Conditions: Dry Eye Syndrome Keratoconjunctivitis Sicca
Keywords: Dry Eye Calcineurin Inhibitors Dry Eye Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 508
Healthy volunteers: no

Brief summary:
A Multi-Center, Phase 2/3, Randomized, Double-Masked, Parallel-Group, Vehicle-Controlled, Clinical Trial to Assess the Safety and Efficacy of Voclosporin Ophthalmic Solution (0.05%, 0.10%, 0.20%) Compared to Vehicle in Subjects with Dry Eye Syndrome.

Detailed description:
This is a Phase 2/3, multi-center, randomized, double-masked, vehicle-controlled study to assess the efficacy and safety of three different concentrations of VOS when administered in both eyes (OU) twice a day (BID) over 12 weeks in subjects with mild to moderate DES. Subjects will undergo a 14- to 17-day run-in period in which VOS vehicle will be self-administered OU, BID. Subjects will be re-assessed to confirm they meet all of the inclusion criteria and none of the exclusion criteria. It is estimated that the study will enroll approximately 480 subjects across approximately 9 study centers. Eligible subjects will be randomized in a 1:1:1:1 ratio to one of the following study treatment groups after the 14- to 17-day run-in period.

Arms:
arm 1: 0.05% VOS, in both eyes (OU) twice a day (BID) over 12 weeks arm 2: 0.10% VOS, in both eyes (OU) twice a day (BID) over 12 weeks arm 3: 0.20% VOS, in both eyes (OU) twice a day (BID) over 12 weeks arm 4: Vehicle Ophthalmic Solution, in both eyes (OU) twice a day (BID) over 12 weeks

Interventions: intervention 1: 0.05% Voclosporin Ophthalmic Solution (VOS) intervention 2: 0.10% VOS intervention 3: 0.20% VOS intervention 4: Vehicle Ophthalmic Solution
Intervention descriptions: intervention 1: 0.05% VOS, in both eyes (OU) twice a day (BID) over 12 weeks intervention 2: 0.10% VOS, in both eyes (OU) twice a day (BID) over 12 weeks intervention 3: 0.20% VOS, in both eyes (OU) twice a day (BID) over 12 weeks intervention 4: Vehicle Ophthalmic Solution, in both eyes (OU) twice a day (BID) over 12 weeks

Protocol document:
Prot_002.pdf: 
This trial will be conducted in compliance with this protocol, ICH GCP and applicable regulatory requirements. 
The information contained in this document is proprietary to Aurinia Pharmaceuticals Inc. and is not to be copied, disclosed or otherwise 
distributed by an outside authority to any person or persons without the prior written permission of Aurinia. 
A Randomized, Double-Masked, Vehicle-Controlled, Dose 
Ranging Study to Assess the Efficacy and Safety of Voclosporin 
Ophthalmic Solution (VOS) in Subjects with Dry Eye Syndrome 
Clinical Protocol Number: 
AUR-VOS-2019-01 
Date: 
26 June 2020 
Version Number: 
3.0 
IND Number: 
102,279 
Study Name: 
AUDREY (AUrinia DRy EYe) 
NCT Number: 
NCT04147650


 
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NAMES AND ADDRESSES 
Sponsor 
Name: 
Aurinia Pharmaceuticals Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Tel: 
 
 
Fax: 
 
 
Clinical Representative 
Name: 
 
 
Company: 
Aurinia Pharmaceuticals Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Email: 
  
 
Chief Medical Officer 
Name: 
 
 
Company: 
Aurinia Pharmaceuticals Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Email: 
 
 
Regulatory Representative 
Name: 
 
 
Company: 
Aurinia Pharmaceuticals Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Email: 
 
 
Trial Statistician 
Name:  
 
 
Company: 
Aurinia Pharmaceuticals Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Email: 
 
 


 
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DECLARATION OF SPONSOR 
Title: A Randomized, Double-Masked, Vehicle-Controlled, Dose Ranging Study to Assess the 
Efficacy and Safety of Voclosporin Ophthalmic Solution (VOS) in Subjects with Dry Eye 
Syndrome 
This study protocol was subjected to critical review. The information it contains is consistent with 
current knowledge of the risks and benefits of the study treatment, as well as with the moral, ethical, 
and scientific principles governing clinical research as set out in the Declaration of Helsinki and 
the International Council for Harmonisation (ICH) on Good Clinical Practice (GCP). 
Sponsor Representatives 
 
 
 
 
Chief Medical Officer 
 
Date (i.e., DD Month Year) 
 
 
 
 
Senior Vice President, Quality and Regulatory 
Affairs 
 
Date (i.e., DD Month Year) 
 


 
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INVESTIGATOR AGREEMENT FORM 
I have read the attached protocol titled: A Randomized, Double-Masked, Vehicle-Controlled, Dose 
Ranging Study to Assess the Efficacy and Safety of Voclosporin Ophthalmic Solution (VOS) in 
Subjects with Dry Eye Syndrome 
I agree to comply with the current International Council for Harmonisation Guidelines on Good 
Clinical Practice and applicable regulations and guidelines. 
I agree to ensure that financial disclosure statements will be completed by: 
• me (including, if applicable, my spouse (or legal partner) and dependent children); 
• my Sub-Investigators 
before the start of the study and to report any changes that affect my financial disclosure status for 
up to 1 year after the study is completed. 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Aurinia Pharmaceuticals Inc. 
Signature by the Investigator on this form documents review, agreement, and approval of the 
requirements contained within this protocol. 
 
 
 
Name 
 
 
Signature 
 
Date (i.e., DD Month Year) 
 


 
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SYNOPSIS 
Title: 
A Randomized, Double-Masked, Vehicle-Controlled, Dose Ranging Study to Assess the 
Efficacy and Safety of Voclosporin Ophthalmic Solution (VOS) in Subjects with Dry Eye 
Syndrome 
Study Product: 
Voclosporin Ophthalmic Solution (VOS) 
Indication: 
Dry Eye Syndrome (DES) 
Phase: 
2/3 
Sponsor: 
Aurinia Pharmaceuticals Inc. 
Study Code: 
AUR-VOS-2019-01 
Objectives: 
To assess the efficacy and safety of three different concentrations of VOS (0.05%, 0.10%, 
and 0.20%) when administered twice a day (BID) in both eyes (OU) over 12 weeks compared 
to vehicle in subjects with DES. 
Design: 
This is a Phase 2/3, multi-center, randomized, double-masked, vehicle-controlled study to 
assess the efficacy and safety of three different concentrations of VOS when administered OU 
BID over 12 weeks in subjects with mild to moderate DES. Subjects will undergo a 2-week 
run-in period in which VOS vehicle will be self-administered OU, BID. Subjects will be re-
assessed to confirm that all participants meet all of the inclusion criteria and none of the 
exclusion criteria. It was estimated that the study would enroll approximately 480 subjects 
(amended to approximately 505 due to COVID-19) across approximately 9 study centers. 
Eligible subjects will be randomized in a 1:1:1:1 ratio to one of the following study treatment 
groups after the 14- to 17-day run-in period. 
Treatment: 
Subjects will be randomized to one of the following treatment groups: 
Investigational product (IP): one drop 0.05% VOS, OU BID over 12 weeks, one drop 0.10% 
VOS OU BID over 12 weeks, or one drop 0.20% VOS OU BID over 12 weeks. 
Comparator: one drop VOS vehicle OU BID over 12 weeks. 
Inclusion Criteria 
Subjects are eligible for participation if they: 
1. Provide written informed consent before any study-specific procedures are 
performed. 
2. Are male or female, with a minimum age of 18 years (or legal age of consent if >18 
years), at the time of screening. 
3. Have a documented history of DES in both eyes supported by a previous clinical 
diagnosis prior to Visit 1  
4. Are willing and able to follow protocol procedures and instructions and can be 
present for the required study visits for the duration of the study. 
5. Have a symptom severity score of ≥30 mm for Eye Dryness on the Individual 
Symptom Severity Assessment Visual Analog Scale (VAS) (0-100 mm) at both Visit 
1 and Visit 2. 
6. Have a best corrected visual acuity (BCVA) in both eyes of +0.7 logarithm of the 
Minimum Angle of Resolution (logMAR) or better as assessed by Early Treatment 
of Diabetic Retinopathy Study (ETDRS) chart at Visit 1. 
7. Have ongoing DES, as defined by at least one eye (if one eye, the same eye) meeting 
both of the following criteria at both Visit 1 and Visit 2:  
a) Have an unanesthetized Schirmer Tear Test (STT) score of ≥1 mm and 
≤10 mm per 5 minutes. 


 
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b) Have a total fluorescein corneal staining (FCS) score of at least 3 [National 
Eye Institute (NEI)/Industry Workshop 0-15 scale]. 
Note: The qualifying eye at Visit 1 must be the same eye at Visit 2. 
8. Have normal lid anatomy 
Exclusion 
Criteria: 
In order for subjects to be eligible, subjects must not: 
1. Be non-compliant during the run-in treatment (non-compliance defined as dosing 
<80% or >120% of the time, calculated by counting the number of returned and 
unused study drug ampules) 
2. Have any known hypersensitivity or contraindication to study treatments (including 
excipients), topical anesthetics, or vital dyes. 
3. Have had any eye surgery in either eye except for cataract surgery or laser-assisted 
in situ keratomileusis (LASIK). 
4. Have undergone cataract or LASIK surgery within 1 year prior to Visit 1. 
5. Have recent or current evidence of ocular infection or inflammation in either eye 
including ocular pemphigoid and Stevens Johnson Syndrome. 
6. Have current evidence of clinically significant blepharitis (defined as requiring lid 
hygiene therapy and additional therapies such as doxycycline or Lipiflow®) or other 
meibomian gland dysfunction, conjunctivitis, or a history of herpes simplex or zoster 
keratitis in either eye. 
7. Have clinically significant ocular disease in either eye (i.e., corneal edema, uveitis, 
severe keratoconjunctivitis sicca) or active ocular allergies that might interfere with 
study procedures or assessments in the opinion of the Investigator. Severe 
keratoconjunctivitis sicca is defined by an FCS score of ≥13. 
8. Be taking or have a known need for any of the following treatment therapies within 
the time frames as specified below: 
a) Any investigational drug or device within 30 days prior to the Screening 
Visit (Visit 1) and subjects may not receive any investigational drug or 
device during the entire study except that which is allowed by the protocol. 
b) Ophthalmic drugs (any topical eye medications) including prescription 
medication and over-the-counter (OTC) agents, from date of Visit 1 to Visit 
7. 
c) Contact lenses 24 hours prior to the Screening Visit (Visit 1) to the end of 
Visit 7. 
d) Any prior use of amiodarone. 
e) Within 72 hours of Visit 1 and for the duration of the study: 
− Oral anti-histamines 
f) 
Within 14 days prior to Visit 1 and for the duration of the study: 
− Xiidra® (lifitegrast) 
g) Within 30 days prior to Visit 1 and for the duration of the study: 
− Calcineurin Inhibitors (CNIs) such as Restasis® (cyclosporin 
ophthalmic emulsion) or CequaTM 
− Topical ocular anti-histamines 
− Ocular, inhaled, or intranasal corticosteroids 
− Topical or oral mast cell stabilizers  
− Topical or nasal vasoconstrictors 
− Topical ocular nonsteroidal anti-inflammatory drugs (NSAIDs) 


 
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− Topical ocular antibiotics 
− True Tear device  
h) Unstable dose within 30 days prior to the Screening Visit (Visit 1) or during 
the study; alteration to the dose or anticipated alterations to the dose of the 
following are disallowed: 
− Tetracyclines 
− Omega 3s or Omega 6s 
i) 
Unstable dose within 60 days prior to the Screening Visit (Visit 1) or during 
the study; alteration to the dose or anticipated alterations to the dose of the 
following are disallowed: 
− Anticholinergics 
− Antidepressants 
− Oral contraceptives 
− Isotretinoin 
− Oral systemic corticosteroids 
− Oral systemic immunosuppressive agents 
j) 
Within 90 days prior to the Screening Visit (Visit 1) or during the study, 
the subject has had cauterization of the punctum or alternations to (insertion 
or removal) punctal plug(s) or nasolacrimal surgery. Note: If a punctal plug 
is in place at the Screening Visit (Visit 1) and it is dislodged during the 
study, the plug should be replaced as soon as possible. 
9. Have clinically significant systemic disease (i.e., uncontrolled diabetes, hepatic, 
renal, endocrine, or cardiovascular disorders) that might interfere with the study. 
10. Have been randomized and treated in a previous study where VOS was the IP. 
11. Be a woman of childbearing potential who is pregnant, nursing, planning a 
pregnancy, or not using a medically acceptable form of birth control. All women of 
childbearing potential must be willing to take a urine pregnancy test at Visit 1 and 
Visit 6.  
12. Have a condition or be in a situation that the Investigator feels may put the subject 
at significant risk, may confound the study results, or may interfere significantly with 
the subject’s participation in the study. 
Primary Endpoint: 
• 
Proportion of subjects with a ≥10 mm increase from baseline in STT at Week 4 in 
the study eye. The study eye will be defined as the qualifying eye that achieves the 
lowest STT score at baseline. Should both eyes be qualifying eyes with identical 
STT scores at baseline, the eye with the worst FCS score will be used. Should these 
scores also be equal, the right eye will be used. 
Key Secondary 
Endpoint: 
• 
Mean change from baseline in Eye Dryness VAS at Week 4 in subjects with a 
baseline Eye Dryness VAS score ≥60mm. 
Secondary 
Endpoints: 
Secondary Endpoints: 
• 
Proportion of subjects with a ≥10 mm increase from baseline in STT at Weeks 2, 8, 
and 12 in the study eye. 
• 
Mean change from baseline in total FCS (NEI/Industry Workshop 0-15 scale) score 
to Weeks 2, 4, 8, and 12 in the study eye. 
• 
Mean change from baseline in FCS score in the 5 regions of the cornea (central, 
superior, inferior, temporal, and nasal) to Weeks 2, 4, 8, and 12 in the study eye. 


 
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• 
Mean change from baseline in STT score to Weeks 2, 4, 8, and 12 in the study eye. 
• 
Mean change from baseline in Eye Dryness VAS (0-100 mm) score to Weeks 2, 4, 
8, and 12 within treatment group. 
• 
Mean change from baseline in Ocular Discomfort VAS (0-100 mm) score to Weeks 
2, 4, 8, and 12.  
• 
Mean change from baseline in Eye Dryness, Burning/Stinging, Itching, Photophobia, 
Eye Pain, Foreign Body Sensation, and Blurred Vision VAS (0-100 mm) score to 
Weeks 2, 4, 8, and 12. 
• 
Mean change from baseline of the sum of Individual Symptom Score (VAS Total 
Symptom Summary Score) to Weeks 2, 4, 8, and 12.  
• 
Mean change from baseline in Symptom Assessment in Dry Eye (SANDE) 
frequency and severity scores to Week 2, 4, 8, and 12. 
Safety Endpoints: 
• 
Treatment-emergent adverse events (TEAEs) 
• 
Change from baseline in BCVA over time 
• 
Changes from baseline in slit-lamp biomicroscopy over time 
• 
Changes from screening in dilated ophthalmoscopy over time 
Procedures: 
Subjects who have provided signed and dated informed consent will be screened for entry 
into this study. Subjects will be evaluated for eligibility according to the protocol 
inclusion/exclusion criteria. Eligible subjects will enter a 14- to 17-day run-in period during 
which time they will receive vehicle drops and will be instructed to instill one drop of vehicle 
OU BID. Subjects will be re-evaluated for eligibility after the run-in period.  
After the run-in period, eligible subjects will be randomly assigned in a 1:1:1:1 ratio to one 
of the four treatment groups: VOS 0.05% BID, VOS 0.1% BID, VOS 0.2% BID, or VOS 
vehicle BID. 
Subjects will self-instill the assigned treatment, one drop OU BID, over 12 weeks. 
Sample Size: 
This study was expected to enroll 480 subjects into 4 treatment arms. This was amended to 
approximately 505 subjects (due to COVID-19) in order to have at least 480 evaluable 
subjects at Week 4. 
A two-group continuity corrected Chi square test with a 0.0166 two-sided significance level 
(adjusted for three treatment comparisons versus placebo) will have at least 80% power to 
detect the difference between a vehicle response rate of 20% (defined as the percentage of 
subjects with a ≥10 mm increase in STT from baseline) and a VOS response rate of 40% when 
the sample size in each group is 120 (total N=480). Response is defined as an increase of ≥10 
mm in STT from baseline to Week 4. 
While the effect of withdrawals will be investigated, subjects withdrawing prior to Week 4 
STT assessment for any reason will be counted as non-responders in the primary analysis and 
therefore no adjustment of sample size for withdrawals is necessary. Subjects providing 
insufficient data to determine response at Week 4 (e.g., early withdrawal) will be analysed as 
non-responders.  
An additional sensitivity analysis will analyse observed responses only. 
This sample size provides greater than 90% power to detect a significant change from baseline 
within any one of the three active treatment groups in the Eye Dryness VAS assuming the 
standard deviation of changes is 40 mm and the mean change from baseline is 20 mm (two-
sided alpha=0.0166). 
The key secondary endpoint is analyzed within the population of subjects with an Eye Dryness 
VAS ≥60 mm at baseline. It is expected that this will reduce the sample size for this analysis 


 
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by 25% (from 120 per group to 90 per group). Assuming a standard deviation of 30 mm for 
change in eye dryness score and an improvement of any active arm compared to placebo 
(alpha=0.0166) of 15 mm, a sample size of 90 subjects per group provides at least 80% power 
to detect a significant difference. 
The study was ongoing at the time of the Coronavirus (COVID-19) pandemic. The impact of 
the pandemic was continually being assessed and it became apparent that a number of subjects 
were unable to attend the primary efficacy visit at Week 4 due to site closure. To account for 
the higher incidence of missing data and ensure data from at least 480 subjects were available 
for analysis of the primary endpoint (STT response at Week 4), the target sample size was 
increased to approximately 505 subjects. 
Statistical 
Methods: 
All statistical analyses will be undertaken at study closure and will incorporate all efficacy 
and safety endpoints. 
Analysis Populations: 
The following analysis populations will be considered: 
• 
Intent-to-Treat Population: The intent-to-treat (ITT) population includes all randomized 
subjects. Subjects in the ITT population will be analyzed as randomized. 
• 
Modified Intent-to-Treat Population: The modified intent-to-treat (mITT) population is 
based on the ITT population and excludes all subjects who were unable to attend their 
primary endpoint assessment at the Week 4 visit due to Coronavirus-related site closure. 
Due to block enrolment, this applies to all subjects at Site 36. Thus, these subjects will 
be excluded from the mITT population. Subjects in this population will be analyzed as 
randomized. The mITT population will be used for the primary assessment of efficacy. 
• 
Per Protocol Population: The per protocol (PP) population includes subjects in the mITT 
population who do not have significant protocol deviations prior to their primary endpoint 
assessment at Week 4 and who complete the Week 4 STT. Protocol deviations will be 
assessed prior to database lock and unmasking. The PP population will be analyzed as 
randomized. 
• 
Safety Population: The safety population includes all randomized subjects who have 
received at least one dose of randomized study treatment. The safety population will be 
analyzed for all safety assessments. Subjects in the safety population will be analyzed as 
treated.  
• 
The run-in population will be used to describe all subjects who entered the run-in period. 
Baseline data will be summarized using the safety, ITT, mITT and PP populations. Safety 
data will be summarized using the safety population, and efficacy analysis will use the ITT, 
mITT and PP populations. 
Methods: 
Efficacy Endpoints: 
Analysis of the primary endpoint, proportion of subjects with a ≥10 mm increase from 
baseline in STT at Week 4 in the study eye, will be conducted on the ITT, mITT and PP 
populations. The response rate for each VOS group compared to vehicle will be determined 
using a logistic regression model including terms for Investigator site, treatment group, and 
baseline STT. Results of this logistic regression will be displayed as odds ratios and two-sided 
adjusted 95% confidence intervals (CI) (VOS compared to vehicle). The proportion of 
subjects exhibiting a response at Week 4 will be summarized by treatment group.  


 
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The key secondary endpoint of mean change from baseline in Eye Dryness VAS in the subset 
of subjects with baseline Eye Dryness VAS ≥60 mm will be analysed using the ITT, mITT 
and the PP populations. Mean change, along with an adjusted 95% CI and p-value, will be 
provided from a General Linear Model including terms for Investigator site, treatment group 
and baseline Eye Dryness VAS. 
Other proportional endpoints (STT response at alternative time points) will be analyzed for 
the ITT population only and summarized in a similar fashion to the primary endpoint. 
Endpoints measured as continuous data (including VAS scores) will be summarized by visit 
for the ITT population only. Mean change from baseline (95% CI) will be provided for within 
treatment group changes and for differences between treatment groups (VOS – vehicle). 
Mixed Effect Model Repeated Measures (MMRM) will also be used to analyze all available 
data for a given endpoint. The MMRM model will include terms for Investigator site, 
treatment group, visit, treatment-by-visit interaction, and applicable baseline measure. Results 
will be expressed as differences between treatment arms (VOS – vehicle) along with 
associated 95% CIs and p-values. 
Safety Endpoints: 
Adverse events will be aggregated by System Organ Class and preferred term and presented 
as summary tables. BCVA will be summarized as a continuous endpoint with results 
displayed as mean changes from baseline for each visit.  
Slit-lamp biomicroscopy and dilated ophthalmoscopy will be summarized using frequency 
counts and shift tables from baseline. 
 


 
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TABLE OF CONTENTS 
NAMES AND ADDRESSES ........................................................................................................ 2 
DECLARATION OF SPONSOR ................................................................................................ 3 
INVESTIGATOR AGREEMENT FORM ................................................................................. 4 
SYNOPSIS ..................................................................................................................................... 5 
TABLE OF CONTENTS ........................................................................................................... 11 
LIST OF FIGURES ...................................................................................................................... 14 
LIST OF APPENDICES ............................................................................................................... 14 
LIST OF ABBREVIATIONS .................................................................................................... 15 
1. 
INTRODUCTION AND BACKGROUND ....................................................................... 17 
1.1 
Nonclinical Studies of Voclosporin in Dry Eye ............................................................... 18 
1.2 
Clinical Studies of Voclosporin in Dry Eye ..................................................................... 20 
1.3 
Study Rationale ................................................................................................................. 21 
2. 
STUDY OBJECTIVES ....................................................................................................... 22 
3. 
CLINICAL HYPOTHESIS ................................................................................................ 23 
4. 
OVERALL STUDY DESIGN ............................................................................................ 24 
5. 
STUDY POPULATION ..................................................................................................... 28 
5.1 
Number of Subjects........................................................................................................... 28 
5.2 
Study Population Characteristics ...................................................................................... 28 
5.3 
Inclusion Criteria .............................................................................................................. 28 
5.4 
Exclusion Criteria ............................................................................................................. 29 
5.5 
Withdrawal Criteria .......................................................................................................... 31 
5.6 
Aurinia Adequate/Effective Contraception ....................................................................... 31 
6. 
STUDY PARAMETERS .................................................................................................... 33 
6.1 
Efficacy Measures ............................................................................................................. 33 
6.1.1 
Primary Efficacy Endpoint ............................................................................................ 33 
6.1.2 
Key Secondary Endpoint ............................................................................................... 33 
6.1.3 
Secondary Endpoints ..................................................................................................... 33 
6.2 
Safety Measures ................................................................................................................ 33 
7. 
RANDOMIZATION, MASKING AND UNMASKING PROCEDURES ..................... 35 
7.1 
Randomization .................................................................................................................. 35 
7.2 
Masking............................................................................................................................. 35 
7.3 
Unmasking ........................................................................................................................ 35 
8. 
STUDY MATERIALS ........................................................................................................ 36 
8.1 
Dosage Forms/Formulation .............................................................................................. 36 
8.1.1 
Study Treatments ........................................................................................................... 36 


 
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8.1.2 
Description and Justification for the Route of Administration, Dosage, Dosage 
Regimen, and Treatment Period .................................................................................... 36 
8.1.3 
Instructions for Use and Administration ........................................................................ 37 
8.2 
Other Study Supplies ........................................................................................................ 37 
9. 
STUDY METHODS AND PROCEDURES ..................................................................... 38 
9.1 
Subject Entry Procedures .................................................................................................. 38 
9.1.1 
Overview ...................................................................................................................... 38 
9.1.2 
Informed Consent .......................................................................................................... 38 
9.1.3 
Washout Intervals .......................................................................................................... 38 
9.1.4 
Procedures for Final Study Entry ................................................................................... 38 
9.1.5 
Methods for Assignment to Treatment Groups ............................................................. 38 
9.2 
Concurrent Therapies ........................................................................................................ 38 
9.2.1 
Prohibited Medications .................................................................................................. 38 
9.2.2 
Rescue Medications ....................................................................................................... 39 
9.2.3 
Special Diets or Activities ............................................................................................. 39 
9.3 
Examination Procedures ................................................................................................... 39 
9.3.1 
Visit 1: Day -17 to -14 Screening and Run-In Period.................................................... 39 
9.3.2 
Visit 2: Day 1-Baseline .................................................................................................. 40 
9.3.3 
Visit 3: Day 14 (±3 days) ............................................................................................... 41 
9.3.4 
Visit 4: Day 28 (±3 days) ............................................................................................... 42 
9.3.5 
Visit 5: Day 56 (±3 days) ............................................................................................... 43 
9.3.6 
Visit 6: Day 84 (±3 days)/Early Termination Visit ....................................................... 44 
9.3.7 
Visit 7: Post-Treatment Safety Follow-Up (+7 days from Visit 6, ±3 days) ................. 44 
9.3.8 
Unscheduled Visits ........................................................................................................ 45 
9.4 
Compliance with Protocol................................................................................................. 45 
9.5 
Subject Disposition ........................................................................................................... 45 
9.5.1 
Completed Subjects ....................................................................................................... 45 
9.5.2 
Discontinued Subjects.................................................................................................... 45 
9.6 
Study Termination ............................................................................................................ 46 
9.7 
Study Duration .................................................................................................................. 46 
9.8 
Monitoring and Quality Assurance ................................................................................... 46 
10. EVALUATION, RECORDING AND REPORTING OF AES AND SAES .................. 47 
10.1 
Definitions......................................................................................................................... 47 
10.1.1 
Adverse Event ................................................................................................................ 47 
10.1.2 
Adverse Drug Reaction .................................................................................................. 47 
10.1.3 
Unexpected ADR ........................................................................................................... 47 
10.1.4 
Serious Adverse Event (SAE) ........................................................................................ 47 
10.1.5 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ........................................ 48 
10.1.6 
Treatment-Emergent Adverse Event (TEAE) ................................................................ 48 
10.2 
Adverse Event Descriptors ............................................................................................... 48 
10.2.1 
Intensity/Severity Categorization .................................................................................. 48 


 
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10.2.2 
Causal Relationship Categorization ............................................................................... 49 
10.2.3 
Outcome Categorization ................................................................................................ 49 
10.2.4 
Symptoms of the Disease Under Study ......................................................................... 49 
10.2.5 
Adverse Events of Special Interest including Abuse, Misuse, Overdose and Medication 
Errors ............................................................................................................................. 50 
10.3 
Reporting Procedure for AEs, SAEs, and Pregnancy ....................................................... 50 
10.3.1 
Adverse Events .............................................................................................................. 50 
10.3.2 
Serious Adverse Events ................................................................................................. 51 
10.3.3 
Pregnancy....................................................................................................................... 53 
11. STATISTICAL HYPOTHESES AND METHODS OF ANALYSES ............................ 55 
11.1 
Analysis Populations ......................................................................................................... 55 
11.2 
Statistical Hypothesis ........................................................................................................ 55 
11.3 
Sample Size ....................................................................................................................... 56 
11.4 
Statistical Analysis ............................................................................................................ 57 
11.4.1 
Unit of Analysis ............................................................................................................. 57 
11.4.2 
Multiplicity Considerations ........................................................................................... 57 
11.4.3 
Primary Efficacy Analyses ............................................................................................ 57 
11.4.4 
Key Secondary Endpoint Analysis ................................................................................ 57 
11.4.5 
Secondary Efficacy Analyses ........................................................................................ 57 
11.4.6 
Safety Variables ............................................................................................................. 58 
11.4.7 
Interim Analyses ............................................................................................................ 58 
12. COMPLIANCE 
WITH 
GOOD 
CLINICAL 
PRACTICES, 
ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES ............................................ 59 
12.1 
Protection of Human Subjects .......................................................................................... 59 
12.1.1 
Subject Informed Consent ............................................................................................. 59 
12.1.2 
Institutional Review Board Approval ............................................................................ 59 
12.2 
Ethical Conduct of the Study ............................................................................................ 59 
12.3 
Subject Confidentiality ..................................................................................................... 59 
12.4 
Documentation .................................................................................................................. 60 
12.4.1 
Retention of Documentation .......................................................................................... 60 
12.5 
Labelling, Packaging, Storage, Accountability, and Return or Disposal of Investigational 
Product .............................................................................................................................. 60 
12.5.1 
Labelling/Packaging ...................................................................................................... 60 
12.5.2 
Storage of Investigational Product ................................................................................. 61 
12.5.3 
Accountability of Investigational Product ..................................................................... 61 
12.5.4 
Return or Disposal of Investigational Product ............................................................... 61 
12.6 
Aurinia Recording of Data on Source Documents and Case Reports Forms (CRFs) ...... 61 
12.7 
Handling of Biological Specimens ................................................................................... 62 
12.8 
Publications ....................................................................................................................... 62 
13. REFERENCES .................................................................................................................... 63 
14. APPENDICES ..................................................................................................................... 65 


 
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LIST OF FIGURES 
Figure 1 
AUDREY (AUR-VOS-2019-01) Study Schematic ............................................... 25 
Figure 2 
Visit-by-Visit Study Flow Chart ............................................................................ 26 
 
LIST OF APPENDICES 
Appendix 1: Schedule of Visits and Measurements ..................................................................... 65 
Appendix 2 : Examination Procedures, Tests, Equipment, and Techniques ................................ 67 
Appendix 3: Daily Dosing Diary .................................................................................................. 73 
 
 


 
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LIST OF ABBREVIATIONS 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AUDREY 
AUrinia DRy EYe 
Aurinia 
Aurinia Pharmaceuticals Inc. 
BCVA 
Best Corrected Visual Acuity 
BID 
Twice daily 
CI 
Confidence interval 
CNI 
Calcineurin inhibitor 
CPM 
Clinical Project Manager 
CRO 
Contract Research Organization 
CsA 
Cyclosporine A 
DED 
Dry Eye Disease 
DES 
Dry Eye Syndrome 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ERG 
Electroretinography 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FCS 
Fluorescein Corneal Staining 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IWRS 
Interactive Web Response System 
KCS 
Keratoconjunctivitis sicca 
LASIK 
Laser-assisted in situ keratomileusis 
LogMAR 
Logarithm of the Minimum Angle of Resolution 


 
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mITT 
Modified Intent-to-Treat 
MMRM 
Mixed Effect Model Repeated Measures 
NEI 
National Eye Institute 
NFAT 
Nuclear Factor of Activated T-cells 
NOAEL 
No observed adverse effect level 
NSAID 
Nonsteroidal Anti-Inflammatory Drug 
NZW 
New Zealand White 
OTC 
Over-the-counter 
OU 
Both eyes 
PP 
Per Protocol 
SAE 
Serious adverse event 
SANDE 
Symptom Assessment in Dry Eye 
STT 
Schirmer Tear Test 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
VAS 
Visual Analog Scale 
VOS 
Voclosporin ophthalmic solution 


 
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1. INTRODUCTION AND BACKGROUND 
Dry eye syndrome (DES) (also known as dry eye disease (DED) and keratoconjunctivitis sicca 
(KCS), herein referred to as DES) is a complex disorder of the ocular surface disease (OSD) 
characterized by tear film instability progressing to tear hyperosmolarity, epithelial damage with 
inflammation, neurogenic inflammation, and eventual fibrosis of the lacrimal gland with reduced 
tear production [(Boboridis and Konstas 2018)]. The Tear Film and Ocular Surface Society Dry 
Eye Workshop group defines global DES as a multi-factorial disease of the ocular surface 
characterized by a loss of homeostasis of the tear film accompanied by ocular symptoms. These 
include tear film instability and hyperosmolarity, ocular surface inflammation and damage, and 
neurosensory abnormalities [(Craig, Nichols et al. 2017)]. The overall incidence of DES has 
significant geographic variation, with published data ranging from 5%-34% of US adults over 50 
years of age. Given the heterogeneity of patients, a retrospective analysis of the US Department of 
Defense Medical Claims Data demonstrated an overall prevalence of 5.3% of adults have DES, 
impacting twice as many women as men, and increasing in prevalence with age. The 2015 US 
Census estimated that up to 16 million people experienced DES in the US [(Dana, Bradley et al. 
2019)]. In patients with DES, tear production has been shown to be increased with the use of 
topical immunosuppressants, including cyclosporine. Symptoms of DES include a sensation of dry 
eyes, foreign body sensation, irritation, burning, tearing, ocular pain, and itching, among others. 
DES affects quality of life and work productivity, and patients with moderate to severe DES may 
experience reduced visual function in addition to ocular dysfunction. Current therapy includes a 
stepped approach, which starts with over-the-counter (OTC) lubricants and artificial tear 
replacements, and then expands to include topical anti-inflammatory therapy and punctal occlusion 
[(Craig, Nichols et al. 2017)]. There are currently three FDA-approved prescription medications 
used for DES, topical cyclosporine ophthalmic solution 0.05% (Restasis®, herein referred to as 
Restasis) [(Restasis® 2017)], lifitegrast ophthalmic solution 5% (Xiidra®, herein referred to as 
Xiidra) [(Xiidra® 2017)], and cyclosporine ophthalmic solution 0.09% (Cequa™, herein referred 
to as Cequa) [(CEQUA® 2018)]. A significant number of patients using Restasis experience the 
following adverse reactions: ocular irritation upon instillation, slow onset of response, and limited 
efficacy [(Restasis® 2017)]. Adverse reactions with Xiidra include instillation irritation, dysgeusia, 
and reduced visual acuity that occurred in 5%-25% of subjects in clinical trials [(Xiidra® 2017)]. 
The most common adverse reactions reported with Cequa were pain on instillation of drops (22% 
of subjects) and conjunctival hyperemia (6% of subjects) [(CEQUA® 2018)]. Despite these 
approved products, an unmet clinical need remains for improved therapeutic options for patients 
with moderate to severe DED. 
In patients with DES, tear production has been shown to be increased with the use of topical 
immunosuppressants, including cyclosporine. It is believed that T-lymphocyte infiltration and 
activation in the lacrimal gland represents an underlying pathogenesis for DES. Calcineurin 
inhibitors reversibly inhibit immunocompetent lymphocytes, particularly T-lymphocytes, in the 
G0 or G1 phase of the cell cycle and also reversibly inhibit the production and release of 
lymphokines [(Granelli-Piperno 1986)]. Calcineurin is a calcium- and calmodulin-dependent 
serine-threonine phosphatase. Calcineurin inhibitors (CNIs) inhibit the ability of calcineurin to 


 
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dephosphorylate the nuclear factor of activated T-cells (NFAT), which is required for translocation 
of NFAT from the cytoplasm to the nucleus, thereby preventing activation of various transcription 
factors necessary for the induction of cytokine genes during T-cell activation (i.e., interleukin-2, 
interleukin-4, tumor necrosis factor-α, granulocyte-macrophage colony stimulating factor, and 
interferon-γ) [(Stepkowski 2000, Wiseman 2016)]. 
Voclosporin (LX214) is a novel next generation CNI that is currently being evaluated for a variety 
of systemic and topical indications. Voclosporin is structurally similar to cyclosporine A (CsA), 
except for a novel modification of a functional group on the amino acid-1 residue of the molecule. 
This alteration has changed how voclosporin binds to calcineurin leading to an improved potency 
when compared to CsA. This modification has also changed the metabolic profile of voclosporin 
by shifting metabolism away from amino acid-1, which is the major site of metabolism for CsA. 
The altered metabolic profile has led to a faster elimination of metabolites resulting in lower 
metabolite exposure compared to CsA. The combination of increased potency and decreased 
metabolite 
exposure, 
for 
voclosporin 
compared 
to 
CsA, 
has 
led 
to 
better 
pharmacokinetic/pharmacodynamic predictability. 
1.1 
Nonclinical Studies of Voclosporin in Dry Eye 
Two Good Laboratory Practice (GCP) toxicology studies [(S07654 2009, S07655 2009)] have 
been conducted to evaluate the safety of voclosporin ophthalmic solution (VOS) in the eye of the 
New Zealand White (NZW) rabbit and the Beagle dog with dosing for 14 days. Test animals were 
euthanized on Day 15, and recovery animals were sacrificed on Day 29. Animals received two, 
four, or eight bilateral topical applications of 0.2% VOS within 8 hours daily, corresponding to 
doses of approximately 0.14, 0.28, and 0.56 mg/eye/day, respectively. Control animals received 8 
doses of the vehicle within 8 hours daily. Safety was evaluated using macroscopic and microscopic 
ophthalmologic evaluations; tonometry; electroretinography (ERG) evaluation; gross and 
microscopic pathology of the eyes (including optic nerve), submandibular lymph nodes, spleen, 
and thymus; and hematology, blood chemistry, and coagulation parameters. Blood voclosporin 
concentrations were obtained on Days 1 and 13 at pre-dose and 8, 8.5, 10, and 12 hours after the 
first VOS instillation.  
In the NZW rabbit study, no VOS ocular treatment-related changes in serum chemistry, 
hematology, coagulation, gross pathology, or organ weights were found at the completion of the 
dosing period or following a 14-day recovery (without treatment). Similarly, no treatment-related 
macroscopic or microscopic ophthalmological changes or effects on intraocular pressure 
associated with the administration of VOS were reported. There were no histologic findings in the 
spleen, thymus, or rostral and caudal sections of the mandibular lymph nodes. A standard battery 
of bilateral full-field flash ERGs was performed; sporadic statistically significant differences were 
seen, but as these were all limited to one eye, were not dose-dependent, and were not supported by 
corresponding changes in related ERG parameters (for example, a change in a-wave implicit time 
was not accompanied by a change in a-wave amplitude), they were judged to have no significance. 
The ocular no observed adverse effect level (NOAEL) for VOS in NZW rabbits was determined 


 
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to be 0.56 mg/eye/day. There was some accumulation of voclosporin in blood over the course of 
the study, with mean trough levels on Day 13 of 0.028, 0.154, and 0.325 ng/mL for the low, mid, 
and high dose groups, respectively. The mean maximum blood concentration achieved 1 hour after 
dosing (high dose group) was 2.29 ng/mL on Day 13. 
In the Beagle dog study, similar results were reported for all safety parameters. The ocular NOAEL 
for VOS in Beagle dogs was determined to be 0.56 mg/eye/day. There was some accumulation of 
voclosporin in blood over the course of the study, with mean trough levels on Day 13 of 0.017, 
0.173, and 0.297 ng/mL for the low, mid, and high dose groups, respectively. The mean maximum 
blood concentration achieved 1 hour after dosing (high dose group) was 1.178 ng/mL on Day 13. 
In an additional 13-week NZW rabbit study [(S08661 2009)] no mortality, systemic toxicity, or 
effects on specific ocular indices were observed following daily bilateral topical ocular 
administration of placebo or VOS (0.2% voclosporin) at a frequency of up to eight times daily 
(hourly intervals; ~0.56 mg/eye/day) for 13 weeks or following a 4-week recovery period. The 
NOAEL for repeat topical ocular administration of VOS (0.2% voclosporin) to male and female 
NZW rabbits for 13 weeks was >0.56 mg/eye/day.  
In summary, the two repeated-dose ocular toxicology studies [(S07654 2009, S07655 2009)] 
demonstrated that there were no specific ocular indices or histopathology, and no systemic toxicity 
observed in either dogs or rabbits with 14 days of dosing. In addition, there was no mortality, 
systemic toxicity, or effects on specific ocular indices observed following daily bilateral topical 
ocular administration of placebo or VOS (0.2% voclosporin) at a frequency of up to eight times 
daily (hourly intervals; ~0.56 mg/eye/day) for 13 weeks or following a 4-week recovery period in 
rabbits. 
In addition to the three repeated dose toxicology studies, the efficacy and safety of VOS 0.2% has 
been evaluated in dogs with naturally occurring KCS [(S15389-00 2017)], diagnosed by the 
Schirmer Tear Test (STT) of >1 mm/min and <8 mm/min in one or both eyes (OU). Thirty-five 
dogs ≥6 months old were randomly assigned in a 3:1 ratio to receive either VOS (n=25) or 
Optimmune® Ophthalmic Ointment (n=10) for 28 days BID. Results showed that treatment with 
VOS resulted in a statistically significant within-group increase in mean STT from baseline of 4.6 
mm/min to each post-treatment visit. Qualitatively, this increase in magnitude was higher than 
seen in the concurrent Optimmune control group. For the Optimmune group, the change from 
baseline to Visit 2, 3, and 4, respectively, was not statistically significant, whereas for the VOS-
treated group, each change from baseline was statistically significant (p<0.0001), demonstrating 
that VOS was effective in treating KCS in dogs. 
In order to determine potential melanin binding of 14C-LX214 (pre-clinical drug product 
formulation), ocular tissue 14C-LX214-derived radioactivity concentrations were compared 
between data obtained from albino NZW rabbits [(S08661 2009)] given a single bilateral 
instillation in a separate study and similarly treated pigmented Dutch-Belted rabbits 
[(S08662 2009)]. Ocular pigments in Dutch-Belted rabbits are widely spread in multiple structures 


 
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including iris (stroma and epithelium), ciliary body (stroma and one epithelial layer), choroid 
(stroma), retina (epithelium), eyelids, and conjunctiva. The total radioactivity in these ocular 
tissues of Dutch-Belted rabbits was not statistically significantly different from NZW rabbits at 
the six sampling time points. Therefore, there was no evidence of melanin binding of 14C-LX214 
after a single ocular administration. These data were confirmed in an in vitro model.  
1.2 
Clinical Studies of Voclosporin in Dry Eye 
Voclosporin ophthalmic solution has been investigated in one Phase 1 dose-escalation study 
(LX214-01) in 30 healthy volunteers, followed by an open-label evaluation of VOS in five subjects 
with mild to moderate DES. In this study, both 0.02% and 0.2% concentrations were found to be 
safe and well tolerated following multiple instillations in healthy subjects. All adverse events (AEs) 
across study cohorts were mild or moderate in severity and all resolved completely, most without 
requiring treatment. Although the sample size was small, results from the five subjects with DES 
suggested VOS may be beneficial in the treatment of DES and is supported by the Ocular Surface 
Disease Index scores, which were improved in all subjects at all time points while on study drug. 
Overall, the results indicated VOS can be used safely when administered BID for two weeks 
[(LX214-01 2009)]. 
Additionally, one Phase 2, Investigator-masked, randomized, parallel-group study was conducted 
in 100 subjects with DES at 7 treatment sites to evaluate the efficacy, safety, and tolerability of 
VOS compared to Restasis [(AUR-VOS-2017-01 2019)]. Results of this study indicated that VOS 
was well tolerated at doses up to 0.2% w/v OU, BID for up to 28 days. 
Clinically relevant and statistically superior treatment effects were observed in favor of VOS at 
most time points for the standard signs of DES, namely change from baseline in STT and 
fluorescein corneal staining (FCS). After 2 weeks of treatment, a benefit of treatment with VOS 
compared with Restasis was observed in these objective signs of DES. This potentially indicates a 
more rapid onset of action and beneficial anti-inflammatory effect for VOS. 
Pre-specified exploratory efficacy analyses also favored VOS, which demonstrated a statistically 
significant difference in the number of subjects achieving a ≥10 mm improvement in STT at Week 
4 in the VOS group (42.9%) compared with the Restasis group (18.4%) (OR=4.40; 95% CI: 1.55, 
12.51; p=0.0055).  
There were marked improvements from baseline in symptom severity at Week 1 with sustained 
improvements at Week 4 in both treatment groups, though there were no statistically significant 
differences between treatment groups. 
Voclosporin ophthalmic solution was well-tolerated over a 4-week treatment period, and no new 
or unexpected safety signals were observed with the use of VOS in DES, though more AEs were 
reported in the VOS group. The overall safety profile was consistent with the expectations for the 
class of drug, the patient population, and concomitant therapies. These data demonstrated the 
positive benefit/risk profile for VOS and support the choice of proceeding with a dose-ranging 


 
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clinical study to further explore safety and efficacy over a longer duration [(AUR-VOS-2017-01 
2019)]. 
1.3 
Study Rationale 
These results from the AUR-VOS-2017-01 study support the conduct of this dose-ranging clinical 
study (AUR-VOS-2019-01, AUrinia DRy EYe (AUDREY)) to explore safety and efficacy over a 
longer duration. Please refer to Section 1.2 of the Investigator’s Brochure (IB) [(VOS-
Investigator's-Brochure 2019)] for additional details supporting the safety and efficacy of VOS in 
subjects with DES.  
 
 


 
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2. STUDY OBJECTIVES 
To assess the efficacy and safety of three different concentrations of VOS (0.05%, 0.10%, and 
0.20%) when administered BID in both eyes (OU) over 12 weeks compared to vehicle in subjects 
with DES. 


 
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3. CLINICAL HYPOTHESIS 
The clinical hypothesis for this study is that at least one of three concentrations of VOS (0.05%, 
0.10%, and 0.20%) when administered OU BID over 4 weeks is significantly different compared 
to vehicle alone for the following DES sign improvement:  
• Proportion of subjects with a ≥10 mm increase from baseline in STT at Week 4 in the study 
eye  


 
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4. OVERALL STUDY DESIGN 
This is a Phase 2/3, multi-center, randomized, double-masked, vehicle-controlled study to assess 
the efficacy and safety of three different concentrations of VOS when administered OU BID over 
12 weeks in subjects with mild to moderate DES. A 14- to 17-day run-in period with VOS vehicle 
will be included. Subjects will undergo a 2-week run-in period in which VOS vehicle will be self-
administered OU, BID. Subjects will be re-assessed to confirm that all participants meet all of the 
inclusion criteria and none of the exclusion criteria. It was estimated that the study would enroll 
approximately 480 subjects (amended to approximately 505 due to COVID-19) across 
approximately 9 study centers. Eligible subjects will be randomized in a 1:1:1:1 ratio to one of the 
following study treatment arms after the 14- to 17-day run-in period: 
• 0.05% VOS BID 
• 0.10% VOS BID 
• 0.20% VOS BID 
• VOS Vehicle BID 
Subjects will be stratified by eye dryness VAS score ≥60 mm and <60 mm. 
See Figure 1 for the AUDREY (AUR-VOS-2019-01) study schematic. 
 








 
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5. STUDY POPULATION 
5.1 
Number of Subjects 
It was estimated that 480 subjects (amended to 505 due to COVID-19) across 9 study centers 
would be enrolled and randomized in a 1:1:1:1 ratio to one of the following study treatment arms: 
• 0.05% VOS BID 
• 0.10% VOS BID 
• 0.20% VOS BID 
• VOS Vehicle BID 
5.2 
Study Population Characteristics 
All subjects must meet all inclusion criteria and none of the exclusion criteria.  
5.3 
Inclusion Criteria 
Subjects are eligible for participation if they: 
1. Provide written informed consent before any study-specific procedures are performed. 
2. Are male or female, with a minimum age of 18 years (or legal age of consent if >18 years), at 
the time of screening. 
3. Have a documented history of DES in both eyes supported by a previous clinical diagnosis 
prior to Visit 1. 
4. Are willing and able to follow protocol procedures and instructions and can be present for the 
required study visits for the duration of the study. 
5. Have a symptom severity score of ≥30 mm for Eye Dryness on the Individual Symptom 
Severity Assessment Visual Analog Scale (VAS) (0-100 mm) at both Visit 1 and 2. 
6. Have a BCVA in both eyes of +0.7 logarithm of the Minimum Angle of Resolution (logMAR) 
or better as assessed by Early Treatment of Diabetic Retinopathy Study (ETDRS) chart at Visit 
1. 
7. Have ongoing DES, as defined by at least one eye (if one eye, the same eye) meeting both of 
the following criteria at both Visit 1 and Visit 2:  
a) 
Have an unanesthetized Schirmer Tear Test (STT) score of ≥1 mm and ≤10 mm per 
5 minutes. 


