Conditions: Dry Eye
Keywords: Dry Eye Calcineurin Inhibitors
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 100
Healthy volunteers: no

Brief summary:
Evaluate the tolerability, efficacy and safety of VOS versus Restasis® in subjects with mild to moderate Dry Eye Disease (DED).

Detailed description:
This is a Phase 2, multi-center, Investigator-masked, randomized, parallel-group study to evaluate the tolerability, efficacy and safety of VOS versus Restasis® over a 28-day treatment period in subjects with mild to moderate DED. Approximately 90 subjects will be randomized to either VOS or Restasis® at approximately 7 centers located in the US

Arms:
arm 1: 0.2% VOS, Twice Daily (BID), both eyes for 28 days arm 2: 0.05% cyclosporine ophthalmic emulsion (Restasis®) BID, both eyes for 28 days

Interventions: intervention 1: Voclosporin Ophthalmic Solution intervention 2: Restasis®
Intervention descriptions: intervention 1: Investigational Drug intervention 2: Comparator

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. 
 
 
 
An Investigator-Masked, Randomized, Parallel-Group Study of 
the Ocular Tolerability of Voclosporin Ophthalmic Solution 
versus Restasis® in Subjects with Dry Eye Disease 
 
Clinical Protocol Number: 
AUR-VOS-2017-01 
 
 
Date: 
02 July 2018 
 
 
Version Number: 
3.0 
 
 
IND Number: 
102,279 
 
 
 
 
 


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NAMES AND ADDRESSES 
Sponsor 
Name: 
Aurinia Pharmaceuticals Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Tel: 
 
 
Fax: 
24 Hour: 
 
 
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: 
 
 


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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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INVESTIGATOR AGREEMENT FORM 
I have read the attached protocol titled: An Investigator-Masked, Randomized, Parallel-Group 
Study of the Ocular Tolerability of Voclosporin Ophthalmic Solution versus Restasis® in 
Subjects with Dry Eye Disease. 
Version Number 3.0/02 July 2018 
I agree to comply with the current International Conference of 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 (e.g., DD Month Year) 
 


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SYNOPSIS 
Title: 
An Investigator-Masked, Randomized, Parallel-Group Study of the Ocular 
Tolerability of Voclosporin Ophthalmic Solution versus Restasis® in Subjects with 
Dry Eye Disease 
Study Product: 
Voclosporin ophthalmic solution (VOS) 
Indication: 
Dry Eye Disease (DED) 
Phase: 
2 
Sponsor: 
Aurinia Pharmaceuticals Inc. 
Study Code: 
AUR-VOS-2017-01 
Objectives: 
Primary Objective 
To assess the ocular tolerability of VOS compared to cyclosporine ophthalmic 
emulsion (Restasis®) in subjects with DED.   
Secondary Objective 
To assess the safety and efficacy of VOS in subjects with DED. 
Design: 
This is a Phase 2, multi-center, Investigator-masked, randomized, parallel-group 
study to evaluate the tolerability, efficacy and safety of VOS versus Restasis® over 
a 28-day treatment period in subjects with mild to moderate DED. Approximately 
90 subjects will be randomized to either VOS or Restasis® at approximately 
7 centers located in the US.   
Treatment: 
Investigational product (IP): 0.2% VOS, twice daily (BID), both eyes (OU) for 
28 days. 
Comparator: 0.05% cyclosporine ophthalmic emulsion (Restasis®) BID, OU for 
28 days.  
The Investigator assessing the ocular signs and subjects will be masked to study 
treatment.   
Inclusion 
Criteria: 
At Visit 1 and Visit 2 (as specified in the Schedule of Events), subjects may be 
eligible for participation if they:  
1. Provide written informed consent before any study-specific procedures are 
performed. 
2. Are male or female subjects with a minimum age of 18 years (or legal age of 
consent if >18 years), at the time of screening (Visit 1). 
3. Are willing and able to follow instructions and can be present for the required 
study visits for the duration of the study. 
4. 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.  


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5. Have a documented history of DED in both eyes supported by a previous 
clinical diagnosis at Visit 1. 
6. Have ongoing DED, as defined by at least one eye (if one eye, the same eye) 
meeting all the following criteria:  
− 
A symptom severity score of ≥30 for Eye Dryness on the Individual 
Symptom Severity Assessment Visual Analog Scale (VAS) (0-100) 
at Visit 2 
− 
An unanesthetized Schirmer Tear Test (STT) score of ≥1 mm and 
≤10 mm per 5 minutes (Note: STT Score obtained at Visit 1) 
− 
Evidence of ocular surface staining (total fluorescein staining score 
of at least 3 [0-15 scale]) at Visit 2. 
7. Have normal lid anatomy at Visit 1. 
Exclusion 
Criteria: 
In order for subjects to be eligible, at Visit 1 and Visit 2 (as specified in the 
Schedule of Events) subjects must not: 
1. Be unable or unwilling to give written informed consent and/or to comply with 
study procedures. 
2. Have any known hypersensitivity or contraindication to study treatments 
(including excipients), topical anesthetics or vital dyes. 
3. Be unable to demonstrate correct instillation of over-the-counter (OTC) ocular 
lubricant during Visit 1. 
4. Report discomfort in both eyes from instillation of OTC ocular lubricant 
during Visit 2 (based on score of ≥30 on the Drop Discomfort VAS).  
5. Have used Restasis® (cyclosporine ophthalmic emulsion) within 30 days prior 
to Visit 1. 
6. Have used Restasis® for more than 1 month (if prior use is reported). 
7. Have used Xiidra® (lifitegrast ophthalmic solution) within 14 days prior to 
Visit 1. 
8. Have had corneal graft surgery in either eye within 1 year of Visit 1.  
9. Have recent or current evidence of ocular infection or inflammation in either 
eye. 
10. Have current evidence of clinically significant blepharitis (defined as requiring 
lid hygiene therapy), conjunctivitis, or a history of herpes simplex or zoster 
keratitis in either eye. 


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11. Have clinically significant ocular disease in either eye (e.g., corneal edema, 
uveitis, severe keratoconjunctivitis sicca) which might interfere with study 
procedures or assessments. 
12. Have any abnormality in either eye preventing reliable applanation tonometry. 
13. Be taking or have known need for any of the known treatment therapies listed 
in Section 7.7 at Visit 1 or during the study. This includes prohibited 
medications prior to Visit 1 as specified in Section 7.7. 
14. Have any known hypersensitivity or contraindication to calcineurin inhibitors. 
15. Have clinically significant systemic disease (e.g., uncontrolled diabetes, 
hepatic, renal, endocrine or cardiovascular disorders) which might interfere 
with the study. 
16. Have participated in any investigational clinical study within 30 days prior to 
Visit 1. 
17. Have altered any systemic medication that could have an effect on dry eye 
signs or symptoms within 30 days prior to Visit 1 or anticipated during the 
study.  
18. Be women of childbearing potential who are pregnant, nursing, planning a 
pregnancy, or not using a medically acceptable form of birth control.  
Primary 
Endpoint: 
Change 
from 
baseline 
in 
Drop 
Discomfort 
VAS 
score 
1-minute  
post-Dose 1 instillation.  
Secondary 
Endpoints: 
Key Secondary Endpoints: 
• 
Change from baseline in Drop Discomfort VAS score  
• 
Change from baseline in each of the 6 Individual Symptom Severity 
Assessments (VAS) scores 
• 
Change from baseline in the sum of the Individual Symptom Severity 
Assessments score (VAS Total Symptom Summary Score)  
• 
Change from baseline in Symptom Assessment in Dry Eye (SANDE) 
score  
• 
Change from baseline in unanesthetized STT score  
• 
Change from baseline in Fluorescein Corneal Staining (FCS) total 
score (National Eye Institute (NEI)/Industry Workshop 0-15 scale)   
Safety Endpoints: 
• 
Treatment-emergent adverse events (TEAEs) 
• 
Change from baseline in BCVA  


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• 
Changes from baseline in Slit-Lamp Biomicroscopy  
• 
Changes from screening in Dilated Ophthalmoscopy 
Procedures: 
At Visit 1 (screening) informed consent will be obtained from subjects and 
eligibility will be determined. A STT will be performed at this visit. The score will 
be used as the baseline and eligibility. During this visit, all subjects will self-
administer an OTC ocular lubricant, Refresh Plus®, OU to assess ability to self-
administer study product. At Visit 2 (Randomization) continued eligibility will be 
confirmed. During this visit, all subjects will self-administer an OTC ocular 
lubricant, Refresh Plus®, OU to evaluate ability to tolerate ocular drops. 
Individuals who are unable to successfully instill the drops or who rate OTC ocular 
lubricant as uncomfortable, based on a post-instillation Drop Discomfort VAS 
score, will not be eligible for participation in the study. (Note:  For subjects meeting 
the Screening and Randomization Criteria, the Visit 2 Drop Discomfort VAS score 
will be used as the baseline value.)   
Eligible subjects will be randomly assigned in a 1:1 ratio to one of the two treatment 
groups: VOS BID or Restasis® BID. The first instillation of IP will be administered, 
at least 2-hours following administration of Refresh Plus® and by clinic personnel 
to both eyes during Visit 2. Investigational Product will be administered to the 
subject by an unmasked dedicated dosing coordinator (the subject and the 
Investigator will be masked to study treatment for the first post-randomization 
instillation). Tolerability, safety and efficacy assessments will be performed at this 
visit. 
At Treatment Visits 3 and 4, tolerability, safety and efficacy evaluations will be 
performed. At the End of Treatment, Visit 5, tolerability, safety and efficacy 
evaluations will be performed. Subjects who discontinue before Visit 5 will 
undergo all Visit 5 evaluations (Early Termination). IP will be administered to the 
subject by an unmasked dedicated dosing coordinator at the clinic visits (single-
masked: the Investigator and study staff will remain masked to study treatment). A 
Drop Discomfort VAS will be administered in the clinic at 1-minute and 5-minutes 
following instillation of IP at Visits 2 through 5 (Investigator is to remain masked). 
With the exception of clinic day visits, subjects will self-administer IP twice a day 
OU over the 4-week treatment period. On the evening of Visits 2 through 4 and in 
the evening prior to Visit 5, the study coordinator will contact the subject by phone 
to prompt administration of IP followed by completion of the dosing diary and the 
Drop Discomfort VAS (1-minute and 5-minutes post-instillation).  
At Visit 6, there will be a 3-day post-treatment Follow-Up, in which safety 
assessments are performed and all remaining study materials are collected. The 
subjects will be instructed to continue to withhold all other concomitant topical 
medications as outlined by the protocol for the duration of their participation 
(through Visit 6). 
Serious adverse events (SAEs) ongoing as of Visit 6 will be followed until they 
have resolved, stabilized in the opinion of the Investigator, or returned to baseline. 
This study will be conducted per the schedule shown in the Schedule of Events 
(Table 1) and the Study Schematic (Figure 1). 
Sample Size: 
The study will include approximately 90 male or female subjects. 


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The primary analysis will use a t-test and will assess the difference in change from 
baseline in Drop Discomfort VAS scores (range 0 to 100 mm) 1-minute  
post-Dose 1 instillation between the two treatment groups.   
A sample size of 38 subjects per group (76 in total) will provide 90% power 
assuming: 
• 
A mean change from baseline Drop Discomfort VAS score of +30 mm for 
subjects randomized to Restasis® 
• 
A mean change from baseline Drop Discomfort VAS score of +15 mm for 
those randomized to VOS 
• 
These assumed mean changes lead to a 15 mm lower change from baseline 
in VAS scores for VOS compared to Restasis® 
• 
A common standard deviation of 20 mm 
• 
A 2-sided alpha of 5% 
Under the same assumptions, the study will have at least 80% power if the common 
standard deviation for the discomfort score were to be 23 mm. 
The study also provides 80% power should the treatment difference in discomfort 
scores be 13 (common standard deviation=20 mm). 
To allow for 15% dropouts, approximately 90 subjects will be randomized. 
Statistical 
Methods: 
The primary endpoint is measured on a VAS and will be summarized and analysed 
as continuous data. Summaries of VAS scores (absolute and change from baseline) 
by treatment group will be displayed for each VAS assessment (minutes 1, 5 and 
overall mean) at each visit. Should the data meet the necessary assumptions 
(normality and equal variance in both treatment groups) then the treatment groups 
will be compared using a t-test. If assumptions are violated, the Wilcoxon rank sum 
test will be used. 




 
 
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Table 1: AUR-VOS-2017-01 Schedule of Events 
 
Visit 
Visit 1 
Screening 
Visit 2 
Pre-
Randomization 
Visit 2 
Randomization 
Visit 3 
Treatment 
Visit 4 
Treatment 
Visit 5 
End of 
Treatment/ 
Early Term1 
Visit 6 
Follow-up2 
Day 
Day -3 to -1 
 
Day 1 
Day 7  
(±2 days) 
Day 14  
(±2 days) 
Day 28  
(±2 days)  
Post-treatment 
FU (+3 days) 
Informed Consent 
 
 
 
 
 
 
 
Demography 
 
 
 
 
 
 
 
Medical/Ophthalmic/ 
Surgical history 
 
 
 
 
 
 
 
Eligibility Criteria Assessment 
 
 
 
 
 
 
 
Concomitant Medications 
Assessment 
 
 
 
 
 
 
 
Urine Pregnancy Test3 
 
 
 
 
 
 
 
SANDE 
 
 
 
 
 
 
 
Individual Symptom Severity 
Assessments using VAS 
 
 
 
 
 
 
 
BCVA 
 
 
 
 
 
 
 
STT  
 
 
 
 
4 
4 
 
Slit-Lamp Biomicroscopy  
 
 
 
 
 
 
 
FCS 
 
 
 
9 
9 
9 
 
Ophthalmoscopy (dilated)  
 
 
 
 
 
 
 


 
 
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Visit 
Visit 1 
Screening 
Visit 2 
Pre-
Randomization 
Visit 2 
Randomization 
Visit 3 
Treatment 
Visit 4 
Treatment 
Visit 5 
End of 
Treatment/ 
Early Term1 
Visit 6 
Follow-up2 
Day 
Day -3 to -1 
 
Day 1 
Day 7  
(±2 days) 
Day 14  
(±2 days) 
Day 28  
(±2 days)  
Post-treatment 
FU (+3 days) 
OTC Ocular Lubricant 
Administration at the Study Site  
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
IP Administration at the Study 
Site 
 
 
5 
 
 
 
 
Drop Discomfort Assessment at 
the Study Site  
 
6 
7 
 
 
 
 
AE Assessment 
 
 
 
 
 
 
 
IP Dispensation  
 
 
 
 
 
 
 
Dosing Diary and VAS Scales 
Dispensation  
 
 
 
 
 
 
 
Subject Contact for Drop 
Discomfort Assessment  
 
 
 
 
8 
 
 
Abbreviations: AE=Adverse event; BCVA= Best Corrected Visual Acuity; FCS= Fluorescein Corneal Staining; IP=Investigation Product; OTC=Over-the-counter; SANDE= Symptom Assessment and Dry Eye; STT=Schirmer 
Tear Test; VAS=Visual Analog Scale. 
1 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 5).  
2 Visit 6 should be conducted 3 days after End of Treatment (+3 Day window).  
3 For women of childbearing potential only.  
4 STT should be performed at least 1 hour after IP instillation and at least 20 minutes after FCS. 
5 IP instillation should be performed at least 2 hours after OTC ocular lubricant (Refresh Plus) instillation.  
6 Post OTC ocular lubricant instillation. 
7 Post IP instillation. 
8 Subjects will be contacted by masked site staff the evening of the Visit 4 and in the evening prior to Visit 5. 
9 FCS should be performed after the Drop Discomfort Assessment.


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TABLE OF CONTENTS 
NAMES AND ADDRESSES ...................................................................................................2 
DECLARATION OF SPONSOR ...........................................................................................4 
INVESTIGATOR AGREEMENT FORM ............................................................................5 
SYNOPSIS ................................................................................................................................6 
TABLE OF CONTENTS ......................................................................................................14 
LIST OF TABLES .................................................................................................................18 
LIST OF ABBREVIATIONS ...............................................................................................19 
1. 
INTRODUCTION AND BACKGROUND ..................................................................21 
1.1 
Background of the Disease and Treatment Options ....................................................21 
1.1.1 
Limitations of Current Treatment .............................................................................21 
1.2 
Rationale for the Use of Calcineurin Inhibitors in Dry Eye Disease ...........................21 
1.2.1 
Non-Clinical Studies of Voclosporin in Dry Eye .....................................................22 
1.2.2 
Clinical Studies of Voclosporin in Dry Eye .............................................................24 
2. 
RATIONALE .................................................................................................................25 
2.1 
Dose Rationale .............................................................................................................25 
3. 
STUDY OBJECTIVES ..................................................................................................26 
3.1 
Primary Objective ........................................................................................................26 
3.2 
Secondary Objective ....................................................................................................26 
3.3 
Endpoints .....................................................................................................................26 
3.3.1 
Primary Endpoint ......................................................................................................26 
3.3.2 
Secondary Endpoints ................................................................................................26 
4. 
INVESTIGATIONAL PLAN .......................................................................................27 
4.1 
Overall Study Design ...................................................................................................27 
4.2 
Duration of Subject Participation and Study ...............................................................28 
5. 
SELECTION, 
WITHDRAWAL 
OF 
SUBJECTS 
AND 
PERMANENT 
DISCONTINUATION OF DRUG ................................................................................29 
5.1 
Number of Subjects......................................................................................................29 
5.2 
Inclusion Criteria .........................................................................................................29 
5.3 
Exclusion Criteria ........................................................................................................30 
5.4 
Adequate/Effective Contraception ...............................................................................31 
5.5 
Withdrawal of Subjects ................................................................................................31 
5.6 
Discontinuation of Study Treatment ............................................................................32 
5.6.1 
Discontinuation of Study Treatment Due to an Adverse Event................................32 
6. 
RANDOMIZATION, MASKING AND UNMASKING PROCEDURES ................33 
6.1 
Randomization .............................................................................................................33 


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6.2 
Masking........................................................................................................................33 
6.3 
Unmasking ...................................................................................................................34 
7. 
STUDY TREATMENTS ...............................................................................................36 
7.1 
Dosage Forms/Formulation .........................................................................................36 
7.1.1 
VOS Study Treatment ...............................................................................................36 
7.1.2 
Restasis® ...................................................................................................................36 
7.2 
Drug Dosage and Administration ................................................................................36 
7.2.1 
Treatment Arms ........................................................................................................36 
7.2.2 
Dosing Guidelines.....................................................................................................36 
7.3 
Package and Labeling ..................................................................................................37 
7.4 
Study Treatment Allocation .........................................................................................37 
7.5 
Site Supply, Storage, Accountability ...........................................................................37 
7.5.1 
Site Supply ................................................................................................................37 
7.5.2 
Storage ......................................................................................................................37 
7.5.3 
Accountability ...........................................................................................................38 
7.6 
Procedures for Overdose ..............................................................................................38 
7.7 
Prohibited Therapy and Concomitant Treatment .........................................................38 
7.7.1 
Prohibited Medications .............................................................................................38 
8. 
STUDY PROCEDURES ...............................................................................................41 
8.1 
Description of Study Assessments ...............................................................................41 
8.1.1 
Dry Eye Disease Activity Assessments ....................................................................41 
8.1.2 
Post-Instillation Tolerability Assessments ...............................................................43 
8.1.3 
Safety Assessments ...................................................................................................43 
8.2 
Schedule of Assessments .............................................................................................45 
8.2.1 
Screening Procedures ................................................................................................45 
8.2.2 
Treatment Procedures ...............................................................................................46 
8.2.3 
Unscheduled Visits ...................................................................................................51 
8.2.4 
End of Study (or Early Discontinuation) Procedures ...............................................51 
8.2.5 
Follow-up Procedures ...............................................................................................51 
9. 
EVALUATION, RECORDING AND REPORTING OF AES AND SAES .............52 
9.1 
Definitions....................................................................................................................52 
9.1.1 
Adverse Event ...........................................................................................................52 
9.1.2 
Adverse Drug Reaction .............................................................................................52 
9.1.3 
Unexpected ADR ......................................................................................................52 
9.1.4 
Serious Adverse Event (SAE)...................................................................................52 
9.1.5 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ...................................53 
9.2 
Adverse Event Descriptors ..........................................................................................53 
9.2.1 
Intensity/Severity Categorization .............................................................................53 
9.2.2 
Causal Relationship Categorization ..........................................................................54 
9.2.3 
Outcome Categorization ...........................................................................................54 


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9.2.4 
Symptoms of the Disease Under Study ....................................................................54 
9.2.5 
Abuse, Misuse, Overdose and Medication Error ......................................................55 
9.3 
Reporting Procedure for AEs, SAEs, and Pregnancy ..................................................55 
9.3.1 
Adverse Events .........................................................................................................55 
9.3.2 
Serious Adverse Events ............................................................................................56 
9.3.3 
Pregnancy..................................................................................................................58 
10. STATISTICAL ANALYSIS .........................................................................................60 
10.1 
Statistical Methods .......................................................................................................60 
10.2 
Sample Size and Power Calculations ...........................................................................60 
10.3 
Populations ...................................................................................................................61 
10.3.1 
Intent-to-Treat Set .....................................................................................................61 
10.3.2 
Per Protocol...............................................................................................................61 
10.3.3 
Safety Set ..................................................................................................................61 
10.4 
Concomitant Therapy...................................................................................................61 
10.5 
Endpoint Evaluations ...................................................................................................61 
10.5.1 
Primary Endpoint ......................................................................................................61 
10.5.2 
Secondary Endpoints ................................................................................................61 
10.6 
Statistical and Analytical Methods ..............................................................................62 
10.6.1 
Primary Analysis.......................................................................................................62 
10.6.2 
Secondary Efficacy Analysis ....................................................................................62 
10.6.3 
Safety Analysis .........................................................................................................62 
10.7 
Safety Evaluations .......................................................................................................62 
10.8 
Interim Analyses ..........................................................................................................63 
10.9 
Other Evaluations.........................................................................................................63 
11. ETHICAL CONDUCT OF THE STUDY ...................................................................64 
11.1 
Informed Consent.........................................................................................................64 
11.2 
Institutional Review Board or EC/IEC ........................................................................64 
12. QUALITY CONTROL AND QUALITY ASSURANCE ...........................................65 
13. ADMINISTRATIVE PROCEDURES .........................................................................66 
13.1 
Sponsor’s Responsibilities ...........................................................................................66 
13.1.1 
Study Supplies ..........................................................................................................66 
13.1.2 
Insurance ...................................................................................................................66 
13.1.3 
Study Monitoring ......................................................................................................66 
13.2 
Investigator’s Responsibilities .....................................................................................67 
13.2.1 
Reporting and Recording of Data .............................................................................67 
13.2.2 
Investigator Training.................................................................................................67 
13.2.3 
Source Documentation ..............................................................................................67 
14. PROCEDURE FOR MODIFICATION OF PROTOCOL OR PREMATURE 
TERMINATION OF THE STUDY .............................................................................68 


 
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14.1 
Protocol Waivers, Deviations and Violations ..............................................................68 
14.2 
Study Termination .......................................................................................................68 
15. POLICY FOR PUBLICATION AND PRESENTATION OF DATA ......................69 
16. REFERENCES ...............................................................................................................70 
17. APPENDICES ................................................................................................................72 


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LIST OF TABLES 
Table 1: AUR-VOS-2017-01 Schedule of Events ...................................................................12 
LIST OF FIGURES 
Figure 1: AUR-VOS-2017-01 Study Schematic......................................................................11 
 
LIST OF APPENDICES 
Appendix 1 Tolerability Assessment .......................................................................................72 
Appendix 2 Eye Dryness Assessments ....................................................................................73 
Appendix 3 Symptom Assessment in Dry Eye (SANDE) .......................................................74 
Appendix 4 Individual Symptom Severity Assessments using Visual Analog Score (VAS) .75 
Appendix 5 Slit-Lamp Biomicroscopy ....................................................................................76 
Appendix 6 Best Corrected Visual Acuity (BCVA) ................................................................78 
Appendix 7 Fluorescein Corneal Staining (FCS) National Eye Institute/Industry Workshop 
Scale ..................................................................................................................79 
Appendix 8 Restasis® Package Insert, July 2017. ...................................................................80 
Appendix 9 Daily Dosing Diary ..............................................................................................87 
 
 


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LIST OF ABBREVIATIONS 
ADR 
Adverse drug reaction 
AE 
Adverse event 
Aurinia 
Aurinia Pharmaceuticals Inc. 
BCVA 
Best Corrected Visual Acuity 
BID 
Twice daily 
CNI 
Calcineurin inhibitor 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
CsA 
Cyclosporine A 
DED 
Dry Eye Disease 
 
 
EC 
Ethics Committee 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ERG 
Electroretinography 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FCS 
Fluorescein Corneal Staining 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 


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IUD 
Intrauterine device 
KCS 
Keratoconjunctivitis sicca 
LogMAR 
Logarithm of the Minimum Angle of Resolution 
NEI 
National Eye Institute 
NFAT 
Nuclear Factor of Activated T-cells 
NSAID 
Nonsteroidal Anti-Inflammatory Drug 
NZW 
New Zealand White 
OD 
Right eye 
OS 
Left eye 
OSDI 
Ocular Surface Disease Index 
OTC 
Over-the-counter 
OU 
Both eyes 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
SAE 
Serious adverse event 
SANDE 
Symptom Assessment in Dry Eye 
SAP 
Statistical Analysis Plan 
SAR 
Serious adverse reaction 
STT 
Schirmer Tear Test 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
UPT 
Urine pregnancy test 
VAS 
Visual Analog Scale 
VOS 
Voclosporin ophthalmic solution 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 


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1. INTRODUCTION AND BACKGROUND 
1.1 
Background of the Disease and Treatment Options  
Dry Eye Disease (DED), also called keratoconjunctivitis sicca (KCS), is a common clinical 
problem as over 7 million people in the United States experience dry eye symptoms.  
Symptoms of DED include a sensation of dry eyes, foreign body sensation, irritation, burning, 
tearing, ocular pain, and itching, among others. DED affects quality of life and work 
productivity, and patients with moderate to severe DED may experience reduced visual 
function in addition to ocular dysfunction.  
DED is a multi-factorial disease, defined by a loss of homeostasis of the tear film and 
accompanied by ocular symptoms, in which tear film instability and hyper-osmolarity, ocular 
surface inflammation and damage, and neuro-sensory abnormalities play etiological roles [1].  
DED patients are classified by the overlapping etiologies of aqueous deficient and evaporative 
dry eye [2]. Evaporative dry eye tends to be more prevalent than aqueous deficient; however, 
as the disease progresses, both components become apparent [1]. The common pathway for 
both groups is that desiccating stress leads to ocular surface inflammation [3-5]. 
1.1.1 Limitations of Current Treatment 
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 [1]. There are currently two FDA-approved 
prescription medications used for DED, topical cyclosporine (Restasis®) [6] and lifitigrast 
(Xiidra®) [7]. A significant number of patients using Restasis® experience the following 
problems: ocular irritation upon instillation, slow onset of response, and limited efficacy 
(Restasis® Package Insert, see Appendix 8). Problems with Xiidra® include instillation 
irritation, dysgeusia and reduced visual acuity which occurred in 5-25% of subjects in clinical 
trials (Xiidra® Package Insert [7]). There is a clear unmet clinical need for improved 
therapeutic options for patients with moderate to severe DED. 
1.2 
Rationale for the Use of Calcineurin Inhibitors in Dry Eye Disease 
In patients with DED, tear production has been shown to be increased with the use of topical 
immunosuppressants, including cyclosporine. It is believed T-lymphocyte infiltration and 
activation in the lacrimal gland represents an underlying pathogenesis for DED. Calcineurin 
inhibitors 
(CNIs) 
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 
[8]. 
Calcineurin 
is 
a 
calcium- 
and 
calmodulin-dependent serine-threonine phosphatase. 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 


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various transcription factors necessary for the induction of cytokine genes during T-cell 
activation (e.g., interleukin-2, interleukin-4, tumor necrosis factor-α, granulocyte-macrophage 
colony stimulating factor, and interferon-γ [9,10]). 
Voclosporin is a 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 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 as compared to CsA. The combination of increased 
potency and decreased metabolite exposure, for voclosporin as compared to CsA, has led to 
better pharmacokinetic (PK)/pharmacodynamic (PD) predictability. 
1.2.1 Non-Clinical Studies of Voclosporin in Dry Eye 
Two Good Laboratory Practice toxicology studies [11,12] 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 evaluation, 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 Day 1 and Day 13 at pre-dose, 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 to be 0.56 mg/eye/day. There 


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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 [13], 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 is >0.56 mg/eye/day.  
In summary, the two repeated-dose ocular toxicology studies [11,12] 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 
the S08711 study.  
In addition to the three repeated dose toxicology studies, the safety and efficacy of VOS 0.2% 
has been evaluated in dogs with naturally occurring KCS [14], 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 twice daily (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 both safe and effective in 
treating KCS in dogs. 
In order to determine potential melanin binding of 
14C-LX214, ocular tissue 
14C-LX214-derived radioactivity concentrations were compared between data obtained from 


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albino NZW rabbits given a single bilateral instillation in a separate study and similarly treated 
pigmented Dutch-Belted rabbits. 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.  
1.2.2 Clinical Studies of Voclosporin in Dry Eye 
VOS has been investigated in one Phase 1 dose-escalation study (LX214-01) at a dose of 0.02% 
and 0.2% in 30 healthy volunteers, followed by an open-label evaluation of 0.2% VOS in 5 
subjects with DED [15]. In that study, both 0.02% and 0.2% concentrations were found to be 
safe and well-tolerated following multiple instillations in healthy subjects. Adverse events 
(AEs) and ocular findings were mild and similar between VOS and placebo groups. Although 
the sample size was small, results from the 5 subjects with DED suggest VOS may be 
beneficial in the treatment of DED and is supported by the Ocular Surface Disease Index 
(OSDI) 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. 
These factors form the basis for the rationale to investigate the safety and efficacy of 
voclosporin in subjects with DED. Study AUR-VOS-2017-01 will evaluate the tolerability and 
efficacy of VOS versus Restasis® in subjects with DED.  


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2. RATIONALE 
2.1 
Dose Rationale 
Based on Phase 1 studies in healthy subjects and all clinical trials to date in the clinical 
development program in other indications, oral voclosporin is generally well tolerated at doses 
up to 0.8 mg/kg BID with no unexpected safety concerns compared to the profile expected for 
CNIs.  
VOS was evaluated in a Phase 1 parallel, randomized, double-masked, placebo-controlled, 
dose-escalation (0.02% and 0.2%) study assessing the safety and tolerability of VOS in healthy 
volunteers, followed by an open-label evaluation of VOS (0.2%) BID in subjects with DED 
(see VOS DED Investigator’s Brochure (IB) [16]). Although the sample size was small, results 
from the five subjects with DED suggest VOS may be beneficial in the treatment of DED and 
is supported by the OSDI scores which were improved in all subjects at all timepoints while 
on study drug. The mean improvement in STT scores between baseline and the end of treatment 
provides further evidence of efficacy. It is anticipated that 0.2% VOS BID will be an effective 
dose in the treatment of immune-mediated ocular surface disease. 


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3. STUDY OBJECTIVES 
3.1 
Primary Objective 
• To assess the ocular tolerability of VOS compared to cyclosporine ophthalmic emulsion 
(Restasis®) in subjects with DED.   
3.2 
Secondary Objective 
• To assess the safety and efficacy of VOS in subjects with DED. 
3.3 
Endpoints 
3.3.1 Primary Endpoint 
• Change from baseline in Drop Discomfort Visual Analogue Scale (VAS) score 1-minute 
post-Dose 1 instillation.  
3.3.2 Secondary Endpoints 
3.3.2.1 Key Secondary Endpoints 
• Change from baseline in Drop Discomfort VAS score 
• Change from baseline in each of the 6 Individual Symptom Severity Assessments (VAS) 
scores  
• Change from baseline in the sum of the Individual Symptom Severity Assessments score 
(VAS Total Symptom Summary Score)  
• Change from baseline in Symptom Assessment in Dry Eye (SANDE) score  
• Change from baseline in unanesthetized STT score  
• Change from baseline in Fluorescein Corneal Staining (FCS) total score (National Eye 
Institute (NEI)/Industry Workshop 0-15 scale)   
3.3.2.2 Other Secondary Safety Endpoints 
• Treatment-emergent adverse events (TEAEs) 
• Change from baseline in Best Corrected Visual Acuity (BCVA) 
• Changes from baseline in Slit-Lamp Biomicroscopy  
• Changes from screening in Dilated Ophthalmoscopy 


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4. INVESTIGATIONAL PLAN 
4.1 
Overall Study Design 
This is a Phase 2, multi-center, Investigator-masked, randomized, parallel-group study to 
evaluate the tolerability, efficacy and safety of VOS versus Restasis® over a 28-day treatment 
period in subjects with mild to moderate DED. Approximately 90 subjects will be randomized 
to either VOS or Restasis® at approximately 7 centers located in the US.   
At Visit 1 (screening), informed consent will be obtained from subjects and eligibility will be 
determined. A STT will be performed at this visit. The score will be used for eligibility and 
baseline. During this visit, all subjects will self-administer an OTC ocular lubricant, Refresh 
Plus®, OU to assess ability to self-administer study product. 
At Visit 2 (Randomization), continued eligibility will be confirmed. During this visit, all 
subjects will self-administer an OTC ocular lubricant, Refresh Plus®, OU to evaluate ability to 
tolerate ocular drops. Individuals who are unable to successfully instill the drops or who rate 
OTC ocular lubricant as uncomfortable, based on a post-instillation Drop Discomfort VAS 
score, will not be eligible for participation in the study. (Note:  For subjects meeting the 
Screening and Randomization Criteria, the Visit 2 Drop Discomfort VAS score will be used 
as the baseline value.)   
Eligible subjects will be randomly assigned in a 1:1 ratio to one of the two treatment groups:  
VOS BID or Restasis® BID. The first instillation of Investigational Product (IP) will be 
administered, at least 2 hours following administration of Refresh Plus® and by clinic personnel 
to both eyes during Visit 2. IP will be administered to the subject by an unmasked dedicated 
dosing coordinator (the subject and the Investigator will be masked to study treatment for the 
first post randomization instillation). Tolerability, safety and efficacy assessments will be 
performed at this visit. 
At Treatment Visits 3 and 4, tolerability, safety and efficacy evaluations will be performed. At 
the End of Treatment, Visit 5, tolerability, safety and efficacy evaluations will be performed.  
Subjects who discontinue before Visit 5 will undergo all Visit 5 evaluations (Early 
Termination). IP will be administered to the subject by an unmasked dedicated dosing 
coordinator at the clinic visits (single-masked: the Investigator and study staff will remain 
masked to study treatment). A Drop Discomfort VAS will be administered in the clinic at 1-
minute and 5-minutes following instillation of IP at Visits 2 through 5 (Investigator is to remain 
masked). With the exception of clinic day visits, subjects will self-administer IP twice a day 
OU over the 4-week treatment period. On the evening of Visits 2 through 4 and in the evening 
prior to Visit 5, site staff will contact the subject by phone to prompt administration of IP 
followed by completion of the dosing diary (See Appendix 9) and the Drop Discomfort VAS 
(1-minute and 5-minutes post-instillation). 


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At Visit 6, there will be a 3-day post-treatment Follow-Up, in which safety assessments are 
performed and all remaining study materials are collected. The subjects will be instructed to 
continue to withhold all other concomitant topical medications as outlined by the protocol for 
the duration of their participation (through Visit 6). 
Serious adverse events (SAEs) ongoing as of Visit 6 will be followed until they have resolved, 
stabilized in the opinion of the Investigator, or returned to baseline. 
This study will be conducted per the schedule shown in the Schedule of Events (Table 1) and 
the Study Schematic (Figure 1). 
4.2 
Duration of Subject Participation and Study 
The expected duration of subject participation is approximately 5 weeks. The treatment 
duration is 28 days with a follow-up visit 3 days after last dose (completion or early 
termination).  


