Clinical trial NCT03652051
Conditions: Meibomian Gland Dysfunction Dry Eye
Sponsor: Azura Ophthalmics
Start date: 2018-09-10; Completion date: 2022-10-19
Enrollment: 321 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
AZ201801 is a multicenter study of AZR-MD-001 ointment and AZR-MD-001 vehicle in patients with Meibomian Gland Dysfunction (MGD) and evaporative Dry Eye Disease (DED)

Detailed description:
AZ201801 is a multicenter, double-masked, vehicle-controlled, randomized, parallel group study carried out in 2 sequentially overlapping cohorts evaluating the safety, efficacy and tolerability of AZR-MD-001 ointment and AZR-MD-001 vehicle in patients with Meibomian Gland Dysfunction (MGD) and evaporative Dry Eye Disease (DED)

Arms: arm 1: AZR-MD-001 Low Dose will be dosed up to once daily. arm 2: AZR-MD-001 Mid Dose will be dosed up to once daily. arm 3: AZR-MD-001 High Dose will be dosed up to once daily. arm 4: AZR-MD-001 Vehicle will be dosed up to once daily.
Interventions: intervention 1: AZR-MD-001 Low Dose intervention 2: AZR-MD-001 Mid Dose intervention 3: AZR-MD-001 High Dose intervention 4: AZR-MD-001 Vehicle
Intervention descriptions: intervention 1: AZR-MD-001 is an ophthalmic ointment intervention 2: AZR-MD-001 is an ophthalmic ointment intervention 3: AZR-MD-001 is an ophthalmic ointment intervention 4: AZR-MD-001 is a vehicle ophthalmic ointment

Protocol documents:
Prot_000.pdf: 
AZR-MD-001 (Selenium disulfide Agonist) 
Protocol AZ201801 
Version 6.0 
19March2021 
 
 
 
A Multicenter, Vehicle-controlled, Randomized Study to 
Evaluate the Safety, Tolerability, Systemic 
Pharmacokinetics, and Pharmacodynamics of AZR-MD-001 
in Patients with Meibomian Gland Dysfunction (MGD) and 
Evaporative Dry Eye Disease (DED) 
 
Protocol Number: 
AZ201801 
National Clinical Trial (NCT) 
Identified Number: 
TBD 
Principal Investigator: 
Stephanie L Watson 
Level 1, Save Sight Institute, Campus of 
Sydney Eye Hospital 8 Macquarie St 
Sydney NSW 2000 Australia 
Sponsor: 
Azura Ophthalmics,  
Level 9, 31 Queen Street 
Melbourne, VIC 300 Australia 
Tel: +1 714-559-8435 
E-mail: 
Charles.Bosworth@azuraophthalmics.com 
Funded by: 
Azura Ophthalmics 
Version and Version Number: 
Amendment 5, 6.0 
Date: 19March2021 


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Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
Section 
1.1, 
Objectives 
Section 
1.2., 
Expansion 
Cohort & 
Section 4.1 
Expansion Cohort: To evaluate the 
safety, tolerability, and 
pharmacodynamics of 2 different 
concentrations of AZR-MD-001 
ointment/semi-solid drug (0.5% and 1.0%) 
applied to the lower lid twice-weekly for 
up to 6 months compared to its placebo 
in patients with meibomian gland 
dysfunction (MGD) and signs and 
symptoms of evaporative dry eye disease 
(DED).  
 
Updated to reflect feedback from FDA 
on MGD as an indication by deleting 
the reference to DED. 
Section 
1.1, 
Clinical 
Hypotheses
,Expansion 
Cohort 
AZR-MD-001 ointment/semi-solid drug 
(0.5% or 1.0%) is more effective than 
placebo for treating MGD as measured 
by the meibomian glands yielding 
liquid secretion score (MGYLS). 
 
Deleted MGS and replaced it with 
MGYLS. 
The Interim Analysis from Cohort 1 of 
AZ201801 suggests that MGYLS has 
more power than MGS for detecting the 
benefit of AZR-MD-001. 


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Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
Section 1.2 
5.5, & 
9.1.2, 
Study 
Population 
Characteris
tics 
Cohort 1: The total number of 
randomized patients for Cohort 1 will be 
approximately 60. Approximately 30 
patients should have a baseline MGS 
score of < 6 and approximately 30 
patients should have a baseline MGS 
score ≥6 and ≤ 12. Based upon data from 
the LipiFlow® development program a 
screen failure rate of ~ 40% is expected. 
Thus, ~84 patients will need to be 
screened to achieve ~60 patients 
randomized to treatment. 
 
Expansion Cohort: The total number of 
randomized patients, with a Total OSDI 
< 34, for the Expansion Cohort will be 
approximately 225. Approximately 112 
patients should have a baseline MGS 
score of < 6 and approximately 112 
patients should have a baseline MGS 
score ≥6 and ≤ 12. Based upon data from 
the LipiFlow® development program a 
screen failure rate of ~ 40% is expected. 
Thus, ~315 patients will need to be 
screened to achieve ~225 patients 
randomized to treatment with a Total 
OSDI < 34.   
 
Clarified the section by separating 
Cohort 1 from the Expansion Cohort. 
Increased the sample size in the 
Expansion Cohort from 50 to 75 
patients a group. 
Section 1.2 
& 5.1, Key 
Inclusion 
Criteria 
Evidence of Evaporative DED MGD at the 
screening and baseline visits: 
 
1. Score ≥6 on the Standard Patient 
Evaluation of Eye Dryness 
questionnaire (SPEED) 
2. Ocular Surface Disease Index 
(OSDI) questionnaire score ≥13 
and < 34 (Cohort 1 only) 
 
Clarified the section by removing 
Evaporative DED and replacing it with 
MGD. The study is targeting the signs 
and symptoms of MGD in the 
Expansion Cohort. 
 
The main inclusion criteria for Total 
OSDI was reset to match Cohort 1. 


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Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
Section 1.2 & 
5.1, Key 
Inclusion 
Criteria 
Women of childbearing potential must have a 
history of bilateral tubal ligation or use oral 
contraceptives, implants, injectables, 
transdermal patch, intrauterine device, or 
double barrier contraceptive for birth control 
during the study. 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.  Complete 
abstinence for four weeks before exposure to 
study medication, throughout the study, and 
for at least four weeks after the last dose of 
study medication is acceptable for study 
inclusion. 
Added “double barrier contraceptive” and 
allowed for “Complete abstinence for four 
weeks before exposure to study medication, 
throughout the study, and for at least four 
weeks after the last dose of study medication 
is acceptable for study inclusion.” 
Added additional flexibility for 
adequate birth control measures.  AZR-
MD-001 represents extremely low risk 
as there is no evidence for measurable 
changes in systemic exposure following 
dosing in Cohort 1. 
Section 1.2 & 
5.2, Key 
Exclusion 
Criteria 
Enrollment in a previous Stage of the current 
study or other Azura study using AZR-MD-
001 
 
Added bold text to assure patients with 
prior exposure to AZR-MD-001 are not 
enrolled into the study. 
Section 1.2 & 
Table 3-1, 
Primary 
Efficacy 
Measures 
Primary Efficacy Sign for MGD: 
• 
US: Change from Baseline to month 3 
in meibomianum glands yielding liquid 
secretion score (MGYLS) (0 to 45 15 scale) 
• 
Regions requiring longer duration of 
follow-up (e.g., EU): Change from Baseline to 
month 6 in meibomianum glands yielding 
liquid secretion score (MGYLS) (0 to 145 
scale) 
Updated primary sign for MGD to 
MGYLS in the Expansion Cohort. 


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Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
Section 1.2 & 
8.1.5 Other 
Efficacy 
Measures 
Other Efficacy Measures: 
• 
Change from Baseline to day 14, 
month 1.5, month 3, and month 4.5 and 
month 6 in MGS (0 to 45 scale) 
• 
Change from Baseline to day 14, 
month 1.5, and month 3 month 4.5 and month 
6 in the number of Meibomian Glands 
Yielding Liquid Secretion (MGYLS) (0 to 15 
scale) 
Proportion of patients with a change from 
baseline in MGYLS score ≥ 5 at each visit 
Updated Other Efficacy Measures to 
reflect MGYLS as a primary sign for 
MGD. 
 
Added responder analyses for MGYLS. 
Section 1.2, 
General 
Statistical 
Methods, 
Primary 
Efficacy 
(MGD) 
The primary efficacy sign for MGD is 
change from baseline in MGYLS.  
Changed primary endpoint to MGYLS. 
Section 1.2, 
Expansion 
Cohort: 
Sample Size 
Calculation:   
Updated means and estimates of variance 
based upon the Cohort 1, final Interim 
Analysis.  
Updated sample size to match Section 
1.2, Study Population Characteristics. 
Figure 1 
The primary endpoints for the US will serve 
as an Interim Analyses for the Month 6 
primary endpoints.  The sample size may be 
adjusted for power or to address any concerns 
for alpha inflation. 
Added note to figure so reviewers catch 
that the sample size can be adjusted 
after the Expansion Cohort Month 3 
analyses to adjust power if necessary or 
if requested by global regulatory 
agencies. 
 
Updated Expansion Cohort sample size. 
Table 1 
Schedule of 
Visits and 
Procedures 
Split Month 1.5 and 4.5 in the Schedule of 
Visits and Procedures. 
Also added “Month = 28 days” below the 
table. 
Sites were getting confused and missing 
the Month 4.5 visit. 
 
Sites requested clarification of length of 
one month. 


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Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
Section 6.1.3 
During the double-masked treatment period, 
each patient (or caregiver) must apply 1 
application of the vehicle (Cohort 1) or 
placebo (Expansion Cohort) assigned 
treatment in the evening to the tarsus of the 
lower lid of both eyes. 
Clarified the text. 
Section 6.2.1 
Whilst patients are dosed at site (i.e., Cohort 
1 all visits, and practice dose at the baseline 
visit only of the Expansion Cohort), they 
will administer their study treatment under 
medical supervision. The date and time of 
each dose administered in the clinic will be 
recorded in the source documents. The dose of 
study treatment and study subject 
identification will be confirmed at the time of 
dosing by a member of the study site staff. 
Clarified the text. 
Section 6.2.1 
The used and unused study drug tubes will 
be collected at each visit from baseline up 
to and including study exit (along with 
any unused tubes) to assess dosing and 
symptom assessment compliance. 
Added bold text. 
Clarified the text. 
Section 9.4.1 & 
9.4.3 
Updated primary endpoint for the Expansion 
Cohort to MGYLS. 
Proportion of patients with a change from 
baseline in MGYLS score of ≥5 
Added bold text. 
Updated to match primary endpoint and 
responder analyses from the full Cohort 
1 Interim Analyses. 
Section 9.4.6 
The primary endpoints for the US will serve 
as an Interim Analyses for the Month 6 
primary endpoints.  The sample size may be 
adjusted for power or to address any 
concerns for alpha inflation. 
Added text at end. 
Added test so reviewers catch that the 
sample size can be adjusted after the 
Expansion Cohort Month 3 analyses to 
adjust power if necessary or if requested 
by global regulatory agencies. 


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Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
Section 14.2 
Changed the figure of the OSDI 
Permission was granted by Allergan to 
use the OSDI in Phase 3.  The 
attachment was updated to match the 
version Allergan sent to AZURA. 
 


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Table of Contents 
 
1 
PROTOCOL SUMMARY ............................................................................................................................ xii 
1.1 
SYNOPSIS ......................................................................................................................................... xii 
1.2 
SCHEMA ......................................................................................................................................... xiii 
1.3 
SCHEDULE OF ACTIVITIES (SOA) COHORT 1 AND EXPANSION COHORT ....................................... xxvi 
2 
INTRODUCTION ......................................................................................................................................... 1 
2.1 
BACKGROUND ................................................................................................................................... 1 
2.2 
STUDY RATIONAL & KNOWN POTENTIAL BENEFITS ......................................................................... 2 
2.3 
RISK/BENEFIT ASSESSMENT .............................................................................................................. 4 
2.3.1 
KNOWN POTENTIAL RISKS ........................................................................................................ 4 
2.3.2 
ASSESSMENT OF POTENTIAL RISKS AND BENIFITS ................................................................... 6 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................................... 7 
4 
STUDY DESIGN .......................................................................................................................................... 9 
4.1 
OVERALL DESIGN .................................................................................................................................. 9 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ....................................................................................... 10 
4.3 
DATA REVIEW COMMITTEE (DRC) .................................................................................................. 12 
4.4 
END OF STUDY DEFINITION ............................................................................................................ 12 
5 
STUDY POPULATION ............................................................................................................................... 13 
5.1 
INCLUSION CRITERIA ....................................................................................................................... 13 
5.2 
EXCLUSION CRITERIA ...................................................................................................................... 14 
5.3 
LIFESTYLE CONSIDERATIONS ........................................................................................................... 16 
5.4 
SCREEN FAILURES............................................................................................................................ 17 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION ......................................................................... 17 
6 
STUDY INTERVENTION ............................................................................................................................ 18 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION .................................................................................. 18 
6.1.1 
STUDY TREATMENT(S)/ FORMULATION(S)/ MEDICAL DEVICE COMPOSITION OR DESIGN ... 18 
6.1.2 
SELECTION OF DOSES IN THE STUDY ...................................................................................... 20 
6.1.3 
DOSING AND ADMINISTRATION ............................................................................................. 20 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY ............................................................... 21 
6.2.1 
ACQUISITION AND ACCOUNTABILITY ..................................................................................... 21 
6.2.2 
FORMULATION, APPEARANCE, PACKAGING, AND LABELING ................................................. 21 
6.2.3 
PRODUCT STORAGE AND STABILITY ....................................................................................... 21 
6.2.4 
PREPARATION ......................................................................................................................... 22 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ................................................ 22 
6.4 
CONCOMITANT THERAPY ............................................................................................................... 24 


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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 .............................................................................................. 25 
8.1 
EFFICACY ASSESSMENTS ................................................................................................................. 25 
8.1.1 
PRIMARY EFFICACY MEASURES .............................................................................................. 25 
8.1.2 
SECONDARY EFFICACY MEASURES ......................................................................................... 26 
8.1.3 
DATA REVIEW COMMITTEE (DRC) .......................................................................................... 26 
8.2 
SAFETY AND OTHER ASSESSMENTS ................................................................................................ 28 
8.2.1 
SAFETY MEASURES .................................................................................................................. 28 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................................ 30 
8.3.1 
DEFINITION OF ADVERSE EVENTS (AE) ................................................................................... 30 
8.3.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)................................................................... 32 
8.3.2.1 
REPORTING OF SERIOUS ADVERSE EVENTS ............................................................................ 32 
8.3.3 
CLASSIFICATION OF AN ADVERSE EVENT ................................................................................ 34 
8.3.3.1 
SEVERITY OF EVENT ................................................................................................................ 34 
8.3.3.2 
RELATIONSHIP TO STUDY INTERVENTION .............................................................................. 34 
8.3.3.3 
ACTION TAKEN ........................................................................................................................ 35 
8.3.4 
TIME PERIOD & FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP ............................ 35 
8.3.4.1 
DOCUMENTATION AND REPORTING OF ADVERSE EVENTS.................................................... 35 
8.3.5 
REPORTING EVENTS TO PARTICIPANTS........................................................................... 36 
8.3.6 
EVENTS OF SPECIAL INTEREST ...................................................................................... 36 
8.3.6.1 
UNEXPECTED ADVERSE REACTION DEFINITION ..................................................................... 36 
8.3.7 
REPORTING OF PREGNANCY........................................................................................... 37 
9 
STATISTICAL CONSIDERATIONS .............................................................................................................. 38 
9.1 
SAMPLE SIZE DETERMINATION ....................................................................................................... 38 
9.2 
POPULATIONS FOR ANALYSES ........................................................................................................ 39 
9.3 
PROTOCOL DEVIATIONS .................................................................................................................. 39 
9.4 
STATISITICAL ANALYSES .................................................................................................................. 39 
9.4.1 
GENERAL APPROACH ....................................................................................................... 39 
9.4.2 
ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) ............................................. 41 
9.4.3 
ANALYSIS OF THE SECONDARY ENDPOINT(S) ........................................................... 41 
9.4.4 
SAFETY ANALYSES ........................................................................................................... 43 
9.4.5 
BASELINE DESCRIPTIVE STATISTICS ........................................................................... 43 
9.4.6 
PLANNED INTERIM ANALYSES ...................................................................................... 43 


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9.4.7 
SUB-GROUP ANALYSES .................................................................................................... 44 
9.4.8 
TABULATION OF INDIVIDUAL PARTICIPANT DATA ................................................. 44 
9.4.9 
EXPLORATORY ANALYSES ............................................................................................. 44 
10 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ................................................. 45 
10.1 
INDEPENDENT ETHICS COMMITTEE ............................................................................................... 45 
10.2 
REGULATORY AUTHORITIES ............................................................................................................ 45 
10.3 
ETHICAL CONDUCT OF THE STUDY ................................................................................................. 45 
10.4 
INFORMED CONSENT PROCESS ...................................................................................................... 45 
10.5 
SUBJECT CONFIDENTIALITY ............................................................................................................. 46 
11 
QUALITY ASSURANCE .......................................................................................................................... 47 
11.1 
AUDIT AND INSPECTION ................................................................................................................. 47 
11.2 
MONITORING .................................................................................................................................. 47 
11.3 
DATA MANAGEMENT AND CODING ............................................................................................... 47 
12 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .......................................... 48 
12.1 
STUDY DISCONTINUATION AND CLOSURE ..................................................................................... 48 
12.2 
FUTURE USE OF STORED SPECIMENS AND DATA ........................................................................... 48 
12.2.1 
HANDLING OF BIOLOGICAL SPECIMENS ................................................................................. 48 
12.3 
KEY ROLES AND STUDY GOVERNANCE ........................................................................................... 49 
12.4 
RETENTION OF DOCUMENTATION ................................................................................................. 49 
12.5 
SOURCE DOCUMENTS ..................................................................................................................... 50 
12.6 
STUDY SUMMARY ........................................................................................................................... 50 
12.7 
INSTITUTIONAL REVIEW BOARD /INDEPENDENT ETHICS COMMITTEE (IEC) RECORDS RETENTION
 
50 
12.8 
PUBLICATION AND DATA SHARING POLICY .................................................................................... 50 
12.9 
CONFLICT OF INTEREST POLICY ...................................................................................................... 51 
12.10 ADDITIONAL CONSIDERATIONS ...................................................................................................... 51 
12.11 ABBREVIATIONS .............................................................................................................................. 52 
12.12 PROTOCOL AMENDMENT HISTORY ................................................................................................ 53 
13 
REFERENCES ........................................................................................................................................ 55 
14 
SUBJECTIVE STUDY SCALES ................................................................................................................. 57 
14.1 
VISUAL ANALOG SCALE (VAS) ......................................................................................................... 57 
14.2 
OCULAR SURFACE DISEASE INDEX (OSDI) ....................................................................................... 58 
14.3 
STANDARD PATIENT EVALUATION OF EYE DRYNESS (SPEED) ........................................................ 60 
14.4 
STUDY MEDICATION TOLERABILITY/COMFORT QUESTIONAIRE .................................................... 61 
15 
SPONSOR APPROVAL(S) ...................................................................................................................... 62 
 


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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 Harmonization 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: 
2a 
Objectives: 
Cohort 1: To evaluate the safety and tolerability of 3 different 
concentrations of AZR-MD-001 ointment/semi-solid drug (0.1%, 0.5% and 
1.0%) applied to the lower lid either twice-weekly or once every evening 
for up to 3 months compared to its vehicle in patients with meibomian 
gland dysfunction (MGD) and signs and symptoms of evaporative Dry Eye 
Disease (DED). 
Expansion 
Cohort: 
To 
evaluate 
the 
safety, 
tolerability, 
and 
pharmacodynamics of 2 different concentrations of AZR-MD-001 
ointment/semi-solid drug (0.5% and 1.0%) applied to the lower lid twice-weekly 
for up to 6 months compared to its placebo in patients with meibomian 
gland dysfunction (MGD).  
 
Clinical Hypotheses: 
Cohort 1: 
At least 1 concentration of AZR-MD-001 ointment/semi-solid drug (i.e., 
0.1%, 0.5%, or 1.0%) has an acceptable safety and tolerability profile 
following twice-weekly, evening ocular administration for the study 
treatment duration. 
At least 1 concentration of AZR-MD-001 ointment/semi-solid drug (i.e. 
0.1%, 0.5%, or 1.0%) has an acceptable safety and tolerability profile 
following once daily, evening ocular administration for the study treatment 
duration. 
At least 1 concentration of AZR-MD-001 ointment/semi-solid drug (i.e., 
0.1%, 0.5%, or 1.0%) is more effective than vehicle for treating MGD as 
measured by the meibum gland secretion score (MGS), the number of 
Meibomian Glands Yielding Liquid Secretion (MGYLS), or the proportion of 
patients improving on both a gland score (e.g., MGS or MGYLS) and a patient 
reported outcome measure (e.g., OSDI). 
At least 1 concentration of AZR-MD-001 ointment/semi-solid drug (i.e., 
0.1%, 0.5%, or 1.0%) is more effective than vehicle for treating Evaporative 
DED as measured by either a sign (e.g., TBUT) or symptom (e.g., eye 
dryness measured by VAS or OSDI). 
 
 


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Clinical Hypotheses: 
Expansion Cohort: 
 
AZR-MD-001 ointment/semi-solid drug (0.5% or 1.0%) 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 (0.5% or 1.0%) is more effective 
than placebo for treating MGD as measured by the meibomian glands 
yielding liquid secretion score (MGYLS). 
AZR-MD-001 ointment/semi-solid drug (0.5% or 1.0%) is more effective 
than placebo for treating symptoms associated with MGD as measured by 
Total Ocular Surface Disease Index (OSDI) score. 
 
1.2 
SCHEMA 
 
Study Design: 
Structure: Multicenter, double-masked, vehicle-controlled, randomized, parallel 
group study carried out in 2 sequential cohorts - Cohort 1: sequential rising 
concentrations of AZR-MD-001 ointment/semi-solid drug (i.e., 0.1%, 0.5%, or 
1.0%) and AZR-MD-001 vehicle dosed twice-weekly and/or once daily in the 
evening; Expansion Cohort: parallel doses of two concentrations of AZR-MD-
001 ointment/semi-solid drug (i.e., 0.5% and 1.0%) and AZR-MD-001 placebo 
dosed twice-weekly in the evening. 
 
Cohort 1: 
 
For Cohort 1, 2 sequential groups of 10 patients each will be followed by 2 
sequential groups of 20 patients each. All patients will be diagnosed with MGD and 
signs and symptoms of Evaporative DED and they will be randomly assigned in a 
4:1 ratio to receive either a single concentration of 
AZR-MD-001 
ointment/semi-solid drug (i.e., 0.1% for Group 1, 0.5% for Group 2, 1.0% for 
Group 3, and a 0.5% for Group 4) or AZR-MD-001 vehicle twice weekly for 1 
month. The patients in either the active or vehicle groups will further be assigned 
in a 1:1 ratio to 1 of 2 treatment regiments at the baseline visit: 1) they will 
receive treatment twice weekly for their entire 3 month treatment period; or 2) 
they will receive treatment twice weekly for the first month of their treatment 
period and will then receive treatment once every evening for months 1 to 3 of 
their treatment period. At the day 14 visit for the 10th patient in groups 1 and 
3  a n d  at month 1.5 for group 2, an unmasked Data Review Committee 
(DRC) will review all the tolerability and safety data for the patients and 
recommend a starting dose for the next group of patients (i.e., the DRC can 
elect not to escalate the dose concentration and can instead repeat a dose that has 
already been tested). At the month 1 visit the investigator will determine, by 
patient, if the treatment was well tolerated. If the regimen was well tolerated, 
the patients will continue their assigned dosing regimen (twice weekly dosing) 
or escalate to once daily dosing, based on their treatment regimen assigned at 
the baseline visit. If the investigator does not feel it is safe to escalate dosing and 
it is safe to continue dosing with the current regimen for a particular patient, 
that patient will be instructed to continue on their current regimen irrespective 
of treatment assignment. 
 


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The DRC will be unmasked to Cohort 1 treatment assignment and will have the 
freedom to evaluate all data throughout the study. To protect the integrity of the 
study, members of the DRC will not disclose study information to members of 
the clinical study team who are overseeing the conduct of the study, study sites, 
personnel, or patients. 
 
For Cohort 1, a screening visit will be followed by a qualification period where 
patients will dose with AZR-MD-001 placebo for 14 days. At the end of the 
qualification period patients who still exhibit signs of MGD and signs and 
symptoms of Evaporative DED will be enrolled into a 3-month treatment 
period. The study flow is shown in Figure 1a. 
 
Expansion Cohort: 
 
When the last patient enrolled in Cohort 1 Group 4 completes the month 3 visit, 
the DRC will evaluate all available safety and efficacy data before recommending 
initiation of the Expansion Cohort. Each concentration of AZR-MD-001 
ointment/semi-solid drug and each frequency of administration will be evaluated 
for safety and tolerability in Cohort 1 before expansion of that same concentration 
and dose regimen in the Expansion Cohort. Two concentrations of AZR-MD-
001 and a single dosing regimen will be selected for the Expansion Cohort (i.e., 
twice-weekly). 
 
For the Expansion Cohort, patients with MGD will be randomly assigned in a 
1:1:1 ratio to receive either a single concentration of AZR-MD-001 
ointment/semi-solid drug (i.e., 0.5% o r  1.0%) or AZR-MD-001 placebo. 
 