 
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b) 
Have a total fluorescein corneal staining (FCS) score of at least 3 [National Eye 
Institute (NEI)/Industry Workshop 0-15 scale]. 
Note: The qualifying eye at Visit 1 must be the same eye at Visit 2. 
8. Have normal lid anatomy 
5.4 
Exclusion Criteria 
In order for subjects to be eligible, (as specified in the Schedule of Events) subjects must not: 
1. Be non-compliant during the run-in treatment (non-compliance defined as dosing <80% 
or >120% of the time, calculated by counting the number of returned and unused study drug 
ampules). 
2. Have any known hypersensitivity or contraindication to study treatments (including excipients), 
topical anesthetics, or vital dyes. 
3. Have had any eye surgery in either eye except for cataract surgery or laser-assisted in situ 
keratomileusis (LASIK). 
4. Have undergone cataract or LASIK surgery within 1 year prior to Visit 1. 
5. Have recent or current evidence of ocular infection or inflammation in either eye including 
ocular pemphigoid and Stevens Johnson Syndrome. 
6. Have current evidence of clinically significant blepharitis (defined as requiring lid hygiene 
therapy and additional therapies such as doxycycline or Lipiflow®) or other meibomian gland 
dysfunction, conjunctivitis, or a history of herpes simplex or zoster keratitis in either eye. 
7. Have clinically significant ocular disease in either eye (i.e., corneal edema, uveitis, severe KCS) 
or active ocular allergies that might interfere with study procedures or assessments in the 
opinion of the Investigator. Severe KCS is defined by an FCS score of ≥13. 
8. Be taking or have a known need for any of the following treatment therapies within the time 
frames as specified below: 
a) 
Any investigational drug or device within 30 days prior to the Screening Visit (Visit 
1) and subjects may not receive any investigational drug or device during the entire 
study except that which is allowed by the protocol. 
b) 
Ophthalmic drugs (any topical eye medications) including prescription medication 
and OTC agents, from date of Visit 1 to Visit 7. 
c) 
Contact lenses 24 hours prior to the Screening Visit (Visit 1) to the end of Visit 7. 


 
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d) 
Any prior use of amiodarone. 
e) 
Within 72 hours of Visit 1 and for the duration of the study: 
− 
Oral antihistamines 
f) 
Within 14 days prior to Visit 1 and for the duration of the study: 
− 
Xiidra® (lifitegrast) 
g) 
Within 30 days prior to Visit 1 and for the duration of the study: 
− 
Calcineurin Inhibitor such as Restasis® (cyclosporin ophthalmic emulsion) 
or CequaTM 
− 
Topical ocular anti-histamines 
− 
Ocular, inhaled, or intranasal corticosteroids 
− 
Topical or oral mast cell stabilizers  
− 
Topical or nasal vasoconstrictors 
− 
Topical ocular nonsteroidal anti-inflammatory drugs (NSAIDs) 
− 
Topical ocular antibiotics 
− 
True Tear device  
h) 
Unstable dose within 30 days prior to the Screening Visit (Visit 1) or during the 
study; alteration to the dose or anticipated alterations to the dose of the following 
are disallowed: 
− 
Tetracyclines 
− 
Omega 3s or Omega 6s 
i) 
Unstable dose within 60 days prior to the Screening Visit (Visit 1) or during the 
study; alteration to the dose or anticipated alterations to the dose of the following 
are disallowed: 
− 
Anticholinergics 
− 
Antidepressants 
− 
Oral contraceptives 


 
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− 
Isotretinoin 
− 
Oral systemic corticosteroids 
− 
Oral systemic immunosuppressive agents 
j) 
Within 90 days prior to the Screening Visit (Visit 1) or during the study, the subject 
has had cauterization of the punctum or alternations to (insertion or removal) 
punctal plug(s) or nasolacrimal surgery. Note: If a punctal plug is in place at the 
Screening Visit (Visit 1) and it is dislodged during the study, the plug should be 
replaced as soon as possible. 
9. Have clinically significant systemic disease (i.e., uncontrolled diabetes, hepatic, renal, 
endocrine or cardiovascular disorders) that might interfere with the study. 
10. Have been randomized and treated in a previous study where VOS was the IP. 
11. Be a woman of childbearing potential who is pregnant, nursing, planning a pregnancy, or not 
using a medically acceptable form of birth control. All women of childbearing potential must 
be willing to take a urine pregnancy test at Visit 1 and Visit 6. Details surrounding adequate 
forms of contraception are outlined in Section 5.6. 
12. Have a condition or be in a situation that the Investigator feels may put the subject at significant 
risk, may confound the study results, or may interfere significantly with the subject’s 
participation in the study. 
5.5 
Withdrawal Criteria 
Subjects may voluntarily withdraw from study participation at any time for any reason. 
Alternatively, subjects may be withdrawn at the Investigator’s discretion if it is in the subject’s 
best interest. 
Every effort should be made for subjects who withdraw from the study (either voluntarily or at the 
Investigator’s discretion) to undergo end-of-study assessments (Visit 6). If possible, the subject 
should also be advised to come into the site for the Follow-Up Visit (Visit 7), 7 days (±3 days) 
after self-instilling the final dose. If a subject refuses end-of-study procedures, the reason for 
refusal should be fully documented in the subject’s source document. It is the subject’s right to 
withdraw from the study without providing a reason. In this case, the source documents and the 
electronic case report form (eCRF) should document the reason for discontinuation as “withdrawal 
of consent.” Withdrawn subjects will not be replaced. 
5.6 
Aurinia Adequate/Effective Contraception 
An adult woman is considered to be of childbearing potential unless she is at least 1 year 
post-menopausal or 3 months post-surgical sterilization. All women of childbearing potential must 


 
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have a negative urine pregnancy test result at Visit 1 and must not intend to become pregnant 
during the study. Women of childbearing potential who are not abstinent must have been using 
one of the following acceptable methods of birth control for the times specified:  
1. Intrauterine device in place for at least 4 weeks prior to Visit 1 through Visit 7 
2. Barrier method (condom or diaphragm) with spermicide from Visit 1 through Visit 7. 
3. Stable hormonal contraceptive for at least 60 days prior to Visit 1 through Visit 7. 
4. In a monogamous relationship with a surgically sterilized (i.e., vasectomized) partner at 
least 6 months prior to Visit 1 through Visit 7. 


 
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6. STUDY PARAMETERS 
6.1 
Efficacy Measures 
6.1.1 Primary Efficacy Endpoint 
Proportion of subjects with a ≥10 mm increase from baseline in STT at Week 4 in the study eye. 
The study eye will be defined as the qualifying eye that achieves the lowest STT score at baseline. 
Should both eyes be qualifying eyes with identical STT scores at baseline, the eye with the worst 
FCS score will be used. Should these scores also be equal, the right eye will be used. 
6.1.2 Key Secondary Endpoint 
Mean change from baseline in Eye Dryness VAS at Week 4 in subjects with a baseline Eye 
Dryness VAS score ≥60 mm. 
6.1.3 Secondary Endpoints 
• Proportion of subjects with a ≥10 mm increase from baseline in STT at Weeks 2, 8, and 12 in 
the study eye. 
• Mean change from baseline in total FCS (NEI/Industry Workshop 0-15 scale) score to Weeks 
2, 4, 8, and 12 in the study eye. 
• Mean change from baseline in FCS score in the 5 regions of the cornea (central, superior, 
inferior, temporal, and nasal) to Weeks 2, 4, 8, and 12 in the study eye. 
• Mean change from baseline in STT score to Weeks 2, 4, 8, and 12 in the study eye. 
• Mean change from baseline in Eye Dryness VAS (0-100 mm) score to Weeks 2, 4, 8, and 12 
within treatment group. 
• Mean change from baseline in Ocular Discomfort VAS (0-100 mm) score to Weeks 2, 4, 8, 
and 12. 
• Mean change from baseline in Eye Dryness, Burning/Stinging, Itching, Photophobia, Eye Pain, 
Foreign Body Sensation, and Blurred Vision VAS (0-100 mm) score to Weeks 2, 4, 8, and 12. 
• Mean change from baseline of the sum of Individual Symptom Score (VAS Total Symptom 
Summary Score) to Weeks 2, 4, 8, and 12.  
• Mean change from baseline in Symptom Assessment in Dry Eye (SANDE) frequency and 
severity scores to Week 2, 4, 8, and 12. 
6.2 
Safety Measures 
• Treatment-emergent adverse events (TEAEs) 


 
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• Change from baseline in BCVA over time 
• Changes from baseline in slit-lamp biomicroscopy over time 
• Changes from screening in dilated ophthalmoscopy over time 


 
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7. RANDOMIZATION, MASKING AND UNMASKING PROCEDURES 
7.1 
Randomization 
All subjects enrolled must be identifiable throughout the study. The Investigator will maintain a 
list of subject numbers and subject names to enable records to be found at a later stage. Subjects 
will be allocated a subject number at screening visit (Visit 1) and registered with an interactive 
web randomization system (IWRS). Subjects meeting the required eligibility criteria will be 
randomized to treatment at Visit 2 (baseline). The randomization will be stratified by Eye Dryness 
score (<60 mm and ≥60 mm). The subjects will be randomized in a ratio 1:1:1:1 to receive either 
VOS vehicle, VOS 0.05%, VOS 0.10%, or VOS 0.20%. The randomization ratio will be 
maintained within each study center. A randomization list will be generated and provided by an 
unmasked statistician.  
7.2 
Masking 
All study personnel and subjects will be masked to the study treatment administered during the 
study. VOS vehicle, 0.05% VOS, 0.10% VOS, and 0.20% VOS will be identical in appearance. 
The treatment group allocated will not be available to the study monitor, project statistician, or the 
project team at Aurinia Pharmaceuticals or the CRO. The site staff, monitors, and study subjects 
will remain masked until the end of the study. In case of emergency, the unmasking process below 
should be followed.  
7.3 
Unmasking 
In the rare event that an AE or pregnancy occurs for which knowledge of the identity of the study 
treatment administered is necessary to manage the subject’s condition, the IWRS code for that 
subject may be broken and the test substance identified. Procedures for unmasking will be provided 
in a separate manual. 
Should unmasking be required, the Investigator should call the Medical Monitor before unmasking 
whenever possible; however, the Investigator is responsible for the medical care of the individual 
study subject and does not require the agreement of the Medical Monitor before unmasking. In the 
event that the Medical Monitor cannot be reached, the Investigator should contact the Project 
Manager at the CRO. The reason for unmasking must be documented. The information on study 
treatment should only be used for decision making in the subject’s further treatment. Details on 
unmasked treatment assignments should not be shared with the Study Monitor and project team. 
Unmasked subjects will be discontinued from the study. 


 
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8. STUDY MATERIALS 
8.1 
Dosage Forms/Formulation 
All study treatment to be used in this study will be manufactured in accordance with current Good 
Manufacturing Practice (GMP). Study treatment will be supplied by Aurinia. 
8.1.1 Study Treatments 
Company Code: 
 
Chemical Name: 
Empirical Formula: 
 
Generic Name: 
VOS 
Dosage Form: 
Voclosporin Ophthalmic Solution is provided as a clear micellar solution in 
single-use blow fill seal ampules for topical ocular administration.  
Strength: 
0.05% VOS, 0.10% VOS, or 0.20% VOS 
Manufacturer:  
Aurinia Pharmaceuticals Inc. 
Study drug will be supplied as a sterile, clear, micellar solution containing 0.05%, 0.10%, or 0.20% 
Active Pharmaceutical Ingredient (voclosporin), in single-use blow fill seal ampules for topical 
ocular administration. 
 
 
 
 
 
The vehicle solution contains all components of the drug product solution with the exception of 
voclosporin. 
8.1.2 
Description and Justification for the Route of Administration, Dosage, 
Dosage Regimen, and Treatment Period 
Topical ophthalmic dosing is the optimal route of administration for dry eye treatments. The 
dosage and dosage regimen were selected based on nonclinical studies described in Section 1.1 
and clinical studies described in Section 1.2. The proposed treatment period of 12 weeks is also 
based on nonclinical and clinical studies and on the immunosuppressive mechanism of action of 
the drug. 


 
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8.1.3 Instructions for Use and Administration 
• At the end of Visit 1, qualified subjects will receive a kit with run-in (vehicle ophthalmic 
solution) for OU, BID dosing until Visit 2. Subjects will be instructed to dose in the morning 
and evening. One drop of the IP will be instilled in each eye BID. Subjects will be instructed 
to bring all used and unused IP to every clinic visit to conduct accountability. 
• At Visit 2, the run-in kit will be collected from subjects for drug accountability. At the end of 
Visit 2, qualified subjects will be randomized using the IWRS and dispensed a kit containing 
either VOS 0.05%, VOS 0.10%, VOS 0.20%, or vehicle for BID dosing until Visit 3. Subjects 
will be instructed not to take the morning dose of run-in on the day of study randomization 
(Visit 2). Instructions regarding timing between doses will remain identical to instructions 
given for the run-in period at Visit 1. 
• At Visit 3, the study drug kit will be collected from subjects for drug accountability. Subjects 
will receive a new kit of study drug assigned via the IWRS (with the same treatment assignment 
that they were randomized to at Visit 2) for BID dosing until Visit 4. 
• At Visit 4, the study drug kit will be collected from subjects for drug accountability. Subjects 
will be dispensed two new kits of study drug assigned via the IWRS (with the same treatment 
assignment that they were randomized to at Visit 2) for BID dosing until Visit 5. 
• At Visit 5, the study drug kits will be collected from subjects for drug accountability. Subjects 
will be dispensed two new kits of study drug assigned via the IWRS (with the same treatment 
assignment that they were randomized to at Visit 2) for BID dosing until Visit 6. 
• At Visits 6, the study drug kits and any leftover IP not previously returned to clinic will be 
collected from subjects for drug accountability.  
• Subjects will be instructed not to take their morning dose of run-in or study drug on the day of 
follow-up visits (Visits 2, 3, 4, 5, and 6) prior to the visit. Subjects will be instructed to store 
study drug at home under refrigeration at 2°C-8°C (36-46°F) in the kit box.  
• If needed, replacement kits are also available to be dispensed to a subject. 
8.2 
Other Study Supplies 
Urine pregnancy tests, Schirmer test strips, sodium fluorescein and tropicamide ophthalmic 
solution will be provided by Sponsor.  


 
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9. STUDY METHODS AND PROCEDURES 
9.1 
Subject Entry Procedures 
9.1.1 Overview 
Subjects as defined by the inclusion and exclusion criteria outlined Sections 5.3 and 5.4. 
9.1.2 Informed Consent 
Prior to a subject’s participation in the trial (i.e., prior to changes in a subject’s medical treatment 
and/or prior to study-related procedures), the study will be discussed with each subject, and 
subjects wishing to participate must give written informed consent using an informed consent form 
(ICF). The ICF must be the most recent version that has received approval/favorable review by a 
properly constituted Institutional Review Board (IRB). 
9.1.3 Washout Intervals 
Prohibited medications, treatments, and activities are outlined in Exclusion Criteria Number 8. 
9.1.4 Procedures for Final Study Entry 
Subjects must meet all of the inclusion and none of the exclusion criteria at both Visit 1 and Visit 
2. No re-screening is permitted. 
9.1.5 Methods for Assignment to Treatment Groups 
Prior to initiation of study run-in (at Visit 1), each subject who qualifies for entry will be assigned 
a screening number. All screening numbers will be assigned in strict numerical sequence at a site, 
and no numbers will be skipped or omitted. If all inclusion and none of the exclusion criteria are 
met at Visits 1 and 2, each qualifying subject will then be assigned a randomization number at the 
end of Visit 2 using an IWRS. 
The randomization number will be recorded on the patient’s source document and eCRF. Aurinia, 
Investigators, and study staff will be masked during the randomization process and throughout the 
study. 
9.2 
Concurrent Therapies 
The use of any concurrent medication, prescription, or OTC is to be recorded on the subject’s 
source document and corresponding eCRF along with the reason the medication was taken. 
Concurrent enrollment in another investigational drug or device study is not permitted. 
9.2.1 Prohibited Medications 
Disallowed medications/treatments during the study are outlined in Exclusion Criteria 8. 


 
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9.2.2 Rescue Medications 
No rescue medications are required for this study. 
9.2.3 Special Diets or Activities 
No special diets or activities are required for this study. 
9.3 
Examination Procedures 
An ICF must be signed and dated by the subject and witness before any study–related procedures 
are performed. Procedures listed below should be performed in the given order. A detailed 
Schedule of Events can be found in Appendix 1: Schedule of Visits and Measurements. 
Procedures listed below can be reviewed in detail in Appendix 2: Examination Procedures, Tests, 
Equipment, and Techniques. 
9.3.1 Visit 1: Day -17 to -14 Screening and Run-In Period 
All subjects will undergo the following screening assessments: 
• Informed Consent/HIPAA: Prior to any changes in a subject’s medical treatment and/or 
invasive procedures, the study will be discussed with each subject and subjects wishing to 
participate must give written informed consent and sign a HIPAA form.  
• Demographic Data and Medical/Medication/Ocular History: Collect and record all 
demographic data, medical history, any medications, and any underlying condition(s). 
Significant non-ocular medical history only within the past year and medications within the 
past 30 days will be captured. Record any medications the subject is taking, as well as those 
the subject may have taken but discontinued within 30 days prior to screening. (Any clinically 
significant findings will be recorded in the Medical Ocular History section of the eCRF).  
• Urine Pregnancy Test (for women of childbearing potential): Women of childbearing potential 
must have a negative urine pregnancy test to continue in the study.  
• SANDE 
• VAS 
• BCVA- Subjects must have a score of ≥0.7 logMAR (Snellen equivalent score of ≥20/100 or 
better) in each eye at Visit 1. 
• Initial review of Inclusion/Exclusion Criteria 
• Slit-lamp biomicroscopy  
• FCS as assessed by the NEI scale for Grading of Fluorescein Staining 


 
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• STT (performed at least 20 minutes after FCS is performed) 
• Dilated ophthalmoscopy  
• Final review of Inclusion/Exclusion Criteria 
• Dispensation of run-in kit and instructions for BID dosing until Visit 2 
− 
Subjects will be instructed to dose in each eye BID (once in the morning and once 
in the evening) 
− 
Subjects will be instructed to not dose with run-in on the morning of their next visit 
(Visit 2)  
• Subject self-administers the first dose of run-in, OU, under the supervision of a trained 
technician 
• Dosing diary will be provided and subjects will be instructed on how to record date and time 
of dosing 
• Qualified subjects will be scheduled for Visit 2 
9.3.2 Visit 2: Day 1-Baseline  
• Collection and review of returned run-in kit for compliance 
• Subject will be asked if he/she dosed with run-in on the morning of the visit; if the subject 
indicates he/she dosed that morning, he/she should wait at least 4 hours from the time of dosing 
before efficacy assessments are performed 
•  Concomitant medication updates 
• AE query (since last visit) 
• SANDE 
• VAS  
• BCVA 
• Slit-lamp biomicroscopy 
• FCS 
• STT (performed at least 20 minutes after FCS is performed) 


 
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• Review of eligibility criteria 
• Randomization 
• 
Dispensation of study drug kit according to randomization for BID dosing until Visit 3  
− 
Subjects will be instructed to dose in each eye two times daily (once in the morning 
and once in the evening). 
− 
Subjects will be instructed to not dose with study drug on the morning of their next 
visit (Visit 3) 
• Subject self-administers the first dose of study drug, OU, under the supervision of a trained 
technician 
• AE query post-instillation 
• Dosing diary will be provided and subjects will be instructed on how to record date and time 
of dosing 
• Schedule subjects for Visit 3 
9.3.3 Visit 3: Day 14 (±3 days) 
• Collection and review of study drug accountability (including dosing diaries) 
• Subject will be asked if he/she dosed with study drug on the morning of the visit; if the subject 
indicates he/she dosed that morning, he/she should wait at least 4 hours from the time of dosing 
before efficacy assessments are performed 
• Concomitant medication updates 
• AE query (since last visit) 
• SANDE 
• VAS 
• BCVA 
• Slit-lamp biomicroscopy 
• FCS 
• STT (performed at least 20 minutes after FCS is performed) 


 
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• Dispensation of study drug kit according to randomization for BID dosing until Visit 4 
− 
Subjects will be instructed to dose in each eye two times daily (once in the morning 
and once in the evening) 
− 
Subjects will be instructed to not dose with study drug on the morning of their next 
visit (Visit 4) 
• Subject self-administers the study drug, OU, under the supervision of a trained technician 
• AE query post-instillation 
• Dosing diary will be provided and subjects will be instructed on how to record date and time 
of dosing 
• Schedule subjects for Visit 4 
9.3.4 Visit 4: Day 28 (±3 days) 
• Collection and review of study drug accountability 
• Subject will be asked if he/she dosed with study drug on the morning of the visit; if the subject 
indicates he/she dosed that morning, he/she should wait at least 4 hours from the time of dosing 
before efficacy assessments are performed 
• Concomitant medication updates 
• AE query (since last visit) 
• SANDE 
• VAS 
• BCVA 
• Slit-lamp biomicroscopy 
• FCS 
• STT (performed at least 20 minutes after FCS is performed) 
• Dispensation of two study drug kits according to randomization for BID dosing until Visit 5 
− 
Subjects will be instructed to dose in each eye BID (once in the morning and once 
in the evening) 


 
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− 
Subjects will be instructed to not dose with study drug on the morning of their next 
visit (Visit 5) 
• Subject self-administers the study drug, OU, under the supervision of a trained technician 
• AE query post-instillation 
• Dosing diary will be provided and subjects will be instructed on how to record date and time 
of dosing 
• Schedule subjects for Visit 5 
9.3.5 Visit 5: Day 56 (±3 days) 
• Collection and review of study drug accountability 
• Subject will be asked if he/she dosed with study drug on the morning of the visit; if the subject 
indicates he/she dosed that morning, he/she should wait at least 4 hours from the time of dosing 
before efficacy assessments are performed 
• Concomitant medication updates 
• AE (since last visit) 
• SANDE 
• VAS  
• BCVA 
• Slit-lamp biomicroscopy 
• FCS 
• STT (performed at least 20 minutes after FCS is performed) 
• Dispensation of two study drug kits according to randomization for BID dosing until Visit 6 
− 
Subjects will be instructed to dose in each eye BID (once in the morning and once 
in the evening) 
− 
Subjects will be instructed to not dose with study drug on the morning of their next 
visit (Visit 6) 
• Subject self-administers the study drug, OU, under the supervision of a trained technician 


 
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• AE query post-dose 
• Dosing diary will be provided and subjects will be instructed on how to record date and time 
of dosing 
• Schedule subjects for Visit 6 
9.3.6 Visit 6: Day 84 (±3 days)/Early Termination Visit 
• Collection and review of study drug accountability 
• Subject will be asked if he/she dosed with study drug on the morning of the visit; if the subject 
indicates he/she dosed that morning, he/she should wait at least 4 hours from the time of dosing 
before efficacy assessments are performed 
• Concomitant medication updates 
• AE query (since last visit) 
• SANDE 
• VAS  
• BCVA 
• Slit-lamp biomicroscopy 
• FCS 
• STT (performed at least 20 minutes after FCS is performed) 
• Dilated ophthalmoscopy 
• Urine pregnancy test 
• AE query post-assessments 
• Schedule subjects for Visit 7 
9.3.7 Visit 7: Post-Treatment Safety Follow-Up (+7 days from Visit 6, ±3 days) 
• Concomitant medication updates 
• AE query  
• BCVA 


 
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• Study Exit 
9.3.8 Unscheduled Visits 
Unscheduled visits may also be performed in order to ensure subject safety. All procedures 
performed at an unscheduled visit will be recorded in the source documents and on the 
Unscheduled Visit eCRF pages. Any procedure indicated in the eCRF that is not performed should 
be indicated as “Not done.” 
Evaluations that may be conducted at an Unscheduled Visit include: 
• Slit-lamp biomicroscopy 
• BCVA 
• Urine pregnancy test 
• Dilated ophthalmoscopy 
• Assessment of AEs 
• Assessment of concomitant medications and/or treatments 
• Any other assessments needed in the judgment of the Investigator 
9.4 
Compliance with Protocol 
Subjects will be instructed on proper instillation and storage of study drug at the end of Visits 1 
through 5 and given written instructions. The subject’s used and unused study drug ampules will 
be collected at each visit from Visit 2 up to and including Visit 6 to assess dosing compliance. 
Dosing compliance will be based on the unused ampule count. If the subject is <80% or >120% 
compliant with dosing based on the expected number of unused ampules, then the subject will be 
deemed non-compliant and a dosing deviation should be recorded at each visit.  
These guidelines will be used by the Investigator for determining the subject’s necessary 
compliance for the study and for recording deviations from this compliance. 
9.5 
Subject Disposition 
9.5.1 Completed Subjects 
A completed subject is one who has not been discontinued from the study. 
9.5.2 Discontinued Subjects 
Subjects may be discontinued prior to their completion of the study due to: 
• AEs 


 
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• unmasking when medically necessary 
• protocol violations 
• administrative reasons (i.e., inability to continue, schedule change) 
• lost to follow-up 
• sponsor termination of study 
• subject choice (i.e., withdrawal of consent) 
• other 
Note: In addition, any subject may be discontinued for any sound medical reason at the discretion 
of the Investigator. 
Notification of a subject discontinuation and the reason for discontinuation will be made to the 
CRO and/or Aurinia and will be clearly documented on the eCRF. Discontinued subjects will not 
be replaced. 
9.6 
Study Termination 
The study may be stopped at any time by the Investigator, Aurinia, and/or the CRO with 
appropriate notification. 
9.7 
Study Duration 
An individual subject’s participation will involve 7 visits over approximately 15 weeks 
(approximately 105 days) from first day of screening phase, the run-in period, treatment phase, 
and follow-up period. 
9.8 
Monitoring and Quality Assurance 
During the course of the study a monitor, or designee, will make routine site visits to review 
protocol compliance, assess study drug accountability, and ensure the study is being conducted 
according to the protocol and pertinent regulatory requirements. The review of the subjects’ 
medical records will be performed in a manner that adequately maintains subject confidentiality. 
Further details of the study monitoring will be outlined in a monitoring plan. 
Regulatory authorities of domestic and foreign agencies, quality assurance and/or their designees 
may carry out on-site inspections and/or audits, which may include source data checks. Therefore, 
direct access to the original source data will be required for inspections and/or audits. All 
inspections and audits will be carried out giving consideration to data protection as well as subject 
confidentiality to the extent that local, state, and federal laws apply. 


 
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10. EVALUATION, RECORDING AND REPORTING OF AES AND SAES 
10.1 Definitions 
10.1.1 Adverse Event 
Any untoward medical occurrence in a subject administered a pharmaceutical product and which 
does not necessarily have a causal relationship with this treatment is an AE. 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 
related to the medicinal (investigational) product. 
10.1.2 Adverse Drug Reaction 
In the pre-approval clinical experience with a new medical product or its new usages, particularly 
as the therapeutic dose(s) may not be established, all unintended responses to a medicinal product 
related to any dose should be considered adverse drug reactions (ADRs). The phrase “responses 
to a medicinal product” means that a causal relationship between a medicinal product and an AE 
is at least a reasonable possibility (i.e., the relationship cannot be ruled out). 
10.1.3 Unexpected ADR 
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
information (e.g., IB for an unapproved investigational medicinal product).  
10.1.4 Serious Adverse Event (SAE) 
An SAE is an untoward medical occurrence that at any dose meets one or more of the following 
criteria: 
• Results in death (Note: death is an outcome, not an event) 
• Is life-threatening (Note: the term “life-threatening” refers to an event in which the subject was 
at immediate risk of death at the time of the event; it does not refer to an event that could 
hypothetically have caused a death had it been more severe) 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Results in a congenital anomaly/birth defect 
• Is a medically important event or reaction 
The definitions and reporting requirements of International Council for Harmonisation (ICH) 
Guidelines for Clinical Safety Data Management, Definitions, and Standards for Expedited 
Reporting, Topic E2 will be adhered to. 


 
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Medical and scientific judgment must be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. These will also 
usually be considered serious. 
Hospitalizations for elective or previously scheduled surgery for pre-existing conditions, which 
have not worsened after initiation of treatment, will not be classed as SAEs. Previously scheduled 
hospitalizations must be documented in the subject’s source documents before the subject signed 
the ICF.  
10.1.5 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
Any ADR that is both serious and unexpected (per the IB) that, based on the opinion of the 
Investigator or Aurinia, is felt to have a reasonable suspected causal relationship to a medicinal 
product is a SUSAR. 
10.1.6 Treatment-Emergent Adverse Event (TEAE) 
Any AE with an onset date between the first dose of randomized study treatment and the last study 
visit (Post-Treatment Safety Follow-Up Visit 7 or last visit attended by the subject). 
10.2 Adverse Event Descriptors 
10.2.1 Intensity/Severity Categorization 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); however, the event itself may be of relatively minor 
medical significance (such as severe headache). This is not the same as “serious,” which is based 
on subject/event outcome or action criteria usually associated with events that pose a threat to a 
subject’s life or functioning. Seriousness (not severity) serves as a guide for defining regulatory 
reporting obligations. 
In general, the intensity of a particular AE to be recorded is the worst intensity experienced by the 
subject during the course of the event. The medical assessment of intensity will be determined by 
using the following definitions: 
• Mild: 
The AE is easily tolerated and does not interfere with usual activity. 
• Moderate: The AE interferes with daily activity, but the subject is still able to function. 
• Severe: 
 The AE is incapacitating, and the subject is unable to work or complete usual 
activity. 


 
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10.2.2 Causal Relationship Categorization 
The Investigator will be required to assess the relationship to study treatment (defined as vehicle 
for run-in period and active drug/vehicle for randomized subjects) for each AE as related or not 
related, in addition to the relationship to disease under study (see Section 10.2.4). An AE will not 
be able to be assessed as related to both disease under study and related to study treatment. 
An Investigator who is qualified in medicine must make the determination of relationship to the 
study treatment and disease under study for each AE and SAE. The Investigator must decide 
whether, in his or her medical judgment, there is a reasonable possibility that the event may have 
been caused by the study treatment. If there is no valid reason for suggesting a relationship, then 
the AE/SAE must be classified as not related. Otherwise, if there is any valid reason, even if 
undetermined or untested, for suspecting a cause and effect relationship between the study 
treatment and the occurrence of the AE/SAE, then the AE/SAE will be considered related. For 
SAEs, the Investigator must provide a brief comment explaining the rationale of his/her assessment 
of causal relationship on the SAE reporting form. 
The following additional guidance may be helpful: 
Term 
Relationship 
Definition 
Related 
Yes 
The temporal relationship of the clinical event to study drug administration indicates 
a causal relationship, and other drugs, therapeutic interventions or underlying 
conditions do not provide a sufficient explanation for the observed event. 
Not related 
No 
The temporal relationship of the clinical event to study drug administration does not 
indicate a causal relationship, or other drugs, therapeutic interventions or underlying 
conditions provide a sufficient explanation for the observed event. 
 
If the causal relationship between an AE/SAE and the study treatment is determined to be “related”, 
the event will be considered to be related to study treatment for the purposes of expedited 
regulatory reporting. In circumstances where the Investigator has not yet provided his/her 
assessment about the relationship, the event will be considered as “related” and qualify for 
expedited regulatory reporting. 
10.2.3 Outcome Categorization 
Outcome may be classified as recovered without sequelae; recovered with sequelae; improved; 
worsened; ongoing; fatal; or unknown. If the outcome is reported as recovered with sequelae for 
an SAE, the Investigator should specify the kind of sequelae on the paper SAE Reporting Form.  
10.2.4 Symptoms of the Disease Under Study 
Symptoms related to DES will not be classified as AEs as long as they are within the normal day-
to-day fluctuation of the disease. An explanation of these circumstances must be written in the 
source documents. 


 
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Worsening of the symptoms, however, will be recorded as an AE and clearly marked as worsening 
or by the subject’s worst observed intensity.  
10.2.5 Adverse Events of Special Interest including Abuse, Misuse, Overdose and 
Medication Errors 
A clinically significant decrease in visual acuity (defined as an increase of ≥0.22 in logMAR score) 
from baseline (Visit 1) will be considered an AE of special interest and must be documented in the 
AE section of the subject’s eCRF and source documentation. If the AE fulfils any seriousness 
criteria, the event must be reported on a paper SAE Reporting Form and documented as serious in 
the AE section of the subject’s eCRF and source documentation. 
Special situations including treatment abuse, misuse, overdose and medication errors causing or 
with the potential to cause harm should be reported as an AE. An event that fulfills the seriousness 
criteria should be reported as a SAE. 
10.3 Reporting Procedure for AEs, SAEs, and Pregnancy 
10.3.1 Adverse Events 
All AEs, regardless of causality, will be reported from time of signing the ICF until Post-Treatment 
Safety Follow-Up Visit 7 and recorded in the subject's source documentation. This applies to all 
AEs regardless of presumed relationship to the study drug.  
For screen failure subjects prior to run-in period, any AEs occurring during the screening period 
will be recorded from the time of signing the ICF in the subject’s source documentation only and 
will not be collected on the eCRF.  
For subjects qualifying for the run-in period all AEs will be recorded in the AE section of the 
subject’s eCRF and source documentation. This applies to all run-in period events between Visit 
1 and Visit 2 whether the subject is subsequently randomized or not.  
For enrolled/randomized subjects, any AEs occurring following first dose of randomized study 
treatment and up to Post-Treatment Safety Follow-Up Visit 7 will be recorded in the AE section 
of the subject’s eCRF and source documentation. 
If any AE is reported, the date of onset, relationship to study treatment, relationship to disease 
under study, any action taken, date of resolution (or the fact that it is still continuing or has become 
chronic), outcome, and whether the AE is serious or not, will be recorded. Use of colloquialisms 
and abbreviations should be avoided. Only one AE term should be recorded in the event field on 
the AE eCRF. Where possible, the Investigator should report a diagnosis rather than signs and 
symptoms or abnormal laboratory values. However, if a constellation of signs and/or symptoms 
cannot be medically characterized as a single diagnosis or syndrome at the time of reporting, each 
individual event should be recorded on the AE eCRF. If a diagnosis is subsequently established, 
all previously reported AEs based on signs and symptoms should be nullified by the Investigator 


 
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and replaced by one AE report based on the single diagnosis, with a starting date that corresponds 
to the starting date of the first symptom of the eventual diagnosis. 
Adverse events leading to discontinuation of study drug must be collected. 
Any AEs with an onset date during the study with follow-up/updated outcomes after the last study 
visit (or last study treatment administration) will be recorded as “ongoing” in the eCRF at the time 
of study completion. Adverse events persisting at the time of study completion will be followed 
by the Investigator through contact with the subject until resolution or stabilization has occurred 
(or the subject is lost to follow-up and cannot be contacted) and recorded in the source 
documentation only. If the subject reports an AE, it is the Investigator’s responsibility to acquire 
sufficient information in order to assess causality. This may require additional laboratory testing, 
physical examinations, telephone contacts, etc. In circumstances where the Investigator is unable 
to contact with the subject, the Investigator must provide a written statement to Aurinia confirming 
that the subject is lost to follow-up. 
In order to avoid bias in eliciting AEs, subjects should be asked a non-leading question, such as 
“How are you feeling?” It is also important to question the subject in a non-leading way about 
changes in their health or concomitant medication usage since their last visit. In addition, any 
symptoms/conditions reported during assessments and deemed to be clinically significant by the 
Investigator will be considered AEs. 
10.3.2 Serious Adverse Events 
For screen failure subjects prior to run-in period, any SAEs occurring during the screening period 
(after informed consent) will be recorded on a paper SAE Reporting Form and in the subject’s 
source documentation only and will not be collected on the eCRF.  
For subjects qualifying for the run-in period, all SAEs will be recorded on the paper SAE Reporting 
Form, in the AE section of the subject’s eCRF and source documentation. This applies to all run-
in period events whether the subject is subsequently randomized or not.  
For enrolled/randomized subjects, any SAEs occurring following first dose of randomized study 
treatment and up to Post-Treatment Safety Follow-Up Visit 7 will be recorded on the paper SAE 
Reporting Form, in the AE section of the subject’s eCRF and source documentation. All SAEs, 
regardless of causality, will be reported to the Clinical Project Manager and Medical Monitor on 
a paper SAE Reporting Form within 24 hours of the Investigator, designee, or site staff’s 
knowledge of the event. 
Note that data collection within the electronic data capture (EDC) system (Subject eCRF) is 
considered complete at the time of the last study visit according to the protocol schedule of 
assessments. Any SAEs with an onset date during the study with follow-up/updated outcomes post 
the last study visit (or last study treatment administration) will be recorded as “ongoing” in the 
eCRF at the time of study completion. For SAEs, the follow-up/resolution will be recorded on a 


 
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paper SAE Reporting Form, and source documentation. If the Investigator has not seen the subject 
at a clinic visit at the end of the reporting period, the Investigator must make reasonable efforts to 
contact the subject to inquire about SAEs. 
A paper SAE Reporting Form will be available for site staff to complete. The Investigator must 
complete, sign, and date the SAE form and verify the accuracy of the information recorded on the 
form with the corresponding source documents. The required contact information for reporting 
SAEs will be provided in the safety manual: 
• Site Staff will contact the Clinical Project Manager (CPM) at the CRO to notify them of an 
SAE via phone or email as soon as the site becomes aware of the event. 
• Site staff will complete a paper SAE Reporting Form and email to the CPM at the CRO and 
the Medical Monitor within 24 hours.  
• If email is unavailable, site staff will call the CPM at the CRO and Medical Monitor within 24 
hours.  
The Investigator is encouraged to discuss with the study Medical Monitor when the issue of 
seriousness is unclear or questionable. 
In addition to assessing the relationship to study treatment, the Investigator will also be required 
to assess the relationship to the disease under study for each SAE as related or not related. An SAE 
will not be able to be assessed as related to both disease under study and related to study treatment.  
All recorded SAEs, regardless of relationship to study treatment or relationship to disease under 
study, will be followed up until resolution, stabilization, or the subject is lost to follow up and 
cannot be contacted. In circumstances where the Investigator is unable to make contact with the 
subject, the Investigator must provide a written statement to Aurinia confirming that the subject is 
lost to follow-up. 
If the subject died, the paper SAE Reporting Form should include the cause of death as the event 
term and whether or not the death was related or unrelated to study treatment or disease under 
study, as well as the autopsy findings, if available. Preliminary reports will be followed by detailed 
descriptions, which will include copies of hospital case reports, autopsy reports/certificates, and 
other documents when requested and applicable. 
Any SAE considered to have a causal relationship (i.e., “related”) to the study treatment and 
discovered by the Investigator at any time after the study will be reported on a paper SAE 
Reporting Form and documented in the safety database only. A rationale for the assessment of a 
causal relationship must be provided by the Investigator.  
Additional follow-up information must be reported to the CRO on a paper SAE Reporting Form, 
and the AE section of the subject’s eCRF updated (until last study visit, see procedures described 


 
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above), within 24 hours of awareness following Investigator (or site) awareness of the information. 
The Investigator should not delay reporting an SAE in order to obtain additional information. 
Additional information, when available, should be reported to the CRO by the reporting procedures 
described above. 
An Investigator who receives an Investigational New Drug (IND) Safety Report describing an 
SAE or other specific safety information (e.g., summary or listing of SAE) from Aurinia will file 
it along with the IB and will notify the IRB/Independent Ethics Committee (IEC) if appropriate, 
according to local requirements. 
Aurinia or its representative will be responsible for determining and, in turn, reporting SAEs to 
Regulatory Authorities according to the applicable regulatory requirements. 
10.3.3 Pregnancy 
All pregnancies will be reported from time of signing the ICF until Post-Treatment Safety Follow-
Up Visit 7. Pregnancies will be recorded in the subject's source documentation and must be 
reported to the CRO by the reporting procedures described below. 
Pregnancy occurring in a female subject should be reported to the CRO Pharmacovigilance within 
24 hours of becoming aware of the event using a paper Pregnancy Reporting Form. Site staff must 
also enter the available pregnancy in the AE section of the subject’s eCRF within 24 hours of 
becoming aware of the event. 
The Investigator should counsel the subject and discuss the risks of continuing with the pregnancy 
and the possible effects on the fetus. The subject must immediately inform the Investigator if she 
becomes pregnant during the study. Monitoring of the pregnancy in the subject should continue 
until conclusion of the pregnancy.  
Female subjects who have a positive pregnancy test during the study will be withdrawn from the 
study treatment and the procedures for withdrawal will be completed. The Medical Monitor must 
be contacted immediately to break the blind (if applicable). 
The outcome of all such pregnancies (including normal births) should be followed up and 
documented, even if the subject was withdrawn from the study. Every effort should be made to 
gather information regarding the pregnancy outcome until 90 days (or otherwise as appropriate) 
post-partum. It will be the responsibility of Aurinia, together with the appropriate support of the 
Investigator, to obtain this information. 
Complications of pregnancy such as abortion (spontaneous or induced), premature birth, or 
congenital abnormality are considered SAEs and should be reported following the reporting 
procedures as outlined in Section 10.3.2, Serious Adverse Events.  


 
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A paper Pregnancy Reporting Form will be available for site staff to complete. The Investigator 
must complete, sign, and date the SAE form and verify the accuracy of the information recorded 
on the form with the corresponding source documents: 
• Site Staff will contact the Clinical Project Manager (CPM) at the CRO to notify them of a 
Pregnancy via phone or email as soon as the site becomes aware of the event. 
• Site staff will complete a paper Pregnancy Reporting Form and email to the CPM at the CRO 
and the Medical Monitor within 24 hours.  
• If email is unavailable, site staff will call the CPM at the CRO and Medical Monitor within 24 
hours. 
 


 
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11. STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
11.1 Analysis Populations 
The following analysis populations will be considered: 
• Intent-to-Treat Population: The intent-to-treat (ITT) population includes all randomized 
subjects. Subjects in the ITT population will be analyzed as randomized. 
• 
Modified Intent-to-Treat Population: The modified intent-to-treat (mITT) population is based 
on the ITT population and excludes all subjects who were unable to attend their primary 
endpoint assessment at the Week 4 visit due to Coronavirus-related site closure. Due to block 
enrolment, this applies to all subjects at Site 36. Thus, these subjects will be excluded from 
the mITT population. Subjects in this population will be analyzed as randomized. The mITT 
population will be used for the primary assessment of efficacy. 
• Per Protocol Population: The per protocol (PP) population includes subjects in the mITT 
population who do not have significant protocol deviations prior to their primary endpoint 
assessment at Week 4 and who complete the Week 4 STT. Protocol deviations will be assessed 
prior to database lock and unmasking. The PP population will be analyzed as randomized. 
• Safety Population: The safety population includes all randomized subjects who have received 
at least one dose of randomized study treatment. The safety population will be analyzed for all 
safety assessments. Subjects in the safety population will be analyzed as treated.  
The run-in population will be used to describe all subjects who entered the run-in period. 
Baseline data will be summarized using the safety, ITT, mITT and PP populations. Safety data 
will be summarized using the safety population, and efficacy analysis will use the ITT, mITT and 
PP populations. 
11.2 Statistical Hypothesis 
The primary endpoint will be tested under the following hypotheses with statistical significance 
declared for any of the three comparisons versus vehicle where a p-value <0.0166 is observed: 
H01: There is no difference between the proportion of subjects with a ≥10 mm change from 
baseline in STT to Week 4 in the study eye for those receiving VOS (0.05%, 0.10%, or 0.20%) 
versus vehicle. 
H11: There is a difference between the proportion of subjects with a ≥10 mm change from 
baseline in STT to Week 4 in the study eye in for those receiving VOS (0.05%, 0.1%, or 0.2%) 
versus vehicle. 
Following a significant result in the primary analysis the three pairwise comparisons for the key 
secondary endpoint will be tested using alpha=0.0166. The hypotheses to be tested are: 


 
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H02: In subjects with baseline eye dryness VAS ≥60 mm, there is no difference between 
the mean change from baseline to Week 4 in the Eye Dryness VAS for those receiving VOS (0.05%, 
0.10%, or 0.20%) versus vehicle. 
H12: In subjects with baseline eye dryness VAS ≥60 mm, there is a difference between the 
mean change from baseline to Week 4 in the eye dryness VAS for those receiving VOS (0.05%, 
0.10%, or 0.20%) versus vehicle. 
For significance to be declared in the key secondary endpoint analysis, the same treatment group 
should show improvement over vehicle in both the primary analysis and the key secondary analysis. 
11.3 Sample Size 
This study was expected to enroll 480 subjects into 4 treatment arms. This was amended to 
approximately 505 subjects (due to COVID-19) in order to have at least 480 evaluable subjects at 
Week 4. A two-group continuity corrected Chi square test with a 0.0166 two-sided significance 
level (adjusted for three treatment comparisons versus placebo) will have at least 80% power to 
detect the difference between a vehicle response rate of 20% (defined as the percentage of subjects 
with a ≥10 mm increase in STT from baseline) and a VOS response rate of 40% when the sample 
size in each group is 120 (total N=480). Response is defined as an increase of ≥10 mm in STT 
from baseline to Week 4. 
While the effect of withdrawals will be investigated, subjects withdrawing prior to Week 4 STT 
assessment for any reason will be counted as non-responders in the primary analysis and therefore 
no adjustment of sample size for withdrawals is necessary. 
This sample size provides greater than 90% power to detect a significant change from baseline 
within any one of the three active treatment groups in the Eye Dryness VAS assuming the standard 
deviation of changes is 40 mm and the mean change from baseline is 20 mm (two-sided 
alpha=0.0166). 
The key secondary endpoint is analyzed within the population of subjects with an Eye Dryness 
VAS ≥60 mm at baseline. It is expected that this will reduce the sample size for this analysis by 
25% (from 120 per group to 90 per group). Assuming a standard deviation of 30 mm for change 
in eye dryness score and an improvement of any active arm compared to placebo (alpha=0.0166) 
of 15 mm, a sample size of 90 subjects per group provides at least 80% power to detect a significant 
difference. 
The study was ongoing at the time of the Coronavirus (COVID-19) pandemic. The impact of the 
pandemic was continually being assessed and it became apparent that a number of subjects were 
unable to attend the primary efficacy visit at Week 4 due to site closure. To account for the higher 
incidence of missing data and ensure data from at least 480 subjects were available for analysis of 
the primary endpoint (STT response at Week 4), the target sample size was increased to 
approximately 505 subjects. 


 
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11.4 Statistical Analysis 
11.4.1 Unit of Analysis 
Safety endpoints will be analyzed for both eyes using study eye and fellow eye (non-study eye) if 
appropriate. For efficacy symptom-related endpoints, the unit of analysis is both eyes. For efficacy 
sign-related endpoints, the unit of analysis will be the study eye as defined by the following: 
Study Eye: The study eye will be defined as the qualifying eye that achieves the lowest STT score 
at baseline (Visit 2). Should both eyes be qualifying eyes with identical STT scores at baseline, 
the eye with the worst FCS score will be used. Should these scores also be equal, the right eye will 
be used. 
11.4.2 Multiplicity Considerations 
To maintain an overall alpha of 0.05, statistical significance of the pairwise treatment comparisons 
will be declared at the 0.05/3=0.0166 level. 
11.4.3 Primary Efficacy Analyses 
Analysis of the primary endpoint, proportion of subjects with ≥10 mm increase from baseline in 
STT at Week 4 in the study eye, will be conducted on the ITT, mITT and PP populations. The 
response rate for each VOS group compared to vehicle will be determined using a logistic 
regression model including terms for Investigator site, treatment group, and baseline STT. Results 
of this logistic regression will be displayed as odds ratios and two-sided adjusted 95% confidence 
intervals (CIs) (VOS compared to vehicle). The proportion of subjects exhibiting a response at 
Week 4 will be summarized by treatment group. 
Subjects providing insufficient data to determine response at Week 4 (e.g. early withdrawal) will 
be analysed as non-responders. 
An additional sensitivity analysis will analyse observed responses only. 
11.4.4 Key Secondary Endpoint Analysis 
The key secondary endpoint of mean change from baseline in Eye Dryness VAS in the subset of 
subjects with baseline Eye Dryness VAS ≥60 mm will be analysed using the ITT, mITT and the 
PP populations. Mean change, along with an adjusted 95% CI and p-value, will be provided from 
a General Linear Model including terms for Investigator site, treatment group and baseline Eye 
Dryness VAS. 
Subjects not providing an Eye Dryness VAS at week 4 will not contribute to this analysis. 
11.4.5 Secondary Efficacy Analyses 
STT response at Weeks 2, 8 and 12 will be analysed in a similar fashion to the primary endpoint 
using the ITT population only. 