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5. SELECTION, WITHDRAWAL OF SUBJECTS AND PERMANENT 
DISCONTINUATION OF DRUG 
5.1 
Number of Subjects 
Approximately 90 subjects will be randomized to either VOS or Restasis®. Approximately 
45 subjects will be assigned to each treatment group. 
5.2 
Inclusion Criteria 
At Visit 1 and Visit 2 (as specified in the Schedule of Events), subjects may be eligible for 
participation if they:  
1. Provide written informed consent before any study-specific procedures are performed. 
2. Are male or female subjects with a minimum age of 18 years (or legal age of consent 
if >18 years), at the time of screening (Visit 1). 
3. Are willing and able to follow instructions and can be present for the required study visits 
for the duration of the study. 
4. 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.  
5. Have a documented history of DED in both eyes supported by a previous clinical diagnosis 
at Visit 1. 
6. Have ongoing DED, as defined by at least one eye (if one eye, the same eye) meeting all 
the following criteria:  
− 
A symptom severity score of ≥30 for Eye Dryness on the Individual Symptom Severity 
Assessment VAS (0-100) at Visit 2 
− 
An unanesthetized STT score of ≥1 mm and ≤10 mm per 5 minutes (Note:  STT Score 
obtained at Visit 1) 
− 
Evidence of ocular surface staining (total fluorescein staining score of at least 3 [0-15 
scale]) at Visit 2 
7. Have normal lid anatomy at Visit 1. 


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5.3 
Exclusion Criteria 
In order for subjects to be eligible at Visit 1 and Visit 2 (as specified in the Schedule of Events), 
subjects must not: 
1. Be unable or unwilling to give written informed consent and/or to comply with study 
procedures. 
2. Have any known hypersensitivity or contraindication to study treatments (including 
excipients), topical anesthetics or vital dyes. 
3. Be unable to demonstrate correct instillation of OTC ocular lubricant during Visit 1. 
4. Report discomfort in both eyes from instillation of OTC ocular lubricant during Visit 2 
(based on score of ≥30 on the Drop Discomfort VAS).  
5. Have used Restasis® (cyclosporine ophthalmic emulsion) within 30 days prior to Visit 1. 
6. Have used Restasis® for more than 1 month (if prior use is reported). 
7. Have used Xiidra® (lifitegrast ophthalmic solution) within 14 days prior to Visit 1. 
8. Have had corneal graft surgery in either eye within 1 year of Visit 1.  
9. Have recent or current evidence of ocular infection or inflammation in either eye. 
10. Have current evidence of clinically significant blepharitis (defined as requiring lid hygiene 
therapy), conjunctivitis, or a history of herpes simplex or zoster keratitis in either eye. 
11. Have clinically significant ocular disease in either eye (e.g., corneal edema, uveitis, severe 
KCS) which might interfere with study procedures or assessments. 
12. Have any abnormality in either eye preventing reliable applanation tonometry.  
13. Be taking or have known need for any of the known treatment therapies listed in Section 
7.7, Prohibited Therapy and Concomitant Treatment at Visit 1 or during the study. This 
includes prohibited medications prior to Visit 1 as specified in Section 7.7, Prohibited 
Therapy and Concomitant Treatment. 
14. Have any known hypersensitivity or contraindication to CNIs.  
15. Have clinically significant systemic disease (e.g., uncontrolled diabetes, hepatic, renal, 
endocrine or cardiovascular disorders) which might interfere with the study.  
16. Have participated in any investigational clinical study within 30 days prior to Visit 1. 


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17. Have altered any systemic medication that could have an effect on dry eye signs or 
symptoms within 30 days prior to Visit 1 or anticipated during the study.  
18. Be women of childbearing potential (WOCBP) who are pregnant, nursing, planning a 
pregnancy, or not using a medically acceptable form of birth control.  
5.4 
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 WOCBP must have a negative 
urine pregnancy test (UPT) 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 (IUD) in place for at least 4 weeks prior to Visit 1 through Visit 5 or 
last administration of IP or until completion of the subject’s first menstrual cycle following 
last administration of the IP, whichever period of time is longer. 
2. Barrier method (condom or diaphragm) with spermicide for at least 4 weeks prior to Visit 
1 through Visit 5 or last administration of the IP or until completion of the subject’s first 
menstrual cycle following last administration of the IP, whichever period of time is longer. 
3. Stable hormonal contraceptive for at least 60 days prior to Visit 1 through Visit 5 or last 
administration of the IP or until completion of the subject’s first menstrual cycle following 
administration of the IP, whichever period of time is longer.  
NOTE: For Depo-Provera injection contraceptives, the statement regarding first menstrual 
cycle following administration of the IP is not applicable as females receiving this form of 
contraception will not have menses. 
4. In a monogamous relationship with a surgically sterilized (i.e., vasectomized) partner at 
least 6 months prior to Visit 1 through Visit 5 or last administration of the IP or until 
completion of the subject’s first menstrual cycle following administration of the IP, 
whichever period of time is longer. 
5.5 
Withdrawal of Subjects 
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 5). If possible, the 
subject should also be advised to come for the Follow-up Visit, 3 days after last dose (Visit 6). 


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If a subject refuses end of study procedures, the reason for refusal should be fully documented 
in the subject’s source document and recorded in the study specific electronic case report form 
(eCRF). It is the subject’s right to withdraw from the study without providing a reason. In this 
case, the source documents and the eCRF should document the reason for discontinuation as 
“withdrawal of consent.” Withdrawn subjects will not be replaced. 
5.6 
Discontinuation of Study Treatment 
If any subject is discontinued from study treatment, the reason for discontinuation will be 
documented in the eCRF. If the reason for discontinuing study treatment is an AE, the specific 
event or test will be recorded in the eCRF. The subject should also be advised to come for the 
Follow-up Visit, 3 days after last dose.  
Subjects who are permanently discontinued from study treatment will be treated as deemed 
appropriate by the Investigator. 
5.6.1 Discontinuation of Study Treatment Due to an Adverse Event 
Subjects may be permanently discontinued from study treatment because of the appearance of 
an unacceptable AE. It is vital to obtain follow-up data on any subject withdrawn because of 
an AE. In any case, every effort must be made to evaluate protocol-specified safety follow-up 
procedures (see Section 9.3, Reporting Procedure for AEs, SAEs, and Pregnancy). If a subject 
is withdrawn due to an AE, the event should be followed by the Investigator through contact 
with the subject until resolution or stabilization has occurred. All AEs should be followed until 
resolution, stabilization or the subject is lost to follow-up and cannot be contacted. 


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6. RANDOMIZATION, MASKING AND UNMASKING PROCEDURES 
6.1 
Randomization 
A computer-generated randomization schedule will be used to assign subjects into treatment 
groups. The randomization ratio will be maintained within each study center. A randomization 
list will be generated and provided by an unmasked statistician.  
The Sponsor, the project teams at the designated Contract Research Organizations (CROs), 
and investigative staff responsible for assessments of study endpoints will be masked to study 
product assignments. There will be an unmasked dedicated dosing coordinator who will 
dispense the IP to the subject and who will perform drug accountability on the returned IP. 
This individual will be otherwise uninvolved in the study operations. Furthermore, there will 
be a Clinical Research Associate (CRA) dedicated to drug accountability who will be 
unmasked to the treatment assignment by default but will be uninvolved in review of the 
clinical trial data beyond the scope of IP accountability. In case of medical emergency, or 
occurrence of an SAE, the randomization code may be unmasked and made available to the 
Investigator, Sponsor, and/or other personnel involved in the monitoring or conduct of this 
study. In the absence of medical need, the randomization code will not be available to the 
above individuals until after the study is completed and the database is locked.  
In the event of a medical need, the Investigator will treat each subject as needed. Since there 
is no specific antidote to VOS, immediate emergency unmasking is not necessary. If the 
Investigator feels it is necessary to unmask a subject’s assignment after an emergency situation, 
the Investigator may call the Medical Monitor and notify the Sponsor. The IP assignment will 
be revealed on a subject-by-subject basis with the approval of the Medical Monitor and 
Sponsor, thus leaving the masking of the remaining subjects intact. 
A randomization schedule will be generated by an unmasked statistician who will also be 
responsible for loading the schedule into the electronic data capture (EDC) system. No other 
 or Aurinia Pharmaceuticals Inc. (Aurinia) staff will have access 
to the schedule. 
Randomization team members will work independently of other team members at the CRO. 
With the exception of the unmasked dedicated dosing coordinator and drug accountability 
CRA, all other study personnel, the Sponsor, and project teams at the CROs involved in the 
study will be masked to study product assignments.  
 
6.2 
Masking 
On Day 1 Dose 1, this study is double-masked. The IP allocation (VOS versus Restasis®) will 
be masked to the Sponsor, the subject and the investigative staff with the exception of an 
unmasked dedicated dosing coordinator and unmasked CRA. The unmasked dedicated dosing 


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coordinator will be responsible for dispensing and retrieving IP to/from subjects, instructing 
subjects regarding dosing of the IP, addressing study subjects’ questions regarding IP, and 
reviewing daily dosing diaries. As a consequence of these interactions, the unmasked dedicated 
dosing coordinator will be unmasked to the study treatment for each subject. In order to ensure 
subject masking, at Visit 2, first dose, the unmasked dedicated dosing coordinator will not 
provide any IP related information prior to instilling the IP. The IP will be instilled in a masked 
manner. Instructions regarding storage and dosing will be provided after this first instillation.  
On Days 2-28, subjects will not have visibility to the study product assignment; however, as 
VOS and Restasis® have different storage conditions and appearance, it may be possible that 
the subjects who have previously used Restasis®, may know that those differ from their prior 
experience. Therefore, the study will be considered Investigator-masked during this timeframe. 
The randomization schedule will be generated by the Randomization Statistician (who is not 
on the project team) or designee and maintained in a secure and limited-access location 
separate from the study Investigator and members of the project team. 
6.3 
Unmasking 
The treatment assignment for an individual subject may be obtained in the case of a medical 
emergency when knowledge of the IP identity is essential for the clinical management of the 
subject. The Investigator must make every effort to contact the study Medical Monitor or the 
Clinical Study Manager before unmasking the treatment assignment.  
In the event of emergency unmasking, the Investigator must inform the Sponsor immediately, 
without revealing to the Sponsor personnel the treatment assignment.  
If unmasking is required for emergency subject management, the Investigator must document 
the medical rationale for unmasking and forward the information to the Sponsor within 
24 hours of unmasking. 
If an SAE is assessed as unexpected and related to the IP, and therefore meets the requirement 
for expedited regulatory submission, the Sponsor’s Drug Safety Surveillance department will 
unmask the treatment assignment for the individual subject. Expedited reports will be 
submitted to Regulatory Authorities in accordance with applicable regulations. Expedited 
reports will be distributed to Investigators without revealing the treatment assignment and will 
be submitted to Institutional Review Boards (IRBs). 
If emergency unmasking is required, withdrawal of the subject from the study is not mandatory 
unless there are other circumstances that require the subject’s discontinuation. At the Sponsor’s 
discretion, the subject may remain in the study without continued use of the IP.  


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In the event of accidental unmasking, the event would be reported as a protocol deviation and 
escalation to the Sponsor. The subject may remain in the study. If identified by the study center, 
a Sub-Investigator may be asked to assume clinical study assessments for a subject if the PI 
was inadvertently unmasked.  


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7. STUDY TREATMENTS 
7.1 
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. 
7.1.1 VOS Study Treatment 
Company Code: 
 
Chemical Name: 
 
Empirical Formula: 
 
Generic Name: 
Voclosporin ophthalmic solution (VOS) 
Dosage Form: 
Voclosporin ophthalmic solution is provided as clear micellar solutions 
in single-use blow/fill/seal ampules for topical ocular administration. 
One drop (~30 μL) of the 0.2% solution contains approximately 0.06 mg 
of voclosporin 
Strength: 
0.2% 
Manufacturer: 
Aurinia Pharmaceuticals Inc. 
7.1.2 Restasis® 
See Package Insert in Appendix 8. 
7.2 
Drug Dosage and Administration 
7.2.1 Treatment Arms 
Investigational Product: 0.2% VOS, BID, OU for 28 days. 
Comparator: 0.05% cyclosporine ophthalmic emulsion (Restasis®) BID, OU for 28 days. 
7.2.2 Dosing Guidelines 
The IP will be administered BID as close to a 12-hour schedule as possible, and with a 
minimum of 8 hours between doses.  
IP will be self-administered by the subjects except for the visit dates where the morning dose 
will be administered by the unmasked dedicated dosing coordinator. 


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If the subject misses a dose by less than 4 hours from the scheduled time, the missed dose will 
be self-administered immediately. The next dose will be administered at the originally 
scheduled time. If the subject misses a dose by more than 4 hours from scheduled time, the 
subject should skip the dose and administer the next dose as regularly scheduled. 
7.3 
Package and Labeling 
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 
Good Clinical Practice (GCP). 
7.4 
Study Treatment Allocation 
Subjects will be randomized to receive either VOS or Restasis® in a 1:1 ratio. Subjects will be 
allocated a kit number for the duration of the study. Subjects will be assigned to treatment 
groups using the randomization module within the EDC system. As eligible subjects are 
enrolled and the corresponding Randomization eCRF completed, a kit number will be 
assigned. 
7.5 
Site Supply, Storage, Accountability 
7.5.1 Site Supply 
Once a site has been approved for study initiation, the site will be supplied with an initial stock 
of IP. Each site will receive one shipment of both Restasis® and VOS prior to study enrollment. 
Additional shipments of both Restasis® and VOS will be provided to each site as needed. 
7.5.2 Storage 
VOS should be stored refrigerated between 2º C and 8º C (36º F to 46º F) but may be brought 
to room temperature prior to use. Subjects should be consistent in their use of VOS IP.  
Opened ampules must not be stored for re-use as the formulation does not contain 
preservatives. 
STUDY DRUG SHOULD NOT BE FROZEN. DO NOT USE IF THE VIAL CONTENT 
DOES NOT APPEAR CLEAR. 
Restasis® should be stored at room temperature (15-25°C/59-77°F). 
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 Unmasked site personnel during normal working hours. This log must be 
available for review by the Unmasked Site Monitor during on-site monitoring visits. 


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7.5.3 Accountability 
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 designee for the central study file. The original will be kept in the site files. 
After completion of the study, or if it is prematurely terminated, all undispensed IP will be 
returned to Aurinia. The decision to destroy IP at a site must be made by Aurinia. If the 
dispensed/returned IP is destroyed at a site, the Investigator must receive Aurinia approval of 
the site’s standard operating procedure addressing the destruction process and forward 
documentation of destruction to Aurinia. 
7.6 
Procedures for Overdose 
Preclinical findings suggest that systemic effects from an overdose are unlikely, as the peak 
blood levels after ocular instillation are below those achieved with oral doses of voclosporin. 
Based on clinical experience with voclosporin, symptomatic treatment of AEs is indicated. In 
the event of overdose, discontinuation of treatment should be considered. 
7.7 
Prohibited Therapy and Concomitant Treatment 
Any concomitant treatment given for any reason during the study must be recorded in the eCRF 
and in the subject’s source documents, including dosage, start and stop dates, and reason for 
use. 
Any class of medications not mentioned in Section 7.7.1, Prohibited Medications and with the 
potential to interfere with evaluation of the study treatment must be discussed and documented 
with the Medical Monitor. 
7.7.1 Prohibited Medications 
The following drugs/therapies shall be prohibited during the study and for the timeframes 
specified below:  A subject should not have received:  
• any investigational drug or device within 30 days prior to the Screening Visit (Visit 1) and 
may not receive any investigational drug or device during the entire study except that which 
is allowed by the protocol 


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• Ophthalmic drugs (any topical eye medications) including prescription medication and 
OTC agents, except IP and study lubricant at Visit 1 and Visit 2, from Visit 1 to Visit 6. 
• Contact lenses during the period from the Screening Visit (Visit 1) to the end of the study 
(Visit 6) 
• Prohibited Medications:   
o Any prior use of amiodarone 
o Within 14 days prior to study and for the duration of the study: 
 Xiidra® (lifitigrast) 
o Within 30 days prior to study and for the duration of the study:   
 Restasis® (cyclosporin ophthalmic emulsion); NOTE:  Any prior use of 
Restasis® may not have exceeded 1 month of continuous use 
 Topical ocular antihistamines 
 Ocular, inhaled or intranasal corticosteroids 
 Topical or oral mast cell stabilizers  
 Oral antihistamines 
 Topical or nasal vasoconstrictors 
 Topical ocular nonsteroidal anti-inflammatory drugs (NSAIDs) 
 Topical ocular antibiotics 
o 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 
o 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 
o Within 90 days prior to the screening visit (Visit 1) or during the study, in the 
study eye 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 screening visit (Visit 1) and it is dislodged during the study, the plug 
should be replaced as soon as possible 
o At screening visit (Visit 1) or any time throughout the study: 
 Chronic oral anti-viral medications for ocular herpetic disease 


 
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8. STUDY PROCEDURES 
8.1 
Description of Study Assessments 
8.1.1 Dry Eye Disease Activity Assessments 
The following assessments will occur as part of the evaluation of DED (see Appendix 2).  
8.1.1.1 Symptom Assessment in Dry Eye (SANDE)  
Subjects will be asked to subjectively rate the frequency and severity of their dry eye symptoms 
at Visits 2, 3, 4 and 5 using the SANDE. The total length of the line from “rarely” to “all the 
time” (frequency of symptoms) and from “very mild” to “very severe” (severity of symptoms) 
is 100 mm. Subjects will be asked to subjectively rate the frequency and severity of their 
symptoms (OU) by placing an “X” on the relevant horizontal line. The length of the line 
between the “rarely” or “very mild” starting point and the first point where the subject’s mark 
crosses each line will be measured and recorded 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 prior to assessing for AEs and prior to any other invasive visit assessment 
(see Appendix 3).  
8.1.1.2 Visual Analogue Scale (VAS) Symptom Assessments  
Individual Symptom Severity Assessments using VAS: 
Subjects will be asked to rate their current symptoms (unrelated to study drug instillation) at 
Visits 2, 3, 4 and 5.  The following six symptoms will be evaluated:  Burning/Stinging, Foreign 
Body Sensation, Photophobia, Eye Pain, Eye Dryness, and Itching. 
The subject will be asked to subjectively rate each of six ocular symptoms (OU) by placing a 
vertical mark on the horizontal line to indicate their level of discomfort. 0 corresponds to “No 
Symptoms” and 100 corresponds to “Severe Symptoms.” 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 (see Appendix 
4).  
8.1.1.3 Fluorescein Corneal Staining (FCS) 
Corneal staining will be performed at Visit 2, 3, 4 and 5. This assessment should be 
performed after the Drop Discomfort Assessment at Visit 3, 4 and 5. Corneal staining 
assessment will be performed using methods developed by the NEI Dry Eye Workshop (see 
Appendix 7). 
Evaluation Technique 
NOTE: All steps in this procedure should be completed for the right eye (OD) prior to 
repeating the procedure for the left eye (OS). 


 
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• Place Slit-Lamp magnification at 10x (it is acceptable to use 16x if no reticle is used) 
• Use a yellow barrier filter (Wratten or Tiffen #11 or #12)  
• Place 5 µL of non-preserved, 2% fluorescein into eye, gently touching the drop at the tip 
to the lower palpebral conjunctiva of the eye 
• In order to thoroughly mix the fluorescein with the tear film, ask the subject to blink several 
times and move his/her eye around 
• Wait 2.5 minutes to assess cornea 
• Measure staining under Cobalt blue light (465 nm to 490 nm) 
• Compare staining with the standard with scoring in each of 5 areas of the 5 corneal sections 
Scoring system 
• Grade each of 5 sections of cornea (superior, inferior, nasal, temporal, central) 
• Provide grades for each of the 5 sections: 
− 
Grade by NEI scale (definition in Appendix 7) as 0, 1 (mild), 2 (moderate), or 3 (severe) 
• Total score is obtained by summing each of the 5 sections of the cornea 
− 
NEI score will be from 0-15. (See Appendix 7). 
8.1.1.4 Unanesthetized Schirmer Tear Test (STT) 
Schirmer Tear Test (without anesthesia) will be conducted at Visit 1, Visit 4 and Visit 5. This 
procedure should be conducted at least 1 hour following administration of IP and at least 20 
minutes following FCS at Visit 4 and Visit 5: 
Identical Schirmer strips will be supplied to each site. When conducting assessments room 
temperature and humidity should be relatively consistent throughout each visit and throughout 
the study.  
• While still in the plastic sheath, fold the notched end of the Schirmer strip at the apex of 
the “v.”  Additionally, make a partial second fold at the halfway point of the strip so that 
the strip does not lie directly in the subject’s line of sight 
• Remove the right eye strip from the sheath 
• Ask the subject to look up and gently draw the right lower lid in a downward and temporal 
direction  


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• Place the rounded end of the strip toward the temporal one-third of the lower eyelid  
• Repeat this procedure in the left eye 
• Darken the room but ensure that the largest letter(s) of a Snellen or ETDRS chart is visible 
• Instruct the subject to relax and look at the chart while blinking normally or have patients 
gently close eyes 
• Remove the strips after 5 minutes 
• After removing the strips, with a sharp pencil draw a horizontal line across the leading edge 
of moisture and a second horizontal line across the lowest point of moisture 
• Using a ruler and/or the millimeters recorded on the strips, measure a point halfway 
between the two lines and record this as the amount of wetting 
8.1.2 Post-Instillation Tolerability Assessments 
8.1.2.1 Drop Discomfort Assessment  
Drop discomfort will be assessed by the subject through a Drop Discomfort VAS (0-100 mm) 
where 0 corresponds to “no discomfort” and 100 corresponds to “maximal discomfort.” (See 
Appendix 1). 
At Visit 2, prior to randomization, in order to evaluate the subject’s ability to tolerate ocular 
drops, all subjects will self-administer an OTC ocular lubricant, Refresh Plus®, OU. Upon 
instillation of the ocular lubricant OU, subjects will be instructed by the site staff to rate their 
eye discomfort at 1-minute and 5-minutes post-instillation by placing a mark on the Discomfort 
VAS. Subjects who rate OTC ocular lubricant as uncomfortable, defined as a VAS score ≥ 30 
mm, will not be eligible for participation in the study. These Drop Discomfort VAS scores will 
be used as the baseline values.  
At Visit 2, after randomization, an unmasked dedicated dosing coordinator will instill the IP 
OU. Subjects will be instructed by a masked site staff to rate their eye discomfort at 1-minute 
and 5-minutes post-instillation of IP as described above.  
Subjects will complete this assessment in the clinic following the AM dose of IP at Visits 2, 3, 
4 and 5 and again at home following the PM dose on the evenings of Visits 2, 3, 4 and the 
evening prior to Visit 5.   
8.1.3 Safety Assessments 
The following assessments will occur as part of the safety evaluation of the subjects: 


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8.1.3.1 Best Corrected Visual Acuity (BCVA)  
BCVA will be conducted at each visit per the Schedule of Events. Visit 1 BCVA will be used 
to assess eligibility, and Visit 2 BCVA will be used as baseline value. Visual acuity testing 
should precede any examination requiring contact with the eye or instillation of study dyes. 
LogMAR visual acuity must be assessed using an ETDRS or modified ETDRS chart. Visual 
acuity testing should be performed with best correction using subject’s own corrective lenses 
(spectacles only) or pinhole refraction. 
An ETDRS or modified ETDRS chart may be used, and charts may be reflectance or 
retro-illuminated. If a 24.5” by 25” chart is used, the subject must view the chart from exactly 
4 meters (13.1 feet). If smaller reproductions (18” by 18”, e.g., Prevent Blindness) are used, 
the subject viewing distance should be exactly 10 feet. Reflectance wall charts should be 
frontally illuminated (60-watt bulb or a well-lit room). 
The subject should be positioned per the elevation of the chart (either seated or standing) so 
that the chart is at a comfortable viewing angle. The right eye should be tested first. The subject 
should attempt to read each letter, line-by-line, left to right, beginning with line 1 at the top of 
the chart. The subject should be told that the chart has letters only, no numbers. If the subject 
reads a number, he or she should be reminded that the chart contains no numbers, and the 
examiner should then request a letter instead of the number. The subject should be asked to 
read slowly, about 1 letter per second, to achieve the best identification of each letter. He/she 
is not to proceed to the next letter until he/she has given a definite response. If the subject 
changes a response before he has read aloud the next letter, then the change must be accepted. 
Maximum effort should be made to identify each letter on the chart encouraging the subject to 
guess. When it becomes evident that no further meaningful readings can be made, the examiner 
should stop the test. The number of letters missed or read incorrectly should be noted (see 
Appendix 6). 
8.1.3.2 Dilated Ophthalmoscopy  
Dilated ophthalmoscopy exam will be performed per the Investigator’s standard procedure at 
Visit 1 and Visit 6.  
The Investigator will determine if findings are within normal limits or are abnormal. For 
abnormal findings at Visit 1, the Investigator will determine whether the abnormality would 
exclude subject from study participation. A clinically significant change from baseline may 
indicate an AE. 


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8.1.3.3 Slit-Lamp Biomicroscopy  
The biomicroscopy exam will be performed at Visit 2 and Visit 5. It should be performed with 
the Slit-Lamp using a beam of width and intensity to provide optimal evaluation of anterior 
segment. 
This procedure will be performed in the same manner for all subjects observed at the 
Investigator’s site (see Appendix 5). 
8.2 
Schedule of Assessments 
A detailed schedule of assessments (including all protocol-required assessments, visits, and 
visit windows) is located on the Schedule of Events (Table 1). No study-related assessments 
will be performed (including changes to current medications to meet study eligibility) until the 
subject has provided signed and dated informed consent. Every effort will be made to keep the 
subject within the requested visit schedule. If a subject is seen outside of the visit window 
listed on the Schedule of Events, the reason must be clearly documented in the source notes.  
8.2.1 Screening Procedures 
8.2.1.1 VISIT 1  
The screening visit will take place within 3 days prior to Visit 2. After obtaining informed 
consent, site staff will perform/assess the following procedures in the order below. There will 
be a collection of information including:  
• Demographics 
• Prior documented DED diagnosis 
• Ocular, general medical and surgical history 
• Concomitant medication history 
• UPT for all eligible WOCBP 
• BCVA assessment 
• Unanesthetized STT  
• Dilated Ophthalmoscopy 
• Assessment of ocular lubricant self-instillation  
• AE assessment 


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• Inclusion and exclusion criteria assessment: Subjects who do not meet the evaluated 
criteria will not continue participation in the study. Any subject who does not meet 
eligibility requirements will be considered a Screen Failure. 
Subjects should be reminded not to use artificial tears or any other OTC or prescription or any 
other topical eye medication except for the IP for the duration of their participation in the study. 
Subject will be scheduled to return for Visit 2 in one to three days. 
8.2.2 Treatment Procedures 
8.2.2.1 VISIT 2  
Pre-Randomization 
The site staff will perform/assess the following procedures:  
• SANDE  
• Individual Symptom Severity Assessments (VAS) 
• AE assessment  
• Concomitant medication review 
• BCVA assessment 
• Self-instillation of ocular lubricant and Drop Discomfort assessment (VAS) 
• Slit-Lamp biomicroscopy  
• FCS  
• Inclusion and exclusion criteria assessment. Any subject who does not meet eligibility 
requirements will be designated as Visit 2 Screen Failure and discontinued from the study 
Upon verification of study eligibility, subjects will be randomized to receive either VOS or 
Restasis®.  
Post-Randomization  
The following procedures will be performed after randomization:  
• IP administration: the unmasked dedicated dosing coordinator will administer the first dose 
of IP to the subject OU 


 
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Note: IP administration should not take place until at least 2 hours after administration 
of ocular lubricant. 
• Drop Discomfort assessment: A masked site staff will administer the Drop Discomfort 
VAS to the subject and instruct the subject to complete the Drop Discomfort VAS at  
1-minute and 5-minutes post-dose 
• Assess for occurrence of any AEs 
• IP dispensation: The unmasked dedicated dosing coordinator will dispense the IP, 
provide instructions for IP administration and storage conditions  
• Dosing Diary and VAS scales dispensation: Train the subjects on the completion of the 
daily dosing diary and VAS scales  
• Evening contact scheduling: Masked site staff will schedule and contact the subject in the 
evening of the clinic visit to prompt administration of the next dose and completion the 
Drop Discomfort VAS  
• Subjects should be reminded to withhold AM dose of IP on morning of next clinic visit 
and to return all used and unused IP 
Subject will be scheduled to return for Visit 3 on Day 7 ±2 days. 
PM Contact with Patient: 
• Masked site staff will call subject to prompt IP administration and will remain on call to 
facilitate completion of the Drop Discomfort VAS at 1-minute and 5-minutes post-dose 
8.2.2.2 VISIT 3 (Treatment Day 7 ±2) 
The site staff will perform/assess the following procedures:  
• SANDE 
• Individual Symptom Severity Assessments (VAS) 
• AE assessment 
• Concomitant medication review 
• Unmasked dedicated dosing coordinator will collect returned carton containing used and 
unused IP ampules 
• Unmasked dedicated dosing coordinator will collect Dosing Diary, Drop Comfort VAS 
and dispense new Dosing Diary and Drop Comfort VAS 


 
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• Unmasked site staff will query the subject regarding compliance with dosing and the 
protocol. If the subject has not been compliant with the dosing regimen, record this in the 
source document and eCRF and discuss proper compliance with the subject 
• BCVA assessment 
• IP Administration:  
− 
The unmasked dedicated dosing coordinator will administer the AM dose of IP in 
the clinic 
• Drop Discomfort VAS: 
− 
The masked site staff will administer the Drop Discomfort VAS at 1-minute and  
5-minutes post-dose 
• Assess for occurrence of any AEs following instillation 
• Unmasked dedicated dosing coordinator will dispense IP to the subject  
• FCS 
• Evening contact scheduling: Masked site staff will schedule and contact the subject in the 
evening of the clinic visit to prompt administration of the next dose and completion the 
Drop Discomfort VAS  
• Remind subject to withhold AM dose of IP on morning of next clinic visit and to return all 
used and unused IP 
Schedule the subject to return in 1 week for Visit 4 on Day 14 ±2 days. 
PM Contact with Patient: 
• Masked site staff will call subject to prompt IP administration and will remain on call to 
facilitate completion of the Drop Discomfort VAS at 1-minute and 5-minutes post-dose 
8.2.2.3 VISIT 4 (Treatment Day 14 ±2) 
The site staff will perform/assess the following procedures: 
• SANDE 
• Individual Symptom Severity Assessments (VAS) 
• AE assessment 


 
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• Concomitant medication review 
• Unmasked dedicated dosing coordinator will collect returned carton containing used and 
unused IP ampules 
• Unmasked dedicated dosing coordinator will collect Dosing Diary, Drop Comfort VAS 
and dispense new Dosing Diary and Drop Comfort VAS. 
• Unmasked site staff will query the subject regarding compliance with dosing and the 
protocol. If the subject has not been compliant with the dosing regimen, record this in the 
source document and eCRF and discuss proper compliance with the subject 
• BCVA assessment 
• IP Administration:  
− 
The unmasked dedicated dosing coordinator will administer the AM dose of IP in 
the clinic.  
• Drop Discomfort VAS: 
− 
The masked site staff will administer the Drop Discomfort VAS at 1-minute and  
5-minutes post-dose 
• Assess for occurrence of any AEs following instillation 
• Unmasked dedicated dosing coordinator will dispense IP to the subject 
• FCS 
• Unanesthetized STT This should be performed no less than 1-hour following the 
administration of IP and at least 20 minutes following FCS 
• Evening contact scheduling: Masked site staff will schedule and contact the subject in the 
evening of the clinic visit to prompt administration of the next dose and completion the 
Drop Discomfort VAS 
• Remind subject to withhold AM dose of IP on morning of next clinic visit and to return all 
used and unused IP 
Schedule the subject to return in 2 weeks for Visit 5 on Day 28 ±2 days.  
PM Contact with Patient: 


 
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• Masked site staff will call subject to prompt IP administration and will remain on call to 
facilitate completion of the Drop Discomfort VAS at 1-minute and 5-minutes post-dose. 
 
8.2.2.4 VISIT 5 (End of Treatment Day 28 ± 2) 
PM Contact with Patient: (Evening Prior to Visit 5) 
• Masked site staff will call subject to prompt IP administration and will remain on call to 
facilitate completion of the Drop Discomfort VAS at 1-minute and 5-minutes post-dose 
During the visit the site staff will perform/assess the following procedures: 
• SANDE 
• Individual Symptom Severity Assessments (VAS) 
• AE assessment 
• Concomitant medication review 
• Unmasked dedicated dosing coordinator will collect returned carton containing used and 
unused IP ampules 
• Unmasked dedicated dosing coordinator will collect Dosing Diary and Drop Comfort 
VAS. 
• Unmasked site staff will query the subject regarding compliance with dosing and the 
protocol. If the subject has not been compliant with the dosing regimen, record this in the 
source document and eCRF and discuss proper compliance with the subject 
• BCVA assessment 
• Slit-Lamp biomicroscopy 
• UPT for WOCBP 
• IP Administration:  
− 
The unmasked dedicated dosing coordinator will administer the AM dose of IP in 
the clinic 
• Drop Discomfort VAS: 


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− 
The masked site staff will administer the Drop Discomfort VAS at 1-minute and 5-
minutes post-dose 
• 
FCS 
• Unanesthetized STT. This should be performed no less than 1-hour following the 
administration of IP and at least 20 minutes following FCS 
Schedule the subject to return in 3 days for the post-treatment follow-up visit. 
 
8.2.3 Unscheduled Visits 
Any visits or procedures performed beyond those specified within the protocol must be 
documented in the Unscheduled Visit pages of the eCRF. Unscheduled visits may include but 
are not limited to reporting adverse events (AEs), changes in concomitant medications, or 
ophthalmic assessments as deemed appropriate by an appropriately qualified physician. If the 
subject is discontinuing study participation at the unscheduled visit, the eCRFs for Visit 5 
should be completed rather than the eCRFs for an Unscheduled Visit. 
8.2.4 End of Study (or Early Discontinuation) Procedures 
On completion of treatment at Day 28 or earlier if subject is discontinued/withdrawn early, all 
assessments for Visit 5 (end of study or early termination, see Section 8.2.2.4) will be 
completed per the Schedule of Events. See also Section 5.5, Withdrawal of Subjects, for further 
information on withdrawal procedures and criteria. 
8.2.5 Follow-up Procedures 
8.2.5.1 VISIT 6 (Post-Treatment Follow-Up +3 Days) 
Visit 6 should be conducted 3 days after End of Treatment (+3 Day window). During the visit, 
the site staff will perform/assess the following procedures: 
• AE assessment 
• Concomitant medication review 
• BCVA assessment 
• Dilated Ophthalmoscopy 
Subjects are discharged from the study and instructed to resume their normal prior ocular 
therapy. 


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9. EVALUATION, RECORDING AND REPORTING OF AES AND 
SAES 
9.1 
Definitions 
9.1.1 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 adverse event 
(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. 
9.1.2 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. 
9.1.3 Unexpected ADR 
An adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g., Investigator's Brochure for an unapproved investigational medicinal 
product).  
9.1.4 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 which 
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 informed consent form (ICF).  
9.1.5 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 suspected unexpected serious adverse reaction (SUSAR). 
9.2 
Adverse Event Descriptors 
9.2.1 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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9.2.2 Causal Relationship Categorization 
An Investigator who is qualified in medicine must make the determination of relationship to 
the study treatment 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. 
9.2.3 Outcome Categorization 
Outcome may be classified as recovered without sequelae; recovered with sequelae; improved; 
worsened; ongoing; ongoing at end of study; 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 SAE reporting form. SAEs that are ongoing at the time of death will have an outcome of 
“unknown” recorded. SAEs resulting in a fatal outcome will have an outcome of “fatal” 
recorded. 
9.2.4 Symptoms of the Disease Under Study 
Symptoms and fluctuations in laboratory parameters related to the disease under study 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 or laboratory parameters, however, will be recorded as an AE and 
clearly marked as worsening or by the subject’s worst observed intensity. The Investigator will 
be required to assess the relationship to disease under study for each AE as related or not 
related. An AE will not be able to be assessed as related to both disease under study and related 
to study treatment. 
9.2.5 Abuse, Misuse, Overdose and Medication Error 
All AEs of special interest such as study treatment abuse, misuse, overdose, and medication 
error must be documented in the subject’s eCRF and source documentation. If any occurrence 
of abuse, misuse, overdose, or medication errors leads to any event that fulfils any seriousness 
criteria, the event has to be reported as an SAE. 
9.3 
Reporting Procedure for AEs, SAEs, and Pregnancy 
9.3.1 Adverse Events 
All AEs observed from time of signing of the ICF will be recorded in the subject's source 
documentation. This applies to all AEs regardless of presumed relationship to the study drug. 
For screen failure subjects, any AEs and SAEs occurring during the screening period (after 
informed consent) will be recorded in the subject’s source documentation only and will not be 
collected on the eCRF. Adverse events leading to discontinuation of study drug must be 
collected. 
If any AE is reported, the date of onset, relationship to disease under study, relationship to 
study treatment, 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 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. 
The AE reporting period begins at the time the ICF is signed by the subject. For screen failure 
subjects, any AEs and SAEs occurring during the screening period will be recorded in the 
subject’s source documentation only. For enrolled subjects (i.e., those who successfully 
complete screening), the AE reporting period ends at the Follow-Up visit (Visit 6). 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 documents. If the subject reports 


 
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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. This 
information should be collected prior to completion of assessments at all study visits (with the 
exception of the SANDE and Individual Symptom Assessment VAS). In addition, any 
symptoms/conditions reported during assessments and deemed to be clinically significant by 
the Investigator will be considered AEs. 
9.3.2 Serious Adverse Events 
For screen failure subjects, any SAEs occurring during the screening period (after informed 
consent) will be recorded in the subject’s source documentation only and will not be collected 
on the eCRF. 
For enrolled subjects (i.e., those who successfully complete screening), all SAEs occurring 
after the signing of the ICF will be reported to 
 within 24 hours 
of the Investigator, designee, or site staff’s knowledge of the event regardless of relationship 
to study drug or relationship to disease under study. For enrolled subjects, all SAEs will be 
reported on a paper SAE Reporting Form, and recorded in the AE section of the subject’s eCRF 
and source documentation. 
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: 
• Site staff will complete the paper SAE report form and fax to 
 at 
 
within 24 hours.  
• Only in cases where the site is unable to fax the SAE form, site staff will send the SAE 
form by email to:
 
Site staff must also enter the available SAE information in the AE section of the subject’s 
eCRF in a timely manner. 
All initial and follow-up SAE must be reported by the Investigator to 
 within 24 hours of 
becoming aware of the event. 