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 6-month treatment period. The study flow is shown in Figure 1b. 
For the Expansion Cohort, the site staff member performing efficacy and safety 
measurements will not be involved in drug dispensing or accountability and should 
remain masked to the treatment received by the patient. 
 
 
Duration: The total duration of study is approximately 3.5 months (from 
screening to study completion for Cohort 1) and is approximately 6.5 months 
(from screening to study completion for the Expansion Cohort). 
 
Study Treatment Groups:  
Cohort 1: 
AZR-MD-001 ointment/semi-solid drug (i.e., 0.1%, 0.5%, or 1.0%). 
 
Expansion Cohort: 
AZR-MD-001 ointment/semi-solid drug (i.e., 0.5% or 1.0%). 
 
 
 
 


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Active Period Control:   
Cohort 1: 
AZR-MD-001 Vehicle 
 
Expansion Cohort : 
AZR-MD-001 Placebo 
Run-In Period/Sample Dosing:  
Cohort 1: 
AZR-MD-001 Placebo 
 
Expansion Cohort : 
“Vaseline” (AZR-MD-001 Placebo) 
 
 
Dosage/Dose Regimen: For Cohort 1, study patients will receive a 2-week run-in 
on AZR-MD-001 placebo to be administered twice-weekly for a period of 2 
weeks. For the Expansion Cohort, patients will dose (sample dose) with AZR-
MD-001 placebo at the baseline visit to confirm their ability to follow dosing 
instructions. Upon meeting inclusion/exclusion criteria patients in Cohort 1 will 
be randomized to AZR-MD-001 ointment/semi-solid drug (i.e., 0.1% 0.5%, 
or 1.0%) or AZR-MD-001 vehicle administered twice-weekly for one month. If 
the regimen was well tolerated, the patients will continue their assigned 
dosing regimen (twice weekly dosing) or escalate to once daily dosing, based 
on their treatment regimen assigned at the baseline visit. If the investigator does 
not feel it is safe to escalate doing frequency, patients in Cohort 1 will be asked 
to continue their twice-weekly dosing regimen. Expansion Cohort patients will 
receive either AZR-MD-001 ointment/semi-solid drug (i.e., 0.5% or 1.0%) or 
AZR-MD-001 placebo twice-weekly for 6 months depending upon the dosing 
regimen recommended by the DRC.  
 
Randomization/Stratification: Patients will be randomized to receive AZR-MD- 
001 ointment/semi-solid drug (i.e., 0.1%, 0.5% or 1.0%) or AZR-MD-001 vehicle 
in a 4:1 treatment allocation ratio for Cohort 1. For the Expansion Cohort, 
patients will be randomized to receive AZR-MD-001 ointment/semi-solid drug 
(i.e., 0.5% or 1.0%) or AZR-MD-001 placebo in a 1:1:1 treatment allocation ratio. 
For Cohort 1 the patients in either the active or vehicle groups will further be 
assigned in a 1:1 ratio to 1 of 2 treatment regiments at the baseline visit: 1) 
they will receive treatment twice weekly for their entire 3 month treatment 
period; or 2) they will receive treatment twice weekly for the first month of their 
treatment period and will then receive treatment once every evening for months 
1 to 3 of their treatment period. 
 
For both Cohorts, 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.  For Cohort 1, Groups 3 
and 4 enrollment should continue until at least ten patients have a MGS score of < 
6 and ten have an MGS score ≥6 and ≤ 12.  


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Visit Schedule:  
 
Cohort 1: 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.  
 
Expansion Cohort: Up to 7 scheduled visits: screening, randomization, day 14, 
month 1.5, month 3, month 4.5 and month 6 (Exit). For patients who discontinue 
the study early, the month 6 visit procedures should be completed. 
 
Study Population Characteristics 
Number of Patients:  
Cohort 1: The total number of randomized patients for Cohort 1 will be 
approximately 60. Approximately 30 patients should have a baseline MGS score 
of < 6 and approximately 30 patients should have a baseline MGS score ≥6 and ≤ 
12. Based upon data from the LipiFlow® development program a screen failure 
rate of ~ 40% is expected. Thus, ~84 patients will need to be screened to achieve 
~60 patients randomized to treatment. 
Expansion Cohort: The total number of randomized patients, with a Total OSDI < 
34, for the Expansion Cohort will be approximately 225. Approximately 112 
patients should have a baseline MGS score of < 6 and approximately 112 patients 
should have a baseline MGS score ≥6 and ≤ 12. Based upon data from the 
LipiFlow® development program a screen failure rate of ~ 40% is expected. Thus, 
~315 patients will need to be screened to achieve ~225 patients randomized to 
treatment with a Total OSDI < 34.   
 
Condition/Disease: Meibomian Gland Dysfunction (MGD) with signs and 
symptoms of Evaporative DED 
 
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 
• 
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 


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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 MGD 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 < 34  
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 of childbearing potential at 
the screening visit 
• 
Women of childbearing potential must have a history of bilateral tubal 
ligation or use oral contraceptives, implants, injectables, transdermal 
patch, intrauterine device, or double barrier contraceptive for birth 
control during the study. 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. 
Complete abstinence for four weeks before exposure to study 
medication, throughout the study, and for at least four weeks after the 
last dose of study medication is acceptable for study inclusion. 
 
Exclusion Criteria: 
• 
Uncontrolled ocular disease (except for MGD and dry eye 
disease/keratoconjunctivitis sicca) 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 a COVID-19 compliant device as required by local 
governance) 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 
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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 patients 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 during the study (e.g., mascara or 
eyeliner) that the investigator feels could interfere with the signs and 
symptoms of either MGD or Evaporative DED 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 
• 
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 


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• 
Patient is an employee at the investigational site or is related to any member 
of the study staff 
• 
Patient cannot tolerate multiple blood draws (Cohort 1 only) 
• 
Pregnant, nursing, or females of childbearing potential and not utilizing 
adequate birth control measures 
• 
Positive urine pregnancy test at the screening visit 
• 
Participation in another clinical trial involving a therapeutic drug or device 
within the past 30 days 
• 
Enrollment in a previous Stage of the current study or other Azura study 
using AZR-MD-001 
• 
The patient has a screening laboratory result (e.g., hematology, serum 
chemistry, or urinalysis) that, in the opinion of the investigator, would make 
the patient unsuitable for study participation (Cohort 1 only) 
 
 
Response 
Measures 
Cohort 1: 
 
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 the number of Meibomian Glands 
Yielding Liquid Secretion (MGYLS) (0 to 15 scale) 
• 
Proportion of patients with improvement on a gland score (i.e., MGS 
or MGYLS) and a patient reported outcome (e.g., total OSDI) 
 
Primary Efficacy for Evaporative DED: 
• 
Change from Baseline to Month 3 in Tear Break-up Time (TBUT) 
• 
Change from Baseline to Month 3 in OSDI (considered an endpoint for 
MGD by FDA in this trial design) 
• 
Change from Baseline to Month 3 in eye dryness measured using a 
visual analogue scale (VAS) 
• 
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 
 
Other Efficacy Measures: 
MGD: 
• 
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 
• 
Change from Baseline to day 14, month 1 and month 1.5 in the number 
of MGYLS (0 to 15 scale) 
• 
MGYLS (0 to 15 scale) 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 
• 
Proportion of patients with a MGS score > 12 at each visit 
 


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Evaporative DED 
• 
Change from Baseline to day 14, month 1 and month 1.5 in TBUT 
• 
TBUT 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 
 
• 
Change from Baseline to day 14, month 1 and month 1.5 in eye dryness 
measured using VAS 
• 
Eye dryness measured using a visual analogue scale (VAS) at each visit 
• 
Patient ocular symptoms and change from baseline (e.g., blurred vision, 
burning, eye pain, light sensitivity, itching, foreign body sensation) across 
visits 
• 
Proportion of patients with a TBUT ≥ 10 seconds at each visit 
• 
Corneal and conjunctival staining (0 to 5 scale) at each visit 
• 
Tear collection (for lipid and other exploratory analyses) (selected sites) 
• 
Proportion of patients with a SPEED < 6 at each visit 
• 
Proportion of patients with a Total OSDI < 13 at each visit 
• 
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 each visit 
 
Exploratory Efficacy Measures: 
• 
Change from Baseline to day 14, month 1, month 1.5, and month 3 in 
Oculus Keratograph 5® measures (selected sites) 
 
Health Outcomes: 
• 
Standard Patient Evaluation of Eye Dryness (SPEED) 
 
Expansion Cohort: 
 
Primary Efficacy Sign for MGD: 
• 
US: Change from Baseline to month 3 in meibomian glands 
yielding liquid secretion score (MGYLS) (0 to 15 scale) 
• 
Regions requiring longer duration of follow-up (e.g., EU): Change 
from Baseline to month 6 in meibomian glands yielding liquid 
secretion score (MGYLS) (0 to 15 scale) 
 
Primary Efficacy Symptom for MGD: 
• 
US: Change from Baseline to month 3 in Total OSDI 
• 
Regions requiring longer duration of follow-up (e.g., EU): Change from 
Baseline to month 6 in Total OSDI 
 
Other Efficacy Measures: 
• 
Change from Baseline to day14, month 1.5, month 3, month 4.5 and 
month 6 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 day 14, month 1.5, and month 4.5 in the 
number of Meibomian Glands Yielding Liquid Secretion (MGYLS) (0 
to 15 scale) 


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• 
MGYLS (0 to 15 scale) at each visit  
• 
Proportion of patients with a change from baseline in MGYLS score ≥ 5 at 
each visit 
• 
Change from Baseline to day14, month 1.5, month 3, month 4.5 and month 6 
in TBUT 
• 
TBUT at each visit 
• 
Proportion of patients with a TBUT score > 5 at each visit 
• 
Change from Baseline to day 14, month 1.5, month 3, month 4.5 
and month 6 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 1.5, month 3, month 4.5 
and month 6 in average visual analogue scale (VAS) 
• 
Average VAS at each visit 
• 
Change from Baseline to day14, month 1.5, month 3, month 4.5 
and month 6 in worst VAS 
• 
Worst VAS at each visit 
• 
Change from Baseline to day 14, month 1.5 and month 4.5 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 and month 6 
• 
Proportion of patients with a Total OSDI < 13 at each visit 
• 
Number of expressible glands yielding clear meibum at day14, month 
1.5, month 3, month 4.5 and month 6 
• 
Eyelid margin erythema/telangiectasias at day14, month 1.5, month 3, 
month 4.5 and month 6 
• 
Corneal and conjunctival staining (0 to 5 scale) at each visit  
 
Cohort 1 & Expansion Cohort: 
 
Safety: 
• 
Adverse events 
• 
Vital signs 
• 
Study medication tolerability as measured by the Ocular Comfort 
Questionnaire (Cohort 1 only) 
• 
Urine pregnancy test 
• 
Best-corrected visual acuity (BCVA; Logarithmic visual acuity chart) 
• 
Biomicroscopy 
• 
Ophthalmoscopy 
• 
Intraocular pressure (IOP) 
• 
Lab analysis of blood and urine (including hematology, chemistry, and 
urinalysis) (Cohort 1 only) 
 
 
 
 
 
 
 
 
 
 
 


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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 (Cohort 1) or Month 1.5 (Expansion Cohort)). 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, 
  
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. 
 
Cohort 1: 
 
Efficacy (MGD): The primary efficacy variables for MGD are change from 
baseline to month 3 in MGS, number of MGYLS, and the proportion of patients 
with numerical improvement on a gland score (i.e., MGS or MGYLS) and 
improvement greater than or equal to the MICD for a patient reported outcome 
(e.g., 4.5 for Total OSDI). A patient will be considered to be a meibum quality 
responder at a post-randomization visit if the MGS score in the study eye is > 
12, MGYLS score > 2, or MGYOLS score > 2. The visit for the primary 
variable is month 3 and the primary analysis population is mITT. Statistical tests 
will be performed for each AZR-MD-001 group versus vehicle group. Odds 
ratio along with 95% CI will be obtained by pairwise comparisons of the proportion 
of responders for each AZR-MD-001 group versus vehicle group using the Logistic 
Regression method stratifying by baseline MGS score for the qualified eye (i.e., < 
6 or ≥ 6 and ≤ 12) and duration of disease (i.e., < 5 years or ≥ 5 years). There will 
be no alpha adjustment for the multiple tests for the pairwise comparisons. 
 
Efficacy (Evaporative DED): The primary efficacy variables for evaporative DED 
are change from baseline to month 3 in Tear Break-up Time (TBUT), OSDI, eye 
dryness measured using a visual analogue scale (VAS), and proportion of 
patients with improvement greater than or equal to the MICD for a patient reported 
outcome (e.g., 4.5 for Total OSDI). The visit for the primary variable is month 
3 and the primary analysis population is mITT. Statistical tests will be performed 
for each AZR-MD-001 group versus vehicle group. Pairwise comparisons of the 
proportion of responders will be performed using the CMH method stratifying by 


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duration of disease. There will be no alpha adjustment for the multiple tests for 
the pairwise comparisons. 
 
A patient will be considered to be an evaporative DED responder at a post-
randomization visit if TBUT > 10 seconds, a Schirmer’s test ≥ 10 mm, a Total OSDI 
< 13, a SPEED Score < 6, or an Average VAS or Worst VAS score decreased by ≥ 
5 is observed. 
 
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. 
 
Expansion Cohort: 
 
Primary Efficacy (MGD):  
The primary efficacy sign for MGD is change from baseline in MGYLS. 
The visit for the primary variable is month 3 for the US and month 6 for regions 
where the longer follow-up is required (such as in EU). The primary analysis 
population is mITT. Statistical testing will be performed for the AZR-MD-001 
group versus placebo group.  
 
The primary efficacy symptom for MGD is change from baseline in Total OSDI. 
The visit for the primary variable is month 3 for the US and month 6 for regions 
where the longer follow-up is required. The primary analysis population is mITT. 
Statistical testing will be performed for the AZR-MD-001 group versus placebo 
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. 
 
Cohort 1: 
 
Sample Size Calculation: The sample size is determined empirically. 
 
Interim Analysis: Interim database locks will be performed when the 10th patient in 
Cohort 1, Group 3 exits the study (First Interim Analysis) and when the last patient 
enrolled in Cohort 1, Group 4 exits the study (Second Interim Analysis). Only data 
collected up to the last patient exiting the study from Cohort 1, Group 3 will be 
included in the first data analysis set. All ongoing patients in Cohort 1, Group 4 will 
remain masked until the second Interim Analysis. 
 
A second interim analysis is planned after the final patient from Cohort 1 exits the 
study (Cohort 1, Group 4). Outcomes from this analysis will assist in the 


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confirmation of the study drug concentration and frequency to be used for the 
Expansion Cohort. 
 
Expansion Cohort: 
 
Sample Size Calculation:  Estimates for sample size calculations are from the final 
Cohort 1 interim analysis from Azura Clinical Protocol AZ201801. The mean 
response of 0.77 and a standard deviation for MGYLS of 2.28 units was observed 
for control and a mean response of 2.77 units and a standard deviation for MGYLS 
of 3.35 units was observed for AZR-MD-001 0.5%  . A sample size of 45 subjects 
per group will have 90% power to detect a difference of 2.0 units between the active 
treatment group and the placebo group using a two-sample t-test at a significance 
level of 0.05. The standard deviation for Total OSDI was 6.31 units for control and 
8.34 units for the high dose. A sample size of 58 subjects per group will have 90% 
power to detect a difference of 4.52 units between the active treatment group and 
the control group using a two-sample t-test at a significance level of 0.05. To allow 
for additional site to site variability the sample size per group will be increased to 
approximately75 patients. 
 
Multiplicity Consideration: To address the multiple primary endpoints defined in this 
study, the primary endpoints have been prioritized into a hierarchical structure. For 
example, in order to test the primary symptom endpoint of Total OSDI, the primary 
sign endpoint of MGYLS must be statistically significantly higher in the AZR-MD-
001 treatment group compared to the vehicle treatment group using a two-sided 
significance level of 0.05. The final order of the endpoints will be defined in the 
Statistical Analysis Plan (SAP) prior to unmasking the study. 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:  An interim analysis (Primary Endpoint for the U.S.) is planned 
after the final enrolled patient completes the month 3 visit. Only an independent 
biostatistician will be unblinded to the treatment patients actually received and only 
summary efficacy and safety tables will be provided.  Outcomes from this analysis 
will assist in the confirmation of the study power calculations and potentially as part 
of a rolling submission to global regulatory agencies.  
 
 
 


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Figure 1 
Study Flow – Multicenter, double-masked, vehicle-controlled, randomized, parallel group study 
carried out in 2 sequentially overlapping cohorts 
 
a: Cohort 1: 
 
 
 
 
b: Expansion Cohort: 
 
 
 
 
The primary endpoints for the US will serve as an Interim Analyses for the Month 6 primary endpoints.  The sample size may be 
adjusted for power or to address any concerns for alpha inflation.  


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1.3 
SCHEDULE OF ACTIVITIES (SOA) COHORT 1 AND EXPANSION COHORT 
 
Table 1 Schedule of Visits and Procedures 
 
Study Period 
Qualification 
Double-Masked Period 
NOTE: The recommended order for the procedures to be 
followed appears in the Procedure Manual 
Screening a 
(Day -14) 
Baseline 
Day 0 
Randomization 
Day 14 
Month 1 
(Coh.1 
only) 
Month 1.5  
Month 3 
(Exit 
Coh.1) 
Month 
4.5 
(Expan.) 
Month 6 
(Exit 
Expan.) 
Visit Window 
± 2 Days 
N/A 
± 2 Days ± 7 Days 
± 7 Days 
± 2 Days 
± 7 Days 
± 2 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) 
X 
X 
X 
X 
 
X 
Pregnancy test (urine) for female patients b 
X 
X 
 
X 
Patient Ocular Symptoms (VAS) 
X 
X 
X 
X 
X 
X 
X 
X 
OSDI 
X 
X 
X 
X 
X 
X 
X 
X 
SPEED 
X 
X 
X 
X 
X 
X 
X 
X 
Best-corrected visual acuity (BCVA) 
X c 
X 
X 
X 
X 
X 
X 
X 
Slit-lamp biomicroscopy (includes eyelid margin 
erythema/telangiectasias and do not touch the 
X 
X 
X 
X 
X 
X 
X 
X 
Oculus Keratograph 5® procedures: 
interferometry, redness test, and/or lower lid 
meibography photograph (selected sites) d 
X 
X 
X 
X 
X 
X 
 
 
LipiView® interferometer (selected sites) d 
X 
X 
X 
X 
X 
X 
 
 
Tear Break Up Time (TBUT) g 
X 
X 
X 
X 
X 
X 
X 
X 
Sodium fluorescein corneal staining, Oxford scale 
X 
X 
X 
X 
X 
X 
X 
X 
Lissamine green conjunctival staining, Oxford scale 
X 
X 
X 
X 
X 
X 
X 
X 


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Study Period 
Qualification 
 
Double-Masked Period 
NOTE: The recommended order for the procedures to be 
followed appears in the Procedure Manual 
Screening a 
(Day -14) 
Baseline 
Day 0 
Randomization 
Day 14 
Month 1 
(Coh.1 
only) 
Month 1.5  
Month 3 
(Exit 
Coh.1) 
Month 
4.5 
(Expan.) 
Month 6 
(Exit 
Expan.) 
Visit Window 
± 2 Days 
N/A 
± 2 Days ± 7 Days 
± 7 Days 
± 2 Days 
± 7 Days 
± 2 Days 
Meibomian gland evaluation (MGE) g 
X 
X 
X 
X 
X 
X 
X 
X 
Schirmer without anesthesia 
X 
X 
X 
X 
 
X 
Tear Collection for biomarker analysis (selected sites) d 
X 
X 
X 
 
 
Intraocular pressure (IOP) 
X 
X 
 
X 
Ophthalmoscopy exam e 
X 
X 
 
X 
Meibography 
X 
X 
 
X 
Lab – Blood safety (chemistry , hematology) 
and urinalysis (Cohort 1 Only) 
X 
X 
 
 
Study medication Tolerability/Comfort Questionnaire 
(Cohort 1 only) f 
X 
X 
X 
X 
X 
 
 
Adverse events/medications/procedures 
X 
X 
X 
X 
X 
X 
X 
X 
Discontinue concomitant medication(s) 
impacting inclusion/exclusion 
X 
Contact IVRS/IWRS for patient randomization number 
X 
Medication dispensing/return 
X (Cohort 1) 
X 
 
X 
X 
X 
X 
X 
Physician Observation of Drug Application 
X (Cohort 1) 
X 
BCVA = Best Corrected Visual Acuity; Coh. = Cohort; Expan. = Expansion; OSDI = Ocular Surface Disease Index; SPEED = Standard Patient Evaluation of Eye Dryness; TBUT = tear break up 
time; VAS = Visual Analogue Scale; PM = Evening, Month = 28 days 
 
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 DED. Patients should wash out from all medication listed in the inclusion/exclusion criteria. The 
screening period includes a 2-week, run-in with AZR-MD-001 placebo for Cohort 1.  Patients who are re-enrolled following an initial screen failure will receive a new screening 
number upon re-screen (i.e., sites should not reuse the old number). 
b For females of childbearing potential. 
c Manifest refraction performed at screening will be used at each visit to obtain BCVA. 
d Performed as a sub-study by selected sites and patients and approved by study sponsor. 
e Ophthalmoscopy examination will be dilated at screening and undilated for study exit unless dilation is necessary 
f Instill dose of medication after completing safety/efficacy measures and ~5 minutes before medication tolerability assessment (see Procedure Manual for more detail). 
g TBUT and MGE should be performed by the same individual for a given patient.  For the Expansion Cohort, 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.


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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 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,


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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); 
3) Increased Tear Break-up Time (TBUT); and 
4) Improved Total OSDI, SPEED and eye dryness scores (measured using a visual 
analogue scale [VAS]) (Blackie et al, 2015). 
 


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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. 
 
Based upon positive efficacy and safety results from clinical study MGSS1 for the ocular 
application of selenium disulfide shampoo (2.5%), Azura Ophthalmics, is further evaluating the 
safety, tolerability and effectiveness of AZR-MD-001 ointment/semi-solid drug, surfactant free, in 
patients with MGD and associated evaporative DED. 


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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 two dosing frequencies (i.e., twice weekly and 
once 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- 
lamp (McDonald-Shadduck’s scale). At the end of the study, eye globes were histopathologically 
examined. 


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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. 
 
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 effectiveness for both MGD and 
evaporative DED, the risk/benefit profile of AZR-MD-001 ointment/semi-solid drug supports 
continued development in the proposed adaptive study design. 


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3 
OBJECTIVES AND ENDPOINTS 
Table 3–1 
Table of Objectives, Endpoint, and Endpoint Justification 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR 
Cohort 1 and Expansion Cohort 
To evaluate the safety, tolerability, 
and pharmacodynamics of 
different concentrations of AZR-
MD-001 ointment/semi- solid 
drug applied to the lower lid either 
twice-weekly or once every 
evening for up to 3 months 
(Cohort 1) or up to 6 months 
(Expansion Cohort).  Systemic 
pharmacokinetics (PK) will only 
be measured in Cohort 1. 
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 (Cohort 1): 
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 the 
number of Meibomian Glands 
Yielding Liquid Secretion (MGYLS) 
(0 to 15 scale) 
• Proportion of patients with improvement 
on a gland score (i.e., MGS or 
MGYLS) and a patient reported 
outcome (e.g., total OSDI) 
Primary Efficacy for Evaporative DED: 
• 
Change from Baseline to Month 3 in 
Tear Break-up Time (TBUT) 
• 
Change from Baseline to Month 3 
in OSDI 
• 
Change from Baseline to Month 3 
in eye dryness measured using a 
visual analogue scale (VAS) 
• 
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 
 
 
The endpoints for safety and 
tolerability are all commonly 
used in ophthalmic drug trials. 
Consistently observed benefits 
for devices designed to treat 
glandular obstruction include: 
• 
Improvement in the 
meibum gland 
secretion score (MGS) 
(0 to 45 scale); 
• 
Increases in the number 
of meibomian glands 
yielding liquid 
secretion (MGYLS) (0 
to 15 scale); 
• 
Increased 
Tear 
Break-up 
Time 
(TBUT); and 
• 
Improved Total OSDI, 
SPEED and eye 
dryness scores 
(measured using a 
visual analogue scale 
[VAS]) (Blackie et al, 
2015). 
. 


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Signal of Efficacy (Expansion Cohort ): 
See Response Measures in the synopsis 
 
Primary Efficacy Sign for MGD: 
• 
US : Change from Baseline to month 3 in 
meibomian glands yielding liquid 
secretion score (MGYLS) (0 to 15 scale) 
• 
Regions requiring longer duration of 
follow-up (e.g., EU): Change from 
Baseline to month 6 in meibomian glands 
yielding liquid secretion score (MGYLS) 
(0 to 15 scale) 
 
Primary Efficacy Symptom for MGD: 
• 
US: Change from Baseline to month 3 in 
Total OSDI 
• 
Regions requiring longer duration of 
follow-up (e.g., EU):  Change from 
Baseline to month 6 in Total OSDI 
 
 


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4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
 
This is a multicenter, double-masked, vehicle-controlled, randomized, parallel group study carried 
out in 2 sequential cohorts: Cohort 1: sequential rising concentrations of AZR-MD-001 
ointment/semi-solid drug (i.e., 0.1%, 0.5% or 1.0%) and AZR-MD-001 vehicle dosed twice-weekly 
and/or once daily in the evening; Expansion Cohort: parallel doses of two concentrations of AZR-
MD-001 ointment/semi-solid drug (i.e., 0.5% or 1.0%) and AZR-MD-001 placebo dosed twice-
weekly in the evening. 
 