 
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Other secondary efficacy endpoints are measured as continuous data and will be summarized by 
visit using observed scores and change from baseline using the ITT population. Mean changes 
along with 95% CIs and p-values will be provided both within treatment group and for all pairwise 
comparisons to vehicle. 
Mixed Effect Model Repeated Measures (MMRM) will also be used to analyze all available data 
for each endpoint. The MMRM model will include terms for Investigator site, treatment, visit, 
treatment by visit interaction and applicable baseline measure. Overall and by-visit results will be 
expressed as differences between treatment arms (VOS–vehicle) along with associated 95% CIs 
and p-values. 
11.4.6 Safety Variables 
Adverse events will be coded using the MedDRA dictionary. Frequencies and percentages of 
subjects with TEAEs, serious TEAEs, and TEAEs causing premature discontinuation will be 
provided by treatment group. An AE is treatment emergent if it occurs after the first dose of 
randomized study treatment and up to last study visit. Furthermore, frequencies will be given of 
subjects with TEAEs by system organ class and preferred term; by system organ class, preferred 
term and maximal severity; by system organ class, preferred term for treatment-related AEs; by 
system organ class and preferred term for SAEs; and by system organ class, preferred term, and 
day of onset. Separate analyses will be performed for ocular specific and all AEs (including 
systemic). 
Other safety endpoints including visual acuity, slit lamp biomicroscopy, dilated ophthalmoscopy 
(fundoscopy), will be summarized by treatment group and visit using descriptive statistics. 
Changes or shifts from baseline will also be summarized where appropriate. Mean changes from 
baseline along with 95% CIs for changes and pairwise comparisons to vehicle will be calculated 
for visual acuity. For assessments performed by eye, study eye and fellow eye will be summarized 
separately. In addition, shifts from baseline to worst on-treatment value for ocular safety 
assessments will be summarized. 
11.4.7 Interim Analyses 
No interim analyses are planned for this study 


 
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12. COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES 
This study will be conducted in compliance with the protocol, current GCPs, including the ICH 
Guidelines, and in general, consistent with the Declaration of Helsinki. In addition, all applicable 
local, state, and federal requirements relevant to the use of IPs in the United States will be adhered 
to. 
12.1 Protection of Human Subjects 
12.1.1 Subject Informed Consent 
Informed consent must take place before any study-specific procedures are initiated. Signed and 
dated written informed consent must be obtained from each subject.  
All informed consent/assent forms must be approved for use by Aurinia and receive 
approval/favorable opinion from an IRB prior to their use. If the consent form requires revision 
(i.e., due to a protocol amendment or significant new safety information), it is the Investigator’s 
responsibility to ensure that the amended informed consent is reviewed and approved by the CRO 
prior to submission to the governing IRB and that it is read, signed, and dated by all subjects 
subsequently enrolled in the study as well as those currently enrolled in the study. 
12.1.2 Institutional Review Board Approval 
This study is to be conducted in accordance with IRB regulations (U.S. 21 Code of Federal 
Regulations [CFR] Part 56.103). The Investigator must obtain appropriate IRB approval before 
initiating the study and re-approval at least annually. 
Only an IRB/ERC approved version of the ICF will be used. 
12.2 Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles that originated with the 
Declaration of Helsinki. 
12.3 Subject Confidentiality 
All personal study subject data collected and processed for the purposes of this study should be 
maintained by the Investigator and his/her staff with adequate precautions as to ensure that the 
confidentiality of the data in accordance with local, state, and federal laws and regulations. 
Monitors, auditors and other authorized representatives of the CRO, Aurinia, the IRB/IEC 
approving this study, the FDA, the Department of Health and Human Services, other domestic 
government agencies, and other foreign regulatory agencies will be granted direct access to the 
study subject’s original medical and study records for verification of the data and/or clinical trial 
procedures. Access to this information will be permitted to the aforementioned individuals to the 
extent permitted by law. 


 
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A report of the results of this study may be published or sent to the appropriate health authorities 
in any country in which the IP may ultimately be marketed, but the subject’s identity will not be 
disclosed in these documents. 
12.4 Documentation 
Source documents may include a subject’s medical records, hospital charts, clinic charts, the 
Investigator’s study subject files, as well as the results of diagnostic tests such as X-rays, laboratory 
tests, and electrocardiograms. The Investigator’s copy of the eCRFs serves as the Investigator’s 
record of a subject’s study-related data. 
12.4.1 Retention of Documentation 
All study related correspondence, subject records, ICFs, records of the distribution and use of all 
IPs, and copies of eCRFs should be maintained on file for 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 until at least 2 years have elapsed since the formal discontinuation 
of clinical development of the IP. These documents will be retained for a longer period if required 
by the applicable regulatory requirements or by an agreement with Aurinia. It is the responsibility 
of Aurinia to inform the Investigator/institution as to when these documents no longer need to be 
retained. 
If the responsible Investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping study records, custody must be transferred to a person who will accept 
the responsibility. Aurinia must be notified in writing of the name and address of the new custodian. 
12.5 Labelling, Packaging, Storage, Accountability, and Return or Disposal of 
Investigational Product 
12.5.1 Labelling/Packaging 
All study treatments provided by Aurinia will be packaged and labeled for Aurinia by 
appropriately qualified vendors according to all applicable local and country regulatory 
requirements. All packaging and labeling operations will be performed according to GMP and 
GCP. 
Run-in and investigational drug will be packaged and labeled into clinical kits. 
 
  
 
 


 
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12.5.2 Storage of Investigational Product 
The study drugs must be stored in a secure area accessible only to the Investigator and his/her 
designees. Study drug(s) must be refrigerated (2-8°C (36-46°F) – do not freeze), protected from 
light, and secured at the investigational site in a locked container.  
Each site should have a thermometer in each storage location that records minimum and maximum 
temperatures daily. Maintenance of a temperature log is mandatory. The log should be updated by 
site personnel during normal working hours. This log must be available for review by the Site 
Monitor during on-site monitoring visits. 
12.5.3 Accountability of Investigational Product 
The Investigator at each site is responsible for IP supplies. The Investigator will ensure that 
adequate records of the receipt, dispensing, and return of the IP are kept and that the IP is used 
only for subjects enrolled in the study. All data regarding the IP must be recorded on the relevant 
forms provided. 
Each study site will maintain a drug inventory/dispensing record for all IP dispensed and returned. 
At the end of the study, one copy of the drug inventory/dispensing record should be sent to Aurinia 
or their designee for the central study file. The original will be kept in the site files. 
12.5.4 Return or Disposal of Investigational Product 
After completion of the study, or if it is prematurely terminated, all IP will be returned to Aurinia 
or their designee. The return or disposal of IP will be specified in writing. 
12.6 Aurinia Recording of Data on Source Documents and Case Reports 
Forms (CRFs) 
All subject data will be captured in the subject source documents, which will be transcribed in the 
eCRFs. The Investigator is responsible for ensuring that study data are completely and accurately 
recorded on each subject’s eCRF, source documents, and all study-related materials. All study data 
should also be attributable, legible, contemporaneous, original, accurate, and complete. Recorded 
datum should only be corrected in a manner that does not obliterate, destroy, or render illegible 
the previous entry (i.e., by drawing a single line through the incorrect entry and writing the revision 
next to the corrected data). An individual who has corrected a data entry should make clear who 
made the correction and when, by adding to the correction his/her initials as well as the date of the 
correction.  
Data entry of all enrolled and randomized subjects will use software that conforms to 21 CFR Part 
11 requirements, and will be performed only by staff who have been trained on the system and 
have access to the system. Data will not be entered for Visit 1 screen failures with the exception 
of demographics and reason for screen failure. An audit trail will be maintained within the 
electronic system to capture all changes made within the eCRF database. After the end of the study 


 
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and database lock, compact discs containing copies of all applicable subjects’ eCRFs will be 
provided to each Investigator Site to be maintained on file by the Investigator. 
12.7 Handling of Biological Specimens 
N/A. 
12.8 Publications 
Authorship and manuscript composition will reflect cooperation among all parties involved in the 
study. Authorship will be established before writing the manuscript. The CRO and Aurinia will 
have the final decision regarding the manuscript and publication. 
 
 


 
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Boboridis, K. G. and A. G. P. Konstas (2018). "Evaluating the novel application of cyclosporine 
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CEQUA® (2018). "Sun Pharma Global FZE " "US Prescribing Information". 
Craig, J. P., K. K. Nichols, E. K. Akpek, B. Caffery, H. S. Dua, C. K. Joo, Z. Liu, J. D. Nelson, J. 
J. Nichols, K. Tsubota and F. Stapleton (2017). "TFOS DEWS II Definition and Classification 
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Dana, R., J. L. Bradley, A. Guerin, I. Pivneva, I. O. Stillman, A. M. Evans and D. A. Schaumberg 
(2019). "Estimated Prevalence and Incidence of Dry Eye Disease Based on Coding Analysis of a 
Large, All-age United States Health Care System." Am J Ophthalmol 202: 47-54. 
Granelli-Piperno, A. A., L. Steinman, RM. (1986). "Lymphokine and nonlympholine mRNA 
levels in stimulated human cells: kinetics, mitogen requirements, and effects of cyclosporin A." J 
Exp Med. 27: 163-922. 
LX214-01 (2009). "Clinical Study Report. A phase 1 dose-escalation study to assess the safety and 
tolerability of LX214 ophthalmic solution in healthy volunteers, followed by an open-label 
evaluation of LX214 ophthalmic solution in subjects with keratoconjunctivitis sicca. Lux 
Biosciences, Inc.; Report No.: LX214-01."Restasis® (2017). "Allergan, Irvine USA. 2017 Jul." 
"US prescribing information". 
S07654 (2009). "14-Day ocular toxicity of LX214 in New Zealand white rabbits with 14-Day 
recovery period." Lux Biosciences, Inc. Report No.: S07654(Apr 3). 
S07655 (2009). "14-Day ocular tolerability and toxicity of LX214 inbeagle dogs with a 14-day 
recovery period." Lux Biosciences, Inc. Report No.: S07655(Apr 8). 
S08661 (2009). "Ocular tissue distribution of 14C-LX214 following a single or multiple 
ophthalmic administration to New Zealand White Rabbit." Lux Biosciences, Inc. Report No.: 
S08661(Mar 23). 
S08662 (2009). "Ocular Tissue Distribution of 14C-LX214 Following a Single Ophthalmic 
Administration to Dutch Belted Rabbits." Sinclair Research Center, Inc. 
S15389-00 (2017). "To evaluate the efficacy of Voclosporin Ophthalmic Solution (0.2% 
voclosporin) in naturally occurring keratoconjunctivitis sicca in client owned dogs with twice-
daily administration." Intervert, Inc(d/b/a Merck Animal Health) Report No.: S15389-00(Apr 28). 
Stepkowski, S. M. (2000). "Molecular targets for existing and novel immunosuppressive drugs." 
Expert Rev Mol Med 2(4): 1-23. 


 
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VOS-Investigator's-Brochure (2019). "Voclosporin Ophthalmic Solution Invesigator's Brochure." 
Version 2.0. 
Wiseman, A. C. (2016). "Immunosuppressive Medications." Clin J Am Soc Nephrol 11(2): 332-
343. 


 
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14. APPENDICES 
Appendix 1: Schedule of Visits and Measurements 
AUR-VOS-2019-01 SCHEDULE OF EVENTS 
Visit 
Visit 1 
Screening 
Visit 2 
Baseline 
Visit 3 
Visit 4 
Visit 5 
Visit 6/ ETV 
Visit 7 
Day/Week 
Day -17 to -14 
Day 1 
Day 14/ 
Week 2 
(±3 days) 
Day 28/ 
Week 4 
(±3 days) 
Day 56/ 
Week 8 
(±3 days) 
Day 84/ 
Week 12 (±3 
days) 
Post- 
Treatment 
Safety FU 
(+7 days from 
Visit 6 (±3 
days)) 
Informed consent 
 
 
 
 
 
 
 
Eligibility criteria 
 
(1) 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
Ocular and non-ocular Medical 
history (including Ocular Surgical 
History, Ocular and Non-Ocular 
Concomitant Medications)  
 
 
 
 
 
 
 
Demography  
 
 
 
 
 
 
 
Concomitant medication updates 
 
 
 
 
 
 
 
AE Query(2) 
 
 
 
 
 
 
 
SANDE(3) 
 
 
 
 
 
 
 
Visual Analog Scale 
(VAS)(3) 
 
 
 
 
 
 
 
BCVA(4) 
 
 
 
 
 
 
 
FCS(5) 
 
 
 
 
 
 
 
STT(5) 
 
 
 
 
 
 
 
Slit-Lamp Biomicroscopy 
 
 
 
 
 
 
 


 
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Visit 
Visit 1 
Screening 
Visit 2 
Baseline 
Visit 3 
Visit 4 
Visit 5 
Visit 6/ ETV 
Visit 7 
Day/Week 
Day -17 to -14 
Day 1 
Day 14/ 
Week 2 
(±3 days) 
Day 28/ 
Week 4 
(±3 days) 
Day 56/ 
Week 8 
(±3 days) 
Day 84/ 
Week 12 (±3 
days) 
Post- 
Treatment 
Safety FU 
(+7 days from 
Visit 6 (±3 
days)) 
Dilated Ophthalmoscopy 
(Fundoscopy) 
 
 
 
 
 
 
 
Run-In dispensation 
 
 
 
 
 
 
 
Study Treatment Dispensation(6) 
 
 
 
 
 
 
 
Dosing Diary and Instruction 
provided 
 
 
 
 
 
 
 
Study Treatment Accountability(7) 
 
 
 
 
 
 
 
Urine pregnancy test(8) 
 
 
 
 
 
 
 
Schedule Next Visit 
 
 
 
 
 
 
 
Study Exit 
 
 
 
 
 
 
 
1 Eligibility criteria will be re-checked after subjects have completed the run-in period.  
2 Adverse event query will be conducted at pre-examination and post-instillation at Visit 2. 3, 4, 5, and 6. 
3  Symptom assessments VAS/SANDE should be performed first prior to or any invasive procedure. SANDE will be performed prior to the Individual Symptom Severity Assessments VAS. 
Symptom Assessment VAS includes Ocular Discomfort, Eye Dryness, Burning/Stinging, Photophobia, Foreign Body Sensation, Eye Pain, Itching and Blurred Vision. 
4  BCVA should be performed prior to any dyes. 
5  STT should be performed at least 20 minutes after FCS is performed. 
6  Study treatment instillations on the date of the visits will be performed after all study procedures have taken place. A new refrigerated IP pack will be administered to subjects at each visit with 
the appropriate number of ampules. 
7  Accountability will be assessed by counting the number of used and unused ampules returned at each visit, beginning at Visit 2. 
8  Urine pregnancy test for women of childbearing potential only. 
Notes: 
AE = Adverse event; BCVA = Best Corrected Visual Acuity; ETV = Early Termination Visit; FCS = Fluorescein Corneal Staining; FU = Follow up; 
SANDE = Symptom Assessment and Dry Eye; STT = Schirmer Tear Test; VAS = Visual Analog Scale. 


 
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Appendix 2: Examination Procedures, Tests, Equipment, and Techniques 
Visual Acuity Procedures (ETDRS Chart) 
LogMAR visual acuity (VA) must be assessed using an Early Treatment Diabetic Retinopathy 
Study (ETDRS) chart. The procedure used will be consistent with the recommendations provided 
for using the ETDRS eye chart. VA should be evaluated at the beginning of each visit in the study 
(i.e., prior to slit-lamp examination). VA testing should be done with most recent correction. 
Equipment 
The VA chart to be used is the ETDRS chart. If smaller reproduction (18" by 18", i.e., from Prevent 
Blindness) wall charts are used, the subject viewing distance should be exactly 10 feet (or as 
specified by the manufacturer). In ALL cases, for purposes of standardizing the testing conditions 
during the study, all sites must use only the Series 2000 Chart 1, and the right eye should be tested 
first. For reflectance (wall) charts, the chart should be placed frontally and well-illuminated. 
Measurement Technique 
The chart should be at a comfortable viewing angle. The right eye should be tested first. The 
subject should attempt to read each letter, line-by-line, left to right, beginning with line 1 at the 
top of the chart. The subject should be told that the chart has letters only, no numbers. If the subject 
reads a number, he or she should be reminded that the chart contains no numbers, and the examiner 
should then request a letter in lieu of the number. The subject should be asked to read slowly, so 
as to achieve the best identification of each letter. He/she is not to proceed to the next letter until 
he/she has given a definite response. 
If the subject changes a response (i.e., 'that was a "C" not an "O"') before he has read aloud the 
next letter, then the change must be accepted. If the subject changes a response having read the 
next letter, then the change is not to be accepted. The examiner should never point to the chart or 
to specific letters on the chart during the test. 
A maximum effort should be made to identify each letter on the chart. When the subject says he 
or she cannot read a letter, he or she should be encouraged to guess. If the subject identifies a letter 
as 1 of 2 letters, he or she should be asked to choose 1 letter and, if necessary, to guess. When it 
becomes evident that no further meaningful readings can be made, despite encouragement to read 
or guess, the examiner should stop the test for that eye. However, all letters on the last line should 
be attempted as letter difficulties vary and the last may be the only one read correctly. The number 
of letters missed or read incorrectly should be noted. 
LogMAR Visual Acuity Calculations 
The last line in which a letter is read correctly will be taken as the base logMAR reading. To this 
value will be added the number "N x 0.02" where 'N' represents the total number of letters missed 
up to and included in the last line read. This total sum represents the logMAR VA for that eye. 


 
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For Example: Subject correctly reads 4 of 5 letters on the 0.2 line, and 2 of 5 letters on the 0.1 line. 
Base logMAR 
= 0.1 
N (total number of letters incorrect on line 0.2 as well as 0.1) 
= 4 
N x T (T=0.02) 
= 0.08 
Base logMAR + (N x T) 
= 0.1 + 0.08 
logMAR VA 
= 0.18 
Repeat the procedure for the left eye. 
In order to provide standardized and well-controlled assessments of VA during the study, all VA 
assessments at a single site must be consistently done using the same lighting conditions and same 
correction if possible during the entire study. If the same correction cannot be used (i.e., a subject 
forgets his glasses), the reason for the change in correction should be documented. 
Best Corrected Visual Acuity (BCVA) 
To provide standardized and well-controlled assessments of visual acuity during the study, 
consistently use the same lighting conditions during the entire study. 
Calculations : logMAR VA = Baseline value + (n x 0.02) 
where: the baseline value is the logMAR number of the last line read (at least 1 letter read correctly 
in this line), and 
“n” is the total number of letters missed up to and including the last line read, and  
“0.02” is the value for each letter 
Slit Lamp Biomicroscopy Procedures 
Slit lamp biomicroscopic observations will be graded as Normal or Abnormal. Abnormal findings 
will be categorized as clinically significant (findings that may interfere with study parameters or 
otherwise confound the data as determined by the Investigator) or not clinically significant (NCS). 
The following will be examined:  
• Cornea  
• Conjunctiva 
• Anterior Chamber 
• Iris 


 
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• Lens 
• Eyelid 
External magnification and biomicroscopy will be performed using a slit-lamp. Magnification will 
be consistent with standard clinical practice. The subject will be seated. 
Dilated Ophthalmoscopy (Fundoscopy) 
Dilated fundoscopy will be performed using indirect ophthalmoscopy. The Investigator will make 
observations of the vitreous, retina, macula, choroid and optic nerve. 
Observations will be graded as Normal or Abnormal. Abnormal findings that are clinically 
significant (as determined by the Investigator that may interfere with study parameters or otherwise 
confound the data) and those that are not clinically significant will be described. A dilated 
fundoscopy examination should be performed if retinal disease is detected.  
• Vitreous: Examination should emphasize the visual axis.  
• Retina, Macula, Choroid: Include an observation of the retina and its blood vessels. Eyes 
should be excluded from the study if active inflammation is present.  
• Optic Nerve: Significant damage or cupping to the optic nerve should be noted. 
It is recommended that tropicamide 1% ophthalmic solution be used to dilate subjects. The use of 
cyclopentolate 1% ophthalmic solution is recommended as secondary dilating medication, should 
the need arise. 
Visual Analogue Scale (VAS) 
Subjects will be asked the following questions regarding ocular discomfort (unrelated to study 
drug instillation) at all visits.  
The subject will be asked to rate each ocular symptom due to dry eye syndrome by placing a 
vertical mark on the horizontal line to indicate the current level of discomfort. 0% corresponds to 
“no discomfort” and 100% corresponds to “maximal discomfort.” The linear dimension of the 
scale is measured in millimeters. This assessment is a general assessment of both eyes. There will 
not be a question for each individual eye. This assessment should be performed following SANDE, 
and prior to assessing for AEs and prior to any other invasive visit assessment. 
Subject Instructions: Please review the symptoms below. After your review, please rate how your 
eyes feel for each of the following symptoms by placing a vertical mark that represents how your 
symptom feels at this moment.  


 
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Burning/ Stinging 
0%                                                                                              100% 
 
 
 
Itching 
0%                                                                                              100% 
 
 
 
Foreign Body Sensation 
0%                                                                                              100% 
 
 
 
Blurred Vision 
0%                                                                                              100% 
 
 
 
Eye Dryness 
0%                                                                                              100% 
 
 
 
Photophobia 
0%                                                                                              100% 
 
 
 
Pain 
0%                                                                                              100% 
 
 
 
Ocular Discomfort 
0%                                                                                              100% 
 
 
 
 


 
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Fluorescein Corneal Staining (FCS) National Eye Institute/Industry Workshop Scale 
 
Diagram of the division of the corneal surface for FCS total score. A standardized grading System 
of 0-3 is used for each of the five areas on each cornea. The maximum score is 15. Grade 0 will be 
specified when no staining is present. 
Unanesthetized Schirmer’s Test 
Schirmer Tear Test will be performed according to the following procedure: 
• Using a sterile Tear Flo Schirmer test strip (Rose Enterprises), a bend in the strip will be made 
in line with the notch in the strip 
• The subject will be instructed to gaze up and in 
• The Schirmer test strip will be placed in the lower temporal lid margin of each eye such that 
the strip fits tightly. Subjects will be instructed to close their eyes 
• After 5 minutes have elapsed, the Schirmer strip will be removed. The length of the moistened 
area will be recorded (mm) for each eye 
 
 


 
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Symptom Assessment in Dry Eye (SANDE) 
 
 
 
 
 


 
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Appendix 3: Daily Dosing Diary 
 

SAP_003.pdf: 
CONFIDENTIAL 
AUR-VOS-2019-01 
Statistical Analysis Plan 
Version 1.0 
26-Jun-2020
Page 1 of 34 
TITLE PAGE 
Protocol Title: 
A Randomized, Double-Masked, Vehicle-Controlled, Dose 
Ranging Study to Assess the Efficacy and Safety of Voclosporin 
Ophthalmic Solution (VOS) in Subjects with Dry Eye Syndrome 
Protocol Number: 
AUR-VOS-2019-01 
Compound Number: 
Voclosporin 
Short Title:  
AUDREY (AUrinia DRy EYe) 
Sponsor Name:  
Aurinia Pharmaceuticals Inc. 
Legal Registered Address: 
#1203 - 4464 Markham Street 
Victoria, BC  
V8Z 7X8  
Canada  
Regulatory Agency Identifier Number(s) 
Registry 
ID 
IND 
102,279 
NCT Number:
NCT04147650


     
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APPROVAL SIGNATURES 
 
Prepared By: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
 
Date (dd-mmm-yyyy) 
 
 
 
 
Approved By: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
 
Date (dd-mmm-yyyy) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
Signature 
 
Date (dd-mmm-yyyy) 


     
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TABLE OF CONTENTS 
TITLE PAGE .................................................................................................................................1 
APPROVAL SIGNATURES ........................................................................................................2 
TABLE OF CONTENTS ..............................................................................................................3 
LIST OF TABLES .........................................................................................................................5 
VERSION HISTORY ....................................................................................................................6 
1. 
INTRODUCTION ..........................................................................................................7 
1.1. 
Objectives and Endpoints .................................................................................................7 
1.2. 
Study Design ...................................................................................................................19 
2. 
STATISTICAL HYPOTHESES .................................................................................20 
3. 
SAMPLE SIZE DETERMINATION .........................................................................21 
4. 
POPULATIONS FOR ANALYSIS .............................................................................22 
5. 
STATISTICAL ANALYSES .......................................................................................23 
5.1. 
General Considerations ...................................................................................................23 
5.1.1. 
Decision Criteria .............................................................................................................23 
5.1.2. 
Unit of Analysis ..............................................................................................................23 
5.1.3. 
Calculation of Study Day ................................................................................................23 
5.1.4. 
Baseline ...........................................................................................................................24 
5.1.5. 
Visit Windowing for Analysis ........................................................................................24 
5.1.6. 
Analysis Timelines..........................................................................................................24 
5.1.7. 
Use of Study Site in analysis models ..............................................................................24 
5.1.8. 
Handling of Missing Data ...............................................................................................24 
5.2. 
Participant Dispositions ..................................................................................................25 
5.3. 
Primary Endpoint Analysis .............................................................................................25 
5.3.1. 
Definition of endpoint .....................................................................................................26 
5.3.2. 
Main analytical approach ................................................................................................26 
5.3.3. 
Sensitivity analysis..........................................................................................................26 
5.3.4. 
Supplementary analyses ..................................................................................................26 
5.4. 
Secondary Endpoints Analysis .......................................................................................26 
5.4.1. 
Key/Confirmatory secondary endpoint ...........................................................................26 
5.4.2. 
Supportive secondary endpoint(s)...................................................................................27 
5.5. 
Tertiary/Exploratory Endpoints Analysis .......................................................................28 
5.6. 
Safety Analyses...............................................................................................................28 
5.6.1. 
Extent of Compliance and Exposure ...............................................................................28 
5.6.2. 
Adverse Events ...............................................................................................................29 
5.6.3. 
Best Corrected Visual Acuity .........................................................................................30 
5.6.4. 
Slit-Lamp Biomicroscopy ...............................................................................................30 
5.6.5. 
Dilated Ophthalmoscopy ................................................................................................30 
5.7. 
Other Analyses ................................................................................................................31 


     
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5.8. 
Interim Analyses .............................................................................................................31 
6. 
SUPPORTING DOCUMENTATION ........................................................................32 
6.1. 
Appendix 1 List of Abbreviations ..................................................................................32 
6.2. 
Appendix 2: Changes to Protocol-Planned Analyses .....................................................32 
6.3. 
Appendix 3: Other Data ..................................................................................................33 
6.3.1. 
Study performance ..........................................................................................................33 
6.3.2. 
Baseline Characteristics and Demography .....................................................................33 
6.3.3. 
Medical History ..............................................................................................................33 
6.3.4. 
Prior and Concomitant Medications ...............................................................................33 
6.3.5. 
Subject Data Listings ......................................................................................................33 
7. 
REFERENCES .............................................................................................................34 
 
 


     
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LIST OF TABLES 
 
Table 1  
SAP Version History Summary .......................................................................... 6 
Table 2 
Estimand Details ................................................................................................. 8 
 
LIST OF FIGURES 
 
Figure 1 
AUDREY (AUR-VOS-2019-01) Study Schematic .......................................... 19 
 


     
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VERSION HISTORY 
This Statistical Analysis Plan (SAP) for study AUR-VOS-2019-01 is based on protocol Version 
3.0 dated 26th June 2020.  
Table 1  
SAP Version History Summary 
SAP Version 
Approval Date 
Change 
Rationale 
1 
 
Not Applicable 
Original version 
 
 
 
 


     
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1. 
INTRODUCTION 
This document details the planned statistical analysis of safety and efficacy data from the Aurinia 
Dry Eye (AUDREY) protocol (AUR-VCS-2019-01) titled “A Randomized, Double-Masked, 
Vehicle-Controlled, Dose Ranging Study to Assess the Efficacy and Safety of Voclosporin 
Ophthalmic Solution (VOS) in Subjects with Dry Eye Syndrome”. 
The proposed analyses are based on the contents of the final version of the protocol (Version 3.0) 
dated 26th June 2020. 
A complete list of proposed outputs is available in a separate document (AUR-VCS-2019-01-
TFL). 
1.1. 
Objectives and Endpoints 
To assess the efficacy and safety of three different concentrations of VOS (0.05%, 0.10%, and 
0.20%) when administered twice a day (BID) in both eyes (OU) over 12 weeks compared to 
vehicle in subjects with Dry Eye Syndrome (DES). 
The clinical hypothesis for this study is that at least one of three concentrations of VOS (0.05%, 
0.10%, and 0.20%) when administered OU BID over 4 weeks is significantly different compared 
to vehicle alone for the following DES sign endpoint: 
• 
Proportion of subjects with a ≥10 mm increase from baseline in Schirmer Tear Test (STT) at 
Week 4 in the study eye (Section 5.1.2) 


     
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Table 2 
Estimand Details 
Objective 
Clinical Category 
Statistical 
Category 
Estimand/Variable 
Primary Objective  
To assess the efficacy of three different concentrations of VOS (0.05%, 0.10%, and 0.20%) when administered BID OU over 12 weeks compared to 
vehicle in subjects with DES. 
Due to the Coronavirus (COVID-19) pandemic a number of subjects failed to attend Visit 4 where the primary efficacy endpoint was assessed. As 
detailed in Section 6.2, the primary assessment of efficacy will be made using the modified intent-to-treat (mITT) population with the intent-to-treat 
(ITT) being considered a supplementary population. 
 
 
 
 
 


     
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Objective 
Clinical Category 
Statistical 
Category 
Estimand/Variable 
Efficacy Category 1 
Primary 
Variable:  
Proportion of subjects with ≥10 mm increase from baseline in STT at Week 4 in the 
study eye 
Multiple Comparisons Procedure (MCP): 
  
Overall alpha: 5%, 3 treatment comparisons vs vehicle. Statistical significance claimed 
where p<0.0166 
Population:  Modified Intent-to-Treat (mITT) 
Intercurrent event(s) strategy (IES): 
  
Subjects withdrawing from study before Week 4 and/or failing to provide a Week 4 STT 
assessment (for reasons other than Coronavirus) will be analyzed as non-responders 
Population Level Summary (PLS): 
  
Odds ratios (OR) for each active treatment group compared to vehicle (Logistic 
regression) 
Analysis:  
Logistic regression model including covariates: Investigator site, Baseline Eye Dryness 
level (<60mm or ≥60 mm), and Baseline STT 
Sensitivity 
Analysis:  
Logistic regression model without covariates 
Supplementary 
Population:  
Per Protocol (PP) 
Analysis:  
Logistic regression model including covariates: Investigator site, Baseline Eye 
Dryness level, and Baseline STT 


     
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Objective 
Clinical Category 
Statistical 
Category 
Estimand/Variable 
Supplementary 
Population:  
PP 
Analysis:  
Logistic regression model without covariates 
Supplementary 
Population:  
Intent-to-Treat (ITT) 
Analysis:  
Logistic regression model including covariates: Investigator site, Baseline Eye 
Dryness level, and Baseline STT 
Supplementary 
Population:  
ITT 
Analysis:  
Logistic regression model without covariates 
Supplementary 
Population:  
mITT 
IES:  
Analysis of observed STT response only. 
Analysis:  
Logistic regression model including covariates: Investigator site, Baseline Eye 
Dryness level, and Baseline STT 
Supplementary 
Population:  
mITT 
IES:  
Analysis of observed STT response only. 
Analysis:  
Logistic regression model without covariates 


     
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Objective 
Clinical Category 
Statistical 
Category 
Estimand/Variable 
Supplementary 
Population:  
ITT 
IES:  
Analysis of observed STT response only. 
Analysis:  
Logistic regression model including covariates: Investigator site, Baseline Eye 
Dryness level, and Baseline STT 
 
Supplementary 
Population:  
ITT 
IES:  
Analysis of observed STT response only. 
Analysis:  
Logistic regression model without covariates 
 
Supplementary 
Population:  
PP 
IES:  
Analysis of observed STT response only. 
Analysis:  
Logistic regression model including covariates: Investigator site, Baseline Eye 
Dryness level, and Baseline STT 
 
Supplementary 
Population:  
PP 
IES:  
Analysis of observed STT response only. 
Analysis:  
Logistic regression model without covariates 


     
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Objective 
Clinical Category 
Statistical 
Category 
Estimand/Variable 
Efficacy Category 2 
Key Secondary 
Variable:  
Mean change from baseline to Week 4 in Eye Dryness Visual Analogue Scale (VAS) 
MCP:  
Overall alpha: 5%, 3 treatment comparisons vs vehicle. Statistical significance claimed 
where p<0.0166 
Population:  mITT subjects with an Eye Dryness VAS at baseline ≥60 mm 
IES:  
Subjects withdrawing from study before Week 4 and/or failing to provide a week 4 Eye 
Dryness VAS will not contribute to this analysis 
PLS:  
Least Squares mean (LSM) differences between active treatment groups and vehicle 
Analysis:  
Analysis of Covariance (ANCOVA) model including covariates for Investigator site and 
baseline Eye Dryness score. 
Supplementary 
Population:  PP subjects with an Eye Dryness VAS at baseline ≥60 mm 
Analysis:  
ANCOVA model including covariates for Investigator site and baseline Eye Dryness 
score. 
 
Supplementary 
Population:  ITT subjects with an Eye Dryness VAS at baseline ≥60 mm 
Analysis:  
ANCOVA model including covariates for Investigator site and baseline Eye Dryness 
score. 


     
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Objective 
Clinical Category 
Statistical 
Category 
Estimand/Variable 
Efficacy Category 3 
Secondary 
Variable:  
Proportion of subjects with ≥10 mm increase from baseline in STT in the study eye 
analyzed at Weeks 2, 8 and 12 
MCP:  
No adjustment 
Population:  
ITT 
IES:  
All observed data contribute to the analysis. 
PLS:  
OR for each active treatment group compared to vehicle (Logistic regression) 
Analysis:  
Logistic regression model including covariates: Investigator site, Baseline Eye 
Dryness level and Baseline STT 
 
Secondary 
Variable:  
Mean change from baseline in Fluorescein Corneal Staining (FCS) score for the 5 
individual regions of the cornea to Weeks 2, 4, 8 and 12 in the study eye 
MCP:  
No adjustment 
Population:  
ITT 
IES:  
All observed data contribute to the analysis. Mixed Model Repeated Measures 
(MMRM) used for imputation of missing data. 
PLS:  
LSM differences between treatment groups at each time point 
Analysis:  
MMRM model for each of the 5 regions including covariates: Investigator site, Baseline 
Eye Dryness level, Baseline FCS region score, Visit, Treatment group and 
Visit*Treatment interaction 


     
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Objective 
Clinical Category 
Statistical 
Category 
Estimand/Variable 
Secondary 
Variable:  
Mean change from baseline in Total FCS score to Weeks 2, 4, 8 and 12 in the study eye 
MCP:  
No adjustment 
Population:  
ITT 
IES:  
All observed data contribute to the analysis. MMRM used for imputation of missing 
data. 
PLS:  
LSM differences between treatment groups at each time point 
Analysis:  
MMRM model including covariates: Investigator site, Baseline Eye Dryness level, 
Baseline total FCS, Visit, Treatment group and Visit*Treatment interaction 
Secondary 
Variable:  
Mean change from baseline in STT score to Weeks 2, 4, 8 and 12 in the study eye 
MCP:  
No adjustment 
Population:  
ITT 
IES:  
All observed data contribute to the analysis. MMRM used for imputation of missing 
data. 
PLS:  
LSM differences between treatment groups at each time point 
Analysis: 
MMRM model including covariates: Investigator site, Baseline Eye Dryness level, 
Baseline STT, Visit, Treatment group and Visit*Treatment interaction 


     
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Objective 
Clinical Category 
Statistical 
Category 
Estimand/Variable 
Secondary 
Variable:  
Mean change from baseline in Eye Dryness VAS score to Weeks 2, 4, 8 and 12 
MCP:  
No adjustment 
Population:  
ITT 
IES:  
All observed data contribute to the analysis. MMRM used for imputation of missing 
data. 
PLS:  
LSM differences between treatment groups at each time point 
Analysis:  
MMRM model including covariates: Investigator site, Baseline Eye Dryness, Visit, 
Treatment group and Visit*Treatment interaction 
Secondary 
Variable:  
Mean change from baseline in Ocular Discomfort VAS score to Weeks 2, 4, 8 and 12 
MCP:  
No adjustment 
Population:  
ITT 
IES:  
All observed data contribute to the analysis. MMRM used for imputation of missing 
data. 
PLS:  
LSM differences between treatment groups at each time point 
Analysis:  
MMRM model including covariates: Investigator site, Baseline Eye Dryness level, 
Baseline Ocular Discomfort, Visit, Treatment group and Visit*Treatment interaction 


     
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Objective 
Clinical Category 
Statistical 
Category 
Estimand/Variable 
Secondary 
Variable:  
Mean change from baseline in Burning/Stinging, Itching, Photophobia, Eye Pain, 
Foreign Body Sensation and Blurred Vision VAS scores to Weeks 2, 4, 8 and 12 
MCP:  
No adjustment 
Population:  
ITT 
IES:  
All observed data contribute to the analysis. MMRM used for imputation of missing 
data. 
PLS:  
LSM differences between treatment groups at each time point 
Analysis:  
MMRM model for each scale including covariates: Investigator site, Baseline Eye 
Dryness level, Individual Baseline Symptom Score, Visit, Treatment group and 
Visit*Treatment interaction 
Secondary 
Variable:  
Mean change from baseline in the sum of Individual Symptom VAS score to Weeks 2, 
4, 8 and 12 
MCP:  
No adjustment 
Population:  
ITT 
IES:  
All observed data contribute to the analysis. MMRM used for imputation of missing 
data. 
PLS:  
LSM differences between treatment groups at each time point 
Analysis:  
MMRM model including covariates: Investigator site, Baseline Eye Dryness level, 
Baseline Total Symptom Score, Visit, Treatment group and Visit*Treatment 
interaction 


     
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Objective 
Clinical Category 
Statistical 
Category 
Estimand/Variable 
Secondary 
Variable:  
Mean change from baseline in Symptom Assessment in Dry Eye (SANDE) frequency 
and severity scores to Weeks 2, 4, 8 and 12 
MCP:  
No adjustment 
Population:  
ITT 
IES:  
All observed data contribute to the analysis. MMRM used for imputation of missing 
data. 
PLS:  
LSM differences between treatment groups at each time point 
Analysis:  
MMRM model including covariates: Investigator site, Baseline Eye Dryness level, 
Baseline SANDE frequency or severity Score, Visit, Treatment group and 
Visit*Treatment interaction 
 
 
Safety Objective  
To assess the safety of three different concentrations of VOS (0.05%, 0.10%, and 0.20%) when administered twice a day (BID) in both eyes (OU) over 
12 weeks compared to vehicle in subjects with DES. 
Safety Category 1 
AEs (Adverse 
Events) and SAEs 
(Serious AEs) 
Incidence rates to be calculated for ocular and non-ocular AEs, SAEs and various subgroups. 


     
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Objective 
Clinical Category 
Statistical 
Category 
Estimand/Variable 
Best Corrected Visual 
Acuity (BCVA) 
Variable:  
Mean Change from Baseline in BCVA over time 
Population:  
Safety 
Analysis:  
Descriptive 
Slip-Lamp 
Biomicroscopy 
Variable:  
Changes from Baseline in Slit-Lamp Biomicroscopy over time 
Population:  
Safety 
Analysis:  
Descriptive 
Dilated 
Ophthalmoscopy 
Variable:  
Changes from Baseline in Dilated Ophthalmoscopy over time 
Population:  
Safety 
Analysis:  
Descriptive 
 


     
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1.2. 
Study Design 
This is a Phase 2/3, multi-center, randomized, double-masked, vehicle-controlled study to assess 
the efficacy and safety of three different concentrations of VOS when administered OU, BID over 
12 weeks in subjects with mild to moderate DES. Subjects will undergo a 2-week run-in period in 
which VOS vehicle will be self-administered OU, BID. Subjects will be re-assessed to confirm 
that all participants meet all of the inclusion criteria and none of the exclusion criteria. It was 
estimated the study will enroll 480 subjects (updated to 505 subjects due to COVID-19) across 9 
study centers. Eligible subjects will be randomized in a 1:1:1:1 ratio to one of the following study 
treatment arms after the 14- to 17-day run-in period: 
• 
0.05% VOS BID 
• 
0.10% VOS BID 
• 
0.20% VOS BID 
• 
VOS Vehicle BID 
Subjects will be stratified by eye dryness VAS score ≥60 mm and <60 mm. 
See Figure 1 for the AUDREY (AUR-VOS-2019-01) study schematic. 
Figure 1 
AUDREY (AUR-VOS-2019-01) Study Schematic 
 
Notes: V = Visit; VOS = Voclosporin ophthalmic solution 
 
 
 
 


     
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2. 
STATISTICAL HYPOTHESES 
The primary endpoint will be tested under the following hypotheses with statistical significance 
declared for any of the three comparisons versus vehicle where a p-value <0.0166 is observed: 
H01: 
There is no difference between the proportion of subjects with a ≥10 mm change from 
baseline in STT to Week 4 in the study eye for those receiving VOS (0.05%, 0.10%, or 
0.20%) versus vehicle. 
H11: 
There is a difference between the proportion of subjects with a ≥10 mm change from 
baseline in STT to Week 4 in the study eye in for those receiving VOS (0.05%, 0.1%, or 
0.2%) versus vehicle. 
Following a significant result in the primary analysis the three pairwise comparisons for the key 
secondary endpoint will be tested using alpha=0.0166. The hypotheses to be tested are: 
H02: 
In subjects with baseline eye dryness VAS ≥60 mm, there is no difference between the 
mean change from baseline to Week 4 in the Eye Dryness VAS for those receiving VOS 
(0.05%, 0.10%, or 0.20%) versus vehicle. 
H12: 
In subjects with baseline eye dryness VAS ≥60 mm, there is a difference between the mean 
change from baseline to Week 4 in the eye dryness VAS for those receiving VOS (0.05%, 
0.10%, or 0.20%) versus vehicle. 
For significance to be declared in the key secondary endpoint analysis, the same treatment group 
should show improvement over vehicle in both the primary analysis and the key secondary 
analysis. 
In order to maintain the familywise error rate at 5%, the Bonferroni correction will be used with 
statistical significance of the 3 voclosporin vs vehicle comparisons of the primary and key 
secondary endpoints being declared when p<0.0166 
No adjustment is made for multiple secondary or safety endpoints; statistical significance will be 
declared when p<0.05. 


     
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3. 
SAMPLE SIZE DETERMINATION 
This study was expected to enroll 480 subjects (amended to 505 subjects due to COVID-19) into 
4 treatment arms. A two-group continuity corrected Chi square test with a 0.0166 two-sided 
significance level (adjusted for three treatment comparisons versus placebo) will have at least 80% 
power to detect the difference between a vehicle response rate of 20% and a VOS response rate of 
40% when the sample size in each group is 120 (total N=480). Response is defined as an increase 
of ≥10 mm in STT from baseline to Week 4. 
While the effect of withdrawals will be investigated, subjects withdrawing prior to Week 4 STT 
assessment for any reason will be counted as non-responders in the primary analysis and therefore 
no adjustment of sample size for withdrawals is necessary. 
This sample size provides greater than 90% power to detect a significant change from baseline 
within any one of the three active treatment groups in the Eye Dryness VAS assuming the standard 
deviation of changes is 40 mm and the mean change from baseline is 20 mm (two-sided 
alpha=0.0166). 
The key secondary endpoint is analyzed within the population of subjects with an Eye Dryness 
VAS ≥60 mm at baseline. It is expected that this will reduce the sample size for this analysis by 
25% (from 120 per group to 90 per group). Assuming a standard deviation of 30 mm for change 
in eye dryness score and an improvement of any active arm compared to placebo (alpha=0.0166) 
of 15 mm, a sample size of 90 subjects per group provides at least 80% power to detect a significant 
difference. 
The study was ongoing at the time of the Coronavirus (COVID-19) pandemic. The impact of the 
pandemic was continually being assessed and it became apparent that a number of subjects were 
unable to attend the primary efficacy visit at Week 4 due to site closure. To account for the higher 
incidence of missing data and ensure data from at least 480 subjects were available for analysis of 
the primary endpoint (STT response at Week 4), the target sample size was increased to 
approximately 505 subjects. 
 


     
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4. 
POPULATIONS FOR ANALYSIS 
The following analysis populations will be considered: 
• 
Screened Population: all subjects who sign informed consent 
• 
Run-In Population: all subjects who received at least one dose of run-in medication. 
• 
Intent-to-Treat Population: the ITT population includes all randomized subjects. Subjects in 
the ITT population will be analyzed as randomized. 
• 
Modified Intent-to-Treat Population: the mITT population is based on the ITT population and 
excludes all subjects who were unable to attend their primary endpoint assessment at the Week 
4 visit due to Coronavirus-related site closure. Due to block enrolment, this applies to all 
subjects at Site 36. Thus, these subjects will be excluded from the mITT population. Subjects 
in this population will be analyzed as randomized. As detailed in Section 6.2, the mITT 
population will be used for the primary assessment of efficacy. 
• 
Per Protocol Population: The PP population includes subjects in the mITT population who do 
not have significant protocol deviations prior to their primary endpoint assessment at Week 4 
and who complete the Week 4 STT. Protocol deviations will be assessed prior to database 
lock and unmasking. The PP population will be analyzed as randomized. 
• 
Safety Population: The safety population includes all randomized subjects who have received 
at least one dose of randomized study treatment. The safety population will be analyzed for 
all safety assessments. Subjects in the safety population will be analyzed as treated.  
The run-in population will be used to describe all subjects who entered the run-in period. 
Baseline data will be summarized using the safety, ITT, PP and mITT populations. Safety data 
will be summarized using the safety population, and efficacy analysis will use the ITT, PP and 
mITT populations. 
Assignment of treatment group for the safety population will be made using an individual subject’s 
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5. 
STATISTICAL ANALYSES 
5.1. 
General Considerations 
All statistical analyses and reporting will be performed using the SAS® System Version 9.4 or 
later.  
Unless otherwise specified, continuous variables will be summarized with descriptive statistics (n, 
mean, median, standard deviation, standard error, minimum, and maximum), and categorical 
variables will be summarized with counts and percentages. 
All statistical models, unless otherwise specified, will include terms for the randomization strata 
(Eye Dryness), investigator site, appropriate baseline measure and treatment group. Where 
baseline score and randomization strata provide the same data (e.g., in the analysis of Eye 
Dryness), only baseline score will be used in the model. The eye dryness stratification level used 
in the modeling process will be a subject’s actual baseline eye dryness level (<60mm or ≥60mm) 
even if this is different to the level recorded at randomization.  
5.1.1. 
Decision Criteria 
All tests will be 2-sided with statistical significance being declared at the nominal 5% level. For 
the 5% error rate to be maintained in the primary and subsequently in the key secondary analyses, 
each voclosporin vs vehicle comparison will be tested at the 0.0166 alpha level. Confidence 
intervals (CI) will be labeled as nominal 95% CI and will be constructed as 98.33% CI. 
Intervals for secondary and safety analyses will be labeled and constructed as 95% CIs. 
5.1.2. 
Unit of Analysis 
Safety endpoints will be analyzed for each eye. For efficacy symptom-related endpoints, the unit 
of analysis is both eyes. For efficacy sign-related endpoints, the unit of analysis will be the study 
eye as defined by the following: 
Study Eye: The study eye will be defined as the qualifying eye that achieves the lowest STT score 
at baseline (Visit 2). Should both eyes be qualifying eyes with identical STT scores at baseline, 
the eye with the worst FCS score will be used. Should these scores also be equal, the right eye will 
be used. 
5.1.3. 
Calculation of Study Day 
Study day will be calculated as the number of days from first dose of study drug (Day 1):  
• 
Date of event – date of first dose of study drug + 1, for events on or after first dose  
• 
Date of event – date of first dose of study drug, for events before first dose  
To this end, Day 0 remains undefined. 