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All SAEs, regardless of causality, will be reported from the time the ICF is signed until 30 days 
following the last study visit or 30 days after last study treatment administration in subjects 
who withdraw or discontinue prior to study completion. No formal study visit is required but 
Investigators must report any SAEs that occur during this 30-day period on a paper SAE 
Reporting Form to 
. 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. 
All recorded SAEs, regardless of relationship to disease under study or relationship to study 
treatment, 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. 
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. A rationale for the 
assessment of a causal relationship must be provided by the Investigator. The Investigator will 
also be required to assess the relationship to 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. Any safety information that is obtained after the follow-up visit 
(Visit 6) will be documented in the safety database only. 
A death occurring during the study or which comes to the attention of the Investigator within 
30 days after the last study visit (including the follow-up visit) or until 30 days after the last 
study treatment administration, whichever is longer, whether considered treatment related or 
not, must be reported to Aurinia. If the subject died, the SAE report should include the cause 
of death as the event term and whether or not the death was related to study treatment, 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. 
Additional follow-up information must be reported to 
 on a paper SAE Reporting Form, 
and the AE section of the subject’s eCRF updated, 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 
 by the reporting procedures described above. 
The Investigator is encouraged to discuss with the study Medical Monitor when the issue of 
seriousness is unclear or questionable. 
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAE) from the Sponsor will file it along with 


 
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the IB and will notify the IRB/Independent Ethics Committee (IEC) if appropriate, according 
to local requirements. 
The Sponsor or its representative will be responsible for determining and, in turn, reporting 
SAEs to Regulatory Authorities according to the applicable regulatory requirements. 
9.3.3 Pregnancy 
Pregnancy occurring in a female subject or in the partner of a male subject should be reported 
to 
 within 24 hours of becoming aware of the event using the Pregnancy Reporting Form. 
The Investigator should counsel the subject, and in the case of a male subject, the subject’s 
partner, discuss the risks of continuing with the pregnancy and the possible effects on the fetus. 
A female subject must immediately inform the Investigator if she becomes pregnant during the 
study. Monitoring of the pregnancy in a female subject should continue until conclusion of the 
pregnancy. In case of a pregnancy in the partner of a male subject, the Investigator should 
obtain informed consent of the pregnant partner prior to monitoring of the pregnancy. 
Women 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). 
All pregnancies, subject or partner of a subject, that occur during the study or come to the 
attention of the Investigator within 30 days after the last study visit (including the Follow-up 
Visit) or until 30 days after last study treatment administration, whichever is longer, must be 
reported to 
 by the reporting procedures described above. 
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 9.3.2, 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 complete the paper Pregnancy report form and fax to 
 
within 24 hours.  


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• Only in cases where the site is unable to fax the Pregnancy report, site staff will send the 
Pregnancy report by email to: 
 


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10. STATISTICAL ANALYSIS 
10.1 Statistical Methods 
Complete details of the statistical and analytical methods will be provided in a formal 
Statistical Analysis Plan (SAP) which will be finalized prior to the database lock. A general 
description of the planned methods is provided below. Any deviation from the SAP will be 
noted and explained in the Clinical Study Report. 
All statistical analyses will be undertaken at study closure and will incorporate all endpoints. 
10.2 Sample Size and Power Calculations 
The study will include approximately 90 male or female subjects. 
The primary analysis will use a t-test and will assess the difference in change from baseline in 
Drop Discomfort VAS scores (range 0 to 100 mm) 1-minute post-Dose 1 instillation between 
the two treatment groups.  
A sample size of 38 subjects per group (76 in total) will provide 90% power assuming: 
• A mean change from baseline Drop Discomfort VAS score of +30 mm for subjects 
randomized to Restasis® 
• A mean change from baseline Drop Discomfort VAS score of +15 mm for those 
randomized to VOS 
• These assumed mean changes lead to a 15 mm lower change from baseline in VAS scores 
for VOS compared to Restasis® 
• A common standard deviation of 20 mm 
• A 2-sided alpha of 5% 
Under the same assumptions, the study will have at least 80% power if the common standard 
deviation for the discomfort score were to be 23 mm. 
The study also provides 80% power should the treatment difference in discomfort scores be 13 
(common standard deviation=20 mm). 
To allow for 15% dropouts, approximately 90 subjects will be randomized. 


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10.3 Populations 
10.3.1 Intent-to-Treat Set 
The tolerability and efficacy analysis will be based on the intent-to-treat (ITT) principles and 
will consist of all randomized subjects who receive at least 1 dose of study treatment.  
10.3.2 Per Protocol  
The per-protocol set will be a subset of subjects in the ITT population who do not have any 
major protocol violations (to be defined prior to unmasking). 
10.3.3 Safety Set 
The safety analysis will consist of all randomized subjects who receive at least 1 dose of study 
treatment. The subjects in this group will be analyzed based on the treatment they received. 
10.4 Concomitant Therapy 
All concomitant medications will be coded by the World Health Organization (WHO) 
Anatomical Therapeutic Chemical Drug Reference List classification. The version used will 
be provided in the Clinical Study Report. 
10.5 Endpoint Evaluations 
10.5.1 Primary Endpoint 
The primary endpoint is the change from baseline to 1-minute post-instillation of IP in Drop 
Discomfort VAS score at Visit 2. The baseline measure will be taken 1-minute following 
Refresh Plus® administration at least 2 hours prior to IP administration. 
10.5.2 Secondary Endpoints 
10.5.2.1 
Key Secondary/Efficacy Endpoints 
• Change from baseline in Drop Discomfort VAS score 
• Change from baseline in each of the 6 Individual Symptom Severity Assessments (VAS) 
• Change from baseline of the sum of the Individual Symptom Severity Assessments (VAS 
Total Symptom Summary Score)  
• Change from baseline in SANDE score  
• Change in unanesthetized STT score  
• Change from baseline in FCS total score (NEI/Industry Workshop 0-15 scale) Safety 
Endpoints 


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10.5.2.2 
Safety Endpoints 
• Treatment-emergent adverse events (TEAEs) 
• Change from baseline in BCVA 
• Changes from baseline in Slit-Lamp Biomicroscopy  
• Changes from screening in Dilated Ophthalmoscopy 
10.6 Statistical and Analytical Methods 
10.6.1 Primary Analysis 
The primary endpoint is measured on a VAS and will be summarized and analyzed as 
continuous data. Summaries of VAS scores (absolute and change from baseline) by treatment 
group will be displayed for each VAS assessment (minutes 1, 5 and overall mean) at each visit. 
Should the data meet the necessary assumptions (normality and equal variance in both 
treatment groups), then the treatment groups will be compared using a t-test. If assumptions 
are violated, the Wilcoxon rank sum test will be used. If needed, transformations will be 
considered in order to meet the necessary assumptions. 
10.6.2 Secondary Efficacy Analysis 
Descriptive statistical summary (sample size, mean, standard deviation, median, minimum and 
maximum) will be presented by treatment group for each endpoint. Changes from 
randomization/baseline will be compared between VOS and Restasis® using a two-sample t-
test or the Wilcoxon rank sum test. Further details will be addressed in the SAP. 
10.6.3 Safety Analysis 
Adverse events will be aggregated by System Organ Class and preferred term and presented 
as summary tables. Other safety endpoints will be summarized by visit as absolute values and 
changes from baseline (as appropriate). Endpoints with specific ranges will have counts of 
values falling outside of the range summarized by visit and overall.  
10.7 Safety Evaluations 
Safety evaluations include: 
• Treatment-emergent adverse events (TEAEs) 
• BCVA 
• Slit-Lamp Biomicroscopy  
• Dilated Ophthalmoscopy 


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10.8 Interim Analyses 
No interim analyses are planned for this study. 
10.9 Other Evaluations 
N/A 


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11. ETHICAL CONDUCT OF THE STUDY 
The study will be conducted according to the principles of the World Medical Association’s 
Declaration of Helsinki and the ICH guidelines for GCP. Aurinia will ensure that the study 
complies with all local, federal, and country regulatory requirements. 
The Investigator must ensure the confidentiality of all subjects participating in the study. 
All anonymous data remains the property of Aurinia. 
11.1 Informed Consent 
The ICF used for the study must comply with the Declaration of Helsinki, federal regulations, 
and ICH guidelines; and must have been approved by the IRB/Ethics Committee (EC)/IEC 
prior to use. The Investigator or an authorized associate must explain the nature of the study 
and the treatment in such a manner that the subject is aware of potential benefits and risks. 
Subjects must also be informed that participation is voluntary and that they may withdraw from 
the study at any time without prejudice. Subjects must be provided sufficient time to consider 
participation, including discussion with family members prior to signing the ICF. 
Documentation of the discussion and the date of informed consent must be recorded in the 
source documentation. After signing the ICF, subjects will be enrolled into the study and 
assigned a subject identification number that will be used on all subject documentation. 
11.2 Institutional Review Board or EC/IEC 
The protocol, any protocol amendments and consent form for the proposed clinical study and 
any other documents required by the local IRB/EC/IEC must be submitted by the Investigator 
for review and approval to the IRB/EC/IEC. The Investigator must also ensure that the 
IRB/EC/IEC reviews the progress of the study on a regular basis and, if necessary, renews its 
approval of the study per local requirements. 


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12. QUALITY CONTROL AND QUALITY ASSURANCE 
The Investigator must ensure that all study-related site source data, study-related documents, 
and reports will be available, and that the provision of direct access for monitoring and auditing 
by Aurinia or its designees will be permitted. In addition, the Investigator must ensure that all 
study-related site source data, study-related documents, and reports will be made available for 
inspection by the appropriate Regulatory Authority and review by the IRB/EC/IEC. 
The Investigator is responsible for notifying Aurinia in advance of an impending regulatory 
inspection. He/she may request that Aurinia provide support for preparation, if necessary. The 
Investigator is required to provide updates to Aurinia on the ongoing activities during the 
inspection, respond to any citations/objectionable findings (i.e., U.S. Food and Drug 
Administration Form 483) and to share any follow-up responses from the Regulatory 
Authority. 
Accurate and reliable data collection will be assured by verification and cross-check of the 
eCRFs against the Investigator’s records by the Study Monitor (source document verification). 
An unmasked Monitor will also review the Investigator’s drug accountability records to ensure 
that the drug supplies are stored and dispensed appropriately. A comprehensive validation 
program will verify the data and queries will be generated for resolution by the Investigator. 
Throughout the study, Aurinia or its designee may review data as deemed necessary. 


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13. ADMINISTRATIVE PROCEDURES 
13.1 Sponsor’s Responsibilities 
13.1.1 Study Supplies 
Sites will be provided with all supplies required to manage this study. This will include but not 
be limited to the following: 
• Investigator file(s) (for filing of all study-related documentation) 
• Contact list of all relevant study personnel 
• eCRF and completion guidelines (or equivalent EDC system) 
• Study reference manual 
• All study forms (e.g., SAE, Pregnancy, Drug Accountability, etc.) 
13.1.2 Insurance 
Aurinia confirms that it carries liability insurance which protects nonemployee physicians or 
Investigators/study staff against claims for which they may become liable as a result of 
damages caused by Aurinia products used in clinical studies. Insurance coverage is not 
extended to damages that the Investigators or third parties may suffer by reason of acts of 
commission or omission on the part of such Investigators or third parties and that are not in 
accordance with accepted common medical practices (lege artis procedures). Aurinia will 
reimburse the subject for all study-related injuries provided that the injury does not arise from 
the subject’s misuse of the IP or failure to follow the Investigator’s instructions. 
13.1.3 Study Monitoring 
The study will be monitored by representatives of Aurinia (or designee, which may include a 
CRO). If not monitored by Aurinia, documentation of delegation will be described in the 
Clinical Trial Agreement. It is understood that the responsible Monitor will contact and visit 
the Investigator regularly and will be allowed, on request, to inspect the various records of the 
study (eCRFs and other pertinent data) provided that subject confidentiality is maintained in 
accordance with local requirements. 
It will be the Monitor's responsibility to inspect the eCRFs at regular intervals throughout the 
study (frequency outlined in a separate procedural document), to verify the adherence to the 
protocol and the completeness, consistency, and accuracy of the data being entered on them. 
The Monitor must have access to subject records needed to verify the entries on the eCRF. The 
Investigator (or his/her deputy) agrees to co-operate with the Monitor to ensure that any 
problems detected in the course of these monitoring visits are resolved. 


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13.2 Investigator’s Responsibilities 
13.2.1 Reporting and Recording of Data 
All required study data must be entered in the eCRF created for the study. Training on the 
system will be provided to all sites, including instructions on how to address missing data, 
corrections, query procedures, and electronic signatures. Only individuals who are identified 
on the authorized signature page may enter/correct data in the eCRF. For those subjects who 
withdraw before completion of the study, all available efficacy and safety data must be entered 
in the eCRF. Incomplete or inconsistent data on the eCRF will result in data queries addressed 
to the Investigator for resolution. 
13.2.2 Investigator Training 
All Investigators and their study personnel will receive training regarding the study procedures, 
study treatments, and GCP/regulations specific to the conduct of clinical studies. This training 
will take place prior to enrollment of the first subject at the study site and must be documented 
and filed in the Investigator’s Study Site File. 
13.2.3 Source Documentation 
The Investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. 
Subject clinical source documents would include subject hospital/clinic records, physician’s 
and nurse’s notes, appointment book, original laboratory reports, signed ICFs, consultant 
letters, and subject enrollment logs. These are to be separate and distinct from eCRFs. All data 
for the study must be available in source documentation, including oral and written 
communication with the subject regarding the study treatment (including the risks and benefits 
of the study). The date of informed consent must be recorded in the source documentation. 
The Investigator must arrange for the retention of all study documentation (such as eCRFs, 
research files, and master files) for the duration specified in their respective site contract. The 
Investigator must keep these documents on file after completion or discontinuation of the study 
according to local governing guidelines. Archived data may be held electronically, provided 
that a back-up copy exists and that a hard copy can be generated if required. 
The Investigator must inform Aurinia immediately if any documents are lost, to be transferred 
to a different facility, or to be transferred to a different owner. 


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14. PROCEDURE FOR MODIFICATION OF PROTOCOL OR 
PREMATURE TERMINATION OF THE STUDY 
14.1 Protocol Waivers, Deviations and Violations 
Protocol waivers shall not be permitted. 
The Investigator should not implement any deviation from, or changes of the protocol without 
written agreement from Aurinia and prior documented approval/favorable opinion from the 
IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) to 
study subjects, or when change(s) involves only logistical or administrative aspects of the 
study. If the Investigator must implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to study subjects without prior written approval, the 
implemented deviation or change and the reasons for it should be submitted in a timely manner 
to Aurinia and to the IRB/IEC as required by applicable local requirements. 
The Investigator, or person designated by the Investigator, will document and record the 
preventative and/or corrective measures for any deviation from the approved protocol. 
Accidental deviations from the protocol including violations of inclusion/exclusion criteria 
will be assessed as minor or major on a case-by-case basis. The criteria describing the 
deviation(s) and how they will be handled will be documented in the SAP. 
Any amendment to the protocol requires written approval/favorable opinion by the IRB/IEC 
prior to its implementation unless there are overriding safety reasons. 
In some instances, an amendment may require a change to the ICF. The Investigator must 
receive an IRB/IEC approval/favorable opinion concerning the reviewed document prior to 
administering to study subjects. 
14.2 Study Termination 
Aurinia reserves the right to terminate the study in its entirety or at a site at any time. Reasons 
for termination may include but are not limited to the following: unsatisfactory subject 
enrollment with respect to quality and/or quantity, site is unable to comply with the 
requirements of the protocol or GCP, or data recording is inaccurate and/or incomplete. 
In terminating the study, Aurinia and the Investigator will assure that adequate consideration 
is given to the protection of the subjects. Both parties will arrange the procedures on an 
individual basis after review and consultation and in accordance with the study contract. 


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15. POLICY FOR PUBLICATION AND PRESENTATION OF DATA 
Aurinia is committed to the timely communication of data from clinical research trials, 
following the Pharmaceutical Research and Manufacturers of America principles (The 
Pharmaceutical Research and Manufacturers of America (PhrMa), Principals on Conduct of 
Clinical Trials/Communication of Clinical Trials; December 2014). Where possible, 
authorship will be agreed at the beginning of the study. The authors will form a publication 
committee and this committee will propose and develop appropriate scientific manuscripts or 
abstracts from the study data. Investigators may not present or publish partial or complete study 
results individually. Any manuscript or abstract proposed by the Investigators must be 
reviewed and approved in writing by Aurinia before submission for publication. Names of all 
Investigators participating in the study will be included in the publication. 
The publication committee for a study will comprise of authors selected in adherence with the 
International Committee of Medical Journal Editors criteria (International Committee of 
Medical Journal Editors criteria; ICMJE.org) for authorship. If studies are multicenter, it may 
be appropriate to assign group authorship. 
In addition, certain Aurinia employees involved in the design and conception of the protocol, 
study management and data analysis and interpretation are qualified authors and will be 
included in the publication committee. 


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16. REFERENCES  
1. Craig JP, Nichols KK, Akpek EK, Caffery B, Dua HS, Joo CK et al. TFOS DEWS II 
Definition and Classification Report. Ocul Surf. 2017;15:276-83.  
2. The definition and classification of dry eye disease report of the Definition and 
Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul 
Surf. 20017 Apr;5(2):75-92. 
3. Chauhan S, Dana R. Role of Th17 Cells in the Immunopathogenesis of Dry Eye 
Disease. Mucosal Immunol. 2009 Jul;2(4):375–6. 
4. Pflugfelder SC, Solomon A, Stern ME. The diagnosis and management of dry eye: a 
twenty-five-year review. Cornea. 2000;19(5):644–9.  
5. Stevenson W, Chauhan SK, Dana R. Dry eye disease: An immune-mediated ocular 
surface disorder. Arch Ophthalmol. 2012 Jan;130(1):90-100. 
6. Restasis® (cyclosporine ophthalmic emulsion) 0.05% for topical ophthalmic use. 
Allergan, Irvine USA. 2017 Jul. 
7. Xiidra® (lifitegrast ophthalmic solution) 5%, for topical ophthalmic use. Shire US Inc, 
Lexington USA. 2017 Nov. 
8. Granelli-Piperno A, Andrus L, Steinman RM. Lymphokine and nonlymphokine mRNA 
levels in stimulated human cells: kinetics, mitogen requirements, and effects of 
cyclosporine A. J Exp Med. 1986 Apr;163:922-37. 
9. Stepkowski S.M. Molecular targets for existing and novel immunosuppressive drugs. 
Expert Rev Mol Med. 2000. p. 1-6. 
10. Wiseman AC. Immunosuppressive medications. Clin J Am Soc Nephrol. 2016 
Feb;11:332-43. 
11. S07654 – 14-Day ocular tolerability and toxicity of LX214 in New Zealand whit rabbits 
with 14-Day recovery period. Lux Biosciences, Inc.; 2009 Apr 3. Report No.: S07654. 
12. S07655 – 14-Day ocular tolerability and toxicity of LX214 in beagle dogs with 14-day 
recovery period. Lux Biosciences, Inc.; 2009 Apr 8. Report No.: S07655. 
13. S08661 – Ocular tissue distribution of 14C-LX214 following a single or multiple 
ophthalmic administration to New Zealand White Rabbit. Lux Biosciences, Inc 23 Mar 
2009. Report No.: S08661. 


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14. S15389-00 – To evaluate the efficacy of Voclosporin Ophthalmic Solution (0.2% 
voclosporin) in naturally occurring keratoconjunctivitis sicca in client owned dogs with 
twice-daily administration. Intervet Inc (d/b/a Merck Animal Health), 28 Apr 2017. 
Report No.: S15389-00. 
15. Clinical Study Report LX214-01. 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. Final report. Lux Biosciences Inc. 2010 Jul 02. 
16. Investigator’s Brochure Voclosporin Ophthalmic Solution Dry Eye Disease. Final 
Report V1.0. Aurinia Pharmaceuticals Inc.; 30 January 2018. 
 
 
 
 


 
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17. APPENDICES 
Appendix 1 Tolerability Assessment 
Drop Discomfort Assessment (Tolerability Assessment): 
Subject will rate Drop Discomfort using a VAS. Subject will complete this assessment in the 
clinic following dosing of OTC ocular lubricant at Visit 2 and in the clinic following the AM 
dose of IP at Visits 2, 3, 4 and 5 and again at home following the PM dose of IP on the evenings 
of Visits 2, 3, 4 and the evening prior to Visit 5. The assessment will be completed at 1-minute 
and 5-minutes post-instillation of OTC ocular lubricant or IP. 
Subject Instructions: Please rate how your eyes feel following instillation of the study drug by placing a vertical 
mark on the horizontal line. 0 corresponds to “no discomfort” and 100 corresponds to “maximal discomfort” 
You will rate your Drop Discomfort at 1-minute and 5- minutes following instillation of the study drug.  
 
 
Eye Discomfort 
 
 0                                                                                                100 
|                                                                                                     |        
 
 
 
 
 
 
 
 
 


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Appendix 2 Eye Dryness Assessments 
The following assessments are included as a part of the overall assessment of the presence and 
severity of DED: 
• Fluorescein Corneal Staining (FCS) 
• Unanesthetized STT 
• SANDE 
• Individual Symptom Severity Assessments  
o VAS assessments of six symptoms: Burning/Stinging, Foreign Body Sensation, 
Photophobia, Eye Pain, Eye Dryness, Itching 
 


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Appendix 3 Symptom Assessment in Dry Eye (SANDE) 
 
 


 
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Appendix 4 Individual Symptom Severity Assessments using Visual Analog Score 
(VAS) 
 
 
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 
|                                                                                                     |        
 
Foreign Body 
Sensation (grain of 
sand/grittiness) 
 
  0                                                                                               100 
|                                                                                                     |        
 
Photophobia 
 
  0                                                                                               100 
|                                                                                                     |        
 
Eye Pain 
 
  0                                                                                               100 
|                                                                                                     |        
 
Eye Dryness 
 
  0                                                                                               100 
|                                                                                                     |        
 
Itching 
 
  0                                                                                               100 
|                                                                                                     |        
 
 
 
 
 


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Appendix 5 Slit-Lamp Biomicroscopy 
This procedure will be the performed in the same manner for all subjects observed at the 
Investigator’s site.  
Lashes  
             
0 = Normal 
 
1 = Abnormal 
Eyelid Erythema 
  
 
0 = Normal, without any redness 
 
 
1 = Abnormal 
Edema  
 
   
 
  0 = Normal, no swelling of the lid tissue 
 
  1 = Abnormal 
Conjunctiva Edema 
  
   
 
  0 = Normal, no swelling of the conjunctiva 
 
 
  1 = Abnormal 
Cornea Infiltrates 
 
 
 0 = Absent 
 
 
 1 = Present 
Endothelial Changes 
 
 0 = Normal, None 
 
 1 = Abnormal, pigment, keratoprecipitates, guttata 
Edema 
  
 
 0 = Normal None, transparent and clear 
 
 1 = Abnormal 
Anterior Chamber Cells 
 
  
 0 = Normal, No cells seen 
 
  
 1 = Abnormal (+ to +++ cells) 
Flare 
 
  
 0 = Normal, No Tyndall effect 
   
  
 1 = Abnormal, Tyndall beam in the anterior chamber 
Lens Pathology 
 


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0 = Normal; no opacity in the lens 
1 = Abnormal; existing opacity in the lens; aphakic or pseudophakic eyes or 
other abnormal findings. 
Sclera Injection 
 
0 = Normal, without any redness  
 
1 = Abnormal 
 


 
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Appendix 6 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 
 
 
 


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Appendix 7 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. 
 
 
 


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Appendix 8 Restasis® Package Insert, July 2017. 
 
 
 
 
 


 
 
HIGHLIGHTS OF PRESCRIBING INFORMATION 
These highlights do not include all the information needed to use 
RESTASIS® 0.05% safely and effectively. See full prescribing 
information for RESTASIS®. 
 
RESTASIS® (cyclosporine ophthalmic emulsion) 0.05% 
For topical ophthalmic use 
Initial U.S. Approval: 1983 
 
 
____________________________INDICATIONS AND USAGE_______________________________ 
RESTASIS® is a calcineurin inhibitor immunosuppressant indicated to 
increase tear production in patients whose tear production is presumed to be 
suppressed due to ocular inflammation associated with keratoconjunctivitis 
sicca  Increased tear production was not seen in patients currently taking 
topical anti-inflammatory drugs or using punctal plugs  (1) 
 
________________________DOSAGE AND ADMINISTRATION_________________________ 
Instill one drop of RESTASIS® ophthalmic emulsion twice a day in each eye 
approximately 12 hours apart  (2) 
 
 
 
 
 
_______________________DOSAGE FORMS AND STRENGTHS_______________________ 
Cyclosporine ophthalmic emulsion 0 5 mg/mL (3) 
 
_________________________________CONTRAINDICATIONS________________________________ 
• 
Hypersensitivity (4) 
 
_________________________WARNINGS AND PRECAUTIONS__________________________ 
• 
To avoid the potential for eye injury and contamination, be careful not to 
touch the vial tip to your eye or other surfaces  (5 1) 
 
______________________________ADVERSE REACTIONS___________________________________ 
The most common adverse reaction following the use of RESTASIS® was 
ocular burning (17%)  (6 1) 
 
To report SUSPECTED ADVERSE REACTIONS, contact Allergan at 1-
800-433-8871 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 
 
 
See 17 for PATIENT COUNSELING INFORMATION. 
 
Revised: 07/2017 
 
 
FULL PRESCRIBING INFORMATION: CONTENTS* 
 
1 INDICATIONS AND USAGE 
2 DOSAGE AND ADMINISTRATION 
3 DOSAGE FORMS AND STRENGTHS 
4 CONTRAINDICATIONS 
5 WARNINGS AND PRECAUTIONS 
    5 1 Potential for Eye Injury and Contamination  
    5 2 Use with Contact Lenses  
6 ADVERSE REACTIONS 
    6 1 Clinical Trials Experience 
    6 2 Post-marketing Experience 
8 USE IN SPECIFIC POPULATIONS 
    8 1 Pregnancy 
    8 2 Lactation 
    8 4 Pediatric Use 
    8 5 Geriatric Use 
 
 
 
     
11 DESCRIPTION 
12 CLINICAL PHARMACOLOGY 
    12 1 Mechanism of Action 
    12 3 Pharmacokinetics  
13 NONCLINICAL TOXICOLOGY 
    13 1 Carcinogenesis, Mutagenesis, Impairment of Fertility 
14 CLINICAL STUDIES 
16 HOW SUPPLIED/STORAGE AND HANDLING 
17 PATIENT COUNSELING INFORMATION 
 
* Sections or subsections omitted from the full prescribing information are not 
listed  
 


 
 
FULL PRESCRIBING INFORMATION 
 
1 
INDICATIONS AND USAGE 
RESTASIS® ophthalmic emulsion is indicated to increase tear production in patients whose tear production is 
presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca. Increased tear 
production was not seen in patients currently taking topical anti-inflammatory drugs or using punctal plugs. 
 
2 
DOSAGE AND ADMINISTRATION 
Invert the unit dose vial a few times to obtain a uniform, white, opaque emulsion before using. Instill one drop 
of RESTASIS® ophthalmic emulsion twice a day in each eye approximately 12 hours apart. RESTASIS® can 
be used concomitantly with lubricant eye drops, allowing a 15-minute interval between products. Discard vial 
immediately after use. 
 
3 
DOSAGE FORMS AND STRENGTHS 
Ophthalmic emulsion containing cyclosporine 0.5 mg/mL 
 
4 
CONTRAINDICATIONS 
RESTASIS® is contraindicated in patients with known or suspected hypersensitivity to any of the ingredients in 
the formulation. 
 
5 
WARNINGS AND PRECAUTIONS 
 
5.1  
 
Potential for Eye Injury and Contamination 
Be careful not to touch the vial tip to your eye or other surfaces to avoid potential for eye injury and 
contamination. 
 
5.2  
 
Use with Contact Lenses 
RESTASIS® should not be administered while wearing contact lenses. Patients with decreased tear production 
typically should not wear contact lenses. If contact lenses are worn, they should be removed prior to the 
administration of the emulsion. Lenses may be reinserted 15 minutes following administration of RESTASIS® 
ophthalmic emulsion. 
 
6 
ADVERSE REACTIONS 
 
The following serious adverse reactions are described elsewhere in the labeling:  
• Potential for Eye Injury and Contamination [see Warnings and Precautions (5.1)] 
 
6.1 
Clinical Trials Experience  
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the 
clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not 
reflect the rates observed in practice. 
 
In clinical trials, the most common adverse reaction following the use of RESTASIS® was ocular burning 
(17%). 
 
Other reactions reported in 1% to 5% of patients included conjunctival hyperemia, discharge, epiphora, eye 
pain, foreign body sensation, pruritus, stinging, and visual disturbance (most often blurring). 
 


 
 
6.2 
Post-marketing Experience 
The following adverse reactions have been identified during post approval use of RESTASIS®. Because these 
reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably 
estimate their frequency or establish a causal relationship to drug exposure.  
 
Reported reactions have included: hypersensitivity (including eye swelling, urticaria, rare cases of severe 
angioedema, face swelling, tongue swelling, pharyngeal edema, and dyspnea); and superficial injury of the eye 
(from the vial tip touching the eye during administration).  
 
8 
USE IN SPECIFIC POPULATIONS 
 
8.1  
 
Pregnancy 
Risk Summary 
Clinical administration of cyclosporine ophthalmic emulsion 0.05% is not detected systemically following 
topical ocular administration [see Clinical Pharmacology (12.3)], and maternal use is not expected to result in 
fetal exposure to the drug. Oral administration of cyclosporine to pregnant rats or rabbits did not produce 
teratogenicity at clinically relevant doses [see Data]. 
Data 
Animal Data 
At maternally toxic doses (30 mg/kg/day in rats and 100 mg/kg/day in rabbits), cyclosporine oral solution 
(USP) was teratogenic as indicated by increased pre- and postnatal mortality, reduced fetal weight and skeletal 
retardations. These doses (normalized to body surface area) are 5,000 and 32,000 times greater, respectively, 
than the daily recommended human dose of one drop (approximately 28 mcL) of cyclosporine ophthalmic 
emulsion 0.05% twice daily into each eye of a 60 kg person (0.001 mg/kg/day), assuming that the entire dose is 
absorbed. No evidence of embryofetal toxicity was observed in rats or rabbits receiving cyclosporine during 
organogenesis at oral doses up to 17 mg/kg/day or 30 mg/kg/day, respectively. These doses in rats and rabbits 
are approximately 3,000 and 10,000 times greater, respectively, than the daily recommended human dose. 
An oral dose of 45 mg/kg/day cyclosporine administered to rats from Day 15 of pregnancy until Day 21 
postpartum produced maternal toxicity and an increase in postnatal mortality in offspring. This dose is 7,000 
times greater than the daily recommended human dose. No adverse effects in dams or offspring were observed 
at oral doses up to 15 mg/kg/day (2,000 times greater than the daily recommended human dose). 
 
8.2  
 
Lactation 
Risk Summary 
Cyclosporine is known to appear in human milk following systemic administration, but its presence in human 
milk following topical treatment has not been investigated. Although blood concentrations are undetectable 
following topical administration of RESTASIS® ophthalmic emulsion [see Clinical Pharmacology (12.3)], 
caution should be exercised when RESTASIS® is administered to a nursing woman. The developmental and 
health benefits of breastfeeding should be considered along with the mother’s clinical need for RESTASIS® and 
any potential adverse effects on the breast-fed child from cyclosporine. 
 
8.4  
 
Pediatric Use 
Safety and efficacy have not been established in pediatric patients below the age of 16. 
 


 
 
8.5  
 
Geriatric Use 
No overall difference in safety or effectiveness has been observed between elderly and younger patients. 
 
11 
DESCRIPTION 
RESTASIS® (cyclosporine ophthalmic emulsion) 0.05% contains a topical calcineurin inhibitor 
immunosuppressant with anti-inflammatory effects. Cyclosporine’s chemical name is Cyclo[[(E)-(2S,3R,4R)-3-
hydroxy-4-methyl-2-(methylamino)-6-octenoyl]-L-2-aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-
N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl] and it has the 
following structure: 
 
Structural Formula 
 
                                                
Formula: C62H111N11O12        Mol. Wt.: 1202.6 
 
Cyclosporine is a fine white powder. RESTASIS® appears as a white opaque to slightly translucent 
homogeneous emulsion. It has an osmolality of 230 to 320 mOsmol/kg and a pH of 6.5-8.0. Each mL of 
RESTASIS® ophthalmic emulsion contains: Active: cyclosporine 0.05%. Inactives: glycerin; castor oil; 
polysorbate 80; carbomer copolymer type A; purified water; and sodium hydroxide to adjust pH. 
 
12 
CLINICAL PHARMACOLOGY 
 
12.1 
 
Mechanism of Action 
Cyclosporine is an immunosuppressive agent when administered systemically. 
 
In patients whose tear production is presumed to be suppressed due to ocular inflammation associated with 
keratoconjunctivitis sicca, cyclosporine emulsion is thought to act as a partial immunomodulator. The exact 
mechanism of action is not known. 
 
12.3 
 
Pharmacokinetics 
Blood cyclosporine A concentrations were measured using a specific high pressure liquid chromatography-mass 
spectrometry assay. Blood concentrations of cyclosporine, in all the samples collected, after topical 
administration of RESTASIS® 0.05%, twice daily, in humans for up to 12 months, were below the quantitation 
limit of 0.1 ng/mL. There was no detectable drug accumulation in blood during 12 months of treatment with 
RESTASIS® ophthalmic emulsion. 
 


 
 
13 
NONCLINICAL TOXICOLOGY 
 
13.1 
 
Carcinogenesis, Mutagenesis, Impairment of Fertility  
Carcinogenesis 
Systemic carcinogenicity studies were conducted in male and female mice and rats. In the 78-week oral (diet) 
mouse study, at doses of 1, 4, and 16 mg/kg/day, evidence of a statistically significant trend was found for 
lymphocytic lymphomas in females, and the incidence of hepatocellular carcinomas in mid-dose males 
significantly exceeded the control value. 
 
In the 24-month oral (diet) rat study, conducted at 0.5, 2, and 8 mg/kg/day, pancreatic islet cell adenomas 
significantly exceeded the control rate in the low dose level. The hepatocellular carcinomas and pancreatic islet 
cell adenomas were not dose related. The low doses in mice and rats are approximately 80 times greater 
(normalized to body surface area) than the daily recommended human dose of one drop (approximately 28 
mcL) of 0.05% RESTASIS® twice daily into each eye of a 60 kg person (0.001 mg/kg/day), assuming that the 
entire dose is absorbed.  
 
Mutagenesis 
Cyclosporine has not been found to be mutagenic/genotoxic in the Ames Test, the V79-HGPRT Test, the 
micronucleus test in mice and Chinese hamsters, the chromosome-aberration tests in Chinese hamster bone-
marrow, the mouse dominant lethal assay, and the DNA-repair test in sperm from treated mice. A study 
analyzing sister chromatid exchange (SCE) induction by cyclosporine using human lymphocytes in vitro gave 
indication of a positive effect (i.e., induction of SCE). 
 