Cohort 1: 
 
For Cohort 1, 2 sequential groups of 10 patients each will be followed by 2 sequential groups of 20 
patients each. All patients will be diagnosed with MGD and signs and symptoms of Evaporative 
DED and they will be randomly assigned in a 4:1 ratio to receive either a single concentration of 
AZR-MD-001 ointment/semi-solid drug (i.e., 0.1% for Group 1, 0.5% for Group 2, 1.0% for Group 
3, and a 0.5% for Group 4) or AZR-MD-001 vehicle twice weekly for 1 month. The patients in 
either the active or vehicle groups will further be assigned in a 1:1 ratio to 1 of 2 treatment regiments 
at the baseline visit: 1) they will receive treatment twice weekly for their entire 3 month treatment 
period; or 2) they will receive treatment twice weekly for the first month of their treatment period 
and will then receive treatment once every evening for months 1 to 3 of their treatment period. At 
the day 14 visit for the 10th patient in groups 1 and 3 and at month 1.5 for group 2, an unmasked 
Data Review Committee (DRC) will review all the tolerability and safety data for the patients and 
recommend a starting dose for the next group of patients (i.e., the DRC can elect not to escalate the 
dose concentration and can instead repeat a dose that has already been tested). At the month 1 visit 
the investigator will determine, by patient, if the treatment was well tolerated. If the regimen was 
well tolerated, the patients will continue their assigned dosing regimen (twice weekly dosing) or 
escalate to once daily dosing, based on their treatment regimen assigned at the baseline visit. If the 
investigator does not feel it is safe to escalate dosing and it is safe to continue dosing with the 
current regimen for a particular patient, that patient will be instructed to continue on their current 
regimen irrespective of treatment assignment. 
 
The DRC will be unmasked to Cohort 1 treatment assignment and will have the freedom to evaluate 
all data throughout the study. To protect the integrity of the study, members of the DRC will not 
disclose study information to members of the clinical study team who are overseeing the conduct 
of the study, study sites, personnel, or patients. 
 
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with AZR-MD-001 placebo for 14 days. At the end of the baseline period patients who still exhibit 
signs of MGD and signs and symptoms of Evaporative DED will be enrolled into a 3-month 
treatment period. The study flow is shown in Figure 1a. 
 
Expansion Cohort: 
 
When the last patient enrolled in Cohort 1, Group 4 completes the month 3 visit, the DRC will 
evaluate all available safety and efficacy data before recommending initiation of the Expansion 
Cohort. Each concentration of AZR-MD-001 ointment/semi-solid drug and each frequency of 
administration will be evaluated for safety and tolerability in Cohort 1 before expansion of that 
same concentration and dose regimen in the Expansion Cohort. Two concentrations of AZR-MD-
001 and a single dosing regimen will be selected for the Expansion Cohort (i.e., twice-weekly). 
 
For the Expansion Cohort, patients with MGD will be randomly assigned in a 1:1:1 ratio to receive 
either a single concentration of AZR-MD-001 ointment/semi-solid drug (i.e., 0.5% or 1.0%) or 
AZR-MD-001 placebo. 
 
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 6-month treatment period. The study flow is 
shown in Figure 1b. 
 
The total duration of study is approximately 3.5 months (from screening to study completion) for 
Cohort 1 and is approximately 6.5 months (from screening to study completion) for the Expansion 
Cohort. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
While there are no approved pharmacological treatments for terminal duct obstruction from 
hyperkeratinization associated with MGD, compounds that reduce disulfide bonds (S-S) have 
shown promise. Akyol-Salman and colleagues (2010) used N-acetyl-cysteine (NAC) in 20 patients 
with MGD and demonstrated a statistically significant improvement in TBUT and symptoms (e.g., 
itching) by 1 month (Akyol-Salman et al, 2010; Akyol-Salman et al, 2012). Selenium sulfide as a 
0.5% ointment 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 
 
 


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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. 
 
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. 
 
Based upon positive results from clinical study MGSS1 and good safety and tolerability across 5 
clinical studies with doses of selenium disulfide up to 2.5% twice weekly or 0.5% BID, Azura 
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ointment/semi-solid drug, surfactant free, in patients with MGD and associated evaporative DED. 
Azura Ophthalmics believes that the use of topical ophthalmic selenium sulfide in over 300 patients 
corroborated by preclinical ocular tolerability results in female albino rabbits with exaggerated 
dosing up to 2.5% selenium disulfide, once daily supports the proposed adaptive Phase 2 study 
design. 
4.3 
DATA REVIEW COMMITTEE (DRC) 
 
A DRC consisting of physicians and trained study personnel, in addition to ad hoc internal/external 
experts, will assess study treatment effects. The composition, qualifications and activities of the 
committee are described in the DRC Charter. The DRC will review available data to determine the 
appropriateness of continuing dosing and enrollment in Cohort 1. Based on review of data from 
all executed Cohort 1 groups, the DRC will recommend whether to proceed to the Expansion 
Cohort and the dose levels to be employed. The DRC may recommend at any time during Cohort 
1 to de-escalate, delay, or to stop patient recruitment. The number of treatment groups, doses, and 
number of patients pergroup in the Expansion Cohort will be based on recommendations by the 
DRC following review of available Cohort 1 data. Details of the planned analyses will be 
provided in the DRC analysis plan. The DRC may also request ad-hoc review of masked or 
unmasked data at any time throughout the course of Cohort 1 to evaluate new findings or 
recommend changes to study progression. 
 
4.4 
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. 
 
 


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5 
STUDY POPULATION 
 
The study will consist of patients with Meibomian Gland Dysfunction (MGD) with signs and 
symptoms of Evaporative DED. 
 
5.1 
INCLUSION CRITERIA 
 
• Male or female, 18 years of age or older at screening visit 
• Capable of understanding and willing to provide written informed consent and likely 
to complete the entire course of study according to instructions 
• Written authorization for use and release of health and research study information 
has been obtained 
• Best-corrected visual acuity (BCVA) of 20/40 or better (Snellen equivalent), using the 
logarithm of the minimum angle of resolution (LogMAR) in each eye at the screening 
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 MGD 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 < 34  
And 
o TBUT < 10 seconds in both eyes 


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• Demonstrated ability to follow dosing instructions at the baseline visit 
• A negative pregnancy test result for all women of childbearing potential at the screening 
visit 
• Women of childbearing potential must have a history of bilateral tubal ligation or use oral 
contraceptives, implants, injectables, transdermal patch, intrauterine device, or double 
barrier contraceptive for birth control during the study. 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. Complete abstinence for four 
weeks before exposure to study medication, throughout the study, and for at least four 
weeks after the last dose of study medication is acceptable for study inclusion. 
 
5.2 
EXCLUSION CRITERIA 
 
 
• Uncontrolled ocular disease (except for MGD and dry eye disease/keratoconjunctivitis 
sicca) 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 a COVID-
19 compliant device as required by local governance) 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 patients 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 during the study (e.g., mascara or eyeliner) that the 
investigator feels could interfere with the signs and symptoms of either MGD or Evaporative 
DED 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) 


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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 
• 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 
• Patient cannot tolerate multiple blood draws (Cohort 1 only) 
• Pregnant, nursing, or females of childbearing potential and not utilizing adequate birth 
control measures 
• Positive urine pregnancy test at the screening visit 
• Participation in another clinical trial involving a therapeutic drug or device within the 
past 30 days 
• Enrollment in a previous Stage of the current study or other Azura study using AZR-MD-
001 
• The patient has a screening laboratory result (e.g., hematology, serum chemistry, or 
urinalysis) that, in the opinion of the investigator, would make the patient unsuitable for 
study participation (Cohort 1 only) 
 
 


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5.3 
LIFESTYLE CONSIDERATIONS 
 
To be eligible for this study patient must comply with the following: 
 
• Patients should not have LipiFlow® or other lid-heating therapy, meibomian gland 
probing, or therapeutic gland expression in either eye within 6 months of the 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. 
• 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 (e.g., mascara or 
eyeliner) that the investigator feels could interfere with the signs and symptoms of either 
MGD or Evaporative DED or tattooing of the lids 
 
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 
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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 
requirements and to respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse event (SAE). 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of 
normal variability in safety measures may be rescreened one additional time. Individuals who 
do not meet the criteria for participation in the trial in Cohort 1 but who may be eligible under 
the revised criteria for the Expansion cohort may be re-screened 1 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 
 
Cohort 1: The total number of randomized patients for the study Cohort 1 will be approximately 
60. Approximately 30 patients should have a baseline MGS score of < 6 and approximately 30 
patients should have a baseline MGS score ≥6 and ≤ 12. Based upon data from the LipiFlow® 
development program a screen failure rate of ~ 40% is expected. Thus, ~84 patients will need to 
be screened to achieve ~60 patients randomized to treatment. 
 
Expansion Cohort: The total number of randomized patients, with a Total OSDI < 34, for the 
Expansion Cohort will be approximately 225. Approximately 112 patients should have a baseline 
MGS score of < 6 and approximately 112 patients should have a baseline MGS score ≥6 and ≤ 
12. Based upon data from the LipiFlow® development program a screen failure rate of ~ 40% is 
expected. Thus, ~315 patients will need to be screened to achieve ~225 patients randomized to 
treatment with a Total OSDI < 34.   
 
Patients who have not been dosed with study drug can be reallocated from discontinued groups 
to increase the power in Cohort 1 groups that are continued at the discretion of the DRC. 
 
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. 
 
 


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6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 
STUDY TREATMENT(S)/ FORMULATION(S)/ MEDICAL 
DEVICE COMPOSITION OR DESIGN 
 
All concentrations of AZR-MD-001 Ophthalmic Ointment contain the drug product, AZR-MD- 
001 (0.1%, 0.5%, o r  1.0%), and suitable excipient. The only excipient in the formulation 
is Petrolatum white. The AZR-MD-001 placebo to be used during the 14 day run-in period 
between the Screening and Baseline visits for Cohort 1 and during the treatment period for the 
Expansion Cohort contains only Petrolatum white. The AZR-MD-001 placebo (labelled 
“Vaseline”) to be used at the Baseline visit of the Expansion Cohort contains only Petrolatum white. 
The AZR-MD-001 vehicle to be used during the active treatment period between the Baseline 
and Month 3 visits for Cohort 1 contains only Petrolatum white and yellow iron oxide to match 
both the texture and colour of the active product. 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 
 
Investigational Product 
Product name: 
AZR-MD-001 
 (Selenium 
disulfide 
API in ointment/semi- 
solid Petrolatum white) 
Vehicle (Cohort 1 only) 
Placebo (Cohort 1& 
Expansion) 
Formulation 
description: 
AZR-MD-001 is an 
orange opaque 
dispersion ointment 
with an odour faintly of 
hydrogen sulfide 
Ointment will match 
AZR-MD-001’s 
texture and 
approximate its orange 
colour 
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): 
Active:  
0.1%/5mg (Cohort 1) 
0.5%/5mg (Cohort 1 & 
Expansion) 
1.0%/5mg(Cohort 1 & 
Expansion) 
2.5%/5mg (Not tested, but 
available) 
Vehicle 
Yellow iron oxide 
(colour) 
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 
An orange 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 
 


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6.1.2 
SELECTION OF DOSES IN THE STUDY 
 
Azura Ophthalmics is further evaluating the safety, tolerability and effectiveness of AZR-MD-001 
ointment/semi-solid drug, surfactant free, in topical ophthalmic concentrations between 0.1% and 
2.5% based upon positive results from clinical study MGSS1 using a 2.5% selenium disulfide 
concentration, published clinical studies (see the Investigators’ Brochure for more detail) 
demonstrating the safe and effective treatment of seborrheic blepharitis with selenium sulfide 
exposures up to 0.5% twice-daily, pre-clinical safety data with exaggerated dosing up to 2.5% with 
the clinical formulation and the maximum concentration fulfils 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 pharmacist 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 in a concentration range between 0.1% to 2.5% is likely to safely and effectively treat 
MGD with or without associated evaporative dry eye disease. 
 
6.1.3 
DOSING AND ADMINISTRATION 
 
For Cohort 1, the study medication will be self-administered by the patient (or administered by 
a caregiver) at the study site after all procedures have been completed for the run-in and post-
randomization visits. At these visits, each patient will be asked to stay at the site for 30 
minutes after study drug administration. No other dosing will be done in office as the product 
will be dosed in the evening only. 
 
For the Expansion Cohort, the study medication will be self-administered by the patient at the 
study site after all procedures have been completed for the baseline visit only using “Vaseline”. 
At this visit, each patient will be asked to stay at the site for 30 minutes after study drug 
administration.  No other dosing will be done in office as the product will be dosed in the evening 
only. 
 
Patients (or a caregiver) will apply a dose of approximately 5 mg using a dosing aid supplied by 
Azura Ophthalmics. Patients will then use their washed index finger (Cohort 1 and Expansion 
Cohort) or an applicator (Cohort 1 only) to apply the drug to the tarsus of the lower lid of both 


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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 (see the Dosing Instruction Sheet 
for more detail). 
 
During the double-masked treatment period, each patient (or caregiver) must apply 1 application 
of the assigned treatment in the evening to the tarsus of the lower lid of both eyes. 
 
Multi-dose tubes of the masked study medication are each to be used for only 30 days to both 
eyes. The patient should be instructed to place the used tube in the used tube bag after 30 days 
and should return used and unused tubes at the next study visit to the study site. 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 
ACQUISITION AND ACCOUNTABILITY 
 
Whilst patients are dosed at site (i.e., Cohort 1 all visits, and practice dose at the baseline visit 
only of the Expansion Cohort), they will administer their study treatment under medical 
supervision. The date and time of each dose administered in the clinic will be recorded in the 
source documents. The dose of study treatment and study subject identification will be confirmed 
at the time of dosing by a member of the study site staff. 
 
Patients will be instructed on proper instillation and storage of study drug at the end of each 
visit, and will be given written instructions and may also watch an instructional video at the 
baseline visit. The used study drug tubes will be collected at each visit from baseline up to and 
including study exit (along with any unused tubes) to assess dosing and symptom assessment 
compliance. Dosing compliance will be based off of the used and unused tube count. If the subject 
is less than 80% or more than 125% compliant with dosing based on the expected number of used 
tubes, then the subject will be deemed non-compliant and a deviation should be recorded. 
 
6.2.2 
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 at site, 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. 
 
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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 account 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, 
following end of study and drug reconciliation by the site CRA. 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. 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 
 
During the Cohort 1 run-in period, the patients will all be supplied with AZR-MD-001 placebo. 
Patients will be informed that they will receive only placebo during the 2-week run-in period. 
Patients (or a caregiver) will apply approximately 5 mg using a dosing aid supplied by Azura 
Ophthalmics. Patients will use their washed index finger or an applicator (Cohort 1 only) 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. 
During the Expansion Cohort qualification period, the patients will all be supplied with AZR-
MD-001 placebo (“Vaseline”) at the baseline visit (single dose). During the active treatment period, 
patients (or a caregiver) will apply approximately 5 mg 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. 
 
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clinical study will be given dosing instructions, will be observed by site personnel applying study 
placebo at the baseline visit, and will have access to instructional dosing videos. Only patients 
demonstrating compliance with the provided dosing instructions can be enrolled into the clinical 
study. 
 
Following the run-in period in Cohort 1, the patient, investigator, site personnel, 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. The 
AZR-MD-001 vehicle was designed to have the same appearance as the active drug. 
 
Following the qualification period in the Expansion Cohort, 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 6 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 colour between the 
active and placebo 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.  
 
For Cohort 1, patients will be randomized to receive AZR-MD-001 ointment/semi-solid drug (i.e., 
0.1%, 0.5% or 1.0%) or AZR-MD-001 vehicle in a 4:1 treatment allocation ratio. For the 
Expansion Cohort, patients will be randomized to receive AZR-MD-001 ointment/semi-solid drug 
(i.e., 0.5% or 1.0%) or AZR-MD-001 placebo in a 1:1:1 ratio on day 0. 
 
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 for either Cohort 1 or 
the Expansion Cohort. 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 randomization number. 
 
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. 
 
 


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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 worsening signs or symptoms of MGD and/or 
dry eye disease during the course of the study, patients will be provided an appropriate rescue 
regimen by the investigator/treating clinician, and may be exited from the study. 
 
Dosing Hylo-Forte® (or an equivalent product) approximately 5 minutes before study ointment 
has been reported to enhance either the safety or tolerability of AZR-MD-001. 
 
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 
• 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 your site CRA and Azura Ophthalmics, and should be clearly 
documented on the appropriate eCRF. 
 
 


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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 site staff member. 
 
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. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS 
 
8.1.1 
COHORT 1: PRIMARY EFFICACY MEASURES  
 
Primary efficacy measures are divided into endpoints for MGD and endpoints for evaporative dry 
eye (EDE). The primary efficacy measures for MGD are change from baseline to Month 3 in 
meibum gland secretion score (MGS) (0 to 45 scale), change from baseline to Month 3 in the 
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proportion of patients improving on both a gland score (e.g., MGS or MGYLS) and a patient 
reported outcome measure (e.g., OSDI). A patient will be considered to be a meibum quality 
responder at a post-randomization visit if the MGS score in the study eye is > 12, MGYLS 
score > 2, or MGYOLS score > 2. The primary efficacy measures for EDE are change from 
baseline to Month 3 in Tear Break-up Time (TBUT), change from Baseline to Month 3 in OSDI 
measures, change from baseline to Month 3 in eye dryness measured using a visual analogue 
scale (VAS), and 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.  A patient will be considered to be an evaporative DED responder at a post-randomization visit 
if TBUT > 10 seconds, a Schirmer’s test ≥ 10 mm, a Total OSDI < 13, or a SPEED Score < 6, or 
an Average VAS or Worst VAS score decreased by ≥ 5 is observed. 
 
8.1.2 
COHORT 1: SECONDARY EFFICACY MEASURES 
Secondary efficacy measures include the meibum gland secretion score (MGS), the number of 
Meibomian Glands Yielding Liquid Secretion (MGYLS), TBUT, OSDI measures, visual analogue 
scale (VAS), Schirmer’s test without anesthesia, conjunctival redness score, sodium fluorescein 
corneal staining (Oxford scale), and lissamine green conjunctival staining. Refer to Section 1 for 
a complete list and specific timings of additional efficacy measures. 
 
8.1.3 
COHORT 1: DATA REVIEW COMMITTEE (DRC) 
 
 
Safety oversight will be under the direction of a DRC composed of individuals with the appropriate 
expertise (see Section 4.3). Members of the DRC should be independent from the study conduct 
and free of conflict of interest, or measures should be in place to minimize perceived conflict of 
interest. The DRC should meet at least monthly to assess safety and efficacy data on each arm of 
the study. The data of the first Cohort will be reviewed by the DRC prior to proceeding to the 
next dose level. The DRC will operate under the rules of an approved charter that will be written 
and reviewed at the organizational meeting of the DRC. At this time, each data element that the 
DRC needs to assess will be clearly defined. The DRC will provide its input to Azura 
Ophthalmics, the IEC and regulatory authorities as necessary. 
Interim safety and preliminary efficacy evaluations will be performed and reviewed by the DRC 
when the first 10 patients in Cohort 1, Group 3 completes the Month 3 visit (First Interim Analysis) 
and when the last patient enrolled in Cohort 1, Group 4 completes the Month 3 visit (Second 
Interim Analysis). There is no plan to stop the study for efficacy on the basis of the interim 
analyses. However, termination due to futility may occur. Statistical significance will be declared 
at the time of the interim analysis.  
 
 
 


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8.1.4 
EXPANSION COHORT: PRIMARY EFFICACY MEASURES  
 
The primary efficacy sign for MGD is change from baseline in MGYLS. The visit for the 
primary variable is month 3 for the US and month 6 for regions (e.g. EU) where the longer 
follow-up is required. The primary analysis population is mITT. Statistical testing will be 
performed for the AZR-MD-001 group versus placebo group.  
 
The primary efficacy symptom for MGD is change from baseline in Total OSDI. The visit for 
the primary variable is month 3 for the US and month 6 for regions (e.g. EU) where the longer 
follow-up is required. The primary analysis population is mITT. Statistical testing will be 
performed for the AZR-MD-001 group versus placebo group. 
 
8.1.5 
EXPANSION COHORT: SECONDARY EFFICACY MEASURES  
 
Refer to Section 1 for a complete list and specific timings of additional efficacy measures. 
 
Secondary efficacy measures include: 
• 
Change from Baseline to day 14, month 1.5, month 3, month 4.5 and month 6 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 1.5,  and month 4.5 in the number of 
Meibomian Glands Yielding Liquid Secretion (MGYLS) (0 to 15 scale) 
• 
MGYLS (0 to 15 scale) at each visit  
• 
Proportion of patients with a change from baseline in MGYLS score ≥ 5 at each visit 
• 
Change from Baseline to day14, month 1.5, month 3, month 4.5 and month 6 in 
TBUT 
• 
TBUT at each visit 
• 
Proportion of patients with a TBUT score > 5 at each visit 
• 
Change from Baseline to day14, month 1.5, month 3, month 4.5 and month 6 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 day14, month 1.5, month 3, month 4.5 and month 6 in 
average visual analogue scale (VAS) 


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• 
Average VAS at each visit 
• 
Change from Baseline to day14, month 1.5, month 3, month 4.5 and month 6 in 
worst VAS 
• 
Worst VAS at each visit 
• 
Change from Baseline to day 14, month 1.5 and month 4.5 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 
and month 6 
• 
Proportion of patients with a Total OSDI < 13 at each visit 
• 
Number of expressible glands yielding clear meibum at day14, month 1.5, month 3, 
month 4.5 and month 6 
• 
Eyelid margin erythema/telangiectasias at day14, month 1.5, month 3, month 4.5 and 
month 6 
• 
Corneal and conjunctival staining (0 to 5 scale) at each visit 
 
8.1.6 
EXPANSION COHORT: DATA REVIEW COMMITTEE (DRC) 
 
There is no DRC for the Expansion Cohort. 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
 
8.2.1 
SAFETY MEASURES 
 
The following safety measures will be examined: 
 
• adverse events (ocular and nonocular) 
 
• study medication tolerability as measured by the Ocular Comfort Questionnaire (Cohort 1 
only) 
 
• best-corrected visual acuity (BCVA) 
 
• slit-lamp biomicroscopy 
 
• intraocular pressure (IOP) 
 
• ophthalmoscopy 


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• photographic conjunctival hyperemia assessment 
 
• vital signs (pulse rate, blood pressure) 
 
• laboratory tests (chemistry, hematology, urinalysis (excluding creatinine analysis)) (Cohort 
1 only) 
 
• urine pregnancy test 
 
For Cohort 1, laboratory test results will be forwarded from the local laboratory to the study site 
and to Azura Ophthalmics or its designee. The laboratory results from screening should be 
reviewed prior to randomization. Laboratory tests at screening may be repeated once at the 
discretion of the investigator and pending discussion with Azura Ophthalmics Medical 
Monitor, to confirm exclusionary status. Study treatment will be performed only if the 
investigator deems the laboratory results to be acceptable. The most current specimen results 
will be reviewed prior to randomization. The investigator will review all laboratory results for 
the clinical significance of any abnormalities. Evaluation and management of abnormal laboratory 
results should be conducted according to local site practice. Clinically significant abnormalities are 
to be recorded on an adverse event electronic case report form (eCRF) page. 
 
  


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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 
(eCRF). 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 within 24 hours for 
the attention of the product safety scientist at: 


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Syneos Health Safety and Pharmacovigilance fax/email details: 
Attention: Safety & Pharmacovigilance 
Local Toll-Free Fax (Australia): 1800 256 952 
Local Toll-Free Fax (New Zealand): 0800 456 231 
Alternate (Global) Fax: +1 877 464 7787 
Email: SafetyReporting@SyneosHealth.com  
 
For medical emergencies contact: 
Dr Kiran Haridas (Medical Monitor) phone : +91-9945385388  
Dr. Jyoti Puri (back- up Medical Monitor), phone: +91 7303111499 
 
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 Syneos Health (previously named INC Research) will promptly notify all 
relevant investigators and the regulatory authorities of findings that could adversely affect the 
safety of patients, 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, Syneos 
Health, 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 or 
chemicals. 
 
 


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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 patients 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. 
 
Patients 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. 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 treatment assignment for the patient can be determined by designated site personnel accessing 
the IWRS system via password protected access. 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 Syneos Health 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. 
 
 


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8.3.7 
REPORTING OF PREGNANCY 
 
If a female becomes pregnant during the study, the investigator will notify Azura Ophthalmics 
immediately after the pregnancy is confirmed and the patient will be exited from the study after 
appropriate safety follow-up. The investigator will (1) notify the patient’s physician that the patient 
was being treated with an investigational drug, and (2) follow the progress of the pregnancy. The 
investigator must document the outcome of the pregnancy and provide a copy of the 
documentation to Azura Ophthalmics. 
 
 
 


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9 
STATISTICAL CONSIDERATIONS 
 
The statistical analysis plan (SAP) will provide a detailed description of the planned statistical 
analysis. 
 
9.1 
SAMPLE SIZE DETERMINATION 
 
9.1.1 
COHORT 1 
 
The sample size is determined empirically. 
 