     
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5.1.4. 
Baseline 
For on-treatment comparisons, baseline is defined as the last non-missing value (either scheduled 
or unscheduled) following run-in and before the subject receives the first dose of randomized study 
drug on Day 1. As subjects progress from the end of run-in directly to the start of randomized 
study treatment, baseline data will come from Visit 2 (Day 1).  
Visual acuity assessments are occasionally repeated as unscheduled visits a few minutes after the 
visit assessment (for example, due to dirty glasses). Such unscheduled assessments on the same 
day as the baseline visit will be available to be selected as the baseline value. 
For summaries of changes over the run-in period, baseline will be defined as the screening visit 
with changes from the screening visit (Visit 1) to the baseline visit (Visit 2) being described. 
5.1.5. 
Visit Windowing for Analysis 
All data collected will be summarized and analyzed as belonging to the closest protocol-scheduled 
visit. 
Subjects with multiple sets of data within a single visit window will contribute their data collected 
closest to the scheduled visit day. Should two sets of data be equidistant, the later shall be used. 
All data will be listed. 
5.1.6. 
Analysis Timelines 
All statistical analysis will be undertaken following database lock. 
5.1.7. 
Use of Study Site in Analysis Models 
By default, study site will be included in all analysis models to adjust for any differences that may 
exist. Should the addition of study site to the models cause issue (e.g., convergence of a logistic 
model), sites will be combined in the following iterative manner prior to analysis: 
• 
The site causing issue will be combined with the site with the lowest number of subjects and 
the model re-run. 
• 
If issues persist, the combining of sites will continue in a similar fashion.  
5.1.8. 
Handling of Missing Data 
Response endpoints will be analyzed at specific time points. Subjects with missing responses will 
be included as non-responders in the primary analysis. 
Endpoints measured on the continuous scale (including VASs) and collected / analyzed at multiple 
visits will be analyzed using MMRM in order to account for incomplete data. 
Missing and partial start and stop dates will be imputed for analysis purposes as follows (medical 
history partial dates will not be imputed): 


     
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• 
Should the data available be sufficient to deduce that the event or medication started prior to 
first dose of randomized study medication, the date will be imputed as being as late as possible 
(as close to randomized study medication start as possible). For example, if only the year 2017 
is known and randomized study medication started in 2020, 31st Dec 2017 will be imputed. 
• 
Should the data available be sufficient to deduce that the event or medication started 
subsequent to the first dose of randomized study medication, the date will be imputed as being 
as early as possible (as close to randomized study medication start as possible). For example, 
if only the year 2020 is known and randomized study medication started in 2019, 1st Jan 2020 
will be imputed. 
• 
Should the data available be ambiguous as to whether the event or medication started during 
randomized dosing then the date of the first dose of randomized study medication will be 
imputed. For example, if only December 2019 is known and randomized study medication 
started on 15th December 2019, 15th Dec 2019 will be imputed.  
• 
Stop dates will never be imputed to be earlier than their corresponding start date. 
5.2. 
Participant Dispositions 
Subject disposition will be summarized as follows: 
The number of subjects who failed screening and the reasons for failure will be tabulated for the 
Screened Population. 
The number of subjects who entered the vehicle run-in period, completed run-in or the reason for 
failure will be tabulated for the run-in population. 
Numbers of subjects randomized and who are in the safety population will be summarized by 
treatment group and overall for the safety population. 
Numbers of subjects randomized and who are in each analysis population (ITT, mITT and PP) will 
be summarized by treatment group and overall. This summary will be repeated for individual levels 
of the stratification variable. 
Reasons for withdrawal from the study (including number of subjects completing) will be 
summarized by treatment group and overall. 
Reasons for exclusion from the PP analysis population will be summarized by treatment group and 
overall. 
Visit participation will be summarized following the visit windowing algorithm. 
5.3. 
Primary Endpoint Analysis 
The primary endpoint is the proportion of subjects with ≥10 mm increase from baseline in STT at 
Week 4 in their study eye (see Table 2). 


     
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Due to COVID-19, the primary assessment of efficacy will be made using the mITT population. 
5.3.1. 
Definition of endpoint 
The primary endpoint is a response endpoint with subjects who have increased their STT score by 
≥10 mm between baseline and week 4 (following visit windowing) being defined as responders. 
All subjects who have insufficient data to ascertain a response will be analysed as non-responders. 
5.3.2. 
Main analytical approach 
The response for each subject in the mITT population will be analyzed using a logistic regression 
model including covariates for investigator site, baseline eye dryness level and baseline STT score. 
Response rates for each arm will be displayed along with Odds Ratios for each active voclosporin 
arm compared to the vehicle arm. Nominal 95% CIs and p-values for each comparison will be 
provided. 
5.3.3. 
Sensitivity analysis 
To assess the impact of covariates in the primary model, the primary analysis will be repeated 
using a logistic model without covariates. 
5.3.4. 
Supplementary analyses 
To assess the impact of subjects who violated key aspects of the protocol, the primary model will 
be run using the PP population (with and without covariates). 
To assess the impact of omitting subjects who failed to provide a valid STT at Week 4 due to 
COVID-19 reasons, the primary model will be run using the ITT population (with and without 
covariates). 
To assess the impact of assuming all subjects with missing data are non-responders, the primary 
model will be run using a dataset of observed responses only for the ITT, mITT and PP populations 
(with and without covariates). 
5.4. 
Secondary Endpoints Analysis 
5.4.1. 
Key/Confirmatory secondary endpoint 
The key secondary endpoint is the mean change from baseline to Week 4 in the Eye Dryness VAS. 
The population will be all mITT subjects with a baseline Eye Dryness VAS ≥60 mm (see Table 
2). 
5.4.1.1. 
Definition of endpoint 
This endpoint is defined as the difference between Week 4 Eye Dryness VAS and the baseline Eye 
Dryness VAS (after visit windowing). Subjects without a Week 4 Eye Dryness VAS score will not 
contribute to this analysis. 


     
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5.4.1.2. 
Main analytical approach 
This data will be analyzed using an ANCOVA model including covariates for Investigator site, 
baseline Eye Dryness score and treatment group. 
Mean changes for each arm will be displayed along with least squares mean changes and 
differences between least squares mean changes for each active voclosporin arm compared to the 
vehicle arm. Nominal 95% CIs and p-values for each comparison will be provided. 
Statistical significance of a treatment group comparison will only be claimed following 
significance in the primary endpoint analysis for the same dose level. 
5.4.1.3. 
Sensitivity analysis 
No sensitivity analyses are planned for this endpoint. 
5.4.1.4. 
Supplementary analyses 
To assess the impact of subjects who violated key aspects of the protocol, the analysis will be run 
using the ITT and PP populations. 
5.4.2. 
Supportive secondary endpoint(s) 
Other supportive secondary endpoints are described in Table 2. Details of their analysis are below. 
5.4.2.1. 
Schirmer Tear Test at other visits 
Observed STT responses at Weeks 2, 8 and 12 will be analyzed in a similar fashion to the primary 
endpoint using the ITT population only. 
5.4.2.2. 
Total FCS score 
Mean change in Total FCS score at Weeks 2, 4, 8 and 12 will be analyzed using MMRM analysis. 
Under the missing at random assumption the MMRM model estimates the mean treatment effect 
assuming that, following withdrawal, subjects would have continued in a similar fashion to other 
subjects on the same arm who have similar covariates and similar data (up to the point of 
withdrawal). 
The model will include terms for investigator site, baseline Eye Dryness level, treatment, visit, 
treatment by visit interaction and baseline Total FCS score. 
Mean changes for each visit and each arm will be displayed along with least squares mean changes 
and differences between least squares mean changes for each visit (and overall) for each active 
voclosporin arm compared to the vehicle arm. Associated 95% CIs and p-values for each 
comparison will be provided. 
Mean change over the run-in period will be summarized. 


     
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5.4.2.3. 
FCS score for the 5 individual regions 
The FCS scores for each individual region will be analyzed in a similar fashion to the Total FCS 
score. 
5.4.2.4. 
Schirmer Tear Test Score 
The STT score will be analyzed in a similar fashion to the Total FCS score. 
5.4.2.5. 
Eye Dryness Score 
Eye dryness scores will be analyzed in a similar fashion to the Total FCS score. 
Eye Dryness scores will additionally be assessed with respect to changes from baseline within 
treatment group. P-values and associated 95% CIs for changes from baseline for each treatment 
group will be provided from the MMRM model. Note that as baseline Eye Dryness will be a 
covariate in the model, Eye Dryness baseline level will not be included in the model. 
5.4.2.6. 
Ocular Discomfort Score 
Ocular discomfort score will be analyzed in a similar fashion to the Total FCS score. 
5.4.2.7. 
Individual Symptom Severity Scores 
Individual symptom severity scores (Burning/Stinging, Itching, Photophobia, Eye Pain, Foreign 
Body Sensation and Blurred Vision) will be analyzed in a similar fashion to the Total FCS score. 
5.4.2.8. 
Total Symptom Severity Score 
Total symptom severity score will be analyzed in a similar fashion to the Total FCS score. 
5.4.2.9. 
SANDE Severity and Frequency Scores 
SANDE severity and frequency scores will be analyzed in a similar fashion to the Total FCS score. 
5.5. 
Tertiary/Exploratory Endpoints Analysis 
There are no further efficacy endpoints defined for analysis. 
5.6. 
Safety Analyses 
Safety summaries and analyses will comprise study drug exposure, adverse events, Best Corrected 
Visual Acuity, Slit-Lamp Biomicroscopy and Dilated Ophthalmoscopy. Each is described in the 
following sections. 
5.6.1. 
Extent of Compliance and Exposure 
Compliance will be summarized separately for the run-in period and the randomized treatment 
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Compliance will be calculated for the run-in period and the treatment period as follows: 
𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 % = 100 ∗ 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷−𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅
(𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑖𝑖𝑖𝑖 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃) ∗2
 
Note: Days in the run-in period will not include the day of randomization (Day 1) 
 
 
Compliance will be summarized using the safety, ITT, mITT and PP populations using the 
following categories: 
• 
<80% 
• 
80 to 120% 
• 
>120% 
Exposure to study drug will be summarized as a duration. 
Duration will be calculated as: Last Dose Day – First Dose Day + 1. It will be summarized using 
the following categories: 
• 
<1 week 
• 
1 to <4 weeks 
• 
4 to <8 weeks 
• 
≥8 weeks 
5.6.2. 
Adverse Events 
A treatment-emergent adverse event is defined as any AE with an onset date on or after the first 
dose of randomized study treatment (Day 1). 
Any AE with an onset date between the date of first dose of run-in medication and the day prior to 
the first dose of randomized study treatment is defined as a run-in AE. 
Adverse event summary tables will be produced separately for ocular events and non-ocular events. 
Summary tables will include proportions of subjects experiencing events as well as counts of the 
event in question. For summaries by severity, where only the most severe events are counted, 
summaries will not include event counts. 
Summaries of treatment-emergent adverse events (TEAE) by decreasing frequency of System 
Organ Class, decreasing frequency of Preferred Term and treatment group will include: 
• 
All events 
• 
All events by severity 
• 
Treatment-related events 


     
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• 
Disease-related events 
• 
Events Resulting in study drug interruption 
• 
Events Resulting in study drug discontinuation 
• 
Events Resulting in death 
• 
Above summaries (other than by severity and Resulting in death) repeated for serious TEAEs 
An overall summary table with the numbers of subjects and events in each of the above categories 
will be created. 
A table of all TEAEs by decreasing frequency of Preferred Term will be produced. 
A summary of all run-in events will be produced by decreasing frequency of System Organ Class 
and decreasing frequency of Preferred Term. Summaries of treatment-related, disease-related and 
serious events will also be produced for the run-in period. 
Separate listings of all serious TEAEs, all TEAEs resulting in death and all serious non-TEAEs 
will be produced. 
Adverse event coding will use the Medical Dictionary for Regulatory Activities (MedDRA) with 
the version used being specified on relevant outputs. 
5.6.3. 
Best Corrected Visual Acuity 
The BCVA logMAR (logarithm base 10 of the minimal angle of resolution) score will be 
summarized for each eye by visit as absolute values and change from baseline. 95% CIs for change 
from baseline within each treatment group will be provided. Treatment comparisons will be 
provided for descriptive purposes. 
Mean change over the run-in period will be summarized. 
5.6.4. 
Slit-Lamp Biomicroscopy 
The proportions of subjects with normal or abnormal results in each category for each eye will be 
summarized by visit. 
A shift table will also be produced showing the changes from baseline to on-treatment results for 
each category. 
5.6.5. 
Dilated Ophthalmoscopy 
The proportions of subjects with normal or abnormal results in each category for each eye will be 
summarized by each visit. 
A shift table will also be produced showing the changes from baseline to on-treatment result for 
each category. 


     
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5.7. 
Other Analyses 
Not Applicable. 
5.8. 
Interim Analyses 
No interim analysis is planned. 


     
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Page 32 of 34 
 
6. 
SUPPORTING DOCUMENTATION 
6.1. 
Appendix 1 List of Abbreviations 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
AUDREY 
Aurinia Dry Eye  
BID 
Twice daily 
CI 
Confidence Interval 
DES 
Dry Eye Syndrome 
FCS 
Fluorescein Corneal Staining 
IES 
Intercurrent Events Strategy 
ITT 
Intent-to-Treat 
LSM 
Least Squares Mean 
MCP 
Multiple Comparisons Procedure 
mITT 
Modified Intent-to-Treat 
MMRM 
Mixed Model Repeated Measures 
OR 
Odds Ratio 
OD 
Right Eye 
OS 
Left Eye 
OU 
Both Eyes 
PLS 
Population Level Summary 
STT 
Schirmer Tear Test 
TEAE 
Treatment-Emergent Adverse Event 
VAS 
Visual Analogue Scale 
VOS 
Voclosporin Ophthalmic Solution 
6.2. 
Appendix 2: Changes to Protocol-Planned Analyses 
All analysis will be performed as specified in Protocol version 3.0 dated 26th June 2020. 


     
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6.3. 
Appendix 3: Other Data 
6.3.1. 
Study performance 
A table showing the earliest and latest date of informed consent, earliest and latest randomization 
and the latest last contact date will be produced. 
6.3.2. 
Baseline Characteristics and Demography 
Demographic variables (age, sex, race and ethnicity) will be summarized by treatment group and 
overall for the Safety, ITT, mITT and PP populations. Demography tables will be run for each 
study site individually. 
6.3.3. 
Medical History 
Medical history will be summarized for the Safety and the ITT populations. Ocular and non-ocular 
histories will be summarized separately by System Organ Class and Preferred Terms. 
6.3.4. 
Prior and Concomitant Medications 
Prior and concomitant medications will be summarized by Anatomical Therapeutic Chemical 
(ATC) level 2 and Preferred Terms for the safety and ITT populations. Tables will be produced 
separately for ocular and non-ocular medications for: 
• 
Prior Medications (defined as medications that start and stop prior to the start of the first dose 
of study medication). 
• 
Prior and Concomitant Medications (defined as medications that are being taken at the time 
of the first dose of study medication). 
• 
Concomitant Medications (defined as those medications that start following the first dose of 
study medication). 
All medical procedures will be listed. 
6.3.5. 
Subject Data Listings 
All data collected on the database will be included in subject data listings. 


     
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7. 
REFERENCES 
None. 

Prot_001.pdf: 
This trial will be conducted in compliance with this protocol, ICH GCP and applicable regulatory requirements. 
The information contained in this document is proprietary to Aurinia Pharmaceuticals Inc. and is not to be copied, disclosed or 
otherwise distributed by an outside authority to any person or persons without the prior written permission of Aurinia. 
A Randomized, Double-Masked, Vehicle-Controlled, Dose 
Ranging Study to Assess the Efficacy and Safety of Voclosporin 
Ophthalmic Solution (VOS) in Subjects with Dry Eye Syndrome 
Clinical Protocol Number: 
AUR-VOS-2019-01 
Date: 
04 September 2019 
Version Number: 
2.0 
IND Number: 
102,279 
Study Name: 
AUDREY (AUrinia DRy EYe) 
NCT Number: 
NCT04147650


 
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NAMES AND ADDRESSES 
Sponsor 
Name: 
Aurinia Pharmaceuticals Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Tel: 
 
 
Fax: 
 
 
Clinical Representative 
Name: 
 
 
Company: 
Aurinia Pharmaceuticals Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Email: 
  
 
Chief Medical Officer 
Name: 
 
 
Company: 
Aurinia Pharmaceuticals Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Email: 
 
 
Regulatory Representative 
Name: 
 
 
Company: 
Aurinia Pharmaceuticals Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Email: 
 
 
Trial Statistician 
Name:  
 
 
Company: 
Aurinia Pharmaceuticals Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Email: 
 


 
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DECLARATION OF SPONSOR 
Title: A Randomized, Double-Masked, Vehicle-Controlled, Dose Ranging Study to Assess the 
Efficacy and Safety of Voclosporin Ophthalmic Solution (VOS) in Subjects with Dry Eye 
Syndrome 
This study protocol was subjected to critical review. The information it contains is consistent 
with current knowledge of the risks and benefits of the study treatment, as well as with the 
moral, ethical, and scientific principles governing clinical research as set out in the Declaration 
of Helsinki and the International Council for Harmonisation (ICH) on Good Clinical Practice 
(GCP). 
Sponsor Representatives 
 
 
 
 
Chief Medical Officer 
 
Date (i.e., DD Month Year) 
 
 
 
 
Vice President, Quality and Regulatory 
Affairs 
 
Date (i.e., DD Month Year) 
 


 
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INVESTIGATOR AGREEMENT FORM 
I have read the attached protocol titled: A Randomized, Double-Masked, Vehicle-Controlled, 
Dose Ranging Study to Assess the Efficacy and Safety of Voclosporin Ophthalmic Solution 
(VOS) in Subjects with Dry Eye Syndrome 
I agree to comply with the current International Council for Harmonisation Guidelines on Good 
Clinical Practice and applicable regulations and guidelines. 
I agree to ensure that financial disclosure statements will be completed by: 
• me (including, if applicable, my spouse (or legal partner) and dependent children); 
• my Sub-Investigators 
before the start of the study and to report any changes that affect my financial disclosure status 
for up to 1 year after the study is completed. 
I agree to ensure that the confidential information contained in this document will not be used 
for any purpose other than the evaluation or conduct of the clinical investigation without the 
prior written consent of Aurinia Pharmaceuticals Inc. 
Signature by the Investigator on this form documents review, agreement, and approval of the 
requirements contained within this protocol. 
 
 
 
Name 
 
 
Signature 
 
Date (i.e., DD Month Year) 
 


 
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SYNOPSIS 
Title: 
A Randomized, Double-Masked, Vehicle-Controlled, Dose Ranging Study to Assess the 
Efficacy and Safety of Voclosporin Ophthalmic Solution (VOS) in Subjects with Dry Eye 
Syndrome 
Study Product: 
Voclosporin Ophthalmic Solution (VOS) 
Indication: 
Dry Eye Syndrome (DES) 
Phase: 
2/3 
Sponsor: 
Aurinia Pharmaceuticals Inc. 
Study Code: 
AUR-VOS-2019-01 
Objectives: 
To assess the efficacy and safety of three different concentrations of VOS (0.05%, 0.10%, 
and 0.20%) when administered twice a day (BID) in both eyes (OU) over 12 weeks 
compared to vehicle in subjects with DES. 
Design: 
This is a Phase 2/3, multi-center, randomized, double-masked, vehicle-controlled study to 
assess the efficacy and safety of three different concentrations of VOS when administered 
OU BID over 12 weeks in subjects with mild to moderate DES. Subjects will undergo a 
2-week run-in period in which VOS vehicle will be self-administered OU, BID. Subjects 
will be re-assessed to confirm that all participants meet all of the inclusion criteria and 
none of the exclusion criteria. It is estimated that the study will enroll approximately 480 
subjects across approximately 9 study centers. Eligible subjects will be randomized in a 
1:1:1:1 ratio to one of the following study treatment groups after the 14- to 17-day run-in 
period. 
Treatment: 
Subjects will be randomized to one of the following treatment groups: 
Investigational product (IP): one drop 0.05% VOS, OU BID over 12 weeks, one drop 
0.10% VOS OU BID over 12 weeks, or one drop 0.20% VOS OU BID over 12 weeks. 
Comparator: one drop VOS vehicle OU BID over 12 weeks. 
Inclusion Criteria 
Subjects are eligible for participation if they: 
1. Provide written informed consent before any study-specific procedures are 
performed. 
2. Are male or female, with a minimum age of 18 years (or legal age of consent 
if >18 years), at the time of screening. 
3. Have a documented history of DES in both eyes supported by a previous clinical 
diagnosis prior to Visit 1  
4. Are willing and able to follow protocol procedures and instructions and can be 
present for the required study visits for the duration of the study. 
5. Have a symptom severity score of ≥30 mm for Eye Dryness on the Individual 
Symptom Severity Assessment Visual Analog Scale (VAS) (0-100 mm) at both 
Visit 1 and Visit 2. 
6. Have a best corrected visual acuity (BCVA) in both eyes of +0.7 logarithm of 
the Minimum Angle of Resolution (logMAR) or better as assessed by Early 
Treatment of Diabetic Retinopathy Study (ETDRS) chart at Visit 1. 
7. Have ongoing DES, as defined by at least one eye (if one eye, the same eye) 
meeting both of the following criteria at both Visit 1 and Visit 2:  
a) Have an unanesthetized Schirmer Tear Test (STT) score of ≥1 mm and 
≤10 mm per 5 minutes. 


 
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b) Have a total fluorescein corneal staining (FCS) score of at least 3 
[National Eye Institute (NEI)/Industry Workshop 0-15 scale]. 
Note: The qualifying eye at Visit 1 must be the same eye at Visit 2. 
8. Have normal lid anatomy 
Exclusion 
Criteria: 
In order for subjects to be eligible, subjects must not: 
1. Be non-compliant during the run-in treatment (non-compliance defined as dosing 
<80% or >120% of the time, calculated by counting the number of returned and 
unused study drug ampules) 
2. Have any known hypersensitivity or contraindication to study treatments 
(including excipients), topical anesthetics, or vital dyes. 
3. Have had any eye surgery in either eye except for cataract surgery or laser-
assisted in situ keratomileusis (LASIK). 
4. Have undergone cataract or LASIK surgery within 1 year prior to Visit 1. 
5. Have recent or current evidence of ocular infection or inflammation in either eye 
including ocular pemphigoid and Stevens Johnson Syndrome. 
6. Have current evidence of clinically significant blepharitis (defined as requiring 
lid hygiene therapy and additional therapies such as doxycycline or Lipiflow®) 
or other meibomian gland dysfunction, conjunctivitis, or a history of herpes 
simplex or zoster keratitis in either eye. 
7. Have clinically significant ocular disease in either eye (i.e., corneal edema, 
uveitis, severe keratoconjunctivitis sicca) or active ocular allergies that might 
interfere with study procedures or assessments in the opinion of the Investigator. 
Severe keratoconjunctivitis sicca is defined by an FCS score of ≥13. 
8. Be taking or have a known need for any of the following treatment therapies 
within the time frames as specified below: 
a) Any investigational drug or device within 30 days prior to the Screening 
Visit (Visit 1) and subjects may not receive any investigational drug or 
device during the entire study except that which is allowed by the 
protocol. 
b) Ophthalmic drugs (any topical eye medications) including prescription 
medication and over-the-counter (OTC) agents, from date of Visit 1 to 
Visit 7. 
c) Contact lenses 24 hours prior to the Screening Visit (Visit 1) to the end 
of Visit 7. 
d) Any prior use of amiodarone. 
e) Within 72 hours of Visit 1 and for the duration of the study: 
− Oral anti-histamines 
f) 
Within 14 days prior to Visit 1 and for the duration of the study: 
− Xiidra® (lifitegrast) 
g) Within 30 days prior to Visit 1 and for the duration of the study: 
− Calcineurin Inhibitors (CNIs) such as Restasis® (cyclosporin 
ophthalmic emulsion) or CequaTM 
− Topical ocular anti-histamines 
− Ocular, inhaled, or intranasal corticosteroids 
− Topical or oral mast cell stabilizers  
− Topical or nasal vasoconstrictors 


 
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− Topical 
ocular 
nonsteroidal 
anti-inflammatory 
drugs 
(NSAIDs) 
− Topical ocular antibiotics 
− True Tear device  
h) Unstable dose within 30 days prior to the Screening Visit (Visit 1) or 
during the study; alteration to the dose or anticipated alterations to the 
dose of the following are disallowed: 
− Tetracyclines 
− Omega 3s or Omega 6s 
i) 
Unstable dose within 60 days prior to the Screening Visit (Visit 1) or 
during the study; alteration to the dose or anticipated alterations to the 
dose of the following are disallowed: 
− Anticholinergics 
− Antidepressants 
− Oral contraceptives 
− Isotretinoin 
− Oral systemic corticosteroids 
− Oral systemic immunosuppressive agents 
j) 
Within 90 days prior to the Screening Visit (Visit 1) or during the study, 
the subject has had cauterization of the punctum or alternations to 
(insertion or removal) punctal plug(s) or nasolacrimal surgery. Note: If 
a punctal plug is in place at the Screening Visit (Visit 1) and it is 
dislodged during the study, the plug should be replaced as soon as 
possible. 
9. Have clinically significant systemic disease (i.e., uncontrolled diabetes, hepatic, 
renal, endocrine, or cardiovascular disorders) that might interfere with the study. 
10. Have been randomized and treated in a previous study where VOS was the IP. 
11. Be a woman of childbearing potential who is pregnant, nursing, planning a 
pregnancy, or not using a medically acceptable form of birth control. All women 
of childbearing potential must be willing to take a urine pregnancy test at Visit 1 
and Visit 6.  
12. Have a condition or be in a situation that the Investigator feels may put the 
subject at significant risk, may confound the study results, or may interfere 
significantly with the subject’s participation in the study. 
Primary 
Endpoint: 
• 
Proportion of subjects with a ≥10 mm increase from baseline in STT at Week 4 
in the study eye. The study eye will be defined as the qualifying eye that achieves 
the lowest STT score at baseline. Should both eyes be qualifying eyes with 
identical STT scores at baseline, the eye with the worst FCS score will be used. 
Should these scores also be equal, the right eye will be used. 
Key Secondary 
Endpoint: 
• 
Mean change from baseline in Eye Dryness VAS at Week 4 in subjects with a 
baseline Eye Dryness VAS score ≥60mm. 
Secondary 
Endpoints: 
Secondary Endpoints: 
• 
Proportion of subjects with a ≥10 mm increase from baseline in STT at Weeks 
2, 8, and 12 in the study eye. 
• 
Mean change from baseline in total FCS (NEI/Industry Workshop 0-15 scale) 
score to Weeks 2, 4, 8, and 12 in the study eye. 


 
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• 
Mean change from baseline in FCS score in the 5 regions of the cornea (central, 
superior, inferior, temporal, and nasal) to Weeks 2, 4, 8, and 12 in the study eye. 
• 
Mean change from baseline in STT score to Weeks 2, 4, 8, and 12 in the study 
eye. 
• 
Mean change from baseline in Eye Dryness VAS (0-100 mm) score to Weeks 2, 
4, 8, and 12 within treatment group. 
• 
Mean change from baseline in Ocular Discomfort VAS (0-100 mm) score to 
Weeks 2, 4, 8, and 12.  
• 
Mean change from baseline in Eye Dryness, Burning/Stinging, Itching, 
Photophobia, Eye Pain, Foreign Body Sensation, and Blurred Vision VAS 
(0-100 mm) score to Weeks 2, 4, 8, and 12. 
• 
Mean change from baseline of the sum of Individual Symptom Score (VAS Total 
Symptom Summary Score) to Weeks 2, 4, 8, and 12.  
• 
Mean change from baseline in Symptom Assessment in Dry Eye (SANDE) 
frequency and severity scores to Week 2, 4, 8, and 12. 
Safety Endpoints: 
• 
Treatment-emergent adverse events (TEAEs) 
• 
Change from baseline in BCVA over time 
• 
Changes from baseline in slit-lamp biomicroscopy over time 
• 
Changes from screening in dilated ophthalmoscopy over time 
Procedures: 
Subjects who have provided signed and dated informed consent will be screened for entry 
into this study. Subjects will be evaluated for eligibility according to the protocol 
inclusion/exclusion criteria. Eligible subjects will enter a 14- to 17-day run-in period 
during which time they will receive vehicle drops and will be instructed to instill one drop 
of vehicle OU BID. Subjects will be re-evaluated for eligibility after the run-in period.  
After the run-in period, eligible subjects will be randomly assigned in a 1:1:1:1 ratio to 
one of the four treatment groups: VOS 0.05% BID, VOS 0.1% BID, VOS 0.2% BID, or 
VOS vehicle BID. 
Subjects will self-instill the assigned treatment, one drop OU BID, over 12 weeks. 
Sample Size: 
This study is expected to enroll 480 subjects into 4 treatment arms. A two-group continuity 
corrected Chi square test with a 0.0166 two-sided significance level (adjusted for three 
treatment comparisons versus placebo) will have at least 80% power to detect the 
difference between a vehicle response rate of 20% (defined as the percentage of subjects 
with a ≥10 mm increase in STT from baseline) and a VOS response rate of 40% when the 
sample size in each group is 120 (total N=480). Response is defined as an increase of ≥10 
mm in STT from baseline to Week 4. 
While the effect of withdrawals will be investigated, subjects withdrawing prior to Week 
4 STT assessment for any reason will be counted as non-responders in the primary analysis 
and therefore no adjustment of sample size for withdrawals is necessary. Subjects 
providing insufficient data to determine response at Week 4 (e.g., early withdrawal) will 
be analysed as non-responders.  
An additional sensitivity analysis will analyse observed responses only. 
This sample size provides greater than 90% power to detect a significant change from 
baseline within any one of the three active treatment groups in the Eye Dryness VAS 
assuming the standard deviation of changes is 40 mm and the mean change from baseline 
is 20 mm (two-sided alpha=0.0166). 


 
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The key secondary endpoint is analyzed within the population of subjects with an Eye 
Dryness VAS ≥60 mm at baseline. It is expected that this will reduce the sample size for 
this analysis by 25% (from 120 per group to 90 per group). Assuming a standard deviation 
of 30 mm for change in eye dryness score and an improvement of any active arm compared 
to placebo (alpha=0.0166) of 15 mm, a sample size of 90 subjects per group provides at 
least 80% power to detect a significant difference. 
Statistical 
Methods: 
All statistical analyses will be undertaken at study closure and will incorporate all efficacy 
and safety endpoints. 
Analysis Populations: 
The following analysis populations will be considered: 
• 
Intent-to-Treat Population – The intent-to-treat (ITT) population includes all 
randomized subjects. Subjects in the ITT population will be analyzed as randomized. 
• 
Per Protocol Population – The per protocol (PP) population includes subjects in the 
ITT population who do not have significant protocol deviations prior to their primary 
endpoint assessment at Week 4 and who complete the Week 4 STT. Protocol 
deviations will be assessed prior to database lock and unmasking. The PP population 
will be analyzed as randomized. 
• 
Safety Population – The safety population includes all randomized subjects who have 
received at least one dose of randomized study treatment. The safety population will 
be analyzed for all safety assessments. Subjects in the safety population will be 
analyzed as treated.  
• 
The run-in population will be used to describe all subjects who entered the run-in 
period. 
Baseline data will be summarized using the safety, ITT, and PP populations. Safety data 
will be summarized using the safety population, and efficacy analysis will use the ITT and 
PP populations. 
Methods: 
Efficacy Endpoints: 
Analysis of the primary endpoint, proportion of subjects with a ≥10 mm increase from 
baseline in STT at Week 4 in the study eye, will be conducted on the ITT and PP 
populations. The response rate for each VOS group compared to vehicle will be 
determined using a logistic regression model including terms for Investigator site, 
treatment group, and baseline STT. Results of this logistic regression will be displayed as 
odds ratios and two-sided adjusted 95% confidence intervals (CI) (VOS compared to 
vehicle). The proportion of subjects exhibiting a response at Week 4 will be summarized 
by treatment group.  
The key secondary endpoint of mean change from baseline in Eye Dryness VAS in the 
subset of subjects with baseline Eye Dryness VAS ≥60 mm will be analysed using the ITT 
and the PP populations. Mean change, along with an adjusted 95% CI and p-value, will 
be provided from a General Linear Model including terms for Investigator site, treatment 
group and baseline Eye Dryness VAS. 
Other proportional endpoints (STT response at alternative time points) will be analyzed 
and summarized in a similar fashion to the primary endpoint. 
Endpoints measured as continuous data (including VAS scores) will be summarized by 
visit for the ITT population only. Mean change from baseline (95% CI) will be provided 
for within treatment group changes and for differences between treatment groups (VOS 
– vehicle). 


 
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Mixed Effect Model Repeated Measures (MMRM) will also be used to analyze all 
available data for a given endpoint. The MMRM model will include terms for Investigator 
site, treatment group, visit, treatment-by-visit interaction, and applicable baseline 
measure. Results will be expressed as differences between treatment arms (VOS – 
vehicle) along with associated 95% CIs and p-values. 
Safety Endpoints: 
Adverse events will be aggregated by System Organ Class and preferred term and 
presented as summary tables. BCVA will be summarized as a continuous endpoint with 
results displayed as mean changes from baseline for each visit. Slit-lamp biomicroscopy 
and dilated ophthalmoscopy will be summarized using frequency counts and shift tables 
from baseline. 
 


 
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TABLE OF CONTENTS 
NAMES AND ADDRESSES ...................................................................................................2 
DECLARATION OF SPONSOR ...........................................................................................3 
INVESTIGATOR AGREEMENT FORM ............................................................................4 
SYNOPSIS ................................................................................................................................5 
TABLE OF CONTENTS ......................................................................................................11 
LIST OF FIGURES .................................................................................................................14 
LIST OF APPENDICES ..........................................................................................................14 
LIST OF ABBREVIATIONS ...............................................................................................15 
1. 
INTRODUCTION AND BACKGROUND ..................................................................17 
1.1 
Nonclinical Studies of Voclosporin in Dry Eye ..........................................................18 
1.2 
Clinical Studies of Voclosporin in Dry Eye ................................................................20 
1.3 
Study Rationale ............................................................................................................21 
2. 
STUDY OBJECTIVES ..................................................................................................22 
3. 
CLINICAL HYPOTHESIS ...........................................................................................23 
4. 
OVERALL STUDY DESIGN .......................................................................................24 
5. 
STUDY POPULATION ................................................................................................28 
5.1 
Number of Subjects......................................................................................................28 
5.2 
Study Population Characteristics .................................................................................28 
5.3 
Inclusion Criteria .........................................................................................................28 
5.4 
Exclusion Criteria ........................................................................................................29 
5.5 
Withdrawal Criteria .....................................................................................................31 
5.6 
Aurinia Adequate/Effective Contraception..................................................................32 
6. 
STUDY PARAMETERS ...............................................................................................33 
6.1 
Efficacy Measures ........................................................................................................33 
6.1.1 
Primary Efficacy Endpoint .......................................................................................33 
6.1.2 
Key Secondary Endpoint ..........................................................................................33 
6.1.3 
Secondary Endpoints ................................................................................................33 
6.2 
Safety Measures ...........................................................................................................34 
7. 
RANDOMIZATION, MASKING AND UNMASKING PROCEDURES ................35 
7.1 
Randomization .............................................................................................................35 
7.2 
Masking........................................................................................................................35 
7.3 
Unmasking ...................................................................................................................35 
8. 
STUDY MATERIALS ...................................................................................................36 
8.1 
Dosage Forms/Formulation .........................................................................................36 
8.1.1 
Study Treatments ......................................................................................................36 


 
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8.1.2 
Description and Justification for the Route of Administration, Dosage, Dosage 
Regimen, and Treatment Period ...............................................................................36 
8.1.3 
Instructions for Use and Administration ...................................................................37 
8.2 
Other Study Supplies ...................................................................................................37 
9. 
STUDY METHODS AND PROCEDURES ................................................................38 
9.1 
Subject Entry Procedures .............................................................................................38 
9.1.1 
Overview ...................................................................................................................38 
9.1.2 
Informed Consent .....................................................................................................38 
9.1.3 
Washout Intervals .....................................................................................................38 
9.1.4 
Procedures for Final Study Entry..............................................................................38 
9.1.5 
Methods for Assignment to Treatment Groups ........................................................38 
9.2 
Concurrent Therapies ...................................................................................................38 
9.2.1 
Prohibited Medications .............................................................................................38 
9.2.2 
Rescue Medications ..................................................................................................38 
9.2.3 
Special Diets or Activities ........................................................................................39 
9.3 
Examination Procedures ..............................................................................................39 
9.3.1 
Visit 1: Day -17 to -14 Screening and Run-In Period...............................................39 
9.3.2 
Visit 2: Day 1-Baseline .............................................................................................40 
9.3.3 
Visit 3: Day 14 (±3 days) ..........................................................................................41 
9.3.4 
Visit 4: Day 28 (±3 days) ..........................................................................................42 
9.3.5 
Visit 5: Day 56 (±3 days) ..........................................................................................43 
9.3.6 
Visit 6: Day 84 (±3 days)/Early Termination Visit ..................................................44 
9.3.7 
Visit 7: Post-Treatment Safety Follow-Up (+7 days from Visit 6, ±3 days) ............44 
9.3.8 
Unscheduled Visits ...................................................................................................45 
9.4 
Compliance with Protocol............................................................................................45 
9.5 
Subject Disposition ......................................................................................................45 
9.5.1 
Completed Subjects ..................................................................................................45 
9.5.2 
Discontinued Subjects...............................................................................................45 
9.6 
Study Termination .......................................................................................................46 
9.7 
Study Duration .............................................................................................................46 
9.8 
Monitoring and Quality Assurance ..............................................................................46 
10. EVALUATION, RECORDING AND REPORTING OF AES AND SAES .............48 
10.1 
Definitions....................................................................................................................48 
10.1.1 
Adverse Event ...........................................................................................................48 
10.1.2 
Adverse Drug Reaction .............................................................................................48 
10.1.3 
Unexpected ADR ......................................................................................................48 
10.1.4 
Serious Adverse Event (SAE)...................................................................................48 
10.1.5 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ...................................49 
10.1.6 
Treatment-Emergent Adverse Event (TEAE) ...........................................................49 
10.2 
Adverse Event Descriptors ..........................................................................................49 
10.2.1 
Intensity/Severity Categorization .............................................................................49 


 
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10.2.2 
Causal Relationship Categorization ..........................................................................50 
10.2.3 
Outcome Categorization ...........................................................................................50 
10.2.4 
Symptoms of the Disease Under Study ....................................................................51 
10.2.5 
Adverse Events of Special Interest including Abuse, Misuse, Overdose and 
Medication Errors .....................................................................................................51 
10.3 
Reporting Procedure for AEs, SAEs, and Pregnancy ..................................................51 
10.3.1 
Adverse Events .........................................................................................................51 
10.3.2 
Serious Adverse Events ............................................................................................52 
10.3.3 
Pregnancy..................................................................................................................54 
11. STATISTICAL HYPOTHESES AND METHODS OF ANALYSES .......................56 
11.1 
Analysis Populations ....................................................................................................56 
11.2 
Statistical Hypothesis ...................................................................................................56 
11.3 
Sample Size ..................................................................................................................57 
11.4 
Statistical Analysis .......................................................................................................57 
11.4.1 
Unit of Analysis ........................................................................................................57 
11.4.2 
Multiplicity Considerations ......................................................................................58 
11.4.3 
Primary Efficacy Analyses .......................................................................................58 
11.4.4 
Key Secondary Endpoint Analysis ...........................................................................58 
11.4.5 
Secondary Efficacy Analyses ...................................................................................58 
11.4.6 
Safety Variables ........................................................................................................59 
11.4.7 
Interim Analyses .......................................................................................................59 
12. COMPLIANCE 
WITH 
GOOD 
CLINICAL 
PRACTICES, 
ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES .......................................60 
12.1 
Protection of Human Subjects .....................................................................................60 
12.1.1 
Subject Informed Consent ........................................................................................60 
12.1.2 
Institutional Review Board Approval .......................................................................60 
12.2 
Ethical Conduct of the Study .......................................................................................60 
12.3 
Subject Confidentiality ................................................................................................60 
12.4 
Documentation .............................................................................................................61 
12.4.1 
Retention of Documentation .....................................................................................61 
12.5 
Labelling, Packaging, Storage, Accountability, and Return or Disposal of 
Investigational Product ................................................................................................61 
12.5.1 
Labelling/Packaging .................................................................................................61 
12.5.2 
Storage of Investigational Product ............................................................................62 
12.5.3 
Accountability of Investigational Product ................................................................62 
12.5.4 
Return or Disposal of Investigational Product ..........................................................62 
12.6 
Aurinia Recording of Data on Source Documents and Case Reports Forms (CRFs) .62 
12.7 
Handling of Biological Specimens ..............................................................................63 
12.8 
Publications ..................................................................................................................63 
13. REFERENCES ...............................................................................................................64 
14. APPENDICES ................................................................................................................66 


 
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LIST OF FIGURES 
Figure 1 
AUDREY (AUR-VOS-2019-01) Study Schematic ..........................................25 
Figure 2 
Visit-by-Visit Study Flow Chart .......................................................................26 
 
LIST OF APPENDICES 
Appendix 1: Schedule of Visits and Measurements ................................................................66 
Appendix 2 : Examination Procedures, Tests, Equipment, and Techniques ...........................68 
Appendix 3: Daily Dosing Diary .............................................................................................74 
 
 


 
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LIST OF ABBREVIATIONS 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AUDREY 
AUrinia DRy EYe 
Aurinia 
Aurinia Pharmaceuticals Inc. 
BCVA 
Best Corrected Visual Acuity 
BID 
Twice daily 
CI 
Confidence interval 
CNI 
Calcineurin inhibitor 
CPM 
Clinical Project Manager 
CRO 
Contract Research Organization 
CsA 
Cyclosporine A 
DED 
Dry Eye Disease 
DES 
Dry Eye Syndrome 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ERG 
Electroretinography 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FCS 
Fluorescein Corneal Staining 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IWRS 
Interactive Web Response System 
KCS 
Keratoconjunctivitis sicca 
LASIK 
Laser-assisted in situ keratomileusis 
LogMAR 
Logarithm of the Minimum Angle of Resolution 


 
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MMRM 
Mixed Effect Model Repeated Measures 
NEI 
National Eye Institute 
NFAT 
Nuclear Factor of Activated T-cells 
NOAEL 
No observed adverse effect level 
NSAID 
Nonsteroidal Anti-Inflammatory Drug 
NZW 
New Zealand White 
OTC 
Over-the-counter 
OU 
Both eyes 
PP 
Per Protocol 
SAE 
Serious adverse event 
SANDE 
Symptom Assessment in Dry Eye 
STT 
Schirmer Tear Test 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
VAS 
Visual Analog Scale 
VOS 
Voclosporin ophthalmic solution 


 
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1. INTRODUCTION AND BACKGROUND 
Dry eye syndrome (DES) (also known as dry eye disease (DED) and keratoconjunctivitis sicca 
(KCS), herein referred to as DES) is a complex disorder of the ocular surface disease (OSD) 
characterized by tear film instability progressing to tear hyperosmolarity, epithelial damage 
with inflammation, neurogenic inflammation, and eventual fibrosis of the lacrimal gland with 
reduced tear production [(Boboridis and Konstas 2018)]. The Tear Film and Ocular Surface 
Society Dry Eye Workshop group defines global DES as a multi-factorial disease of the ocular 
surface characterized by a loss of homeostasis of the tear film accompanied by ocular 
symptoms. These include tear film instability and hyperosmolarity, ocular surface 
inflammation and damage, and neurosensory abnormalities [(Craig, Nichols et al. 2017)]. The 
overall incidence of DES has significant geographic variation, with published data ranging 
from 5%-34% of US adults over 50 years of age. Given the heterogeneity of patients, a 
retrospective analysis of the US Department of Defense Medical Claims Data demonstrated an 
overall prevalence of 5.3% of adults have DES, impacting twice as many women as men, and 
increasing in prevalence with age. The 2015 US Census estimated that up to 16 million people 
experienced DES in the US [(Dana, Bradley et al. 2019)]. In patients with DES, tear production 
has been shown to be increased with the use of topical immunosuppressants, including 
cyclosporine. Symptoms of DES include a sensation of dry eyes, foreign body sensation, 
irritation, burning, tearing, ocular pain, and itching, among others. DES affects quality of life 
and work productivity, and patients with moderate to severe DES may experience reduced 
visual function in addition to ocular dysfunction. Current therapy includes a stepped approach, 
which starts with over-the-counter (OTC) lubricants and artificial tear replacements, and then 
expands to include topical anti-inflammatory therapy and punctal occlusion [(Craig, Nichols 
et al. 2017)]. There are currently three FDA-approved prescription medications used for DES, 
topical cyclosporine ophthalmic solution 0.05% (Restasis®, herein referred to as Restasis) 
[(Restasis® 2017)], lifitegrast ophthalmic solution 5% (Xiidra®, herein referred to as Xiidra) 
[(Xiidra® 2017)], and cyclosporine ophthalmic solution 0.09% (Cequa™, herein referred to as 
Cequa) [(CEQUA® 2018)]. A significant number of patients using Restasis experience the 
following adverse reactions: ocular irritation upon instillation, slow onset of response, and 
limited efficacy [(Restasis® 2017)]. Adverse reactions with Xiidra include instillation irritation, 
dysgeusia, and reduced visual acuity that occurred in 5%-25% of subjects in clinical trials 
[(Xiidra® 2017)]. The most common adverse reactions reported with Cequa were pain on 
instillation of drops (22% of subjects) and conjunctival hyperemia (6% of subjects) [(CEQUA® 
2018)]. Despite these approved products, an unmet clinical need remains for improved 
therapeutic options for patients with moderate to severe DED. 
In patients with DES, tear production has been shown to be increased with the use of topical 
immunosuppressants, including cyclosporine. It is believed that T-lymphocyte infiltration and 
activation in the lacrimal gland represents an underlying pathogenesis for DES. Calcineurin 
inhibitors reversibly inhibit immunocompetent lymphocytes, particularly T-lymphocytes, in 
the G0 or G1 phase of the cell cycle and also reversibly inhibit the production and release of 
lymphokines [(Granelli-Piperno 1986)]. Calcineurin is a calcium- and calmodulin-dependent 