Impairment of Fertility 
No impairment in fertility was demonstrated in studies in male and female rats receiving oral doses of 
cyclosporine up to 15 mg/kg/day (approximately 2,000 times the human daily dose of 0.001 mg/kg/day 
normalized to body surface area) for 9 weeks (male) and 2 weeks (female) prior to mating. 
 
14 
CLINICAL STUDIES  
 
Four multicenter, randomized, adequate and well-controlled clinical studies were performed in approximately 
1,200 patients with moderate to severe keratoconjunctivitis sicca. RESTASIS® demonstrated statistically 
significant increases in Schirmer wetting of 10 mm versus vehicle at six months in patients whose tear 
production was presumed to be suppressed due to ocular inflammation. This effect was seen in approximately 
15% of RESTASIS® ophthalmic emulsion-treated patients versus approximately 5% of vehicle-treated patients. 
Increased tear production was not seen in patients currently taking topical anti-inflammatory drugs or using 
punctal plugs. 
 
No increase in bacterial or fungal ocular infections was reported following administration of RESTASIS®. 
 
16 
HOW SUPPLIED/STORAGE AND HANDLING 
 
RESTASIS® ophthalmic emulsion is packaged in sterile, preservative-free single-use vials. Each vial contains 
0.4 mL fill in a 0.9 mL LDPE vial; 30 or 60 vials are packaged in a polypropylene tray with an aluminum 
peelable lid. The entire contents of each tray (30 vials or 60 vials) must be dispensed intact. 
 
30 Vials 0.4 mL each - NDC 0023-9163-30 
60 Vials 0.4 mL each - NDC 0023-9163-60 
 
Storage: Store at 15°-25 °C (59°-77 °F). 


 
 
 
17 
PATIENT COUNSELING INFORMATION 
 
Handling the Container 
Advise patients to not allow the tip of the vial to touch the eye or any surface, as this may contaminate the 
emulsion. Advise patients to not touch the vial tip to their eye to avoid the potential for injury to the eye [see 
Warnings and Precautions (5.1)]. 
 
Use with Contact Lenses 
RESTASIS® should not be administered while wearing contact lenses. Patients with decreased tear production 
typically should not wear contact lenses. Advise patients that if contact lenses are worn, they should be removed 
prior to the administration of the emulsion. Lenses may be reinserted 15 minutes following administration of 
RESTASIS® ophthalmic emulsion [see Warnings and Precautions (5.2)]. 
 
Administration 
Advise patients that the emulsion from one individual single-use vial is to be used immediately after opening 
for administration to one or both eyes, and the remaining contents should be discarded immediately after 
administration. 
 
© 2017 Allergan. All rights reserved. 
All trademarks are the property of their respective owners.  
 
 
 
 
 
Patented. See www.allergan.com/patents 
Irvine, CA 92612 
Made in the U.S.A. 
 
71876US19 


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Appendix 9 Daily Dosing Diary 
Subjects will be asked to record each day the following information related to administration 
of study drug: 
• Date 
• Time of Administration 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_003.pdf: 
Voclosporin ophthalmic solution 
Aurinia Pharmaceuticals Inc. 
Protocol AUR-VOS-2017-01 
IND 102,279 
     
 
CONFIDENTIAL 
 
Page 1 of 38 
 
 
STATISTICAL ANALYSIS PLAN 
 
PROTOCOL TITLE: 
An Investigator-Masked, Randomized, Parallel-Group Study of 
the Ocular Tolerability of Voclosporin Ophthalmic Solution 
versus Restasis® in Subjects with Dry Eye Disease 
PROTOCOL NUMBER: 
AUR-VOS-2017-01 
STUDY DRUG: 
Voclosporin ophthalmic solution 
DEVELOPMENT PHASE: 
Phase 2 
SPONSOR: 
Aurinia Pharmaceuticals Inc. 
 
#1203 - 4464 Markham Street 
 
Victoria, BC 
 
V8Z 7X8 
 
Canada 
 
IND Number:  
102,279 
 
VERSION: 
Final 1.0 
 
VERSION DATE:  
13 September, 2018 
 
 
 
 
 
 
  




Voclosporin ophthalmic solution 
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Protocol AUR-VOS-2017-01 
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CONFIDENTIAL 
 
Page 3 of 38 
 
TABLE OF CONTENTS 
Signature Page .................................................................................................................................2 
TABLE of Contents .........................................................................................................................3 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1.0 
INTRODUCTION ........................................................................................................8 
2.0 
STUDY DESCRIPTION ............................................................................................10 
2.1 
Objectives ...................................................................................................................10 
2.2 
Study Design ...............................................................................................................10 
2.3 
Inclusion Criteria ........................................................................................................11 
2.4 
Exclusion Criteria .......................................................................................................12 
2.5 
Randomization ............................................................................................................13 
3.0 
STUDY ASSESSMENTS ..........................................................................................14 
3.1 
Description of Study Assessments ..............................................................................14 
3.1.1 
Symptom Assessment in Dry Eye (SANDE) .............................................................14 
3.1.2 
Individual Symptom Severity Assessments using VAS: ............................................14 
3.1.3 
Fluorescein Corneal Staining ......................................................................................14 
3.1.4 
Unanesthetized Schirmer Tear Test ............................................................................15 
3.1.5 
Drop Discomfort Assessment .....................................................................................15 
3.1.6 
Best Corrected Visual Acuity (BCVA) ......................................................................15 
3.1.7 
Ophthalmoscopy .........................................................................................................15 
3.1.8 
Slit-Lamp Biomicroscopy ...........................................................................................16 
3.2 
Adverse and Serious Adverse Events .........................................................................16 
3.2.1 
Adverse Event (AE) ....................................................................................................16 
3.2.2 
Adverse Drug Reaction (ADR) ..................................................................................16 
3.2.3 
Serious Adverse Event ................................................................................................16 
3.2.4 
Suspected Unexpected Serious Adverse Reaction (SUSAR) .....................................17 
3.2.5 
Treatment-Emergent Adverse Event (TEAE) ............................................................17 
3.2.6 
Intensity/Severity Categorization ...............................................................................17 
3.2.7 
Causal Relationship Categorization ............................................................................17 
3.2.8 
Outcome Categorization .............................................................................................18 
3.2.9 
Symptoms of the Disease Under Study ......................................................................18 
4.0 
SAMPLE SIZE AND POWER CONSIDERATIONS ...............................................19 


Voclosporin ophthalmic solution 
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Protocol AUR-VOS-2017-01 
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CONFIDENTIAL 
 
Page 4 of 38 
 
5.0 
ANALYSIS POPULATIONS ....................................................................................20 
5.1 
Efficacy Analysis Populations ....................................................................................20 
5.1.1 
Intent-to-Treat Set .......................................................................................................20 
5.1.2 
Per Protocol Set ..........................................................................................................20 
5.1.3 
Safety Analysis Set .....................................................................................................20 
6.0 
HANDLING OF MISSING DATA ............................................................................21 
6.1  
Conventions for Missing and Partial Dates ................................................................21 
6.2  
Missing/Partial Start/Stop Date of Adverse Events and Concomitant 
Medications .................................................................................................................21 
6.3  
Missing Last Dates of Study Drug Dosing .................................................................22 
6.4  
Missing Diagnosis Dates ............................................................................................22 
6.5  
Missing Safety Data ....................................................................................................22 
7.0 
STATISTICAL ANALYSIS ......................................................................................23 
7.1 
Calculation of Study Day: ..........................................................................................23 
7.2 
Subject Disposition .....................................................................................................23 
7.3 
Demographic and Baseline Characteristics ................................................................24 
7.4 
Treatment Compliance and Exposure .........................................................................24 
7.5 
Study Endpoints ..........................................................................................................25 
7.5.1 
Primary Endpoint ........................................................................................................25 
7.5.2 
Key Secondary/Efficacy Endpoints ............................................................................25 
7.5.3 
Safety Endpoints .........................................................................................................26 
7.5.4 
Exploratory Endpoints ................................................................................................26 
7.6 
Methods of Analysis ...................................................................................................26 
7.6.1 
Ordinal and Continuous Variables ..............................................................................26 
7.6.2 
Endpoints measured as a Proportions .........................................................................27 
7.6.3 
Other Variables ...........................................................................................................27 
8.0 
SAFETY EVALUATIONS ........................................................................................28 
8.1 
Adverse Events ...........................................................................................................28 
8.2 
Concomitant Medications ...........................................................................................29 
8.3 
Dry Eye History and Medical History ........................................................................29 
8.4 
Slit-Lamp Biomicroscopy ...........................................................................................29 
8.5 
Ophthalmoscopy/Dilated Fundoscopy ........................................................................30 
8.6 
Urine Pregnancy Test .................................................................................................30 


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9. 
CHANGES FROM THE PROTOCOL ......................................................................31 
10. 
INTERIM ANALYSIS ...............................................................................................32 
11. 
TABLES, LISTINGS AND FIGURES ......................................................................33 
APPENDIX 1: SCHEDULE OF EVENTS ...................................................................................37 


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LIST OF ABBREVIATIONS   
ADR 
Adverse drug reaction 
AE 
Adverse event 
ATC-WHO-DD 
Anatomical Therapeutic Chemical (Classification System)-World 
Health Organization-Drug Dictionary 
Aurinia 
Aurinia Pharmaceuticals Inc. 
BCVA 
Best Corrected Visual Acuity 
BID 
Twice daily 
CNI 
Calcineurin inhibitor 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
CsA 
Cyclosporine A 
DED 
Dry eye disease 
eCRF 
Electronic case report form 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FCS 
Fluorescein Corneal Staining 
FDA 
Food and Drug Administration 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug 
IP 
Investigational Product 
ITT 
Intent-to-treat 
KCS 
Keratoconjunctivitis sicca 
LogMAR 
Logarithm of the Minimum Angle of Resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
NEI 
National Eye Institute 
NFAT 
Nuclear Factor of Activated T-cells 
OD 
Oculus dexter (Right eye) 
OS 
Oculus sinister (Left eye) 


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OSDI 
Ocular Surface Disease Index 
OTC 
Over the counter 
OU 
Oculus uterque (Both eyes) 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
SAE 
Serious adverse event 
SANDE 
Symptom Assessment in Dry Eye 
SAP 
Statistical Analysis Plan 
STT 
Schirmer Tear Test 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
UPT 
Urine pregnancy test 
VAS 
Visual Analog Scale 
VOS 
Voclosporin ophthalmic solution 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 


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1.0 
INTRODUCTION 
Dry eye disease (DED), also called keratoconjunctivitis sicca (KCS), is a common clinical problem 
as over 7 million people in the United States experience dry eye symptoms. Symptoms of DED 
include a sensation of dry eyes, foreign body sensation, irritation, burning, tearing, ocular pain, 
and itching, among others. DED affects quality of life and work productivity, and patients with 
moderate to severe DED may experience reduced visual function in addition to ocular dysfunction. 
DED is a multi-factorial disease, defined by a loss of homeostasis of the tear film and accompanied 
by ocular symptoms, in which tear film instability and hyper-osmolarity, ocular surface 
inflammation and damage, and neuro-sensory abnormalities play etiological roles.  
DED patients are classified by the overlapping etiologies of aqueous deficient and evaporative dry 
eye. Evaporative dry eye tends to be more prevalent than aqueous deficient; however, as the 
disease progresses, both components become apparent. The common pathway for both groups is 
that desiccating stress leads to ocular surface inflammation. 
In patients with DED, tear production has been shown to be increased with the use of topical 
immunosuppressants, including cyclosporine. It is believed T-lymphocyte infiltration and 
activation in the lacrimal gland represents an underlying pathogenesis for DED. Calcineurin 
inhibitors (CNIs) 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 [9]. Calcineurin is a calcium- and calmodulin-dependent serine-threonine 
phosphatase. 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 (e.g., interleukin-2, interleukin-4, tumor necrosis factor-
α, granulocyte-macrophage colony stimulating factor, and interferon-γ [11,13]). 
Voclosporin is a 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 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 as compared to CsA. The combination of increased potency and decreased metabolite 
exposure, for voclosporin as compared to CsA, has led to better pharmacokinetic 
(PK)/pharmacodynamic (PD) predictability. 
Voclosporin ophthalmic solution (VOS) 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 5 
subjects with DED. In that study, both 0.02% and 0.2% concentrations were found to be safe and 
well tolerated following multiple instillations in healthy subjects. Adverse events (AEs) and ocular 


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findings were mild and similar between VOS and placebo groups. Although the sample size was 
small, results from the 5 subjects with DED suggest VOS may be beneficial in the treatment of 
DED and is supported by the Ocular Surface Disease Index (OSDI) 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. 
These factors form the basis for the rationale to investigate the safety and efficacy of voclosporin 
in subjects with DED.  Study AUR-VOS-2017-01 will evaluate the tolerability, efficacy and safety 
of VOS versus Restasis® in subjects with DED. 


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2.0 
STUDY DESCRIPTION 
2.1 
Objectives 
• To assess the ocular tolerability of VOS compared to cyclosporine ophthalmic emulsion 
(Restasis®) in subjects with DED. 
• To assess the safety and efficacy of VOS in subjects with DED. 
2.2 
Study Design 
This is a Phase 2, multi-center, Investigator-masked, randomized, parallel-group study to evaluate 
the tolerability, efficacy and safety of VOS versus Restasis® over a 28-day treatment period in 
subjects with mild to moderate DED.  Approximately 90 subjects will be randomized to either 
VOS or Restasis® at approximately 7 centers located in the US.   
At Visit 1 (screening), informed consent will be obtained from subjects and eligibility will be 
determined. A Schirmer Tear Test (STT) will be performed at this visit. The score will be used for 
eligibility and baseline.  During this visit, all subjects will self-administer an over-the-counter 
(OTC) ocular lubricant, Refresh Plus®, in both eyes (OU) to assess ability to self-administer study 
product. 
At Visit 2 (Pre-Randomization), continued eligibility will be confirmed. During this visit, all 
subjects will self-administer an OTC ocular lubricant, Refresh Plus®, OU to evaluate ability to 
tolerate ocular drops.  Individuals who are unable to successfully instill the drops or who rate OTC 
ocular lubricant as uncomfortable, based on a 1-minute and 5-minute post-instillation Drop 
Discomfort Visual Analog Scale (VAS) score, will not be eligible for participation in the study.  
(Note:  For subjects meeting the Screening and Randomization Criteria, the Visit 2 (pre-
randomization) Drop Discomfort VAS score measured at minutes 1 and 5 will be used as the 
baseline value.)   
Eligible subjects will be randomly assigned in a 1:1 ratio to one of the two treatment groups: VOS 
BID or Restasis® BID.  The first instillation of Investigational Product (IP) will be administered, 
at least 2 hours following administration of Refresh Plus® and by clinic personnel to OU during 
Visit 2.  IP will be administered to the subject by a dedicated dosing coordinator (the subject and 
the Investigator will be masked to study treatment for the first post randomization instillation). 
Tolerability and safety assessments will be performed at this visit. 
At Treatment Visits 3, 4 and 5 (End of Treatment), tolerability, safety and efficacy evaluations 
will be performed.  Subjects who discontinue IP before Visit 5 will undergo all Visit 5 evaluations 
(early termination).  IP will be administered to the subject by a dedicated dosing coordinator at the 
clinic visits (single masked: the Investigator and study staff will remain masked to study 
treatment). A Drop Discomfort VAS will be administered in the clinic at 1 and 5 minutes following 
instillation of IP at Visits 2 through Visit 5.  With the exception of clinic day visits, subjects will 
self-administer IP twice a day OU over the 4-week treatment period.  On the evening of Visits 2, 


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3 and 4 and in the evening prior to Visit 5, site staff will contact the subject by phone to prompt 
administration of IP followed by completion of the dosing diary and the Drop Discomfort VAS 
(1- and 5-minutes post-instillation). 
At Visit 6, there will be a 3-day post-treatment Follow-Up, in which safety assessments are 
performed and all remaining study materials are collected.  The subjects will be instructed to 
continue to withhold all other concomitant topical medications as outlined by the protocol for the 
duration of their participation (through Visit 6). 
Serious adverse events (SAEs) ongoing as of Visit 6 will be followed until they have resolved, 
stabilized in the opinion of the Investigator, or returned to baseline. 
This study will be conducted per the schedule shown in the Schedule of Events Table. 
2.3 
Inclusion Criteria 
At Visit 1 and Visit 2 subjects may be eligible for participation if they:  
1. 
Provide written informed consent before any study-specific procedures are performed. 
2. 
Are male or female subjects with a minimum age of 18 (or legal age of consent if >18 years) 
years, at the time of screening (Visit 1). 
3. 
Are willing and able to follow instructions and can be present for the required study visits 
for the duration of the study. 
4. 
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.  
5. 
Have a documented history of DED in both eyes supported by a previous clinical diagnosis 
at Visit 1. 
6. 
Have ongoing DED, as defined by at least one eye (if one eye, the same eye) meeting all 
the following criteria:  
− 
A symptom severity score of ≥ 30 for Eye Dryness on a VAS (0-100) at Visit 2 
− 
An unanesthetized STT score of ≥ 1 mm and ≤ 10 mm per 5 minutes (Note:  STT 
Score obtained at Visit 1) 
− 
Evidence of ocular surface staining (total fluorescein staining score of at least 3 [0-
15 scale]) at Visit 2 
7. 
Have normal lid anatomy at Visit 1. 


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2.4 
Exclusion Criteria 
In order for subjects to be eligible at Visit 1 and Visit 2 subjects must not: 
1. 
Be unable or unwilling to give written informed consent and/or to comply with study 
procedures. 
2. 
Have any known hypersensitivity or contraindication to study treatments (including 
excipients), topical anesthetics or vital dyes. 
3. 
Be unable to demonstrate correct instillation of OTC ocular lubricant during Visit 1. 
4. 
Report discomfort from instillation of OTC ocular lubricant during Visit 2 (based on score 
of ≥ 30 on the Drop Discomfort VAS).  
5. 
Have used Restasis® (cyclosporine ophthalmic solution) within 30 days prior to Visit 1. 
6. 
Have used Restasis® for more than 1 month (if prior use is reported). 
7. 
Have used Xiidra® (lifitegrast ophthalmic solution) within 14 days prior to Visit 1. 
8. 
Have had corneal graft surgery in either eye within 1 year of Visit 1.  
9. 
Have recent or current evidence of ocular infection or inflammation in either eye. 
10. 
Have current evidence of clinically significant blepharitis (defined as requiring lid hygiene 
therapy), conjunctivitis, or a history of herpes simplex or zoster keratitis in either eye. 
11. 
Have clinically significant ocular disease in either eye (e.g., corneal edema, uveitis, severe 
KCS) which might interfere with study procedures or assessments. 
12. 
Have any abnormality in either eye preventing reliable applanation tonometry.  
13. 
Be taking or known need for any of the known treatment therapies listed in Section 7.7, 
Prohibited Therapy and Concomitant Treatment, of the protocol at Visit 1 or during the 
study. This includes prohibited medications prior to Visit 1 as specified in Section 7.7, 
Prohibited Therapy and Concomitant Treatment. 
14. 
Have any known hypersensitivity or contraindication to CNIs.  
15. 
Have clinically significant systemic disease (e.g., uncontrolled diabetes, hepatic, renal, 
endocrine or cardiovascular disorders) which might interfere with the study.  
16. 
Have participated in any investigational clinical study within 30 days prior to Visit 1. 


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17. 
Have altered systemic medication that could have an effect on dry eye signs or symptoms 
within 30 days prior to Visit 1 or anticipated during the study.  
18. 
Be women of childbearing potential (WOCBP) who are pregnant, nursing, planning a 
pregnancy, or not using a medically acceptable form of birth control. 
2.5 
Randomization 
A computer-generated randomization schedule will be used to assign subjects into treatment 
groups.  The randomization will be stratified on study center. 


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3.0 
STUDY ASSESSMENTS 
3.1 
Description of Study Assessments 
3.1.1 
Symptom Assessment in Dry Eye (SANDE)  
Subjects will be asked to subjectively rate the frequency and severity of their dry eye symptoms at 
Visits 2, 3, 4 and 5 using the SANDE.  The total length of the line from “rarely” to “all the time” 
(frequency of symptoms) and from “very mild” to “very severe” (severity of symptoms) is 100 
mm. Subjects will be asked to subjectively rate the frequency and severity of their symptoms (OU) 
by placing an “X” on the relevant horizontal line. The length of the line between the “rarely” or 
“very mild” starting point and the first point where the subject’s mark crosses each line will be 
measured and recorded 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 prior to 
assessing for AEs and prior to any other invasive visit assessment.  
3.1.2 
Individual Symptom Severity Assessments using VAS: 
Subjects will be asked to rate their current symptoms (unrelated to study drug instillation) at Visits 
2, 3, 4 and 5.   The following six symptoms will be evaluated:  Burning/Stinging, Foreign Body 
Sensation, Photophobia, Eye Pain, Eye Dryness, and Itching. 
The subject will be asked to subjectively rate each of six ocular symptom (OU) by placing a 
vertical mark on the horizontal line to indicate their level of discomfort. 0 corresponds to “No 
Symptoms” and 100 corresponds to “Severe Symptoms.” 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.  
3.1.3 
Fluorescein Corneal Staining  
Corneal staining will be performed at Visit 2, 3, 4 and 5.  Corneal staining assessment will be 
performed using methods developed by the NEI Dry Eye Workshop.  FCS should take place 
after the Discomfort assessment at Visits 3, Visit 4 and Visit 5. 
This assessment will be measured and summarized in each eye separately. 
Scoring system 
• Grade each of 5 sections of cornea (superior, inferior, nasal, temporal, central) 
• Provide grades for each of the 5 sections: 
o Grade by NEI scale as 0, 1 (mild), 2 (moderate), or 3 (severe) 
• Total score is obtained by summing each of the 5 sections of the cornea 
o NEI score will be from 0-15 


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3.1.4 
Unanesthetized Schirmer Tear Test 
Schirmer Tear Test (without anesthesia) will be conducted at Visit 1, Visit 4 and Visit 5. At Visit 
1, the STT test will be performed prior to the OTC self-instillation test and following dilated 
ophthalmoscopy as per the protocol.  This procedure should be conducted 1 hour following 
administration of IP and at least 20 minutes following FCS at Visit 4 and Visit 5.  Using a ruler 
and/or the millimeters recorded on the strips, measure a point halfway between the two lines and 
record this as the amount of wetting. 
This assessment will be measured and summarized in each eye separately. 
3.1.5 
Drop Discomfort Assessment  
Drop discomfort will be assessed by the subject through a Drop Discomfort VAS (0-100 mm) 
where 0 corresponds to “no discomfort” and 100 corresponds to “maximal discomfort”. This 
assessment is a general assessment of both eyes.  There will not be a question for each individual 
eye. 
At Visit 2, prior to randomization, in order to evaluate the subject’s ability to tolerate ocular drops, 
all subjects will self-administer an OTC ocular lubricant, Refresh Plus®, in both eyes. Upon 
instillation of the ocular lubricant in both eyes, subjects will be instructed by the site staff to rate 
their eye discomfort at 1- and 5- minutes post-instillation by placing a mark on the Discomfort 
VAS. Subjects who rate OTC ocular lubricant as uncomfortable, defined as a VAS score ≥ 30 mm 
at 1 minute will not be eligible for participation in the study.  These Drop Discomfort VAS scores 
will be used as the baseline values.  
At Visit 2, after randomization, a dosing coordinator will instill the IP in both eyes. Subjects will 
be instructed by a masked site staff to rate their eye discomfort at 1- and 5-minutes post-instillation 
of IP as described above.   
Subjects will complete this assessment in the clinic following the AM dose of IP at Visits 2, 3, 4 
and 5 and again at home following the PM dose on the evenings of Visits 2, 3, 4 and the evening 
prior to Visit 5.   
3.1.6 
Best Corrected Visual Acuity (BCVA)  
BCVA will be conducted at each visit per the Schedule of Events.  Visual acuity testing should 
precede any examination requiring contact with the eye or instillation of study dyes. LogMAR 
visual acuity must be assessed using an ETDRS or modified ETDRS chart. Visual acuity testing 
should be performed with best correction using subject’s own corrective lenses (spectacles only) 
or pinhole refraction.  This assessment will be measured and summarized in each eye separately. 
The number of letters missed or read incorrectly should be noted. 
3.1.7 
Ophthalmoscopy  
Dilated ophthalmoscopy exam will be performed per the Investigator’s standard procedure at Visit 
1 and Visit 6.   


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The Investigator will determine if findings are within normal limits or are abnormal.  For abnormal 
findings at Visit 1, the Investigator will determine whether the abnormality would exclude subject 
from study participation. A clinically significant change from baseline may indicate an AE. This 
assessment will be measured and summarized in each eye separately. 
3.1.8 
Slit-Lamp Biomicroscopy  
The biomicroscopy exam will be performed at Visit 2 and Visit 5.  It should be performed with 
the Slit-Lamp using a beam of width and intensity to provide optimal evaluation of anterior 
segment.  Normal or abnormal assessments will be made for each of the 11 individual criteria. 
This assessment will be measured and summarized in each eye separately. 
This procedure will be performed in the same manner for all subjects observed at the Investigator’s 
site. 
3.2 
Adverse and Serious Adverse Events 
3.2.1 
Adverse Event (AE) 
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 adverse event (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. 
3.2.2 
Adverse Drug Reaction (ADR) 
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. 
3.2.3 
Serious Adverse Event  
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 which 
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 


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• Results in a congenital anomaly/birth defect 
• Is a medically important event or reaction 
3.2.4 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
Any ADR that is both serious and unexpected (per the Investigator’s Brochure [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 suspected unexpected serious adverse reaction (SUSAR). 
3.2.5 
Treatment-Emergent Adverse Event (TEAE) 
A treatment emergent adverse event (TEAE) is defined as any AE that has an onset on or after the 
first dose of IP/study drug and on or before the last dose of IP/study drug plus3days. 
3.2.6 
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. 
3.2.7 
Causal Relationship Categorization 
An Investigator who is qualified in medicine must make the determination of relationship to the 
study treatment 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: 


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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. 
3.2.8 
Outcome Categorization 
Outcome may be classified as recovered without sequelae; recovered with sequelae; improved; 
worsened; ongoing; ongoing at end of study; 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 
SAE reporting form. SAEs that are ongoing at the time of death will have an outcome of 
“unknown” recorded. SAEs resulting in a fatal outcome will have an outcome of “fatal” recorded. 
3.2.9 
Symptoms of the Disease Under Study 
Symptoms and fluctuations in laboratory parameters related to the disease under study will not be 
classed 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 or laboratory parameters, however, will be recorded as an AE and 
clearly marked as worsening or by the subject’s worst observed intensity. The Investigator will be 
required to assess the relationship to disease under study for each AE as related or not related. An 
AE will not be able to be assessed as related to both disease under study and related to study 
treatment. 


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4.0 
SAMPLE SIZE AND POWER CONSIDERATIONS 
The study will include approximately 90 male or female subjects. 
The primary analysis will use a t-test and will assess the difference in change from baseline in 
Drop Discomfort VAS scores (range 0 to 100 mm) 1-minute post-Dose 1 instillation between the 
two treatment groups.   
A sample size of 38 subjects per group (76 in total) will provide 90% power assuming: 
• A mean change from baseline Drop Discomfort VAS score of +30 mm for subjects 
randomized to Restasis® 
• A mean change from baseline Drop Discomfort VAS score of +15 mm for those 
randomized to VOS 
• These assumed mean changes lead to a 15 mm lower change from baseline in VAS 
scores for VOS compared to Restasis® 
• A common standard deviation of 20 mm 
• A 2-sided alpha of 5% 
Under the same assumptions, the study will have at least 80% power if the common standard 
deviation for the discomfort score were to be 23 mm. 
The study also provides 80% power should the treatment difference in discomfort scores be 13 
(common standard deviation=20 mm). 
To allow for 15% dropouts, approximately 90 subjects will be randomized. 
It is interesting to note that a power of 80% is achieved by this sample size when the treatment 
difference (VOS- Restasis®) is 12 mm in favor of VOS and alpha is 10%.  


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5.0 
ANALYSIS POPULATIONS 
Three populations will be used for analysis. 
5.1 
Efficacy Analysis Populations 
5.1.1 
Intent-to-Treat Set 
The tolerability and efficacy analysis will be based on the intent-to-treat (ITT) principles and will 
consist of all randomized subjects who receive at least 1 dose of study treatment.  The subjects in 
this group will be analyzed based on the planned treatment. 
5.1.2 
Per Protocol Set 
The per-protocol set will be a subset of subjects in the ITT population who do not have any major 
protocol violations (to be defined prior to unmasking).  The subjects in this group will be analyzed 
based on the treatment they received.  
5.1.3 
Safety Analysis Set 
The safety analysis set will consist of all randomized subjects who receive at least 1 dose of study 
treatment. The subjects in this group will be analyzed based on the treatment they received. 


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6.0 
HANDLING OF MISSING DATA 
No specific methods for handling of missing data are proposed. Observed cases will be analyzed. 
6.1 Conventions for Missing and Partial Dates 
All rules explained below for partial/missing dates will be followed unless contradicted by any 
other data recorded on the electronic Case Report Form (eCRF). 
All dates presented in the individual subject listings will be as recorded on the eCRF (i.e., not 
completed as per the below rules). 
6.2 Missing/Partial Start/Stop Date of Adverse Events and Concomitant Medications  
Missing and partial start and stop date will be imputed for analysis purposes as follows 
Partial or missing stop date will be imputed as follows: 
• If the stop date is completely missing and the event has resolved or the subject has stopped 
taking the concomitant medication, the stop date will be imputed as the date of the subject’s 
last clinic visit in the study. 
• If only the year is known, the stop date will be imputed as “31-Dec” of that year or as the date 
of the subject’s last clinic visit in the study if in the same year. 
• If the month and year are known, the stop date will be imputed as the last day of that month 
unless the stop date corresponds to the same month as the subject’s last clinic visit in which 
case the date of subject’s last clinic visit in the study will be used instead. 
Missing start date will be imputed as follows: 
• If the stop date occurs on or after the start of study drug or the event/concomitant medication 
is ongoing, the start date will be imputed as the date of the first dose of study drug.  
• If the stop date occurs before the start of study drug, the start date of the event/concomitant 
medication will be imputed as the subject’s screening date or the stop date of the 
event/concomitant medication whichever the earlier. 
Partial start date (year present, but month and day missing) 
• If the stop date occurs on or after the start of study drug or the event/concomitant medication 
is ongoing, and the year is the same as the year of first dosing the start date will be imputed as 
“01-Jan” of the same year or the date of the first dose of study drug whichever is latest. If the 
year is different from the year of first dosing “01-Jan” will be used. 


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• If the stop date occurs before the start of study drug, the start date of the event/concomitant 
medication will be imputed as the “01-Jan” of the same year. 
Partial start date (month and year present, but day missing) 
• If the stop date occurs on or after the start of study drug or the event/concomitant medication 
is ongoing, the start date will be imputed as the first day of the same month and year unless 
this partial start date is in same month as the first dose of study drug in which case the date of 
first dose of study drug will be used.  
• If the stop date occurs before the start of study drug, the start date will be imputed as the first 
day of the month and year of the partial stop date. 
6.3 Missing Last Dates of Study Drug Dosing 
If the date of last dose of study drug is completely missing, then the date of last dose of study drug 
will be taken for analysis purposes as the date when the subject would have run out of study drug 
assuming full compliance from the date the study drug was last dispensed or the date of subject’s 
last clinic visit in the study or early withdrawal or death whichever is earlier. 
If only the month and year of the last dose was recorded, then the date of last dosing will be taken 
for analysis purposes as the date the subject would have run out of study drug assuming full 
compliance from the date the study drug was last dispensed, the last day of the month of the 
recorded last dose or the date of subject’s last clinic visit in the study or early withdrawal or death 
whichever the earlier. 
6.4 Missing Diagnosis Dates   
If the month and year are present but the day is missing, the diagnosis date will be set to first day 
of the relevant month. If only the year is recorded the diagnosis date will be set as “01-Jan” for 
that year.  
6.5 Missing Safety Data 
A treatment-related TEAE is defined as a TEAE that is assessed by the Investigator or Sponsor as 
being related to study drug. If a TEAE has a missing relationship to study drug it is assumed to be 
related to the study drug for analysis purposes. 
 
A disease-related TEAE is defined as a TEAE that is assessed by the Investigator or Sponsor as 
being related to the disease under study. If a TEAE has a missing relationship to the disease under 
study it is assumed to be related to the disease under study for analysis purposes unless the TEAE 
is assessed by the investigator as treatment-related. 
Missing severity assessments will be summarised as severe. 


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7.0 
STATISTICAL ANALYSIS 
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. 
7.1 
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. 
 
Definition of Baseline:  
Study day will be calculated as the number of days from first dose of IP/study drug (Day 1). 
Baseline measurements will be the last measurement for the corresponding variable prior to the 
first randomized dose on Day 1.    
Out of Window and Unscheduled Visits: 
The protocol defined windows for scheduled visits will not be used in the analyses by visit.  Data 
will be assigned to the scheduled visit closer in time to the actual visit.   Unscheduled visit data 
will only be used in an analysis if there are no other available data closer in time to a scheduled 
visit.  All unscheduled visit data will be included in data listings. 
7.2 
Subject Disposition 
Subject disposition, including the number of subjects randomized, treated, and completing the 
study (and completing each study visit), will be tabulated by treatment group. The percentage of 
subjects treated and completing the study will be based on the total number randomized. A subject 
data listing will be provided. 
Eligibility criteria exemptions and major protocol deviations will be summarized by treatment 
group and presented in a listing. Major protocol deviations may include the following: violation 
of inclusion or exclusion criteria, using prohibited medications, non-adherence to study treatment 
schedule, and unblinding of the masked assessor at day 1 study drug dosing. A guideline for 
classification of patients as belonging to the per protocol analysis dataset will be documented prior 
to database unmasking as will the masked review of patient data for purposes of classification. 


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The total number and percentage of subjects included in each of the analysis datasets will be 
summarized by treatment group, with percentages based on the total number of randomized 
subjects. A subject data listing will be provided. 
Discontinuations and the reasons for discontinuation from study medication will be summarized 
for all randomized subjects. Summaries will include the number and percentage of subjects within 
each treatment group. Reasons for Discontinuation or Early Termination/Study Withdrawal 
following the receipt of study drug will include the following: 
• Intolerable Adverse Event 
• Death 
• Lost to Follow Up 
• Physician Decision 
• Prohibited Medication Required 
• Pregnancy 
• Protocol Noncompliance 
• Site Terminated By Sponsor 
• Study Terminated By Sponsor 
• Withdrawal of Consent 
• Lack of Efficacy 
• OTHER: specify  
 
A subject data listing will be provided. 
7.3 
Demographic and Baseline Characteristics 
Subject demographic and baseline characteristics will be summarized for the ITT analysis 
population; however, should there be a reasonable difference in the size of the ITT and safety 
analysis populations, demographic and baseline characteristics will be summarized for both. The 
comparability of groups used in comparison analyses will be characterized in tables of 
demographic data. Summary tables will be supported with individual subject data listings. 
Continuous variables such as age will be summarized using descriptive statistics (n, mean, standard 
deviation, median, minimum, and maximum), and categorical variables such as gender, race, 
ethnicity, will be summarized using counts and percentages of subjects.  
7.4 
Treatment Compliance and Exposure 
The duration of drug exposure and % compliance will be summarized by treatment group.   
Duration of drug exposure will be calculated for each subject as the last date of dosing minus the 
first date of dosing + 1. The number and percentage of subjects by treatment group will be 
summarized according to the following duration-of-exposure categories: ‘< 1 wk’, ‘1 to < 3 wks’, 
3 to < 5 wks’ and ≥ 5 wks.’ 