9.1.2 
EXPANSION COHORT  
 
Estimates for sample size calculations are from the final Cohort 1 interim analysis from Azura Clinical 
Protocol AZ201801. The mean response of 0.77 and a standard deviation for MGYLS of 2.28 units 
was observed for control and a mean response of 2.77 units and a standard deviation for MGYLS of 
3.35 units was observed for AZR-MD-001 0.5%. A sample size of 45 subjects per group will have 
90% power to detect a difference of 2.0 units between the active treatment group and the placebo 
group using a two-sample t-test at a significance level of 0.05. The standard deviation for Total OSDI 
was 6.31 units for control and 8.34 units for the high dose. A sample size of 58 subjects per group will 
have 90% power to detect a difference of 4.52 units between the active treatment group and the control 
group using a two-sample t-test at a significance level of 0.05. To allow for additional site to site 
variability the sample size per group will be increased to approximately75 patients. 
 
Multiplicity Consideration: To address the multiple primary endpoints defined in this study, the 
primary endpoints have been prioritized into a hierarchical structure. For example, in order to test the 
primary symptom endpoint of Total OSDI, the primary sign endpoint of MGYLS must be statistically 
significantly higher in the AZR-MD-001 treatment group compared to the vehicle treatment group 
using a two-sided significance level of 0.05 for a given concentration. The final order of the endpoints 
will be defined in the Statistical Analysis Plan (SAP) prior to unmasking the study. 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 (Primary efficacy endpoint for the US):  An interim analysis is planned after the final 
enrolled patient completes the month 3 visit. Only an independent biostatistician will be unblinded to 
the treatment patients actually received and only summary efficacy and safety tables will be provided.  
Outcomes from this analysis will assist in the confirmation of the study power calculations and 
potentially as part of a rolling submission to global regulatory agencies.  
 
 
 


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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 
population. In these analyses, non-missing values recorded at visit 3 or later will be used to replace 
missing data at visits where data are not recorded. 
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 member. 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-
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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. 
Cohort 1: Efficacy (MGD): 
 
The primary efficacy variables for MGD are change from baseline to month 3 in MGS, number of 
MGYLS, and the proportion of patients improving on both a gland score (e.g., MGS or MGYLS) 
and a patient reported outcome measure (e.g., OSDI). A patient will be considered to be a meibum 
quality responder at a post-randomization visit if the MGS score in the study eye is > 12, MGYLS 
score > 2, or MGYOLS score > 2. The visit for the primary variable is month 3 and the primary 
analysis population is mITT. Statistical tests will be performed for each AZR-MD- 001 group 
versus vehicle group. Odds ratio along with 95% CI will be obtained by pairwise comparisons of 
the proportion of responders for each AZR-MD- 001 group versus vehicle group using the Logistic 
Regression method stratifying by baseline MGS score for the qualified eye (i.e., < 6 or ≥ 6 and ≤ 
12) and duration of disease (i.e., < 5 years or ≥ 5 years). There will be no alpha adjustment for 
the multiple tests for the pairwise comparisons. 
Cohort 1: Efficacy (Evaporative DED): 
 
The primary efficacy variables for evaporative DED are change from baseline to month 3 in Tear 
Break-up Time (TBUT), OSDI, eye dryness measured using a visual analogue scale (VAS), and 
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. A patient will be 
considered to be an evaporative DED responder at a post-randomization visit if TBUT > 10 
seconds, a Schirmer’s test ≥ 10 mm, a Total OSDI < 13, a SPEED Score < 6, or an Average VAS 
or Worst VAS score decreased by ≥ 5 is observed.  
 
Separate analyses will be performed for each definition of a responder. The visit for the primary 
variable is month 3 and the primary analysis population is mITT. Statistical tests will be performed 
for each AZR-MD-001 group versus vehicle group. Odds ratio along with 95% CI will be 
obtained by pairwise comparisons of the proportion of responders for each AZR-MD- 001 group 
versus vehicle group using the Logistic Regression method stratifying by baseline MGS score for 
the qualified eye (i.e., < 6 or ≥ 6 and ≤ 12) and duration of disease (i.e., < 5 years or ≥ 5 years). 
There will be no alpha adjustment for the multiple tests for the pairwise comparisons. 
Expansion Cohort: Efficacy (MGD): 
 
Co-primary endpoints of change from baseline in signs (MGYLS) and symptoms (Total OSDI) will 
be employed: 
 
• For the US, the primary efficacy sign for MGD is change from baseline to month 3 in 
MGYLS. For regions (e.g. EU) requiring 6 months of efficacy data, the primary efficacy 
variables for MGD is change from baseline to month 6 in MGYLS.  


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• For the US, the primary efficacy symptoms for MGD is change from baseline to month 3 in 
Total OSDI. For regions (e.g. EU) requiring 6 months of efficacy data, the primary efficacy 
variables for MGD is change from baseline to month 6 in Total OSDI.   
 
To address the multiple primary endpoints defined in the Expansion Cohort, the primary endpoints 
have been prioritized into a hierarchical structure.  For example, in order to test the primary symptom 
endpoint of Total OSDI, the primary sign endpoint of MGYLS must be statistically significantly higher 
in the AZR-MD-001 treatment group compared to the placebo treatment group for the same 
concentration (i.e., 0.5% or 1.0%) using a two-sided significance level of 0.05.  The final order of the 
endpoints will be defined in the Statistical Analysis Plan (SAP) prior to unmasking the study. Using 
this strategy, the family-wise Type I error rate will be maintained at the 0.05 significance level for the 
two primary endpoints for each concentration.  
 
Safety (both Cohorts): 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. 
 
9.4.2 
ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
The primary efficacy variables (see Section 8.1) 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/placebo) as factors in the model. 
Pairwise comparisons will be performed for each AZR-MD-001 ointment/semi-solid drug treatment 
group versus vehicle/placebo using t-tests of the least square means from this model. Two-sided 
confidence intervals (95%) will be provided for the differences between treatments. To support 
regions (e.g. EU) requiring 6 months of efficacy data in the Expansion Cohort, the same model will 
be applied at 6 months. 
 
Details of other efficacy analyses will be provided in the statistical analysis plan. 
 
9.4.3 
ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
The secondary efficacy variables (see Section 8.1) 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/placebo) as factors in the model. 
Pairwise comparisons will be performed for each AZR-MD-001 ointment/semi-solid drug treatment 
group versus vehicle/placebo using t-tests of the least square means from this model. Two-sided 
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regions (e.g. EU) requiring 6 months of efficacy data in the Expansion Cohort, the same model will 
be applied at 6 months. 
 
Descriptive statistics (change from baseline variables) will be tabulated for the following within 
treatment group changes in the mITT population: 
 
• Cohort 1: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 
 
Expansion Cohort: 
• Patients in the AZR-MD-001 ointment/semi-solid drug treatment group: changes from 
baseline to days 14, month 1.5, month 3, month 4.5 and month 6 
• Patients in the AZR-MD-001 placebo group: changes from baseline to days 14, month 1.5, 
month 3, month 4.5 and month 6 
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 change from baseline 
in MGYLS score of ≥5; Proportion of patients with a MGYLOS score of >2; Proportion of patients 
with a TBUT > 10 seconds at each visit; Proportion of patients with a Schirmer’s test ≥ 10 mm at 
each visit; Proportion of patients with a Total OSDI < 13 at each visit; and Proportion of patients 
with a SPEED Score < 6; Proportion of patients with an Average VAS or Worst VAS score decreased 
by ≥ 5 at each visit. 
 
Cohort 1: 
• 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. 
 
Expansion Cohort: 
• Patients in the AZR-MD-001 ointment/semi-solid drug treatment group: changes from 
baseline to days 14, month 1.5, month 3, month 4.5 and month 6 
• Patients in the AZR-MD-001 placebo group: changes from baseline to days 14, month 1.5, 
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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 
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 
 
 
Two official interim analyses are planned for Cohort 1 of the study. The first interim analysis is 
planned for after the 10th patient in Cohort 1, Group 3 exits the study. Only data collected up to the 
last patient exiting the study from Cohort 1, Group 3 will be included in the first interim analysis. 
All ongoing patients in Cohort 1 will remain masked until the second interim analysis.  
 
A second interim analysis is planned after the final patient from Cohort 1 exits the study (Cohort 1, 
Group 4). Outcomes from this analysis will assist in the confirmation of the study drug concentration 
and frequency to be used for the Expansion Cohort. 
 
One interim analyses is planned for the Expansion Cohort of the study. The interim analysis is 
planned for after the last enrolled patient completes the month 3 visit. Only data collected up to the 
month 3 visit will be included in the interim analysis.  The primary endpoints for the US will serve 
as an Interim Analyses for the Month 6 primary endpoints.  The sample size may be adjusted for 
power or to address any concerns for alpha inflation. 
 


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A final database lock will occur at the completion of the Expansion Cohort and the safety, 
tolerability, and efficacy data from Cohort 1 and the Expansion Cohort will be analyzed separately 
and in a combined fashion. At the final analysis, statistical significance will be declared for 2-sided 
p-values ≤ 0.05. 
Given the exploratory nature of Cohort 1 no adjustments for multiplicity will be applied across the 
primary or secondary endpoints in this cohort.  Multiplicity will be controlled across the primary 
endpoints in the Expansion Cohort as described in Section 9.4.1. 
 
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 participants, 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 patients 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 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 


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time to consider the study. Participants 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. Participants 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 patients 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 regulatory authorities such as the United States (US) FDA, as well 
as that of any other applicable agency(ies), will be granted direct access to the study patients’ 
original medical records for verification of clinical study procedures and/or data, without 
violating the confidentiality of the patients to the extent permitted by the law and regulations. In 
any presentations of the results of this study or in publications, the patients’ identity will remain 
confidential. 
 
 
 


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11 
QUALITY ASSURANCE 
 
11.1 
AUDIT AND INSPECTION 
 
Study centers and study documentation may be subject to Quality Assurance audit during the 
course of the study by 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 an eCRF. Data collection must be completed for 
each subject who signs an informed consent form (ICF) and is administered study drug. 
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. 
 
 
 


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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 
• 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 
 
All samples will be returned to Azura Ophthalmics or Azura Ophthalmics designee at the 
completion of the study. Azura Ophthalmics shall have full ownership rights to any biological 
specimens/samples derived from the study. 
 
12.2.1.1 
COHORT 1: BLOOD AND URINE SAMPLES 
FOR SAFETY ANALYSIS 
 
Samples of blood (nonfasting) and urine will be evaluated for blood chemistry (Albumin, Blood 
urea nitrogen, Glucose, Alkaline phosphatase, Calcium, Potassium, Alanine aminotransferase, 
Chloride, Sodium, Aspartate aminotransferase, Creatinine, Total bilirubin, Total protein, Whole 
blood selenium), hematology (Hematocrit, Differential count, Red blood cells, Hemoglobin, 
Basophils, White blood cells, Mean corpuscular hemoglobin, Eosinophils, Lymphocytes, 
Monocytes, Neutrophils, Platelet count, Mean corpuscular hemoglobin concentration, Mean 


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corpuscular volume and coagulation (Prothrombin time, International normalized ratio, Partial 
thromboplastin time) at a local clinical laboratory with certification from a recognized 
accreditation agency. Urinalysis (Blood, Glucose, Protein, Ketones) will be performed at site using 
a dipstick test.  Details of sample collection are found in the procedure manual. 
 
12.2.1.2 
TEAR SAMPLES 
 
Details of sample collection and handling are found in the procedure manual. 
 
All samples will be stored at the clinical site until shipment to the bioanalytical laboratory. 
 
12.3 
KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Medical Monitor 
DRC Chair 
Stephanie L Watson, M.D. 
Dr Kiran Haridas MD MBA. 
Patty Delaney 
Sydney Cornea Clinic, 
Syneos Health 
Azura Ophthalmics 
Level 1, Save Sight Institute, 
Campus of Sydney Eye Hospital  
8 Macquarie St Sydney NSW 
2000 Australia 
Syneos Health 
Bangalore 
560076 India 
Level 9, 31 Queen Street 
Melbourne, VIC 300 Australia 
+61 (2) 9389 0666 
+91-9535990731 or 
+91-9945385388 
+1 (860) 460-1981 
stephanie.watson@sydney.edu.au 
kiran.haridas@syneoshealth.com 
patty.delaney@azuraophthalmics.com 
 
 
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 


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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. 
 
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. 


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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 
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 Harmonization 
ICH GCP 
International Conference on Harmonization 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 
Amendment 1, 
Version 2.0 
6/May/18 
Added a top dose of 1.0%, 
allowed 14 days in use, included 
AZR-MD- 001 placebo for the 
run-in period, and allowed for the 
use of an instructional dosing 
video. 
New data on stability, 
tolerability and toxicology with 
the clinical formulation has 
been collected. The 
Investigator’s Brochure, 
Protocol, ICF, and dosing 
instructions are all being 
updated to reflect this new 
information. 
Amendment 2, 
Version 3.0 
14/Jan/19 
Added a top dose of 2.5%, added 
Cohort 1, Group 4, designed all groups 
in Cohort 1 to have a similar design to 
Cohort , Group 1, allowed 30 days in 
use, included an interim analysis, 
clarified that no creatinine analysis is 
part of the Urinalysis test, TBUT and 
MGE to be performed by the same 
investigator for a given patient, screen 
fail patients who are re-enrolled will 
receive a new screening number (not 
reusing the old number), and added 
endpoints for MGD and Evaporative 
DED. 
Clinical data collected in Cohort 1, 
Groups 1 & 2 on 0.1% and 0.5% 
support the safety profile of AZR-
MD-001.  To enable a greater range 
for safety testing 2.5% AZR-MD-
001 was added to the protocol.  The 
remaining changes incorporate 
existing memos to the trial master 
file and informal feedback from 
regulatory agencies on potential 
trial endpoints. 
Amendment 3, 
Version 4.0 
27/Jan/20 
Added a second interim analysis after 
the final patient from Cohort 1 exits the 
study (Cohort 1, Group 4).  
Outcomes from this analysis will 
assist in the confirmation of the 
study drug concentration and 
frequency to be used for the 
Expansion Cohort. 
Amendment 4, 
Version 5.0 
4/Sep/20 
For the Expansion Cohort: Defined the 
dose groups and dosing frequency, 
removed the cap on the OSDI for study 
entry, prospectively defined the 
primary endpoint(s), changed the 
control to AZR-MD-001 placebo, 
removed the run-in on AZR-MD-001 
placebo, allowed for a month 3 interim 
analysis in the Expansion Cohort, 
extended the study to 6 months and 
added a month 4.5 visit.  
Outcomes from the Expansion 
Cohort will serve as the first 
confirmatory study of the safety and 
efficacy of AZR-MD-001. 


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Amendment 5, 
Version 6.0 
19/Mar/21 
Updated based upon outcomes from 
the final Cohort 1 analyses that 
impact power calculations and 
suggest less variability in symptom 
endpoints for a baseline Total OSDI < 
34. 
Outcomes from the Expansion 
Cohort will serve as the first 
confirmatory study of the safety 
and efficacy of AZR-MD-001. 


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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, vol. 
47, 749-752. 
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, May 13, 2009. Available at: 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, and 
pthophysiology of the meibomian glands.  Investigative Ophthalmology and Visual 
Science. 2011;52(4):1938-1978. 


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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. 


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14.3 
STANDARD PATIENT EVALUATION OF EYE DRYNESS 
(SPEED) 
 
 


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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. 
 
 


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15 
SPONSOR APPROVAL(S) 
 
 
 
 
Protocol Title: 
A Multicenter, Vehicle-controlled, Randomized Study to Evaluate 
the Safety, Tolerability, Systemic Pharmacokinetics, and 
Pharmacodynamics of AZR-MD-001 in Patients with Meibomian 
Gland Dysfunction (MGD) and Evaporative Dry Eye Disease (DED) 
Protocol Number: 
AZ201801 
Final Date: 
19 March 2021 
 
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: 
AZR-MD-001 Sterile Ophthalmic Ointment 
 
Statistical Analysis Plan Study AZ201801 Expansion Cohort 
Page 1 of 57 
 
Confidential 
Azura Ophthalmics LTD 
 
 
Statistical Analysis Plan for Three Month Primary Analysis 
 
Sponsor Name:  Azura Ophthalmics 
 
Protocol Number:  AZ201801 Expansion Cohort 
 
Protocol Title:  A Multicenter, Vehicle-controlled, Randomized Study to Evaluate the Safety, 
Tolerability, Systemic Pharmacokinetics, and Pharmacodynamics of AZR-MD-001 in Patients 
with Meibomian Gland Dysfunction (MGD) and Evaporative Dry Eye Disease (DED) 
 
Protocol Version and Date:  Amendment 5, version 6.0 – 19 March 2021  
and All Country-Specific Addenda 
 
Cohort:  Expansion Cohort 
 
 
 
Syneos Health Project Code:  1010854 
 
Authors:  
Yogesh Sable, Principal Statistician, Syneos Health 
  
 
Venita DePuy, Owner, Bowden Analytics 
 
 
Notice of Confidential and Proprietary Information 
The information contained in this document is confidential belonging to Azura Ophthalmics 
LTD.  Acceptance of this document constitutes agreement by the recipient that no information 
contained herein will be published or disclosed without prior written authorization from an 
official of Azura Ophthalmics LTD.  However, this document may be disclosed to appropriate 
Institutional Review Board and Ethics Committees or duly authorized representatives of a 
national regulatory authority, under the condition that they are requested to keep it 
confidential.  In the event of an actual or suspected breach of this obligation, Syneos Health 
should be notified immediately. 
 


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REVISION HISTORY 
Version # 
Date 
(DD-Mmm-YYYY) 
Revision Summary 
Final v1.0 
22-Apr-2022 
Initial Release Version of Expansion Cohort SAP 
 
 


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I confirm that I have reviewed this document and agree with the content. 
Approvals 
Syneos Health Approval 
 
Bowden Analytics Approval 
Azura Ophthalmics Approval 
 


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TABLE OF CONTENTS 
REVISION HISTORY.................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ 4 
LIST OF TABLES .......................................................................................................................... 6 
LIST OF APPENDICES ................................................................................................................. 6 
LIST OF ABBREVIATIONS ......................................................................................................... 7 
1. 
PURPOSE ............................................................................................................................... 9 
1.1. 
Responsibilities ............................................................................................................. 9 
1.2. 
Timings of Analyses ..................................................................................................... 9 
2. 
STUDY OBJECTIVES ......................................................................................................... 10 
2.1. 
Primary Objective ....................................................................................................... 10 
2.2. 
Brief Description ......................................................................................................... 10 
2.3. 
Determination of Sample Size .................................................................................... 11 
2.3.1. 
Initial Determination of Sample Size ................................................................ 11 
2.3.2. 
Sample Size Re-Estimation .............................................................................. 11 
2.4. 
Treatment Assignment and Masking .......................................................................... 12 
2.5. 
Administration of Study Medication .......................................................................... 13 
2.6. 
Study Procedures and Flowchart ................................................................................ 13 
3. 
ENDPOINTS ........................................................................................................................ 16 
3.1. 
Efficacy Endpoints ...................................................................................................... 16 
3.1.1. 
Primary Efficacy Endpoints .............................................................................. 16 
3.1.2. 
Secondary Efficacy Endpoints .......................................................................... 16 
3.1.3. 
Exploratory Efficacy Endpoints ........................................................................ 17 
3.1.3.1. 
Exploratory Efficacy Endpoints Evaluated At Month 3 ......................... 17 
3.1.3.2. 
Exploratory Efficacy Endpoints Evaluated After Completion of 
Safety Follow-up Period ......................................................................... 17 
3.2. 
Safety Endpoints ......................................................................................................... 18 
4. 
ANALYSIS SETS ................................................................................................................ 19 
4.1. 
Intent-to-Treat Analysis Set ........................................................................................ 19 
4.2. 
Modified Intent-to-Treat Analysis Set ........................................................................ 19 
4.3. 
Per-Protocol Analysis Set, Month 3 ........................................................................... 19 
4.4. 
Per-Protocol Analysis Set, Month 6 (PP6) ................................................................. 19 
4.5. 
Pre-Randomization Vaseline Application Set ............................................................ 19 
4.6. 
Safety Set .................................................................................................................... 20 
5. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS .................................................. 20 
5.1. 
General Methods ......................................................................................................... 20 
5.2. 
Key Definitions ........................................................................................................... 23 


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5.2.1. 
Date of First Dose of Study Treatment ............................................................. 23 
5.2.2. 
Baseline Values ................................................................................................. 23 
5.2.3. 
Study Day ......................................................................................................... 24 
5.2.4. 
Change from Baseline to Post Study Medication Visits ................................... 24 
5.2.5. 
Tear Break-up Time .......................................................................................... 24 
5.2.6. 
Ocular Surface Disease Index Total Score and Subscale Scores ...................... 24 
5.2.7. 
Visual Analogue Scale ...................................................................................... 24 
5.2.8. 
Standard Patient Evaluation of Eye Dryness .................................................... 25 
5.2.9. 
Best Corrected Visual Acquity Logarithm of the Minimal Angle of 
Resolution ......................................................................................................... 25 
5.3. 
Missing Data ............................................................................................................... 25 
5.3.1. 
Multiple Imputation .......................................................................................... 26 
5.3.1.1. 
Multiple Imputation for Primary Analysis .............................................. 26 
5.3.1.2. 
Multiple Imputation for Exploratory Analyses ....................................... 27 
5.3.2. 
Last Observation Carried Forward ................................................................... 27 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ............................................ 28 
6.1. 
Patient Disposition and Withdrawals .......................................................................... 28 
6.2. 
Demographic and Other Baseline Characteristics ...................................................... 28 
6.3. 
Medical History .......................................................................................................... 28 
7. 
PROTOCOL DEVIATIONS ................................................................................................ 29 
8. 
EFFICACY ........................................................................................................................... 29 
8.1. 
Primary Efficacy Endpoints and Analysis .................................................................. 30 
8.1.1. 
Primary Efficacy Endpoints .............................................................................. 30 
8.1.2. 
Sensitivity Analyses of Primary Efficacy Endpoints ........................................ 31 
8.1.2.1. 
Last Observation Carried Forward .......................................................... 31 
8.1.2.2. 
Evaluation of Potentially Confounding Medications/Therapies at 
Month 3 ................................................................................................... 31 
8.2. 
Secondary Efficacy Endpoints and Analyses ............................................................. 32 
8.2.1. 
Key Secondary Efficacy Analyses .................................................................... 32 
8.2.2. 
Secondary Efficacy Analyses ........................................................................... 33 
8.3. 
Exploratory Efficacy Analyses ................................................................................... 34 
8.3.1. 
Exploratory Efficacy Analyses Performed at Month 3 ..................................... 34 
8.3.2. 
Exploratory Efficacy Analyses Performed at Month 6 ..................................... 36 
9. 
ANALYSIS OF PHARMACOKINETICS ........................................................................... 38 
10. SAFETY ............................................................................................................................... 38 
10.1. Extent of Exposure and Compliance ........................................................................... 38 
10.2. Adverse Events ........................................................................................................... 39 
10.3. Prior and Concomitant Medication ............................................................................. 40 


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10.4. Laboratory Evaluations ............................................................................................... 41 
10.5. Best-corrected Visual Aacuity; Logarithmic Visual Acuity Chart ............................. 41 
10.6. Vital Signs ................................................................................................................... 41 
10.7. Slit-lamp Biomicroscopy, Including Conjunctival Hyperemia .................................. 42 
10.8. Ophthalmoscopy ......................................................................................................... 42 
10.9. Intraocular Pressure .................................................................................................... 42 
10.10. Meibography/Meiboscopy .......................................................................................... 42 
11. INTERIM ANALYSES ........................................................................................................ 42 
12. CHANGES FROM ANALYSIS PLANNED IN PROTOCOL ............................................ 42 
13. REFERENCE LIST .............................................................................................................. 44 
14. PROGRAMMING CONSIDERATIONS ............................................................................ 44 
14.1. General Considerations ............................................................................................... 45 
14.2. Table and Listing Formatting...................................................................................... 45 
14.2.1. 
General .............................................................................................................. 45 
14.2.2. 
Headers ............................................................................................................. 45 
14.2.3. 
Display Titles .................................................................................................... 46 
14.2.4. 
Body of the Data Display .................................................................................. 46 
14.2.4.1. 
General Conventions ............................................................................... 46 
14.2.4.2. 
Table Conventions .................................................................................. 46 
14.2.4.3. 
Listing Conventions ................................................................................ 47 
14.2.5. 
Footnotes ........................................................................................................... 47 
15. APPENDICES ...................................................................................................................... 48 
 
LIST OF TABLES 
Table 1 
Integrated Analyses Change from Baseline to Month 3 ................................... 11 
Table 2 
Schedule of Activities ....................................................................................... 14 
Table 3 
Mapping of Unscheduled and Early Termination Visits .................................. 21 
Table 4 
Reporting Precision ........................................................................................... 23 
 
LIST OF APPENDICES 
Appendix 1 
Visual Analogue Scale (VAS) ................................................................ 48 
Appendix 2 
Ocular Surface Disease Index (OSDI) .................................................... 49 
Appendix 3 
Standard Patient Evaluation of Eye Dryness (SPEED) Questionnaire ... 50 
Appendix 4 
List of Tables and Listings Produced at the 3 Month Analysis .............. 51 


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Appendix 5 
List of Tables and Listings Produced at the end of the Safety 
Follow-up Period ........................................................................................................ 55 
 