 
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serine-threonine phosphatase. Calcineurin inhibitors (CNIs) inhibit the ability of calcineurin to 
dephosphorylate the nuclear factor of activated T-cells (NFAT), which is required for 
translocation of NFAT from the cytoplasm to the nucleus, thereby preventing activation of 
various transcription factors necessary for the induction of cytokine genes during T-cell 
activation (i.e., interleukin-2, interleukin-4, tumor necrosis factor-α, granulocyte-macrophage 
colony stimulating factor, and interferon-γ) [(Stepkowski 2000, Wiseman 2016)]. 
Voclosporin (LX214) is a novel next generation CNI that is currently being evaluated for a 
variety of systemic and topical indications. Voclosporin is structurally similar to cyclosporine 
A (CsA), except for a novel modification of a functional group on the amino acid-1 residue of 
the molecule. This alteration has changed how voclosporin binds to calcineurin leading to an 
improved potency when compared to CsA. This modification has also changed the metabolic 
profile of voclosporin by shifting metabolism away from amino acid-1, which is the major site 
of metabolism for CsA. The altered metabolic profile has led to a faster elimination of 
metabolites resulting in lower metabolite exposure compared to CsA. The combination of 
increased potency and decreased metabolite exposure, for voclosporin compared to CsA, has 
led to better pharmacokinetic/pharmacodynamic predictability. 
1.1 
Nonclinical Studies of Voclosporin in Dry Eye 
Two Good Laboratory Practice (GCP) toxicology studies [(S07654 2009, S07655 2009)] have 
been conducted to evaluate the safety of voclosporin ophthalmic solution (VOS) in the eye of 
the New Zealand White (NZW) rabbit and the Beagle dog with dosing for 14 days. Test 
animals were euthanized on Day 15, and recovery animals were sacrificed on Day 29. Animals 
received two, four, or eight bilateral topical applications of 0.2% VOS within 8 hours daily, 
corresponding to doses of approximately 0.14, 0.28, and 0.56 mg/eye/day, respectively. 
Control animals received 8 doses of the vehicle within 8 hours daily. Safety was evaluated 
using 
macroscopic 
and 
microscopic 
ophthalmologic 
evaluations; 
tonometry; 
electroretinography (ERG) evaluation; gross and microscopic pathology of the eyes (including 
optic nerve), submandibular lymph nodes, spleen, and thymus; and hematology, blood 
chemistry, and coagulation parameters. Blood voclosporin concentrations were obtained on 
Days 1 and 13 at pre-dose and 8, 8.5, 10, and 12 hours after the first VOS instillation.  
In the NZW rabbit study, no VOS ocular treatment-related changes in serum chemistry, 
hematology, coagulation, gross pathology, or organ weights were found at the completion of 
the dosing period or following a 14-day recovery (without treatment). Similarly, no 
treatment-related macroscopic or microscopic ophthalmological changes or effects on 
intraocular pressure associated with the administration of VOS were reported. There were no 
histologic findings in the spleen, thymus, or rostral and caudal sections of the mandibular 
lymph nodes. A standard battery of bilateral full-field flash ERGs was performed; sporadic 
statistically significant differences were seen, but as these were all limited to one eye, were not 
dose-dependent, and were not supported by corresponding changes in related ERG parameters 
(for example, a change in a-wave implicit time was not accompanied by a change in a-wave 


 
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amplitude), they were judged to have no significance. The ocular no observed adverse effect 
level (NOAEL) for VOS in NZW rabbits was determined to be 0.56 mg/eye/day. There was 
some accumulation of voclosporin in blood over the course of the study, with mean trough 
levels on Day 13 of 0.028, 0.154, and 0.325 ng/mL for the low, mid, and high dose groups, 
respectively. The mean maximum blood concentration achieved 1 hour after dosing (high dose 
group) was 2.29 ng/mL on Day 13. 
In the Beagle dog study, similar results were reported for all safety parameters. The ocular 
NOAEL for VOS in Beagle dogs was determined to be 0.56 mg/eye/day. There was some 
accumulation of voclosporin in blood over the course of the study, with mean trough levels on 
Day 13 of 0.017, 0.173, and 0.297 ng/mL for the low, mid, and high dose groups, respectively. 
The mean maximum blood concentration achieved 1 hour after dosing (high dose group) was 
1.178 ng/mL on Day 13. 
In an additional 13-week NZW rabbit study [(S08661 2009)] no mortality, systemic toxicity, 
or effects on specific ocular indices were observed following daily bilateral topical ocular 
administration of placebo or VOS (0.2% voclosporin) at a frequency of up to eight times daily 
(hourly intervals; ~0.56 mg/eye/day) for 13 weeks or following a 4-week recovery period. The 
NOAEL for repeat topical ocular administration of VOS (0.2% voclosporin) to male and 
female NZW rabbits for 13 weeks was >0.56 mg/eye/day.  
In summary, the two repeated-dose ocular toxicology studies [(S07654 2009, S07655 2009)] 
demonstrated that there were no specific ocular indices or histopathology, and no systemic 
toxicity observed in either dogs or rabbits with 14 days of dosing. In addition, there was no 
mortality, systemic toxicity, or effects on specific ocular indices observed following daily 
bilateral topical ocular administration of placebo or VOS (0.2% voclosporin) at a frequency of 
up to eight times daily (hourly intervals; ~0.56 mg/eye/day) for 13 weeks or following a 4-week 
recovery period in rabbits. 
In addition to the three repeated dose toxicology studies, the efficacy and safety of VOS 0.2% 
has been evaluated in dogs with naturally occurring KCS [(S15389-00 2017)], diagnosed by 
the Schirmer Tear Test (STT) of >1 mm/min and <8 mm/min in one or both eyes (OU). Thirty-
five dogs ≥6 months old were randomly assigned in a 3:1 ratio to receive either VOS (n=25) 
or Optimmune® Ophthalmic Ointment (n=10) for 28 days BID. Results showed that treatment 
with VOS resulted in a statistically significant within-group increase in mean STT from 
baseline of 4.6 mm/min to each post-treatment visit. Qualitatively, this increase in magnitude 
was higher than seen in the concurrent Optimmune control group. For the Optimmune group, 
the change from baseline to Visit 2, 3, and 4, respectively, was not statistically significant, 
whereas for the VOS-treated group, each change from baseline was statistically significant 
(p<0.0001), demonstrating that VOS was effective in treating KCS in dogs. 
In order to determine potential melanin binding of 14C-LX214 (pre-clinical drug product 
formulation), ocular tissue 14C-LX214-derived radioactivity concentrations were compared 


 
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between data obtained from albino NZW rabbits [(S08661 2009)] given a single bilateral 
instillation in a separate study and similarly treated pigmented Dutch-Belted rabbits [(S08662 
2009)]. Ocular pigments in Dutch-Belted rabbits are widely spread in multiple structures 
including iris (stroma and epithelium), ciliary body (stroma and one epithelial layer), choroid 
(stroma), retina (epithelium), eyelids, and conjunctiva. The total radioactivity in these ocular 
tissues of Dutch-Belted rabbits was not statistically significantly different from NZW rabbits 
at the six sampling time points. Therefore, there was no evidence of melanin binding of 14C-
LX214 after a single ocular administration. These data were confirmed in an in vitro model.  
1.2 
Clinical Studies of Voclosporin in Dry Eye 
Voclosporin ophthalmic solution has been investigated in one Phase 1 dose-escalation study 
(LX214-01) in 30 healthy volunteers, followed by an open-label evaluation of VOS in five 
subjects with mild to moderate DES. In this study, both 0.02% and 0.2% concentrations were 
found to be safe and well tolerated following multiple instillations in healthy subjects. All 
adverse events (AEs) across study cohorts were mild or moderate in severity and all resolved 
completely, most without requiring treatment. Although the sample size was small, results 
from the five subjects with DES suggested VOS may be beneficial in the treatment of DES 
and is supported by the Ocular Surface Disease Index scores, which were improved in all 
subjects at all time points while on study drug. Overall, the results indicated VOS can be used 
safely when administered BID for two weeks [(LX214-01 2009)]. 
Additionally, one Phase 2, Investigator-masked, randomized, parallel-group study was 
conducted in 100 subjects with DES at 7 treatment sites to evaluate the efficacy, safety, and 
tolerability of VOS compared to Restasis [(AUR-VOS-2017-01 2019)]. Results of this study 
indicated that VOS was well tolerated at doses up to 0.2% w/v OU, BID for up to 28 days. 
Clinically relevant and statistically superior treatment effects were observed in favor of VOS 
at most time points for the standard signs of DES, namely change from baseline in STT and 
fluorescein corneal staining (FCS). After 2 weeks of treatment, a benefit of treatment with 
VOS compared with Restasis was observed in these objective signs of DES. This potentially 
indicates a more rapid onset of action and beneficial anti-inflammatory effect for VOS. 
Pre-specified exploratory efficacy analyses also favored VOS, which demonstrated a 
statistically significant difference in the number of subjects achieving a ≥10 mm improvement 
in STT at Week 4 in the VOS group (42.9%) compared with the Restasis group (18.4%) 
(OR=4.40; 95% CI: 1.55, 12.51; p=0.0055).  
There were marked improvements from baseline in symptom severity at Week 1 with sustained 
improvements at Week 4 in both treatment groups, though there were no statistically 
significant differences between treatment groups. 
Voclosporin ophthalmic solution was well-tolerated over a 4-week treatment period, and no 
new or unexpected safety signals were observed with the use of VOS in DES, though more 


 
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AEs were reported in the VOS group. The overall safety profile was consistent with the 
expectations for the class of drug, the patient population, and concomitant therapies. These 
data demonstrated the positive benefit/risk profile for VOS and support the choice of 
proceeding with a dose-ranging clinical study to further explore safety and efficacy over a 
longer duration [(AUR-VOS-2017-01 2019)]. 
1.3 
Study Rationale 
These results from the AUR-VOS-2017-01 study support the conduct of this dose-ranging 
clinical study (AUR-VOS-2019-01, AUrinia DRy EYe (AUDREY)) to explore safety and 
efficacy over a longer duration. Please refer to Section 1.2 of the Investigator’s Brochure (IB) 
[(VOS-Investigator's-Brochure 2019)] for additional details supporting the safety and efficacy 
of VOS in subjects with DES.  
 
 


 
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2. STUDY OBJECTIVES 
To assess the efficacy and safety of three different concentrations of VOS (0.05%, 0.10%, and 
0.20%) when administered BID in both eyes (OU) over 12 weeks compared to vehicle in 
subjects with DES. 


 
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3. CLINICAL HYPOTHESIS 
The clinical hypothesis for this study is that at least one of three concentrations of VOS (0.05%, 
0.10%, and 0.20%) when administered OU BID over 4 weeks is significantly different 
compared to vehicle alone for the following DES sign improvement:  
• Proportion of subjects with a ≥10 mm increase from baseline in STT at Week 4 in the study 
eye  


 
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4. OVERALL STUDY DESIGN 
This is a Phase 2/3, multi-center, randomized, double-masked, vehicle-controlled study to 
assess the efficacy and safety of three different concentrations of VOS when administered OU 
BID over 12 weeks in subjects with mild to moderate DES. A 14- to 17-day run-in period with 
VOS vehicle will be included. Subjects will undergo a 2-week run-in period in which VOS 
vehicle will be self-administered OU, BID. Subjects will be re-assessed to confirm that all 
participants meet all of the inclusion criteria and none of the exclusion criteria. It is estimated 
the study will enroll approximately 480 subjects across approximately 9 study centers. Eligible 
subjects will be randomized in a 1:1:1:1 ratio to one of the following study treatment arms after 
the 14- to 17-day run-in period: 
• 0.05% VOS BID 
• 0.10% VOS BID 
• 0.20% VOS BID 
• VOS Vehicle BID 
Subjects will be stratified by eye dryness VAS score ≥60 mm and <60 mm. 
See Figure 1 for the AUDREY (AUR-VOS-2019-01) study schematic. 
 








 
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5. STUDY POPULATION 
5.1 
Number of Subjects 
It is estimated that 480 subjects across 9 study centers will be enrolled and randomized in a 
1:1:1:1 ratio to one of the following study treatment arms: 
• 0.05% VOS BID 
• 0.10% VOS BID 
• 0.20% VOS BID 
• VOS Vehicle BID 
5.2 
Study Population Characteristics 
All subjects must meet all inclusion criteria and none of the exclusion criteria.  
5.3 
Inclusion Criteria 
Subjects are eligible for participation if they: 
1. Provide written informed consent before any study-specific procedures are performed. 
2. Are male or female, with a minimum age of 18 years (or legal age of consent if >18 years), 
at the time of screening. 
3. Have a documented history of DES in both eyes supported by a previous clinical diagnosis 
prior to Visit 1. 
4. Are willing and able to follow protocol procedures and instructions and can be present for 
the required study visits for the duration of the study. 
5. Have a symptom severity score of ≥30 mm for Eye Dryness on the Individual Symptom 
Severity Assessment Visual Analog Scale (VAS) (0-100 mm) at both Visit 1 and 2. 
6. Have a BCVA in both eyes of +0.7 logarithm of the Minimum Angle of Resolution 
(logMAR) or better as assessed by Early Treatment of Diabetic Retinopathy Study 
(ETDRS) chart at Visit 1. 
7. Have ongoing DES, as defined by at least one eye (if one eye, the same eye) meeting both 
of the following criteria at both Visit 1 and Visit 2:  
a) 
Have an unanesthetized Schirmer Tear Test (STT) score of ≥1 mm and ≤10 mm 
per 5 minutes. 


 
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b) 
Have a total fluorescein corneal staining (FCS) score of at least 3 [National Eye 
Institute (NEI)/Industry Workshop 0-15 scale]. 
Note: The qualifying eye at Visit 1 must be the same eye at Visit 2. 
8. Have normal lid anatomy 
5.4 
Exclusion Criteria 
In order for subjects to be eligible, (as specified in the Schedule of Events) subjects must not: 
1. Be non-compliant during the run-in treatment (non-compliance defined as dosing <80% 
or >120% of the time, calculated by counting the number of returned and unused study 
drug ampules). 
2. Have any known hypersensitivity or contraindication to study treatments (including 
excipients), topical anesthetics, or vital dyes. 
3. Have had any eye surgery in either eye except for cataract surgery or laser-assisted in situ 
keratomileusis (LASIK). 
4. Have undergone cataract or LASIK surgery within 1 year prior to Visit 1. 
5. Have recent or current evidence of ocular infection or inflammation in either eye including 
ocular pemphigoid and Stevens Johnson Syndrome. 
6. Have current evidence of clinically significant blepharitis (defined as requiring lid hygiene 
therapy and additional therapies such as doxycycline or Lipiflow®) or other meibomian 
gland dysfunction, conjunctivitis, or a history of herpes simplex or zoster keratitis in either 
eye. 
7. Have clinically significant ocular disease in either eye (i.e., corneal edema, uveitis, severe 
KCS) or active ocular allergies that might interfere with study procedures or assessments 
in the opinion of the Investigator. Severe KCS is defined by an FCS score of ≥13. 
8. Be taking or have a known need for any of the following treatment therapies within the 
time frames as specified below: 
a) 
Any investigational drug or device within 30 days prior to the Screening Visit 
(Visit 1) and subjects may not receive any investigational drug or device during 
the entire study except that which is allowed by the protocol. 
b) 
Ophthalmic drugs (any topical eye medications) including prescription 
medication and OTC agents, from date of Visit 1 to Visit 7. 


 
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c) 
Contact lenses 24 hours prior to the Screening Visit (Visit 1) to the end of Visit 
7. 
d) 
Any prior use of amiodarone. 
e) 
Within 72 hours of Visit 1 and for the duration of the study: 
− 
Oral antihistamines 
f) 
Within 14 days prior to Visit 1 and for the duration of the study: 
− 
Xiidra® (lifitegrast) 
g) 
Within 30 days prior to Visit 1 and for the duration of the study: 
− 
Calcineurin Inhibitor such as Restasis® (cyclosporin ophthalmic 
emulsion) or CequaTM 
− 
Topical ocular anti-histamines 
− 
Ocular, inhaled, or intranasal corticosteroids 
− 
Topical or oral mast cell stabilizers  
− 
Topical or nasal vasoconstrictors 
− 
Topical ocular nonsteroidal anti-inflammatory drugs (NSAIDs) 
− 
Topical ocular antibiotics 
− 
True Tear device  
h) 
Unstable dose within 30 days prior to the Screening Visit (Visit 1) or during the 
study; alteration to the dose or anticipated alterations to the dose of the 
following are disallowed: 
− 
Tetracyclines 
− 
Omega 3s or Omega 6s 
i) 
Unstable dose within 60 days prior to the Screening Visit (Visit 1) or during the 
study; alteration to the dose or anticipated alterations to the dose of the 
following are disallowed: 
− 
Anticholinergics 


 
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− 
Antidepressants 
− 
Oral contraceptives 
− 
Isotretinoin 
− 
Oral systemic corticosteroids 
− 
Oral systemic immunosuppressive agents 
j) 
Within 90 days prior to the Screening Visit (Visit 1) or during the study, the 
subject has had cauterization of the punctum or alternations to (insertion or 
removal) punctal plug(s) or nasolacrimal surgery. Note: If a punctal plug is in 
place at the Screening Visit (Visit 1) and it is dislodged during the study, the 
plug should be replaced as soon as possible. 
9. Have clinically significant systemic disease (i.e., uncontrolled diabetes, hepatic, renal, 
endocrine or cardiovascular disorders) that might interfere with the study. 
10. Have been randomized and treated in a previous study where VOS was the IP. 
11. Be a woman of childbearing potential who is pregnant, nursing, planning a pregnancy, or 
not using a medically acceptable form of birth control. All women of childbearing potential 
must be willing to take a urine pregnancy test at Visit 1 and Visit 6. Details surrounding 
adequate forms of contraception are outlined in Section 5.6. 
12. Have a condition or be in a situation that the Investigator feels may put the subject at 
significant risk, may confound the study results, or may interfere significantly with the 
subject’s participation in the study. 
5.5 
Withdrawal Criteria 
Subjects may voluntarily withdraw from study participation at any time for any reason. 
Alternatively, subjects may be withdrawn at the Investigator’s discretion if it is in the subject’s 
best interest. 
Every effort should be made for subjects who withdraw from the study (either voluntarily or 
at the Investigator’s discretion) to undergo end-of-study assessments (Visit 6). If possible, the 
subject should also be advised to come into the site for the Follow-Up Visit (Visit 7), 7 days 
(±3 days) after self-instilling the final dose. If a subject refuses end-of-study procedures, the 
reason for refusal should be fully documented in the subject’s source document. It is the 
subject’s right to withdraw from the study without providing a reason. In this case, the source 
documents and the electronic case report form (eCRF) should document the reason for 
discontinuation as “withdrawal of consent.” Withdrawn subjects will not be replaced. 


 
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5.6 
Aurinia Adequate/Effective Contraception 
An adult woman is considered to be of childbearing potential unless she is at least 1 year 
post-menopausal or 3 months post-surgical sterilization. All women of childbearing potential 
must have a negative urine pregnancy test result at Visit 1 and must not intend to become 
pregnant during the study. Women of childbearing potential who are not abstinent must have 
been using one of the following acceptable methods of birth control for the times specified:  
1. Intrauterine device in place for at least 4 weeks prior to Visit 1 through Visit 7 
2. Barrier method (condom or diaphragm) with spermicide from Visit 1 through Visit 7. 
3. Stable hormonal contraceptive for at least 60 days prior to Visit 1 through Visit 7. 
4. In a monogamous relationship with a surgically sterilized (i.e., vasectomized) partner 
at least 6 months prior to Visit 1 through Visit 7. 


 
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6. STUDY PARAMETERS 
6.1 
Efficacy Measures 
6.1.1 Primary Efficacy Endpoint 
Proportion of subjects with a ≥10 mm increase from baseline in STT at Week 4 in the study 
eye. The study eye will be defined as the qualifying eye that achieves the lowest STT score at 
baseline. Should both eyes be qualifying eyes with identical STT scores at baseline, the eye 
with the worst FCS score will be used. Should these scores also be equal, the right eye will be 
used. 
6.1.2 Key Secondary Endpoint 
Mean change from baseline in Eye Dryness VAS at Week 4 in subjects with a baseline Eye 
Dryness VAS score ≥60 mm. 
6.1.3 Secondary Endpoints 
• Proportion of subjects with a ≥10 mm increase from baseline in STT at Weeks 2, 8, and 12 
in the study eye. 
• Mean change from baseline in total FCS (NEI/Industry Workshop 0-15 scale) score to 
Weeks 2, 4, 8, and 12 in the study eye. 
• Mean change from baseline in FCS score in the 5 regions of the cornea (central, superior, 
inferior, temporal, and nasal) to Weeks 2, 4, 8, and 12 in the study eye. 
• Mean change from baseline in STT score to Weeks 2, 4, 8, and 12 in the study eye. 
• Mean change from baseline in Eye Dryness VAS (0-100 mm) score to Weeks 2, 4, 8, and 
12 within treatment group. 
• Mean change from baseline in Ocular Discomfort VAS (0-100 mm) score to Weeks 2, 4, 
8, and 12. 
• Mean change from baseline in Eye Dryness, Burning/Stinging, Itching, Photophobia, Eye 
Pain, Foreign Body Sensation, and Blurred Vision VAS (0-100 mm) score to Weeks 2, 4, 
8, and 12. 
• Mean change from baseline of the sum of Individual Symptom Score (VAS Total Symptom 
Summary Score) to Weeks 2, 4, 8, and 12.  
• Mean change from baseline in Symptom Assessment in Dry Eye (SANDE) frequency and 
severity scores to Week 2, 4, 8, and 12. 


 
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6.2 
Safety Measures 
• Treatment-emergent adverse events (TEAEs) 
• Change from baseline in BCVA over time 
• Changes from baseline in slit-lamp biomicroscopy over time 
• Changes from screening in dilated ophthalmoscopy over time 


 
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7. RANDOMIZATION, MASKING AND UNMASKING PROCEDURES 
7.1 
Randomization 
All subjects enrolled must be identifiable throughout the study. The Investigator will maintain 
a list of subject numbers and subject names to enable records to be found at a later stage. 
Subjects will be allocated a subject number at screening visit (Visit 1) and registered with an 
interactive web randomization system (IWRS). Subjects meeting the required eligibility 
criteria will be randomized to treatment at Visit 2 (baseline). The randomization will be 
stratified by Eye Dryness score (<60 mm and ≥60 mm). The subjects will be randomized in a 
ratio 1:1:1:1 to receive either VOS vehicle, VOS 0.05%, VOS 0.10%, or VOS 0.20%. The 
randomization ratio will be maintained within each study center. A randomization list will be 
generated and provided by an unmasked statistician.  
7.2 
Masking 
All study personnel and subjects will be masked to the study treatment administered during the 
study. VOS vehicle, 0.05% VOS, 0.10% VOS, and 0.20% VOS will be identical in appearance. 
The treatment group allocated will not be available to the study monitor, project statistician, or 
the project team at Aurinia Pharmaceuticals or the CRO. The site staff, monitors, and study 
subjects will remain masked until the end of the study. In case of emergency, the unmasking 
process below should be followed.  
7.3 
Unmasking 
In the rare event that an AE or pregnancy occurs for which knowledge of the identity of the 
study treatment administered is necessary to manage the subject’s condition, the IWRS code 
for that subject may be broken and the test substance identified. Procedures for unmasking will 
be provided in a separate manual. 
Should unmasking be required, the Investigator should call the Medical Monitor before 
unmasking whenever possible; however, the Investigator is responsible for the medical care of 
the individual study subject and does not require the agreement of the Medical Monitor before 
unmasking. In the event that the Medical Monitor cannot be reached, the Investigator should 
contact the Project Manager at the CRO. The reason for unmasking must be documented. The 
information on study treatment should only be used for decision making in the subject’s further 
treatment. Details on unmasked treatment assignments should not be shared with the Study 
Monitor and project team. Unmasked subjects will be discontinued from the study. 


 
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8. STUDY MATERIALS 
8.1 
Dosage Forms/Formulation 
All study treatment to be used in this study will be manufactured in accordance with current 
Good Manufacturing Practice (GMP). Study treatment will be supplied by Aurinia. 
8.1.1 Study Treatments 
Company Code: 
 
Chemical Name: 
Empirical Formula: 
 
Generic Name: 
VOS 
Dosage Form: 
Voclosporin Ophthalmic Solution is provided as a clear micellar 
solution in single-use blow fill seal ampules for topical ocular 
administration.  
Strength: 
0.05% VOS, 0.10% VOS, or 0.20% VOS 
Manufacturer:  
Aurinia Pharmaceuticals Inc. 
Study drug will be supplied as a sterile, clear, micellar solution containing 0.05%, 0.10%, or 
0.20% Active Pharmaceutical Ingredient (voclosporin), in single-use blow fill seal ampules for 
topical ocular administration. 
 
 
 
 
 
 
 
The vehicle solution contains all components of the drug product solution with the exception 
of voclosporin. 
8.1.2 
Description and Justification for the Route of Administration, Dosage, 
Dosage Regimen, and Treatment Period 
Topical ophthalmic dosing is the optimal route of administration for dry eye treatments. The 
dosage and dosage regimen were selected based on nonclinical studies described in Section 1.1 
and clinical studies described in Section 1.2. The proposed treatment period of 12 weeks is 


 
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also based on nonclinical and clinical studies and on the immunosuppressive mechanism of 
action of the drug. 
8.1.3 Instructions for Use and Administration 
• At the end of Visit 1, qualified subjects will receive a kit with run-in (vehicle ophthalmic 
solution) for OU, BID dosing until Visit 2. Subjects will be instructed to dose in the 
morning and evening. One drop of the IP will be instilled in each eye BID. Subjects will 
be instructed to bring all used and unused IP to every clinic visit to conduct accountability. 
• At Visit 2, the run-in kit will be collected from subjects for drug accountability. At the end 
of Visit 2, qualified subjects will be randomized using the IWRS and dispensed a kit 
containing either VOS 0.05%, VOS 0.10%, VOS 0.20%, or vehicle for BID dosing until 
Visit 3. Subjects will be instructed not to take the morning dose of run-in on the day of 
study randomization (Visit 2). Instructions regarding timing between doses will remain 
identical to instructions given for the run-in period at Visit 1. 
• At Visit 3, the study drug kit will be collected from subjects for drug accountability. 
Subjects will receive a new kit of study drug assigned via the IWRS (with the same 
treatment assignment that they were randomized to at Visit 2) for BID dosing until Visit 4. 
• At Visit 4, the study drug kit will be collected from subjects for drug accountability. 
Subjects will be dispensed two new kits of study drug assigned via the IWRS (with the 
same treatment assignment that they were randomized to at Visit 2) for BID dosing until 
Visit 5. 
• At Visit 5, the study drug kits will be collected from subjects for drug accountability. 
Subjects will be dispensed two new kits of study drug assigned via the IWRS (with the 
same treatment assignment that they were randomized to at Visit 2) for BID dosing until 
Visit 6. 
• At Visits 6, the study drug kits and any leftover IP not previously returned to clinic will be 
collected from subjects for drug accountability.  
• Subjects will be instructed not to take their morning dose of run-in or study drug on the 
day of follow-up visits (Visits 2, 3, 4, 5, and 6) prior to the visit. Subjects will be instructed 
to store study drug at home under refrigeration at 2°C-8°C (36-46°F) in the kit box.  
• If needed, replacement kits are also available to be dispensed to a subject. 
8.2 
Other Study Supplies 
Urine pregnancy tests, Schirmer test strips, sodium fluorescein and tropicamide ophthalmic 
solution will be provided by Sponsor.  


 
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9. STUDY METHODS AND PROCEDURES 
9.1 
Subject Entry Procedures 
9.1.1 Overview 
Subjects as defined by the inclusion and exclusion criteria outlined Sections 5.3 and 5.4. 
9.1.2 Informed Consent 
Prior to a subject’s participation in the trial (i.e., prior to changes in a subject’s medical 
treatment and/or prior to study-related procedures), the study will be discussed with each 
subject, and subjects wishing to participate must give written informed consent using an 
informed consent form (ICF). The ICF must be the most recent version that has received 
approval/favorable review by a properly constituted Institutional Review Board (IRB). 
9.1.3 Washout Intervals 
Prohibited medications, treatments, and activities are outlined in Exclusion Criteria Number 8. 
9.1.4 Procedures for Final Study Entry 
Subjects must meet all of the inclusion and none of the exclusion criteria at both Visit 1 and 
Visit 2. No re-screening is permitted. 
9.1.5 Methods for Assignment to Treatment Groups 
Prior to initiation of study run-in (at Visit 1), each subject who qualifies for entry will be 
assigned a screening number. All screening numbers will be assigned in strict numerical 
sequence at a site, and no numbers will be skipped or omitted. If all inclusion and none of the 
exclusion criteria are met at Visits 1 and 2, each qualifying subject will then be assigned a 
randomization number at the end of Visit 2 using an IWRS. 
The randomization number will be recorded on the patient’s source document and eCRF. 
Aurinia, Investigators, and study staff will be masked during the randomization process and 
throughout the study. 
9.2 
Concurrent Therapies 
The use of any concurrent medication, prescription, or OTC is to be recorded on the subject’s 
source document and corresponding eCRF along with the reason the medication was taken. 
Concurrent enrollment in another investigational drug or device study is not permitted. 
9.2.1 Prohibited Medications 
Disallowed medications/treatments during the study are outlined in Exclusion Criteria 8. 
9.2.2 Rescue Medications 


 
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No rescue medications are required for this study. 
9.2.3 Special Diets or Activities 
No special diets or activities are required for this study. 
9.3 
Examination Procedures 
An ICF must be signed and dated by the subject and witness before any study–related 
procedures are performed. Procedures listed below should be performed in the given order. A 
detailed Schedule of Events can be found in Appendix 1: Schedule of Visits and Measurements. 
Procedures listed below can be reviewed in detail in Appendix 2: Examination Procedures, 
Tests, Equipment, and Techniques. 
9.3.1 Visit 1: Day -17 to -14 Screening and Run-In Period 
All subjects will undergo the following screening assessments: 
• Informed Consent/HIPAA: Prior to any changes in a subject’s medical treatment and/or 
invasive procedures, the study will be discussed with each subject and subjects wishing to 
participate must give written informed consent and sign a HIPAA form.  
• Demographic Data and Medical/Medication/Ocular History: Collect and record all 
demographic data, medical history, any medications, and any underlying condition(s). 
Significant non-ocular medical history only within the past year and medications within 
the past 30 days will be captured. Record any medications the subject is taking, as well as 
those the subject may have taken but discontinued within 30 days prior to screening. (Any 
clinically significant findings will be recorded in the Medical Ocular History section of the 
eCRF).  
• Urine Pregnancy Test (for women of childbearing potential): Women of childbearing 
potential must have a negative urine pregnancy test to continue in the study.  
• SANDE 
• VAS 
• BCVA- Subjects must have a score of ≥0.7 logMAR (Snellen equivalent score of ≥20/100 
or better) in each eye at Visit 1. 
• Initial review of Inclusion/Exclusion Criteria 
• Slit-lamp biomicroscopy  
• FCS as assessed by the NEI scale for Grading of Fluorescein Staining 


 
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• STT (performed at least 20 minutes after FCS is performed) 
• Dilated ophthalmoscopy  
• Final review of Inclusion/Exclusion Criteria 
• Dispensation of run-in kit and instructions for BID dosing until Visit 2 
− 
Subjects will be instructed to dose in each eye BID (once in the morning and 
once in the evening) 
− 
Subjects will be instructed to not dose with run-in on the morning of their next 
visit (Visit 2)  
• Subject self-administers the first dose of run-in, OU, under the supervision of a trained 
technician 
• Dosing diary will be provided and subjects will be instructed on how to record date and 
time of dosing 
• Qualified subjects will be scheduled for Visit 2 
9.3.2 Visit 2: Day 1-Baseline  
• Collection and review of returned run-in kit for compliance 
• Subject will be asked if he/she dosed with run-in on the morning of the visit; if the subject 
indicates he/she dosed that morning, he/she should wait at least 4 hours from the time of 
dosing before efficacy assessments are performed 
•  Concomitant medication updates 
• AE query (since last visit) 
• SANDE 
• VAS  
• BCVA 
• Slit-lamp biomicroscopy 
• FCS 
• STT (performed at least 20 minutes after FCS is performed) 


 
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• Review of eligibility criteria 
• Randomization 
• 
Dispensation of study drug kit according to randomization for BID dosing until Visit 3  
− 
Subjects will be instructed to dose in each eye two times daily (once in the 
morning and once in the evening). 
− 
Subjects will be instructed to not dose with study drug on the morning of their 
next visit (Visit 3) 
• Subject self-administers the first dose of study drug, OU, under the supervision of a trained 
technician 
• AE query post-instillation 
• Dosing diary will be provided and subjects will be instructed on how to record date and 
time of dosing 
• Schedule subjects for Visit 3 
9.3.3 Visit 3: Day 14 (±3 days) 
• Collection and review of study drug accountability (including dosing diaries) 
• Subject will be asked if he/she dosed with study drug on the morning of the visit; if the 
subject indicates he/she dosed that morning, he/she should wait at least 4 hours from the 
time of dosing before efficacy assessments are performed 
• Concomitant medication updates 
• AE query (since last visit) 
• SANDE 
• VAS 
• BCVA 
• Slit-lamp biomicroscopy 
• FCS 
• STT (performed at least 20 minutes after FCS is performed) 


 
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• Dispensation of study drug kit according to randomization for BID dosing until Visit 4 
− 
Subjects will be instructed to dose in each eye two times daily (once in the 
morning and once in the evening) 
− 
Subjects will be instructed to not dose with study drug on the morning of their 
next visit (Visit 4) 
• Subject self-administers the study drug, OU, under the supervision of a trained technician 
• AE query post-instillation 
• Dosing diary will be provided and subjects will be instructed on how to record date and 
time of dosing 
• Schedule subjects for Visit 4 
9.3.4 Visit 4: Day 28 (±3 days) 
• Collection and review of study drug accountability 
• Subject will be asked if he/she dosed with study drug on the morning of the visit; if the 
subject indicates he/she dosed that morning, he/she should wait at least 4 hours from the 
time of dosing before efficacy assessments are performed 
• Concomitant medication updates 
• AE query (since last visit) 
• SANDE 
• VAS 
• BCVA 
• Slit-lamp biomicroscopy 
• FCS 
• STT (performed at least 20 minutes after FCS is performed) 
• Dispensation of two study drug kits according to randomization for BID dosing until Visit 
5 
− 
Subjects will be instructed to dose in each eye BID (once in the morning and 
once in the evening) 


 
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− 
Subjects will be instructed to not dose with study drug on the morning of their 
next visit (Visit 5) 
• Subject self-administers the study drug, OU, under the supervision of a trained technician 
• AE query post-instillation 
• Dosing diary will be provided and subjects will be instructed on how to record date and 
time of dosing 
• Schedule subjects for Visit 5 
9.3.5 Visit 5: Day 56 (±3 days) 
• Collection and review of study drug accountability 
• Subject will be asked if he/she dosed with study drug on the morning of the visit; if the 
subject indicates he/she dosed that morning, he/she should wait at least 4 hours from the 
time of dosing before efficacy assessments are performed 
• Concomitant medication updates 
• AE (since last visit) 
• SANDE 
• VAS  
• BCVA 
• Slit-lamp biomicroscopy 
• FCS 
• STT (performed at least 20 minutes after FCS is performed) 
• Dispensation of two study drug kits according to randomization for BID dosing until Visit 
6 
− 
Subjects will be instructed to dose in each eye BID (once in the morning and 
once in the evening) 
− 
Subjects will be instructed to not dose with study drug on the morning of their 
next visit (Visit 6) 
• Subject self-administers the study drug, OU, under the supervision of a trained technician 


 
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• AE query post-dose 
• Dosing diary will be provided and subjects will be instructed on how to record date and 
time of dosing 
• Schedule subjects for Visit 6 
9.3.6 Visit 6: Day 84 (±3 days)/Early Termination Visit 
• Collection and review of study drug accountability 
• Subject will be asked if he/she dosed with study drug on the morning of the visit; if the 
subject indicates he/she dosed that morning, he/she should wait at least 4 hours from the 
time of dosing before efficacy assessments are performed 
• Concomitant medication updates 
• AE query (since last visit) 
• SANDE 
• VAS  
• BCVA 
• Slit-lamp biomicroscopy 
• FCS 
• STT (performed at least 20 minutes after FCS is performed) 
• Dilated ophthalmoscopy 
• Urine pregnancy test 
• AE query post-assessments 
• Schedule subjects for Visit 7 
9.3.7 Visit 7: Post-Treatment Safety Follow-Up (+7 days from Visit 6, ±3 days) 
• Concomitant medication updates 
• AE query  
• BCVA 


 
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• Study Exit 
9.3.8 Unscheduled Visits 
Unscheduled visits may also be performed in order to ensure subject safety. All procedures 
performed at an unscheduled visit will be recorded in the source documents and on the 
Unscheduled Visit eCRF pages. Any procedure indicated in the eCRF that is not performed 
should be indicated as “Not done.” 
Evaluations that may be conducted at an Unscheduled Visit include: 
• Slit-lamp biomicroscopy 
• BCVA 
• Urine pregnancy test 
• Dilated ophthalmoscopy 
• Assessment of AEs 
• Assessment of concomitant medications and/or treatments 
• Any other assessments needed in the judgment of the Investigator 
9.4 
Compliance with Protocol 
Subjects will be instructed on proper instillation and storage of study drug at the end of Visits 1 
through 5 and given written instructions. The subject’s used and unused study drug ampules 
will be collected at each visit from Visit 2 up to and including Visit 6 to assess dosing 
compliance. Dosing compliance will be based on the unused ampule count. If the subject is 
<80% or >120% compliant with dosing based on the expected number of unused ampules, then 
the subject will be deemed non-compliant and a dosing deviation should be recorded at each 
visit.  
These guidelines will be used by the Investigator for determining the subject’s necessary 
compliance for the study and for recording deviations from this compliance. 
9.5 
Subject Disposition 
9.5.1 Completed Subjects 
A completed subject is one who has not been discontinued from the study. 
9.5.2 Discontinued Subjects 
Subjects may be discontinued prior to their completion of the study due to: 


 
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• AEs 
• unmasking when medically necessary 
• protocol violations 
• administrative reasons (i.e., inability to continue, schedule change) 
• lost to follow-up 
• sponsor termination of study 
• subject choice (i.e., withdrawal of consent) 
• other 
Note: In addition, any subject may be discontinued for any sound medical reason at the 
discretion of the Investigator. 
Notification of a subject discontinuation and the reason for discontinuation will be made to the 
CRO and/or Aurinia and will be clearly documented on the eCRF. Discontinued subjects will 
not be replaced. 
9.6 
Study Termination 
The study may be stopped at any time by the Investigator, Aurinia, and/or the CRO with 
appropriate notification. 
9.7 
Study Duration 
An individual subject’s participation will involve 7 visits over approximately 15 weeks 
(approximately 105 days) from first day of screening phase, the run-in period, treatment phase, 
and follow-up period. 
9.8 
Monitoring and Quality Assurance 
During the course of the study a monitor, or designee, will make routine site visits to review 
protocol compliance, assess study drug accountability, and ensure the study is being conducted 
according to the protocol and pertinent regulatory requirements. The review of the subjects’ 
medical records will be performed in a manner that adequately maintains subject 
confidentiality. Further details of the study monitoring will be outlined in a monitoring plan. 
Regulatory authorities of domestic and foreign agencies, quality assurance and/or their 
designees may carry out on-site inspections and/or audits, which may include source data 
checks. Therefore, direct access to the original source data will be required for inspections 


 
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and/or audits. All inspections and audits will be carried out giving consideration to data 
protection as well as subject confidentiality to the extent that local, state, and federal laws apply. 


 
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10. EVALUATION, RECORDING AND REPORTING OF AES AND 
SAES 
10.1 Definitions 
10.1.1 Adverse Event 
Any untoward medical occurrence in a subject administered a pharmaceutical product and 
which does not necessarily have a causal relationship with this treatment is an AE. 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 related to the medicinal (investigational) product. 
10.1.2 Adverse Drug Reaction 
In the pre-approval clinical experience with a new medical product or its new usages, 
particularly as the therapeutic dose(s) may not be established, all unintended responses to a 
medicinal product related to any dose should be considered adverse drug reactions (ADRs). 
The phrase “responses to a medicinal product” means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility (i.e., the relationship cannot 
be ruled out). 
10.1.3 Unexpected ADR 
An adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g., IB for an unapproved investigational medicinal product).  
10.1.4 Serious Adverse Event (SAE) 
An SAE is an untoward medical occurrence that at any dose meets one or more of the following 
criteria: 
• Results in death (Note: death is an outcome, not an event) 
• Is life-threatening (Note: the term “life-threatening” refers to an event in which the subject 
was at immediate risk of death at the time of the event; it does not refer to an event that 
could hypothetically have caused a death had it been more severe) 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Results in a congenital anomaly/birth defect 
• Is a medically important event or reaction 


 
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The definitions and reporting requirements of International Council for Harmonisation (ICH) 
Guidelines for Clinical Safety Data Management, Definitions, and Standards for Expedited 
Reporting, Topic E2 will be adhered to. 
Medical and scientific judgment must be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes listed in the definition above. These 
will also usually be considered serious. 
Hospitalizations for elective or previously scheduled surgery for pre-existing conditions, 
which have not worsened after initiation of treatment, will not be classed as SAEs. Previously 
scheduled hospitalizations must be documented in the subject’s source documents before the 
subject signed the ICF.  
10.1.5 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
Any ADR that is both serious and unexpected (per the IB) that, based on the opinion of the 
Investigator or Aurinia, is felt to have a reasonable suspected causal relationship to a medicinal 
product is a SUSAR. 
10.1.6 Treatment-Emergent Adverse Event (TEAE) 
Any AE with an onset date between the first dose of randomized study treatment and the last 
study visit (Post-Treatment Safety Follow-Up Visit 7 or last visit attended by the subject). 
10.2 Adverse Event Descriptors 
10.2.1 Intensity/Severity Categorization 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); however, the event itself may be of relatively 
minor medical significance (such as severe headache). This is not the same as “serious,” which 
is based on subject/event outcome or action criteria usually associated with events that pose a 
threat to a subject’s life or functioning. Seriousness (not severity) serves as a guide for defining 
regulatory reporting obligations. 
In general, the intensity of a particular AE to be recorded is the worst intensity experienced by 
the subject during the course of the event. The medical assessment of intensity will be 
determined by using the following definitions: 
• Mild: 
The AE is easily tolerated and does not interfere with usual activity. 
• Moderate: The AE interferes with daily activity, but the subject is still able to function. 


 
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• Severe: 
 The AE is incapacitating, and the subject is unable to work or complete usual 
activity. 
10.2.2 Causal Relationship Categorization 
The Investigator will be required to assess the relationship to study treatment (defined as 
vehicle for run-in period and active drug/vehicle for randomized subjects) for each AE as 
related or not related, in addition to the relationship to disease under study (see Section 10.2.4). 
An AE will not be able to be assessed as related to both disease under study and related to 
study treatment. 
An Investigator who is qualified in medicine must make the determination of relationship to 
the study treatment and disease under study for each AE and SAE. The Investigator must 
decide whether, in his or her medical judgment, there is a reasonable possibility that the event 
may have been caused by the study treatment. If there is no valid reason for suggesting a 
relationship, then the AE/SAE must be classified as not related. Otherwise, if there is any valid 
reason, even if undetermined or untested, for suspecting a cause and effect relationship 
between the study treatment and the occurrence of the AE/SAE, then the AE/SAE will be 
considered related. For SAEs, the Investigator must provide a brief comment explaining the 
rationale of his/her assessment of causal relationship on the SAE reporting form. 
The following additional guidance may be helpful: 
Term 
Relationship 
Definition 
Related 
Yes 
The temporal relationship of the clinical event to study drug administration 
indicates a causal relationship, and other drugs, therapeutic interventions or 
underlying conditions do not provide a sufficient explanation for the observed 
event. 
Not related 
No 
The temporal relationship of the clinical event to study drug administration does 
not indicate a causal relationship, or other drugs, therapeutic interventions or 
underlying conditions provide a sufficient explanation for the observed event. 
 
If the causal relationship between an AE/SAE and the study treatment is determined to be 
“related”, the event will be considered to be related to study treatment for the purposes of 
expedited regulatory reporting. In circumstances where the Investigator has not yet provided 
his/her assessment about the relationship, the event will be considered as “related” and qualify 
for expedited regulatory reporting. 
10.2.3 Outcome Categorization 
Outcome may be classified as recovered without sequelae; recovered with sequelae; improved; 
worsened; ongoing; fatal; or unknown. If the outcome is reported as recovered with sequelae 
for an SAE, the Investigator should specify the kind of sequelae on the paper SAE Reporting 
Form.  