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A subject data listing will be provided. 
7.5 
Study Endpoints 
7.5.1 
Primary Endpoint 
The primary endpoint is the change from baseline to 1-minute post-instillation of IP in Drop 
Discomfort VAS score at Visit 2.  The baseline measure will be taken 1-minute following Refresh 
Plus® administration at least 2 hours prior to IP administration. 
7.5.2 
Key Secondary/Efficacy Endpoints 
• Change from baseline in Drop Discomfort VAS score (both eyes assessed together) 
o Summarized and analyzed for change from baseline to 1-minute and 5-minute post 
instillation, for the AM and PM doses on Visits 2 (randomization), 3, 4 and 5 (15 
analyses in addition to the primary endpoint).  An overall analysis of all discomfort 
scores will be undertaken 
• Change from baseline in each of the 6 Individual Symptom Severity Assessments (VAS) 
(both eyes assessed together) 
o Summarized and analyzed for change from baseline to visit 3, 4 and 5.  An overall 
analysis for each VAS incorporating all visits will be undertaken 
• Change from baseline of the sum of the Individual Symptom Severity Assessments (VAS 
Total Symptom Summary Score) (both eyes assessed together) 
o Summarized and analyzed for change from baseline to visit 3, 4 and 5.  An overall 
analysis incorporating all visits will be undertaken 
• Change from baseline in SANDE score (both eyes assessed together) 
o Summarized and analyzed for change from baseline to visit 3, 4 and 5.  An overall 
analysis incorporating all visits will be undertaken 
• Change in unanesthetized STT score (each eye assessed individually) 
o Summarized and analyzed for change from baseline to visit 4 and 5 
• Change from baseline in FCS total score (NEI/Industry Workshop 0-15 scale) Safety 
Endpoints (each eye assessed individually) 
o Summarized and analyzed for change from baseline to visit 3, 4 and 5.  An overall 
analysis incorporating all visits will be undertaken 


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7.5.3 
Safety Endpoints 
• Treatment-emergent adverse events (TEAEs) 
• Change from screening in BCVA (each eye assessed individually) 
• Changes from baseline in Slit-Lamp Biomicroscopy (each eye assessed individually) 
• Changes from screening in Dilated Ophthalmoscopy (each eye assessed individually) 
7.5.4 
Exploratory Endpoints 
Four additional composite endpoints have been defined as exploratory endpoints.  These endpoints 
will be assessed for each subject in their eye that achieves the worst 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. 
• Proportion of patients achieving an improvement from baseline in the STT of ≥ 5mm at 
visits 4 and 5 
• Proportion of patients achieving an improvement from baseline in the STT of ≥ 10mm at 
visits 4 and 5 
• Proportion of patients achieving an improvement from baseline in the STT of ≥ 5mm along 
with any improvement in FCS total score at visits 4 and 5 
• Proportion of patients achieving an improvement from baseline in the STT of ≥ 10mm 
along with any improvement in FCS total score at visits 4 and 5 
7.6 
Methods of Analysis 
7.6.1 
Ordinal and Continuous Variables 
All endpoints, other than TEAE, slit-lamp biomicroscopy and ophthalmoscopy, are measured on 
a VAS or ordinal scale and will be summarized and analyzed as continuous data.   
Summaries of scores (absolute and change from baseline) by treatment group will be displayed for 
each assessment time (where applicable) at each visit.  Treatment comparisons will made using a 
t-test from an ANCOVA model including terms for treatment group, investigator site and baseline 
score.  Results will be summarized by the estimate of treatment difference, a 95% CI for the 
treatment difference and a p-value.  If assumptions are violated, the Wilcoxon rank sum test will 
be used. If required, transformations may be considered in order to meet the necessary 
assumptions. 
For variables assessed at multiple time points and/or multiple visits the individual analyses will be 
complemented by an overall supplementary analysis incorporating all data collected for the 
endpoint in question.  Endpoints will be analyzed using a Mixed Effect Model Repeated Measures 


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(MMRM) analysis with treatment group, visit, treatment-by-visit interaction, baseline score and 
investigator site included as covariates in the model.  Results will be expressed as differences 
between treatment groups (along with the associated 95% CI).   Least Square (LS) means and 
corresponding 95% CIs for the change in baseline values will be presented for each visit.  Where 
endpoints are collected multiple times within a visit additional covariates will be added to the 
model.  E.g. time post dose (1 minute / 5 minutes) and AM or PM assessment.  The model will be 
fitted using an unstructured covariance matrix.  Should this model fail to converge, an 
autoregressive covariance matrix will be used.  The covariance matrix used will be referenced in 
table footnotes.  The Kenward-Roger degree of freedom adjustment will be applied.  In order to 
aid the modelling process it is possible that smaller centers will need to be combined.  If necessary, 
the smallest center will be combined with the next smallest, and so on. 
7.6.2 
Endpoints measured as a Proportions 
The proportion of subjects achieving the endpoint will be summarized at each visit.  Results of the 
proportional endpoints will be expressed as an odds ratio and an associated 2-sided confidence 
interval for voclosporin compared to Restasis®.  The logistic model used will include terms for 
treatment group, baseline STT score and investigator site.  Odds ratios greater than unity will mean 
the odds of achieving the endpoint are greater for voclosporin than for Restasis® and therefor 
indicate a benefit of voclosporin.  The p-value for the treatment difference will also be reported.    
7.6.3 
Other Variables 
For TEAEs, slit-lamp biomicroscopy and ophthalmoscopy findings, see Safety Evaluations below. 


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8.0 
SAFETY EVALUATIONS 
8.1 
Adverse Events 
For screen failure subjects, any AEs and SAEs occurring during the screening period (after 
informed consent) will be recorded in the subject’s source documentation only and will not be 
collected on the eCRF.  
For enrolled subjects, all AEs and SAEs will be recorded in the AE section of the subject’s eCRF 
and source documentation. 
A treatment emergent adverse event (TEAE) is defined as any AE that has an onset on or after the 
first dose of IP/study drug and on or before the last dose of IP/study drug plus 3 days. Only 
treatment-emergent events will be summarized. All events in the clinical database regardless of 
when they occurred will be provided in data listings i.e., for enrolled subjects, data listings will 
have screening AEs/SAEs and TEAEs/serious TEAEs. Adverse events will be presented by 
Medical Dictionary of Regulatory Activities (MedDRA) primary system organ class (SOC) and 
preferred term (PT). 
An overall summary will be presented which gives the number and percentage of subjects within 
each treatment group (n (%)), and the number of events (E) that experienced: 
• Any TEAE 
• Any Treatment-Related TEAE 
• Any Disease-Related TEAE 
• Any Serious TEAE 
• Any Serious Treatment-Related TEAE 
• Any Serious Disease-Related TEAE. 
• Any TEAE Leading to Study Drug Discontinuation 
• Any Treatment-Related TEAE Leading to Study Drug Discontinuation 
• Any Disease-Related TEAE Leading to Study Drug Discontinuation  
• Any TEAE with Outcome of Death 
• Any Treatment-Related TEAE with Outcome of Death 
• Any Disease-Related TEAE with Outcome of Death 


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In summary tables, ocular AEs recorded once for each eye separately but in the same timeframe 
will be summarized once at the greater intensity and relationship to study drug.  The number and 
percentage of subjects experiencing one or more events within a MedDRA SOC and PT class 
without regard to intensity, relationship, or seriousness will be tabulated by treatment group. 
Additional tables for TEAEs and Serious TEAEs will display events by SOC, PT, and maximum 
intensity. 
The following Adverse Event listings will be provided: 
• Listing of TEAEs by treatment group ordered by subject, SOC, PT, and date (study day) 
• Listing of serious TEAEs by treatment group ordered by subject, SOC, PT, and onset date 
(study day) 
• Listing of TEAEs leading to study drug interruption or discontinuation 
• Listing of TEAEs resulting in death 
• Listing of all AEs not classified as Treatment Emergent 
8.2 
 Concomitant Medications 
All concomitant medications listed on the case report form will be provided in data listings in the 
clinical study report. Each medication will be mapped to their corresponding Preferred Term from 
the ATC-WHO-DD. A frequency distribution of all concomitant medications used during the study 
will be provided for each treatment group.  Medications used prior to randomization but stopped 
prior to randomization will be summarized separately from those used concomitantly. A subject 
data listing will be provided. 
8.3 
Dry Eye History and Medical History 
History terms will be classified according to the MedDRA system to the levels of SOC and primary 
PT. 
An overall summary will be presented which gives the number and percentage of subjects within 
each treatment group that experienced each condition or procedure. A subject data listing will be 
provided. 
8.4 
Slit-Lamp Biomicroscopy 
The observations from the Slit-Lamp Biomicroscopy will be summarized in frequency tables based 
on the Normal / Abnormal assessment at each visit for each measure.  Shift tables (From: 
Normal/Abnormal To: Normal/Abnormal) will be provided for each individual assessment as a 
measure of change from baseline for each visit.  A subject data listing will be provided. 


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8.5 
Ophthalmoscopy/Dilated Fundoscopy 
The observations from the Dilated Ophthalmoscopy exam will be summarized in frequency tables 
based on the Normal / Abnormal assessment at each visit for each measure separately.  Shift tables 
(From: Normal/Abnormal To: Normal/Abnormal) will be provided for each individual assessment 
as a measure of change from baseline for each visit.  A subject data listing will be provided. 
8.6 
Urine Pregnancy Test 
A listing of urine pregnancy test results will be provided. 


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9. 
CHANGES FROM THE PROTOCOL 
Four additional composite endpoints have been defined for analysis that were not defined in the 
protocol.  These composite endpoint use both the STT and the FCS assessments and full details 
are set out in sections 7.5.4 and 7.6.2. 
 


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10. 
INTERIM ANALYSIS 
No interim analyses are planned. 








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List of Listings 
Listing 
Number 
Listing Title 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX 1: SCHEDULE OF EVENTS 
 
 
 
Visit 
Visit 1 
Screening 
Visit 2 
Pre-
Randomizati
on 
Visit 2 
Randomizati
on 
Visit 3 
Treatment 
Visit 4 
Treatment 
Visit 5 
End of 
Treatment/ 
Early Term1 
Visit 6 
Follow-up2 
Day 
Day -3 to -1 
 
Day 1 
Day 7  
(±2 days) 
Day 14  
(±2 days) 
Day 28  
(±2 days)  
Post-
treatment 
FU (+3 days) 
Informed Consent 
 
 
 
 
 
 
 
Demography 
 
 
 
 
 
 
 
Medical/Ophthalmic/ 
Surgical history 
 
 
 
 
 
 
 
 
Eligibility Criteria 
Assessment 
 
 
 
 
 
 
 
Concomitant 
Medications Assessment 
 
 
 
 
 
 
 
Urine Pregnancy Test3 
 
 
 
 
 
 
 
SANDE 
 
 
 
 
 
 
 
Individual Symptom 
Severity Assessments 
using VAS 
 
 
 
 
 
 
 
BCVA 
 
 
 
 
 
 
 
STT  
 
 
 
 
4 
4 
 
Slit-Lamp 
Biomicroscopy  
 
 
 
 
 
 
 
FCS 
 
 
 
9 
9 
9 
 
Ophthalmoscopy 
(dilated)  
 
 
 
 
 
 
 
 
 
 


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Visit 
Visit 1 
Screening 
Visit 2 
Pre-
Randomizati
on 
Visit 2 
Randomizati
on 
Visit 3 
Treatment 
Visit 4 
Treatment 
Visit 5 
End of 
Treatment/ 
Early Term1 
Visit 6 
Follow-up2 
Day 
Day -3 to -1 
 
Day 1 
Day 7  
(±2 days) 
Day 14  
(±2 days) 
Day 28  
(±2 days)  
Post-
treatment 
FU (+3 days) 
OTC Ocular Lubricant 
Administration at the 
Study Site  
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
IP Administration at the 
Study Site 
 
 
5 
 
 
 
 
Drop Discomfort 
Assessment at the Study 
Site  
 
6 
7 
 
 
 
 
AE Assessment 
 
 
 
 
 
 
 
IP Dispensation  
 
 
 
 
 
 
 
Dosing Diary and VAS 
Scales Dispensation  
 
 
 
 
 
 
 
Subject Contact for 
Drop Discomfort 
Assessment  
 
 
 
 
8 
 
 
Abbreviations: AE=Adverse event; BCVA= Best Corrected Visual Acuity; FCS= Fluorescein Corneal Staining; IP=Investigation Product; 
OTC=Over-the-counter; SANDE= Symptom Assessment and Dry Eye; STT=Schirmer Tear Test; VAS=Visual Analog Scale. 
1 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 5).  
2 Visit 6 should be conducted 3 days after End of Treatment (+3 Day window).  
3 For women of childbearing potential only.  
4 STT should be performed at least 1 hour after IP instillation and at least 20 minutes after FCS. 
5 IP instillation should be performed at least 2 hours after OTC ocular lubricant (Refresh Plus) instillation.  
6 Post OTC ocular lubricant instillation. 
7 Post IP instillation. 
8 Subjects will be contacted by masked site staff the evening of the Visit 4 and in the evening prior to Visit 5. 
9 FCS should be performed after the Drop Discomfort Assessment. 

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. 
An Investigator-Masked, Randomized, Parallel-Group Study of 
the Ocular Tolerability of Voclosporin Ophthalmic Solution 
versus Restasis® in Subjects with Dry Eye Disease 
Clinical Protocol Number: 
AUR-VOS-2017-01 
Date: 
20 June 2018 
Version Number: 
2.0 
IND Number: 
102,279 


AUR-VOS-2017-01, Version 2.0 
Confidential 
20 June 2018 
Page 2 of 86 
NAMES AND ADDRESSES 
Sponsor 
Name: 
Aurinia Pharmaceuticals Inc. 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
Tel: 
Fax: 
24 Hour: 
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: 


AUR-VOS-2017-01, Version 2.0 
Confidential 
20 June 2018 
Page 3 of 86 
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: 


AUR-VOS-2017-01, Version 2.0 
Confidential 
20 June 2018 
Page 4 of 86 
DECLARATION OF SPONSOR 
Title: An Investigator-Masked, Randomized, Parallel-Group Study of the Ocular Tolerability 
of Voclosporin Ophthalmic Solution versus Restasis® in Subjects with Dry Eye Disease 
Version Number/Date: Final Version 2.0/20 June 2018 
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 Conference of Harmonisation on Good Clinical Practice. 
Sponsor Representatives 
Chief Medical Officer 
Date (e.g., DD Month Year) 
Vice President, Quality and Regulatory 
Affairs 
Date (e.g., DD Month Year) 
20June 2018
20 June 2018


AUR-VOS-2017-01, Version 2.0 
Confidential 
20 June 2018 
Page 5 of 86 
INVESTIGATOR AGREEMENT FORM 
I have read the attached protocol titled: An Investigator-Masked, Randomized, Parallel-Group 
Study of the Ocular Tolerability of Voclosporin Ophthalmic Solution versus Restasis® in 
Subjects with Dry Eye Disease. 
Version Number 2.0/20 June 2018 
I agree to comply with the current International Conference of 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 (e.g., DD Month Year) 


AUR-VOS-2017-01, Version 2.0 
Confidential 
20 June 2018 
Page 6 of 86 
SYNOPSIS 
Title: 
An Investigator-Masked, Randomized, Parallel-Group Study of the Ocular 
Tolerability of Voclosporin Ophthalmic Solution versus Restasis® in Subjects with 
Dry Eye Disease 
Study Product: 
Voclosporin ophthalmic solution (VOS) 
Indication: 
Dry Eye Disease (DED) 
Phase: 
2 
Sponsor: 
Aurinia Pharmaceuticals Inc. 
Study Code: 
AUR-VOS-2017-01 
Objectives: 
Primary Objective 
To assess the ocular tolerability of VOS compared to cyclosporine ophthalmic 
emulsion (Restasis®) in subjects with DED.   
Secondary Objective 
To assess the safety and efficacy of VOS in subjects with DED. 
Design: 
This is a Phase 2, multi-center, Investigator-masked, randomized, parallel-group 
study to evaluate the tolerability, efficacy and safety of VOS versus Restasis® over 
a 28-day treatment period in subjects with mild to moderate DED. Approximately 
90 subjects will be randomized to either VOS or Restasis® at approximately 
7 centers located in the US.   
Treatment: 
Investigational product (IP): 0.2% VOS, twice daily (BID), both eyes (OU) for 
28 days. 
Comparator: 0.05% cyclosporine ophthalmic emulsion (Restasis®) BID, OU for 
28 days.  
The Investigator assessing the ocular signs and subjects will be masked to study 
treatment.   
Inclusion 
Criteria: 
At Visit 1 and Visit 2 (as specified in the Schedule of Events), subjects may be 
eligible for participation if they:  
1.
Provide written informed consent before any study-specific procedures are
performed.
2.
Are male or female subjects with a minimum age of 18 years (or legal age of
consent if >18 years), at the time of screening (Visit 1).
3.
Are willing and able to follow instructions and can be present for the required
study visits for the duration of the study.
4.
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.


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5.
Have a documented history of DED in both eyes supported by a previous
clinical diagnosis at Visit 1.
6.
Have ongoing DED, as defined by at least one eye (if one eye, the same eye)
meeting all the following criteria:
−
A symptom severity score of ≥30 for Eye Dryness on a Visual Analog
Scale (VAS) (0-100) at Visit 2
−
An unanesthetized Schirmer Tear Test (STT) score of ≥1 mm and
≤10 mm per 5 minutes (Note: STT Score obtained at Visit 1)
−
Evidence of ocular surface staining (total fluorescein staining score
of at least 3 [0-15 scale]) at Visit 2.
7.
Have normal lid anatomy at Visit 1.
Exclusion 
Criteria: 
In order for subjects to be eligible, at Visit 1 and Visit 2 (as specified in the 
Schedule of Events) subjects must not: 
1.
Be unable or unwilling to give written informed consent and/or to comply with
study procedures.
2.
Have any known hypersensitivity or contraindication to study treatments
(including excipients), topical anesthetics or vital dyes.
3.
Be unable to demonstrate correct instillation of over-the-counter (OTC) ocular
lubricant during Visit 1.
4.
Report discomfort in both eyes from instillation of OTC ocular lubricant
during Visit 2 (based on score of ≥30 on the Drop Discomfort VAS).
5.
Have used Restasis® (cyclosporine ophthalmic emulsion) within 30 days prior
to Visit 1.
6.
Have used Restasis® for more than 1 month (if prior use is reported).
7.
Have used Xiidra® (lifitegrast ophthalmic solution) within 14 days prior to
Visit 1.
8.
Have had corneal graft surgery in either eye within 1 year of Visit 1.
9.
Have recent or current evidence of ocular infection or inflammation in either
eye.
10. Have current evidence of clinically significant blepharitis (defined as requiring 
lid hygiene therapy), conjunctivitis, or a history of herpes simplex or zoster
keratitis in either eye.


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11. Have clinically significant ocular disease in either eye (e.g., corneal edema,
uveitis, severe keratoconjunctivitis sicca) which might interfere with study
procedures or assessments.
12. Have any abnormality in either eye preventing reliable applanation tonometry.
13. Be taking or have known need for any of the known treatment therapies listed
in Section 7.7 at Visit 1 or during the study. This includes prohibited
medications prior to Visit 1 as specified in Section 7.7.
14. Have any known hypersensitivity or contraindication to calcineurin inhibitors.
15. Have clinically significant systemic disease (e.g., uncontrolled diabetes,
hepatic, renal, endocrine or cardiovascular disorders) which might interfere
with the study.
16. Have participated in any investigational clinical study within 30 days prior to
Visit 1.
17. Have altered any systemic medication that could have an effect on dry eye
signs or symptoms within 30 days prior to Visit 1 or anticipated during the
study.
18. Be women of childbearing potential who are pregnant, nursing, planning a
pregnancy, or not using a medically acceptable form of birth control.
Primary 
Endpoint: 
Change 
from 
baseline 
in 
Drop 
Discomfort 
VAS 
score 
1-minute 
post-Dose 1 instillation.  
Secondary 
Endpoints: 
Key Secondary Endpoints: 
•
Change from baseline in Drop Discomfort VAS score
•
Change from baseline in each of the 6 Individual Symptom Severity
Assessments (VAS) scores
•
Change from baseline in the sum of the Individual Symptom Severity
Assessments score (VAS Total Symptom Summary Score)
•
Change from baseline in Symptom Assessment in Dry Eye (SANDE)
score
•
Change from baseline in unanesthetized STT score
•
Change from baseline in Fluorescein Corneal Staining (FCS) total
score (National Eye Institute (NEI)/Industry Workshop 0-15 scale)
Safety Endpoints: 
•
Treatment-emergent adverse events (TEAEs)
•
Change from baseline in BCVA


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•
Changes from baseline in Slit-Lamp Biomicroscopy
•
Changes from screening in Dilated Ophthalmoscopy
Procedures: 
At Visit 1 (screening) informed consent will be obtained from subjects and 
eligibility will be determined. A STT will be performed at this visit. The score will 
be used as the baseline and eligibility. During this visit, all subjects will self-
administer an OTC ocular lubricant, Refresh Plus®, OU to assess ability to self-
administer study product. At Visit 2 (Randomization) continued eligibility will be 
confirmed. During this visit, all subjects will self-administer an OTC ocular 
lubricant, Refresh Plus®, OU to evaluate ability to tolerate ocular drops. 
Individuals who are unable to successfully instill the drops or who rate OTC ocular 
lubricant as uncomfortable, based on a post-instillation Drop Discomfort VAS 
score, will not be eligible for participation in the study. (Note:  For subjects meeting 
the Screening and Randomization Criteria, the Visit 2 Drop Discomfort VAS score 
will be used as the baseline value.)   
Eligible subjects will be randomly assigned in a 1:1 ratio to one of the two treatment 
groups: VOS BID or Restasis® BID. The first instillation of IP will be administered, 
at least 2-hours following administration of Refresh Plus® and by clinic personnel 
to both eyes during Visit 2. Investigational Product will be administered to the 
subject by an unmasked dedicated dosing coordinator (the subject and the 
Investigator will be masked to study treatment for the first post-randomization 
instillation). Tolerability, safety and efficacy assessments will be performed at this 
visit. 
At Treatment Visits 3 and 4, tolerability, safety and efficacy evaluations will be 
performed. At the End of Treatment, Visit 5, tolerability, safety and efficacy 
evaluations will be performed. Subjects who discontinue before Visit 5 will 
undergo all Visit 5 evaluations (Early Termination). IP will be administered to the 
subject by an unmasked dedicated dosing coordinator at the clinic visits (single-
masked: the Investigator and study staff will remain masked to study treatment). A 
Drop Discomfort VAS will be administered in the clinic at 1-minute and 5-minutes 
following instillation of IP at Visits 2 through 5 (Investigator is to remain masked). 
With the exception of clinic day visits, subjects will self-administer IP twice a day 
OU over the 4-week treatment period. On the evening of Visits 2 through 4 and in 
the evening prior to Visit 5, the study coordinator will contact the subject by phone 
to prompt administration of IP followed by completion of the dosing diary and the 
Drop Discomfort VAS (1-minute and 5-minutes post-instillation).  
At Visit 6, there will be a 3-day post-treatment Follow-Up, in which safety 
assessments are performed and all remaining study materials are collected. The 
subjects will be instructed to continue to withhold all other concomitant topical 
medications as outlined by the protocol for the duration of their participation 
(through Visit 6). 
Serious adverse events (SAEs) ongoing as of Visit 6 will be followed until they 
have resolved, stabilized in the opinion of the Investigator, or returned to baseline. 
This study will be conducted per the schedule shown in the Schedule of Events 
(Table 1) and the Study Schematic (Figure 1). 
Sample Size: 
The study will include approximately 90 male or female subjects. 


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The primary analysis will use a t-test and will assess the difference in change from 
baseline in Drop Discomfort VAS scores (range 0 to 100 mm) 1-minute 
post-Dose 1 instillation between the two treatment groups.   
A sample size of 38 subjects per group (76 in total) will provide 90% power 
assuming: 
•
A mean change from baseline Drop Discomfort VAS score of +30 mm for
subjects randomized to Restasis®
•
A mean change from baseline Drop Discomfort VAS score of +15 mm for
those randomized to VOS
•
These assumed mean changes lead to a 15 mm lower change from baseline
in VAS scores for VOS compared to Restasis®
•
A common standard deviation of 20 mm
•
A 2-sided alpha of 5%
Under the same assumptions, the study will have at least 80% power if the common 
standard deviation for the discomfort score were to be 23 mm. 
The study also provides 80% power should the treatment difference in discomfort 
scores be 13 (common standard deviation=20 mm). 
To allow for 15% dropouts, approximately 90 subjects will be randomized. 
Statistical 
Methods: 
The primary endpoint is measured on a VAS and will be summarized and analysed 
as continuous data. Summaries of VAS scores (absolute and change from baseline) 
by treatment group will be displayed for each VAS assessment (minutes 1, 5 and 
overall mean) at each visit. Should the data meet the necessary assumptions 
(normality and equal variance in both treatment groups) then the treatment groups 
will be compared using a t-test. If assumptions are violated, the Wilcoxon rank sum 
test will be used. 


Day-3 
to -1 
Screen 
Day 
Day 1 
-3 to -1 
I Visit ·1 
Visit 2 
l 
' 
Screening Pre-Randomization/ 
Randomization 
AUR-VOS-2017-01, Version 2.0 
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Figure 1: AUR-VOS-2017-01 Study Schematic 
Day7 
Day 14 
+/-2 Days 
+/-2 Days 
Visit 3 
Visit4 
i 
Treatment Visits 
Follow­
Up 
Day28 
+/-2 Days 
Visit 5 
i 
Off Treatment 
Post-
treatment 
FU +3 Days 
Visit6 ( 
1 
Follow-Up 
Confidential 
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Table 1: AUR-VOS-2017-01 Schedule of Events 
Visit 
Visit 1 
Screening 
Visit 2 
Pre-
Randomization 
Visit 2 
Randomization 
Visit 3 
Treatment 
Visit 4 
Treatment 
Visit 5 
End of 
Treatment/ 
Early Term1 
Visit 6 
Follow-up2 
Day 
Day -3 to -1 
Day 1 
Day 7 
(±2 days) 
Day 14 
(±2 days) 
Day 28 
(±2 days) 
Post-treatment 
FU (+3 days) 
Informed Consent 
 
Demography 
 
Medical/Ophthalmic/ 
Surgical history 
 
Eligibility Criteria Assessment 
 
 
Concomitant Medications 
Assessment 
 
 
 
 
 
 
Urine Pregnancy Test3 
 
 
SANDE 
 
 
 
 
Individual Symptom Severity 
Assessments using VAS 
 
 
 
 
BCVA 
 
 
 
 
 
 
STT 
 
4
Slit-Lamp Biomicroscopy 
 
 
FCS 
 
 
 
 
Ophthalmoscopy (dilated) 

 


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Visit 
Visit 1 
Screening 
Visit 2 
Pre-
Randomization 
Visit 2 
Randomization 
Visit 3 
Treatment 
Visit 4 
Treatment 
Visit 5 
End of 
Treatment/ 
Early Term1 
Visit 6 
Follow-up2 
Day 
Day -3 to -1 
Day 1 
Day 7 
(±2 days) 
Day 14 
(±2 days) 
Day 28 
(±2 days) 
Post-treatment 
FU (+3 days) 
OTC Ocular Lubricant 
Administration at the Study Site 
 
 
Randomization 
 
IP Administration at the Study 
Site 
5
 
 
 
Drop Discomfort Assessment at 
the Study Site  
6
7
 
 
 
AE Assessment 
 
 
 
 
 
 
 
IP Dispensation 
 
 
 
Dosing Diary and VAS Scales 
Dispensation  
 
 
 
Subject Contact for Drop 
Discomfort Assessment  
 
 
8
Abbreviations: AE=Adverse event; BCVA= Best Corrected Visual Acuity; FCS= Fluorescein Corneal Staining; IP=Investigation Product; OTC=Over-the-counter; SANDE= Symptom Assessment and Dry Eye; STT=Schirmer 
Tear Test; VAS=Visual Analog Scale. 
1 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 5).  
2 Visit 6 should be conducted 3 days after End of Treatment (+3 Day window).  
3 For women of childbearing potential only.  
4 STT should be performed at least 1 hour after IP instillation and at least 20 minutes after FCS. 
5 IP instillation should be performed at least 2 hours after OTC ocular lubricant (Refresh Plus) instillation.  
6 Post OTC ocular lubricant instillation. 
7 Post IP instillation 
8 Subjects will be contacted by masked site staff the evening of the Visit 4 and in the evening prior to Visit 5.


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TABLE OF CONTENTS 
NAMES AND ADDRESSES ...................................................................................................2 
DECLARATION OF SPONSOR ...........................................................................................4 
INVESTIGATOR AGREEMENT FORM ............................................................................5 
SYNOPSIS ................................................................................................................................6 
TABLE OF CONTENTS ......................................................................................................14 
LIST OF TABLES .................................................................................................................18 
LIST OF ABBREVIATIONS ...............................................................................................19 
1.
INTRODUCTION AND BACKGROUND ..................................................................21 
1.1 
Background of the Disease and Treatment Options ....................................................21 
1.1.1 
Limitations of Current Treatment .............................................................................21 
1.2 
Rationale for the Use of Calcineurin Inhibitors in Dry Eye Disease ...........................21 
1.2.1 
Non-Clinical Studies of Voclosporin in Dry Eye .....................................................22 
1.2.2 
Clinical Studies of Voclosporin in Dry Eye .............................................................24 
2.
RATIONALE .................................................................................................................25 
2.1 
Dose Rationale .............................................................................................................25 
3.
STUDY OBJECTIVES ..................................................................................................26 
3.1 
Primary Objective ........................................................................................................26 
3.2 
Secondary Objective ....................................................................................................26 
3.3 
Endpoints .....................................................................................................................26 
3.3.1 
Primary Endpoint ......................................................................................................26 
3.3.2 
Secondary Endpoints ................................................................................................26 
4.
INVESTIGATIONAL PLAN .......................................................................................27 
4.1 
Overall Study Design ...................................................................................................27 
4.2 
Duration of Subject Participation and Study ...............................................................28 
5.
SELECTION, 
WITHDRAWAL 
OF 
SUBJECTS 
AND 
PERMANENT
DISCONTINUATION OF DRUG ................................................................................29 
5.1 
Number of Subjects......................................................................................................29 
5.2 
Inclusion Criteria .........................................................................................................29 
5.3 
Exclusion Criteria ........................................................................................................29 
5.4 
Adequate/Effective Contraception ...............................................................................31 
5.5 
Withdrawal of Subjects ................................................................................................31 
5.6 
Discontinuation of Study Treatment ............................................................................32 
5.6.1 
Discontinuation of Study Treatment Due to an Adverse Event................................32 
6.
RANDOMIZATION, MASKING AND UNMASKING PROCEDURES ................33 
6.1 
Randomization .............................................................................................................33 


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6.2 
Masking........................................................................................................................33 
6.3 
Unmasking ...................................................................................................................34 
7.
STUDY TREATMENTS ...............................................................................................36 
7.1 
Dosage Forms/Formulation .........................................................................................36 
7.1.1 
VOS Study Treatment ...............................................................................................36 
7.1.2 
Restasis® ...................................................................................................................36 
7.2 
Drug Dosage and Administration ................................................................................36 
7.2.1 
Treatment Arms ........................................................................................................36 
7.2.2 
Dosing Guidelines.....................................................................................................36 
7.3 
Package and Labeling ..................................................................................................37 
7.4 
Study Treatment Allocation .........................................................................................37 
7.5 
Site Supply, Storage, Accountability ...........................................................................37 
7.5.1 
Site Supply ................................................................................................................37 
7.5.2 
Storage ......................................................................................................................37 
7.5.3 
Accountability ...........................................................................................................38 
7.6 
Procedures for Overdose ..............................................................................................38 
7.7 
Prohibited Therapy and Concomitant Treatment .........................................................38 
7.7.1 
Prohibited Medications .............................................................................................38 
8.
STUDY PROCEDURES ...............................................................................................41 
8.1 
Description of Study Assessments ...............................................................................41 
8.1.1 
Dry Eye Disease Activity Assessments ....................................................................41 
8.1.2 
Post-Instillation Tolerability Assessments ...............................................................43 
8.1.3 
Safety Assessments ...................................................................................................43 
8.2 
Schedule of Assessments .............................................................................................45 
8.2.1 
Screening Procedures ................................................................................................45 
8.2.2 
Treatment Procedures ...............................................................................................46 
8.2.3 
Unscheduled Visits ...................................................................................................51 
8.2.4 
End of Study (or Early Discontinuation) Procedures ...............................................51 
8.2.5 
Follow-up Procedures ...............................................................................................51 
9.
EVALUATION, RECORDING AND REPORTING OF AES AND SAES .............52 
9.1 
Definitions....................................................................................................................52 
9.1.1 
Adverse Event ...........................................................................................................52 
9.1.2 
Adverse Drug Reaction .............................................................................................52 
9.1.3 
Unexpected ADR ......................................................................................................52 
9.1.4 
Serious Adverse Event (SAE)...................................................................................52 
9.1.5 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ...................................53 
9.2 
Adverse Event Descriptors ..........................................................................................53 
9.2.1 
Intensity/Severity Categorization .............................................................................53 
9.2.2 
Causal Relationship Categorization ..........................................................................54 
9.2.3 
Outcome Categorization ...........................................................................................54 


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9.2.4 
Symptoms of the Disease Under Study ....................................................................54 
9.2.5 
Abuse, Misuse, Overdose and Medication Error ......................................................55 
9.3 
Reporting Procedure for AEs, SAEs, and Pregnancy ..................................................55 
9.3.1 
Adverse Events .........................................................................................................55 
9.3.2 
Serious Adverse Events ............................................................................................56 
9.3.3 
Pregnancy..................................................................................................................58 
10. STATISTICAL ANALYSIS .........................................................................................59 
10.1 
Statistical Methods .......................................................................................................59 
10.2 
Sample Size and Power Calculations ...........................................................................59 
10.3 
Populations ...................................................................................................................60 
10.3.1 
Intent-to-Treat Set .....................................................................................................60 
10.3.2 
Per Protocol...............................................................................................................60 
10.3.3 
Safety Set ..................................................................................................................60 
10.4 
Concomitant Therapy...................................................................................................60 
10.5 
Endpoint Evaluations ...................................................................................................60 
10.5.1 
Primary Endpoint ......................................................................................................60 
10.5.2 
Secondary Endpoints ................................................................................................60 
10.6 
Statistical and Analytical Methods ..............................................................................61 
10.6.1 
Primary Analysis.......................................................................................................61 
10.6.2 
Secondary Efficacy Analysis ....................................................................................61 
10.6.3 
Safety Analysis .........................................................................................................61 
10.7 
Safety Evaluations .......................................................................................................61 
10.8 
Interim Analyses ..........................................................................................................62 
10.9 
Other Evaluations.........................................................................................................62 
11. ETHICAL CONDUCT OF THE STUDY ...................................................................63 
11.1 
Informed Consent.........................................................................................................63 
11.2 
Institutional Review Board or EC/IEC ........................................................................63 
12. QUALITY CONTROL AND QUALITY ASSURANCE ...........................................64 
13. ADMINISTRATIVE PROCEDURES .........................................................................65 
13.1 
Sponsor’s Responsibilities ...........................................................................................65 
13.1.1 
Study Supplies ..........................................................................................................65 
13.1.2 
Insurance ...................................................................................................................65 
13.1.3 
Study Monitoring ......................................................................................................65 
13.2 
Investigator’s Responsibilities .....................................................................................66 
13.2.1 
Reporting and Recording of Data .............................................................................66 
13.2.2 
Investigator Training.................................................................................................66 
13.2.3 
Source Documentation ..............................................................................................66 
14. PROCEDURE FOR MODIFICATION OF PROTOCOL OR PREMATURE
TERMINATION OF THE STUDY .............................................................................67 


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14.1 
Protocol Waivers, Deviations and Violations ..............................................................67 
14.2 
Study Termination .......................................................................................................67 
15. POLICY FOR PUBLICATION AND PRESENTATION OF DATA ......................68 
16. REFERENCES ...............................................................................................................69 
17. APPENDICES ................................................................................................................71 


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LIST OF TABLES 
Table 1: AUR-VOS-2017-01 Schedule of Events ...................................................................12 
LIST OF FIGURES 
Figure 1: AUR-VOS-2017-01 Study Schematic......................................................................11 
LIST OF APPENDICES 
Appendix 1 Tolerability Assessment .......................................................................................71 
Appendix 2 Eye Dryness Assessments ....................................................................................72 
Appendix 3 Symptom Assessment in Dry Eye (SANDE) .......................................................73 
Appendix 4 Individual Symptom Severity Assessments using Visual Analog Score (VAS) .74 
Appendix 5 Slit-Lamp Biomicroscopy ....................................................................................75 
Appendix 6 Best Corrected Visual Acuity (BCVA) ................................................................77 
Appendix 7 Fluorescein Corneal Staining (FCS) National Eye Institute/Industry Workshop 
Scale ..................................................................................................................78 
Appendix 8 Restasis® Package Insert, July 2017. ...................................................................79 
Appendix 9 Daily Dosing Diary ..............................................................................................86 


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LIST OF ABBREVIATIONS 
ADR 
Adverse drug reaction 
AE 
Adverse event 
Aurinia 
Aurinia Pharmaceuticals Inc. 
BCVA 
Best Corrected Visual Acuity 
BID 
Twice daily 
CNI 
Calcineurin inhibitor 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
CsA 
Cyclosporine A 
DED 
Dry Eye Disease 
EC 
Ethics Committee 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ERG 
Electroretinography 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FCS 
Fluorescein Corneal Staining 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 


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IUD 
Intrauterine device 
KCS 
Keratoconjunctivitis sicca 
LogMAR 
Logarithm of the Minimum Angle of Resolution 
NEI 
National Eye Institute 
NFAT 
Nuclear Factor of Activated T-cells 
NSAID 
Nonsteroidal Anti-Inflammatory Drug 
NZW 
New Zealand White 
OD 
Right eye 
OS 
Left eye 
OSDI 
Ocular Surface Disease Index 
OTC 
Over-the-counter 
OU 
Both eyes 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
SAE 
Serious adverse event 
SANDE 
Symptom Assessment in Dry Eye 
SAP 
Statistical Analysis Plan 
SAR 
Serious adverse reaction 
STT 
Schirmer Tear Test 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
UPT 
Urine pregnancy test 
VAS 
Visual Analog Scale 
VOS 
Voclosporin ophthalmic solution 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 


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1.
INTRODUCTION AND BACKGROUND
1.1 
Background of the Disease and Treatment Options
Dry Eye Disease (DED), also called keratoconjunctivitis sicca (KCS), is a common clinical 
problem as over 7 million people in the United States experience dry eye symptoms. 
Symptoms of DED include a sensation of dry eyes, foreign body sensation, irritation, burning, 
tearing, ocular pain, and itching, among others. DED affects quality of life and work 
productivity, and patients with moderate to severe DED may experience reduced visual 
function in addition to ocular dysfunction.  
DED is a multi-factorial disease, defined by a loss of homeostasis of the tear film and 
accompanied by ocular symptoms, in which tear film instability and hyper-osmolarity, ocular 
surface inflammation and damage, and neuro-sensory abnormalities play etiological roles [1].  
DED patients are classified by the overlapping etiologies of aqueous deficient and evaporative 
dry eye [2].  Evaporative dry eye tends to be more prevalent than aqueous deficient; however, 
as the disease progresses, both components become apparent [1].  The common pathway for 
both groups is that desiccating stress leads to ocular surface inflammation [3-5]. 
1.1.1 Limitations of Current Treatment 
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 [1]. There are currently two FDA-approved 
prescription medications used for DED, topical cyclosporine (Restasis®) [6] and lifitigrast 
(Xiidra®) [7]. A significant number of patients using Restasis® experience the following 
problems: ocular irritation upon instillation, slow onset of response, and limited efficacy 
(Restasis® Package Insert, see Appendix 8). Problems with Xiidra® include instillation 
irritation, dysgeusia and reduced visual acuity which occurred in 5-25% of subjects in clinical 
trials (Xiidra® Package Insert [7]). There is a clear unmet clinical need for improved 
therapeutic options for patients with moderate to severe DED. 
1.2 
Rationale for the Use of Calcineurin Inhibitors in Dry Eye Disease 
In patients with DED, tear production has been shown to be increased with the use of topical 
immunosuppressants, including cyclosporine. It is believed T-lymphocyte infiltration and 
activation in the lacrimal gland represents an underlying pathogenesis for DED. Calcineurin 
inhibitors 
(CNIs) 
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 
[8]. 
Calcineurin 
is 
a 
calcium- 
and
calmodulin-dependent serine-threonine phosphatase. 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


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various transcription factors necessary for the induction of cytokine genes during T-cell 
activation (e.g., interleukin-2, interleukin-4, tumor necrosis factor-α, granulocyte-macrophage 
colony stimulating factor, and interferon-γ [9,10]). 
Voclosporin is a 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 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 as compared to CsA. The combination of increased 
potency and decreased metabolite exposure, for voclosporin as compared to CsA, has led to 
better pharmacokinetic (PK)/pharmacodynamic (PD) predictability. 
1.2.1 Non-Clinical Studies of Voclosporin in Dry Eye 
Two Good Laboratory Practice toxicology studies [11,12] 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 evaluation, 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 Day 1 and Day 13 at pre-dose, 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 to be 0.56 mg/eye/day. There 


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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 [13], 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 is >0.56 mg/eye/day.  
In summary, the two repeated-dose ocular toxicology studies [11,12] 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 
the S08711 study.  
In addition to the three repeated dose toxicology studies, the safety and efficacy of VOS 0.2% 
has been evaluated in dogs with naturally occurring KCS [14], 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 twice daily (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 both safe and effective in 
treating KCS in dogs. 
In order to determine potential melanin binding of 
14C-LX214, ocular tissue 
14C-LX214-derived radioactivity concentrations were compared between data obtained from 


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albino NZW rabbits given a single bilateral instillation in a separate study and similarly treated 
pigmented Dutch-Belted rabbits. 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.  
1.2.2 Clinical Studies of Voclosporin in Dry Eye 
VOS has been investigated in one Phase 1 dose-escalation study (LX214-01) at a dose of 0.02% 
and 0.2% in 30 healthy volunteers, followed by an open-label evaluation of 0.2% VOS in 5 
subjects with DED [15]. In that study, both 0.02% and 0.2% concentrations were found to be 
safe and well-tolerated following multiple instillations in healthy subjects. Adverse events 
(AEs) and ocular findings were mild and similar between VOS and placebo groups. Although 
the sample size was small, results from the 5 subjects with DED suggest VOS may be 
beneficial in the treatment of DED and is supported by the Ocular Surface Disease Index 
(OSDI) 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. 
These factors form the basis for the rationale to investigate the safety and efficacy of 
voclosporin in subjects with DED.  Study AUR-VOS-2017-01 will evaluate the tolerability 
and efficacy of VOS versus Restasis® in subjects with DED.  