LIST OF ABBREVIATIONS 
Abbreviation 
Description 
ANCOVA 
analysis of covariance 
ATC 
anatomical therapeutic chemical 
BCVA 
best-corrected visual acuity 
CMH 
cochran-mantel-haenszel 
CRF 
case report form 
DED 
dry eye disease 
eCRF 
electronic case report forms 
ET 
early termination 
IOP 
intraocular pressure 
ITT 
intent-to-treat 
IWRS 
interactive web response system 
LogMAR 
logarithm of the minimal angle of resolution 
LOCF 
last observation carried forward 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGD 
meibomian gland dysfunction 
MGS 
meibomian gland score  
MGYLS 
meibomian glands yielding liquid secretion 
MGYOLS 
meibomian glands yielding optimal liquid secretion 
MI 
multiple imputation 
mITT 
modified intent-to-treat 
OSDI 
Ocular Surface Disease Index 
PP 
Per-Protocol 
PP6 
Per-Protocol Analysis Set, Month 6 
PT 
Preferred Term 
SAE 
serious adverse events 
SAP 
Statistical Analysis Plan 


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Abbreviation 
Description 
SOC 
System Organ Class 
SPEED 
Standard Patient Evaluation of Eye Dryness questionnaire  
TBUT 
tear break-up time 
TEAE 
treatment-emergent adverse event 
WHODRUG 
World Health Organization Drug Dictionary 
VAS 
visual analogue scale 
 


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1. PURPOSE 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings and summary 
tables which will be produced, and the statistical methodologies that will be used, are complete 
and appropriate to allow valid conclusions regarding the study objectives described under Azura 
Ophthalmics Protocol AZ201801 titled “A Multicenter, Vehicle-controlled, Randomized Study 
to Evaluate the Safety, Tolerability, Systemic Pharmacokinetics, and Pharmacodynamics of 
AZR-MD-001 in Patients with Meibomian Gland Dysfunction (MGD) and Evaporative Dry Eye 
Disease (DED)”, Version Amendment 5, 6.0 dated 19 March 2021 and all country-specific 
addenda.  This SAP supports the analyses for health authorities that will accept the Month 3 
timepoint for the primary efficacy endpoint. 
In accordance with the US FDA pre-IND meeting minutes (Question 19), this SAP is only for the 
Expansion Cohort; a separate AZ201801 SAP covers Cohort 1.  No analyses of the combined 
cohorts are planned. 
1.1. 
Responsibilities 
Syneos Health will perform the statistical analyses and are responsible for the production and 
quality control of all tables and listings consistent with a Phase 3 confirmatory study. 
1.2. 
Timings of Analyses 
The primary analysis for the AZ201801 Expansion Cohort will occur after the final enrolled 
patient completes the Month 3 visit.  All patients will be followed for safety for an additional 
3 months.  The analysis of data collected during this additional safety follow-up, including 
supplemental safety analyses and exploratory efficacy analyses, is covered by this SAP. 
Prior to the 3 month database freeze and subsequent unmasking of specific study team members, 
the data for the primary efficacy endpoints (changes from baseline to Month 3 in meibomian 
glands yielding liquid secretion [MGYLS] and Ocular Surface Disease Index [OSDI] total score) 
will be evaluated in a masked fashion, in order to re-open enrollment to additional patients if the 
variability is higher than expected, as described in Section 2.3. 
If additional patients are enrolled, the 3-month database freeze, unmasking of specific study team 
members, and analyses will be conducted after the last of those additional patients completes the 
Month 3 visit. 
The unmasking of specific study team members following the Month 3 database freeze is 
documented in the AZ201801 Expansion Cohort Unmasked Data Access Plan, which details 
how a specific group of individuals will be unmasked in order to perform the Month 3 analyses, 
while the study execution team will remain masked to treatments until all patients have 


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completed Month 6.  All data collected through Month 3 will be cleaned prior to freezing the 
database.  All data collected through Month 6 will be cleaned prior to database lock and 
unmasking of the rest of the study team.   
The primary safety analysis will be performed after all patients have either completed the 
Month 3 visit or discontinued from the study.  An additional 3-month safety follow-up (including 
Month 4.5 and Month 6 visits) will be conducted, and supplemental safety results will be 
produced after the completion of the Month 6 visits (study completion).  Exploratory efficacy 
analyses, utilizing efficacy data collected during the safety follow-up period, will also be 
performed after the completion of the Month 6 visits. 
2. STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective is to evaluate the safety and efficacy of 2 different concentrations of 
AZR-MD-001 ointment/semi-solid drug applied to the lower lid twice-weekly for up to 
6 months, as compared to placebo, in patients with MGD. 
2.2. 
Brief Description 
The study is a multi-center, double-masked, placebo-controlled, randomized, parallel group 
study carried out in 2 sequential cohorts.  The Expansion Cohort includes parallel doses of 
2 concentrations of AZR-MD-001 ointment/semi-solid drug (0.5% and 1.0%) and placebo, dosed 
twice-weekly in the evening.  Patients are to be followed for 6 months.  Primary efficacy 
analyses will be performed based on the 3-month data, and exploratory efficacy analyses will be 
performed on data collected during the subsequent 3-month safety follow-up. 
Inclusion and exclusion criteria are provided in AZ201801 Protocol Sections 5.1 and Section 5.2.   
Key inclusion criteria require patients have meibomian gland secretion (MGS) scores of ≤12 in 
both eyes at the Screening and Baseline visits; reported dry eye signs and symptoms within the 
past 3 months; Standard Patient Evaluation of Eye Dryness questionnaire (SPEED) score ≥6; 
OSDI questionnaire total score ≥13 and <34; and tear break-up time (TBUT) <10 seconds in 
both eyes.   
Exclusion criteria include best corrected visual acuity (BCVA) worse than 20/40 in either eye; 
anticipated contact lens use; Schirmer’s tear test without anesthesia ≤5 mm in either eye at the 
baseline visit; or corneal staining ≥3 (between 33 and 100 dots) using the Oxford Scheme. 


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2.3. 
Determination of Sample Size 
2.3.1. 
Initial Determination of Sample Size 
Estimates for Expansion Cohort sample size calculations are from the integrated analysis of 
AZ201801 Cohort 1, AZ202001, SOVS2019-070, and SOVS2020-080, limited to the mITT 
Analyzable population (refer to the integrated Clinical Study Report).  The means and standard 
deviations of the changes from baseline at Month 3, after applying last observation carried 
forward (LOCF) imputation, are utilized (Table 1). 
Table 1 
Integrated Analyses Change from Baseline to Month 3 
 
AZR-MD-001 0.5% 
Mean (SD) 
AZR-MD-001 1.0%  
Mean (SD) 
Placebo  
Mean (SD) 
MGYLS 
2.77 (3.35) 
3.79 (4.11) 
0.77 (2.28) 
OSDI 
-8.36 (9.06) 
-5.33 (8.39) 
-0.81 (6.31) 
Abbreviations:  MGYLS = meibomian glands yielding liquid secretion; OSDI = Ocular Surface Disease Index; 
SD = standard deviation. 
 
The study was designed to have 95% power to detect treatment differences between 
AZR-MD-001 0.5% and placebo, and between AZR-MD-001 1.0% and placebo, which requires 
72 patients per treatment arm.  To allow for additional site-to-site variability, the sample size per 
group was increased to 75 randomized patients per arm.  
The total number of randomized patients for the Expansion Cohort will be approximately 
225 (75× 3).  Approximately 112 patients should have a baseline MGS score of <6 and 
approximately 112 patients should have a baseline MGS score ≥6 and ≤12.  Based upon data 
from the LipiFlow® development program, a screen failure rate of ~ 40% is expected.  Thus, 
~315 patients will need to be screened to achieve ~225 patients randomized to treatment.  
2.3.2. 
Sample Size Re-Estimation 
As described in Section 1.2, additional patients may be enrolled if the observed variability within 
the Expansion Cohort is higher than anticipated, after the evaluation of the MGYLS and OSDI 
total score changes from baseline to Month 3 using LOCF imputation.  The standard deviation of 
the pooled treatment groups will be calculated in a masked fashion for both MGYLS and OSDI 
total score and compared to the pooled standard deviations of 3.63 (MGYLS) and 8.71 (OSDI) 
from the integrated study.  No unmasking will be performed as part of this re-estimation. 
The power calculations from the integrated studies will be re-derived based on pooled standard 
deviations (resulting in 0.918 for the MGYLS comparison of AZR-MD-001 0.5% to placebo, 
and >0.999 for the other comparisons), for the sole purpose of providing a basis for comparison 
to the power re-calculations based on the pooled standard deviations from the Expansion Cohort.  


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Patients may be added up to the specified numbers, to maintain the current power of the study, if 
possible.  For example: 
• If the pooled standard deviation is 3.64-3.85 for MGYLS or 8.72-9.64 for OSDI total 
score, up to 30 additional patients may be randomized (10 per treatment arm).   
• If the pooled standard deviation is 3.86-4.07 for MGYLS or 9.65-10.20 for OSDI total 
score, up to 60 additional patients may be randomized (20 per treatment arm).   
• If the pooled standard deviation is 4.08-4.29 for MGYLS or 10.21-10.74 for OSDI total 
score, up to 90 additional patients may be randomized (30 per treatment arm).   
The specific sample sizes needed will be recalculated using the initial mean changes from 
baseline from the integrated studies, in conjunction with the pooled standard deviations from the 
Expansion Cohort, using the following pseudocode: 
proc power; 
  twosamplemeans test=diff dist=normal groupmeans=(2.77 0.77)    
  stddev=xxx sides=2 power=.918 npergroup=.; 
  run; 
proc power; 
  twosamplemeans test=diff dist=normal groupmeans=(3.79 0.77)   
  stddev=xxx sides=2 power=.999 npergroup=.; 
  run; 
proc power; 
twosamplemeans test=diff dist=normal groupmeans=(-8.36 -0.81)    
stddev=xxx   sides=2 power=.999 npergroup=.; 
  run; 
proc power; 
  twosamplemeans test=diff dist=normal groupmeans=(-5.33 -0.81)    
  stddev=xxx sides=2 power=.999 npergroup=.; 
  run; 
 
If additional patients are added, the database freeze and unmasking of specific team members 
will be postponed until after those patients complete their Month 3 visit. 
2.4. 
Treatment Assignment and Masking 
At the Baseline visit, patients meeting all study criteria will be stratified by disease duration 
(<5 or 5+ years) and baseline MGS score in the study eye (<6 or 6-≤12).  Patients will be 
randomized in a 1:1:1 ratio, within each of the 4 strata, to AZR-MD-001 0.5%, AZR-MD-001 
1.0%, or placebo.  The interactive web response system (IWRS) system will provide both a 
patient randomization number and study kit number to use for that patient. 
Patients will be dispensed Vaseline (in a separate kit from study kit, and identified by a Vaseline 
kit number), and will administer it while onsite during the Baseline visit.  Patients demonstrating 
the ability to correctly apply the ointment will be randomized and subsequently dispensed the 


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study kit (AZR-MD-001 0.5%, AZR-MD-001 1.0%, or placebo), to be administered twice 
weekly at home.  All study kit medication will be provided in identical tubes and cartons to 
maintain masking of the study.  The placebo packaging was designed to have the same 
appearance as the AZR-MD-001 treatment. 
Upon database freeze, a designated team (as described in the AZ201801 Expansion Cohort 
Unmasked Data Access Plan) will be unmasked in order to conduct the Month 3 analyses, and 
those team members will not participate in study execution after unmasking.  The remainder of 
the study personnel will be unmasked after all patients have completed Month 6, and the 
database has been locked. 
2.5. 
Administration of Study Medication 
Vaseline will be administered while at the study site, during the Baseline visit. 
Subsequently, patients (or a caregiver) will apply a dose of approximately 5 mg for each 
application of the randomized study treatment, applied twice weekly in the evenings as described 
in AZ201801 Protocol Section 6.1.3. 
Multi-dose tubes of the masked study medication are each to be used for only 30 days for both 
eyes.  The number of used tubes, unused returned tubes, and unreturned tubes will be recorded at 
subsequent visits.   
2.6. 
Study Procedures and Flowchart 
Table 2 provides the schedule of activities. 


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Table 2 
Schedule of Activities 
Study Period 
Qualification 
Double-Masked Period 
Three Month Efficacy Evaluation 
Safety Follow-Up 
 
Screening a  
(Day -14) 
Baseline 
Day 0 
Randomization 
Day 14 
Month 1.5 
Month 3 
Month 4.5 
Month 6 
Visit Window 
± 2 Days 
N/A 
± 2 Days 
± 7 Days 
± 2 Days 
± 7 Days 
± 2 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) 
X 
X 
 
 
X 
 
X 
Pregnancy test (urine) for female patients b 
X 
 
 
 
 
 
 
Patient Ocular Symptoms (VAS) 
X 
X 
X 
X 
X 
X 
X 
OSDI 
X 
X 
X 
X 
X 
X 
X 
SPEED 
X 
X 
X 
X 
X 
X 
X 
BCVA 
XC 
X 
X 
X 
X 
X 
X 
Slit-lamp biomicroscopy (includes eyelid margin 
erythema/telangiectasias) 
X 
X 
X 
X 
X 
X 
X 
TBUTd 
X 
X 
X 
X 
X 
X 
X 
Sodium fluorescein corneal staining, Oxford 
scale 
X 
X 
X 
X 
X 
X 
X 
Lissamine green conjunctival staining, Oxford 
scale 
X 
X 
X 
X 
X 
X 
X 


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Study Period 
Qualification 
Double-Masked Period 
Three Month Efficacy Evaluation 
Safety Follow-Up 
 
Screening a  
(Day -14) 
Baseline 
Day 0 
Randomization 
Day 14 
Month 1.5 
Month 3 
Month 4.5 
Month 6 
Visit Window 
± 2 Days 
N/A 
± 2 Days 
± 7 Days 
± 2 Days 
± 7 Days 
± 2 Days 
MGEd 
X 
X 
X 
X 
X 
X 
X 
Schirmer without anesthesia 
X 
X 
 
 
X 
 
X 
IOP 
X 
 
 
 
X 
 
X 
Ophthalmoscopy exam e 
X 
 
 
 
X 
 
X 
Meibography 
X 
 
 
 
X 
 
X 
Adverse events/medications/procedures 
X 
X 
X 
X 
X 
X 
X 
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 
 
X 
 
 
 
 
 
Abbreviations:  BCVA = best-corrected visual acuity; DED = dry eye disease; IOP = intraocular pressure; MGD = meibomian gland dysfunction; 
MGE = meibomian gland evaluation; OSDI = ocular surface disease index; SPEED = standard patient evaluation of eye dryness; TBUT = tear break-up time; 
VAS = visual analogue scale. 
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 DED.  Patients should wash out from all medication 
listed in the inclusion/exclusion criteria.  Patients who are re-enrolled following an initial screen failure will receive a new screening number. 
b For females of childbearing potential. 
c Manifest refraction performed at screening will be used at each visit to obtain BCVA. 
d TBUT and MGE should be performed by the same individual for a given patient.  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.  
e Ophthalmoscopy examination will be dilated at screening and undilated for study exit unless dilation is necessary. 


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3. ENDPOINTS 
3.1. 
Efficacy Endpoints 
3.1.1. 
Primary Efficacy Endpoints 
Primary efficacy measures are divided into endpoints for primary efficacy signs and primary 
efficacy symptoms for MGD. 
• The primary efficacy sign for MGD is the Change from Baseline at Month 3 in MGYLS 
(0 to 15 scale; higher scores are better). 
• The primary efficacy symptom for MGD is the Change from Baseline at Month 3 in 
OSDI total score (0 to 100 scale; lower scores are better). 
3.1.2. 
Secondary Efficacy Endpoints 
The key secondary efficacy endpoints include: 
• MGYLS 
o Proportion of patients with a change from baseline in MGYLS score ≥5 at Day 14, 
Month 1.5, and Month 3 
• OSDI 
o Proportion of patients with OSDI total score < 13 at Day 14, Month 1.5, and Month 3. 
• SPEED 
o Change from Baseline at Day 14, Month 1.5, and Month 3 in SPEED. 
• Eye Dryness Visual Analogue Scale (VAS) 
o Change from Baseline at Day 14, Month 1.5, and Month 3 for Eye Dryness VAS. 
The secondary efficacy endpoints include: 
• MGS (0 to 45 scale; higher scores are better) 
o Change from Baseline at Day 14, Month 1.5, and Month 3 in MGS. 
o Proportion of patients with MGS score >12 at Day 14, Month 1.5, and Month 3. 
• MGYLS 
o Change from Baseline at Day 14 and Month 1.5 in MGYLS 
• OSDI 
o Change from Baseline at Day 14 and Month 1.5 in OSDI total score. 


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3.1.3. 
Exploratory Efficacy Endpoints 
3.1.3.1. 
Exploratory Efficacy Endpoints Evaluated At Month 3 
• MGYLS 
o Proportion of patients with MGYLS >2 at Day 14, Month 1.5, and Month 3. 
• Meibomian Glands Yielding Optimal Liquid Secretion (MGYOLS, e.g., number of 
expressible glands yielding clear meibum) 
o Change from Baseline at Day 14, Month 1.5, and Month 3 in MGYOLS. 
o Proportion of patients with MGYOLS score >2 at Day 14, Month 1.5, and Month 3. 
• OSDI total score and subscales 
o Proportion of patients with OSDI total score Decrease from Baseline >4.5 at Month 3 
(4.5 is the minimally important clinical difference for early to moderate disease). 
o Change from Baseline at Day 14, Month 1.5, and Month 3 in OSDI subscales 
• SPEED 
o Proportion of patients with SPEED <6 at Day 14, Month 1.5, and Month 3  
• TBUT 
o Change from Baseline at Day 14, Month 1.5, and Month 3 in TBUT. 
o Proportion of patients with TBUT score >5 at Day 14, Month 1.5, and Month 3. 
o Proportion of patients with TBUT score >10 at Day 14, Month 1.5, and Month 3. 
• Schirmer’s Test without Anesthesia 
o Change from Baseline at Day 14, Month 1.5, and Month 3 in Schirmer’s test. 
o Proportion of patients with Schirmer’s test result ≥10mm at Day 14, Month 1.5, and 
Month 3. 
• VAS 
o Change from Baseline at Day 14, Month 1.5, and Month 3 in individual VAS results 
(besides eye dryness), Average VAS, and Worst VAS, separately. 
o Proportion of patients with score decreased by ≥5, separately for Average VAS and 
Worst VAS, at Day 14, Month 1.5, and Month 3. 
• Other 
o Eyelid margin erythema/telangiectasias at Day 14, Month 1.5, and Month 3. 
o Corneal and conjunctival staining (0 to 5 scale) at Day 14, Month 1.5, and Month 3. 
3.1.3.2. 
Exploratory Efficacy Endpoints Evaluated After Completion of Safety Follow-up 
Period 
• MGYLS 
o Change from Baseline at Month 4.5 and Month 6 in MGYLS. 
o Proportion of patients with a change from baseline in MGYLS score ≥5 at Month 4.5 
and Month 6. 
o Proportion of patients with MGYLS > 2 at Month 4.5 and Month 6. 


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• OSDI total score and subscales 
o Change from Baseline at Month 4.5 and Month 6 in OSDI total score 
o Proportion of patients with OSDI total score < 13 at Month 4.5 and Month 6 
o Proportion of patients with OSDI total score Decrease from Baseline >4.5 at Month 6. 
o Change from Baseline at Month 4.5 and Month 6 in OSDI subscales. 
• SPEED 
o Change from Baseline at Month 4.5 and Month 6 in SPEED 
o Proportion of patients with SPEED <6 at Month 4.5 and Month 6 
• VAS 
o Change from Baseline at Month 4.5 and Month 6 in individual VAS results, Average 
VAS, and Worst VAS, separately. 
o Proportion of patients with score decreased by ≥5, separately for Average VAS and 
Worst VAS, at Month 4.5 and Month 6. 
• MGS 
o Change from Baseline at Month 4.5 and Month 6 in MGS. 
o Proportion of patients with MGS score >12 at Month 4.5 and Month 6. 
• MGYOLS 
o Change from Baseline at Month 4.5 and Month 6 in MGYOLS. 
o Proportion of patients with MGYOLS score >2 at Month 4.5 and Month 6. 
• TBUT 
o Change from Baseline at Month 4.5 and Month 6 in TBUT. 
o Proportion of patients with TBUT score >5 at Month 4.5 and Month 6. 
o Proportion of patients with TBUT score >10 at Month 4.5 and Month 6. 
• Schirmer’s Test without Anesthesia 
o Change from Baseline at Month 4.5 and Month 6 in Schirmer’s test. 
o Proportion of patients with Schirmer’s test result ≥ 10mm at Month 4.5 and Month 6. 
• Other 
o Eyelid margin erythema/telangiectasias at Month 4.5 and Month 6. 
o Corneal and conjunctival staining (0 to 5 scale) at Month 4.5 and Month 6. 
3.2. 
Safety Endpoints 
Safety endpoints will be evaluated through Month 3, and supplemental safety analyses (including 
information collected through Month 6) will be evaluated at the end of the safety follow-up 
period.  Safety endpoints include: 
• Adverse events 
• Vital signs 
• BCVA (Logarithmic visual acuity chart) 
• Biomicroscopy (Slit Lamp) 


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• Ophthalmoscopy 
• Intraocular pressure (IOP)  
• Conjunctival hyperemia (redness)  
4. ANALYSIS SETS 
4.1. 
Intent-to-Treat Analysis Set  
The Intent-to-Treat (ITT) Set will include all patients who were randomized.  Patients will be 
analyzed according to treatment as randomized.  The ITT Set will be used for analyses of 
efficacy data. 
4.2. 
Modified Intent-to-Treat Analysis Set 
The Modified Intent-to-Treat (mITT) Set will be comprised of all randomized patients who meet 
inclusion/exclusion criteria, have MGS values at randomization, have baseline OSDI <34, and 
received 1 or more applications of randomized study treatment.  All patients in the mITT Set will 
be analyzed by the treatment as randomized.  This population will be used for primary efficacy 
analyses. 
4.3. 
Per-Protocol Analysis Set, Month 3 
The Per-Protocol (PP) Set will be comprised of all mITT patients who do not have a Grade 4 or 
Grade 5 protocol deviation impacting Baseline through Month 3 (as per Section 7).  Deviations 
which end before the Baseline visit date or begin after the Month 3 visit will not impact inclusion 
in the PP Set.  All patients in the PP Set will be analyzed by the treatment as randomized.  The 
PP Set will be used for primary efficacy analyses. 
4.4. 
Per-Protocol Analysis Set, Month 6 (PP6) 
The Per-Protocol Analysis Set, Month 6 (PP6) will be comprised of all mITT patients who do 
not have a Grade 4 or Grade 5 protocol deviation impacting Baseline through Month 6 (as per 
Section 7).  Deviations which end before the Baseline visit date will not impact inclusion in the 
PP6 Set.  All patients in the PP6 Set will be analyzed by the treatment as randomized.  The PP6 
Set will be used for exploratory efficacy analyses. 
4.5. 
Pre-Randomization Vaseline Application Set  
The pre-randomization Vaseline Application Set will include all patients who were applied 
Vaseline during the Baseline visit, prior to randomization.  This set will be used for summaries 
of any adverse events due to Vaseline application at the Baseline visit. 


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Vaseline administration is documented by a positive response to the question, ‘Did the patient 
apply the ointment over the full lower eyelid length (nasal to temporal)?’ on the Physician 
Observation of Drug Application electronic case report form (eCRF), or, for negative responses 
to that question, a non-zero response to the subsequent question, ‘If not, to what percentage of 
the lower lid margin was the ointment applied?’.   
4.6. 
Safety Set  
The Safety Set will include all patients who were administered at least one dose of randomized 
study medication.  Patients will be analyzed according to treatment received.  The Safety Set will 
be used for all analyses of safety data. 
5. GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
5.1. 
General Methods 
All analyses and summaries will be produced using SAS® version 9.4 (or higher).  Data will be 
summarized descriptively by treatment group. 
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 covariance (ANCOVA) techniques.  Categorical variables will be summarized by sample size 
(N), frequency count, and percent, and will be analyzed using Cochran-Mantel-Haenszel (CMH) 
to evaluate the difference between treatments, controlling for disease duration category and 
baseline MGS score category.  If CMH comparisons are not estimable, Pearson’s chi-square test 
or Fisher’s exact test (if the expected cell count is <5 in 25% or more of the cells) will be used.  
For analysis purposes, assessments at unscheduled visits will be mapped to the nearest 
scheduled visit (e.g., analysis visit), using the following approach, as summarized in Table 3.  
All unscheduled visits prior to the Baseline visit date, or in patients who have not had a Baseline 
visit, will be mapped to the Screening visit. 
For assessments scheduled for every study visit:  Study visits are scheduled to occur at 14, 42, 
84, 126, and 168 days after the Baseline visit for the Day 14, Month 1.5, Month 3, Month 4.5, 
and Month 6 visits respectively.  Therefore, the numbers of days between those visits, not 
counting the actual visit days, are 13, 27, 41, 41, and 41.  Dividing those periods in half and 
rounding down, the windows around visits should extend to 6, 13, 20, 20, and 20 days after the 
scheduled visit day.  The next window should start the day after the prior window ends, resulting 
in the following windows:  
• Baseline visit date through Baseline visit date + 6:  mapped to Baseline visit. 
• Baseline visit date + 7 through Baseline visit date + 26:  mapped to Day 14 visit. 