 
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10.2.4 Symptoms of the Disease Under Study 
Symptoms related to DES will not be classified as AEs as long as they are within the normal 
day-to-day fluctuation of the disease. An explanation of these circumstances must be written 
in the source documents. 
Worsening of the symptoms, however, will be recorded as an AE and clearly marked as 
worsening or by the subject’s worst observed intensity.  
10.2.5 Adverse Events of Special Interest including Abuse, Misuse, Overdose and 
Medication Errors 
A clinically significant decrease in visual acuity (defined as an increase of ≥0.22 in logMAR 
score) from baseline (Visit 1) will be considered an AE of special interest and must be 
documented in the AE section of the subject’s eCRF and source documentation. If the AE 
fulfils any seriousness criteria, the event must be reported on a paper SAE Reporting Form and 
documented as serious in the AE section of the subject’s eCRF and source documentation. 
Special situations including treatment abuse, misuse, overdose and medication errors causing 
or with the potential to cause harm should be reported as an AE. An event that fulfills the 
seriousness criteria should be reported as a SAE. 
10.3 Reporting Procedure for AEs, SAEs, and Pregnancy 
10.3.1 Adverse Events 
All AEs, regardless of causality, will be reported from time of signing the ICF until Post-
Treatment Safety Follow-Up Visit 7 and recorded in the subject's source documentation. This 
applies to all AEs regardless of presumed relationship to the study drug.  
For screen failure subjects prior to run-in period, any AEs occurring during the screening 
period will be recorded from the time of signing the ICF in the subject’s source documentation 
only and will not be collected on the eCRF.  
For subjects qualifying for the run-in period all AEs will be recorded in the AE section of the 
subject’s eCRF and source documentation. This applies to all run-in period events between 
Visit 1 and Visit 2 whether the subject is subsequently randomized or not.  
For enrolled/randomized subjects, any AEs occurring following first dose of randomized study 
treatment and up to Post-Treatment Safety Follow-Up Visit 7 will be recorded in the AE 
section of the subject’s eCRF and source documentation. 
If any AE is reported, the date of onset, relationship to study treatment, relationship to disease 
under study, any action taken, date of resolution (or the fact that it is still continuing or has 
become chronic), outcome, and whether the AE is serious or not, will be recorded. Use of 
colloquialisms and abbreviations should be avoided. Only one AE term should be recorded in 


 
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the event field on the AE eCRF. Where possible, the Investigator should report a diagnosis 
rather than signs and symptoms or abnormal laboratory values. However, if a constellation of 
signs and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at 
the time of reporting, each individual event should be recorded on the AE eCRF. If a diagnosis 
is subsequently established, all previously reported AEs based on signs and symptoms should 
be nullified by the Investigator and replaced by one AE report based on the single diagnosis, 
with a starting date that corresponds to the starting date of the first symptom of the eventual 
diagnosis. 
Adverse events leading to discontinuation of study drug must be collected. 
Any AEs with an onset date during the study with follow-up/updated outcomes after the last 
study visit (or last study treatment administration) will be recorded as “ongoing” in the eCRF 
at the time of study completion. Adverse events persisting at the time of study completion will 
be followed by the Investigator through contact with the subject until resolution or stabilization 
has occurred (or the subject is lost to follow-up and cannot be contacted) and recorded in the 
source documentation only. If the subject reports an AE, it is the Investigator’s responsibility 
to acquire sufficient information in order to assess causality. This may require additional 
laboratory testing, physical examinations, telephone contacts, etc. In circumstances where the 
Investigator is unable to contact with the subject, the Investigator must provide a written 
statement to Aurinia confirming that the subject is lost to follow-up. 
In order to avoid bias in eliciting AEs, subjects should be asked a non-leading question, such 
as “How are you feeling?” It is also important to question the subject in a non-leading way 
about changes in their health or concomitant medication usage since their last visit. In addition, 
any symptoms/conditions reported during assessments and deemed to be clinically significant 
by the Investigator will be considered AEs. 
10.3.2 Serious Adverse Events 
For screen failure subjects prior to run-in period, any SAEs occurring during the screening 
period (after informed consent) will be recorded on a paper SAE Reporting Form and in the 
subject’s source documentation only and will not be collected on the eCRF.  
For subjects qualifying for the run-in period, all SAEs will be recorded on the paper SAE 
Reporting Form, in the AE section of the subject’s eCRF and source documentation. This 
applies to all run-in period events whether the subject is subsequently randomized or not.  
For enrolled/randomized subjects, any SAEs occurring following first dose of randomized 
study treatment and up to Post-Treatment Safety Follow-Up Visit 7 will be recorded on the 
paper SAE Reporting Form, in the AE section of the subject’s eCRF and source documentation. 
All SAEs, regardless of causality, will be reported to the Clinical Project Manager and Medical 
Monitor on a paper SAE Reporting Form within 24 hours of the Investigator, designee, or site 
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Note that data collection within the electronic data capture (EDC) system (Subject eCRF) is 
considered complete at the time of the last study visit according to the protocol schedule of 
assessments. Any SAEs with an onset date during the study with follow-up/updated outcomes 
post the last study visit (or last study treatment administration) will be recorded as “ongoing” 
in the eCRF at the time of study completion. For SAEs, the follow-up/resolution will be 
recorded on a paper SAE Reporting Form, and source documentation. If the Investigator has 
not seen the subject at a clinic visit at the end of the reporting period, the Investigator must 
make reasonable efforts to contact the subject to inquire about SAEs. 
A paper SAE Reporting Form will be available for site staff to complete. The Investigator must 
complete, sign, and date the SAE form and verify the accuracy of the information recorded on 
the form with the corresponding source documents. The required contact information for 
reporting SAEs will be provided in the safety manual: 
• Site Staff will contact the Clinical Project Manager (CPM) at the CRO to notify them of 
an SAE via phone or email as soon as the site becomes aware of the event. 
• Site staff will complete a paper SAE Reporting Form and email to the CPM at the CRO 
and the Medical Monitor within 24 hours.  
• If email is unavailable, site staff will call the CPM at the CRO and Medical Monitor within 
24 hours.  
The Investigator is encouraged to discuss with the study Medical Monitor when the issue of 
seriousness is unclear or questionable. 
In addition to assessing the relationship to study treatment, the Investigator will also be 
required to assess the relationship to the disease under study for each SAE as related or not 
related. An SAE will not be able to be assessed as related to both disease under study and 
related to study treatment.  
All recorded SAEs, regardless of relationship to study treatment or relationship to disease 
under study, will be followed up until resolution, stabilization, or the subject is lost to follow 
up and cannot be contacted. In circumstances where the Investigator is unable to make contact 
with the subject, the Investigator must provide a written statement to Aurinia confirming that 
the subject is lost to follow-up. 
If the subject died, the paper SAE Reporting Form should include the cause of death as the 
event term and whether or not the death was related or unrelated to study treatment or disease 
under study, as well as the autopsy findings, if available. Preliminary reports will be followed 
by detailed descriptions, which will include copies of hospital case reports, autopsy 
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Any SAE considered to have a causal relationship (i.e., “related”) to the study treatment and 
discovered by the Investigator at any time after the study will be reported on a paper SAE 
Reporting Form and documented in the safety database only. A rationale for the assessment of 
a causal relationship must be provided by the Investigator.  
Additional follow-up information must be reported to the CRO on a paper SAE Reporting 
Form, and the AE section of the subject’s eCRF updated (until last study visit, see procedures 
described above), within 24 hours of awareness following Investigator (or site) awareness of 
the information. The Investigator should not delay reporting an SAE in order to obtain 
additional information. Additional information, when available, should be reported to the CRO 
by the reporting procedures described above. 
An Investigator who receives an Investigational New Drug (IND) Safety Report describing an 
SAE or other specific safety information (e.g., summary or listing of SAE) from Aurinia will 
file it along with the IB and will notify the IRB/Independent Ethics Committee (IEC) if 
appropriate, according to local requirements. 
Aurinia or its representative will be responsible for determining and, in turn, reporting SAEs 
to Regulatory Authorities according to the applicable regulatory requirements. 
10.3.3 Pregnancy 
All pregnancies will be reported from time of signing the ICF until Post-Treatment Safety 
Follow-Up Visit 7. Pregnancies will be recorded in the subject's source documentation and 
must be reported to the CRO by the reporting procedures described below. 
Pregnancy occurring in a female subject should be reported to the CRO Pharmacovigilance 
within 24 hours of becoming aware of the event using a paper Pregnancy Reporting Form. Site 
staff must also enter the available pregnancy in the AE section of the subject’s eCRF within 
24 hours of becoming aware of the event. 
The Investigator should counsel the subject and discuss the risks of continuing with the 
pregnancy and the possible effects on the fetus. The subject must immediately inform the 
Investigator if she becomes pregnant during the study. Monitoring of the pregnancy in the 
subject should continue until conclusion of the pregnancy.  
Female subjects who have a positive pregnancy test during the study will be withdrawn from 
the study treatment and the procedures for withdrawal will be completed. The Medical Monitor 
must be contacted immediately to break the blind (if applicable). 
The outcome of all such pregnancies (including normal births) should be followed up and 
documented, even if the subject was withdrawn from the study. Every effort should be made 
to gather information regarding the pregnancy outcome until 90 days (or otherwise as 
appropriate) post-partum. It will be the responsibility of Aurinia, together with the appropriate 
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Complications of pregnancy such as abortion (spontaneous or induced), premature birth, or 
congenital abnormality are considered SAEs and should be reported following the reporting 
procedures as outlined in Section 10.3.2, Serious Adverse Events.  
A paper Pregnancy Reporting Form will be available for site staff to complete. The Investigator 
must complete, sign, and date the SAE form and verify the accuracy of the information 
recorded on the form with the corresponding source documents: 
• Site Staff will contact the Clinical Project Manager (CPM) at the CRO to notify them of a 
Pregnancy via phone or email as soon as the site becomes aware of the event. 
• Site staff will complete a paper Pregnancy Reporting Form and email to the CPM at the 
CRO and the Medical Monitor within 24 hours.  
• If email is unavailable, site staff will call the CPM at the CRO and Medical Monitor within 
24 hours. 
 


 
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11. STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
11.1 Analysis Populations 
The following analysis populations will be considered: 
• Intent-to-Treat Population – The intent-to-treat (ITT) population includes all randomized 
subjects. Subjects in the ITT population will be analyzed as randomized. 
• Per Protocol Population – The per protocol (PP) population includes subjects in the ITT 
population who do not have significant protocol deviations prior to their primary endpoint 
assessment at Week 4 and who complete the Week 4 STT. Protocol deviations will be 
assessed prior to database lock and unmasking. The PP population will be analyzed as 
randomized. 
• Safety Population – The safety population includes all randomized subjects who have 
received at least one dose of randomized study treatment. The safety population will be 
analyzed for all safety assessments. Subjects in the safety population will be analyzed as 
treated.  
• The run-in population will be used to describe all subjects who entered the run-in period. 
Baseline data will be summarized using the safety, ITT, and PP populations. Safety data will 
be summarized using the safety population, and efficacy analysis will use the ITT and PP 
populations. 
11.2 Statistical Hypothesis 
The primary endpoint will be tested under the following hypotheses with statistical 
significance declared for any of the three comparisons versus vehicle where a p-value <0.0166 
is observed: 
H01: There is no difference between the proportion of subjects with a ≥10 mm change 
from baseline in STT to Week 4 in the study eye for those receiving VOS (0.05%, 0.10%, or 
0.20%) versus vehicle. 
H11: There is a difference between the proportion of subjects with a ≥10 mm change 
from baseline in STT to Week 4 in the study eye in for those receiving VOS (0.05%, 0.1%, or 
0.2%) versus vehicle. 
Following a significant result in the primary analysis the three pairwise comparisons for the 
key secondary endpoint will be tested using alpha=0.0166. The hypotheses to be tested are: 
 
H02: In subjects with baseline eye dryness VAS ≥60 mm, there is no difference between 
the mean change from baseline to Week 4 in the Eye Dryness VAS for those receiving VOS 
(0.05%, 0.10%, or 0.20%) versus vehicle. 


 
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H12: In subjects with baseline eye dryness VAS ≥60 mm, there is a difference between 
the mean change from baseline to Week 4 in the eye dryness VAS for those receiving VOS 
(0.05%, 0.10%, or 0.20%) versus vehicle. 
For significance to be declared in the key secondary endpoint analysis, the same treatment 
group should show improvement over vehicle in both the primary analysis and the key 
secondary analysis. 
11.3 Sample Size 
This study is expected to enroll 480 subjects into 4 treatment arms. A two-group continuity 
corrected Chi square test with a 0.0166 two-sided significance level (adjusted for three 
treatment comparisons versus placebo) will have at least 80% power to detect the difference 
between a vehicle response rate of 20% (defined as the percentage of subjects with a ≥10 mm 
increase in STT from baseline) and a VOS response rate of 40% when the sample size in each 
group is 120 (total N=480). Response is defined as an increase of ≥10 mm in STT from baseline 
to Week 4. 
While the effect of withdrawals will be investigated, subjects withdrawing prior to Week 4 
STT assessment for any reason will be counted as non-responders in the primary analysis and 
therefore no adjustment of sample size for withdrawals is necessary. 
This sample size provides greater than 90% power to detect a significant change from baseline 
within any one of the three active treatment groups in the Eye Dryness VAS assuming the 
standard deviation of changes is 40 mm and the mean change from baseline is 20 mm (two-
sided alpha=0.0166). 
The key secondary endpoint is analyzed within the population of subjects with an Eye Dryness 
VAS ≥60 mm at baseline. It is expected that this will reduce the sample size for this analysis 
by 25% (from 120 per group to 90 per group). Assuming a standard deviation of 30 mm for 
change in eye dryness score and an improvement of any active arm compared to placebo 
(alpha=0.0166) of 15 mm, a sample size of 90 subjects per group provides at least 80% power 
to detect a significant difference. 
11.4 Statistical Analysis 
11.4.1 Unit of Analysis 
Safety endpoints will be analyzed for both eyes using study eye and fellow eye (non-study eye) 
if appropriate. For efficacy symptom-related endpoints, the unit of analysis is both eyes. For 
efficacy sign-related endpoints, the unit of analysis will be the study eye as defined by the 
following: 
Study Eye: The study eye will be defined as the qualifying eye that achieves the lowest STT 
score at baseline (Visit 2). Should both eyes be qualifying eyes with identical STT scores at 


 
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baseline, the eye with the worst FCS score will be used. Should these scores also be equal, the 
right eye will be used. 
11.4.2 Multiplicity Considerations 
To maintain an overall alpha of 0.05, statistical significance of the pairwise treatment 
comparisons will be declared at the 0.05/3=0.0166 level. 
11.4.3 Primary Efficacy Analyses 
Analysis of the primary endpoint, proportion of subjects with ≥10 mm increase from baseline 
in STT at Week 4 in the study eye, will be conducted on the ITT and PP populations. The 
response rate for each VOS group compared to vehicle will be determined using a logistic 
regression model including terms for Investigator site, treatment group, and baseline STT. 
Results of this logistic regression will be displayed as odds ratios and two-sided adjusted 95% 
confidence intervals (CIs) (VOS compared to vehicle). The proportion of subjects exhibiting a 
response at Week 4 will be summarized by treatment group. 
Subjects providing insufficient data to determine response at Week 4 (e.g. early withdrawal) 
will be analysed as non-responders. 
An additional sensitivity analysis will analyse observed responses only. 
11.4.4 Key Secondary Endpoint Analysis 
The key secondary endpoint of mean change from baseline in Eye Dryness VAS in the subset 
of subjects with baseline Eye Dryness VAS ≥60 mm will be analysed using the ITT and the 
PP populations. Mean change, along with an adjusted 95% CI and p-value, will be provided 
from a General Linear Model including terms for Investigator site, treatment group and 
baseline Eye Dryness VAS. 
Subjects not providing an Eye Dryness VAS at week 4 will not contribute to this analysis. 
11.4.5 Secondary Efficacy Analyses 
STT response at Weeks 2, 8 and 12 will be analysed in a similar fashion to the primary endpoint 
using the ITT population only. 
Other secondary efficacy endpoints are measured as continuous data and will be summarized 
by visit using observed scores and change from baseline using the ITT population. Mean 
changes along with 95% CIs and p-values will be provided both within treatment group and 
for all pairwise comparisons to vehicle. 
Mixed Effect Model Repeated Measures (MMRM) will also be used to analyze all available 
data for each endpoint. The MMRM model will include terms for Investigator site, treatment, 
visit, treatment by visit interaction and applicable baseline measure. Overall and by-visit 


 
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results will be expressed as differences between treatment arms (VOS–vehicle) along with 
associated 95% CIs and p-values. 
11.4.6 Safety Variables 
Adverse events will be coded using the MedDRA dictionary. Frequencies and percentages of 
subjects with TEAEs, serious TEAEs, and TEAEs causing premature discontinuation will be 
provided by treatment group. An AE is treatment emergent if it occurs after the first dose of 
randomized study treatment and up to last study visit. Furthermore, frequencies will be given 
of subjects with TEAEs by system organ class and preferred term; by system organ class, 
preferred term and maximal severity; by system organ class, preferred term for treatment-
related AEs; by system organ class and preferred term for SAEs; and by system organ class, 
preferred term, and day of onset. Separate analyses will be performed for ocular specific and 
all AEs (including systemic). 
Other safety endpoints including visual acuity, slit lamp biomicroscopy, dilated 
ophthalmoscopy (fundoscopy), will be summarized by treatment group and visit using 
descriptive statistics. Changes or shifts from baseline will also be summarized where 
appropriate. Mean changes from baseline along with 95% CIs for changes and pairwise 
comparisons to vehicle will be calculated for visual acuity. For assessments performed by eye, 
study eye and fellow eye will be summarized separately. In addition, shifts from baseline to 
worst on-treatment value for ocular safety assessments will be summarized. 
11.4.7 Interim Analyses 
No interim analyses are planned for this study 


 
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12. COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES 
This study will be conducted in compliance with the protocol, current GCPs, including the ICH 
Guidelines, and in general, consistent with the Declaration of Helsinki. In addition, all 
applicable local, state, and federal requirements relevant to the use of IPs in the United States 
will be adhered to. 
12.1 Protection of Human Subjects 
12.1.1 Subject Informed Consent 
Informed consent must take place before any study-specific procedures are initiated. Signed 
and dated written informed consent must be obtained from each subject.  
All informed consent/assent forms must be approved for use by Aurinia and receive 
approval/favorable opinion from an IRB prior to their use. If the consent form requires revision 
(i.e., due to a protocol amendment or significant new safety information), it is the Investigator’s 
responsibility to ensure that the amended informed consent is reviewed and approved by the 
CRO prior to submission to the governing IRB and that it is read, signed, and dated by all 
subjects subsequently enrolled in the study as well as those currently enrolled in the study. 
12.1.2 Institutional Review Board Approval 
This study is to be conducted in accordance with IRB regulations (U.S. 21 Code of Federal 
Regulations [CFR] Part 56.103). The Investigator must obtain appropriate IRB approval before 
initiating the study and re-approval at least annually. 
Only an IRB/ERC approved version of the ICF will be used. 
12.2 Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles that originated with the 
Declaration of Helsinki. 
12.3 Subject Confidentiality 
All personal study subject data collected and processed for the purposes of this study should 
be maintained by the Investigator and his/her staff with adequate precautions as to ensure that 
the confidentiality of the data in accordance with local, state, and federal laws and regulations. 
Monitors, auditors and other authorized representatives of the CRO, Aurinia, the IRB/IEC 
approving this study, the FDA, the Department of Health and Human Services, other domestic 
government agencies, and other foreign regulatory agencies will be granted direct access to the 
study subject’s original medical and study records for verification of the data and/or clinical 
trial procedures. Access to this information will be permitted to the aforementioned individuals 
to the extent permitted by law. 


 
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A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the IP may ultimately be marketed, but the subject’s identity 
will not be disclosed in these documents. 
12.4 Documentation 
Source documents may include a subject’s medical records, hospital charts, clinic charts, the 
Investigator’s study subject files, as well as the results of diagnostic tests such as X-rays, 
laboratory tests, and electrocardiograms. The Investigator’s copy of the eCRFs serves as the 
Investigator’s record of a subject’s study-related data. 
12.4.1 Retention of Documentation 
All study related correspondence, subject records, ICFs, records of the distribution and use of 
all IPs, and copies of eCRFs should be maintained on file for 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 until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the IP. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with Aurinia. It is the responsibility of Aurinia to inform the Investigator/institution 
as to when these documents no longer need to be retained. 
If the responsible Investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping study records, custody must be transferred to a person who will accept 
the responsibility. Aurinia must be notified in writing of the name and address of the new 
custodian. 
12.5 Labelling, Packaging, Storage, Accountability, and Return or Disposal 
of Investigational Product 
12.5.1 Labelling/Packaging 
All study treatments provided by Aurinia will be packaged and labeled for Aurinia by 
appropriately qualified vendors according to all applicable local and country regulatory 
requirements. All packaging and labeling operations will be performed according to GMP and 
GCP. 
Run-in and investigational drug will be packaged and labeled into clinical kits. 
 
  
 
 


 
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12.5.2 Storage of Investigational Product 
The study drugs must be stored in a secure area accessible only to the Investigator and his/her 
designees. Study drug(s) must be refrigerated (2-8°C (36-46 °F) – do not freeze), protected 
from light, and secured at the investigational site in a locked container.  
Each site should have a thermometer in each storage location that records minimum and 
maximum temperatures daily. Maintenance of a temperature log is mandatory. The log should 
be updated by site personnel during normal working hours. This log must be available for 
review by the Site Monitor during on-site monitoring visits. 
12.5.3 Accountability of Investigational Product 
The Investigator at each site is responsible for IP supplies. The Investigator will ensure that 
adequate records of the receipt, dispensing, and return of the IP are kept and that the IP is used 
only for subjects enrolled in the study. All data regarding the IP must be recorded on the 
relevant forms provided. 
Each study site will maintain a drug inventory/dispensing record for all IP dispensed and 
returned. At the end of the study, one copy of the drug inventory/dispensing record should be 
sent to Aurinia or their designee for the central study file. The original will be kept in the site 
files. 
12.5.4 Return or Disposal of Investigational Product 
After completion of the study, or if it is prematurely terminated, all IP will be returned to 
Aurinia or their designee. The return or disposal of IP will be specified in writing. 
12.6 Aurinia Recording of Data on Source Documents and Case Reports 
Forms (CRFs) 
All subject data will be captured in the subject source documents, which will be transcribed in 
the eCRFs. The Investigator is responsible for ensuring that study data are completely and 
accurately recorded on each subject’s eCRF, source documents, and all study-related materials. 
All study data should also be attributable, legible, contemporaneous, original, accurate, and 
complete. Recorded datum should only be corrected in a manner that does not obliterate, 
destroy, or render illegible the previous entry (i.e., by drawing a single line through the 
incorrect entry and writing the revision next to the corrected data). An individual who has 
corrected a data entry should make clear who made the correction and when, by adding to the 
correction his/her initials as well as the date of the correction.  
Data entry of all enrolled and randomized subjects will use software that conforms to 21 CFR 
Part 11 requirements, and will be performed only by staff who have been trained on the system 
and have access to the system. Data will not be entered for Visit 1 screen failures with the 
exception of demographics and reason for screen failure. An audit trail will be maintained 
within the electronic system to capture all changes made within the eCRF database. After the 


 
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end of the study and database lock, compact discs containing copies of all applicable subjects’ 
eCRFs will be provided to each Investigator Site to be maintained on file by the Investigator. 
12.7 Handling of Biological Specimens 
N/A. 
12.8 Publications 
Authorship and manuscript composition will reflect cooperation among all parties involved in 
the study. Authorship will be established before writing the manuscript. The CRO and Aurinia 
will have the final decision regarding the manuscript and publication. 
 
 


 
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levels in stimulated human cells: kinetics, mitogen requirements, and effects of cyclosporin 
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LX214-01 (2009). "Clinical Study Report. A phase 1 dose-escalation study to assess the safety 
and tolerability of LX214 ophthalmic solution in healthy volunteers, followed by an open-label 
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Biosciences, Inc.;  Report No.: LX214-01."Restasis® (2017). "Allergan, Irvine USA. 2017 
Jul." "US prescribing information". 
S07654 (2009). "14-Day ocular toxicity of LX214 in New Zealand white rabbits with 14-Day 
recovery period." Lux Biosciences, Inc. Report No.: S07654(Apr 3). 
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recovery period." Lux Biosciences, Inc. Report No.: S07655(Apr 8). 
S08661 (2009). "Ocular tissue distribution of 14C-LX214 following a single or multiple 
ophthalmic administration to New Zealand White Rabbit." Lux Biosciences, Inc. Report No.: 
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S08662 (2009). "Ocular Tissue Distribution of 14C-LX214 Following a Single Ophthalmic 
Administration to Dutch Belted Rabbits." Sinclair Research Center, Inc. 
S15389-00 (2017). "To evaluate the efficacy of Voclosporin Ophthalmic Solution (0.2% 
voclosporin) in naturally occurring keratoconjunctivitis sicca in client owned dogs with twice-
daily administration." Intervert, Inc(d/b/a Merck Animal Health) Report No.: S15389-00(Apr 
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Stepkowski, S. M. (2000). "Molecular targets for existing and novel immunosuppressive 
drugs." Expert Rev Mol Med 2(4): 1-23. 
VOS-Investigator's-Brochure (2019). "Voclosporin Ophthalmic Solution Invesigator's 
Brochure." Version 2.0. 
Wiseman, A. C. (2016). "Immunosuppressive Medications." Clin J Am Soc Nephrol 11(2): 
332-343. 


 
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14. APPENDICES 
Appendix 1: Schedule of Visits and Measurements 
AUR-VOS-2019-01 SCHEDULE OF EVENTS 
Visit 
Visit 1 
Screening 
Visit 2 
Baseline 
Visit 3 
Visit 4 
Visit 5 
Visit 6/ ETV 
Visit 7 
Day/Week 
Day -17 to -14 
Day 1 
Day 14/ 
Week 2 
(±3 days) 
Day 28/ 
Week 4 
(±3 days) 
Day 56/ 
Week 8 
(±3 days) 
Day 84/ 
Week 12 
(±3 days) 
Post- 
Treatment 
Safety FU 
(+7 days from 
Visit 6 (±3 
days)) 
Informed consent 
 
 
 
 
 
 
 
Eligibility criteria 
 
(1) 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
Ocular and non-ocular Medical 
history (including Ocular 
Surgical History, Ocular and 
Non-Ocular Concomitant 
Medications)  
 
 
 
 
 
 
 
Demography  
 
 
 
 
 
 
 
Concomitant medication updates 
 
 
 
 
 
 
 
AE Query(2) 
 
 
 
 
 
 
 
SANDE(3) 
 
 
 
 
 
 
 
Visual Analog Scale 
(VAS)(3) 
 
 
 
 
 
 
 
BCVA(4) 
 
 
 
 
 
 
 
FCS(5) 
 
 
 
 
 
 
 
STT(5) 
 
 
 
 
 
 
 
Slit-Lamp Biomicroscopy 
 
 
 
 
 
 
 


 
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Visit 
Visit 1 
Screening 
Visit 2 
Baseline 
Visit 3 
Visit 4 
Visit 5 
Visit 6/ ETV 
Visit 7 
Day/Week 
Day -17 to -14 
Day 1 
Day 14/ 
Week 2 
(±3 days) 
Day 28/ 
Week 4 
(±3 days) 
Day 56/ 
Week 8 
(±3 days) 
Day 84/ 
Week 12 
(±3 days) 
Post- 
Treatment 
Safety FU 
(+7 days from 
Visit 6 (±3 
days)) 
Dilated Ophthalmoscopy 
(Fundoscopy) 
 
 
 
 
 
 
 
Run-In dispensation 
 
 
 
 
 
 
 
Study Treatment Dispensation(6) 
 
 
 
 
 
 
 
Dosing Diary and Instruction 
provided 
 
 
 
 
 
 
 
Study Treatment Accountability(7) 
 
 
 
 
 
 
 
Urine pregnancy test(8) 
 
 
 
 
 
 
 
Schedule Next Visit 
 
 
 
 
 
 
 
Study Exit 
 
 
 
 
 
 
 
1 Eligibility criteria will be re-checked after subjects have completed the run-in period.  
2 Adverse event query will be conducted at pre-examination and post-instillation at Visit 2. 3, 4, 5, and 6. 
3  Symptom assessments VAS/SANDE should be performed first prior to or any invasive procedure. SANDE will be performed prior to the Individual Symptom Severity Assessments VAS. 
Symptom Assessment VAS includes Ocular Discomfort, Eye Dryness, Burning/Stinging, Photophobia, Foreign Body Sensation, Eye Pain, Itching and Blurred Vision. 
4  BCVA should be performed prior to any dyes. 
5  STT should be performed at least 20 minutes after FCS is performed. 
6  Study treatment instillations on the date of the visits will be performed after all study procedures have taken place. A new refrigerated IP pack will be administered to subjects at each visit with 
the appropriate number of ampules. 
7  Accountability will be assessed by counting the number of used and unused ampules returned at each visit, beginning at Visit 2. 
8  Urine pregnancy test for women of childbearing potential only. 
Notes: 
AE = Adverse event; BCVA = Best Corrected Visual Acuity; ETV = Early Termination Visit; FCS = Fluorescein Corneal Staining; FU = Follow up; 
SANDE = Symptom Assessment and Dry Eye; STT = Schirmer Tear Test; VAS = Visual Analog Scale. 


 
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Appendix 2 : Examination Procedures, Tests, Equipment, and Techniques 
Visual Acuity Procedures (ETDRS Chart) 
LogMAR visual acuity (VA) must be assessed using an Early Treatment Diabetic Retinopathy 
Study (ETDRS) chart. The procedure used will be consistent with the recommendations 
provided for using the ETDRS eye chart. VA should be evaluated at the beginning of each visit 
in the study (i.e., prior to slit-lamp examination). VA testing should be done with most recent 
correction. 
Equipment 
The VA chart to be used is the ETDRS chart. If smaller reproduction (18" by 18", i.e., from 
Prevent Blindness) wall charts are used, the subject viewing distance should be exactly 10 feet 
(or as specified by the manufacturer). In ALL cases, for purposes of standardizing the testing 
conditions during the study, all sites must use only the Series 2000 Chart 1, and the right eye 
should be tested first. For reflectance (wall) charts, the chart should be placed frontally and 
well-illuminated. 
Measurement Technique 
The chart should be at a comfortable viewing angle. The right eye should be tested first. The 
subject should attempt to read each letter, line-by-line, left to right, beginning with line 1 at the 
top of the chart. The subject should be told that the chart has letters only, no numbers. If the 
subject reads a number, he or she should be reminded that the chart contains no numbers, and 
the examiner should then request a letter in lieu of the number. The subject should be asked to 
read slowly, so as to achieve the best identification of each letter. He/she is not to proceed to 
the next letter until he/she has given a definite response. 
If the subject changes a response (i.e., 'that was a "C" not an "O"') before he has read aloud the 
next letter, then the change must be accepted. If the subject changes a response having read the 
next letter, then the change is not to be accepted. The examiner should never point to the chart 
or to specific letters on the chart during the test. 
A maximum effort should be made to identify each letter on the chart. When the subject says 
he or she cannot read a letter, he or she should be encouraged to guess. If the subject identifies 
a letter as 1 of 2 letters, he or she should be asked to choose 1 letter and, if necessary, to guess. 
When it becomes evident that no further meaningful readings can be made, despite 
encouragement to read or guess, the examiner should stop the test for that eye. However, all 
letters on the last line should be attempted as letter difficulties vary and the last may be the 
only one read correctly. The number of letters missed or read incorrectly should be noted. 


 
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LogMAR Visual Acuity Calculations 
The last line in which a letter is read correctly will be taken as the base logMAR reading. To 
this value will be added the number "N x 0.02" where 'N' represents the total number of letters 
missed up to and included in the last line read. This total sum represents the logMAR VA for 
that eye. 
For Example: Subject correctly reads 4 of 5 letters on the 0.2 line, and 2 of 5 letters on the 0.1 
line. 
Base logMAR 
= 0.1 
N (total number of letters incorrect on line 0.2 as well as 0.1) 
= 4 
N x T (T=0.02) 
= 0.08 
Base logMAR + (N x T) 
= 0.1 + 0.08 
logMAR VA 
= 0.18 
Repeat the procedure for the left eye. 
In order to provide standardized and well-controlled assessments of VA during the study, all 
VA assessments at a single site must be consistently done using the same lighting conditions 
and same correction if possible during the entire study. If the same correction cannot be used 
(ie, a subject forgets his glasses), the reason for the change in correction should be documented. 
Best Corrected Visual Acuity (BCVA) 
To provide standardized and well-controlled assessments of visual acuity during the study, 
consistently use the same lighting conditions during the entire study. 
Calculations : logMAR VA = Baseline value + (n x 0.02) 
where: the baseline value is the logMAR number of the last line read (at least 1 letter read 
correctly in this line), and 
“n” is the total number of letters missed up to and including the last line read, and  
“0.02” is the value for each letter 
Slit Lamp Biomicroscopy Procedures 
Slit lamp biomicroscopic observations will be graded as Normal or Abnormal. Abnormal 
findings will be categorized as clinically significant (findings that may interfere with study 
parameters or otherwise confound the data as determined by the Investigator) or not clinically 
significant (NCS). The following will be examined:  


 
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• Cornea  
• Conjunctiva 
• Anterior Chamber 
• Iris 
• Lens 
• Eyelid 
External magnification and biomicroscopy will be performed using a slit-lamp. Magnification 
will be consistent with standard clinical practice. The subject will be seated. 
Dilated Ophthalmoscopy (Fundoscopy) 
Dilated fundoscopy will be performed using indirect ophthalmoscopy. The Investigator will 
make observations of the vitreous, retina, macula, choroid and optic nerve. 
Observations will be graded as Normal or Abnormal. Abnormal findings that are clinically 
significant (as determined by the Investigator that may interfere with study parameters or 
otherwise confound the data) and those that are not clinically significant will be described. A 
dilated fundoscopy examination should be performed if retinal disease is detected.  
• Vitreous: Examination should emphasize the visual axis.  
• Retina, Macula, Choroid: Include an observation of the retina and its blood vessels. Eyes 
should be excluded from the study if active inflammation is present.  
• Optic Nerve: Significant damage or cupping to the optic nerve should be noted. 
It is recommended that tropicamide 1% ophthalmic solution be used to dilate subjects. The use 
of cyclopentolate 1% ophthalmic solution is recommended as secondary dilating medication, 
should the need arise. 
Visual Analogue Scale (VAS) 
Subjects will be asked the following questions regarding ocular discomfort (unrelated to study 
drug instillation) at all visits.  
The subject will be asked to rate each ocular symptom due to dry eye syndrome by placing a 
vertical mark on the horizontal line to indicate the current level of discomfort. 0% corresponds 
to “no discomfort” and 100% corresponds to “maximal discomfort.” The linear dimension of 
the scale is measured in millimeters. This assessment is a general assessment of both eyes. 
There will not be a question for each individual eye. This assessment should be performed 


 
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following SANDE, and prior to assessing for AEs and prior to any other invasive visit 
assessment. 
Subject Instructions: Please review the symptoms below. After your review, please rate how 
your eyes feel for each of the following symptoms by placing a vertical mark that represents 
how your symptom feels at this moment.  
Burning/ Stinging 
0%                                                                                              100% 
 
 
 
Itching 
0%                                                                                              100% 
 
 
 
Foreign Body Sensation 
0%                                                                                              100% 
 
 
 
Blurred Vision 
0%                                                                                              100% 
 
 
 
Eye Dryness 
0%                                                                                              100% 
 
 
 
Photophobia 
0%                                                                                              100% 
 
 
 
Pain 
0%                                                                                              100% 
 
 
 
Ocular Discomfort 
0%                                                                                              100% 
 
 
 
 
 


 
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Fluorescein Corneal Staining (FCS) National Eye Institute/Industry Workshop Scale 
 
Diagram of the division of the corneal surface for FCS total score. A standardized grading 
System of 0-3 is used for each of the five areas on each cornea. The maximum score is 15. 
Grade 0 will be specified when no staining is present. 
Unanesthetized Schirmer’s Test 
Schirmer Tear Test will be performed according to the following procedure: 
• Using a sterile Tear Flo Schirmer test strip (Rose Enterprises), a bend in the strip will be 
made in line with the notch in the strip 
• The subject will be instructed to gaze up and in 
• The Schirmer test strip will be placed in the lower temporal lid margin of each eye such 
that the strip fits tightly. Subjects will be instructed to close their eyes 
• After 5 minutes have elapsed, the Schirmer strip will be removed. The length of the 
moistened area will be recorded (mm) for each eye 
 
 


 
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Symptom Assessment in Dry Eye (SANDE) 
 
 
 
 
 


 
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Appendix 3: Daily Dosing Diary 
 

Prot_000.pdf: 
This trial will be conducted in compliance with this protocol, ICH GCP and applicable regulatory requirements. 
The information contained in this document is proprietary to Aurinia Pharmaceuticals Inc. and is not to be copied, disclosed or 
otherwise distributed by an outside authority to any person or persons without the prior written permission of Aurinia. 
A Randomized, Double-Masked, Vehicle-Controlled, Dose 
Ranging Study to Assess the Efficacy and Safety of Voclosporin 
Ophthalmic Solution (VOS) in Subjects with Dry Eye Syndrome 
Clinical Protocol Number: 
AUR-VOS-2019-01 
Date: 
26 July 2019 
Version Number: 
1.0 
IND Number: 
102,279 
Study Name: 
AUDREY (AUrinia DRy EYe) 
NCT Number:
NCT04147650


 
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NAMES AND ADDRESSES 
Sponsor 
Name: 
Aurinia Pharmaceuticals Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Tel: 
 
 
Fax: 
 
 
Clinical Representative 
Name: 
 
 
Company: 
Aurinia Pharmaceuticals Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Email: 
  
 
Chief Medical Officer 
Name: 
 
 
Company: 
Aurinia Pharmaceuticals Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Email: 
 
 
Regulatory Representative 
Name: 
 
 
Company: 
Aurinia Pharmaceuticals Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Email: 
 
 
Trial Statistician 
Name:  
 
 
Company: 
Aurinia Pharmaceuticals Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Email: 
 


 
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DECLARATION OF SPONSOR 
Title: A Randomized, Double-Masked, Vehicle-Controlled, Dose Ranging Study to Assess the 
Efficacy and Safety of Voclosporin Ophthalmic Solution (VOS) in Subjects with Dry Eye 
Syndrome 
This study protocol was subjected to critical review. The information it contains is consistent 
with current knowledge of the risks and benefits of the study treatment, as well as with the 
moral, ethical, and scientific principles governing clinical research as set out in the Declaration 
of Helsinki and the International Council for Harmonisation (ICH) on Good Clinical Practice 
(GCP). 
Sponsor Representatives 
 
 
 
 
Chief Medical Officer 
 
Date (i.e., DD Month Year) 
 
 
 
 
Vice President, Quality and Regulatory 
Affairs 
 
Date (i.e., DD Month Year) 
 


 
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INVESTIGATOR AGREEMENT FORM 
I have read the attached protocol titled: A Randomized, Double-Masked, Vehicle-Controlled, 
Dose Ranging Study to Assess the Efficacy and Safety of Voclosporin Ophthalmic Solution 
(VOS) in Subjects with Dry Eye Syndrome 
I agree to comply with the current International Council for Harmonisation Guidelines on Good 
Clinical Practice and applicable regulations and guidelines. 
I agree to ensure that financial disclosure statements will be completed by: 
• me (including, if applicable, my spouse (or legal partner) and dependent children); 
• my Sub-Investigators 
before the start of the study and to report any changes that affect my financial disclosure status 
for up to 1 year after the study is completed. 
I agree to ensure that the confidential information contained in this document will not be used 
for any purpose other than the evaluation or conduct of the clinical investigation without the 
prior written consent of Aurinia Pharmaceuticals Inc. 
Signature by the Investigator on this form documents review, agreement, and approval of the 
requirements contained within this protocol. 
 
 
 
Name 
 
 
Signature 
 
Date (i.e., DD Month Year) 
 


 
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SYNOPSIS 
Title: 
A Randomized, Double-Masked, Vehicle-Controlled, Dose Ranging Study to Assess the 
Efficacy and Safety of Voclosporin Ophthalmic Solution (VOS) in Subjects with Dry Eye 
Syndrome 
Study Product: 
Voclosporin Ophthalmic Solution (VOS) 
Indication: 
Dry Eye Syndrome (DES) 
Phase: 
2/3 
Sponsor: 
Aurinia Pharmaceuticals Inc. 
Study Code: 
AUR-VOS-2019-01 
Objectives: 
To assess the efficacy and safety of three different concentrations of VOS (0.05%, 0.10%, 
and 0.20%) when administered twice a day (BID) in both eyes (OU) over 12 weeks 
compared to vehicle in subjects with DES. 
Design: 
This is a Phase 2/3, multi-center, randomized, double-masked, vehicle-controlled study to 
assess the efficacy and safety of three different concentrations of VOS when administered 
OU BID over 12 weeks in subjects with mild to moderate DES. Subjects will undergo a 
2-week run-in period in which VOS vehicle will be self-administered OU, BID. Subjects 
will be re-assessed to confirm that all participants meet all of the inclusion criteria and 
none of the exclusion criteria. It is estimated that the study will enroll approximately 480 
subjects across approximately 9 study centers. Eligible subjects will be randomized in a 
1:1:1:1 ratio to one of the following study treatment groups after the 14- to 17-day run-in 
period. 
Treatment: 
Subjects will be randomized to one of the following treatment groups: 
Investigational product (IP): one drop 0.05% VOS, OU BID over 12 weeks, one drop 
0.10% VOS OU BID over 12 weeks, or one drop 0.20% VOS OU BID over 12 weeks. 
Comparator: one drop VOS vehicle OU BID over 12 weeks. 
Inclusion Criteria 
Subjects are eligible for participation if they: 
1. Provide written informed consent before any study-specific procedures are 
performed. 
2. Are male or female, with a minimum age of 18 years (or legal age of consent 
if >18 years), at the time of screening. 
3. Have a documented history of DES in both eyes supported by a previous clinical 
diagnosis prior to Visit 1  
4. Are willing and able to follow protocol procedures and instructions and can be 
present for the required study visits for the duration of the study. 
5. Have a symptom severity score of ≥30 mm for Eye Dryness on the Individual 
Symptom Severity Assessment Visual Analog Scale (VAS) (0-100 mm) at both 
Visit 1 and Visit 2. 
6. Have a best corrected visual acuity (BCVA) in both eyes of +0.7 logarithm of 
the Minimum Angle of Resolution (logMAR) or better as assessed by Early 
Treatment of Diabetic Retinopathy Study (ETDRS) chart at Visit 1. 
7. Have ongoing DES, as defined by at least one eye (if one eye, the same eye) 
meeting both of the following criteria at both Visit 1 and Visit 2:  
a) Have an unanesthetized Schirmer Tear Test (STT) score of ≥1 mm and 
≤10 mm per 5 minutes. 


 
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b) Have a total fluorescein corneal staining (FCS) score of at least 3 
[National Eye Institute (NEI)/Industry Workshop 0-15 scale]. 
Note: The qualifying eye at Visit 1 must be the same eye at Visit 2. 
8. Have normal lid anatomy 
Exclusion 
Criteria: 
In order for subjects to be eligible, subjects must not: 
1. Be non-compliant during the run-in treatment (non-compliance defined as dosing 
<80% or >120% of the time, calculated by counting the number of returned and 
unused study drug ampules) 
2. Have any known hypersensitivity or contraindication to study treatments 
(including excipients), topical anesthetics, or vital dyes. 
3. Have had any eye surgery in either eye except for cataract surgery or laser-
assisted in situ keratomileusis (LASIK). 
4. Have undergone cataract or LASIK surgery within 1 year prior to Visit 1. 
5. Have recent or current evidence of ocular infection or inflammation in either eye 
including ocular pemphigoid and Stevens Johnson Syndrome. 
6. Have current evidence of clinically significant blepharitis (defined as requiring 
lid hygiene therapy and additional therapies such as doxycycline or Lipiflow®) 
or other meibomian gland dysfunction, conjunctivitis, or a history of herpes 
simplex or zoster keratitis in either eye. 
7. Have clinically significant ocular disease in either eye (i.e., corneal edema, 
uveitis, severe keratoconjunctivitis sicca) or active ocular allergies that might 
interfere with study procedures or assessments in the opinion of the Investigator. 
Severe keratoconjunctivitis sicca is defined by an FCS score of ≥13. 
8. Be taking or have a known need for any of the following treatment therapies 
within the time frames as specified below: 
a) Any investigational drug or device within 30 days prior to the Screening 
Visit (Visit 1) and subjects may not receive any investigational drug or 
device during the entire study except that which is allowed by the 
protocol. 
b) Ophthalmic drugs (any topical eye medications) including prescription 
medication and over-the-counter (OTC) agents, from Visit 1 to Visit 7. 
c) Contact lenses 24 hours prior to the Screening Visit (Visit 1) to the end 
of Visit 7. 
d) Any prior use of amiodarone. 
e) Within 72 hours of Visit 1 and for the duration of the study: 
− Oral anti-histamines 
f) 
Within 14 days prior to Visit 1 and for the duration of the study: 
− Xiidra® (lifitegrast) 
g) Within 30 days prior to Visit 1 and for the duration of the study: 
− Calcineurin Inhibitors (CNIs) such as Restasis® (cyclosporin 
ophthalmic emulsion) or CequaTM 
− Topical ocular anti-histamines 
− Ocular, inhaled, or intranasal corticosteroids 
− Topical or oral mast cell stabilizers  
− Oral anti-histamines 
− Topical or nasal vasoconstrictors 


 
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− Topical 
ocular 
nonsteroidal 
anti-inflammatory 
drugs 
(NSAIDs) 
− Topical ocular antibiotics 
− True Tear device  
h) Unstable dose within 30 days prior to the Screening Visit (Visit 1) or 
during the study; alteration to the dose or anticipated alterations to the 
dose of the following are disallowed: 
− Tetracyclines 
− Omega 3s or Omega 6s 
i) 
Unstable dose within 60 days prior to the Screening Visit (Visit 1) or 
during the study; alteration to the dose or anticipated alterations to the 
dose of the following are disallowed: 
− Anticholinergics 
− Antidepressants 
− Oral contraceptives 
− Isotretinoin 
− Oral systemic corticosteroids 
− Oral systemic immunosuppressive agents 
j) 
Within 90 days prior to the Screening Visit (Visit 1) or during the study, 
the subject has had cauterization of the punctum or alternations to 
(insertion or removal) punctal plug(s) or nasolacrimal surgery. Note: If 
a punctal plug is in place at the Screening Visit (Visit 1) and it is 
dislodged during the study, the plug should be replaced as soon as 
possible. 
9. Have clinically significant systemic disease (i.e., uncontrolled diabetes, hepatic, 
renal, endocrine, or cardiovascular disorders) that might interfere with the study. 
10. Have been randomized and treated in a previous study where VOS was the IP. 
11. Be a woman of childbearing potential who is pregnant, nursing, planning a 
pregnancy, or not using a medically acceptable form of birth control. All women 
of child-bearing potential must be willing to take a urine pregnancy test at Visit 
1 and Visit 6.  
12. Have a condition or be in a situation that the Investigator feels may put the 
subject at significant risk, may confound the study results, or may interfere 
significantly with the subject’s participation in the study. 
Primary 
Endpoint: 
• 
Proportion of subjects with a ≥10 mm increase from baseline in STT at Week 4 
in the study eye. The study eye will be defined as the eye that achieves the lowest 
STT score at baseline. Should a subject have identical STT scores in both eyes 
at baseline, the eye with the worst FCS score will be used. Should these scores 
also be equal, the right eye will be used. 
Key Secondary 
Endpoint: 
• 
Mean change from baseline in Eye Dryness VAS at Week 4 in subjects with a 
baseline Eye Dryness VAS score ≥60mm. 
Secondary 
Endpoints: 
Secondary Endpoints: 
• 
Proportion of subjects with a ≥10 mm increase from baseline in STT at Weeks 
2, 8, and 12 in the study eye. 
• 
Mean change from baseline in total FCS (NEI/Industry Workshop 0-15 scale) 
score to Weeks 2, 4, 8, and 12 in the study eye. 


 
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• 
Mean change from baseline in FCS score in the 5 regions of the cornea (central, 
superior, inferior, temporal, and nasal) to Weeks 2, 4, 8, and 12 in the study eye. 
• 
Mean change from baseline in STT score to Weeks 2, 4, 8, and 12 in the study 
eye. 
• 
Mean change from baseline in Eye Dryness VAS (0-100 mm) score to Weeks 2, 
4, 8, and 12 within treatment group. 
• 
Mean change from baseline in Ocular Discomfort VAS (0-100 mm) score to 
Weeks 2, 4, 8, and 12.  
• 
Mean change from baseline in Eye Dryness, Burning/Stinging, Itching, 
Photophobia, Eye Pain, Foreign Body Sensation, and Blurred Vision VAS 
(0-100 mm) score to Weeks 2, 4, 8, and 12. 
• 
Mean change from baseline of the sum of Individual Symptom Score (VAS Total 
Symptom Summary Score) to Weeks 2, 4, 8, and 12.  
• 
Mean change from baseline in Symptom Assessment in Dry Eye (SANDE) 
frequency and severity scores to Week 2, 4, 8, and 12. 
Safety Endpoints: 
• 
Treatment-emergent adverse events (TEAEs) 
• 
Change from baseline in BCVA over time 
• 
Changes from baseline in slit-lamp biomicroscopy over time 
• 
Changes from screening in dilated ophthalmoscopy over time 
Procedures: 
Subjects who have provided signed and dated informed consent will be screened for entry 
into this study. Subjects will be evaluated for eligibility according to the protocol 
inclusion/exclusion criteria. Eligible subjects will enter a 14- to 17-day run-in period 
during which time they will receive vehicle drops and will be instructed to instill one drop 
of vehicle OU BID. Subjects will be re-evaluated for eligibility after the run-in period.  
After the run-in period, eligible subjects will be randomly assigned in a 1:1:1:1 ratio to 
one of the four treatment groups: VOS 0.05% BID, VOS 0.1% BID, VOS 0.2% BID, or 
VOS vehicle BID. 
Subjects will self-instill the assigned treatment, one drop OU BID, over 12 weeks. 
Sample Size: 
This study is expected to enroll 480 subjects into 4 treatment arms. A two-group continuity 
corrected Chi square test with a 0.0166 two-sided significance level (adjusted for three 
treatment comparisons versus placebo) will have at least 80% power to detect the 
difference between a vehicle response rate of 20% (defined as the percentage of subjects 
with a ≥10 mm increase in STT from baseline) and a VOS response rate of 40% when the 
sample size in each group is 120 (total N=480). Response is defined as an increase of ≥10 
mm in STT from baseline to Week 4. 
While the effect of withdrawals will be investigated, subjects withdrawing prior to Week 
4 STT assessment for any reason will be counted as non-responders in the primary analysis 
and therefore no adjustment of sample size for withdrawals is necessary. Subjects 
providing insufficient data to determine response at Week 4 (e.g., early withdrawal) will 
be analysed as non-responders.  
An additional sensitivity analysis will analyse observed responses only. 
This sample size provides greater than 90% power to detect a significant change from 
baseline within any one of the three active treatment groups in the Eye Dryness VAS 
assuming the standard deviation of changes is 40 mm and the mean change from baseline 
is 20 mm (two-sided alpha=0.0166). 