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2.
RATIONALE
2.1 
Dose Rationale
Based on Phase 1 studies in healthy subjects and all clinical trials to date in the clinical 
development program in other indications, oral voclosporin is generally well tolerated at doses 
up to 0.8 mg/kg BID with no unexpected safety concerns compared to the profile expected for 
CNIs.  
VOS was evaluated in a Phase 1 parallel, randomized, double-masked, placebo-controlled, 
dose-escalation (0.02% and 0.2%) study assessing the safety and tolerability of VOS in healthy 
volunteers, followed by an open-label evaluation of VOS (0.2%) BID in subjects with DED 
(see VOS DED Investigator’s Brochure (IB) [16]). Although the sample size was small, results 
from the five subjects with DED suggest VOS may be beneficial in the treatment of DED and 
is supported by the OSDI scores which were improved in all subjects at all timepoints while 
on study drug. The mean improvement in STT scores between baseline and the end of treatment 
provides further evidence of efficacy. It is anticipated that 0.2% VOS BID will be an effective 
dose in the treatment of immune-mediated ocular surface disease. 


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3.
STUDY OBJECTIVES
3.1 
Primary Objective
•
To assess the ocular tolerability of VOS compared to cyclosporine ophthalmic emulsion
(Restasis®) in subjects with DED.
3.2 
Secondary Objective 
•
To assess the safety and efficacy of VOS in subjects with DED.
3.3 
Endpoints 
3.3.1 Primary Endpoint 
•
Change from baseline in Drop Discomfort Visual Analogue Scale (VAS) score 1-minute
post-Dose 1 instillation.
3.3.2 Secondary Endpoints 
3.3.2.1 Key Secondary Endpoints 
•
Change from baseline in Drop Discomfort VAS score
•
Change from baseline in each of the 6 Individual Symptom Severity Assessments (VAS)
scores
•
Change from baseline in the sum of the Individual Symptom Severity Assessments score
(VAS Total Symptom Summary Score)
•
Change from baseline in Symptom Assessment in Dry Eye (SANDE) score
•
Change from baseline in unanesthetized STT score
•
Change from baseline in Fluorescein Corneal Staining (FCS) total score (National Eye
Institute (NEI)/Industry Workshop 0-15 scale)
3.3.2.2 Other Secondary Safety Endpoints 
•
Treatment-emergent adverse events (TEAEs)
•
Change from baseline in Best Corrected Visual Acuity (BCVA)
•
Changes from baseline in Slit-Lamp Biomicroscopy
•
Changes from screening in Dilated Ophthalmoscopy


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4.
INVESTIGATIONAL PLAN
4.1 
Overall Study Design
This is a Phase 2, multi-center, Investigator-masked, randomized, parallel-group study to 
evaluate the tolerability, efficacy and safety of VOS versus Restasis® over a 28-day treatment 
period in subjects with mild to moderate DED.  Approximately 90 subjects will be randomized 
to either VOS or Restasis® at approximately 7 centers located in the US.   
At Visit 1 (screening), informed consent will be obtained from subjects and eligibility will be 
determined.  A STT will be performed at this visit. The score will be used for eligibility and 
baseline.  During this visit, all subjects will self-administer an OTC ocular lubricant, Refresh 
Plus®, OU to assess ability to self-administer study product. 
At Visit 2 (Randomization), continued eligibility will be confirmed.  During this visit, all 
subjects will self-administer an OTC ocular lubricant, Refresh Plus®, OU to evaluate ability to 
tolerate ocular drops. Individuals who are unable to successfully instill the drops or who rate 
OTC ocular lubricant as uncomfortable, based on a post-instillation Drop Discomfort VAS 
score, will not be eligible for participation in the study. (Note:  For subjects meeting the 
Screening and Randomization Criteria, the Visit 2 Drop Discomfort VAS score will be used 
as the baseline value.)   
Eligible subjects will be randomly assigned in a 1:1 ratio to one of the two treatment groups:  
VOS BID or Restasis® BID.  The first instillation of Investigational Product (IP) will be 
administered, at least 2 hours following administration of Refresh Plus® and by clinic personnel 
to both eyes during Visit 2.  IP will be administered to the subject by an unmasked dedicated 
dosing coordinator (the subject and the Investigator will be masked to study treatment for the 
first post randomization instillation). Tolerability, safety and efficacy assessments will be 
performed at this visit. 
At Treatment Visits 3 and 4, tolerability, safety and efficacy evaluations will be performed.  At 
the End of Treatment, Visit 5, tolerability, safety and efficacy evaluations will be performed. 
Subjects who discontinue before Visit 5 will undergo all Visit 5 evaluations (Early 
Termination). IP will be administered to the subject by an unmasked dedicated dosing 
coordinator at the clinic visits (single-masked: the Investigator and study staff will remain 
masked to study treatment). A Drop Discomfort VAS will be administered in the clinic at 1-
minute and 5-minutes following instillation of IP at Visits 2 through 5 (Investigator is to remain 
masked).  With the exception of clinic day visits, subjects will self-administer IP twice a day 
OU over the 4-week treatment period.  On the evening of Visits 2 through 4 and in the evening 
prior to Visit 5, site staff will contact the subject by phone to prompt administration of IP 
followed by completion of the dosing diary (See Appendix 9) and the Drop Discomfort VAS 
(1-minute and 5-minutes post-instillation). 


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At Visit 6, there will be a 3-day post-treatment Follow-Up, in which safety assessments are 
performed and all remaining study materials are collected. The subjects will be instructed to 
continue to withhold all other concomitant topical medications as outlined by the protocol for 
the duration of their participation (through Visit 6). 
Serious adverse events (SAEs) ongoing as of Visit 6 will be followed until they have resolved, 
stabilized in the opinion of the Investigator, or returned to baseline. 
This study will be conducted per the schedule shown in the Schedule of Events (Table 1) and 
the Study Schematic (Figure 1). 
4.2 
Duration of Subject Participation and Study 
The expected duration of subject participation is approximately 5 weeks. The treatment 
duration is 28 days with a follow-up visit 3 days after last dose (completion or early 
termination).  


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5.
SELECTION, WITHDRAWAL OF SUBJECTS AND PERMANENT
DISCONTINUATION OF DRUG
5.1 
Number of Subjects 
Approximately 90 subjects will be randomized to either VOS or Restasis®.  Approximately 
45 subjects will be assigned to each treatment group. 
5.2 
Inclusion Criteria 
At Visit 1 and Visit 2 (as specified in the Schedule of Events), subjects may be eligible for 
participation if they:  
1. Provide written informed consent before any study-specific procedures are performed.
2. Are male or female subjects with a minimum age of 18 years (or legal age of consent
if >18 years), at the time of screening (Visit 1).
3. Are willing and able to follow instructions and can be present for the required study visits
for the duration of the study.
4. 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.
5. Have a documented history of DED in both eyes supported by a previous clinical diagnosis
at Visit 1.
6. Have ongoing DED, as defined by at least one eye (if one eye, the same eye) meeting all
the following criteria:
−
A symptom severity score of ≥30 for Eye Dryness on a VAS (0-100) at Visit 2
−
An unanesthetized STT score of ≥1 mm and ≤10 mm per 5 minutes (Note:  STT Score
obtained at Visit 1)
−
Evidence of ocular surface staining (total fluorescein staining score of at least 3 [0-15
scale]) at Visit 2
7. Have normal lid anatomy at Visit 1.
5.3 
Exclusion Criteria 
In order for subjects to be eligible at Visit 1 and Visit 2 (as specified in the Schedule of Events), 
subjects must not: 


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1. Be unable or unwilling to give written informed consent and/or to comply with study
procedures.
2. Have any known hypersensitivity or contraindication to study treatments (including
excipients), topical anesthetics or vital dyes.
3. Be unable to demonstrate correct instillation of OTC ocular lubricant during Visit 1.
4. Report discomfort in both eyes from instillation of OTC ocular lubricant during Visit 2
(based on score of ≥30 on the Drop Discomfort VAS).
5. Have used Restasis® (cyclosporine ophthalmic emulsion) within 30 days prior to Visit 1.
6. Have used Restasis® for more than 1 month (if prior use is reported).
7. Have used Xiidra® (lifitegrast ophthalmic solution) within 14 days prior to Visit 1.
8. Have had corneal graft surgery in either eye within 1 year of Visit 1.
9. Have recent or current evidence of ocular infection or inflammation in either eye.
10. Have current evidence of clinically significant blepharitis (defined as requiring lid hygiene
therapy), conjunctivitis, or a history of herpes simplex or zoster keratitis in either eye.
11. Have clinically significant ocular disease in either eye (e.g., corneal edema, uveitis, severe
KCS) which might interfere with study procedures or assessments.
12. Have any abnormality in either eye preventing reliable applanation tonometry.
13. Be taking or have known need for any of the known treatment therapies listed in Section
7.7, Prohibited Therapy and Concomitant Treatment at Visit 1 or during the study. This
includes prohibited medications prior to Visit 1 as specified in Section 7.7, Prohibited
Therapy and Concomitant Treatment.
14. Have any known hypersensitivity or contraindication to CNIs.
15. Have clinically significant systemic disease (e.g., uncontrolled diabetes, hepatic, renal,
endocrine or cardiovascular disorders) which might interfere with the study.
16. Have participated in any investigational clinical study within 30 days prior to Visit 1.
17. Have altered any systemic medication that could have an effect on dry eye signs or
symptoms within 30 days prior to Visit 1 or anticipated during the study.


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18. Be women of childbearing potential (WOCBP) who are pregnant, nursing, planning a
pregnancy, or not using a medically acceptable form of birth control.
5.4 
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 WOCBP must have a negative 
urine pregnancy test (UPT) 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 (IUD) in place for at least 4 weeks prior to Visit 1 through Visit 5 or
last administration of IP or until completion of the subject’s first menstrual cycle following
last administration of the IP, whichever period of time is longer.
2. Barrier method (condom or diaphragm) with spermicide for at least 4 weeks prior to Visit
1 through Visit 5 or last administration of the IP or until completion of the subject’s first
menstrual cycle following last administration of the IP, whichever period of time is longer.
3. Stable hormonal contraceptive for at least 60 days prior to Visit 1 through Visit 5 or last
administration of the IP or until completion of the subject’s first menstrual cycle following
administration of the IP, whichever period of time is longer.
NOTE: For Depo-Provera injection contraceptives, the statement regarding first menstrual
cycle following administration of the IP is not applicable as females receiving this form of
contraception will not have menses.
4. In a monogamous relationship with a surgically sterilized (i.e., vasectomized) partner at
least 6 months prior to Visit 1 through Visit 5 or last administration of the IP or until
completion of the subject’s first menstrual cycle following administration of the IP,
whichever period of time is longer.
5.5 
Withdrawal of Subjects 
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 5). If possible, the 
subject should also be advised to come for the Follow-up Visit, 3 days after last dose (Visit 6). 
If a subject refuses end of study procedures, the reason for refusal should be fully documented 
in the subject’s source document and recorded in the study specific electronic case report form 
(eCRF). It is the subject’s right to withdraw from the study without providing a reason. In this 


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case, the source documents and the eCRF should document the reason for discontinuation as 
“withdrawal of consent.” Withdrawn subjects will not be replaced. 
5.6 
Discontinuation of Study Treatment 
If any subject is discontinued from study treatment, the reason for discontinuation will be 
documented in the eCRF. If the reason for discontinuing study treatment is an AE, the specific 
event or test will be recorded in the eCRF. The subject should also be advised to come for the 
Follow-up Visit, 3 days after last dose.  
Subjects who are permanently discontinued from study treatment will be treated as deemed 
appropriate by the Investigator. 
5.6.1 Discontinuation of Study Treatment Due to an Adverse Event 
Subjects may be permanently discontinued from study treatment because of the appearance of 
an unacceptable AE. It is vital to obtain follow-up data on any subject withdrawn because of 
an AE. In any case, every effort must be made to evaluate protocol-specified safety follow-up 
procedures (see Section 9.3, Reporting Procedure for AEs, SAEs, and Pregnancy). If a subject 
is withdrawn due to an AE, the event should be followed by the Investigator through contact 
with the subject until resolution or stabilization has occurred. All AEs should be followed until 
resolution, stabilization or the subject is lost to follow-up and cannot be contacted. 


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6.
RANDOMIZATION, MASKING AND UNMASKING PROCEDURES
6.1 
Randomization
A computer-generated randomization schedule will be used to assign subjects into treatment 
groups.  The randomization ratio will be maintained within each study center.  A randomization 
list will be generated and provided by an unmasked statistician.  
The Sponsor, the project teams at the designated Contract Research Organizations (CROs), 
and investigative staff responsible for assessments of study endpoints will be masked to study 
product assignments. There will be an unmasked dedicated dosing coordinator who will 
dispense the IP to the subject and who will perform drug accountability on the returned IP. 
This individual will be otherwise uninvolved in the study operations. Furthermore, there will 
be a Clinical Research Associate (CRA) dedicated to drug accountability who will be 
unmasked to the treatment assignment by default but will be uninvolved in review of the 
clinical trial data beyond the scope of IP accountability. In case of medical emergency, or 
occurrence of an SAE, the randomization code may be unmasked and made available to the 
Investigator, Sponsor, and/or other personnel involved in the monitoring or conduct of this 
study. In the absence of medical need, the randomization code will not be available to the 
above individuals until after the study is completed and the database is locked.   
In the event of a medical need, the Investigator will treat each subject as needed. Since there 
is no specific antidote to VOS, immediate emergency unmasking is not necessary. If the 
Investigator feels it is necessary to unmask a subject’s assignment after an emergency situation, 
the Investigator may call the Medical Monitor and notify the Sponsor. The IP assignment will 
be revealed on a subject-by-subject basis with the approval of the Medical Monitor and 
Sponsor, thus leaving the masking of the remaining subjects intact. 
A randomization schedule will be generated by an unmasked statistician who will also be 
responsible for loading the schedule into the electronic data capture (EDC) system. No other 
 or Aurinia Pharmaceuticals Inc. (Aurinia) staff will have access 
to the schedule. 
Randomization team members will work independently of other team members at the CRO. 
With the exception of the unmasked dedicated dosing coordinator and drug accountability 
CRA, all other study personnel, the Sponsor, and project teams at the CROs involved in the 
study will be masked to study product assignments.   
6.2 
Masking 
On Day 1 Dose 1, this study is double-masked. The IP allocation (VOS versus Restasis®) will 
be masked to the Sponsor, the subject and the investigative staff with the exception of an 
unmasked dedicated dosing coordinator and unmasked CRA. The unmasked dedicated dosing 


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coordinator will be responsible for dispensing and retrieving IP to/from subjects, instructing 
subjects regarding dosing of the IP, addressing study subjects’ questions regarding IP, and 
reviewing daily dosing diaries. As a consequence of these interactions, the unmasked dedicated 
dosing coordinator will be unmasked to the study treatment for each subject. In order to ensure 
subject masking, at Visit 2, first dose, the unmasked dedicated dosing coordinator will not 
provide any IP related information prior to instilling the IP. The IP will be instilled in a masked 
manner.  Instructions regarding storage and dosing will be provided after this first instillation.  
On Days 2-28, subjects will not have visibility to the study product assignment; however, as 
VOS and Restasis® have different storage conditions and appearance, it may be possible that 
the subjects who have previously used Restasis®, may know that those differ from their prior 
experience. Therefore, the study will be considered Investigator-masked during this timeframe. 
The randomization schedule will be generated by the Randomization Statistician (who is not 
on the project team) or designee and maintained in a secure and limited-access location 
separate from the study Investigator and members of the project team. 
6.3 
Unmasking 
The treatment assignment for an individual subject may be obtained in the case of a medical 
emergency when knowledge of the IP identity is essential for the clinical management of the 
subject. The Investigator must make every effort to contact the study Medical Monitor or the 
Clinical Study Manager before unmasking the treatment assignment.  
In the event of emergency unmasking, the Investigator must inform the Sponsor immediately, 
without revealing to the Sponsor personnel the treatment assignment.  
If unmasking is required for emergency subject management, the Investigator must document 
the medical rationale for unmasking and forward the information to the Sponsor within 
24 hours of unmasking. 
If an SAE is assessed as unexpected and related to the IP, and therefore meets the requirement 
for expedited regulatory submission, the Sponsor’s Drug Safety Surveillance department will 
unmask the treatment assignment for the individual subject. Expedited reports will be 
submitted to Regulatory Authorities in accordance with applicable regulations. Expedited 
reports will be distributed to Investigators without revealing the treatment assignment and will 
be submitted to Institutional Review Boards (IRBs). 
If emergency unmasking is required, withdrawal of the subject from the study is not mandatory 
unless there are other circumstances that require the subject’s discontinuation. At the Sponsor’s 
discretion, the subject may remain in the study without continued use of the IP.   


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In the event of accidental unmasking, the event would be reported as a protocol deviation and 
escalation to the Sponsor. The subject may remain in the study. If identified by the study center, 
a Sub-Investigator may be asked to assume clinical study assessments for a subject if the PI 
was inadvertently unmasked.  


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7.
STUDY TREATMENTS
7.1 
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. 
7.1.1 VOS Study Treatment 
Company Code: 
Chemical Name: 
Empirical Formula: 
Generic Name: 
Voclosporin ophthalmic solution (VOS) 
Dosage Form: 
Voclosporin ophthalmic solution is provided as clear micellar solutions 
in single-use blow/fill/seal ampules for topical ocular administration. 
One drop (~30 μL) of the 0.2% solution contains approximately 0.06 mg 
of voclosporin 
Strength: 
0.2% 
Manufacturer: 
Aurinia Pharmaceuticals Inc. 
7.1.2 Restasis® 
See Package Insert in Appendix 8. 
7.2 
Drug Dosage and Administration 
7.2.1 Treatment Arms 
Investigational Product: 0.2% VOS, BID, OU for 28 days. 
Comparator: 0.05% cyclosporine ophthalmic emulsion (Restasis®) BID, OU for 28 days. 
7.2.2 Dosing Guidelines 
The IP will be administered BID as close to a 12-hour schedule as possible, and with a 
minimum of 8 hours between doses.  
IP will be self-administered by the subjects except for the visit dates where the morning dose 
will be administered by the unmasked dedicated dosing coordinator. 


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If the subject misses a dose by less than 4 hours from the scheduled time, the missed dose will 
be self-administered immediately. The next dose will be administered at the originally 
scheduled time. If the subject misses a dose by more than 4 hours from scheduled time, the 
subject should skip the dose and administer the next dose as regularly scheduled. 
7.3 
Package and Labeling 
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 
Good Clinical Practice (GCP). 
7.4 
Study Treatment Allocation 
Subjects will be randomized to receive either VOS or Restasis® in a 1:1 ratio. Subjects will be 
allocated a kit number for the duration of the study.  Subjects will be assigned to treatment 
groups using the randomization module within the EDC system.  As eligible subjects are 
enrolled and the corresponding Randomization eCRF completed, a kit number will be 
assigned. 
7.5 
Site Supply, Storage, Accountability 
7.5.1 Site Supply 
Once a site has been approved for study initiation, the site will be supplied with an initial stock 
of IP. Each site will receive one shipment of both Restasis® and VOS prior to study enrollment. 
Additional shipments of both Restasis® and VOS will be provided to each site as needed. 
7.5.2 Storage 
VOS should be stored refrigerated between 2º C and 8º C (36º F to 46º F) but may be brought 
to room temperature prior to use. Subjects should be consistent in their use of VOS IP.  
Opened ampules must not be stored for re-use as the formulation does not contain 
preservatives. 
STUDY DRUG SHOULD NOT BE FROZEN. DO NOT USE IF THE VIAL CONTENT 
DOES NOT APPEAR CLEAR. 
Restasis® should be stored at room temperature (15-25°C/59-77°F). 
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 Unmasked site personnel during normal working hours. This log must be 
available for review by the Unmasked Site Monitor during on-site monitoring visits. 


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7.5.3 Accountability 
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 designee for the central study file. The original will be kept in the site files. 
After completion of the study, or if it is prematurely terminated, all undispensed IP will be 
returned to Aurinia. The decision to destroy IP at a site must be made by Aurinia. If the 
dispensed/returned IP is destroyed at a site, the Investigator must receive Aurinia approval of 
the site’s standard operating procedure addressing the destruction process and forward 
documentation of destruction to Aurinia. 
7.6 
Procedures for Overdose 
Preclinical findings suggest that systemic effects from an overdose are unlikely, as the peak 
blood levels after ocular instillation are below those achieved with oral doses of voclosporin. 
Based on clinical experience with voclosporin, symptomatic treatment of AEs is indicated. In 
the event of overdose, discontinuation of treatment should be considered. 
7.7 
Prohibited Therapy and Concomitant Treatment 
Any concomitant treatment given for any reason during the study must be recorded in the eCRF 
and in the subject’s source documents, including dosage, start and stop dates, and reason for 
use. 
Any class of medications not mentioned in Section 7.7.1, Prohibited Medications and with the 
potential to interfere with evaluation of the study treatment must be discussed and documented 
with the Medical Monitor. 
7.7.1 Prohibited Medications 
The following drugs/therapies shall be prohibited during the study and for the timeframes 
specified below:  A subject should not have received:  
•
any investigational drug or device within 30 days prior to the Screening Visit (Visit 1) and
may not receive any investigational drug or device during the entire study except that which
is allowed by the protocol


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•
Ophthalmic drugs (any topical eye medications) including prescription medication and
OTC agents, except IP and study lubricant at Visit 1 and Visit 2, from Visit 1 to Visit 6.
•
Contact lenses during the period from the Screening Visit (Visit 1) to the end of the study
(Visit 6)
•
Prohibited Medications:
o
Any prior use of amiodarone
o
Within 14 days prior to study and for the duration of the study:

Xiidra® (lifitigrast)
o
Within 30 days prior to study and for the duration of the study:

Restasis® (cyclosporin ophthalmic emulsion); NOTE:  Any prior use of
Restasis® may not have exceeded 1 month of continuous use

Topical ocular antihistamines

Ocular, inhaled or intranasal corticosteroids

Topical or oral mast cell stabilizers

Oral antihistamines

Topical or nasal vasoconstrictors

Topical ocular nonsteroidal anti-inflammatory drugs (NSAIDs)

Topical ocular antibiotics
o
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
o
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
o
Within 90 days prior to the screening visit (Visit 1) or during the study, in the
study eye 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 screening visit (Visit 1) and it is dislodged during the study, the plug
should be replaced as soon as possible
o
At screening visit (Visit 1) or any time throughout the study:

Chronic oral anti-viral medications for ocular herpetic disease


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8.
STUDY PROCEDURES
8.1 
Description of Study Assessments
8.1.1 Dry Eye Disease Activity Assessments
The following assessments will occur as part of the evaluation of DED (see Appendix 2).
8.1.1.1 Symptom Assessment in Dry Eye (SANDE) 
Subjects will be asked to subjectively rate the frequency and severity of their dry eye symptoms 
at Visits 2, 3, 4 and 5 using the SANDE.  The total length of the line from “rarely” to “all the 
time” (frequency of symptoms) and from “very mild” to “very severe” (severity of symptoms) 
is 100 mm. Subjects will be asked to subjectively rate the frequency and severity of their 
symptoms (OU) by placing an “X” on the relevant horizontal line. The length of the line 
between the “rarely” or “very mild” starting point and the first point where the subject’s mark 
crosses each line will be measured and recorded 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 prior to assessing for AEs and prior to any other invasive visit assessment 
(see Appendix 3).  
8.1.1.2 Visual Analogue Scale (VAS) Symptom Assessments 
Individual Symptom Severity Assessments using VAS: 
Subjects will be asked to rate their current symptoms (unrelated to study drug instillation) at 
Visits 2, 3, 4 and 5.   The following six symptoms will be evaluated:  Burning/Stinging, Foreign 
Body Sensation, Photophobia, Eye Pain, Eye Dryness, and Itching. 
The subject will be asked to subjectively rate each of six ocular symptoms (OU) by placing a 
vertical mark on the horizontal line to indicate their level of discomfort. 0 corresponds to “No 
Symptoms” and 100 corresponds to “Severe Symptoms.” 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 (see Appendix 
4).  
8.1.1.3 Fluorescein Corneal Staining (FCS) 
Corneal staining will be performed at Visit 2, 3, 4 and 5.  Corneal staining assessment will be 
performed using methods developed by the NEI Dry Eye Workshop (see Appendix 7). 
Evaluation Technique 
NOTE: All steps in this procedure should be completed for the right eye (OD) prior to 
repeating the procedure for the left eye (OS). 
•
Place Slit-Lamp magnification at 10x (it is acceptable to use 16x if no reticle is used)


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•
Use a yellow barrier filter (Wratten or Tiffen #11 or #12)
•
Place 5 µL of non-preserved, 2% fluorescein into eye, gently touching the drop at the tip
to the lower palpebral conjunctiva of the eye
•
In order to thoroughly mix the fluorescein with the tear film, ask the subject to blink several
times and move his/her eye around
•
Wait 2.5 minutes to assess cornea
•
Measure staining under Cobalt blue light (465 nm to 490 nm)
•
Compare staining with the standard with scoring in each of 5 areas of the 5 corneal sections
Scoring system 
•
Grade each of 5 sections of cornea (superior, inferior, nasal, temporal, central)
•
Provide grades for each of the 5 sections:
−
Grade by NEI scale (definition in Appendix 7) as 0, 1 (mild), 2 (moderate), or 3 (severe)
•
Total score is obtained by summing each of the 5 sections of the cornea
−
NEI score will be from 0-15. (See Appendix 7).
8.1.1.4 Unanesthetized Schirmer Tear Test (STT) 
Schirmer Tear Test (without anesthesia) will be conducted at Visit 1 and Visit 5.  This 
procedure should be conducted at least 1 hour following administration of IP and at least 20 
minutes following FCS at Visit 5: 
Identical Schirmer strips will be supplied to each site.  When conducting assessments room 
temperature and humidity should be relatively consistent throughout each visit and throughout 
the study.  
•
While still in the plastic sheath, fold the notched end of the Schirmer strip at the apex of
the “v.”  Additionally, make a partial second fold at the halfway point of the strip so that
the strip does not lie directly in the subject’s line of sight
•
Remove the right eye strip from the sheath
•
Ask the subject to look up and gently draw the right lower lid in a downward and temporal
direction
•
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•
Repeat this procedure in the left eye
•
Darken the room but ensure that the largest letter(s) of a Snellen or ETDRS chart is visible
•
Instruct the subject to relax and look at the chart while blinking normally or have patients
gently close eyes
•
Remove the strips after 5 minutes
•
After removing the strips, with a sharp pencil draw a horizontal line across the leading edge
of moisture and a second horizontal line across the lowest point of moisture
•
Using a ruler and/or the millimeters recorded on the strips, measure a point halfway
between the two lines and record this as the amount of wetting
8.1.2 Post-Instillation Tolerability Assessments 
8.1.2.1 Drop Discomfort Assessment  
Drop discomfort will be assessed by the subject through a Drop Discomfort VAS (0-100 mm) 
where 0 corresponds to “no discomfort” and 100 corresponds to “maximal discomfort.” (See 
Appendix 1). 
At Visit 2, prior to randomization, in order to evaluate the subject’s ability to tolerate ocular 
drops, all subjects will self-administer an OTC ocular lubricant, Refresh Plus®, OU. Upon 
instillation of the ocular lubricant OU, subjects will be instructed by the site staff to rate their 
eye discomfort at 1-minute and 5-minutes post-instillation by placing a mark on the Discomfort 
VAS. Subjects who rate OTC ocular lubricant as uncomfortable, defined as a VAS score ≥ 30 
mm, will not be eligible for participation in the study. These Drop Discomfort VAS scores will 
be used as the baseline values.  
At Visit 2, after randomization, an unmasked dedicated dosing coordinator will instill the IP 
OU. Subjects will be instructed by a masked site staff to rate their eye discomfort at 1-minute 
and 5-minutes post-instillation of IP as described above.   
Subjects will complete this assessment in the clinic following the AM dose of IP at Visits 2, 3, 
4 and 5 and again at home following the PM dose on the evenings of Visits 2, 3, 4 and the 
evening prior to Visit 5.   
8.1.3 Safety Assessments 
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8.1.3.1 Best Corrected Visual Acuity (BCVA) 
BCVA will be conducted at each visit per the Schedule of Events.  Visit 1 BCVA will be used 
to assess eligibility, and Visit 2 BCVA will be used as baseline value. Visual acuity testing 
should precede any examination requiring contact with the eye or instillation of study dyes. 
LogMAR visual acuity must be assessed using an ETDRS or modified ETDRS chart. Visual 
acuity testing should be performed with best correction using subject’s own corrective lenses 
(spectacles only) or pinhole refraction. 
An ETDRS or modified ETDRS chart may be used, and charts may be reflectance or 
retro-illuminated.  If a 24.5” by 25” chart is used, the subject must view the chart from exactly 
4 meters (13.1 feet).  If smaller reproductions (18” by 18”, e.g., Prevent Blindness) are used, 
the subject viewing distance should be exactly 10 feet. Reflectance wall charts should be 
frontally illuminated (60-watt bulb or a well-lit room). 
The subject should be positioned per the elevation of the chart (either seated or standing) so 
that the chart is at a comfortable viewing angle. The right eye should be tested first. The subject 
should attempt to read each letter, line-by-line, left to right, beginning with line 1 at the top of 
the chart. The subject should be told that the chart has letters only, no numbers. If the subject 
reads a number, he or she should be reminded that the chart contains no numbers, and the 
examiner should then request a letter instead of the number. The subject should be asked to 
read slowly, about 1 letter per second, to achieve the best identification of each letter. He/she 
is not to proceed to the next letter until he/she has given a definite response. If the subject 
changes a response before he has read aloud the next letter, then the change must be accepted. 
Maximum effort should be made to identify each letter on the chart encouraging the subject to 
guess. When it becomes evident that no further meaningful readings can be made, the examiner 
should stop the test. The number of letters missed or read incorrectly should be noted (see 
Appendix 6). 
8.1.3.2 Dilated Ophthalmoscopy  
Dilated ophthalmoscopy exam will be performed per the Investigator’s standard procedure at 
Visit 1 and Visit 6.  
The Investigator will determine if findings are within normal limits or are abnormal. For 
abnormal findings at Visit 1, the Investigator will determine whether the abnormality would 
exclude subject from study participation. A clinically significant change from baseline may 
indicate an AE. 