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• Baseline visit date + 27 through Baseline visit date + 61:  mapped to Month 1.5 visit. 
• Baseline visit date + 62 through Baseline visit date + 103:  mapped to Month 3 visit. 
• Baseline visit date + 104 through Baseline visit date + 145:  mapped to Month 4.5 visit. 
• Baseline visit date + 146 or later:  mapped to Month 6 visit. 
For assessments not scheduled at every study visit:  The same approach will be used, omitting 
the visits without planned assessments from the algorithm.  For example, vital signs and 
Schirmer’s assessment are planned for Baseline, Month 3, and Month 6 visits.  The numbers of 
days between those visits are 83 in both cases, resulting in the first 41 days of the period being 
assigned to the earlier visit.  Therefore: 
• Baseline visit date through the Baseline visit date + 41 would be assigned to the Baseline 
visit;  
• Baseline visit date + 42 through Baseline visit date + 125 would be assigned to the 
Month 3 visit, and  
• Baseline visit date + 126 or later to the Month 3 visit. 
In cases where an assessment is not scheduled to be performed at the Baseline visit, but is 
scheduled only at the Screening visit, Month 3, and Month 6, (such as IOP, meibography, or 
ophthalmology), visits prior to and including the Baseline visit will be windowed to the 
Screening visit, and visits between the Baseline and Month 3 visits will be windowed to 
Month 3.  Visits between Month 3 and Month 6 will be split as described above. 
Assessments conducted at the time of early termination (defined as assessments performed on 
the date of early termination or recorded on the same date as an End of Study visit is entered in 
the subject visit case report form [CRF] page) will also be mapped to the nearest planned visit, as 
described for unscheduled visits. 
Table 3 
Mapping of Unscheduled and Early Termination Visits 
Visit 
Date with 
Regards to 
Baseline Visit 
Study 
Day 
Analysis Visit Mapping 
Assessments 
Performed Each Visit 
Assessments 
Performed at 
Screening, Baseline, 
Month 3, and Month 6 
Assessments 
Performed at 
Screening, Month 3, 
and Month 6 
Screening 
Baseline -14 d 
-14 
Screening 
Screening 
Screening 
Baseline 
Baseline 
1 
Baseline 
Baseline 
… 
… 
Month 3 
Baseline + 6 d 
7 
Baseline + 7 d 
8 
Day 14 
… 
… 
Day 14 
Baseline + 14 d 
15 


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Visit 
Date with 
Regards to 
Baseline Visit 
Study 
Day 
Analysis Visit Mapping 
Assessments 
Performed Each Visit 
Assessments 
Performed at 
Screening, Baseline, 
Month 3, and Month 6 
Assessments 
Performed at 
Screening, Month 3, 
and Month 6 
… 
… 
Baseline + 26 d 
27 
Baseline + 27 d 
28 
Month 1.5 
… 
… 
Baseline + 41 d 
42 
Month 1.5 
Baseline + 42 d 
43 
Month 3 
… 
… 
Baseline+61 d 
62 
Baseline+62 d 
63 
Month 3 
… 
… 
Month 3 
Baseline + 84 d 
85 
… 
… 
Baseline+103 d 
104 
Baseline+104 d 
105 
Month 4.5 
… 
… 
Baseline+125 d 
126 
Month 4.5 
Baseline+126 d 
127 
Month 6 
Month 6 
… 
… 
Baseline+145 d 
146 
Baseline+146 d 
147 
Month 6 
… 
… 
Month 6 
Baseline + 168 d 
169 
 
… 
… 
End of Study 
Abbreviations:  d = day(s). 
Note:  Ellipses indicate all dates between the prior and subsequent lines. 
 
If multiple assessments are mapped to the same analysis visit (such as the scheduled visit and 
1+ unscheduled visits), the following approach will be used: 
• If only 1 non-missing result is present, that result will be used for summaries and 
analyses. 
• If >1 non-missing result is present, the result collected later (chronologically) will be 
used for summaries and analyses. 


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All relevant patient data will be included in the listings.  All information entered into the 
database will be included in patient data listings, including data not used for analysis purposes.  
Data will be listed by the nominal time point collected (whether a scheduled visit or unscheduled 
visit).  Listings will display treatment as randomized.  In the event that actual treatment differs 
from treatment as randomized, a footnote will be added to listings as appropriate, to provide 
specific information. 
Summary statistics will be presented to the degree of precision provided in Table 4. 
Table 4 
Reporting Precision 
Statistics 
Degree of Precision 
Mean, Median, Quartiles, Confidence intervals 
One more decimal place than the raw data 
Standard deviation (SD), Standard error (SE) 
Two more decimal places than the raw data 
Minimum, Maximum 
The same number of decimal places as the raw data 
p-value 
Rounded to 4 decimal places and formatted as 0.xxxx; 
values smaller than 0.0001 as ‘<0.0001’ 
Percent 
One decimal place 
 
All fractional numeric values will be presented with a zero to the left of the decimal point (for 
example, 0.12-0.30, not .12-.30). 
5.2. 
Key Definitions 
5.2.1. 
Date of First Dose of Study Treatment 
The date of first dose of study treatment will be the date of the Baseline visit, at which the 
randomized study treatment is dispensed.  Patients are to be instructed to apply the first dose at 
home that evening.  Patients who do not have confirmation of study treatment administration 
(defined as non-zero number of doses taken, on a study drug compliance eCRF at the Month 1.5 
visit) will not have a date of first dose defined.  If a patient takes zero doses before the Month 1.5 
visit but does take subsequent doses, the date of first dose will reflect the date of dispensation of 
the first study treatment applied. 
5.2.2. 
Baseline Values 
The baseline assessment will be the last available measurement taken on or before the date of 
first dose of study treatment, including any assessments at unscheduled visits.  Measurements 
taken on the date of first dose of study treatment will be considered to be taken prior to first dose.  
Baseline values are typically collected at the Baseline visit. 


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5.2.3. 
Study Day 
Study day is calculated as (date - first dose date of study medication +1) for dates on or after first 
dose, and (date - first dose date) for dates before the first dose date.  Therefore, the first dose date 
is Study Day 1, and the day immediately prior is Study Day -1.  The first dose date of study 
medication will be based on the application of Vaseline while onsite during the Baseline visit.  
The first application of randomized study medication is expected to be applied that evening. 
5.2.4. 
Change from Baseline to Post Study Medication Visits 
Change from Baseline is (value - baseline value) and is calculated for subjects with both 
non-missing baseline values and non-missing post-baseline values. 
5.2.5. 
Tear Break-up Time 
The TBUT for a patient is calculated as average of 3 separate measurements for each eye 
separately.  
5.2.6. 
Ocular Surface Disease Index Total Score and Subscale Scores 
The OSDI questionnaire, provided in Appendix 2, 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 the time.  There 
are 7 questions related to visual functioning that allow a response of “N/A” (not applicable).  
The OSDI total score (on a scale of 0 to 100) is be calculated from the raw scores of each of the 
12 questions based on the formula: ([sum of scores for all questions answered]×100)/([total 
number of questions answered]×4), where questions answered with N/A are considered 
unanswered and excluded from the calculation  Higher scores represent greater disability. 
Subscale scores are calculated similarly, where the Ocular Symptoms subscale includes the 
5 questions on light sensitivity, gritty feeling, painful/sore eyes, blurred vision, and poor vision; 
the Vision Related Function subscale includes the 4 questions on problems reading, driving at 
night, working with a computer, or watching TV; and the Environmental Triggers subscale 
includes questions about windy conditions, low humidity, and air conditioning. 
5.2.7. 
Visual Analogue Scale 
Individual visual analogue scales will be completed for 7 different symptoms, as provided in 
Appendix 1.  Lower values indicate better results:  
• burning/stinging 
• itching 


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• foreign body sensation 
• eye discomfort 
• eye dryness 
• photophobia 
• pain 
The mean of the completed VAS scores will be calculated to produce the Average VAS score. 
The Worst VAS will be defined as the individual VAS with the highest (worst) score at baseline.  
If two or more VAS results are tied for the highest score at baseline, the average of those two 
(or more) will be used as the Worst VAS.  Changes from baseline at subsequent visits will then 
be calculated based on the average of those scores at subsequent visits. 
5.2.8. 
Standard Patient Evaluation of Eye Dryness 
The SPEED score will be calculated based on occurrence, frequency, and severity of the 
4 symptoms of dryness, grittiness or scratchiness, soreness or irritation, burning or watering, and 
eye fatigue as shown in Appendix 3.  Frequency is evaluated on a 4-point scale (0=never to 
3=constant) and severity on a 5-point scale (0=no problem to 4=intolerable) for each symptom.  
The total SPEED score is derived as the sum of the frequency and severity scores across all 
4 symptoms, with a range of possible values of 0 to 28, where higher scores indicate increasing 
severity.  
5.2.9. 
Best Corrected Visual Acquity Logarithm of the Minimal Angle of Resolution 
Logarithm of the Minimal Angle of Resolution (LogMAR) will be calculated from the total letter 
score as LogMAR = 1.7-0.02×(total letter score), for each eye. 
5.3. 
Missing Data 
Missing efficacy data will be handled as follows: 
• The primary efficacy analyses and most other efficacy analyses will utilize multiple 
imputation. 
• Sensitivity analyses will be performed on the primary using the LOCF approach, where 
non-missing post-baseline values are carried forward to subsequent visits. 
Prior to performing imputation or analyses, results from unscheduled visits and early termination 
(ET) visits (defined as per Section 5.1) will be mapped to the closest scheduled visit (Day 14, 
Month 1.5, Month 3, Month 4.5, or Month 6).  In other words, a patient with an ET visit at 
Day 40 would have its those results mapped to the Month 1.5 visit. 


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Actual item results will be imputed, and any subscale scores, total scores, changes from baseline, 
responder status, etc. will be derived from the imputed values where necessary. 
For safety analyses, where incomplete dates are present, medications will be categorized as 
concomitant, and adverse events as treatment-emergent, unless sufficient information is present 
to definitely determine that the medication usage completed, or event resolved, prior to the first 
dose of study medication.  
5.3.1. 
Multiple Imputation  
Missing data will be imputed via multiple imputation (MI) using a Markov Chain Monte Carlo 
(MCMC) approach.  This approach is suitable for non-monotone missingness (missed visits 
followed by completed visits), incorporates all available observed data as the basis for imputing 
values, and utilizes the same method to handle all missing data (i.e., not differentiating by cause 
of missingness).  Studies have shown that MI is statistically superior to more traditional methods 
of imputation (e.g., LOCF; e.g., DeSouza et al., 2009; Tang et al., 2005). 
5.3.1.1. 
Multiple Imputation for Primary Analysis 
Multiple imputation will be performed separately for each assessment; in other words, MGYLS 
values will not be used to impute OSDI values.  The same seed number (utilized in SAS® PROC 
MI) of 135790 will be used throughout.  For each MI, 20 imputations will be created, analyses 
performed on each imputed dataset separately, and results combined using PROC 
MIANALYZE.  The appropriate minimum and maximum values will be used for each variable, 
and results rounded to the same precision as collected values.  Multiple imputation will be 
limited to patients in the analysis population being used, and will include values that are eligible 
for use in summaries and analyses as described in Section 5.1 (e.g., unscheduled and early 
termination visits will be mapped to scheduled visits, and visits with >1 non-missing values 
mapped to that visit will utilize the later result), through the Month 3 visit.  Screening visit 
values will not be incorporated into the multiple imputation.  
The following variables will be included in the multiple imputation model, as numeric variables: 
• Treatment group (split into three dichotomous variables) 
• Randomization criteria (disease duration category and baseline MGS score category) 
• Age 
• Sex 
• Analysis value (MGYLS or OSDI total score) for each scheduled visit 
The following pseudocode will be used: 
proc mi data=xxx seed=135790 nimpute=20 out=yyy   
 
 
minimum = 0 0 0 18 0 0 0  0  0  0  0    


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maximum = 1 1 1 99 1 1 1  xx xx xx xx  
  
 
round =   1 1 1 1  1 1 1  1  1  1  1  ; 
var Dur5yr MGSless6 male age trt0_5 trt1_0 trtpbo  
  
 
Day1 Day14 Day45 Day90; 
mcmc chain=multiple displayinit; 
 
run; 
 
<proc genmod, etc.> 
 
Proc mianalyze data=xxx (drop=effect); 
 
by trt01pn; 
 
modeleffects LSM; 
 
stderr; 
 
run; 
 
5.3.1.2. 
Multiple Imputation for Exploratory Analyses 
A second multiple imputation will be performed similarly for each assessment, utilizing the data 
through Month 6, for exploratory efficacy analyses performed after the completion of the safety 
follow-up period.  For each of the initial 20 imputations created through Month 3, an additional 
20 imputations will be created to impute Month 4.5 and Month 6.  Subsequent analyses of the 
20×20=400 imputations will be performed separately for each imputation, then results combined 
using PROC MIANALYZE. 
The following pseudocode will be used, in addition to the prior pseudocode: 
proc mi data=yyy (rename=(_imputation_=Imp1)) seed=1357902 nimpute=20 out=zzz   
 
 
minimum = 0 0 0 18 0 0 0  0  0  0  0  0  0   
  
 
maximum = 1 1 1 99 1 1 1  xx xx xx xx xx xx 
  
 
round =   1 1 1 1  1 1 1  1  1  1  1  1  1 ; 
 
by Imp1; 
var Dur5yr MGSless6 male age trt0_5 trt1_0 trtpbo  
  
 
Day1 Day14 Day45 Day90 Day135 Day180; 
mcmc chain=multiple displayinit; 
 
run; 
5.3.2. 
Last Observation Carried Forward 
The LOCF approach will be used to impute primary efficacy data for sensitivity analyses, where 
specified.  Post-baseline values may be carried forward (i.e., scheduled visits at Day 14 or later, 
any post-baseline unscheduled or early termination visits that occur on or after Day 14), but 
values prior to first application of randomized study treatment will not be used for imputation.  
Further details are provided in Section 8.1.2. 


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6. DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
6.1. 
Patient Disposition and Withdrawals 
Patient disposition and follow-up will be summarized by treatment group and overall, reflecting 
completion or withdrawal through Month 3.  This disposition summary will be based on the 
ITT Set, and will tabulate inclusion in analysis sets, completion status, and reason for 
withdrawal.  Numbers of screen failures will also be presented. 
Reason for screen failures and reason for withdrawal before treatment assignment/randomization 
will be listed separately from completion and withdrawal information for patients enrolled in the 
study.  
After the completion of the safety follow-up period, an additional summary of disposition 
through Month 6 will be created as part of the supplemental safety analyses. 
6.2. 
Demographic and Other Baseline Characteristics 
Demographic data and baseline disease characteristics will be summarized by treatment, using 
the Safety and ITT analysis sets.  Demographic data will include age, sex, childbearing potential 
(if applicable), race, and ethnicity.  Baseline characteristics will include height, weight, duration 
of meibomian gland disease (i.e., <5 years or ≥5 years), study eye (left or right), and baseline 
MGS score in the study eye (<6 or 6-12). 
6.3. 
Medical History 
Non-ophthalmic history will be recorded by body system, medical condition, or surgery, and 
start and end dates.  Ophthalmic history will be recorded by specific location (e.g., left lower 
eyelid or right eye); ocular disease, condition, or procedure; start and end dates; and whether 
medication is currently being taken for that condition.  All medical history will be coded 
according to the Medical Dictionary for Regulatory Activities (MedDRA®), using System Organ 
Class (SOC) and Preferred Term (PT). 
Ophthalmic and non-ophthalmic medical history will be summarized separately by treatment, 
SOC, and PT, using the Safety Set.  The number and percent of patients with ophthalmic and 
non-ophthalmic history will also be presented. 
Non-Ophthalmic and ophthalmic medical history will be listed separately. 


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7. PROTOCOL DEVIATIONS 
All protocol deviations will be identified, categorized, and graded by the investigator and an 
interdisciplinary team.  An additional review by a multi-disciplinary team, for adherence to the 
grading, will be completed prior to database freeze, and unmasking of specific study personnel.  
Please refer to Protocol Deviation Definitions – Three Month Analysis for additional details 
regarding protocol deviation definitions and classifications.   
Deviations will be graded as one of the following: 
• Grade 1:  No impact on data quality or patient safety 
• Grade 2:  Minor impact on data quality 
• Grade 3:  Minor impact on patient safety 
• Grade 4:  Major impact on data quality or patient safety  
• Grade 5:  Death 
All patients with Grade 4 or Grade 5 deviations affecting Baseline through Month 3 will be 
excluded from the PP analysis set.  All patients with Grade 4 or Grade 5 deviations affecting 
Baseline through Month 6 will be excluded from the PP6 analysis set. 
Grade 2, 3, 4, and 5 protocol deviations through Month 3 will be summarized by deviation type, 
grade, and treatment, as well as listed by patient.  As part of the supplemental safety analyses, 
Grade 2, 3, 4, and 5 protocol deviations through Month 6 will be similarly summarized and 
listed. 
8. EFFICACY 
Efficacy analyses will be performed on the ITT Set.  The primary analyses will be repeated on 
the mITT Set (if different from the ITT Set) and PP Set.  If the primary analyses are notably 
different between the ITT and mITT sets, additional analyses of the other efficacy endpoints may 
be performed on the mITT Set.  
In addition to those analyses, which are performed at the 3-month time point, additional 
exploratory analyses will be performed at the 6 month time point, using data collected during the 
3 month safety follow-up period.  These analyses will also be performed on the ITT Set, with 
MGYLS and OSDI total score analyses repeated on the mITT and PP6 sets.  P-values for 
analyses of data collected during the 3-month safety follow-up period (e.g., Month 4.5 and 
Month 6) are provided for descriptive purposes only. 


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Endpoints will be summarized descriptively, for all scheduled assessment time points.  Actual 
values and changes from baseline will be summarized descriptively for all time points at which 
the endpoint is collected. 
Dichotomous endpoints will be analyzed using a CMH test to compare each AZR-MD-001 
treatment arm to placebo, controlling for disease duration category and baseline MGS score 
category.  If CMH comparisons are not estimable, Pearson’s chi-square or Fisher’s Exact will be 
used, as described in Section 8.2 and Section 8.3. 
8.1. 
Primary Efficacy Endpoints and Analysis 
These endpoints will be analyzed using the ITT, mITT, and PP sets, with the primary analysis 
being performed on the ITT Set.  Multiple imputation will be applied, unless otherwise indicated.  
Responder criteria based on eye-specific measurements (MGYLS, etc.) are calculated for the 
study eye only.  These analyses will include all data collected through Month 3. 
8.1.1. 
Primary Efficacy Endpoints  
The primary efficacy variables are: 
• change from baseline to Month 3 in MGYLS  
• change from baseline to Month 3 in OSDI total score 
The primary efficacy endpoints will be evaluated using the following hierarchical approach. For 
each endpoint, the subsequent endpoint will not be evaluated unless the prior endpoint is 
significant at α=0.05.  Therefore, this hierarchical approach controls for the family-wise Type I 
error and does not require adjustment for multiplicity, as per Dmitrienko and D’Agostino, 2013. 
a) Change from baseline to Month 3 in MGYLS, comparing AZR-MD-001 0.5% to 
placebo. 
b) Change from baseline to Month 3 in OSDI total score, comparing AZR-MD-001 0.5% to 
placebo. 
c) Change from baseline to Month 3 in MGYLS, comparing AZR-MD-001 1.0% to 
placebo. 
d) Change from baseline to Month 3 in OSDI total score, comparing AZR-MD-001 1.0% to 
placebo. 
Multiple imputation will be applied, as described in Section 5.3.  Analyses will be performed as 
follows. 
Change from baseline in MGYLS will be analyzed at Month 3 using an ANCOVA model with 
(continuous) baseline MGYLS score as a covariate and treatment (AZR-MD-001 ointment/semi-


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solid drug or placebo), duration of disease category (i.e., <5 or ≥5 years), and baseline MGS 
score category (< 6 or ≥6 and ≤12) as factors in the model.  This ANCOVA model will also be 
performed for each AZR-MD-001 ointment/semi-solid drug dosing level versus placebo.  The 
least square means for the differences between treatments will be presented along with two-sided 
(95%) confidence intervals. 
The following pseudocode will be used: 
PROC GENMOD data=xxx; 
BY visit; 
CLASS treatment (ref = ‘AZR-MD-001 PLACEBO’) duration baseMGS; 
MODEL chg =treatment base duration baseMGS; 
LSMEANS treatment; 
run; 
 
Change from baseline in OSDI total score will be analyzed at Month 3 using the same 
methodology as the change from baseline in MGYLS, using an ANCOVA model with 
(continuous) baseline OSDI total score as a covariate and treatment, duration of disease category, 
and baseline MGS score category as factors in the model. 
8.1.2. 
Sensitivity Analyses of Primary Efficacy Endpoints  
8.1.2.1. 
Last Observation Carried Forward 
The primary efficacy analyses will also be performed using LOCF imputation as a sensitivity 
analysis.  This analysis will use the ITT Set. 
The change from baseline in MGYLS and OSDI total scores will be analyzed as described in 
Section 8.1.1, based on observations using LOCF imputation as described in Section 5.3.2. 
8.1.2.2. 
Evaluation of Potentially Confounding Medications/Therapies at Month 3 
The use of potentially confounding medications or therapies at Month 3 will be evaluated by 
tabulating the number of patients with medications that potentially affect Month 3 OSDI results, 
and, if a sufficient number of patients meet those criteria, repeating the OSDI analysis with a 
dichotomous variable indicating the presence/absence of such medications or therapies. 
Potentially confounding medications or therapies will be identified as those having a Grade 4 
protocol deviation with deviation class of concomitant medications/therapies.  The duration of 
the deviation will include both the duration of medication/therapy usage and the subsequent 
washout period.  Therefore, any such deviation whose start and stop dates overlap with the 
Month 3 visit date record on the Study Visits eCRF, will classify that patient as having a 
potentially confounding treatment for the Month 3 visit.  


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The number of patients with potentially confounding treatments at the Month 3 visit will be 
tabulated.  Those patients will also be flagged in listings.  If >10% of patients in the ITT Set have 
potentially confounding treatments at Month 3, an additional sensitivity analysis of the OSDI 
change from baseline will be performed.  Specifically, the change from baseline in OSDI will be 
analyzed using an ANCOVA model similar to that described in Section 8.1, with baseline 
MGYLS score as a covariate and treatment, duration of disease category, and baseline MGS 
score category as factors, with the presence of a potentially confounding treatment at Month 3 
(i.e., yes or no) as an additional factor in the model.  This analysis will be performed on the 
ITT Set, using multiple imputation. 
The following pseudocode will be used: 
PROC GENMOD data=xxx; 
Where visit=’Month 3’; 
CLASS treatment (ref = ‘AZR-MD-001 PLACEBO’) duration baseMGS; 
MODEL chg =treatment base duration baseMGS confound; 
LSMEANS treatment; 
run; 
 
If this analysis is performed, the p-value associated with the presence of potentially confounding 
treatment will be presented in conjunction with the other OSDI results, and the least squares 
means and treatment differences from this model will be presented. 
8.2. 
Secondary Efficacy Endpoints and Analyses 
The following endpoints will be presented using the ITT Set.  Multiple imputation will be 
applied, as described in Section 5.3.  These analyses will include all data collected through 
Month 3. 
8.2.1. 
Key Secondary Efficacy Analyses   
Proportion of MGYLS responders based on change from baseline ≥5 will be analyzed 
through Month 3 using a CMH test to compare the proportions between each AZR-MD-001 
group and placebo, stratifying by disease duration category (i.e., <5 or ≥5 years) and baseline 
MGS score category (<6 or ≥6 and ≤12).  If the CMH statistic is not estimable, the treatment 
difference will be evaluated using Pearson’s chi-square test, or Fisher’s exact test (if the 
expected cell count is <5 for at least 25% of the cells).   
The following pseudocode will be used: 
PROC FREQ data=xxx; 
 
BY visit; 
 
TABLE baseMGS * duration * treatment * response/CMH; 
 
ODS OUTPUT  CMH = outcmh (where=(STATISTIC=2)); 


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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; 
 
Proportion of OSDI responders based on OSDI total score <13 will be analyzed through 
Month 3 as described for the proportion of MGYLS responders, using a CMH test 
(or chi-square/Fisher’s Exact if CMH is not estimable) to evaluate the difference between 
treatments, controlling for duration of disease category and baseline MGS score category. 
Change from baseline in SPEED score at Day 14, Month 1.5 and Month 3 will be analyzed as 
described for MGYLS in Section 8.1.1. 
Change from baseline in Eye Dryness VAS at Day 14, Month 1.5 and Month 3 will be 
analyzed as described for MGYLS in Section 8.1.1. 
8.2.2. 
Secondary Efficacy Analyses   
Change from baseline in MGS will be analyzed through Month 3 using an ANCOVA model 
with (continuous) baseline MGS score as a covariate and treatment (AZR-MD-001 
ointment/semi-solid drug or placebo) and duration of disease category (i.e., <5 or ≥5 years) as 
factors in the model.  This ANCOVA model will be performed for each AZR-MD-001 
ointment/semi-solid drug dosing level versus placebo.  The least square means for the differences 
between treatments will be presented along with two-sided (95%) confidence intervals. 
The following pseudocode will be used: 
PROC GENMOD data=xxx; 
BY visit; 
CLASS treatment (ref = ‘AZR-MD-001 PLACEBO’) duration; 
MODEL chg =treatment base duration; 
LSMEANS treatment; 
run; 
 
Proportion of MGS responders based on MGS >12 will be analyzed at Day 14, Month 1.5, 
and Month 3 as described for the proportion of MGYLS responders, using a CMH test 
(or chi-square/Fisher’s Exact if CMH is not estimable) to evaluate the difference between 
treatments, controlling for duration of disease category and baseline MGS score category. 
Change from baseline in MGYLS at Day 14 and Month 1.5 will be analyzed as described for 
Month 3 in Section 8.1.1. 