 
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The key secondary endpoint is analyzed within the population of subjects with an Eye 
Dryness VAS ≥60 mm at baseline. It is expected that this will reduce the sample size for 
this analysis by 25% (from 120 per group to 90 per group). Assuming a standard deviation 
of 30 mm for change in eye dryness score and an improvement of any active arm compared 
to placebo (alpha=0.0166) of 15 mm, a sample size of 90 subjects per group provides at 
least 80% power to detect a significant difference. 
Statistical 
Methods: 
All statistical analyses will be undertaken at study closure and will incorporate all efficacy 
and safety endpoints. 
Analysis Populations: 
The following analysis populations will be considered: 
• 
Intent-to-Treat Population – The intent-to-treat (ITT) population includes all 
randomized subjects. Subjects in the ITT population will be analyzed as randomized. 
• 
Per Protocol Population – The per protocol (PP) population includes subjects in the 
ITT population who do not have significant protocol deviations prior to their primary 
endpoint assessment at Week 4 and who complete the Week 4 STT. Protocol 
deviations will be assessed prior to database lock and unmasking. The PP population 
will be analyzed as randomized. 
• 
Safety Population – The safety population includes all randomized subjects who have 
received at least one dose of randomized study treatment. The safety population will 
be analyzed for all safety assessments. Subjects in the safety population will be 
analyzed as treated.  
• 
The run-in population will be used to describe all subjects who entered the run-in 
period. 
Baseline data will be summarized using the safety, ITT, and PP populations. Safety data 
will be summarized using the safety population, and efficacy analysis will use the ITT and 
PP populations. 
Methods: 
Efficacy Endpoints: 
Analysis of the primary endpoint, proportion of subjects with a ≥10 mm increase from 
baseline in STT at Week 4 in the study eye, will be conducted on the ITT and PP 
populations. The response rate for each VOS group compared to vehicle will be 
determined using a logistic regression model including terms for Investigator site, 
treatment group, and baseline STT. Results of this logistic regression will be displayed as 
odds ratios and two-sided adjusted 95% confidence intervals (CI) (VOS compared to 
vehicle). The proportion of subjects exhibiting a response at Week 4 will be summarized 
by treatment group.  
The key secondary endpoint of mean change from baseline in Eye Dryness VAS in the 
subset of subjects with baseline Eye Dryness VAS ≥60 mm will be analysed using the ITT 
and the PP populations. Mean change, along with an adjusted 95% CI and p-value, will 
be provided from a General Linear Model including terms for Investigator site, treatment 
group and baseline Eye Dryness VAS. 
Other proportional endpoints (STT response at alternative time points) will be analyzed 
and summarized in a similar fashion to the primary endpoint. 
Endpoints measured as continuous data (including VAS scores) will be summarized by 
visit for the ITT population only. Mean change from baseline (95% CI) will be provided 
for within treatment group changes and for differences between treatment groups (VOS 
– vehicle). 


 
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Mixed Effect Model Repeated Measures (MMRM) will also be used to analyze all 
available data for a given endpoint. The MMRM model will include terms for Investigator 
site, treatment group, visit, treatment-by-visit interaction, and applicable baseline 
measure. Results will be expressed as differences between treatment arms (VOS – 
vehicle) along with associated 95% CIs and p-values. 
Safety Endpoints: 
Adverse events will be aggregated by System Organ Class and preferred term and 
presented as summary tables. BCVA will be summarized as a continuous endpoint with 
results displayed as mean changes from baseline for each visit. Slit-lamp biomicroscopy 
and dilated ophthalmoscopy will be summarized using frequency counts and shift tables 
from baseline. 
 


 
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TABLE OF CONTENTS 
NAMES AND ADDRESSES ...................................................................................................2 
DECLARATION OF SPONSOR ...........................................................................................3 
INVESTIGATOR AGREEMENT FORM ............................................................................4 
SYNOPSIS ................................................................................................................................5 
TABLE OF CONTENTS ......................................................................................................11 
LIST OF FIGURES .................................................................................................................14 
LIST OF APPENDICES ..........................................................................................................14 
LIST OF ABBREVIATIONS ...............................................................................................15 
1. 
INTRODUCTION AND BACKGROUND ..................................................................17 
1.1 
Nonclinical Studies of Voclosporin in Dry Eye ..........................................................18 
1.2 
Clinical Studies of Voclosporin in Dry Eye ................................................................20 
1.3 
Study Rationale ............................................................................................................21 
2. 
STUDY OBJECTIVES ..................................................................................................22 
3. 
CLINICAL HYPOTHESIS ...........................................................................................23 
4. 
OVERALL STUDY DESIGN .......................................................................................24 
5. 
STUDY POPULATION ................................................................................................28 
5.1 
Number of Subjects......................................................................................................28 
5.2 
Study Population Characteristics .................................................................................28 
5.3 
Inclusion Criteria .........................................................................................................28 
5.4 
Exclusion Criteria ........................................................................................................29 
5.5 
Withdrawal Criteria .....................................................................................................31 
5.6 
Aurinia Adequate/Effective Contraception..................................................................32 
6. 
STUDY PARAMETERS ...............................................................................................33 
6.1 
Efficacy Measures ........................................................................................................33 
6.1.1 
Primary Efficacy Endpoint .......................................................................................33 
6.1.2 
Key Secondary Endpoint ..........................................................................................33 
6.1.3 
Secondary Endpoints ................................................................................................33 
6.2 
Safety Measures ...........................................................................................................34 
7. 
RANDOMIZATION, MASKING AND UNMASKING PROCEDURES ................35 
7.1 
Randomization .............................................................................................................35 
7.2 
Masking........................................................................................................................35 
7.3 
Unmasking ...................................................................................................................35 
8. 
STUDY MATERIALS ...................................................................................................36 
8.1 
Dosage Forms/Formulation .........................................................................................36 
8.1.1 
Study Treatments ......................................................................................................36 


 
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8.1.2 
Description and Justification for the Route of Administration, Dosage, Dosage 
Regimen, and Treatment Period ...............................................................................36 
8.1.3 
Instructions for Use and Administration ...................................................................37 
8.2 
Other Study Supplies ...................................................................................................37 
9. 
STUDY METHODS AND PROCEDURES ................................................................38 
9.1 
Subject Entry Procedures .............................................................................................38 
9.1.1 
Overview ...................................................................................................................38 
9.1.2 
Informed Consent .....................................................................................................38 
9.1.3 
Washout Intervals .....................................................................................................38 
9.1.4 
Procedures for Final Study Entry..............................................................................38 
9.1.5 
Methods for Assignment to Treatment Groups ........................................................38 
9.2 
Concurrent Therapies ...................................................................................................38 
9.2.1 
Prohibited Medications .............................................................................................38 
9.2.2 
Rescue Medications ..................................................................................................38 
9.2.3 
Special Diets or Activities ........................................................................................39 
9.3 
Examination Procedures ..............................................................................................39 
9.3.1 
Visit 1: Day -17 to -14 Screening and Run-In Period...............................................39 
9.3.2 
Visit 2: Day 1-Baseline .............................................................................................40 
9.3.3 
Visit 3: Day 14 (±3 days) ..........................................................................................41 
9.3.4 
Visit 4: Day 28 (±3 days) ..........................................................................................42 
9.3.5 
Visit 5: Day 56 (±3 days) ..........................................................................................43 
9.3.6 
Visit 6: Day 84 (±3 days)/Early Termination Visit ..................................................44 
9.3.7 
Visit 7: Post-Treatment Safety Follow-Up (+7 days from Visit 6, ±3 days) ............44 
9.3.8 
Unscheduled Visits ...................................................................................................45 
9.4 
Compliance with Protocol............................................................................................45 
9.5 
Subject Disposition ......................................................................................................45 
9.5.1 
Completed Subjects ..................................................................................................45 
9.5.2 
Discontinued Subjects...............................................................................................45 
9.6 
Study Termination .......................................................................................................46 
9.7 
Study Duration .............................................................................................................46 
9.8 
Monitoring and Quality Assurance ..............................................................................46 
10. EVALUATION, RECORDING AND REPORTING OF AES AND SAES .............47 
10.1 
Definitions....................................................................................................................47 
10.1.1 
Adverse Event ...........................................................................................................47 
10.1.2 
Adverse Drug Reaction .............................................................................................47 
10.1.3 
Unexpected ADR ......................................................................................................47 
10.1.4 
Serious Adverse Event (SAE)...................................................................................47 
10.1.5 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ...................................48 
10.1.6 
Treatment-Emergent Adverse Event (TEAE) ...........................................................48 
10.2 
Adverse Event Descriptors ..........................................................................................48 
10.2.1 
Intensity/Severity Categorization .............................................................................48 


 
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10.2.2 
Causal Relationship Categorization ..........................................................................49 
10.2.3 
Outcome Categorization ...........................................................................................49 
10.2.4 
Symptoms of the Disease Under Study ....................................................................50 
10.2.5 
Adverse Events of Special Interest including Abuse, Misuse, Overdose and 
Medication Errors .....................................................................................................50 
10.3 
Reporting Procedure for AEs, SAEs, and Pregnancy ..................................................50 
10.3.1 
Adverse Events .........................................................................................................50 
10.3.2 
Serious Adverse Events ............................................................................................51 
10.3.3 
Pregnancy..................................................................................................................53 
11. STATISTICAL HYPOTHESES AND METHODS OF ANALYSES .......................55 
11.1 
Analysis Populations ....................................................................................................55 
11.2 
Statistical Hypothesis ...................................................................................................55 
11.3 
Sample Size ..................................................................................................................56 
11.4 
Statistical Analysis .......................................................................................................56 
11.4.1 
Unit of Analysis ........................................................................................................56 
11.4.2 
Multiplicity Considerations ......................................................................................57 
11.4.3 
Primary Efficacy Analyses .......................................................................................57 
11.4.4 
Key Secondary Endpoint Analysis ...........................................................................57 
11.4.5 
Secondary Efficacy Analyses ...................................................................................57 
11.4.6 
Safety Variables ........................................................................................................58 
11.4.7 
Interim Analyses .......................................................................................................58 
12. COMPLIANCE 
WITH 
GOOD 
CLINICAL 
PRACTICES, 
ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES .......................................59 
12.1 
Protection of Human Subjects .....................................................................................59 
12.1.1 
Subject Informed Consent ........................................................................................59 
12.1.2 
Institutional Review Board Approval .......................................................................59 
12.2 
Ethical Conduct of the Study .......................................................................................59 
12.3 
Subject Confidentiality ................................................................................................59 
12.4 
Documentation .............................................................................................................60 
12.4.1 
Retention of Documentation .....................................................................................60 
12.5 
Labelling, Packaging, Storage, Accountability, and Return or Disposal of 
Investigational Product ................................................................................................60 
12.5.1 
Labelling/Packaging .................................................................................................60 
12.5.2 
Storage of Investigational Product ............................................................................61 
12.5.3 
Accountability of Investigational Product ................................................................61 
12.5.4 
Return or Disposal of Investigational Product ..........................................................61 
12.6 
Aurinia Recording of Data on Source Documents and Case Reports Forms (CRFs) .61 
12.7 
Handling of Biological Specimens ..............................................................................62 
12.8 
Publications ..................................................................................................................62 
13. REFERENCES ...............................................................................................................63 
14. APPENDICES ................................................................................................................65 


 
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LIST OF FIGURES 
Figure 1 
AUDREY (AUR-VOS-2019-01) Study Schematic ..........................................25 
Figure 2 
Visit-by-Visit Study Flow Chart .......................................................................26 
 
LIST OF APPENDICES 
Appendix 1: Schedule of Visits and Measurements ................................................................65 
Appendix 2: Examination Procedures, Tests, Equipment, and Techniques ............................67 
Appendix 3: Daily Dosing Diary .............................................................................................73 
 
 


 
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LIST OF ABBREVIATIONS 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AUDREY 
AUrinia DRy EYe 
Aurinia 
Aurinia Pharmaceuticals Inc. 
BCVA 
Best Corrected Visual Acuity 
BID 
Twice daily 
CI 
Confidence interval 
CNI 
Calcineurin inhibitor 
CPM 
Clinical Project Manager 
CRO 
Contract Research Organization 
CsA 
Cyclosporine A 
DED 
Dry Eye Disease 
DES 
Dry Eye Syndrome 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ERG 
Electroretinography 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FCS 
Fluorescein Corneal Staining 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IWRS 
Interactive Web Response System 
KCS 
Keratoconjunctivitis sicca 
LASIK 
Laser-assisted in situ keratomileusis 
LogMAR 
Logarithm of the Minimum Angle of Resolution 


 
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MMRM 
Mixed Effect Model Repeated Measures 
NEI 
National Eye Institute 
NFAT 
Nuclear Factor of Activated T-cells 
NOAEL 
No observed adverse effect level 
NSAID 
Nonsteroidal Anti-Inflammatory Drug 
NZW 
New Zealand White 
OTC 
Over-the-counter 
OU 
Both eyes 
PP 
Per Protocol 
SAE 
Serious adverse event 
SANDE 
Symptom Assessment in Dry Eye 
STT 
Schirmer Tear Test 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
VAS 
Visual Analog Scale 
VOS 
Voclosporin ophthalmic solution 


 
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1. INTRODUCTION AND BACKGROUND 
Dry eye syndrome (DES) (also known as dry eye disease (DED) and keratoconjunctivitis sicca 
(KCS), herein referred to as DES) is a complex disorder of the ocular surface disease (OSD) 
characterized by tear film instability progressing to tear hyperosmolarity, epithelial damage 
with inflammation, neurogenic inflammation, and eventual fibrosis of the lacrimal gland with 
reduced tear production [(Boboridis and Konstas 2018)]. The Tear Film and Ocular Surface 
Society Dry Eye Workshop group defines global DES as a multi-factorial disease of the ocular 
surface characterized by a loss of homeostasis of the tear film accompanied by ocular 
symptoms. These include tear film instability and hyperosmolarity, ocular surface 
inflammation and damage, and neurosensory abnormalities [(Craig, Nichols et al. 2017)]. The 
overall incidence of DES has significant geographic variation, with published data ranging 
from 5%-34% of US adults over 50 years of age. Given the heterogeneity of patients, a 
retrospective analysis of the US Department of Defense Medical Claims Data demonstrated an 
overall prevalence of 5.3% of adults have DES, impacting twice as many women as men, and 
increasing in prevalence with age. The 2015 US Census estimated that up to 16 million people 
experienced DES in the US [(Dana, Bradley et al. 2019)]. In patients with DES, tear production 
has been shown to be increased with the use of topical immunosuppressants, including 
cyclosporine. Symptoms of DES include a sensation of dry eyes, foreign body sensation, 
irritation, burning, tearing, ocular pain, and itching, among others. DES affects quality of life 
and work productivity, and patients with moderate to severe DES may experience reduced 
visual function in addition to ocular dysfunction. Current therapy includes a stepped approach, 
which starts with over-the-counter (OTC) lubricants and artificial tear replacements, and then 
expands to include topical anti-inflammatory therapy and punctal occlusion [(Craig, Nichols 
et al. 2017)]. There are currently three FDA-approved prescription medications used for DES, 
topical cyclosporine ophthalmic solution 0.05% (Restasis®, herein referred to as Restasis) 
[(Restasis® 2017)], lifitegrast ophthalmic solution 5% (Xiidra®, herein referred to as Xiidra) 
[Xiidra® 2017], and cyclosporine ophthalmic solution 0.09% (Cequa™, herein referred to as 
Cequa) [(CEQUA® 2018)]. A significant number of patients using Restasis experience the 
following adverse reactions: ocular irritation upon instillation, slow onset of response, and 
limited efficacy [(Restasis® 2017)]. Adverse reactions with Xiidra include instillation 
irritation, dysgeusia, and reduced visual acuity that occurred in 5%-25% of subjects in clinical 
trials [Xiidra® 2017]. The most common adverse reactions reported with Cequa were pain on 
instillation of drops (22% of subjects) and conjunctival hyperemia (6% of subjects) 
[(CEQUA® 2018)]. Despite these approved products, an unmet clinical need remains for 
improved therapeutic options for patients with moderate to severe DED. 
In patients with DES, tear production has been shown to be increased with the use of topical 
immunosuppressants, including cyclosporine. It is believed that T-lymphocyte infiltration and 
activation in the lacrimal gland represents an underlying pathogenesis for DES. Calcineurin 
inhibitors reversibly inhibit immunocompetent lymphocytes, particularly T-lymphocytes, in 
the G0 or G1 phase of the cell cycle and also reversibly inhibit the production and release of 
lymphokines [(Granelli-Piperno 1986)]. Calcineurin is a calcium- and calmodulin-dependent 


 
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serine-threonine phosphatase. Calcineurin inhibitors (CNIs) inhibit the ability of calcineurin to 
dephosphorylate the nuclear factor of activated T-cells (NFAT), which is required for 
translocation of NFAT from the cytoplasm to the nucleus, thereby preventing activation of 
various transcription factors necessary for the induction of cytokine genes during T-cell 
activation (i.e., interleukin-2, interleukin-4, tumor necrosis factor-α, granulocyte-macrophage 
colony stimulating factor, and interferon-γ) [(Stepkowski 2000, Wiseman 2016)]. 
Voclosporin (LX214) is a novel next generation CNI that is currently being evaluated for a 
variety of systemic and topical indications. Voclosporin is structurally similar to cyclosporine 
A (CsA), except for a novel modification of a functional group on the amino acid-1 residue of 
the molecule. This alteration has changed how voclosporin binds to calcineurin leading to an 
improved potency when compared to CsA. This modification has also changed the metabolic 
profile of voclosporin by shifting metabolism away from amino acid-1, which is the major site 
of metabolism for CsA. The altered metabolic profile has led to a faster elimination of 
metabolites resulting in lower metabolite exposure compared to CsA. The combination of 
increased potency and decreased metabolite exposure, for voclosporin compared to CsA, has 
led to better pharmacokinetic/pharmacodynamic predictability. 
1.1 
Nonclinical Studies of Voclosporin in Dry Eye 
Two Good Laboratory Practice (GCP) toxicology studies [(S07654 2009, S07655 2009)] have 
been conducted to evaluate the safety of voclosporin ophthalmic solution (VOS) in the eye of 
the New Zealand White (NZW) rabbit and the Beagle dog with dosing for 14 days. Test 
animals were euthanized on Day 15, and recovery animals were sacrificed on Day 29. Animals 
received two, four, or eight bilateral topical applications of 0.2% VOS within 8 hours daily, 
corresponding to doses of approximately 0.14, 0.28, and 0.56 mg/eye/day, respectively. 
Control animals received 8 doses of the vehicle within 8 hours daily. Safety was evaluated 
using 
macroscopic 
and 
microscopic 
ophthalmologic 
evaluations; 
tonometry; 
electroretinography (ERG) evaluation; gross and microscopic pathology of the eyes (including 
optic nerve), submandibular lymph nodes, spleen, and thymus; and hematology, blood 
chemistry, and coagulation parameters. Blood voclosporin concentrations were obtained on 
Days 1 and 13 at pre-dose and 8, 8.5, 10, and 12 hours after the first VOS instillation.  
In the NZW rabbit study, no VOS ocular treatment-related changes in serum chemistry, 
hematology, coagulation, gross pathology, or organ weights were found at the completion of 
the dosing period or following a 14-day recovery (without treatment). Similarly, no 
treatment-related macroscopic or microscopic ophthalmological changes or effects on 
intraocular pressure associated with the administration of VOS were reported. There were no 
histologic findings in the spleen, thymus, or rostral and caudal sections of the mandibular 
lymph nodes. A standard battery of bilateral full-field flash ERGs was performed; sporadic 
statistically significant differences were seen, but as these were all limited to one eye, were not 
dose-dependent, and were not supported by corresponding changes in related ERG parameters 
(for example, a change in a-wave implicit time was not accompanied by a change in a-wave 


 
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amplitude), they were judged to have no significance. The ocular no observed adverse effect 
level (NOAEL) for VOS in NZW rabbits was determined to be 0.56 mg/eye/day. There was 
some accumulation of voclosporin in blood over the course of the study, with mean trough 
levels on Day 13 of 0.028, 0.154, and 0.325 ng/mL for the low, mid, and high dose groups, 
respectively. The mean maximum blood concentration achieved 1 hour after dosing (high dose 
group) was 2.29 ng/mL on Day 13. 
In the Beagle dog study, similar results were reported for all safety parameters. The ocular 
NOAEL for VOS in Beagle dogs was determined to be 0.56 mg/eye/day. There was some 
accumulation of voclosporin in blood over the course of the study, with mean trough levels on 
Day 13 of 0.017, 0.173, and 0.297 ng/mL for the low, mid, and high dose groups, respectively. 
The mean maximum blood concentration achieved 1 hour after dosing (high dose group) was 
1.178 ng/mL on Day 13. 
In an additional 13-week NZW rabbit study [(S08661 2009)] no mortality, systemic toxicity, 
or effects on specific ocular indices were observed following daily bilateral topical ocular 
administration of placebo or VOS (0.2% voclosporin) at a frequency of up to eight times daily 
(hourly intervals; ~0.56 mg/eye/day) for 13 weeks or following a 4-week recovery period. The 
NOAEL for repeat topical ocular administration of VOS (0.2% voclosporin) to male and 
female NZW rabbits for 13 weeks was >0.56 mg/eye/day.  
In summary, the two repeated-dose ocular toxicology studies [(S07654 2009, S07655 2009)] 
demonstrated that there were no specific ocular indices or histopathology, and no systemic 
toxicity observed in either dogs or rabbits with 14 days of dosing. In addition, there was no 
mortality, systemic toxicity, or effects on specific ocular indices observed following daily 
bilateral topical ocular administration of placebo or VOS (0.2% voclosporin) at a frequency of 
up to eight times daily (hourly intervals; ~0.56 mg/eye/day) for 13 weeks or following a 4-week 
recovery period in rabbits. 
In addition to the three repeated dose toxicology studies, the efficacy and safety of VOS 0.2% 
has been evaluated in dogs with naturally occurring KCS [(S15389-00 2017)], diagnosed by 
the Schirmer Tear Test (STT) of >1 mm/min and <8 mm/min in one or both eyes (OU). Thirty-
five dogs ≥6 months old were randomly assigned in a 3:1 ratio to receive either VOS (n=25) 
or Optimmune® Ophthalmic Ointment (n=10) for 28 days BID. Results showed that treatment 
with VOS resulted in a statistically significant within-group increase in mean STT from 
baseline of 4.6 mm/min to each post-treatment visit. Qualitatively, this increase in magnitude 
was higher than seen in the concurrent Optimmune control group. For the Optimmune group, 
the change from baseline to Visit 2, 3, and 4, respectively, was not statistically significant, 
whereas for the VOS-treated group, each change from baseline was statistically significant 
(p<0.0001), demonstrating that VOS was effective in treating KCS in dogs. 
In order to determine potential melanin binding of 14C-LX214 (pre-clinical drug product 
formulation), ocular tissue 14C-LX214-derived radioactivity concentrations were compared 


 
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between data obtained from albino NZW rabbits [(S08661 2009)] given a single bilateral 
instillation in a separate study and similarly treated pigmented Dutch-Belted rabbits (S08662 
2009). Ocular pigments in Dutch-Belted rabbits are widely spread in multiple structures 
including iris (stroma and epithelium), ciliary body (stroma and one epithelial layer), choroid 
(stroma), retina (epithelium), eyelids, and conjunctiva. The total radioactivity in these ocular 
tissues of Dutch-Belted rabbits was not statistically significantly different from NZW rabbits 
at the six sampling time points. Therefore, there was no evidence of melanin binding of 14C-
LX214 after a single ocular administration. These data were confirmed in an in vitro model.  
1.2 
Clinical Studies of Voclosporin in Dry Eye 
Voclosporin ophthalmic solution has been investigated in one Phase 1 dose-escalation study 
(LX214-01) in 30 healthy volunteers, followed by an open-label evaluation of VOS in five 
subjects with mild to moderate DES. In this study, both 0.02% and 0.2% concentrations were 
found to be safe and well tolerated following multiple instillations in healthy subjects. All 
adverse events (AEs) across study cohorts were mild or moderate in severity and all resolved 
completely, most without requiring treatment. Although the sample size was small, results 
from the five subjects with DES suggested VOS may be beneficial in the treatment of DES 
and is supported by the Ocular Surface Disease Index scores, which were improved in all 
subjects at all time points while on study drug. Overall, the results indicated VOS can be used 
safely when administered BID for two weeks [(LX214-01 2009)]. 
Additionally, one Phase 2, Investigator-masked, randomized, parallel-group study was 
conducted in 100 subjects with DES at 7 treatment sites to evaluate the efficacy, safety, and 
tolerability of VOS compared to Restasis [(AUR-VOS-2017-01 2019)]. Results of this study 
indicated that VOS was well tolerated at doses up to 0.2% w/v OU, BID for up to 28 days. 
Clinically relevant and statistically superior treatment effects were observed in favor of VOS 
at most time points for the standard signs of DES, namely change from baseline in STT and 
fluorescein corneal staining (FCS). After 2 weeks of treatment, a benefit of treatment with 
VOS compared with Restasis was observed in these objective signs of DES. This potentially 
indicates a more rapid onset of action and beneficial anti-inflammatory effect for VOS. 
Pre-specified exploratory efficacy analyses also favored VOS, which demonstrated a 
statistically significant difference in the number of subjects achieving a ≥10 mm improvement 
in STT at Week 4 in the VOS group (42.9%) compared with the Restasis group (18.4%) 
(OR=4.40; 95% CI: 1.55, 12.51; p=0.0055).  
There were marked improvements from baseline in symptom severity at Week 1 with sustained 
improvements at Week 4 in both treatment groups, though there were no statistically 
significant differences between treatment groups. 
Voclosporin ophthalmic solution was well-tolerated over a 4-week treatment period, and no 
new or unexpected safety signals were observed with the use of VOS in DES, though more 


 
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AEs were reported in the VOS group. The overall safety profile was consistent with the 
expectations for the class of drug, the patient population, and concomitant therapies. These 
data demonstrated the positive benefit/risk profile for VOS and support the choice of 
proceeding with a dose-ranging clinical study to further explore safety and efficacy over a 
longer duration [(AUR-VOS-2017-01 2019)]. 
1.3 
Study Rationale 
These results from the AUR-VOS-2017-01 study support the conduct of this dose-ranging 
clinical study (AUR-VOS-2019-01, AUrinia DRy EYe (AUDREY)) to explore safety and 
efficacy over a longer duration. Please refer to Section 1.2 of the Investigator’s Brochure (IB) 
[(VOS-Investigator's-Brochure 2019)] for additional details supporting the safety and efficacy 
of VOS in subjects with DES.  
 
 


 
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2. STUDY OBJECTIVES 
To assess the efficacy and safety of three different concentrations of VOS (0.05%, 0.10%, and 
0.20%) when administered BID in both eyes (OU) over 12 weeks compared to vehicle in 
subjects with DES. 


 
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3. CLINICAL HYPOTHESIS 
The clinical hypothesis for this study is that at least one of three concentrations of VOS (0.05%, 
0.10%, and 0.20%) when administered OU BID over 4 weeks is significantly different 
compared to vehicle alone for the following DES sign improvement:  
• Proportion of subjects with a ≥10 mm increase from baseline in STT at Week 4 in the study 
eye  


 
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4. OVERALL STUDY DESIGN 
This is a Phase 2/3, multi-center, randomized, double-masked, vehicle-controlled study to 
assess the efficacy and safety of three different concentrations of VOS when administered OU 
BID over 12 weeks in subjects with mild to moderate DES. A 14- to 17-day run-in period with 
VOS vehicle will be included. Subjects will undergo a 2-week run-in period in which VOS 
vehicle will be self-administered OU, BID. Subjects will be re-assessed to confirm that all 
participants meet all of the inclusion criteria and none of the exclusion criteria. It is estimated 
the study will enroll approximately 480 subjects across approximately 9 study centers. Eligible 
subjects will be randomized in a 1:1:1:1 ratio to one of the following study treatment arms after 
the 14- to 17-day run-in period: 
• 0.05% VOS BID 
• 0.10% VOS BID 
• 0.20% VOS BID 
• VOS Vehicle BID 
Subjects will be stratified by eye dryness VAS score ≥60 mm and <60 mm. 
See Figure 1 for the AUDREY (AUR-VOS-2019-01) study schematic. 
 








 
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5. STUDY POPULATION 
5.1 
Number of Subjects 
It is estimated that 480 subjects across 9 study centers will be enrolled and randomized in a 
1:1:1:1 ratio to one of the following study treatment arms: 
• 0.05% VOS BID 
• 0.10% VOS BID 
• 0.20% VOS BID 
• VOS Vehicle BID 
5.2 
Study Population Characteristics 
All subjects must meet all inclusion criteria and none of the exclusion criteria.  
5.3 
Inclusion Criteria 
Subjects are eligible for participation if they: 
1. Provide written informed consent before any study-specific procedures are performed. 
2. Are male or female, with a minimum age of 18 years (or legal age of consent if >18 years), 
at the time of screening. 
3. Have a documented history of DES in both eyes supported by a previous clinical diagnosis 
prior to Visit 1. 
4. Are willing and able to follow protocol procedures and instructions and can be present for 
the required study visits for the duration of the study. 
5. Have a symptom severity score of ≥30 mm for Eye Dryness on the Individual Symptom 
Severity Assessment Visual Analog Scale (VAS) (0-100 mm) at both Visit 1 and 2. 
6. Have a BCVA in both eyes of +0.7 logarithm of the Minimum Angle of Resolution 
(logMAR) or better as assessed by Early Treatment of Diabetic Retinopathy Study 
(ETDRS) chart at Visit 1. 
7. Have ongoing DES, as defined by at least one eye (if one eye, the same eye) meeting both 
of the following criteria at both Visit 1 and Visit 2:  
a) 
Have an unanesthetized Schirmer Tear Test (STT) score of ≥1 mm and ≤10 mm 
per 5 minutes. 


 
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b) 
Have a total fluorescein corneal staining (FCS) score of at least 3 [National Eye 
Institute (NEI)/Industry Workshop 0-15 scale]. 
Note: The qualifying eye at Visit 1 must be the same eye at Visit 2. 
8. Have normal lid anatomy 
5.4 
Exclusion Criteria 
In order for subjects to be eligible, (as specified in the Schedule of Events) subjects must not: 
1. Be non-compliant during the run-in treatment (non-compliance defined as dosing <80% 
or >120% of the time, calculated by counting the number of returned and unused study 
drug ampules). 
2. Have any known hypersensitivity or contraindication to study treatments (including 
excipients), topical anesthetics, or vital dyes. 
3. Have had any eye surgery in either eye except for cataract surgery or laser-assisted in situ 
keratomileusis (LASIK). 
4. Have undergone cataract or LASIK surgery within 1 year prior to Visit 1. 
5. Have recent or current evidence of ocular infection or inflammation in either eye including 
ocular pemphigoid and Stevens Johnson Syndrome. 
6. Have current evidence of clinically significant blepharitis (defined as requiring lid hygiene 
therapy and additional therapies such as doxycycline or Lipiflow®) or other meibomian 
gland dysfunction, conjunctivitis, or a history of herpes simplex or zoster keratitis in either 
eye. 
7. Have clinically significant ocular disease in either eye (i.e., corneal edema, uveitis, severe 
KCS) or active ocular allergies that might interfere with study procedures or assessments 
in the opinion of the Investigator. Severe KCS is defined by an FCS score of ≥13. 
8. Be taking or have a known need for any of the following treatment therapies within the 
time frames as specified below: 
a) 
Any investigational drug or device within 30 days prior to the Screening Visit 
(Visit 1) and subjects may not receive any investigational drug or device during 
the entire study except that which is allowed by the protocol. 
b) 
Ophthalmic drugs (any topical eye medications) including prescription 
medication and OTC agents, from Visit 1 to Visit 7. 


 
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c) 
Contact lenses 24 hours prior to the Screening Visit (Visit 1) to the end of Visit 
7. 
d) 
Any prior use of amiodarone. 
e) 
Within 72 hours of Visit 1 and for the duration of the study: 
− 
Oral antihistamines 
f) 
Within 14 days prior to Visit 1 and for the duration of the study: 
− 
Xiidra® (lifitegrast) 
g) 
Within 30 days prior to Visit 1 and for the duration of the study: 
− 
Calcineurin Inhibitor such as Restasis® (cyclosporin ophthalmic 
emulsion) or CequaTM 
− 
Topical ocular anti-histamines 
− 
Ocular, inhaled, or intranasal corticosteroids 
− 
Topical or oral mast cell stabilizers  
− 
Oral anti-histamines 
− 
Topical or nasal vasoconstrictors 
− 
Topical ocular nonsteroidal anti-inflammatory drugs (NSAIDs) 
− 
Topical ocular antibiotics 
− 
True Tear device  
h) 
Unstable dose within 30 days prior to the Screening Visit (Visit 1) or during the 
study; alteration to the dose or anticipated alterations to the dose of the 
following are disallowed: 
− 
Tetracyclines 
− 
Omega 3s or Omega 6s 
i) 
Unstable dose within 60 days prior to the Screening Visit (Visit 1) or during the 
study; alteration to the dose or anticipated alterations to the dose of the 
following are disallowed: 


 
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− 
Anticholinergics 
− 
Antidepressants 
− 
Oral contraceptives 
− 
Isotretinoin 
− 
Oral systemic corticosteroids 
− 
Oral systemic immunosuppressive agents 
j) 
Within 90 days prior to the Screening Visit (Visit 1) or during the study, the 
subject has had cauterization of the punctum or alternations to (insertion or 
removal) punctal plug(s) or nasolacrimal surgery. Note: If a punctal plug is in 
place at the Screening Visit (Visit 1) and it is dislodged during the study, the 
plug should be replaced as soon as possible. 
9. Have clinically significant systemic disease (i.e., uncontrolled diabetes, hepatic, renal, 
endocrine or cardiovascular disorders) that might interfere with the study. 
10. Have been randomized and treated in a previous study where VOS was the IP. 
11. Be a woman of childbearing potential who is pregnant, nursing, planning a pregnancy, or 
not using a medically acceptable form of birth control. All women of child-bearing 
potential must be willing to take a urine pregnancy test at Visit 1 and Visit 6. Details 
surrounding adequate forms of contraception are outlined in Section 5.6. 
12. Have a condition or be in a situation that the Investigator feels may put the subject at 
significant risk, may confound the study results, or may interfere significantly with the 
subject’s participation in the study. 
5.5 
Withdrawal Criteria 
Subjects may voluntarily withdraw from study participation at any time for any reason. 
Alternatively, subjects may be withdrawn at the Investigator’s discretion if it is in the subject’s 
best interest. 
Every effort should be made for subjects who withdraw from the study (either voluntarily or 
at the Investigator’s discretion) to undergo end-of-study assessments (Visit 6). If possible, the 
subject should also be advised to come into the site for the Follow-Up Visit (Visit 7), 7 days 
(±3 days) after self-instilling the final dose. If a subject refuses end-of-study procedures, the 
reason for refusal should be fully documented in the subject’s source document. It is the 
subject’s right to withdraw from the study without providing a reason. In this case, the source 


 
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documents and the electronic case report form (eCRF) should document the reason for 
discontinuation as “withdrawal of consent.” Withdrawn subjects will not be replaced. 
5.6 
Aurinia Adequate/Effective Contraception 
An adult woman is considered to be of childbearing potential unless she is at least 1 year 
post-menopausal or 3 months post-surgical sterilization. All women of child-bearing potential 
must have a negative urine pregnancy test result at Visit 1 and must not intend to become 
pregnant during the study. Women of child bearing potential who are not abstinent must have 
been using one of the following acceptable methods of birth control for the times specified:  
1. Intrauterine device in place for at least 4 weeks prior to Visit 1 through Visit 7 
2. Barrier method (condom or diaphragm) with spermicide from Visit 1 through Visit 7. 
3. Stable hormonal contraceptive for at least 60 days prior to Visit 1 through Visit 7.In a 
monogamous relationship with a surgically sterilized (i.e., vasectomized) partner at 
least 6 months prior to Visit 1 through Visit 7. 


 
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6. STUDY PARAMETERS 
6.1 
Efficacy Measures 
6.1.1 Primary Efficacy Endpoint 
Proportion of subjects with a ≥10 mm increase from baseline in STT at Week 4 in the study 
eye. The study eye will be defined as the eye that achieves the lowest STT score at baseline. 
Should a subject have identical STT scores in both eyes at baseline, the eye with the worst FCS 
score will be used. Should these scores also be equal, the right eye will be used. 
6.1.2 Key Secondary Endpoint 
Mean change from baseline in Eye Dryness VAS at Week 4 in subjects with a baseline Eye 
Dryness VAS score ≥60 mm. 
6.1.3 Secondary Endpoints 
• Proportion of subjects with a ≥10 mm increase from baseline in STT at Weeks 2, 8, and 12 
in the study eye. 
• Mean change from baseline in total FCS (NEI/Industry Workshop 0-15 scale) score to 
Weeks 2, 4, 8, and 12 in the study eye. 
• Mean change from baseline in FCS score in the 5 regions of the cornea (central, superior, 
inferior, temporal, and nasal) to Weeks 2, 4, 8, and 12 in the study eye. 
• Mean change from baseline in STT score to Weeks 2, 4, 8, and 12 in the study eye. 
• Mean change from baseline in Eye Dryness VAS (0-100 mm) score to Weeks 2, 4, 8, and 
12 within treatment group. 
• Mean change from baseline in Ocular Discomfort VAS (0-100 mm) score to Weeks 2, 4, 
8, and 12. 
• Mean change from baseline in Eye Dryness, Burning/Stinging, Itching, Photophobia, Eye 
Pain, Foreign Body Sensation, and Blurred Vision VAS (0-100 mm) score to Weeks 2, 4, 
8, and 12. 
• Mean change from baseline of the sum of Individual Symptom Score (VAS Total Symptom 
Summary Score) to Weeks 2, 4, 8, and 12.  
• Mean change from baseline in Symptom Assessment in Dry Eye (SANDE) frequency and 
severity scores to Week 2, 4, 8, and 12. 


 
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6.2 
Safety Measures 
• Treatment-emergent adverse events (TEAEs) 
• Change from baseline in BCVA over time 
• Changes from baseline in slit-lamp biomicroscopy over time 
• Changes from screening in dilated ophthalmoscopy over time 


 
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7. RANDOMIZATION, MASKING AND UNMASKING PROCEDURES 
7.1 
Randomization 
All subjects enrolled must be identifiable throughout the study. The Investigator will maintain 
a list of subject numbers and subject names to enable records to be found at a later stage. 
Subjects will be allocated a subject number at screening visit (Visit 1) and registered with an 
interactive web randomization system (IWRS). Subjects meeting the required eligibility 
criteria will be randomized to treatment at Visit 2 (baseline). The randomization will be 
stratified by Eye Dryness score (<60 mm and ≥60 mm). The subjects will be randomized in a 
ratio 1:1:1:1 to receive either VOS vehicle, VOS 0.05%, VOS 0.10%, or VOS 0.20%. The 
randomization ratio will be maintained within each study center. A randomization list will be 
generated and provided by an unmasked statistician.  
7.2 
Masking 
All study personnel and subjects will be masked to the study treatment administered during the 
study. VOS vehicle, 0.05% VOS, 0.10% VOS, and 0.20% VOS will be identical in appearance. 
The treatment group allocated will not be available to the study monitor, project statistician, or 
the project team at Aurinia Pharmaceuticals or the CRO. The site staff, monitors, and study 
subjects will remain masked until the end of the study. In case of emergency, the unmasking 
process below should be followed.  
7.3 
Unmasking 
In the rare event that an AE or pregnancy occurs for which knowledge of the identity of the 
study treatment administered is necessary to manage the subject’s condition, the IWRS code 
for that subject maybe broken and the test substance identified. Procedures for unmasking will 
be provided in a separate manual. 
Should unmasking be required, the Investigator should call Medical Monitor before unmasking 
whenever possible; however, the Investigator is responsible for the medical care of the 
individual study subject and does not require the agreement of the Medical Monitor before 
unmasking. In the event that the Medical Monitor cannot be reached, the Investigator should 
contact the Project Manager at the CRO. The reason for unmasking must be documented. The 
information on study treatment should only be used for decision making in the subject’s further 
treatment. Details on unmasked treatment assignments should not be shared with the Study 
Monitor and project team. Unmasked subjects will be discontinued from the study. 


 
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8. STUDY MATERIALS 
8.1 
Dosage Forms/Formulation 
All study treatment to be used in this study will be manufactured in accordance with current 
Good Manufacturing Practice (GMP). Study treatment will be supplied by Aurinia. 
8.1.1 Study Treatments 
Company Code: 
 
Chemical Name: 
Empirical Formula: 
 
Generic Name: 
VOS 
Dosage Form: 
Voclosporin Ophthalmic Solution is provided as a clear micellar 
solution in single-use blow fill seal ampules for topical ocular 
administration.  
Strength: 
0.05% VOS, 0.10% VOS, or 0.20% VOS 
Manufacturer:  
Aurinia Pharmaceuticals Inc. 
Study drug will be supplied as a sterile, clear, micellar solution containing 0.05%, 0.10%, or 
0.20% Active Pharmaceutical Ingredient (voclosporin), in single-use blow fill seal ampules for 
topical ocular administration. 
 
 
 
 
 
 
 
The vehicle solution contains all components of the drug product solution with the exception 
of voclosporin. 
8.1.2 
Description and Justification for the Route of Administration, Dosage, 
Dosage Regimen, and Treatment Period 
Topical ophthalmic dosing is the optimal route of administration for dry eye treatments. The 
dosage and dosage regimen were selected based on nonclinical studies described in Section 1.1 
and clinical studies described in Section 1.2. The proposed treatment period of 12 weeks is 


 
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also based on nonclinical and clinical studies and on the immunosuppressive mechanism of 
action of the drug. 
8.1.3 Instructions for Use and Administration 
• At the end of Visit 1, qualified subjects will receive a kit with run-in (vehicle ophthalmic 
solution) for OU, BID dosing until Visit 2. Subjects will be instructed to dose in the 
morning and evening. One drop of the IP will be instilled in each eye BID. Subjects will 
be instructed to bring all used and unused IP to every clinic visit to conduct accountability. 
• At Visit 2, the run-in kit will be collected from subjects for drug accountability. At the end 
of Visit 2, qualified subjects will be randomized using the IWRS and dispensed a kit 
containing either VOS 0.05%, VOS 0.10%, VOS 0.20%, or vehicle for BID dosing until 
Visit 3. Subjects will be instructed not to take the morning dose of run-in on the day of 
study randomization (Visit 2). Instructions regarding timing between doses will remain 
identical to instructions given for the run-in period at Visit 1. 
• At Visit 3, the study drug kit will be collected from subjects for drug accountability. 
Subjects will receive a new kit of study drug assigned via the IWRS (with the same 
treatment assignment that they were randomized to at Visit 2) for BID dosing until Visit 4. 
• At Visit 4, the study drug kit will be collected from subjects for drug accountability. 
Subjects will be dispensed two new kits of study drug assigned via the IWRS (with the 
same treatment assignment that they were randomized to at Visit 2) for BID dosing until 
Visit 5. 
• At Visit 5, the study drug kits will be collected from subjects for drug accountability. 
Subjects will be dispensed two new kits of study drug assigned via the IWRS (with the 
same treatment assignment that they were randomized to at Visit 2) for BID dosing until 
Visit 6. 
• At Visits 6, the study drug kits and any leftover IP not previously returned to clinic will be 
collected from subjects for drug accountability.  
• Subjects will be instructed not to take their morning dose of run-in or study drug on the 
day of follow-up visits (Visits 2, 3, 4, 5, and 6) prior to the visit. Subjects will be instructed 
to store study drug at home under refrigeration at 2°C-8°C (36-46°F) in the kit box.  
• If needed, replacement kits are also available to be dispensed to a subject. 
8.2 
Other Study Supplies 
Urine pregnancy tests, Schirmer test strips, sodium fluorescein and tropicamide ophthalmic 
solution will be provided by Sponsor.  