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8.1.3.3 Slit-Lamp Biomicroscopy  
The biomicroscopy exam will be performed at Visit 2 and Visit 5. It should be performed with 
the Slit-Lamp using a beam of width and intensity to provide optimal evaluation of anterior 
segment. 
This procedure will be performed in the same manner for all subjects observed at the 
Investigator’s site (see Appendix 5). 
8.2 
Schedule of Assessments 
A detailed schedule of assessments (including all protocol-required assessments, visits, and 
visit windows) is located on the Schedule of Events (Table 1). No study-related assessments 
will be performed (including changes to current medications to meet study eligibility) until the 
subject has provided signed and dated informed consent. Every effort will be made to keep the 
subject within the requested visit schedule. If a subject is seen outside of the visit window 
listed on the Schedule of Events, the reason must be clearly documented in the source notes.  
8.2.1 Screening Procedures 
8.2.1.1 VISIT 1  
The screening visit will take place within 3 days prior to Visit 2. After obtaining informed 
consent, site staff will perform/assess the following procedures in the order below. There will 
be a collection of information including:  
•
Demographics
•
Prior documented DED diagnosis
•
Ocular, general medical and surgical history
•
Concomitant medication history
•
UPT for all eligible WOCBP
•
BCVA assessment
•
Unanesthetized STT
•
Dilated Ophthalmoscopy
•
Assessment of ocular lubricant self-instillation
•
AE assessment


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•
Inclusion and exclusion criteria assessment: Subjects who do not meet the evaluated
criteria will not continue participation in the study. Any subject who does not meet
eligibility requirements will be considered a Screen Failure.
Subjects should be reminded not to use artificial tears or any other OTC or prescription or any 
other topical eye medication except for the IP for the duration of their participation in the study. 
Subject will be scheduled to return for Visit 2 in one to three days. 
8.2.2 Treatment Procedures 
8.2.2.1 VISIT 2  
Pre-Randomization 
The site staff will perform/assess the following procedures: 
•
SANDE
•
Individual Symptom Severity Assessments (VAS)
•
AE assessment
•
Concomitant medication review
•
BCVA assessment
•
Self-instillation of ocular lubricant and Drop Discomfort assessment (VAS)
•
Slit-Lamp biomicroscopy
•
FCS
•
Inclusion and exclusion criteria assessment. Any subject who does not meet eligibility
requirements will be designated as Visit 2 Screen Failure and discontinued from the study
Upon verification of study eligibility, subjects will be randomized to receive either VOS or 
Restasis®.  
Post-Randomization  
The following procedures will be performed after randomization: 
•
IP administration: the unmasked dedicated dosing coordinator will administer the first dose
of IP to the subject OU


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Note: IP administration should not take place until at least 2 hours after administration 
of ocular lubricant. 
•
Drop Discomfort assessment: A masked site staff will administer the Drop Discomfort
VAS to the subject and instruct the subject to complete the Drop Discomfort VAS at
1-minute and 5-minutes post-dose
•
Assess for occurrence of any AEs
•
IP dispensation: The unmasked dedicated dosing coordinator will dispense the IP,
provide instructions for IP administration and storage conditions
•
Dosing Diary and VAS scales dispensation: Train the subjects on the completion of the
daily dosing diary and VAS scales
•
Evening contact scheduling: Masked site staff will schedule and contact the subject in the
evening of the clinic visit to prompt administration of the next dose and completion the
Drop Discomfort VAS
•
Subjects should be reminded to withhold AM dose of IP on morning of next clinic visit
and to return all used and unused IP
Subject will be scheduled to return for Visit 3 on Day 7 ±2 days. 
PM Contact with Patient: 
•
Masked site staff will call subject to prompt IP administration and will remain on call to
facilitate completion of the Drop Discomfort VAS at 1-minute and 5-minutes post-dose
8.2.2.2 VISIT 3 (Treatment Day 7 ±2) 
The site staff will perform/assess the following procedures: 
•
SANDE
•
Individual Symptom Severity Assessments (VAS)
•
AE assessment
•
Concomitant medication review
•
Unmasked dedicated dosing coordinator will collect returned carton containing used and
unused IP ampules
•
Unmasked dedicated dosing coordinator will collect Dosing Diary, Drop Comfort VAS
and dispense new Dosing Diary and Drop Comfort VAS


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•
Unmasked site staff will query the subject regarding compliance with dosing and the
protocol. If the subject has not been compliant with the dosing regimen, record this in the
source document and eCRF and discuss proper compliance with the subject
•
BCVA assessment
•
FCS
•
IP Administration:
−
The unmasked dedicated dosing coordinator will administer the AM dose of IP in
the clinic
•
Drop Discomfort VAS:
−
The masked site staff will administer the Drop Discomfort VAS at 1-minute and
5-minutes post-dose
•
Assess for occurrence of any AEs following instillation
•
Unmasked dedicated dosing coordinator will dispense IP to the subject
•
Evening contact scheduling: Masked site staff will schedule and contact the subject in the
evening of the clinic visit to prompt administration of the next dose and completion the
Drop Discomfort VAS
•
Remind subject to withhold AM dose of IP on morning of next clinic visit and to return all
used and unused IP
Schedule the subject to return in 1 week for Visit 4 on Day 14 ±2 days. 
PM Contact with Patient: 
•
Masked site staff will call subject to prompt IP administration and will remain on call to
facilitate completion of the Drop Discomfort VAS at 1-minute and 5-minutes post-dose
8.2.2.3 VISIT 4 (Treatment Day 14 ±2) 
The site staff will perform/assess the following procedures: 
•
SANDE
•
Individual Symptom Severity Assessments (VAS)
•
AE assessment


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•
Concomitant medication review
•
Unmasked dedicated dosing coordinator will collect returned carton containing used and
unused IP ampules
•
Unmasked dedicated dosing coordinator will collect Dosing Diary, Drop Comfort VAS
and dispense new Dosing Diary and Drop Comfort VAS.
•
Unmasked site staff will query the subject regarding compliance with dosing and the
protocol. If the subject has not been compliant with the dosing regimen, record this in the
source document and eCRF and discuss proper compliance with the subject
•
BCVA assessment
•
FCS
•
IP Administration:
−
The unmasked dedicated dosing coordinator will administer the AM dose of IP in
the clinic.
•
Drop Discomfort VAS:
−
The masked site staff will administer the Drop Discomfort VAS at 1-minute and
5-minutes post-dose
•
Assess for occurrence of any AEs following instillation
•
Unmasked dedicated dosing coordinator will dispense IP to the subject
•
Evening contact scheduling: Masked site staff will schedule and contact the subject in the
evening of the clinic visit to prompt administration of the next dose and completion the
Drop Discomfort VAS
•
Remind subject to withhold AM dose of IP on morning of next clinic visit and to return all
used and unused IP
Schedule the subject to return in 2 weeks for Visit 5 on Day 28 ±2 days. 
PM Contact with Patient: 
•
Masked site staff will call subject to prompt IP administration and will remain on call to
facilitate completion of the Drop Discomfort VAS at 1-minute and 5-minutes post-dose.


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8.2.2.4 VISIT 5 (End of Treatment Day 28 ± 2) 
PM Contact with Patient: (Evening Prior to Visit 5) 
•
Masked site staff will call subject to prompt IP administration and will remain on call to
facilitate completion of the Drop Discomfort VAS at 1-minute and 5-minutes post-dose
During the visit the site staff will perform/assess the following procedures: 
•
SANDE
•
Individual Symptom Severity Assessments (VAS)
•
AE assessment
•
Concomitant medication review
•
Unmasked dedicated dosing coordinator will collect returned carton containing used and
unused IP ampules
•
Unmasked dedicated dosing coordinator will collect Dosing Diary and Drop Comfort
VAS.
•
Unmasked site staff will query the subject regarding compliance with dosing and the
protocol. If the subject has not been compliant with the dosing regimen, record this in the
source document and eCRF and discuss proper compliance with the subject
•
BCVA assessment
•
Slit-Lamp biomicroscopy
•
FCS
•
UPT for WOCBP
•
IP Administration:
−
The unmasked dedicated dosing coordinator will administer the AM dose of IP in
the clinic
•
Drop Discomfort VAS:
−
The masked site staff will administer the Drop Discomfort VAS at 1-minute and 5-
minutes post-dose


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•
Unanesthetized STT. This should be performed no less than 1-hour following the
administration of IP and at least 20 minutes following FCS
Schedule the subject to return in 3 days for the post-treatment follow-up visit. 
8.2.3 Unscheduled Visits 
Any visits or procedures performed beyond those specified within the protocol must be 
documented in the Unscheduled Visit pages of the eCRF. Unscheduled visits may include but 
are not limited to reporting adverse events (AEs), changes in concomitant medications, or 
ophthalmic assessments as deemed appropriate by an appropriately qualified physician. If the 
subject is discontinuing study participation at the unscheduled visit, the eCRFs for Visit 5 
should be completed rather than the eCRFs for an Unscheduled Visit. 
8.2.4 End of Study (or Early Discontinuation) Procedures 
On completion of treatment at Day 28 or earlier if subject is discontinued/withdrawn early, all 
assessments for Visit 5 (end of study or early termination, see Section 8.2.2.4) will be 
completed per the Schedule of Events. See also Section 5.5, Withdrawal of Subjects, for further 
information on withdrawal procedures and criteria. 
8.2.5 Follow-up Procedures 
8.2.5.1 VISIT 6 (Post-Treatment Follow-Up +3 Days) 
Visit 6 should be conducted 3 days after End of Treatment (+3 Day window). During the visit, 
the site staff will perform/assess the following procedures: 
•
AE assessment
•
Concomitant medication review
•
BCVA assessment
•
Dilated Ophthalmoscopy
Subjects are discharged from the study and instructed to resume their normal prior ocular 
therapy. 


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9.
EVALUATION, RECORDING AND REPORTING OF AES AND
SAES
9.1 
Definitions 
9.1.1 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 adverse event 
(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. 
9.1.2 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. 
9.1.3 Unexpected ADR 
An adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g., Investigator's Brochure for an unapproved investigational medicinal 
product).  
9.1.4 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 which
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 informed consent form (ICF).  
9.1.5 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 suspected unexpected serious adverse reaction (SUSAR). 
9.2 
Adverse Event Descriptors 
9.2.1 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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9.2.2 Causal Relationship Categorization 
An Investigator who is qualified in medicine must make the determination of relationship to 
the study treatment 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. 
9.2.3 Outcome Categorization 
Outcome may be classified as recovered without sequelae; recovered with sequelae; improved; 
worsened; ongoing; ongoing at end of study; 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 SAE reporting form. SAEs that are ongoing at the time of death will have an outcome of 
“unknown” recorded. SAEs resulting in a fatal outcome will have an outcome of “fatal” 
recorded. 
9.2.4 Symptoms of the Disease Under Study 
Symptoms and fluctuations in laboratory parameters related to the disease under study 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 or laboratory parameters, however, will be recorded as an AE and 
clearly marked as worsening or by the subject’s worst observed intensity. The Investigator will 
be required to assess the relationship to disease under study for each AE as related or not 
related. An AE will not be able to be assessed as related to both disease under study and related 
to study treatment. 
9.2.5 Abuse, Misuse, Overdose and Medication Error 
All AEs of special interest such as study treatment abuse, misuse, overdose, and medication 
error must be documented in the subject’s eCRF and source documentation. If any occurrence 
of abuse, misuse, overdose, or medication errors leads to any event that fulfils any seriousness 
criteria, the event has to be reported as an SAE. 
9.3 
Reporting Procedure for AEs, SAEs, and Pregnancy 
9.3.1 Adverse Events 
All AEs observed from time of signing of the ICF will be recorded in the subject's source 
documentation. This applies to all AEs regardless of presumed relationship to the study drug. 
For screen failure subjects, any AEs and SAEs occurring during the screening period (after 
informed consent) will be recorded in the subject’s source documentation only and will not be 
collected on the eCRF. Adverse events leading to discontinuation of study drug must be 
collected. 
If any AE is reported, the date of onset, relationship to disease under study, relationship to 
study treatment, 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 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. 
The AE reporting period begins at the time the ICF is signed by the subject. For screen failure 
subjects, any AEs and SAEs occurring during the screening period will be recorded in the 
subject’s source documentation only. For enrolled subjects (i.e., those who successfully 
complete screening), the AE reporting period ends at the Follow-Up visit (Visit 6). 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 documents. If the subject reports 


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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. This 
information should be collected prior to completion of assessments at all study visits (with the 
exception of the SANDE and Individual Symptom Assessment VAS). In addition, any 
symptoms/conditions reported during assessments and deemed to be clinically significant by 
the Investigator will be considered AEs. 
9.3.2 Serious Adverse Events 
For screen failure subjects, any SAEs occurring during the screening period (after informed 
consent) will be recorded in the subject’s source documentation only and will not be collected 
on the eCRF. 
For enrolled subjects (i.e., those who successfully complete screening), all SAEs occurring 
after the signing of the ICF will be reported to 
) within 24 hours 
of the Investigator, designee, or site staff’s knowledge of the event regardless of relationship 
to study drug or relationship to disease under study. For enrolled subjects, all SAEs will be 
recorded in the AE section of the subject’s eCRF and source documentation. 
In the event that the site experiences a temporary disruption of the EDC system a back-up 
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: 
•
Site staff will complete the paper SAE report form and fax to
 within 
24 hours.
•
Only in cases where the site is unable to fax the SAE form, site staff will send the SAE
form by email to:
Site staff must enter the SAE information into the EDC system in a timely manner. 
All initial and follow-up SAE must be reported by the Investigator to 
 within 24 hours of 
becoming aware of the event. 
All SAEs, regardless of causality, will be reported from the time the ICF is signed until 30 days 
following the last study visit or 30 days after last study treatment administration in subjects 


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who withdraw or discontinue prior to study completion. No formal study visit is required but 
Investigators must report any SAEs that occur during this 30-day period on the eCRF. 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. 
All recorded SAEs, regardless of relationship to disease under study or relationship to study 
treatment, 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. 
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. A rationale for the 
assessment of a causal relationship must be provided by the Investigator. The Investigator will 
also be required to assess the relationship to 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. Any safety information that is obtained after the follow-up visit 
(Visit 6) will be documented in the safety database only. 
A death occurring during the study or which comes to the attention of the Investigator within 
30 days after the last study visit (including the follow-up visit) or until 30 days after the last 
study treatment administration, whichever is longer, whether considered treatment related or 
not, must be reported to Aurinia. If the subject died, the SAE report should include the cause 
of death as the event term and whether or not the death was related to study treatment, 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. 
Additional follow-up information must be reported in the eCRF 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 
 by the reporting procedures described above. 
The Investigator is encouraged to discuss with the study Medical Monitor when the issue of 
seriousness is unclear or questionable. 
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAE) from the Sponsor will file it along with 
the IB and will notify the IRB/Independent Ethics Committee (IEC) if appropriate, according 
to local requirements. 
The Sponsor or its representative will be responsible for determining and, in turn, reporting 
SAEs to Regulatory Authorities according to the applicable regulatory requirements. 


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9.3.3 Pregnancy 
Pregnancy occurring in a female subject or in the partner of a male subject should be reported 
to 
 within 24 hours of becoming aware of the event using the pregnancy eCRF. The 
Investigator should counsel the subject, and in the case of a male subject, the subject’s partner, 
discuss the risks of continuing with the pregnancy and the possible effects on the fetus. A 
female subject must immediately inform the Investigator if she becomes pregnant during the 
study. Monitoring of the pregnancy in a female subject should continue until conclusion of the 
pregnancy. In case of a pregnancy in the partner of a male subject, the Investigator should 
obtain informed consent of the pregnant partner prior to monitoring of the pregnancy. 
Women 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). 
All pregnancies, subject or partner of a subject, that occur during the study or come to the 
attention of the Investigator within 30 days after the last study visit (including the Follow-up 
Visit) or until 30 days after last study treatment administration, whichever is longer, must be 
reported to 
 by the reporting procedures described above. 
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 9.3.2, Serious Adverse Events.  
In the event that the site experiences a temporary disruption of the EDC system, a back-up 
paper Pregnancy Reporting Form will be available for site staff to complete. The Investigator 
must complete, sign and date the Pregnancy form and verify the accuracy of the information 
recorded on the form with the corresponding source documents. 
•
Site staff will complete the paper Pregnancy report form and fax to
within 24 hours.
•
Only in cases where the site is unable to fax the Pregnancy report, site staff will send the
Pregnancy report by email to:


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10. STATISTICAL ANALYSIS
10.1 Statistical Methods
Complete details of the statistical and analytical methods will be provided in a formal 
Statistical Analysis Plan (SAP) which will be finalized prior to the database lock. A general 
description of the planned methods is provided below. Any deviation from the SAP will be 
noted and explained in the Clinical Study Report. 
All statistical analyses will be undertaken at study closure and will incorporate all endpoints. 
10.2 Sample Size and Power Calculations 
The study will include approximately 90 male or female subjects. 
The primary analysis will use a t-test and will assess the difference in change from baseline in 
Drop Discomfort VAS scores (range 0 to 100 mm) 1-minute post-Dose 1 instillation between 
the two treatment groups.  
A sample size of 38 subjects per group (76 in total) will provide 90% power assuming: 
•
A mean change from baseline Drop Discomfort VAS score of +30 mm for subjects
randomized to Restasis®
•
A mean change from baseline Drop Discomfort VAS score of +15 mm for those
randomized to VOS
•
These assumed mean changes lead to a 15 mm lower change from baseline in VAS scores
for VOS compared to Restasis®
•
A common standard deviation of 20 mm
•
A 2-sided alpha of 5%
Under the same assumptions, the study will have at least 80% power if the common standard 
deviation for the discomfort score were to be 23 mm. 
The study also provides 80% power should the treatment difference in discomfort scores be 13 
(common standard deviation=20 mm). 
To allow for 15% dropouts, approximately 90 subjects will be randomized. 


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10.3 Populations 
10.3.1 Intent-to-Treat Set 
The tolerability and efficacy analysis will be based on the intent-to-treat (ITT) principles and 
will consist of all randomized subjects who receive at least 1 dose of study treatment.  
10.3.2 Per Protocol 
The per-protocol set will be a subset of subjects in the ITT population who do not have any 
major protocol violations (to be defined prior to unmasking). 
10.3.3 Safety Set 
The safety analysis will consist of all randomized subjects who receive at least 1 dose of study 
treatment. The subjects in this group will be analyzed based on the treatment they received. 
10.4 Concomitant Therapy 
All concomitant medications will be coded by the World Health Organization (WHO) 
Anatomical Therapeutic Chemical Drug Reference List classification. The version used will 
be provided in the Clinical Study Report. 
10.5 Endpoint Evaluations 
10.5.1 Primary Endpoint 
The primary endpoint is the change from baseline to 1-minute post-instillation of IP in Drop 
Discomfort VAS score at Visit 2. The baseline measure will be taken 1-minute following 
Refresh Plus® administration at least 2 hours prior to IP administration. 
10.5.2 Secondary Endpoints 
10.5.2.1 
Key Secondary/Efficacy Endpoints 
•
Change from baseline in Drop Discomfort VAS score
•
Change from baseline in each of the 6 Individual Symptom Severity Assessments (VAS)
•
Change from baseline of the sum of the Individual Symptom Severity Assessments (VAS
Total Symptom Summary Score)
•
Change from baseline in SANDE score
•
Change in unanesthetized STT score
•
Change from baseline in FCS total score (NEI/Industry Workshop 0-15 scale) Safety
Endpoints


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10.5.2.2 
Safety Endpoints 
•
Treatment-emergent adverse events (TEAEs)
•
Change from baseline in BCVA
•
Changes from baseline in Slit-Lamp Biomicroscopy
•
Changes from screening in Dilated Ophthalmoscopy
10.6 Statistical and Analytical Methods 
10.6.1 Primary Analysis 
The primary endpoint is measured on a VAS and will be summarized and analyzed as 
continuous data. Summaries of VAS scores (absolute and change from baseline) by treatment 
group will be displayed for each VAS assessment (minutes 1, 5 and overall mean) at each visit. 
Should the data meet the necessary assumptions (normality and equal variance in both 
treatment groups), then the treatment groups will be compared using a t-test. If assumptions 
are violated, the Wilcoxon rank sum test will be used. If needed, transformations will be 
considered in order to meet the necessary assumptions. 
10.6.2 Secondary Efficacy Analysis 
Descriptive statistical summary (sample size, mean, standard deviation, median, minimum and 
maximum) will be presented by treatment group for each endpoint. Changes from 
randomization/baseline will be compared between VOS and Restasis® using a two-sample t-
test or the Wilcoxon rank sum test. Further details will be addressed in the SAP. 
10.6.3 Safety Analysis 
Adverse events will be aggregated by System Organ Class and preferred term and presented 
as summary tables. Other safety endpoints will be summarized by visit as absolute values and 
changes from baseline (as appropriate). Endpoints with specific ranges will have counts of 
values falling outside of the range summarized by visit and overall.  
10.7 Safety Evaluations 
Safety evaluations include: 
•
Treatment-emergent adverse events (TEAEs)
•
BCVA
•
Slit-Lamp Biomicroscopy
•
Dilated Ophthalmoscopy


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10.8 Interim Analyses 
No interim analyses are planned for this study. 
10.9 Other Evaluations 
N/A 


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11. ETHICAL CONDUCT OF THE STUDY
The study will be conducted according to the principles of the World Medical Association’s 
Declaration of Helsinki and the ICH guidelines for GCP. Aurinia will ensure that the study 
complies with all local, federal, and country regulatory requirements. 
The Investigator must ensure the confidentiality of all subjects participating in the study. 
All anonymous data remains the property of Aurinia. 
11.1 Informed Consent 
The ICF used for the study must comply with the Declaration of Helsinki, federal regulations, 
and ICH guidelines; and must have been approved by the IRB/Ethics Committee (EC)/IEC 
prior to use. The Investigator or an authorized associate must explain the nature of the study 
and the treatment in such a manner that the subject is aware of potential benefits and risks. 
Subjects must also be informed that participation is voluntary and that they may withdraw from 
the study at any time without prejudice. Subjects must be provided sufficient time to consider 
participation, including discussion with family members prior to signing the ICF. 
Documentation of the discussion and the date of informed consent must be recorded in the 
source documentation. After signing the ICF, subjects will be enrolled into the study and 
assigned a subject identification number that will be used on all subject documentation. 
11.2 Institutional Review Board or EC/IEC 
The protocol, any protocol amendments and consent form for the proposed clinical study and 
any other documents required by the local IRB/EC/IEC must be submitted by the Investigator 
for review and approval to the IRB/EC/IEC. The Investigator must also ensure that the 
IRB/EC/IEC reviews the progress of the study on a regular basis and, if necessary, renews its 
approval of the study per local requirements. 


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12. QUALITY CONTROL AND QUALITY ASSURANCE
The Investigator must ensure that all study-related site source data, study-related documents, 
and reports will be available, and that the provision of direct access for monitoring and auditing 
by Aurinia or its designees will be permitted. In addition, the Investigator must ensure that all 
study-related site source data, study-related documents, and reports will be made available for 
inspection by the appropriate Regulatory Authority and review by the IRB/EC/IEC. 
The Investigator is responsible for notifying Aurinia in advance of an impending regulatory 
inspection. He/she may request that Aurinia provide support for preparation, if necessary. The 
Investigator is required to provide updates to Aurinia on the ongoing activities during the 
inspection, respond to any citations/objectionable findings (i.e., U.S. Food and Drug 
Administration Form 483) and to share any follow-up responses from the Regulatory 
Authority. 
Accurate and reliable data collection will be assured by verification and cross-check of the 
eCRFs against the Investigator’s records by the Study Monitor (source document verification). 
An unmasked Monitor will also review the Investigator’s drug accountability records to ensure 
that the drug supplies are stored and dispensed appropriately. A comprehensive validation 
program will verify the data and queries will be generated for resolution by the Investigator. 
Throughout the study, Aurinia or its designee may review data as deemed necessary. 


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13. ADMINISTRATIVE PROCEDURES
13.1 Sponsor’s Responsibilities
13.1.1 Study Supplies
Sites will be provided with all supplies required to manage this study. This will include but not 
be limited to the following: 
•
Investigator file(s) (for filing of all study-related documentation)
•
Contact list of all relevant study personnel
•
eCRF and completion guidelines (or equivalent EDC system)
•
Study reference manual
•
All study forms (e.g., SAE, Pregnancy, Drug Accountability, etc.)
13.1.2 Insurance 
Aurinia confirms that it carries liability insurance which protects nonemployee physicians or 
Investigators/study staff against claims for which they may become liable as a result of 
damages caused by Aurinia products used in clinical studies. Insurance coverage is not 
extended to damages that the Investigators or third parties may suffer by reason of acts of 
commission or omission on the part of such Investigators or third parties and that are not in 
accordance with accepted common medical practices (lege artis procedures). Aurinia will 
reimburse the subject for all study-related injuries provided that the injury does not arise from 
the subject’s misuse of the IP or failure to follow the Investigator’s instructions. 
13.1.3 Study Monitoring 
The study will be monitored by representatives of Aurinia (or designee, which may include a 
CRO). If not monitored by Aurinia, documentation of delegation will be described in the 
Clinical Trial Agreement. It is understood that the responsible Monitor will contact and visit 
the Investigator regularly and will be allowed, on request, to inspect the various records of the 
study (eCRFs and other pertinent data) provided that subject confidentiality is maintained in 
accordance with local requirements. 
It will be the Monitor's responsibility to inspect the eCRFs at regular intervals throughout the 
study (frequency outlined in a separate procedural document), to verify the adherence to the 
protocol and the completeness, consistency, and accuracy of the data being entered on them. 
The Monitor must have access to subject records needed to verify the entries on the eCRF. The 
Investigator (or his/her deputy) agrees to co-operate with the Monitor to ensure that any 
problems detected in the course of these monitoring visits are resolved. 


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13.2 Investigator’s Responsibilities 
13.2.1 Reporting and Recording of Data 
All required study data must be entered in the eCRF created for the study. Training on the 
system will be provided to all sites, including instructions on how to address missing data, 
corrections, query procedures, and electronic signatures. Only individuals who are identified 
on the authorized signature page may enter/correct data in the eCRF. For those subjects who 
withdraw before completion of the study, all available efficacy and safety data must be entered 
in the eCRF. Incomplete or inconsistent data on the eCRF will result in data queries addressed 
to the Investigator for resolution. 
13.2.2 Investigator Training 
All Investigators and their study personnel will receive training regarding the study procedures, 
study treatments, and GCP/regulations specific to the conduct of clinical studies. This training 
will take place prior to enrollment of the first subject at the study site and must be documented 
and filed in the Investigator’s Study Site File. 
13.2.3 Source Documentation 
The Investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. 
Subject clinical source documents would include subject hospital/clinic records, physician’s 
and nurse’s notes, appointment book, original laboratory reports, signed ICFs, consultant 
letters, and subject enrollment logs. These are to be separate and distinct from eCRFs. All data 
for the study must be available in source documentation, including oral and written 
communication with the subject regarding the study treatment (including the risks and benefits 
of the study). The date of informed consent must be recorded in the source documentation. 
The Investigator must arrange for the retention of all study documentation (such as eCRFs, 
research files, and master files) for the duration specified in their respective site contract. The 
Investigator must keep these documents on file after completion or discontinuation of the study 
according to local governing guidelines. Archived data may be held electronically, provided 
that a back-up copy exists and that a hard copy can be generated if required. 
The Investigator must inform Aurinia immediately if any documents are lost, to be transferred 
to a different facility, or to be transferred to a different owner. 


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14. PROCEDURE FOR MODIFICATION OF PROTOCOL OR
PREMATURE TERMINATION OF THE STUDY
14.1 Protocol Waivers, Deviations and Violations 
Protocol waivers shall not be permitted. 
The Investigator should not implement any deviation from, or changes of the protocol without 
written agreement from Aurinia and prior documented approval/favorable opinion from the 
IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) to 
study subjects, or when change(s) involves only logistical or administrative aspects of the 
study. If the Investigator must implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to study subjects without prior written approval, the 
implemented deviation or change and the reasons for it should be submitted in a timely manner 
to Aurinia and to the IRB/IEC as required by applicable local requirements. 
The Investigator, or person designated by the Investigator, will document and record the 
preventative and/or corrective measures for any deviation from the approved protocol. 
Accidental deviations from the protocol including violations of inclusion/exclusion criteria 
will be assessed as minor or major on a case-by-case basis. The criteria describing the 
deviation(s) and how they will be handled will be documented in the SAP. 
Any amendment to the protocol requires written approval/favorable opinion by the IRB/IEC 
prior to its implementation unless there are overriding safety reasons. 
In some instances, an amendment may require a change to the ICF. The Investigator must 
receive an IRB/IEC approval/favorable opinion concerning the reviewed document prior to 
administering to study subjects. 
14.2 Study Termination 
Aurinia reserves the right to terminate the study in its entirety or at a site at any time. Reasons 
for termination may include but are not limited to the following: unsatisfactory subject 
enrollment with respect to quality and/or quantity, site is unable to comply with the 
requirements of the protocol or GCP, or data recording is inaccurate and/or incomplete. 
In terminating the study, Aurinia and the Investigator will assure that adequate consideration 
is given to the protection of the subjects. Both parties will arrange the procedures on an 
individual basis after review and consultation and in accordance with the study contract. 


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15. POLICY FOR PUBLICATION AND PRESENTATION OF DATA
Aurinia is committed to the timely communication of data from clinical research trials, 
following the Pharmaceutical Research and Manufacturers of America principles (The 
Pharmaceutical Research and Manufacturers of America (PhrMa), Principals on Conduct of 
Clinical Trials/Communication of Clinical Trials; December 2014). Where possible, 
authorship will be agreed at the beginning of the study. The authors will form a publication 
committee and this committee will propose and develop appropriate scientific manuscripts or 
abstracts from the study data. Investigators may not present or publish partial or complete study 
results individually. Any manuscript or abstract proposed by the Investigators must be 
reviewed and approved in writing by Aurinia before submission for publication. Names of all 
Investigators participating in the study will be included in the publication. 
The publication committee for a study will comprise of authors selected in adherence with the 
International Committee of Medical Journal Editors criteria (International Committee of 
Medical Journal Editors criteria; ICMJE.org) for authorship. If studies are multicenter, it may 
be appropriate to assign group authorship. 
In addition, certain Aurinia employees involved in the design and conception of the protocol, 
study management and data analysis and interpretation are qualified authors and will be 
included in the publication committee. 


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16. REFERENCES
1. Craig JP, Nichols KK, Akpek EK, Caffery B, Dua HS, Joo CK et al. TFOS DEWS II
Definition and Classification Report. Ocul Surf. 2017;15:276-83.
2. The definition and classification of dry eye disease report of the Definition and
Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul
Surf. 20017 Apr;5(2):75-92.
3. Chauhan S, Dana R. Role of Th17 Cells in the Immunopathogenesis of Dry Eye
Disease. Mucosal Immunol. 2009 Jul;2(4):375–6.
4. Pflugfelder SC, Solomon A, Stern ME. The diagnosis and management of dry eye: a
twenty-five-year review. Cornea. 2000;19(5):644–9.
5.
Stevenson W, Chauhan SK, Dana R. Dry eye disease: An immune-mediated ocular
surface disorder. Arch Ophthalmol. 2012 Jan;130(1):90-100.
6. Restasis® (cyclosporine ophthalmic emulsion) 0.05% for topical ophthalmic use.
Allergan, Irvine USA. 2017 Jul.
7. Xiidra® (lifitegrast ophthalmic solution) 5%, for topical ophthalmic use. Shire US Inc,
Lexington USA. 2017 Nov.
8. Granelli-Piperno A, Andrus L, Steinman RM. Lymphokine and nonlymphokine mRNA
levels in stimulated human cells: kinetics, mitogen requirements, and effects of
cyclosporine A. J Exp Med. 1986 Apr;163:922-37.
9. Stepkowski S.M. Molecular targets for existing and novel immunosuppressive drugs.
Expert Rev Mol Med. 2000. p. 1-6.
10. Wiseman AC. Immunosuppressive medications. Clin J Am Soc Nephrol. 2016
Feb;11:332-43.
11. S07654 – 14-Day ocular tolerability and toxicity of LX214 in New Zealand whit rabbits
with 14-Day recovery period. Lux Biosciences, Inc.; 2009 Apr 3. Report No.: S07654.
12. S07655 – 14-Day ocular tolerability and toxicity of LX214 in beagle dogs with 14-day
recovery period. Lux Biosciences, Inc.; 2009 Apr 8. Report No.: S07655.
13. S08661 – Ocular tissue distribution of 14C-LX214 following a single or multiple
ophthalmic administration to New Zealand White Rabbit. Lux Biosciences, Inc 23 Mar
2009. Report No.: S08661.


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14. S15389-00 – To evaluate the efficacy of Voclosporin Ophthalmic Solution (0.2%
voclosporin) in naturally occurring keratoconjunctivitis sicca in client owned dogs with
twice-daily administration. Intervet Inc (d/b/a Merck Animal Health), 28 Apr 2017.
Report No.: S15389-00.
15. Clinical Study Report LX214-01. 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. Final report. Lux Biosciences Inc. 2010 Jul 02.
16. Investigator’s Brochure Voclosporin Ophthalmic Solution Dry Eye Disease. Final
Report V1.0. Aurinia Pharmaceuticals Inc.; 30 January 2018.


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17. APPENDICES
Appendix 1 Tolerability Assessment 
Drop Discomfort Assessment (Tolerability Assessment): 
Subject will rate Drop Discomfort using a VAS. Subject will complete this assessment in the 
clinic following dosing of OTC ocular lubricant at Visit 2 and in the clinic following the AM 
dose of IP at Visits 2, 3, 4 and 5 and again at home following the PM dose of IP on the evenings 
of Visits 2, 3, 4 and the evening prior to Visit 5. The assessment will be completed at 1-minute 
and 5-minutes post-instillation of OTC ocular lubricant or IP. 
Subject Instructions: Please rate how your eyes feel following instillation of the study drug by placing a vertical 
mark on the horizontal line. 0 corresponds to “no discomfort” and 100 corresponds to “maximal discomfort” 
You will rate your Drop Discomfort at 1-minute and 5- minutes following instillation of the study drug.  
Eye Discomfort  0
    100 
|       
     |      


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Appendix 2 Eye Dryness Assessments 
The following assessments are included as a part of the overall assessment of the presence and 
severity of DED: 
•
Fluorescein Corneal Staining (FCS)
•
Unanesthetized STT
•
SANDE
•
Individual Symptom Severity Assessments
o
VAS assessments of six symptoms: Burning/Stinging, Foreign Body Sensation,
Photophobia, Eye Pain, Eye Dryness, Itching


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Appendix 3 Symptom Assessment in Dry Eye (SANDE) 


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Appendix 4 Individual Symptom Severity Assessments using Visual Analog Score 
(VAS) 
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 
|
|      
Foreign Body 
Sensation (grain of 
sand/grittiness) 
  0
100 
|
|       
Photophobia 
  0
100 
|
 |      
Eye Pain 
  0
100 
|
 |      
Eye Dryness 
  0
100 
|
 |      
Itching 
  0
100 
|
 |      


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Appendix 5 Slit-Lamp Biomicroscopy 
This procedure will be the performed in the same manner for all subjects observed at the 
Investigator’s site.  
Lashes 
0 = Normal 
1 = Abnormal 
Eyelid Erythema 
0 = Normal, without any redness 
1 = Abnormal 
Edema 
  0 = Normal, no swelling of the lid tissue 
  1 = Abnormal 
Conjunctiva Edema 
  
  0 = Normal, no swelling of the conjunctiva 
  1 = Abnormal 
Cornea Infiltrates 
 0 = Absent 
 1 = Present 
Endothelial Changes 
 0 = Normal, None 
 1 = Abnormal, pigment, keratoprecipitates, guttata 
Edema 
 0 = Normal None, transparent and clear 
 1 = Abnormal 
Anterior Chamber Cells 
 0 = Normal, No cells seen 
 1 = Abnormal (+ to +++ cells) 
Flare 
 0 = Normal, No Tyndall effect 
 1 = Abnormal, Tyndall beam in the anterior chamber 
Lens Pathology 


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0 = Normal; no opacity in the lens 
1 = Abnormal; existing opacity in the lens; aphakic or pseudophakic eyes or 
other abnormal findings. 
Sclera Injection 
0 = Normal, without any redness 
1 = Abnormal 


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Appendix 6 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 


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Appendix 7 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. 


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Appendix 8 Restasis® Package Insert, July 2017. 