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Change from baseline in OSDI total score at Day 14 and Month 1.5 will be analyzed as 
described for Month 3 in Section 8.1.1. 
8.3. 
Exploratory Efficacy Analyses 
The following endpoints will be presented using the ITT Set, unless otherwise specified.  Where 
applicable, actual values and changes from baseline will be summarized descriptively for all time 
points at which the endpoint is collected. 
8.3.1. 
Exploratory Efficacy Analyses Performed at Month 3 
Proportion of MGYLS responders based on MGYLS > 2 will be analyzed through Month 3 
as described for the proportion of MGYLS responders, using a CMH test (or chi-square/Fisher’s 
Exact if CMH is not estimable) to evaluate the difference between treatments, controlling for 
duration of disease category and baseline MGS score category.   
Change from baseline in MGYOLS at Day 14, Month 1.5 and Month 3 will be analyzed as 
described for MGYLS in Section 8.1.1. 
Proportion of MGYOLS responders based on MGYOLS >2 will be analyzed through 
Month 3 as described for the proportion of MGYLS responders, using a CMH test 
(or chi-square/Fisher’s Exact if CMH is not estimable) to evaluate the difference between 
treatments, controlling for duration of disease category and baseline MGS score category. 
Proportion of OSDI responders based on a reduction of >4.5 will be analyzed through 
Month 3 as described for the proportion of MGYLS responders, using a CMH test 
(or chi square/Fisher’s Exact if CMH is not estimable) to evaluate the difference between 
treatments, controlling for duration of disease category and baseline MGS score category. 
Change from baseline in OSDI subscales at Day 14, Month 1.5 and Month 3 will be analyzed 
as described for MGYLS in Section 8.1.1. 
Proportion of SPEED responders based on SPEED <6 will be analyzed through Month 3 as 
described for the proportion of MGYLS responders, using a CMH test (or chi-square/Fisher’s 
Exact if CMH is not estimable) to evaluate the difference between treatments, controlling for 
duration of disease category and baseline MGS score category.   
Change from baseline in TBUT at Day 14, Month 1.5 and Month 3 will be analyzed as 
described for MGYLS in Section 8.1.1. 
Proportions of TBUT >5 and >10 responders will be analyzed through Month 3 as described 
for the proportion of MGYLS responders, using a CMH test (or chi-square/Fisher’s Exact if 


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CMH is not estimable) to evaluate the difference between treatments, controlling for duration of 
disease category and baseline MGS score category. 
Change from baseline in Average VAS and Worst VAS at Day 14, Month 1.5 and Month 3 
will be analyzed as described for MGYLS in Section 8.1.1. 
Proportion of Average VAS responders based on decrease ≥5 and proportion of Worst VAS 
responders based on decrease ≥5 will be analyzed through Month 3 as described for the 
proportion of MGYLS responders, using a CMH test (or chi-square/Fisher’s Exact if CMH is not 
estimable) to evaluate the difference between treatments, controlling for duration of disease 
category and baseline MGS score category.   
Change from Schirmer’s assessment at Day 14, Month 1.5 and Month 3 will be analyzed as 
described for MGYLS in Section 8.1.1. 
Proportion of Schirmer’s ≥10 mm responders will be analyzed through Month 3 as described 
for the proportion of MGYLS responders, using a CMH test (or chi-square/Fisher’s Exact if 
CMH is not estimable) to evaluate the difference between treatments, controlling for duration of 
disease category and baseline MGS score category. 
Change from baseline in Burning/Stinging VAS, Itching VAS, Foreign Body Sensation 
VAS, Eye Discomfort VAS, Photophobia VAS, and Pain VAS at Day 14, Month 1.5 and 
Month 3 will be analyzed as described for MGYLS in Section 8.1.1. 
Proportion of patients with clinical cure, defined as having MGYLS change from baseline ≥5 
and OSDI total score <13, will be analyzed through Month 3 as described for the proportion of 
MGYLS responders, using a CMH test (or chi-square/Fisher’s Exact if CMH is not estimable) to 
evaluate the difference between treatments, controlling for duration of disease category and 
baseline MGS score category.   
Eyelid margin erythema and telangiectasias results will be summarized by time point, in 
conjunction with other findings from the slit lamp examination.  Actual values and shifts from 
baseline through Month 3 will be summarized by parameter and time point.  Changes from 
baseline will be analyzed at each time point using CMH statistics to evaluate the differences 
between each AZR-MD-001 treatment group and placebo, controlling for baseline value, using 
the following pseudocode: 
PROC FREQ data=xxx; 
BY visit;   
TABLE treatment * base * result / CMH; 
ODS output CMH=outcmh (where=(ALTHYPOTHESIS=’General Association’)); 
run; 
 


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Corneal and conjunctival staining (sodium fluorescein corneal staining and lissamine green 
conjunctival staining) are assessed on a 6-point scale using grades 0, I, II, III, IV, and V, and are 
summarized by grade and shift from baseline.  Shift from baseline through Month 3 will be 
analyzed using CMH statistics as described for eyelid margin erythema and telangiectasias. 
8.3.2. 
Exploratory Efficacy Analyses Performed at Month 6 
These analyses will be performed using the ITT, mITT, and PP6 sets, as indicated.  P-values will 
be provided for descriptive purposes only. 
Change from baseline in MGYLS at Month 4.5 and Month 6 will be analyzed as described for 
MGYLS in Section 8.1.1.  This analysis will utilize multiple imputation based on data from the 
entire 6-month study duration, as described in Section 5.3.1.2, on the ITT, mITT, and PP6 sets.  
It will be repeated using LOCF on the ITT Set, as described in Section 8.1.2.1.   
Change from baseline in OSDI total score at Month 4.5 and Month 6 will be analyzed as 
described for MGYLS in Section 8.1.1.  This analysis will utilize multiple imputation based on 
data from the entire 6-month study duration, as described in Section 5.3.1.2, on the ITT, mITT, 
and PP6 sets.  It will be repeated using LOCF on the ITT Set, as described in Section 8.1.2.1.  
Additionally, an analysis of potentially confounding medication, as described in Section 8.1.2.2, 
will be performed at Month 6, utilizing the ITT Set with multiple imputation. 
Proportion of MGYLS responders based on change from baseline ≥5 at Month 4.5 and 
Month 6 will be analyzed as described in Section 8.2.1, using a CMH test (or chi-square/Fisher’s 
Exact if CMH is not estimable) to evaluate the difference between treatments, controlling for 
duration of disease category and baseline MGS score category. 
Proportion of OSDI responders based on OSDI total score <13 at Month 4.5 and Month 6 
will be analyzed as described in Section 8.2.1, using a CMH test (or chi-square/Fisher’s Exact if 
CMH is not estimable) to evaluate the difference between treatments, controlling for duration of 
disease category and baseline MGS score category.   
Change from baseline in SPEED score at Month 4.5 and Month 6 will be analyzed as 
described for MGYLS in Section 8.1.1. 
Change from baseline in individual VAS scores, Average VAS, and Worst VAS at 
Month 4.5 and Month 6 will be analyzed separately as described for MGYLS in Section 8.1.1. 
Change from baseline in MGS at Month 4.5 and Month 6 will be analyzed using an ANCOVA 
model with (continuous) baseline MGS score as a covariate, and treatment and duration of 
disease category as factors, as described in Section 8.2.2.   


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Proportion of MGS responders based on MGS >12 at Month 4.5 and Month 6 will be 
analyzed as described for the proportion of MGYLS responders, using a CMH test (or 
chi-square/Fisher’s Exact if CMH is not estimable) as described in Section 8.2.2. 
Proportion of MGYLS responders based on MGYLS > 2 at Month 4.5 and Month 6 will be 
analyzed as described for the proportion of MGYLS responders, using a CMH test 
(or chi-square/Fisher’s Exact if CMH is not estimable), as described in Section 8.2.2. 
Change from baseline in MGYOLS at Month 4.5 and Month 6 will be analyzed as described 
for MGYLS in Section 8.1.1. 
Proportion of MGYOLS responders based on MGYOLS > 2 at Month 4.5 and Month 6 will 
be analyzed as described for the proportion of MGYLS responders, using a CMH test 
(or chi-square/Fisher’s Exact if CMH is not estimable), as described in Section 8.3.1. 
Proportion of OSDI responders based on a reduction of >4.5 at Month 4.5 and Month 6 will 
be analyzed as described for the proportion of MGYLS responders, using a CMH test 
(or chi square/Fisher’s Exact if CMH is not estimable), as described in Section 8.3.1. 
Change from baseline in OSDI subscales at Month 4.5 and Month 6 will be analyzed as 
described for MGYLS in Section 8.1.1. 
Proportion of SPEED responders based on SPEED <6 at Month 4.5 and Month 6 will be 
analyzed as described for the proportion of MGYLS responders, using a CMH test 
(or chi-square/Fisher’s Exact if CMH is not estimable), as described in Section 8.3.1. 
Change from baseline in TBUT at Month 4.5 and Month 6 will be analyzed as described for 
MGYLS in Section 8.1.1. 
Proportions of TBUT >5 and >10 responders at Month 4.5 and Month 6 will be analyzed as 
described for the proportion of MGYLS responders, using a CMH test (or chi-square/Fisher’s 
Exact if CMH is not estimable), as described in Section 8.3.1. 
Proportion of Average VAS responders based on decrease ≥5 and proportion of Worst VAS 
responders based on decrease ≥5 at Month 4.5 and Month 6 will be analyzed as described for 
the proportion of MGYLS responders, using a CMH test (or chi-square/Fisher’s Exact if CMH is 
not estimable) to evaluate the difference between treatments, controlling for duration of disease 
category and baseline MGS score category.   
Change from Schirmer’s assessment at Month 4.5 and Month 6 will be analyzed as described 
for MGYLS in Section 8.1.1. 


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Proportion of Schirmer’s ≥10mm responders at Month 4.5 and Month 6 will be analyzed as 
described for the proportion of MGYLS responders, using a CMH test (or chi-square/Fisher’s 
Exact if CMH is not estimable), as described in Section 8.3.1.   
Proportion of patients with clinical cure, defined as having MGYLS change from baseline ≥5 
and OSDI total score <13, will be analyzed at Month 4.5 and Month 6 as described for the 
proportion of MGYLS responders, using a CMH test (or chi-square/Fisher’s Exact if CMH is not 
estimable), as described in Section 8.3.1.   
Eyelid margin erythema and telangiectasias changes from baseline will be analyzed at Month 
4.5 and Month 6, using CMH statistics as described in Section 8.3.1.  
Corneal and conjunctival staining shifts from baseline will be analyzed using CMH statistics, 
as described in Section 8.3.1. 
9. ANALYSIS OF PHARMACOKINETICS 
Pharmacokinetics are not measured in the Expansion Cohort. 
10. SAFETY 
The Safety Set will be used for safety analyses reports.  Safety will be assessed based on adverse 
events, vital signs, BCVA (Logarithmic visual acuity chart), biomicroscopy, ophthalmoscopy, 
IOP, and conjunctival hyperemia (redness). 
The primary safety analysis will be performed after all patients have completed the Month 3 visit 
or discontinued from the study.  An additional 3-month safety follow-up (including Month 4.5 
and Month 6 visits) will be conducted, and supplemental safety results will be produced after the 
completion of the Month 6 visits. 
A combined analysis of Cohort 1 and Expansion Cohort data will not be produced, as Cohort 1 
includes different dosing regimens (once daily vs. twice weekly) as well as including different 
treatments (AZR-MD-001 0.1%, vehicle). 
10.1. Extent of Exposure and Compliance 
During the Baseline visit, the patient will be dispensed Vaseline, which will be administered 
while on site and the prospective patient will be observed by the physician or a designee.  
Eligible patients will also be dispensed randomized study medication (AZR-MD-001 or 
placebo), which will be administered twice weekly at home.  Patients are expected to apply the 
first application of randomized study medication on the same date, in the evening.   


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Application, dispensation, and return of randomized study treatment will be listed 
chronologically by patient and visit.  A separate listing of Physician Observation of Drug 
Application, for observation of Vaseline applied during the Baseline visit, will be provided. 
Compliance for randomized study treatment, in the form of numbers of doses administered and 
missed, is collected in 6-week intervals.  Approximately 12 doses are expected to be 
administered during each of those 6-week periods, but slightly more or less may be expected 
depending on actual visit dates and visit windows.  The expected number of doses for a given 
period is calculated as 2*(end date - start date + 1)/7, rounded to the nearest whole number.  
Compliance is then calculated as 100*(number of doses taken)/(number of expected doses).  
Overall compliance for the 3 month study period will be based on the expected numbers of doses 
calculated as 2×([Month 3 visit date or date of discontinuation]-[date of first dose] +1) /7, for the 
3 month study period, and 2×([Month 6 visit date or date of discontinuation]-[date of first 
dose]+1)/7, for the 6 month period including follow-up.  The number of patients with compliance 
<80%, 80%-120%, and >120% will be tabulated.  
For the safety follow-up period, if the final study drug is returned after the Month 6 visit (based 
on the visit date as compared to the final study drug return date), compliance will be calculated 
based on the Month 6 visit date.  If dates of dispensation or return are not recorded on the eCRF 
(e.g., visit restrictions were in place and study treatment was mailed to patients), compliance 
calculations will be based on the assumption that 12 doses should have been administered. 
Compliance through the Month 3 visit will be presented at the completion of the 3-month study 
period.  Compliance through the end of the safety follow-up period (i.e., through Month 6) will 
be presented as part of the supplemental safety analyses. 
10.2. Adverse Events  
Adverse events will be classified into SOC and PT using MedDRA version 20.0 or higher.  
Treatment-emergent adverse events (TEAEs) are defined as events beginning or worsening on or 
after the date of first dose of study medication.  If the start date of the event is incomplete or 
missing, the event will be categorized as a TEAE unless sufficient information (from partial start 
date, or from end date) clearly indicates that the event started prior to the date of first dose.  If 
event severity or relationship to study intervention is missing, the event will be summarized at 
the worst possible severity (severe) and strongest possible relationship (very likely/certain). 
All events attributed to the application of Vaseline during the Baseline visit will be noted in the 
verbatim event term by the investigator and identified programmatically from the verbatim term.  
All such events will be listed by patient, and summarized by SOC and PT overall, since patients 


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are not randomized to treatment at the time of Vaseline application.  AEs attributed to 
application of Vaseline will also be listed. 
Adverse events will be listed by subject, event, and date, with non-TEAEs flagged in the listings, 
as follows: 
• All adverse events 
• All serious adverse events (SAEs) 
• Adverse events leading to drug withdrawal 
TEAEs will be summarized by treatment as follows, using both numbers of events and number 
and percent of patients.  Patients are counted at most one-time per SOC and at most one time per 
PT, at the highest recorded severity or relationship (where applicable).  A patient with multiple 
events within an SOC or PT will have all events reflected in the total numbers of events in that 
classification. 
• Overall summary of events and patients with different types of TEAEs. 
• Summary of TEAEs by SOC and PT. 
• Summary of Ophthalmic TEAEs by SOC and PT. 
• Summary of Ophthalmic TEAEs Occurring in the Study Eye by SOC and PT. 
• Summary of Ophthalmic TEAEs Occurring in the Non-Study Eye by SOC and PT. 
• Summary of Non-Ophthalmic TEAEs by SOC and PT. 
• Summary of Serious TEAEs by SOC and PT. 
• Summary of TEAEs Leading to Drug Withdrawal by SOC and PT. 
• Summary of TEAEs Possibly, Probably, or Certainly Related to Study Intervention by 
SOC and PT. 
• Summary of TEAEs by SOC, PT, and Severity. 
• Summary of TEAEs by SOC, PT, and Relationship to Study Intervention. 
• Summary of TEAEs by SOC, PT, and Site. 
• Summary of TEAEs by PT. 
10.3. Prior and Concomitant Medication 
Prior and concomitant medications and treatments will be coded using the World Health 
Organization Drug Dictionary (WHODRUG). 
Medications used prior to the date of first dose of study medication will be classified as prior 
medication, and those used on or after the date of the first study treatment (including Vaseline) 
will be classified as concomitant medications (including those started prior to the first study 


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treatment which is ongoing during the study).  A medication may be classified as both prior and 
concomitant. 
Medication with a missing or partial start date will be considered as prior medication if the first 
date implied by the available start date is prior to the first study treatment date.  Medications with 
partial end dates will be considered as concomitant if the last available date implied by the 
available data is on or after the first study treatment date.  
Concomitant medication will be summarised by treatment, Anatomical Therapeutic Chemical 
(ATC) Level 4, PT, and category (Non-ophthalmic medication and ophthalmic medication), 
using the Safety Set. 
Prior and concomitant medications will be listed.  Ophthalmic medications in the study eye will 
be flagged in the prior and concomitant medication listing.  Medication use through the Month 3 
visit will be presented at the end of the 3-month study period, and medication use through the 
end of the safety follow-up period (i.e., through Month 6) will be presented as part of 
supplemental safety analyses. 
10.4. Laboratory Evaluations 
Aside from urine pregnancy test, clinical laboratory samples are not collected in the Expansion 
Cohort. 
Urine pregnancy test data will be listed chronologically by patient and visit. 
10.5. Best-corrected Visual Aacuity; Logarithmic Visual Acuity Chart 
BCVA Total letter score, LogMAR (calculated as per Section 5.2.9), axis, and cylinder will be 
summarized by time point, and treatment, using absolute values and changes from baseline.  
Changes in letter scores will also be tabulated as: increases of 5 or more letters, decreases of 5 or 
more letters, or changes of less than 5 letters; and increases of 10 or more letters, decreases of 
10 or more letters, or changes of less than 10 letters.  Results for sphere refraction will be 
tabulated.  All results, including Snellen equivalents, will be listed chronologically by patient and 
visit. 
10.6. Vital Signs  
Vital signs will consist of systolic and diastolic blood pressure (mmHg) and pulse rate (bpm).  
Vital signs data (absolute values) will be summarized by parameter, time point, and treatment, 
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10.7. Slit-lamp Biomicroscopy, Including Conjunctival Hyperemia 
Slit-lamp biomicroscopy results, including the safety endpoint of conjunctival hyperemia 
(redness), will be summarized in a shift table as described in Section 8.3.  CMH analyses will 
only be performed for the exploratory efficacy endpoints of study eye erythema and 
telangiectasias.  Results will be listed chronologically. 
10.8. Ophthalmoscopy 
Lens status (categorized as phakic, pseudophakic, or aphakic) will be summarized by time point, 
and treatment using a shift table.  Cataract status (rated on a 4-point scale from None to Severe), 
vitreous (normal or abnormal), and fundus (normal or abnormal) will be recorded for phakic 
eyes, and also tabulated in a shift table.  Ophthalmoscopy results, including specifics of any 
vitreous or fundus abnormalities, will be listed chronologically by patient and visit.  Dilation 
status (dilated or undilated) will be presented in listings, but both dilated and undilated results 
will be tabulated together in a shift table. 
10.9. Intraocular Pressure 
IOP results will be categorized as <18, 18-25, or >25 mmHg separately in the study eye and 
non-study eye and summarized using a shift table.  Results will be listed chronologically by 
patient and visit. 
10.10. Meibography/Meiboscopy 
Meibography results will be collected in each eye and summarized using a shift table. 
11. INTERIM ANALYSES 
No official interim analysis will be performed. 
As described in Section 1.2 and Section 2.3.2, a sample size re-estimation will be performed, in a 
masked fashion, after all patients complete Month 3.  These analyses will be limited to 
calculation of pooled standard deviations for MGYLS and OSDI total score, and the sample size 
re-estimation using pseudocode presented in Section 2.3.2.  No data summaries or comparisons 
between treatment groups will be created, and no unmasking will occur. 
12. CHANGES FROM ANALYSIS PLANNED IN PROTOCOL 
The following are some changes in the analysis of the Expansion Cohort, as compared to 
protocol. 


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• The primary objective of the study was shifted from evaluating safety and tolerability, to 
evaluating safety and efficacy, following discussion with the FDA. 
• Some secondary endpoints described in protocol errors 8.1.2, 8.1.5, and 9.4.3 have been 
reclassified as exploratory efficacy analyses.  Results (i.e., actual values) for efficacy 
assessments were listed as endpoints in the protocol but are not explicit endpoints in the 
SAP; actual values are summarized in conjunction with changes from baseline 
throughout. 
• Clinical cure, as stated in AZ201801 Protocol Section 9.4.3, has been redefined as having 
MGYLS change from baseline ≥5 and OSDI total score <13, to correspond with 
responder criteria for the primary endpoints, and is evaluated using the CMH test instead 
of a shift table. 
• The ITT analysis set has been added as the primary efficacy analysis set, per feedback 
from the FDA. 
• While the mITT Set is defined in the AZ201801 Protocol Section 9.2 as being all 
randomized patients who have values at randomization and post-baseline values, the 
definition has been simplified to be randomized patients who met inclusion/exclusion 
criteria and had post-baseline values.  However, it is expected that randomized patients 
do have values collected at the time of randomization (baseline visit).  Further, since 
randomized study treatment is not administered onsite during this cohort, the mITT now 
requires that subjects be administered 1+ doses of randomized study treatment. 
• The mITT2 population, defined in protocol synopsis as patients in the mITT Set who 
have baseline MGS scores of 6-12 but not included in the description of analysis sets in 
protocol section 9.2, is not utilized in the Expansion Cohort analyses. 
• Pairwise comparisons between active and placebo groups in ANCOVA models are based 
on least square means of the differences, which use a z test as produced by the software 
(not a t-test, as stated in AZ201801 Protocol Section 9.4.3). 
• Responder analyses will be performed using CMH analyses, in lieu of logistic regression 
as described in AZ201801 Protocol Section 9.4.3.  This non-parametric approach permits 
a treatment comparison while controlling for covariates, without assuming an underlying 
distribution. 
• The subgroup analyses specified in AZ201801 Protocol Section 9.4.7 are not utilized in 
the Expansion Cohort analyses.  


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• Urine pregnancy test results will not be evaluated as a safety endpoint. 
13. REFERENCE LIST 
DeSouza CM, Legedza ATR, Sankoh AJ. An overview of practical approaches for handling 
missing data in clinical trials. J Biopharm Stat. 2009 Nov;19(6):1055-1073. 
Dmitrienko A, D’Agostino R Sr. Traditional multiplicity adjustment methods in clinical trials. 
Stat Med. 2013 Dec 20;32(29):5172–5218. 
Tang L, Song J, Belin TR, Unützer J. A comparison of imputation methods in a longitudinal 
randomized clinical trial. Stat Med. 2005 Jul 30;24(14), 2111-2128. 
14. PROGRAMMING CONSIDERATIONS 
All statistical computations and construction of tables and listings will be performed using SAS® 
for Windows Version 9.4 or higher (SAS® Institute Inc., Cary, NC, USA). 
The table and listing shells will be developed in a separate document and approved by the 
sponsor and other stakeholders.  Any subsequent changes determined to be necessary will be 
documented and approved by the sponsor and statistical team.  SDTM datasets will be created 
from the clinical database and external data, following the Study Data Tabulation Model 
Implementation Guide version 3.2 or higher.  Analysis will be based on ADaM datasets created 
from the SDTM datasets and will follow the Analysis Dataset Model Implementation Guide 
version 1.3 or higher.  
Patient participation will be ongoing at the time of the analyses based on Month 3 data, and some 
patients could have already completed the Month 4.5 and/or Month 6 visits at that time.  At the 
time of the Month 3 sample size re-estimation, data necessary for the re-estimation (e.g., 
Screening and Baseline visit information and all MGYLS and OSDI assessments through 
Month 3) will be fully cleaned for all patients.  At the time of the Month 3 database freeze, data 
will be fully cleaned through the Month 3 visit for all patients.  All patient information in the 
database will be transferred to the statistical team for analyses.  The statistical team will 
programmatically limit the data used in analysis datasets, tables, and listings to the information 
collected through Month 3, including any unscheduled visits collected during that time and any 
early termination visits in subjects who did not have a Month 3 visit.  Tables and listings 
presenting information such as disposition, adverse events, medications, and other information 
not summarized in a by-visit fashion will be presented through Month 3.   
Any adverse events that are ongoing at the Month 3 visit and resolve after the Month 3 visit, 
even if resolution information has been entered in the database at the time of database freeze, 
will programmatically have the stop date removed, be categorized as Ongoing, and have 


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outcome assigned to Not Yet Resolved.  Any patients who do not have a Month 3 visit but are 
not discontinued (i.e., did not attend Month 3 visit but remained on trial) will utilize the expected 
date of the Month 3 visit in this algorithm. 
Similarly, non-study medications (e.g., prior and concomitant) that are ongoing at the Month 3 
visit and have end date information entered in the database from a later study visit (e.g., 
Month 4.5 or 6) at the time of database freeze, will be programmatically have stop date removed, 
and be categorized as Ongoing. 
After all patients have completed the Month 6 visit (e.g., completed the safety follow-up period), 
all patient data after the Month 3 visit will be fully cleaned, and the database locked.  
14.1. General Considerations 
• One SAS program can create multiple tables (or listings).  One program is expected to 
create both the 3-month and 6-month output (e.g., one program is used to create both 
Table 17 and Table 17.1, or to create Listing 1 and Listing 1.1). 
• Output files will be delivered in Word format.  Tables and listings (TLs) will be bundled 
separately with a table of contents for each.  
14.2. Table and Listing Formatting 
14.2.1. 
General 
• All TLs will be produced in landscape format, using the Courier New font, size 8 with 
approximately 1-inch margin on all 4 sides. 
• Each table or listing will have a solid line at the top, one underneath the column headers, 
and one underneath the body of the text. 
14.2.2. 
Headers 
• All output should have the following header at the top left of each page: 
Protocol AZ201801 Expansion Cohort 
Azura Ophthalmics 
• All output should have Page n of N at the top right corner of each page.  TLs should be 
internally paginated in relation to the total length (i.e., the page number should appear 
sequentially as page n of N, where N is the total number of pages in the table).  