 
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9. STUDY METHODS AND PROCEDURES 
9.1 
Subject Entry Procedures 
9.1.1 Overview 
Subjects as defined by the inclusion and exclusion criteria outlined Sections 5.3 and 5.4. 
9.1.2 Informed Consent 
Prior to a subject’s participation in the trial (i.e., prior to changes in a subject’s medical 
treatment and/or prior to study-related procedures), the study will be discussed with each 
subject, and subjects wishing to participate must give written informed consent using an 
informed consent form (ICF). The ICF must be the most recent version that has received 
approval/favorable review by a properly constituted Institutional Review Board (IRB). 
9.1.3 Washout Intervals 
Prohibited medications, treatments, and activities are outlined in Exclusion Criteria Number 8. 
9.1.4 Procedures for Final Study Entry 
Subjects must meet all of the inclusion and none of the exclusion criteria at both Visit 1 and 
Visit 2. No re-screening is permitted. 
9.1.5 Methods for Assignment to Treatment Groups 
Prior to initiation of study run-in (at Visit 1), each subject who qualifies for entry will be 
assigned a screening number. All screening numbers will be assigned in strict numerical 
sequence at a site, and no numbers will be skipped or omitted. If all inclusion and none of the 
exclusion criteria are met at Visits 1 and 2, each qualifying subject will then be assigned a 
randomization number at the end of Visit 2 using an IWRS. 
The randomization number will be recorded on the patient’s source document and eCRF. 
Aurinia, Investigators, and study staff will be masked during the randomization process and 
throughout the study. 
9.2 
Concurrent Therapies 
The use of any concurrent medication, prescription, or OTC is to be recorded on the subject’s 
source document and corresponding eCRF along with the reason the medication was taken. 
Concurrent enrollment in another investigational drug or device study is not permitted. 
9.2.1 Prohibited Medications 
Disallowed medications/treatments during the study are outlined in Exclusion Criteria 8. 
9.2.2 Rescue Medications 


 
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No rescue medications are required for this study. 
9.2.3 Special Diets or Activities 
No special diets or activities are required for this study. 
9.3 
Examination Procedures 
An ICF must be signed and dated by the subject and witness before any study–related 
procedures are performed. Procedures listed below should be performed in the given order. A 
detailed Schedule of Events can be found in Appendix 1: Schedule of Visits and Measurements. 
Procedures listed below can be reviewed in detail in Appendix 2: Examination Procedures, 
Tests, Equipment, and Techniques. 
9.3.1 Visit 1: Day -17 to -14 Screening and Run-In Period 
All subjects will undergo the following screening assessments: 
• Informed Consent/HIPAA: Prior to any changes in a subject’s medical treatment and/or 
invasive procedures, the study will be discussed with each subject and subjects wishing to 
participate must give written informed consent and sign a HIPAA form.  
• Demographic Data and Medical/Medication/Ocular History: Collect and record all 
demographic data, medical history, any medications, and any underlying condition(s). 
Significant non-ocular medical history only within the past year and medications within 
the past 30 days will be captured. Record any medications the subject is taking, as well as 
those the subject may have taken but discontinued within 30 days prior to screening. (Any 
clinically significant findings will be recorded in the Medical Ocular History section of the 
eCRF).  
• Urine Pregnancy Test (for women of childbearing potential): Women of childbearing 
potential must have a negative urine pregnancy test to continue in the study.  
• SANDE 
• VAS 
• BCVA- Subjects must have a score of ≥0.7 logMAR (Snellen equivalent score of ≥20/100 
or better) in each eye at Visit 1. 
• Initial review of Inclusion/Exclusion Criteria 
• Slit-lamp biomicroscopy  
• FCS as assessed by the NEI scale for Grading of Fluorescein Staining 


 
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• STT (performed at least 20 minutes after FCS is performed) 
• Dilated ophthalmoscopy  
• Final review of Inclusion/Exclusion Criteria 
• Dispensation of run-in kit and instructions for BID dosing until Visit 2 
− 
Subjects will be instructed to dose in each eye BID (once in the morning and 
once in the evening) 
− 
Subjects will be instructed to not dose with run-in on the morning of their next 
visit (Visit 2)  
• Subject self-administers the first dose of run-in, OU, under the supervision of a trained 
technician 
• Dosing diary will be provided and subjects will be instructed on how to record date and 
time of dosing 
• Qualified subjects will be scheduled for Visit 2 
9.3.2 Visit 2: Day 1-Baseline  
• Collection and review of returned run-in kit for compliance 
• Subject will be asked if he/she dosed with run-in on the morning of the visit; if the subject 
indicates he/she dosed that morning, he/she should wait at least 4 hours from the time of 
dosing before efficacy assessments are performed 
•  Concomitant medication updates 
• AE query (since last visit) 
• SANDE 
• VAS  
• BCVA 
• Slit-lamp biomicroscopy 
• FCS 
• STT (performed at least 20 minutes after FCS is performed) 


 
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• Review of eligibility criteria 
• Randomization 
• 
Dispensation of study drug kit according to randomization for BID dosing until Visit 3  
− 
Subjects will be instructed to dose in each eye two times daily (once in the 
morning and once in the evening). 
− 
Subjects will be instructed to not dose with study drug on the morning of their 
next visit (Visit 3) 
• Subject self-administers the first dose of run-in, OU, under the supervision of a trained 
technician 
• AE query post-instillation 
• Dosing diary will be provided and subjects will be instructed on how to record date and 
time of dosing 
• Schedule subjects for Visit 3 
9.3.3 Visit 3: Day 14 (±3 days) 
• Collection and review of study drug accountability (including dosing diaries) 
• Subject will be asked if he/she dosed with study drug on the morning of the visit; if the 
subject indicates he/she dosed that morning, he/she should wait at least 4 hours from the 
time of dosing before efficacy assessments are performed 
• Concomitant medication updates 
• AE query (since last visit) 
• SANDE 
• VAS 
• BCVA 
• Slit-lamp biomicroscopy 
• FCS 
• STT (performed at least 20 minutes after FCS is performed) 


 
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• Dispensation of study drug kit according to randomization for BID dosing until Visit 4 
− 
Subjects will be instructed to dose in each eye two times daily (once in the 
morning and once in the evening) 
− 
Subjects will be instructed to not dose with study drug on the morning of their 
next visit (Visit 4) 
• AE query post-instillation 
• Dosing diary will be provided and subjects will be instructed on how to record date and 
time of dosing 
• Schedule subjects for Visit 4 
9.3.4 Visit 4: Day 28 (±3 days) 
• Collection and review of study drug accountability 
• Subject will be asked if he/she dosed with study drug on the morning of the visit; if the 
subject indicates he/she dosed that morning, he/she should wait at least 4 hours from the 
time of dosing before efficacy assessments are performed 
• Concomitant medication updates 
• AE query (since last visit) 
• SANDE 
• VAS 
• BCVA 
• Slit-lamp biomicroscopy 
• FCS 
• STT (performed at least 20 minutes after FCS is performed) 
• Dispensation of two study drug kits according to randomization for BID dosing until Visit 
5 
− 
Subjects will be instructed to dose in each eye BID (once in the morning and 
once in the evening) 


 
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− 
Subjects will be instructed to not dose with study drug on the morning of their 
next visit (Visit 5) 
• AE query post-instillation 
• Dosing diary will be provided and subjects will be instructed on how to record date and 
time of dosing 
• Schedule subjects for Visit 5 
9.3.5 Visit 5: Day 56 (±3 days) 
• Collection and review of study drug accountability 
• Subject will be asked if he/she dosed with study drug on the morning of the visit; if the 
subject indicates he/she dosed that morning, he/she should wait at least 4 hours from the 
time of dosing before efficacy assessments are performed 
• Concomitant medication updates 
• AE (since last visit) 
• SANDE 
• VAS  
• BCVA 
• Slit-lamp biomicroscopy 
• FCS 
• STT (performed at least 20 minutes after FCS is performed) 
• Dispensation of two study drug kits according to randomization for BID dosing until Visit 
6 
− 
Subjects will be instructed to dose in each eye BID (once in the morning and 
once in the evening) 
− 
Subjects will be instructed to not dose with study drug on the morning of their 
next visit (Visit 6) 
• AE query post-dose 


 
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• Dosing diary will be provided and subjects will be instructed on how to record date and 
time of dosing 
• Schedule subjects for Visit 6 
9.3.6 Visit 6: Day 84 (±3 days)/Early Termination Visit 
• Collection and review of study drug accountability 
• Subject will be asked if he/she dosed with study drug on the morning of the visit; if the 
subject indicates he/she dosed that morning, he/she should wait at least 4 hours from the 
time of dosing before efficacy assessments are performed 
• Concomitant medication updates 
• AE query (since last visit) 
• SANDE 
• VAS  
• BCVA 
• Slit-lamp biomicroscopy 
• FCS 
• STT ((performed at least 20 minutes after FCS is performed) 
• Dilated ophthalmoscopy 
• Urine pregnancy test 
• AE query post-assessments 
• Schedule subjects for Visit 7 
9.3.7 Visit 7: Post-Treatment Safety Follow-Up (+7 days from Visit 6, ±3 days) 
• Concomitant medication updates 
• AE query  
• BCVA 
• Study Exit 


 
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9.3.8 Unscheduled Visits 
Unscheduled visits may also be performed in order to ensure subject safety. All procedures 
performed at an unscheduled visit will be recorded in the source documents and on the 
Unscheduled Visit eCRF pages. Any procedure indicated in the eCRF that is not performed 
should be indicated as “Not done.” 
Evaluations that may be conducted at an Unscheduled Visit include: 
• Slit-lamp biomicroscopy 
• BCVA 
• Urine pregnancy test 
• Dilated ophthalmoscopy 
• Assessment of AEs 
• Assessment of concomitant medications and/or treatments 
• Any other assessments needed in the judgment of the Investigator 
9.4 
Compliance with Protocol 
Subjects will be instructed on proper instillation and storage of study drug at the end of Visits 1 
through 5 and given written instructions. The subject’s used and unused study drug ampules 
will be collected at each visit from Visit 2 up to and including Visit 6 to assess dosing 
compliance. Dosing compliance will be based on the unused ampule count. If the subject is 
<80% or >120% compliant with dosing based on the expected number of unused ampules, then 
the subject will be deemed non-compliant and a dosing deviation should be recorded at each 
visit.  
These guidelines will be used by the Investigator for determining the subject’s necessary 
compliance for the study and for recording deviations from this compliance. 
9.5 
Subject Disposition 
9.5.1 Completed Subjects 
A completed subject is one who has not been discontinued from the study. 
9.5.2 Discontinued Subjects 
Subjects may be discontinued prior to their completion of the study due to: 
• AEs 


 
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• unmasking when medically necessary 
• protocol violations 
• administrative reasons (i.e., inability to continue, schedule change) 
• lost to follow-up 
• sponsor termination of study 
• subject choice (i.e., withdrawal of consent) 
• other 
Note: In addition, any subject may be discontinued for any sound medical reason at the 
discretion of the Investigator. 
Notification of a subject discontinuation and the reason for discontinuation will be made to the 
CRO and/or Aurinia and will be clearly documented on the eCRF. Discontinued subjects will 
not be replaced. 
9.6 
Study Termination 
The study may be stopped at any time by the Investigator, Aurinia, and/or the CRO with 
appropriate notification. 
9.7 
Study Duration 
An individual subject’s participation will involve 7 visits over approximately 15 weeks 
(approximately 105 days) from first day of screening phase, the run-in period, treatment phase, 
and follow-up period. 
9.8 
Monitoring and Quality Assurance 
During the course of the study a monitor, or designee, will make routine site visits to review 
protocol compliance, assess study drug accountability, and ensure the study is being conducted 
according to the protocol and pertinent regulatory requirements. The review of the subjects’ 
medical records will be performed in a manner that adequately maintains subject 
confidentiality. Further details of the study monitoring will be outlined in a monitoring plan. 
Regulatory authorities of domestic and foreign agencies, quality assurance and/or their 
designees may carry out on-site inspections and/or audits, which may include source data 
checks. Therefore, direct access to the original source data will be required for inspections 
and/or audits. All inspections and audits will be carried out giving consideration to data 
protection as well as subject confidentiality to the extent that local, state, and federal laws apply. 


 
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10. EVALUATION, RECORDING AND REPORTING OF AES AND 
SAES 
10.1 Definitions 
10.1.1 Adverse Event 
Any untoward medical occurrence in a subject administered a pharmaceutical product and 
which does not necessarily have a causal relationship with this treatment is an AE. 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 related to the medicinal (investigational) product. 
10.1.2 Adverse Drug Reaction 
In the pre-approval clinical experience with a new medical product or its new usages, 
particularly as the therapeutic dose(s) may not be established, all unintended responses to a 
medicinal product related to any dose should be considered adverse drug reactions (ADRs). 
The phrase “responses to a medicinal product” means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility (i.e., the relationship cannot 
be ruled out). 
10.1.3 Unexpected ADR 
An adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g., IB for an unapproved investigational medicinal product).  
10.1.4 Serious Adverse Event (SAE) 
An SAE is an untoward medical occurrence that at any dose meets one or more of the following 
criteria: 
• Results in death (Note: death is an outcome, not an event) 
• Is life-threatening (Note: the term “life-threatening” refers to an event in which the subject 
was at immediate risk of death at the time of the event; it does not refer to an event that 
could hypothetically have caused a death had it been more severe) 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Results in a congenital anomaly/birth defect 
• Is a medically important event or reaction 


 
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The definitions and reporting requirements of International Council for Harmonisation (ICH) 
Guidelines for Clinical Safety Data Management, Definitions, and Standards for Expedited 
Reporting, Topic E2 will be adhered to. 
Medical and scientific judgment must be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes listed in the definition above. These 
will also usually be considered serious. 
Hospitalizations for elective or previously scheduled surgery for pre-existing conditions, 
which have not worsened after initiation of treatment, will not be classed as SAEs. Previously 
scheduled hospitalizations must be documented in the subject’s source documents before the 
subject signed the ICF.  
10.1.5 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
Any ADR that is both serious and unexpected (per the IB) that, based on the opinion of the 
Investigator or Aurinia, is felt to have a reasonable suspected causal relationship to a medicinal 
product is a SUSAR. 
10.1.6 Treatment-Emergent Adverse Event (TEAE) 
Any AE with an onset date between the first dose of randomized study treatment and the last 
study visit (Post-Treatment Safety Follow-Up Visit 7 or last visit attended by the subject). 
10.2 Adverse Event Descriptors 
10.2.1 Intensity/Severity Categorization 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); however, the event itself may be of relatively 
minor medical significance (such as severe headache). This is not the same as “serious,” which 
is based on subject/event outcome or action criteria usually associated with events that pose a 
threat to a subject’s life or functioning. Seriousness (not severity) serves as a guide for defining 
regulatory reporting obligations. 
In general, the intensity of a particular AE to be recorded is the worst intensity experienced by 
the subject during the course of the event. The medical assessment of intensity will be 
determined by using the following definitions: 
• Mild: 
The AE is easily tolerated and does not interfere with usual activity. 
• Moderate: The AE interferes with daily activity, but the subject is still able to function. 


 
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• Severe: 
 The AE is incapacitating, and the subject is unable to work or complete usual 
activity. 
10.2.2 Causal Relationship Categorization 
The Investigator will be required to assess the relationship to study treatment (defined as 
vehicle for run-in period and active drug/vehicle for randomized subjects) for each AE as 
related or not related, in addition to the relationship to disease under study (see Section 10.2.4). 
An AE will not be able to be assessed as related to both disease under study and related to 
study treatment. 
An Investigator who is qualified in medicine must make the determination of relationship to 
the study treatment and disease under study for each AE and SAE. The Investigator must 
decide whether, in his or her medical judgment, there is a reasonable possibility that the event 
may have been caused by the study treatment. If there is no valid reason for suggesting a 
relationship, then the AE/SAE must be classified as not related. Otherwise, if there is any valid 
reason, even if undetermined or untested, for suspecting a cause and effect relationship 
between the study treatment and the occurrence of the AE/SAE, then the AE/SAE will be 
considered related. For SAEs, the Investigator must provide a brief comment explaining the 
rationale of his/her assessment of causal relationship on the SAE reporting form. 
The following additional guidance may be helpful: 
Term 
Relationship 
Definition 
Related 
Yes 
The temporal relationship of the clinical event to study drug administration 
indicates a causal relationship, and other drugs, therapeutic interventions or 
underlying conditions do not provide a sufficient explanation for the observed 
event. 
Not related 
No 
The temporal relationship of the clinical event to study drug administration does 
not indicate a causal relationship, or other drugs, therapeutic interventions or 
underlying conditions provide a sufficient explanation for the observed event. 
 
If the causal relationship between an AE/SAE and the study treatment is determined to be 
“related”, the event will be considered to be related to study treatment for the purposes of 
expedited regulatory reporting. In circumstances where the Investigator has not yet provided 
his/her assessment about the relationship, the event will be considered as “related” and qualify 
for expedited regulatory reporting. 
10.2.3 Outcome Categorization 
Outcome may be classified as recovered without sequelae; recovered with sequelae; improved; 
worsened; ongoing; fatal; or unknown. If the outcome is reported as recovered with sequelae 
for an SAE, the Investigator should specify the kind of sequelae on the paper SAE Reporting 
Form.  


 
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10.2.4 Symptoms of the Disease Under Study 
Symptoms related to DES will not be classified as AEs as long as they are within the normal 
day-to-day fluctuation of the disease. An explanation of these circumstances must be written 
in the source documents. 
Worsening of the symptoms, however, will be recorded as an AE and clearly marked as 
worsening or by the subject’s worst observed intensity.  
10.2.5 Adverse Events of Special Interest including Abuse, Misuse, Overdose and 
Medication Errors 
A clinically significant decrease in visual acuity (defined as an increase of ≥0.22 in logMAR 
score) from baseline (Visit 1) will be considered an AE of special interest and must be 
documented in the AE section of the subject’s eCRF and source documentation. If the AE 
fulfils any seriousness criteria, the event must be reported on a paper SAE Reporting Form and 
documented as serious in the AE section of the subject’s eCRF and source documentation. 
Special situations including treatment abuse, misuse, overdose and medication errors causing 
or with the potential to cause harm should be reported as an AE. An event that fulfills the 
seriousness criteria should be reported as a SAE. 
10.3 Reporting Procedure for AEs, SAEs, and Pregnancy 
10.3.1 Adverse Events 
All AEs, regardless of causality, will be reported from time of signing the ICF until Post-
Treatment Safety Follow-Up Visit 7 and recorded in the subject's source documentation. This 
applies to all AEs regardless of presumed relationship to the study drug.  
For screen failure subjects prior to run-in period, any AEs occurring during the screening 
period will be recorded from the time of signing the ICF in the subject’s source documentation 
only and will not be collected on the eCRF.  
For subjects qualifying for the run-in period all AEs will be recorded in the AE section of the 
subject’s eCRF and source documentation. This applies to all run-in period events between 
Visit 1 and Visit 2 whether the subject is subsequently randomized or not.  
For enrolled/randomized subjects, any AEs occurring following first dose of randomized study 
treatment and up to Post-Treatment Safety Follow-Up Visit 7 will be recorded in the AE 
section of the subject’s eCRF and source documentation. 
If any AE is reported, the date of onset, relationship to study treatment, relationship to disease 
under study, any action taken, date of resolution (or the fact that it is still continuing or has 
become chronic), outcome, and whether the AE is serious or not, will be recorded. Use of 
colloquialisms and abbreviations should be avoided. Only one AE term should be recorded in 


 
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the event field on the AE eCRF. Where possible, the Investigator should report a diagnosis 
rather than signs and symptoms or abnormal laboratory values. However, if a constellation of 
signs and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at 
the time of reporting, each individual event should be recorded on the AE eCRF. If a diagnosis 
is subsequently established, all previously reported AEs based on signs and symptoms should 
be nullified by the Investigator and replaced by one AE report based on the single diagnosis, 
with a starting date that corresponds to the starting date of the first symptom of the eventual 
diagnosis. 
Adverse events leading to discontinuation of study drug must be collected. 
Any AEs with an onset date during the study with follow-up/updated outcomes after the last 
study visit (or last study treatment administration) will be recorded as “ongoing” in the eCRF 
at the time of study completion. Adverse events persisting at the time of study completion will 
be followed by the Investigator through contact with the subject until resolution or stabilization 
has occurred (or the subject is lost to follow-up and cannot be contacted) and recorded in the 
source documentation only. If the subject reports an AE, it is the Investigator’s responsibility 
to acquire sufficient information in order to assess causality. This may require additional 
laboratory testing, physical examinations, telephone contacts, etc. In circumstances where the 
Investigator is unable to contact with the subject, the Investigator must provide a written 
statement to Aurinia confirming that the subject is lost to follow-up. 
In order to avoid bias in eliciting AEs, subjects should be asked a non-leading question, such 
as “How are you feeling?” It is also important to question the subject in a non-leading way 
about changes in their health or concomitant medication usage since their last visit. In addition, 
any symptoms/conditions reported during assessments and deemed to be clinically significant 
by the Investigator will be considered AEs. 
10.3.2 Serious Adverse Events 
For screen failure subjects prior to run-in period, any SAEs occurring during the screening 
period (after informed consent) will be recorded on a paper SAE Reporting Form and in the 
subject’s source documentation only and will not be collected on the eCRF.  
For subjects qualifying for the run-in period, all SAEs will be recorded on the paper SAE 
Reporting Form, in the AE section of the subject’s eCRF and source documentation. This 
applies to all run-in period events whether the subject is subsequently randomized or not.  
For enrolled/randomized subjects, any SAEs occurring following first dose of randomized 
study treatment and up to Post-Treatment Safety Follow-Up Visit 7 will be recorded on the 
paper SAE Reporting Form, in the AE section of the subject’s eCRF and source documentation. 
All SAEs, regardless of causality, will be reported to the Clinical Project Manager and Medical 
Monitor on a paper SAE Reporting Form within 24 hours of the Investigator, designee, or site 
staff’s knowledge of the event. 


 
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Note that data collection within the electronic data capture (EDC) system (Subject eCRF) is 
considered complete at the time of the last study visit according to the protocol schedule of 
assessments. Any SAEs with an onset date during the study with follow-up/updated outcomes 
post the last study visit (or last study treatment administration) will be recorded as “ongoing” 
in the eCRF at the time of study completion. For SAEs, the follow-up/resolution will be 
recorded on a paper SAE Reporting Form, and source documentation. If the Investigator has 
not seen the subject at a clinic visit at the end of the reporting period, the Investigator must 
make reasonable efforts to contact the subject to inquire about SAEs. 
A paper SAE Reporting Form will be available for site staff to complete. The Investigator must 
complete, sign, and date the SAE form and verify the accuracy of the information recorded on 
the form with the corresponding source documents. The required contact information for 
reporting SAEs will be provided in the safety manual: 
• Site Staff will contact the Clinical Project Manager (CPM) at the CRO to notify them of 
an SAE via phone or email as soon as the site becomes aware of the event. 
• Site staff will complete a paper SAE Reporting Form and email to the CPM at the CRO 
and the Medical Monitor within 24 hours.  
• If email is unavailable, site staff will call the CPM at the CRO and Medical Monitor within 
24 hours.  
The Investigator is encouraged to discuss with the study Medical Monitor when the issue of 
seriousness is unclear or questionable. 
In addition to assessing the relationship to study treatment, the Investigator will also be 
required to assess the relationship to the disease under study for each SAE as related or not 
related. An SAE will not be able to be assessed as related to both disease under study and 
related to study treatment.  
All recorded SAEs, regardless of relationship to study treatment or relationship to disease 
under study, will be followed up until resolution, stabilization, or the subject is lost to follow 
up and cannot be contacted. In circumstances where the Investigator is unable to make contact 
with the subject, the Investigator must provide a written statement to Aurinia confirming that 
the subject is lost to follow-up. 
If the subject died, the paper SAE Reporting Form should include the cause of death as the 
event term and whether or not the death was related or unrelated to study treatment or disease 
under study, as well as the autopsy findings, if available. Preliminary reports will be followed 
by detailed descriptions, which will include copies of hospital case reports, autopsy 
reports/certificates, and other documents when requested and applicable. 


 
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Any SAE considered to have a causal relationship (i.e., “related”) to the study treatment and 
discovered by the Investigator at any time after the study will be reported on a paper SAE 
Reporting Form and documented in the safety database only. A rationale for the assessment of 
a causal relationship must be provided by the Investigator.  
Additional follow-up information must be reported to the CRO on a paper SAE Reporting 
Form, and the AE section of the subject’s eCRF updated (until last study visit, see procedures 
described above), within 24 hours of awareness following Investigator (or site) awareness of 
the information. The Investigator should not delay reporting an SAE in order to obtain 
additional information. Additional information, when available, should be reported to the CRO 
by the reporting procedures described above. 
An Investigator who receives an Investigational New Drug (IND) Safety Report describing an 
SAE or other specific safety information (e.g., summary or listing of SAE) from Aurinia will 
file it along with the IB and will notify the IRB/Independent Ethics Committee (IEC) if 
appropriate, according to local requirements. 
Aurinia or its representative will be responsible for determining and, in turn, reporting SAEs 
to Regulatory Authorities according to the applicable regulatory requirements. 
10.3.3 Pregnancy 
All pregnancies will be reported from time of signing the ICF until Post-Treatment Safety 
Follow-Up Visit 7. Pregnancies will be recorded in the subject's source documentation and 
must be reported to the CRO by the reporting procedures described below. 
Pregnancy occurring in a female subject should be reported to the CRO Pharmacovigilance 
within 24 hours of becoming aware of the event using a paper Pregnancy Reporting Form. Site 
staff must also enter the available pregnancy in the AE section of the subject’s eCRF within 
24 hours of becoming aware of the event. 
The Investigator should counsel the subject and discuss the risks of continuing with the 
pregnancy and the possible effects on the fetus. The subject must immediately inform the 
Investigator if she becomes pregnant during the study. Monitoring of the pregnancy in the 
subject should continue until conclusion of the pregnancy.  
Female subjects who have a positive pregnancy test during the study will be withdrawn from 
the study treatment and the procedures for withdrawal will be completed. The Medical Monitor 
must be contacted immediately to break the blind (if applicable). 
The outcome of all such pregnancies (including normal births) should be followed up and 
documented, even if the subject was withdrawn from the study. Every effort should be made 
to gather information regarding the pregnancy outcome until 90 days (or otherwise as 
appropriate) post-partum. It will be the responsibility of Aurinia, together with the appropriate 
support of the Investigator, to obtain this information. 


 
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Complications of pregnancy such as abortion (spontaneous or induced), premature birth, or 
congenital abnormality are considered SAEs and should be reported following the reporting 
procedures as outlined in Section 10.3.2, Serious Adverse Events.  
A paper Pregnancy Reporting Form will be available for site staff to complete. The Investigator 
must complete, sign, and date the SAE form and verify the accuracy of the information 
recorded on the form with the corresponding source documents: 
• Site Staff will contact the Clinical Project Manager (CPM) at the CRO to notify them of a 
Pregnancy via phone or email as soon as the site becomes aware of the event. 
• Site staff will complete a paper Pregnancy Reporting Form and email to the CPM at the 
CRO and the Medical Monitor within 24 hours.  
• If email is unavailable, site staff will call the CPM at the CRO and Medical Monitor within 
24 hours. 
 


 
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11. STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
11.1 Analysis Populations 
The following analysis populations will be considered: 
• Intent-to-Treat Population – The intent-to-treat (ITT) population includes all randomized 
subjects. Subjects in the ITT population will be analyzed as randomized. 
• Per Protocol Population – The per protocol (PP) population includes subjects in the ITT 
population who do not have significant protocol deviations prior to their primary endpoint 
assessment at Week 4 and who complete the Week 4 STT. Protocol deviations will be 
assessed prior to database lock and unmasking. The PP population will be analyzed as 
randomized. 
• Safety Population – The safety population includes all randomized subjects who have 
received at least one dose of randomized study treatment. The safety population will be 
analyzed for all safety assessments. Subjects in the safety population will be analyzed as 
treated.  
• The run-in population will be used to describe all subjects who entered the run-in period. 
Baseline data will be summarized using the safety, ITT, and PP populations. Safety data will 
be summarized using the safety population, and efficacy analysis will use the ITT and PP 
populations. 
11.2 Statistical Hypothesis 
The primary endpoint will be tested under the following hypotheses with statistical 
significance declared for any of the three comparisons versus vehicle where a p-value <0.0166 
is observed: 
H01: There is no difference between the proportion of subjects with a ≥10 mm change 
from baseline in STT to Week 4 in the study eye for those receiving VOS (0.05%, 0.10%, or 
0.20%) versus vehicle. 
H11: There is a difference between the proportion of subjects with a ≥10 mm change 
from baseline in STT to Week 4 in the study eye in for those receiving VOS (0.05%, 0.1%, or 
0.2%) versus vehicle. 
Following a significant result in the primary analysis the three pairwise comparisons for the 
key secondary endpoint will be tested using alpha=0.0166. The hypotheses to be tested are: 
 
H02: In subjects with baseline eye dryness VAS ≥60 mm, there is no difference between 
the mean change from baseline to Week 4 in the Eye Dryness VAS for those receiving VOS 
(0.05%, 0.10%, or 0.20%) versus vehicle. 


 
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H12: In subjects with baseline eye dryness VAS ≥60 mm, there is a difference between 
the mean change from baseline to Week 4 in the eye dryness VAS for those receiving VOS 
(0.05%, 0.10%, or 0.20%) versus vehicle. 
For significance to be declared in the key secondary endpoint analysis, the same treatment 
group should show improvement over vehicle in both the primary analysis and the key 
secondary analysis. 
11.3 Sample Size 
This study is expected to enroll 480 subjects into 4 treatment arms. A two-group continuity 
corrected Chi square test with a 0.0166 two-sided significance level (adjusted for three 
treatment comparisons versus placebo) will have at least 80% power to detect the difference 
between a vehicle response rate of 20% (defined as the percentage of subjects with a ≥10 mm 
increase in STT from baseline) and a VOS response rate of 40% when the sample size in each 
group is 120 (total N=480). Response is defined as an increase of ≥10 mm in STT from baseline 
to Week 4. 
While the effect of withdrawals will be investigated, subjects withdrawing prior to Week 4 
STT assessment for any reason will be counted as non-responders in the primary analysis and 
therefore no adjustment of sample size for withdrawals is necessary. 
This sample size provides greater than 90% power to detect a significant change from baseline 
within any one of the three active treatment groups in the Eye Dryness VAS assuming the 
standard deviation of changes is 40 mm and the mean change from baseline is 20 mm (two-
sided alpha=0.0166). 
The key secondary endpoint is analyzed within the population of subjects with an Eye Dryness 
VAS ≥60 mm at baseline. It is expected that this will reduce the sample size for this analysis 
by 25% (from 120 per group to 90 per group). Assuming a standard deviation of 30 mm for 
change in eye dryness score and an improvement of any active arm compared to placebo 
(alpha=0.0166) of 15 mm, a sample size of 90 subjects per group provides at least 80% power 
to detect a significant difference. 
11.4 Statistical Analysis 
11.4.1 Unit of Analysis 
Safety endpoints will be analyzed for both eyes using study eye and fellow eye (non-study eye) 
if appropriate. For efficacy symptom-related endpoints, the unit of analysis is both eyes. For 
efficacy sign-related endpoints, the unit of analysis will be the study eye as defined by the 
following: 
Study Eye: The study eye will be defined as the eye that achieves the lowest STT score at 
baseline (Visit 2). Should a subject have identical STT scores in both eyes at baseline, the eye 


 
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with the worst FCS score will be used. Should these scores also be equal, the right eye will be 
used. 
11.4.2 Multiplicity Considerations 
To maintain an overall alpha of 0.05, statistical significance of the pairwise treatment 
comparisons will be declared at the 0.05/3=0.0166 level. 
11.4.3 Primary Efficacy Analyses 
Analysis of the primary endpoint, proportion of subjects with ≥10 mm increase from baseline 
in STT at Week 4 in the study eye, will be conducted on the ITT and PP populations. The 
response rate for each VOS group compared to vehicle will be determined using a logistic 
regression model including terms for Investigator site, treatment group, and baseline STT. 
Results of this logistic regression will be displayed as odds ratios and two-sided adjusted 95% 
confidence intervals (CIs) (VOS compared to vehicle). The proportion of subjects exhibiting a 
response at Week 4 will be summarized by treatment group. 
Subjects providing insufficient data to determine response at Week 4 (e.g. early withdrawal) 
will be analysed as non-responders. 
An additional sensitivity analysis will analyse observed responses only. 
11.4.4 Key Secondary Endpoint Analysis 
The key secondary endpoint of mean change from baseline in Eye Dryness VAS in the subset 
of subjects with baseline Eye Dryness VAS ≥60 mm will be analysed using the ITT and the 
PP populations. Mean change, along with an adjusted 95% CI and p-value, will be provided 
from a General Linear Model including terms for Investigator site, treatment group and 
baseline Eye Dryness VAS. 
Subjects not providing an Eye Dryness VAS at week 4 will not contribute to this analysis. 
11.4.5 Secondary Efficacy Analyses 
STT response at Weeks 2, 8 and 12 will be analysed in a similar fashion to the primary endpoint 
using the ITT population only. 
Other secondary efficacy endpoints are measured as continuous data and will be summarized 
by visit using observed scores and change from baseline using the ITT population. Mean 
changes along with 95% CIs and p-values will be provided both within treatment group and 
for all pairwise comparisons to vehicle. 
Mixed Effect Model Repeated Measures (MMRM) will also be used to analyze all available 
data for each endpoint. The MMRM model will include terms for Investigator site, treatment, 
visit, treatment by visit interaction and applicable baseline measure. Overall and by-visit 


 
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results will be expressed as differences between treatment arms (VOS–vehicle) along with 
associated 95% CIs and p-values. 
11.4.6 Safety Variables 
Adverse events will be coded using the MedDRA dictionary. Frequencies and percentages of 
subjects with TEAEs, serious TEAEs, and TEAEs causing premature discontinuation will be 
provided by treatment group. An AE is treatment emergent if it occurs after the first dose of 
randomized study treatment and up to last study visit. Furthermore, frequencies will be given 
of subjects with TEAEs by system organ class and preferred term; by system organ class, 
preferred term and maximal severity; by system organ class, preferred term for treatment-
related AEs; by system organ class and preferred term for SAEs; and by system organ class, 
preferred term, and day of onset. Separate analyses will be performed for ocular specific and 
all AEs (including systemic). 
Other safety endpoints including visual acuity, slit lamp biomicroscopy, dilated 
ophthalmoscopy (fundoscopy), will be summarized by treatment group and visit using 
descriptive statistics. Changes or shifts from baseline will also be summarized where 
appropriate. Mean changes from baseline along with 95% CIs for changes and pairwise 
comparisons to vehicle will be calculated for visual acuity. For assessments performed by eye, 
study eye and fellow eye will be summarized separately. In addition, shifts from baseline to 
worst on-treatment value for ocular safety assessments will be summarized. 
11.4.7 Interim Analyses 
No interim analyses are planned for this study 


 
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12. COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES 
This study will be conducted in compliance with the protocol, current GCPs, including the ICH 
Guidelines, and in general, consistent with the Declaration of Helsinki. In addition, all 
applicable local, state, and federal requirements relevant to the use of IPs in the United States 
will be adhered to. 
12.1 Protection of Human Subjects 
12.1.1 Subject Informed Consent 
Informed consent must take place before any study-specific procedures are initiated. Signed 
and dated written informed consent must be obtained from each subject.  
All informed consent/assent forms must be approved for use by Aurinia and receive 
approval/favorable opinion from an IRB prior to their use. If the consent form requires revision 
(i.e., due to a protocol amendment or significant new safety information), it is the Investigator’s 
responsibility to ensure that the amended informed consent is reviewed and approved by the 
CRO prior to submission to the governing IRB and that it is read, signed, and dated by all 
subjects subsequently enrolled in the study as well as those currently enrolled in the study. 
12.1.2 Institutional Review Board Approval 
This study is to be conducted in accordance with IRB regulations (U.S. 21 Code of Federal 
Regulations [CFR] Part 56.103). The Investigator must obtain appropriate IRB approval before 
initiating the study and re-approval at least annually. 
Only an IRB/ERC approved version of the ICF will be used. 
12.2 Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles that originated with the 
Declaration of Helsinki. 
12.3 Subject Confidentiality 
All personal study subject data collected and processed for the purposes of this study should 
be maintained by the Investigator and his/her staff with adequate precautions as to ensure that 
the confidentiality of the data in accordance with local, state, and federal laws and regulations. 
Monitors, auditors and other authorized representatives of the CRO, Aurinia, the IRB/IEC 
approving this study, the FDA, the Department of Health and Human Services, other domestic 
government agencies, and other foreign regulatory agencies will be granted direct access to the 
study subject’s original medical and study records for verification of the data and/or clinical 
trial procedures. Access to this information will be permitted to the aforementioned individuals 
to the extent permitted by law. 


 
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A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the IP may ultimately be marketed, but the subject’s identity 
will not be disclosed in these documents. 
12.4 Documentation 
Source documents may include a subject’s medical records, hospital charts, clinic charts, the 
Investigator’s study subject files, as well as the results of diagnostic tests such as X-rays, 
laboratory tests, and electrocardiograms. The Investigator’s copy of the eCRFs serves as the 
Investigator’s record of a subject’s study-related data. 
12.4.1 Retention of Documentation 
All study related correspondence, subject records, ICFs, records of the distribution and use of 
all IPs, and copies of eCRFs should be maintained on file for 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 until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the IP. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with Aurinia. It is the responsibility of Aurinia to inform the Investigator/institution 
as to when these documents no longer need to be retained. 
If the responsible Investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping study records, custody must be transferred to a person who will accept 
the responsibility. Aurinia must be notified in writing of the name and address of the new 
custodian. 
12.5 Labelling, Packaging, Storage, Accountability, and Return or Disposal 
of Investigational Product 
12.5.1 Labelling/Packaging 
All study treatments provided by Aurinia will be packaged and labeled for Aurinia by 
appropriately qualified vendors according to all applicable local and country regulatory 
requirements. All packaging and labeling operations will be performed according to GMP and 
GCP. 
Run-in and investigational drug will be packaged and labeled into clinical kits. 
 
  
 
 
 


 
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12.5.2 Storage of Investigational Product 
The study drugs must be stored in a secure area accessible only to the Investigator and his/her 
designees. Study drug(s) must be refrigerated (2-8°C (36-46 °F) – do not freeze), protected 
from light, and secured at the investigational site in a locked container.  
Each site should have a thermometer in each storage location that records minimum and 
maximum temperatures daily. Maintenance of a temperature log is mandatory. The log should 
be updated by site personnel during normal working hours. This log must be available for 
review by the Site Monitor during on-site monitoring visits. 
12.5.3 Accountability of Investigational Product 
The Investigator at each site is responsible for IP supplies. The Investigator will ensure that 
adequate records of the receipt, dispensing, and return of the IP are kept and that the IP is used 
only for subjects enrolled in the study. All data regarding the IP must be recorded on the 
relevant forms provided. 
Each study site will maintain a drug inventory/dispensing record for all IP dispensed and 
returned. At the end of the study, one copy of the drug inventory/dispensing record should be 
sent to Aurinia or their designee for the central study file. The original will be kept in the site 
files. 
12.5.4 Return or Disposal of Investigational Product 
After completion of the study, or if it is prematurely terminated, all IP will be returned to 
Aurinia or their designee. The return or disposal of IP will be specified in writing. 
12.6 Aurinia Recording of Data on Source Documents and Case Reports 
Forms (CRFs) 
All subject data will be captured in the subject source documents, which will be transcribed in 
the eCRFs. The Investigator is responsible for ensuring that study data are completely and 
accurately recorded on each subject’s eCRF, source documents, and all study-related materials. 
All study data should also be attributable, legible, contemporaneous, original, accurate, and 
complete. Recorded datum should only be corrected in a manner that does not obliterate, 
destroy, or render illegible the previous entry (i.e., by drawing a single line through the 
incorrect entry and writing the revision next to the corrected data). An individual who has 
corrected a data entry should make clear who made the correction and when, by adding to the 
correction his/her initials as well as the date of the correction.  
Data entry of all enrolled and randomized subjects will use software that conforms to 21 CFR 
Part 11 requirements, and will be performed only by staff who have been trained on the system 
and have access to the system. Data will not be entered for Visit 1 screen failures with the 
exception of demographics and reason for screen failure. An audit trail will be maintained 
within the electronic system to capture all changes made within the eCRF database. After the 


 
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end of the study and database lock, compact discs containing copies of all applicable subjects’ 
eCRFs will be provided to each Investigator Site to be maintained on file by the Investigator. 
12.7 Handling of Biological Specimens 
N/A. 
12.8 Publications 
Authorship and manuscript composition will reflect cooperation among all parties involved in 
the study. Authorship will be established before writing the manuscript. The CRO and Aurinia 
will have the final decision regarding the manuscript and publication. 
 
 


 
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13. REFERENCES  
AUR-VOS-2017-01 (2019). "Clinical Study Report. An investigator-masked, randomized, 
parallel-group study of the ocular tolerability of voclosporin ophthalmic solution versus 
Restasis® in subjects with dry eye disease. Final report. Aurinia Pharmaceuticals Inc.  
." 
Boboridis, K. G. and A. G. P. Konstas (2018). "Evaluating the novel application of 
cyclosporine 0.1% in ocular surface disease." Expert Opin Pharmacother 19(9): 1027-1039. 
CEQUA® (2018). "Sun Pharma Global FZE " "US Prescribing Information". 
Craig, J. P., K. K. Nichols, E. K. Akpek, B. Caffery, H. S. Dua, C. K. Joo, Z. Liu, J. D. Nelson, 
J. J. Nichols, K. Tsubota and F. Stapleton (2017). "TFOS DEWS II Definition and 
Classification Report." Ocul Surf 15(3): 276-283. 
Dana, R., J. L. Bradley, A. Guerin, I. Pivneva, I. O. Stillman, A. M. Evans and D. A. 
Schaumberg (2019). "Estimated Prevalence and Incidence of Dry Eye Disease Based on 
Coding Analysis of a Large, All-age United States Health Care System." Am J Ophthalmol 
202: 47-54. 
Granelli-Piperno, A. A., L. Steinman, RM. (1986). "Lymphokine and nonlympholine mRNA 
levels in stimulated human cells: kinetics, mitogen requirements, and effects of cyclosporin 
A." J Exp Med. 27: 163-922. 
LX214-01 (2009). "Clinical Study Report. A phase 1 dose-escalation study to assess the safety 
and tolerability of LX214 ophthalmic solution in healthy volunteers, followed by an open-label 
evaluation of LX214 ophthalmic solution in subjects with keratoconjunctivitis sicca. Lux 
Biosciences, Inc.;  Report No.: LX214-01. 
." 
Restasis® (2017). "Allergan, Irvine USA. 2017 Jul." "US prescribing information". 
S07654 (2009). "14-Day ocular toxicity of LX214 in New Zealand white rabbits with 14-Day 
recovery period." Lux Biosciences, Inc. Report No.: S07654(Apr 3). 
S07655 (2009). "14-Day ocular tolerability and toxicity of LX214 inbeagle dogs with a 14-day 
recovery period." Lux Biosciences, Inc. Report No.: S07655(Apr 8). 
S08661 (2009). "Ocular tissue distribution of 14C-LX214 following a single or multiple 
ophthalmic administration to New Zealand White Rabbit." Lux Biosciences, Inc. Report No.: 
S08661(Mar 23). 
S08662 (2009). "Ocular Tissue Distribution of 14C-LX214 Following a Single Ophthalmic 
Administration to Dutch Belted Rabbits." Sinclair Research Center, Inc. 


 
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S15389-00 (2017). "To evaluate the efficacy of Voclosporin Ophthalmic Solution (0.2% 
voclosporin) in naturally occurring keratoconjunctivitis sicca in client owned dogs with twice-
daily administration." Intervert, Inc(d/b/a Merck Animal Health) Report No.: S15389-00(Apr 
28). 
Stepkowski, S. M. (2000). "Molecular targets for existing and novel immunosuppressive 
drugs." Expert Rev Mol Med 2(4): 1-23. 
VOS-Investigator's-Brochure (2019). "Voclosporin Ophthalmic Solution Invesigator's 
Brochure." Version 2.0. 
Wiseman, A. C. (2016). "Immunosuppressive Medications." Clin J Am Soc Nephrol 11(2): 
332-343. 


 
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14. APPENDICES 
Appendix 1: Schedule of Visits and Measurements 
AUR-VOS-2019-01 SCHEDULE OF EVENTS 
Visit 
Visit 1 
Screening 
Visit 2 
Baseline 
Visit 3 
Visit 4 
Visit 5 
Visit 6/ ETV 
Visit 7 
Day/Week 
Day -17 to -14 
Day 1 
Day 14/ 
Week 2 
(±3 days) 
Day 28/ 
Week 4 
(±3 days) 
Day 56/ 
Week 8 
(±3 days) 
Day 84/ 
Week 12 
(±3 days) 
Post- 
Treatment 
Safety FU 
(+7 days from 
Visit 6 (±3 
days)) 
Informed consent 
 
 
 
 
 
 
 
Eligibility criteria 
 
(1) 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
Ocular and non-ocular Medical 
history (including Ocular 
Surgical History, Ocular and 
Non-Ocular Concomitant 
Medications)  
 
 
 
 
 
 
 
Demography  
 
 
 
 
 
 
 
Concomitant medication updates 
 
 
 
 
 
 
 
AE Query(2) 
 
 
 
 
 
 
 
SANDE(3) 
 
 
 
 
 
 
 
Visual Analog Scale 
(VAS)(3) 
 
 
 
 
 
 
 
BCVA(4) 
 
 
 
 
 
 
 
FCS(5) 
 
 
 
 
 
 
 
STT(5) 
 
 
 
 
 
 
 
Slit-Lamp Biomicroscopy 
 
 
 
 
 
 
 


 
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Visit 
Visit 1 
Screening 
Visit 2 
Baseline 
Visit 3 
Visit 4 
Visit 5 
Visit 6/ ETV 
Visit 7 
Day/Week 
Day -17 to -14 
Day 1 
Day 14/ 
Week 2 
(±3 days) 
Day 28/ 
Week 4 
(±3 days) 
Day 56/ 
Week 8 
(±3 days) 
Day 84/ 
Week 12 
(±3 days) 
Post- 
Treatment 
Safety FU 
(+7 days from 
Visit 6 (±3 
days)) 
Dilated Ophthalmoscopy 
(Fundoscopy) 
 
 
 
 
 
 
 
Run-In dispensation 
 
 
 
 
 
 
 
Study Treatment Dispensation(6) 
 
 
 
 
 
 
 
Dosing Diary and Instruction 
provided 
 
 
 
 
 
 
 
Study Treatment Accountability(7) 
 
 
 
 
 
 
 
Urine pregnancy test(8) 
 
 
 
 
 
 
 
Schedule Next Visit 
 
 
 
 
 
 
 
Study Exit 
 
 
 
 
 
 
 
1 Eligibility criteria will be re-checked after subjects have completed the run-in period.  
2 Adverse event query will be conducted at pre-examination and post-instillation at Visit 2. 3, 4, 5, and 6. 
3  Symptom assessments VAS/SANDE should be performed first prior to or any invasive procedure. SANDE will be performed prior to the Individual Symptom Severity Assessments VAS. 
Symptom Assessment VAS includes Ocular Discomfort, Eye Dryness, Burning/Stinging, Photophobia, Foreign Body Sensation, Eye Pain, Itching and Blurred Vision. 
4  BCVA should be performed prior to any dyes. 
5  STT should be performed at least 20 minutes after FCS is performed. 
6  Study treatment instillations on the date of the visits will be performed after all study procedures have taken place. A new refrigerated IP pack will be administered to subjects at each visit with 
the appropriate number of ampules. 
7  Accountability will be assessed by counting the number of used and unused ampules returned at each visit, beginning at Visit 2. 
8  Urine pregnancy test for women of childbearing potential only. 
Notes: 
AE = Adverse event; BCVA = Best Corrected Visual Acuity; ETV = Early Termination Visit; FCS = Fluorescein Corneal Staining; FU = Follow up; 
SANDE = Symptom Assessment and Dry Eye; STT = Schirmer Tear Test; VAS = Visual Analog Scale. 


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


 
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LogMAR Visual Acuity Calculations 
The last line in which a letter is read correctly will be taken as the base logMAR reading. To 
this value will be added the number "N x 0.02" where 'N' represents the total number of letters 
missed up to and included in the last line read. This total sum represents the logMAR VA for 
that eye. 
For Example: Subject correctly reads 4 of 5 letters on the 0.2 line, and 2 of 5 letters on the 0.1 
line. 
Base logMAR 
= 0.1 
N (total number of letters incorrect on line 0.2 as well as 0.1) 
= 4 
N x T (T=0.02) 
= 0.08 
Base logMAR + (N x T) 
= 0.1 + 0.08 
logMAR VA 
= 0.18 
Repeat the procedure for the left eye. 
In order to provide standardized and well-controlled assessments of VA during the study, all 
VA assessments at a single site must be consistently done using the same lighting conditions 
and same correction if possible during the entire study. If the same correction cannot be used 
(ie, a subject forgets his glasses), the reason for the change in correction should be documented. 
Best Corrected Visual Acuity (BCVA) 
To provide standardized and well-controlled assessments of visual acuity during the study, 
consistently use the same lighting conditions during the entire study. 
Calculations : logMAR VA = Baseline value + (n x 0.02) 
where: the baseline value is the logMAR number of the last line read (at least 1 letter read 
correctly in this line), and 
“n” is the total number of letters missed up to and including the last line read, and  
“0.02” is the value for each letter 
Slit Lamp Biomicroscopy Procedures 
Slit lamp biomicroscopic observations will be graded as Normal or Abnormal. Abnormal 
findings will be categorized as clinically significant (findings that may interfere with study 
parameters or otherwise confound the data as determined by the Investigator) or not clinically 
significant (NCS). The following will be examined:  


 
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• Cornea  
• Conjunctiva 
• Anterior Chamber 
• Iris 
• Lens 
• Eyelid 
External magnification and biomicroscopy will be performed using a slit-lamp. Magnification 
will be consistent with standard clinical practice. The subject will be seated. 
Dilated Ophthalmoscopy (Fundoscopy) 
Dilated fundoscopy will be performed using indirect ophthalmoscopy. The Investigator will 
make observations of the vitreous, retina, macula, choroid and optic nerve. 
Observations will be graded as Normal or Abnormal. Abnormal findings that are clinically 
significant (as determined by the Investigator that may interfere with study parameters or 
otherwise confound the data) and those that are not clinically significant will be described. A 
dilated fundoscopy examination should be performed if retinal disease is detected.  
• Vitreous: Examination should emphasize the visual axis.  
• Retina, Macula, Choroid: Include an observation of the retina and its blood vessels. Eyes 
should be excluded from the study if active inflammation is present.  
• Optic Nerve: Significant damage or cupping to the optic nerve should be noted. 
It is recommended that tropicamide 1% ophthalmic solution be used to dilate subjects. The use 
of cyclopentolate 1% ophthalmic solution is recommended as secondary dilating medication, 
should the need arise. 
Visual Analogue Scale (VAS) 
Subjects will be asked the following questions regarding ocular discomfort (unrelated to study 
drug instillation) at all visits.  
The subject will be asked to rate each ocular symptom due to dry eye syndrome by placing a 
vertical mark on the horizontal line to indicate the current level of discomfort. 0% corresponds 
to “no discomfort” and 100% corresponds to “maximal discomfort.” The linear dimension of 
the scale is measured in millimeters. This assessment is a general assessment of both eyes. 
There will not be a question for each individual eye. This assessment should be performed 


 
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following SANDE, and prior to assessing for AEs and prior to any other invasive visit 
assessment. 
Subject Instructions: Please review the symptoms below. After your review, please rate how 
your eyes feel for each of the following symptoms by placing a vertical mark that represents 
how your symptom feels at this moment.  
Burning/ Stinging 
0%                                                                                              100% 
 
 
 
Itching 
0%                                                                                              100% 
 
 
 
Foreign Body Sensation 
0%                                                                                              100% 
 
 
 
Blurred Vision 
0%                                                                                              100% 
 
 
 
Eye Dryness 
0%                                                                                              100% 
 
 
 
Photophobia 
0%                                                                                              100% 
 
 
 
Pain 
0%                                                                                              100% 
 
 
 
Ocular Discomfort 
0%                                                                                              100% 
 
 
 
 
 


 
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Fluorescein Corneal Staining (FCS) National Eye Institute/Industry Workshop Scale 
 
Diagram of the division of the corneal surface for FCS total score. A standardized grading 
System of 0-3 is used for each of the five areas on each cornea. The maximum score is 15. 
Grade 0 will be specified when no staining is present. 
Unanesthetized Schirmer’s Test 
Schirmer Tear Test will be performed according to the following procedure: 
• Using a sterile Tear Flo Schirmer test strip (Rose Enterprises), a bend in the strip will be 
made in line with the notch in the strip 
• The subject will be instructed to gaze up and in 
• The Schirmer test strip will be placed in the lower temporal lid margin of each eye such 
that the strip fits tightly. Subjects will be instructed to close their eyes 
• After 5 minutes have elapsed, the Schirmer strip will be removed. The length of the 
moistened area will be recorded (mm) for each eye 
 
 


 
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Symptom Assessment in Dry Eye (SANDE) 
 
 
 
 
 


 
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Appendix 3: Daily Dosing Diary