 
by SOC and PT will be prepared. Summaries will provide both the number of subjects and the number of 
events within a reporting period. Percentages provided will be the percent of subjects experiencing one 
or more SAEs. A data listing of SAEs will also be provided, displaying details of the event(s) captured on 
the CRF.  
11.4 DRUG OR PROCEDURE RELATED ADVERSE EVENTS 
Summaries of incidence rates of drug and procedure related AEs by SOC and PT will be prepared. 
Related events include those classified as possible, probable, very likely/certain. Events classified as 
unrelated or unlikely will be considered not related. Summaries will provide both the number of subjects 
and the number of events within a reporting period. Percentages provided will be the percent of 
subjects experiencing one or more study intervention related adverse events. Data listings of drug and 
procedure related AEs will also be provided, displaying details of the event(s) captured on the CRF.  
11.5 DEATHS 
Should any subjects die during the course of the trial, relevant information will be supplied in a data 
listing. 
12 OTHER PLANNED ANALYSES 
12.1 PLANNED SUBGROUP ANALYSES 
12.1.1 SEX 
Analyses of the primary efficacy sign and symptom will be repeated by gender.   
12.1.2 MGD DIAGNOSIS AND MGS SCORE 
Patients will be stratified by duration of MGD diagnosis (i.e., < 5 years or ≥ 5 years) and baseline MGS 
score for the qualified eye (i.e., the eye meeting the inclusion/exclusion criteria). If the eyes have the 
same MGS score the right eye will be selected as the study eye. 
 
Thus, subgroup analyses of the primary efficacy sign and symptom are planned for the 4 groups defined 
by the 2 stratification factors: 
1. MGD diagnosis < 5 years and MGS score for the qualified eye < 6 
2. MGD diagnosis < 5 years and MGS score for the qualified eye ≥ 6 and ≤ 12 


 
 
 
 
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3. MGD diagnosis ≥ 5 years and MGS score for the qualified eye < 6 
4. MGD diagnosis ≥ 5 years and MGS score for the qualified eye ≥ 6 and ≤ 12 
13 SUMMARY OF CHANGES FROM THE PROTOCOL 
The following table provides a list of changes from the protocol to the SAP, and the justification for each 
change. 
Section 
Description 
Justification 
9 Efficacy Analyses 
Removed reference to pairwise 
comparisons between treatment 
groups. 
Throughout the protocol, there is 
reference to performing pairwise 
comparisons between treatment groups 
which is thought to be leftover from the 
AZ201801 study where there were more 
than 2 treatment groups. For this study, 
we will use LSMEANS to compare the two 
treatment groups, as applicable.  
14 REPORTING CONVENTIONS 
All reporting will meet the standards of applicable SOPs.