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14.2.3. 
Display Titles 
• The titles should be formatted as follows, with the title text wrapping to a second line 
where necessary.  The title and table designation will be single spaced.  Listings will 
include all available data and will not have an analysis set displayed.  
Table x 
Title Text 
(Analysis Set) 
 
14.2.4. 
Body of the Data Display 
14.2.4.1. 
General Conventions 
Data in the body of a table or listing are formatted as follows: 
• Alphanumeric values that do not wrap are centered; those that do wrap are left-justified  
• Whole numbers (e.g., counts) are centered 
• Numbers containing fractional portions are decimal aligned or centered, as appropriate. 
14.2.4.2. 
Table Conventions 
• Analysis population sizes will be presented for each treatment group in the column 
heading as (N=xx) (or in the row headings if applicable).  This is distinct from the ‘n’ 
used for the descriptive statistics representing the number of patients in the analysis 
population.  
• If the categories of a parameter are ordered, then all categories between the maximum 
and minimum category are presented in the table, even if n=0 for all treatment groups in a 
given category that is between the minimum and maximum level for that parameter.   
• Where percentages are presented in these tables, zero percentages will not be presented; 
that is, it will be presented as 0 and not as 0 (0%). 
• An Unknown or Missing category are added to each parameter for which information is 
not available for 1 or more patients.  
• Percentage values are printed to one decimal place, in parentheses with no spaces, one 
space after the count (e.g., 7 (12.8), 13 (5.4)).  Values that round to 0.0 will be displayed 
as 0.0.  Percentages equating or rounding to 100% are presented as 100, without decimal 
places.  Percent sign may be indicated in column header or row label and not displayed in 
the body of the results, or included in the results (e.g., 7 (12.8%)) as indicated in the 
shells. 
• Missing descriptive statistics or p-values which cannot be estimated are reported as 
“N/E”. 


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• The percentage of patients is normally calculated as a proportion of the number of 
patients assessed in the relevant treatment group (or overall) in the column header.  If the 
percentage is calculated based on a different number, it will be indicated with a footnote 
(such as in a disposition table) or with the inclusion of a “n” line reflecting the 
denominator (such as a by-visit analysis). 
14.2.4.3. 
Listing Conventions 
• Assessments collected at the early termination visit (recorded as occurring at Month 6, 
where the assessment date is equal to the End of Study visit date [in the Subject Visits 
dataset] or the date of early termination [recorded as the date of completion or early 
termination on the End of Study eCRF page, where study completion status is no]) will 
be relabeled to “Early Term” in the listings.  Any assessments recorded as a scheduled 
visit other than Month 6 will not be relabeled in this manner. 
• Missing data will be left blank, unless otherwise specified. 
• Dates are printed in SAS DATE9.format (“ddMMMyyyy”: 01JUL2000).  Missing 
portions of dates may be represented on patient listings as dashes (--JUL2000).  Dates 
that are missing because they are not applicable for the patient will be left blank, unless 
otherwise specified. 
• All observed time values are to be presented using a 24-hour clock HH:MM or 
HH:MM:SS format (e.g., 11:26, or 11:26:45).  Time will only be reported if it was 
measured as part of the study. 
• Where data is presented by study eye vs. non-study eye, patients without study eye 
assigned (i.e., unrandomized patients) will have the right eye displayed in the study eye 
column(s) and left eye displayed in the non-study eye column(s), as indicated in 
footnotes. 
14.2.5. 
Footnotes 
• All footnotes will be left justified with single-line spacing immediately below the solid 
line underneath the data display. 
• Footnotes should always begin with “Note:” if an informational footnote, or [a], [b], etc. 
if a reference footnote.  Each new footnote should start on a new line, where possible.  
• The last line of the footnote section will be a standard source line that indicates the name 
of the program used to produce the data display, date the program was run, whether it is 
draft or final, and the listing source (i.e., ‘Program : myprogram.sas   DRAFT  Listing 
source: xxx). 


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15. APPENDICES 
Appendix 1 
Visual Analogue Scale (VAS) 
 


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Appendix 2 
Ocular Surface Disease Index (OSDI) 
 
 


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Appendix 3 
Standard Patient Evaluation of Eye Dryness (SPEED) Questionnaire 
 
 


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Appendix 4 
List of Tables and Listings Produced at the 3 Month Analysis 
The following tables and listings will be produced at Month 3.  Shells are provided for each 
unique table and listing in a separate document. 
Comprehensive efficacy and safety analyses will be produced after the completion of the 
Month 3 visits.  Additional safety information will be collected through the Month 6 visit and 
presented in supplemental safety tables and listings.  
Table 1 Summary of Patient Disposition Through Month 3 – Expansion Cohort (All Patients) 
Table 2A Summary of Demographic and Baseline Characteristics – Expansion Cohort (Safety Set) 
Table 2B Summary of Demographics and Baseline Characteristics – Expansion Cohort (ITT Analysis Set) 
Table 2C Summary of Demographics and Baseline Characteristics – Expansion Cohort (mITT Analysis Set) 
Table 2D Summary of Demographics and Baseline Characteristics – Expansion Cohort (Per-Protocol Set) 
Table 3A Summary of Ophthalmic Medical History – Expansion Cohort (Safety Set) 
Table 3B Summary of Ophthalmic Medical History – Expansion Cohort (ITT Set) 
Table 3C Summary of Ophthalmic Medical History – Expansion Cohort (mITT Set) 
Table 3D Summary of Ophthalmic Medical History – Expansion Cohort (Per-Protocol Set) 
Table 4A Summary of Non-Ophthalmic Medical History – Expansion Cohort (Safety Set) 
Table 4B Summary of Non-Ophthalmic Medical History – Expansion Cohort (ITT Set) 
Table 4C Summary of Non-Ophthalmic Medical History – Expansion Cohort (mITT Set) 
Table 4D Summary of Non-Ophthalmic Medical History – Expansion Cohort (Per-Protocol Set) 
Table 5A Summary of Protocol Deviations by Grade Through Month 3 – Expansion Cohort (Safety Set) 
Table 5B Summary of Protocol Deviations by Grade Through Month 3 – Expansion Cohort (ITT Analysis Set) 
Table 5C Summary of Protocol Deviations by Grade Through Month 3 – Expansion Cohort (mITT Analysis Set) 
Table 5D Summary of Protocol Deviations by Grade Through Month 3 – Expansion Cohort (Per-Protocol Set) 
Table 6A Analysis of Meibomian Glands Yielding Liquid Secretion (MGYLS) Through Month 3 – Expansion 
Cohort (ITT Analysis Set) 
Table 6B Analysis of Meibomian Glands Yielding Liquid Secretion (MGYLS) Through Month 3 – Expansion 
Cohort (mITT Analysis Set) 
Table 6C Analysis of Meibomian Glands Yielding Liquid Secretion (MGYLS) Through Month 3 – Expansion 
Cohort (PP Analysis Set) 
Table 6D Sensitivity Analysis of Meibomian Glands Yielding Liquid Secretion (MGYLS), based on LOCF 
Imputation Through Month 3 – Expansion Cohort (ITT Analysis Set) 
Table 7A Analysis of Ocular Surface Disease Index (OSDI) Total and Subscale Results Through Month 3 – 
Expansion Cohort (ITT Analysis Set) 
Table 7B Analysis of Ocular Surface Disease Index (OSDI) Total and Subscale Results Through Month 3 – 
Expansion Cohort (mITT Analysis Set) 
Table 7C Analysis of Ocular Surface Disease Index (OSDI) Total and Subscale Results Through Month 3 – 
Expansion Cohort (PP Analysis Set) 


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Table 7D Sensitivity Analysis of Ocular Surface Disease Index (OSDI) Total and Subscale Results, based on 
LOCF Imputation Through Month 3 – Expansion Cohort (ITT Analysis Set) 
Table 8 Analysis of Standard Patient Evaluation of Eye Dryness (SPEED) Through Month 3 – Expansion Cohort 
(ITT Analysis Set) 
Table 9 Analysis of Visual Analogue Scale (VAS) Results Through Month 3 – Expansion Cohort (ITT Analysis 
Set) 
Table 10 Analysis of Meibomian Gland Score Through Month 3 – Expansion Cohort (ITT Analysis Set) 
Table 11 Analysis of Tear Break-up Time (TBUT) Through Month 3 – Expansion Cohort (ITT Analysis Set) 
Table 12 Analysis of Meibomian Glands Yielding Optimal Liquid Secretion (MGYOLS) Through Month 3 – 
Expansion Cohort (ITT Analysis Set) 
Table 13 Analysis of Schirmer’s Test without Anesthesia Through Month 3 – Expansion Cohort (ITT Analysis 
Set) 
Table 14 Analysis of Responder Status Through Month 3 – Expansion Cohort (ITT Analysis Set) 
Table 15A Shift Table and Analysis of Slit Lamp Results, Including Erythema, Telangiectasias, and Conjunctival 
Hyperemia Through Month 3 (ITT Analysis Set) 
Table 15B Shift Table of Slit Lamp Results for Anterior Chamber Cells Through Month 3 (ITT Analysis Set) 
Table 15C Shift Table of Slit Lamp Results for Anterior Chamber Flare Through Month 3 (ITT Analysis Set) 
Table 15D Shift Table of Slit Lamp Results for Anterior Chamber Iris and Pupil Through Month 3 (ITT Analysis 
Set) 
Table 16 Shift Table of Sodium Fluorescein and Lissamine Green Staining Results Through Month 3 – Expansion 
Cohort (Safety Set) 
Table 17 Randomized Study Treatment Exposure and Compliance Through Month 3 – Expansion Cohort  (Safety 
Set) 
Table 18 Overall Summary of Treatment-Emergent Adverse Events Through Month 3 – Expansion Cohort 
(Safety Set) 
Table 19 Summary of Treatment-Emergent Adverse Events, by System Organ Class and Preferred Term Through 
Month 3 – Expansion Cohort (Safety Set) 
Table 20 Summary of Treatment-Emergent Adverse Events Attributed to Vaseline Application at Baseline, by 
System Organ Class and Preferred Term – Expansion Cohort (Pre-Randomization Vaseline Application Set) 
Table 21 Summary of Ophthalmic Treatment-Emergent Adverse Events, by System Organ Class and Preferred 
Term Through Month 3 – Expansion Cohort (Safety Set) 
Table 22 Summary of Ophthalmic Treatment-Emergent Adverse Events, in Study Eye by System Organ Class 
and Preferred Term Through Month 3 – Expansion Cohort (Safety Set) 
Table 26 Summary of Ophthalmic Treatment-Emergent Adverse Events, in Non-Study Eye by System Organ 
Class and Preferred Term Through Month 3 – Expansion Cohort (Safety Set) 
Table 24 Summary of Non-Ophthalmic Treatment-Emergent Adverse Events, by System Organ Class and 
Preferred Term Through Month 3 – Expansion Cohort (Safety Set) 
Table 25 Summary of Serious Treatment-Emergent Adverse Events, by System Organ Class and Preferred Term 
Through Month 3 – Expansion Cohort (Safety Set) 
Table 26 Summary of Treatment-Emergent Adverse Events Leading to Study Drug Withdrawal, by System 
Organ Class and Preferred Term Through Month 3 – Expansion Cohort (Safety Set) 


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Table 27 Summary of Treatment-Emergent Adverse Events Possibly, Probably, or Certainly Related to Study 
Intervention, by System Organ Class and Preferred Term Through Month 3 – Expansion Cohort (Safety Set) 
Table 28 Summary of Treatment-Emergent Adverse Events by Preferred Term Through Month 3 – Expansion 
Cohort (Safety Set) 
Table 29 Summary of Treatment-Emergent Adverse Events, by System Organ Class, Preferred Term and Severity 
Through Month 3 – Expansion Cohort (Safety Set) 
Table 30 Summary of Treatment-Emergent Adverse Events, by System Organ Class, Preferred Term and 
Relationship Through Month 3 – Expansion Cohort (Safety Set) 
Table 31 Summary of Treatment-Emergent Adverse Events, by System Organ Class, Preferred Term and Site 
Through Month 3 – Expansion Cohort (Safety Set) 
Table 32 Summary of Concomitant Medication Through Month 3 – Expansion Cohort (Safety Set) 
Table 33 Summary of Best Corrected Visual Acuity (BCVA) Results Through Month 3 – Expansion Cohort 
(Safety Set) 
Table 34 Summary of Vital Signs Through Month 3 – Expansion Cohort (Safety Set) 
Table 35A Shift Table of Ophthalmoscopy Lens Status Through Month 3 – Expansion Cohort (Safety Set) 
Table 35B Shift Table of Ophthalmoscopy Details Through Month 3 – Expansion Cohort (Safety Set) 
Table 36 Shift Table of Intraocular Pressure Through Month 3 – Expansion Cohort (Safety Set) 
Table 37 Shift Table of Meibography/Meiboscopy Results Through Month 3 – Expansion Cohort (Safety Set) 
Listing 1 Patient Disposition and Analysis Set Inclusion Through Month 3 – Expansion Cohort 
Listing 2 Inclusion and Exclusion Criteria Not Met and Screen Failure Information – Expansion Cohort 
Listing 3 Patient Demographics and Baseline Characteristics – Expansion Cohort 
Listing 4 Ophthalmic Medical History – Expansion Cohort 
Listing 5 Non-Ophthalmic Medical History – Expansion Cohort 
Listing 6 Grade 2 or Higher Protocol Deviations Through Month 3 – Expansion Cohort 
Listing 7 Patient Visits Through Month 3 – Expansion Cohort 
Listing 8 Meibomian Gland Evaluation (MGS, MGYLS, MGYOLS) Through Month 3 – Expansion Cohort  
Listing 9 Ocular Surface Disease Index (OSDI) Through Month 3 – Expansion Cohort 
Listing 10 Standard Patient Evaluation of Eye Dryness (SPEED) Through Month 3 – Expansion Cohort 
Listing 11 Visual Analogue Scale (VAS) Responses Through Month 3 – Expansion Cohort 
Listing 12 Tear Break-up Time (TBUT) Through Month 3 – Expansion Cohort 
Listing 13 Schirmer’s Assessment Results, without Anesthesia, Through Month 3 – Expansion Cohort 
Listing 14 Slit Lamp Examination, Including Erythema, Telangiectasias, and Conjunctival Hyperemia Through 
Month 3 – Expansion Cohort 
Listing 15 Lissamine Green and Sodium Flourescein Staining, Oxford Scale Through Month 3 – Expansion 
Cohort 
Listing 16 Study Drug Dispensation, Return and Compliance Through Month 3 – Expansion Cohort 
Listing 17 Physician Observation of Vaseline Application at Baseline Visit 
Listing 18A Adverse Events Through Month 3 – Expansion Cohort 
Listing 18B Serious Adverse Events Through Month 3 – Expansion Cohort 
Listing 18C Adverse Events Leading to Drug Withdrawal Through Month 3– Expansion Cohort 


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Listing 18D Adverse Events Due to Vaseline Application at Baseline Visit– Expansion Cohort 
Listing 19 Prior and Concomitant Ophthalmic Medications Through Month 3 – Expansion Cohort 
Listing 20 Prior and Concomitant Non-Ophthalmic Medications Through Month 3 – Expansion Cohort 
Listing 21 Urine Pregnancy Test Results Through Month 3 – Expansion Cohort 
Listing 22 Best Corrected Visual Acuity (BCVA) Through Month 3 – Expansion Cohort 
Listing 23 Vital Signs Through Month 3 – Expansion Cohort 
Listing 24 Ophthalmoscopy Results Through Month 3 – Expansion Cohort 
Listing 25 Intraocular Pressure Through Month 3 – Expansion Cohort 
Listing 26 Meibography/Meiboscopy Results Through Month 3 – Expansion Cohort 
 


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Appendix 5 
List of Tables and Listings Produced at the end of the Safety Follow-up 
Period 
The following tables and listings will be produced at the completion of the 3-month safety 
follow-up period (i.e., Month 6), and will include all information from the earlier period.  Shells 
are provided for each unique table and listing in a separate document. 
These tables and listings will be used for supplemental safety analyses, and for additional 
exploratory efficacy analyses. 
Table 1.1 Summary of Patient Disposition – Expansion Cohort (All Patients) 
Table 5.1A Summary of Protocol Deviations by Grade – Expansion Cohort (Safety Set) 
Table 5.1B Summary of Protocol Deviations by Grade – Expansion Cohort (ITT Analysis Set) 
Table 5.1C Summary of Protocol Deviations by Grade – Expansion Cohort (mITT Analysis Set) 
Table 5.1D Summary of Protocol Deviations by Grade – Expansion Cohort (Per-Protocol Set) 
Table 6.1A Analysis of Meibomian Glands Yielding Liquid Secretion (MGYLS) – Expansion Cohort (ITT 
Analysis Set) 
Table 6.1B Analysis of Meibomian Glands Yielding Liquid Secretion (MGYLS) – Expansion Cohort (mITT 
Analysis Set) 
Table 6.1C Analysis of Meibomian Glands Yielding Liquid Secretion (MGYLS) – Expansion Cohort (PP6 
Analysis Set) 
Table 6.1D Sensitivity Analysis of Meibomian Glands Yielding Liquid Secretion (MGYLS), based on LOCF 
Imputation – Expansion Cohort (ITT Analysis Set) 
Table 7.1A Analysis of Ocular Surface Disease Index (OSDI) Total and Subscale Results – Expansion Cohort 
(ITT Analysis Set) 
Table 7.1B Analysis of Ocular Surface Disease Index (OSDI) Total and Subscale Results – Expansion Cohort 
(mITT Analysis Set) 
Table 7.1C Analysis of Ocular Surface Disease Index (OSDI) Total and Subscale Results – Expansion Cohort 
(PP6 Analysis Set) 
Table 7.1D Sensitivity Analysis of Ocular Surface Disease Index (OSDI) Total and Subscale Results, based on 
LOCF Imputation – Expansion Cohort (ITT Analysis Set) 
Table 8.1 Analysis of Standard Patient Evaluation of Eye Dryness (SPEED) – Expansion Cohort (ITT Analysis 
Set) 
Table 9.1 Analysis of Visual Analogue Scale (VAS) Results – Expansion Cohort 
Table 10.1 Analysis of Meibomian Gland Score – Expansion Cohort (ITT Analysis Set) 
Table 11.1 Analysis of Tear Break-up Time (TBUT) – Expansion Cohort (ITT Analysis Set) 
Table 12.1 Analysis of Meibomian Glands Yielding Optimal Liquid Secretion (MGYOLS) – Expansion Cohort 
(ITT Analysis Set) 
Table 13.1 Analysis of Schirmer’s Test without Anesthesia – Expansion Cohort (ITT Analysis Set) 
Table 14.1 Analysis of Responder Status – Expansion Cohort (ITT Analysis Set) 
Table 15A.1 Shift Table and Analysis of Slit Lamp Results, Including Erythema, Telangiectasias, and 
Conjunctival Hyperemia – Expansion Cohort (ITT Analysis Set) 


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Table 15B.1 Shift Table of Slit Lamp Results for Anterior Chamber Cells – Expansion Cohort (ITT Analysis Set) 
Table 15C.1 Shift Table of Slit Lamp Results for Anterior Chamber Flare – Expansion Cohort (ITT Analysis Set) 
Table 15D.1 Shift Table of Slit Lamp Results for Anterior Chamber Iris and Pupil – Expansion Cohort (ITT 
Analysis Set) 
Table 16.1 Shift Table of Sodium Fluorescein Corneal Staining and Lissamine Green Conjunctival Staining 
Results – Expansion Cohort (Safety Set) 
Table 17.1 Randomized Study Treatment Exposure and Compliance – Expansion Cohort (Safety Set) 
Table 18.1 Overall Summary of Treatment-Emergent Adverse Events – Expansion Cohort (Safety Set) 
Table 19.1 Summary of Treatment-Emergent Adverse Events, by System Organ Class and Preferred Term – 
Expansion Cohort (Safety Set) 
Table 21.1 Summary of Ophthalmic Treatment-Emergent Adverse Events, by System Organ Class and Preferred 
Term – Expansion Cohort (Safety Set) 
Table 22.1 Summary of Ophthalmic Treatment-Emergent Adverse Events, in Study Eye by System Organ Class 
and Preferred Term – Expansion Cohort (Safety Set) 
Table 23.1 Summary of Ophthalmic Treatment-Emergent Adverse Events, in Non-Study Eye by System Organ 
Class and Preferred Term – Expansion Cohort (Safety Set) 
Table 24.1 Summary of Non-Ophthalmic Treatment-Emergent Adverse Events, by System Organ Class and 
Preferred Term – Expansion Cohort (Safety Set) 
Table 25.1 Summary of Serious Treatment-Emergent Adverse Events, by System Organ Class and Preferred 
Term – Expansion Cohort (Safety Set) 
Table 26.1 Summary of Treatment-Emergent Adverse Events Leading to Study Drug Withdrawal, by System 
Organ Class and Preferred Term – Expansion Cohort (Safety Set) 
Table 27.1 Summary of Treatment-Emergent Adverse Events Possibly, Probably, or Certainly Related to Study 
Intervention, by System Organ Class and Preferred Term – Expansion Cohort (Safety Set) 
Table 28.1 Summary of Treatment-Emergent Adverse Events by Preferred Term – Expansion Cohort (Safety Set) 
Table 29.1 Summary of Treatment-Emergent Adverse Events, by System Organ Class, Preferred Term and 
Severity – Expansion Cohort (Safety Set) 
Table 30.1 Summary of Treatment-Emergent Adverse Events, by System Organ Class, Preferred Term and 
Relationship – Expansion Cohort (Safety Set) 
Table 31.1 Summary of Treatment-Emergent Adverse Events, by System Organ Class, Preferred Term and Site – 
Expansion Cohort (Safety Set) 
Table 32.1 Summary of Concomitant Medication – Expansion Cohort (Safety Set) 
Table 33.1 Summary of Best Corrected Visual Acuity (BCVA) Results – Expansion Cohort (Safety Set) 
Table 34.1  Summary of Vital Signs – Expansion Cohort (Safety Set) 
Table 35.1A Shift Table of Ophthalmoscopy Lens Status – Expansion Cohort (Safety Set) 
Table 35.1B Shift Table of Ophthalmoscopy Details – Expansion Cohort (Safety Set) 
Table 36.1 Shift Table of Intraocular Pressure – Expansion Cohort (Safety Set) 
Table 37.1 Shift Table of Meibography/Meiboscopy Results – Expansion Cohort (Safety Set) 
Listing 1.1 Patient Disposition and Analysis Set Inclusion – Expansion Cohort 
Listing 6.1 Grade 2 or Higher Protocol Deviations – Expansion Cohort 
Listing 7.1 Patient Visits – Expansion Cohort 


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Listing 8.1 Meibomian Gland Evaluation (MGS, MGYLS, MGYOLS) – Expansion Cohort 
Listing 9.1 Ocular Surface Disease Index (OSDI) – Expansion Cohort 
Listing 10.1 Standard Patient Evaluation of Eye Dryness (SPEED) – Expansion Cohort 
Listing 11.1 Visual Analogue Scale (VAS) Responses – Expansion Cohort 
Listing 12.1 Tear Break-up Time (TBUT) – Expansion Cohort 
Listing 13.1 Schirmer’s Assessment Results, without Anesthesia – Expansion Cohort 
Listing 14.1 Slit Lamp Examination, Including Erythema, Telangiectasias, and Conjunctival Hyperemia – 
Expansion Cohort 
Listing 15.1 Lissamine Green and Sodium Flourescein Staining, Oxford Scale – Expansion Cohort 
Listing 16.1 Study Drug Dispensation, Return and Compliance – Expansion Cohort 
Listing 18.1A Adverse Events – Expansion Cohort 
Listing 18.1B SeriousAdverse Events – Expansion Cohort 
Listing 18.1C Adverse Events Leading to Drug Withdrawal – Expansion Cohort 
Listing 19.1 Prior and Concomitant Ophthalmic Medications – Expansion Cohort 
Listing 20.1 Prior and Concomitant Non-Ophthalmic Medications – Expansion Cohort 
Listing 21.1 Urine Pregnancy Test Results – Expansion Cohort 
Listing 22.1 Best Corrected Visual Acuity (BCVA) – Expansion Cohort 
Listing 23.1 Vital Signs – Expansion Cohort 
Listing 24.1 Ophthalmoscopy Results – Expansion Cohort 
Listing 25.1 Intraocular Pressure – Expansion Cohort 
Listing 26.1 Meibography/Meiboscopy Results – Expansion Cohort