HIGHLIGHTS OF PRESCRIBING INFORMATION 
These highlights do not include all the information needed to use 
RESTASIS® 0.05% safely and effectively. See full prescribing 
information for RESTASIS®. 
RESTASIS® (cyclosporine ophthalmic emulsion) 0.05% 
For topical ophthalmic use 
Initial U.S. Approval: 1983 
____________________________INDICATIONS AND USAGE_______________________________ 
RESTASIS® is a calcineurin inhibitor immunosuppressant indicated to 
increase tear production in patients whose tear production is presumed to be 
suppressed due to ocular inflammation associated with keratoconjunctivitis 
sicca  Increased tear production was not seen in patients currently taking 
topical anti-inflammatory drugs or using punctal plugs  (1) 
________________________DOSAGE AND ADMINISTRATION_________________________ 
Instill one drop of RESTASIS® ophthalmic emulsion twice a day in each eye 
approximately 12 hours apart  (2) 
_______________________DOSAGE FORMS AND STRENGTHS_______________________ 
Cyclosporine ophthalmic emulsion 0 5 mg/mL (3) 
_________________________________CONTRAINDICATIONS________________________________ 
• 
Hypersensitivity (4) 
_________________________WARNINGS AND PRECAUTIONS__________________________ 
• 
To avoid the potential for eye injury and contamination, be careful not to 
touch the vial tip to your eye or other surfaces  (5 1) 
______________________________ADVERSE REACTIONS___________________________________ 
The most common adverse reaction following the use of RESTASIS® was 
ocular burning (17%)  (6 1) 
To report SUSPECTED ADVERSE REACTIONS, contact Allergan at 1-
800-433-8871 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 
See 17 for PATIENT COUNSELING INFORMATION. 
Revised: 07/2017 
FULL PRESCRIBING INFORMATION: CONTENTS* 
1 INDICATIONS AND USAGE 
2 DOSAGE AND ADMINISTRATION 
3 DOSAGE FORMS AND STRENGTHS 
4 CONTRAINDICATIONS 
5 WARNINGS AND PRECAUTIONS 
  5 1 Potential for Eye Injury and Contamination  
    5 2 Use with Contact Lenses  
6 ADVERSE REACTIONS 
  6 1 Clinical Trials Experience 
  6 2 Post-marketing Experience 
8 USE IN SPECIFIC POPULATIONS 
  8 1 Pregnancy 
  8 2 Lactation 
  8 4 Pediatric Use 
  8 5 Geriatric Use 
11 DESCRIPTION 
12 CLINICAL PHARMACOLOGY 
  12 1 Mechanism of Action 
    12 3 Pharmacokinetics  
13 NONCLINICAL TOXICOLOGY 
  13 1 Carcinogenesis, Mutagenesis, Impairment of Fertility 
14 CLINICAL STUDIES 
16 HOW SUPPLIED/STORAGE AND HANDLING 
17 PATIENT COUNSELING INFORMATION 
* Sections or subsections omitted from the full prescribing information are not 
listed


FULL PRESCRIBING INFORMATION 
1 
INDICATIONS AND USAGE 
RESTASIS® ophthalmic emulsion is indicated to increase tear production in patients whose tear production is 
presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca. Increased tear 
production was not seen in patients currently taking topical anti-inflammatory drugs or using punctal plugs. 
2 
DOSAGE AND ADMINISTRATION 
Invert the unit dose vial a few times to obtain a uniform, white, opaque emulsion before using. Instill one drop 
of RESTASIS® ophthalmic emulsion twice a day in each eye approximately 12 hours apart. RESTASIS® can 
be used concomitantly with lubricant eye drops, allowing a 15-minute interval between products. Discard vial 
immediately after use. 
3 
DOSAGE FORMS AND STRENGTHS 
Ophthalmic emulsion containing cyclosporine 0.5 mg/mL 
4 
CONTRAINDICATIONS 
RESTASIS® is contraindicated in patients with known or suspected hypersensitivity to any of the ingredients in 
the formulation. 
5 
WARNINGS AND PRECAUTIONS 
5.1  
Potential for Eye Injury and Contamination 
Be careful not to touch the vial tip to your eye or other surfaces to avoid potential for eye injury and 
contamination. 
5.2  
 
Use with Contact Lenses 
RESTASIS® should not be administered while wearing contact lenses. Patients with decreased tear production 
typically should not wear contact lenses. If contact lenses are worn, they should be removed prior to the 
administration of the emulsion. Lenses may be reinserted 15 minutes following administration of RESTASIS® 
ophthalmic emulsion. 
6 
ADVERSE REACTIONS 
The following serious adverse reactions are described elsewhere in the labeling: 
•
Potential for Eye Injury and Contamination [see Warnings and Precautions (5.1)]
6.1 
Clinical Trials Experience  
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the 
clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not 
reflect the rates observed in practice. 
In clinical trials, the most common adverse reaction following the use of RESTASIS® was ocular burning 
(17%). 
Other reactions reported in 1% to 5% of patients included conjunctival hyperemia, discharge, epiphora, eye 
pain, foreign body sensation, pruritus, stinging, and visual disturbance (most often blurring). 


6.2 
Post-marketing Experience 
The following adverse reactions have been identified during post approval use of RESTASIS®. Because these 
reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably 
estimate their frequency or establish a causal relationship to drug exposure.  
Reported reactions have included: hypersensitivity (including eye swelling, urticaria, rare cases of severe 
angioedema, face swelling, tongue swelling, pharyngeal edema, and dyspnea); and superficial injury of the eye 
(from the vial tip touching the eye during administration).  
8 
USE IN SPECIFIC POPULATIONS 
8.1  
Pregnancy 
Risk Summary 
Clinical administration of cyclosporine ophthalmic emulsion 0.05% is not detected systemically following 
topical ocular administration [see Clinical Pharmacology (12.3)], and maternal use is not expected to result in 
fetal exposure to the drug. Oral administration of cyclosporine to pregnant rats or rabbits did not produce 
teratogenicity at clinically relevant doses [see Data]. 
Data 
Animal Data 
At maternally toxic doses (30 mg/kg/day in rats and 100 mg/kg/day in rabbits), cyclosporine oral solution 
(USP) was teratogenic as indicated by increased pre- and postnatal mortality, reduced fetal weight and skeletal 
retardations. These doses (normalized to body surface area) are 5,000 and 32,000 times greater, respectively, 
than the daily recommended human dose of one drop (approximately 28 mcL) of cyclosporine ophthalmic 
emulsion 0.05% twice daily into each eye of a 60 kg person (0.001 mg/kg/day), assuming that the entire dose is 
absorbed. No evidence of embryofetal toxicity was observed in rats or rabbits receiving cyclosporine during 
organogenesis at oral doses up to 17 mg/kg/day or 30 mg/kg/day, respectively. These doses in rats and rabbits 
are approximately 3,000 and 10,000 times greater, respectively, than the daily recommended human dose. 
An oral dose of 45 mg/kg/day cyclosporine administered to rats from Day 15 of pregnancy until Day 21 
postpartum produced maternal toxicity and an increase in postnatal mortality in offspring. This dose is 7,000 
times greater than the daily recommended human dose. No adverse effects in dams or offspring were observed 
at oral doses up to 15 mg/kg/day (2,000 times greater than the daily recommended human dose). 
8.2  
 
Lactation 
Risk Summary 
Cyclosporine is known to appear in human milk following systemic administration, but its presence in human 
milk following topical treatment has not been investigated. Although blood concentrations are undetectable 
following topical administration of RESTASIS® ophthalmic emulsion [see Clinical Pharmacology (12.3)], 
caution should be exercised when RESTASIS® is administered to a nursing woman. The developmental and 
health benefits of breastfeeding should be considered along with the mother’s clinical need for RESTASIS® and 
any potential adverse effects on the breast-fed child from cyclosporine. 
8.4  
 
Pediatric Use 
Safety and efficacy have not been established in pediatric patients below the age of 16. 


8.5  
 
Geriatric Use 
No overall difference in safety or effectiveness has been observed between elderly and younger patients. 
11 
DESCRIPTION 
RESTASIS® (cyclosporine ophthalmic emulsion) 0.05% contains a topical calcineurin inhibitor 
immunosuppressant with anti-inflammatory effects. Cyclosporine’s chemical name is Cyclo[[(E)-(2S,3R,4R)-3-
hydroxy-4-methyl-2-(methylamino)-6-octenoyl]-L-2-aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-
N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl] and it has the
following structure:
Structural Formula 
Formula: C62H111N11O12        Mol. Wt.: 1202.6 
Cyclosporine is a fine white powder. RESTASIS® appears as a white opaque to slightly translucent 
homogeneous emulsion. It has an osmolality of 230 to 320 mOsmol/kg and a pH of 6.5-8.0. Each mL of 
RESTASIS® ophthalmic emulsion contains: Active: cyclosporine 0.05%. Inactives: glycerin; castor oil; 
polysorbate 80; carbomer copolymer type A; purified water; and sodium hydroxide to adjust pH. 
12 
CLINICAL PHARMACOLOGY 
12.1 
Mechanism of Action 
Cyclosporine is an immunosuppressive agent when administered systemically. 
In patients whose tear production is presumed to be suppressed due to ocular inflammation associated with 
keratoconjunctivitis sicca, cyclosporine emulsion is thought to act as a partial immunomodulator. The exact 
mechanism of action is not known. 
12.3 
 
Pharmacokinetics 
Blood cyclosporine A concentrations were measured using a specific high pressure liquid chromatography-mass 
spectrometry assay. Blood concentrations of cyclosporine, in all the samples collected, after topical 
administration of RESTASIS® 0.05%, twice daily, in humans for up to 12 months, were below the quantitation 
limit of 0.1 ng/mL. There was no detectable drug accumulation in blood during 12 months of treatment with 
RESTASIS® ophthalmic emulsion. 


13 
NONCLINICAL TOXICOLOGY 
13.1 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
Carcinogenesis 
Systemic carcinogenicity studies were conducted in male and female mice and rats. In the 78-week oral (diet) 
mouse study, at doses of 1, 4, and 16 mg/kg/day, evidence of a statistically significant trend was found for 
lymphocytic lymphomas in females, and the incidence of hepatocellular carcinomas in mid-dose males 
significantly exceeded the control value. 
In the 24-month oral (diet) rat study, conducted at 0.5, 2, and 8 mg/kg/day, pancreatic islet cell adenomas 
significantly exceeded the control rate in the low dose level. The hepatocellular carcinomas and pancreatic islet 
cell adenomas were not dose related. The low doses in mice and rats are approximately 80 times greater 
(normalized to body surface area) than the daily recommended human dose of one drop (approximately 28 
mcL) of 0.05% RESTASIS® twice daily into each eye of a 60 kg person (0.001 mg/kg/day), assuming that the 
entire dose is absorbed.  
Mutagenesis 
Cyclosporine has not been found to be mutagenic/genotoxic in the Ames Test, the V79-HGPRT Test, the 
micronucleus test in mice and Chinese hamsters, the chromosome-aberration tests in Chinese hamster bone-
marrow, the mouse dominant lethal assay, and the DNA-repair test in sperm from treated mice. A study 
analyzing sister chromatid exchange (SCE) induction by cyclosporine using human lymphocytes in vitro gave 
indication of a positive effect (i.e., induction of SCE). 
Impairment of Fertility 
No impairment in fertility was demonstrated in studies in male and female rats receiving oral doses of 
cyclosporine up to 15 mg/kg/day (approximately 2,000 times the human daily dose of 0.001 mg/kg/day 
normalized to body surface area) for 9 weeks (male) and 2 weeks (female) prior to mating. 
14 
CLINICAL STUDIES 
Four multicenter, randomized, adequate and well-controlled clinical studies were performed in approximately 
1,200 patients with moderate to severe keratoconjunctivitis sicca. RESTASIS® demonstrated statistically 
significant increases in Schirmer wetting of 10 mm versus vehicle at six months in patients whose tear 
production was presumed to be suppressed due to ocular inflammation. This effect was seen in approximately 
15% of RESTASIS® ophthalmic emulsion-treated patients versus approximately 5% of vehicle-treated patients. 
Increased tear production was not seen in patients currently taking topical anti-inflammatory drugs or using 
punctal plugs. 
No increase in bacterial or fungal ocular infections was reported following administration of RESTASIS®. 
16 
HOW SUPPLIED/STORAGE AND HANDLING 
RESTASIS® ophthalmic emulsion is packaged in sterile, preservative-free single-use vials. Each vial contains 
0.4 mL fill in a 0.9 mL LDPE vial; 30 or 60 vials are packaged in a polypropylene tray with an aluminum 
peelable lid. The entire contents of each tray (30 vials or 60 vials) must be dispensed intact. 
30 Vials 0.4 mL each - NDC 0023-9163-30 
60 Vials 0.4 mL each - NDC 0023-9163-60 
Storage: Store at 15°-25 °C (59°-77 °F). 


17 
PATIENT COUNSELING INFORMATION 
Handling the Container 
Advise patients to not allow the tip of the vial to touch the eye or any surface, as this may contaminate the 
emulsion. Advise patients to not touch the vial tip to their eye to avoid the potential for injury to the eye [see 
Warnings and Precautions (5.1)]. 
Use with Contact Lenses 
RESTASIS® should not be administered while wearing contact lenses. Patients with decreased tear production 
typically should not wear contact lenses. Advise patients that if contact lenses are worn, they should be removed 
prior to the administration of the emulsion. Lenses may be reinserted 15 minutes following administration of 
RESTASIS® ophthalmic emulsion [see Warnings and Precautions (5.2)]. 
Administration 
Advise patients that the emulsion from one individual single-use vial is to be used immediately after opening 
for administration to one or both eyes, and the remaining contents should be discarded immediately after 
administration. 
© 2017 Allergan. All rights reserved. 
All trademarks are the property of their respective owners.  
 
Patented. See www.allergan.com/patents 
Irvine, CA 92612 
Made in the U.S.A. 
71876US19 


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Appendix 9 Daily Dosing Diary 
Subjects will be asked to record each day the following information related to administration 
of study drug: 
•
Date
•
Time of Administration

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. 
 
 
 
An Investigator-Masked, Randomized, Parallel-Group Study of 
the Ocular Tolerability of Voclosporin Ophthalmic Solution 
versus Restasis® in Subjects with Dry Eye Disease 
 
Clinical Protocol Number: 
AUR-VOS-2017-01 
 
 
Date: 
12 March 2018 
 
 
Version Number: 
1.0 
 
 
IND Number: 
102,279 
 
 
 
 
 


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NAMES AND ADDRESSES 
Sponsor 
Name: 
Aurinia Pharmaceuticals Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Tel: 
 
 
Fax: 
24 Hour: 
 
 
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: 
 
 


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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: An Investigator-Masked, Randomized, Parallel-Group Study of the Ocular Tolerability 
of Voclosporin Ophthalmic Solution versus Restasis® in Subjects with Dry Eye Disease 
Version Number/Date: Final Version 1/12March2018 
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 Conference of Harmonisation on Good Clinical Practice. 
Sponsor Representatives 
 
 
Chief Medical Officer 
 
Date (e.g., DD Month Year) 
 
 
 
Vice President, Quality and Regulatory 
Affairs 
 
Date (e.g., DD Month Year) 
13 March 2018
14 March 2018


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INVESTIGATOR AGREEMENT FORM 
I have read the attached protocol titled: An Investigator-Masked, Randomized, Parallel-Group 
Study of the Ocular Tolerability of Voclosporin Ophthalmic Solution versus Restasis® in 
Subjects with Dry Eye Disease. 
Version Number 1/12March2018: 
I agree to comply with the current International Conference of 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 (e.g., DD Month Year) 


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SYNOPSIS 
Title: 
An Investigator-Masked, Randomized, Parallel-Group Study of the Ocular 
Tolerability of Voclosporin Ophthalmic Solution versus Restasis® in Subjects with 
Dry Eye Disease 
Study Product: 
Voclosporin ophthalmic solution (VOS) 
Indication: 
Dry Eye Disease (DED) 
Phase: 
2 
Sponsor: 
Aurinia Pharmaceuticals Inc. 
Study Code: 
AUR-VOS-2017-01 
Objectives: 
Primary Objective 
To assess the ocular tolerability of VOS compared to cyclosporine ophthalmic 
emulsion (Restasis®) in subjects with DED.   
Secondary Objective 
To assess the safety and efficacy of VOS in subjects with DED. 
Design: 
This is a Phase 2, multi-center, Investigator-masked, randomized, parallel-group 
study to evaluate the tolerability, efficacy and safety of VOS versus Restasis® over 
a 28-day treatment period in subjects with mild to moderate DED. Approximately 
60 subjects will be randomized to either VOS or Restasis® at approximately 5 
centers located in the US.   
Treatment: 
Investigational product (IP): 0.2% VOS, twice daily (BID), both eyes (OU) for 28 
days. 
Comparator: 0.05% cyclosporine ophthalmic emulsion (Restasis®) BID, OU for 28 
days.  
The Investigator assessing the ocular signs and subjects will be masked to study 
treatment.   
Inclusion 
Criteria: 
At Visit 1 and Visit 2 (as specified in the Schedule of Events), subjects may be 
eligible for participation if they:  
1. Provide written informed consent before any study-specific procedures are 
performed. 
2. Are male or female subjects with a minimum age of 18 (or legal age of consent 
if >18 years) years, at the time of screening (Visit 1). 
3. Are willing and able to follow instructions and can be present for the required 
study visits for the duration of the study. 
4. 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.  


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5. Have a documented history of DED in both eyes supported by a previous 
clinical diagnosis at Visit 1. 
6. Have ongoing DED, as defined by at least one eye (if one eye, the same eye) 
meeting all the following criteria:  
− 
A symptom severity score of ≥30 for Eye Dryness on a Visual Analog 
Scale (VAS) (0-100) at Visit 2 
− 
An unanesthetized Schirmer Tear Test (STT) score of ≥1 mm and ≤10 
mm per 5 minutes (Note: STT Score obtained at Visit 1) 
− 
Evidence of ocular surface staining (total fluorescein staining score 
of at least 3 [0-15 scale]) at Visit 2. 
7. Have normal lid anatomy at Visit 1. 
Exclusion 
Criteria: 
In order for subjects to be eligible, at Visit 1 and Visit 2 subjects must not: 
1. Be unable or unwilling to give written informed consent and/or to comply with 
study procedures. 
2. Have any known hypersensitivity or contraindication to study treatments 
(including excipients), topical anesthetics or vital dyes. 
3. Be unable to demonstrate correct instillation of over the counter (OTC) ocular 
lubricant during Visit 1. 
4. Report discomfort in both eyes from instillation of OTC ocular lubricant 
during Visit 2 (based on score of ≥30 on the Drop Discomfort VAS.  
5. Have used Restasis® (cyclosporine ophthalmic emulsion) within 30 days prior 
to Visit 1. 
6. Have used Restasis® for more than 1 month. (if prior use is reported.). 
7. Have used Xiidra® (lifitegrast ophthalmic solution) within 14 days prior to 
Visit 1. 
8. Have had corneal graft surgery in either eye within one year of Visit 1.  
9. Have recent or current evidence of ocular infection or inflammation in either 
eye. 
10. Have current evidence of clinically significant blepharitis (defined as 
requiring lid hygiene therapy), conjunctivitis, or a history of herpes simplex 
or zoster keratitis in either eye. 
11. Have clinically significant ocular disease in either eye (e.g., corneal edema, 
uveitis, severe keratoconjunctivitis sicca) which might interfere with study 
procedures or assessments. 
12. Have any abnormality in either eye preventing reliable applanation tonometry. 
13. Be taking or known need for any of the known treatment therapies listed in 
Section 7.7 at Visit 1 or during the study. This includes prohibited medications 
prior to Visit 1 as specified in Section 7.7. 
14. Have any known hypersensitivity or contraindication to calcineurin inhibitors. 
15. Have clinically significant systemic disease (e.g., uncontrolled diabetes, 
hepatic, renal, endocrine or cardiovascular disorders) which might interfere 
with the study at Visit 1 and 2. 


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16. Have participated in any investigational clinical study within 30 days prior to 
Visit 1. 
17. Have altered systemic medication that could have an effect on dry eye signs 
or symptoms within 30 days prior to Visit 1 or anticipated during the study.  
18. Be women of childbearing potential who are pregnant, nursing, planning a 
pregnancy, or not using a medically acceptable form of birth control.  
Primary 
Endpoint: 
Change from baseline in Drop Discomfort VAS score 1-minute post Dose 1 
instillation.  
Secondary 
Endpoints: 
Key Secondary Endpoints: 
• 
Change from baseline in Drop Discomfort VAS score  
• 
Change from baseline in each of the 6 Individual Symptom Severity 
Assessments (VAS) scores 
• 
Change from baseline in the sum of the Individual Symptom Severity 
Assessments score (VAS Total Symptom Summary Score)  
• 
Change from baseline in Symptom Assessment in Dry Eye (SANDE) 
score  
• 
Change from baseline in unanesthetized STT score  
• 
Change from baseline in Fluorescein Corneal Staining (FCS) total 
score (National Eye Institute (NEI)/Industry Workshop 0-15 scale)   
Safety Endpoints: 
• 
Treatment-emergent adverse events (TEAEs) 
• 
Change from screening in BCVA  
• 
Changes from baseline in Slit-Lamp Biomicroscopy  
• 
Changes from screening in Dilated Ophthalmoscopy 
Procedures: 
At Visit 1 (screening) informed consent will be obtained from subjects and 
eligibility will be determined. A Schirmer Tear Test (STT) will be performed at 
this visit. The score will be used as the baseline and eligibility. During this visit, 
all subjects will self-administer an OTC ocular lubricant, Refresh Plus®, in both 
eyes to assess ability to self-administer study product. At Visit 2 (Randomization) 
continued eligibility will be confirmed. During this visit, all subjects will self-
administer an OTC ocular lubricant, Refresh Plus®, in both eyes to evaluate ability 
to tolerate ocular drops. Individuals who are unable to successfully instill the drops 
or who rate OTC ocular lubricant as uncomfortable, based on a post-instillation 
Drop Discomfort VAS score, will not be eligible for participation in the study. 
(Note:  For subjects meeting the Screening and Randomization Criteria, the Visit 2 
Drop Discomfort VAS score will be used as the baseline value.)   


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Eligible subjects will be randomly assigned in a 1:1 ratio to one of the two treatment 
groups: VOS BID or Restasis® BID. The first instillation of IP will be 
administered, at least 2-hours following administration of Refresh Plus® and by 
clinic personnel to both eyes (OU) during Visit 2. Investigational Product will be 
administered to the subject by an unmasked dedicated dosing coordinator (the 
subject and the Investigator will be masked to study treatment for the first post 
randomization instillation). Tolerability, safety and efficacy assessments will be 
performed at this visit. 
At Treatment Visits 3 and 4, tolerability, safety and efficacy evaluations will be 
performed. At the End of Treatment, Visit 5, tolerability, safety and efficacy 
evaluations will be performed. Subjects who discontinue before Visit 5 will 
undergo all Visit 5 evaluations (Early Termination). IP will be administered to the 
subject by a dedicated dosing coordinator at the clinic visits. A Drop Discomfort 
VAS will be administered in the clinic at 1 and 5 minutes following instillation of 
IP at Visits 2 through 5 (Investigator is to remain masked). With the exception of 
clinic day visits, subjects will self-administer IP twice a day OU over the 4-week 
treatment period. On the evening of Visits 2 through 4 and in the evening prior to 
Visit 5, the study coordinator will contact the subject by phone to prompt 
administration of IP followed by completion of the dosing diary and the Drop 
Discomfort VAS (1- minute and 5-minutes post-instillation).  
At Visit 6, there will be a 3-day post-treatment Follow-Up, in which safety 
assessments are performed and all remaining study materials are collected. The 
subjects will be instructed to continue to withhold all other concomitant topical 
medications as outlined by the protocol for the duration of their participation 
(through Visit 6). 
Serious adverse events (SAEs) ongoing as of Visit 6 will be followed until they 
have resolved, stabilized in the opinion of the Investigator, or returned to baseline. 
This study will be conducted per the schedule shown in the Schedule of Events 
(Table 1) and the Study Schematic (Figure 1). 
Sample Size: 
The study will include 60 male or female subjects. 
• 
The primary analysis will assess the difference in change from baseline 
in Drop Discomfort VAS scores 1-minute post-Dose 1 instillation 
between the two treatment groups. 
• 
A sample size of 26 subjects per group (52 in total) will provide at least 
90% power assuming: 
o 
a mean change from baseline Drop Discomfort VAS score of 
+30 mm for subjects randomized to Restasis® 
o 
a mean change from baseline Drop Discomfort VAS score of 
+10 mm for those randomized to VOS 
o 
a common standard deviation of 21 
o 
a 2-sided alpha of 5% 
• 
Under the same assumptions, the study will have at least 80% power if 
the common standard deviation for the discomfort score were to be 25. 
• 
The study also provides 80% power should the treatment difference in 
discomfort scores be 16 (common standard deviation =20). 


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• 
To allow for 15% dropouts, a total of 60 subjects will be randomized. 
Statistical 
Methods: 
The primary endpoint is measured on a VAS and will be summarized and analysed 
as continuous data. Summaries of VAS scores (absolute and change from baseline) 
by treatment group will be displayed for each VAS assessment (minutes 1, 5 and 
overall mean) at each visit. Should the data meet the necessary assumptions 
(normality and equal variance in both treatment groups) then the treatment groups 
will be compared using a t-test. If assumptions are violated, the Wilcoxon rank sum 
test will be used. 


 
 
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Figure 1: AUR-VOS-2017-01 Study Schematic 
 
 
 


 
 
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Table 1: AUR-VOS-2017-01 Schedule of Events 
Visit 
Visit 1 
Screening 
Visit 2 
Pre-
Randomization 
Visit 2 
Randomization 
Visit 3 
Treatment 
Visit 4 
Treatment 
Visit 5 
End of 
Treatment/ 
Early Term 
Visit 6 
Follow-up 
Day 
Day -3 to -1 
 
Day 1 
Day 7 (±2 days) 
Day 14 (±2 days) 
Day 28            
(±2 days)  
Day 31            
(±2 days) 
Informed Consent 
 
 
 
 
 
 
 
Demography 
 
 
 
 
 
 
 
Medical/Ophthalmic/ 
Surgical history 
 
 
 
 
 
 
 
Eligibility Criteria Assessment 
 
 
 
 
 
 
 
Concomitant Medications 
Assessment 
 
 
 
 
 
 
 
Urine Pregnancy Test1 
 
 
 
 
 
 
 
SANDE2 
 
 
 
 
 
 
 
Individual Symptom Severity 
Assessments using VAS3 
 
 
 
 
 
 
 
BCVA4 
 
 
 
 
 
 
 
Ophthalmoscopy (dilated) 
 
 
 
 
 
 
 


 
 
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1 For females of childbearing potential only; 2 Symptom Assessment and Dry Eye; 3 Visual Analog Scale;  
4 Best Corrected Visual Acuity; 5 STT should be performed at least 1 hour after IP instillation and at least 20 minutes after fluorescein corneal staining; 
6 Over the Counter; 7 Investigational Product instillation should be performed at least 2 hours after OTC ocular lubricant (Refresh Plus) instillation;  
8 Post OTC ocular lubricant instillation; 9 Post IP instillation; 10Adverse Event; 
11 Subjects will be contacted the evening of the Visit 4 and in the evening prior to Visit 5. 
Visit 
Visit 1 
Screening 
Visit 2 
Pre-
Randomization 
Visit 2 
Randomization 
Visit 3 
Treatment 
Visit 4 
Treatment 
Visit 5 
End of 
Treatment/ 
Early Term 
Visit 6 
Follow-up 
Day 
Day -3 to -1 
 
Day 1 
Day 7             
(±2 days) 
Day 14            
(±2 days) 
Day 28            
(±2 days) 
Day 31            
(±2 days) 
Slit-Lamp Biomicroscopy  
 
 
 
 
 
 
 
Fluorescein Corneal Staining 
 
 
 
 
 
 
 
Schirmer Test 
5 
 
 
 
 
5 
 
OTC6 Ocular Lubricant 
Administration at the Study Site  
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
Investigational Product 
Administration at the Study Site 
 
 
7 
 
 
 
 
Drop Discomfort Assessment at 
the Study Site  
 
8 
9 
 
 
 
 
AE10 Assessment 
 
 
 
 
 
 
 
Investigational Product 
Dispensation  
 
 
 
 
 
 
 
Dosing Diary and VAS3Scales 
Dispensation  
 
 
 
 
 
 
 
Subject Contact for Drop 
Discomfort Assessment  
 
 
 
 
11 
 
 


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TABLE OF CONTENTS 
NAMES AND ADDRESSES .................................................................................................. 2 
DECLARATION OF SPONSOR .......................................................................................... 4 
INVESTIGATOR AGREEMENT FORM ........................................................................... 5 
SYNOPSIS ............................................................................................................................... 6 
LIST OF TABLES ................................................................................................................ 18 
LIST OF ABBREVIATIONS .............................................................................................. 19 
1. 
INTRODUCTION AND BACKGROUND ................................................................. 22 
1.1 
Background of the Disease and Treatment Options ................................................... 22 
1.1.1 
Limitations of Current Treatment ............................................................................ 22 
1.2 
Rationale for the Use of Calcineurin Inhibitors in Dry Eye Disease .......................... 22 
1.2.1 
Non-Clinical Studies of Voclosporin in Dry Eye .................................................... 23 
1.2.2 
Clinical Studies of Voclosporin in Dry Eye ............................................................ 25 
2. 
RATIONALE ................................................................................................................ 27 
2.1 
Dose Rationale ............................................................................................................ 27 
3. 
STUDY OBJECTIVES ................................................................................................. 28 
3.1 
Primary Objective ....................................................................................................... 28 
3.2 
Secondary Objective ................................................................................................... 28 
3.3 
Endpoints .................................................................................................................... 28 
3.3.1 
Primary Endpoint ..................................................................................................... 28 
3.3.2 
Secondary Endpoints ............................................................................................... 28 
4. 
INVESTIGATIONAL PLAN....................................................................................... 30 
4.1 
Overall Study Design .................................................................................................. 30 
4.2 
Duration of Subject Participation and Study .............................................................. 31 
5. 
SELECTION, 
WITHDRAWAL 
OF 
SUBJECTS 
AND 
PERMANENT 
DISCONTINUATION OF DRUG ............................................................................... 32 
5.1 
Number of Subjects ..................................................................................................... 32 
5.2 
Inclusion Criteria ........................................................................................................ 32 
5.3 
Exclusion Criteria ....................................................................................................... 33 
5.4 
Adequate/Effective Contraception .............................................................................. 34 
5.5 
Withdrawal of Subjects ............................................................................................... 35 
5.6 
Discontinuation of Study Treatment ........................................................................... 35 


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5.6.1 
Discontinuation of Study Treatment Due to an Adverse Event ............................... 35 
6. 
RANDOMIZATION, MASKING AND UNMASKING PROCEDURES ............... 36 
6.1 
Randomization ............................................................................................................ 36 
6.2 
Masking ....................................................................................................................... 37 
6.3 
Unmasking .................................................................................................................. 37 
7. 
STUDY TREATMENTS .............................................................................................. 39 
7.1 
Dosage Forms/Formulation ........................................................................................ 39 
7.1.1 
VOS Study Treatment .............................................................................................. 39 
7.1.2 
Restasis® .................................................................................................................. 39 
7.2 
Drug Dosage and Administration ............................................................................... 39 
7.2.1 
Treatment Arms ....................................................................................................... 39 
7.2.2 
Dosing Guidelines .................................................................................................... 40 
7.3 
Package and Labeling ................................................................................................. 40 
7.4 
Study Treatment Allocation ........................................................................................ 40 
7.5 
Site Supply, Storage, Accountability .......................................................................... 40 
7.5.1 
Site Supply ............................................................................................................... 40 
7.5.2 
Storage ..................................................................................................................... 40 
7.5.3 
Accountability .......................................................................................................... 41 
7.6 
Procedures for Overdose ............................................................................................. 41 
7.7 
Prohibited Therapy and Concomitant Treatment ........................................................ 41 
7.7.1 
Prohibited Medications ............................................................................................ 42 
8. 
STUDY PROCEDURES............................................................................................... 44 
8.1 
Description of Study Assessments .............................................................................. 44 
8.1.1 
Dry Eye Disease Activity Assessments ................................................................... 44 
8.2 
Schedule of Assessments ............................................................................................ 48 
8.2.1 
Screening Procedures ............................................................................................... 49 
8.2.2 
Treatment Procedures .............................................................................................. 49 
8.2.3 
End of Study (or Early Discontinuation) Procedures .............................................. 54 
8.2.4 
Follow-up Procedures .............................................................................................. 55 
9. 
EVALUATION, RECORDING AND REPORTING OF AES AND SAES ............ 56 
9.1 
Definitions ................................................................................................................... 56 
9.1.1 
Adverse Event .......................................................................................................... 56 
9.1.2 
Adverse Drug Reaction ............................................................................................ 56 
9.1.3 
Suspected Adverse Reaction (SAR) ........................................................................ 56 
9.1.4 
Unexpected .............................................................................................................. 56 


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9.1.5 
Life-threatening ....................................................................................................... 56 
9.1.6 
Serious Adverse Event (SAE) .................................................................................. 57 
9.1.7 
Suspected Unexpected Serious Adverse Reaction (SUSAR) .................................. 57 
9.2 
Adverse Event Descriptors ......................................................................................... 58 
9.2.1 
Intensity/Severity Categorization ............................................................................ 58 
9.2.2 
Causal Relationship Categorization ......................................................................... 58 
9.2.3 
Outcome Categorization .......................................................................................... 59 
9.2.4 
Symptoms of the Disease Under Study ................................................................... 59 
9.2.5 
Abuse, Misuse, Overdose and Medication Error ..................................................... 59 
9.3 
Reporting Procedure for AEs, SAEs, and Pregnancy ................................................. 60 
9.3.1 
Adverse Events ........................................................................................................ 60 
9.3.2 
Serious Adverse Events ........................................................................................... 61 
9.3.3 
Pregnancy ................................................................................................................. 63 
10. STATISTICAL ANALYSIS......................................................................................... 65 
10.1 
Statistical Methods ...................................................................................................... 65 
10.2 
Sample Size and Power Calculations .......................................................................... 65 
10.3 
Populations .................................................................................................................. 66 
10.3.1 
Intent-to-Treat Set .................................................................................................... 66 
10.3.2 
Per Protocol .............................................................................................................. 66 
10.3.3 
Safety Set ................................................................................................................. 66 
10.4 
Concomitant Therapy .................................................................................................. 67 
10.5 
Endpoint Evaluations .................................................................................................. 67 
10.5.1 
Primary Endpoint ..................................................................................................... 67 
10.5.2 
Secondary Endpoints ............................................................................................... 67 
10.6 
Statistical and Analytical Methods ............................................................................. 68 
10.6.1 
Primary Analysis ...................................................................................................... 68 
10.6.2 
Secondary Efficacy Analysis ................................................................................... 68 
10.6.3 
Safety Analysis ........................................................................................................ 68 
10.7 
Safety Evaluations ...................................................................................................... 68 
10.8 
Interim Analyses ......................................................................................................... 68 
10.9 
Other Evaluations ........................................................................................................ 69 
11. ETHICAL CONDUCT OF THE STUDY .................................................................. 70 
11.1 
Informed Consent ........................................................................................................ 70 
11.2 
Institutional Review Board or EC/IEC ....................................................................... 70 
12. QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 71 


 
 
 
 
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13. ADMINISTRATIVE PROCEDURES ........................................................................ 72 
13.1 
Sponsor’s Responsibilities .......................................................................................... 72 
13.1.1 
Study Supplies ......................................................................................................... 72 
13.1.2 
Insurance .................................................................................................................. 72 
13.1.3 
Study Monitoring ..................................................................................................... 72 
13.2 
Investigator’s Responsibilities .................................................................................... 73 
13.2.1 
Reporting and Recording of Data ............................................................................ 73 
13.2.2 
Investigator Training ................................................................................................ 73 
13.2.3 
Source Documentation ............................................................................................. 73 
14. PROCEDURE FOR MODIFICATION OF PROTOCOL OR PREMATURE 
TERMINATION OF THE STUDY............................................................................. 75 
14.1 
Protocol Waivers, Deviations and Violations ............................................................. 75 
14.2 
Study Termination ...................................................................................................... 75 
15. POLICY FOR PUBLICATION AND PRESENTATION OF DATA ..................... 77 
16. REFERENCES .............................................................................................................. 78 
17. APPENDICES ............................................................................................................... 80 


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LIST OF TABLES 
Table 1: AUR-VOS-2017- 01 Schedule of Events ................................................................. 12 
LIST OF FIGURES 
Figure 1: AUR-VOS-2017-01 Study Schematic ..................................................................... 11 
LIST OF APPENDICES 
Appendix  1 Tolerability Assessment ..................................................................................... 80 
Appendix  2 EYE DRYNESS ASSESSMENTS .................................................................... 81 
Appendix  3  SANDE ............................................................................................................. 82 
Appendix  4  Individual Symptom Severity Assessments using VAS ................................... 83 
Appendix  5  Slit-Lamp Biomicroscopy ................................................................................. 84 
Appendix  6  Best Corrected Visual Acuity ............................................................................ 86 
Appendix  7  Fluorescein Corneal Staining (FCS) National Eye Institute/Industry Workshop 
Scale ................................................................................................................. 87 
Appendix  8  Restasis® Package Insert ................................................................................... 88 
Appendix  9  Daily Dosing Diary ........................................................................................... 95 
 
 
 


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LIST OF ABBREVIATIONS 
ADR 
Adverse drug reaction 
AE 
Adverse event 
Aurinia 
Aurinia Pharmaceuticals Inc. 
BCVA 
BID 
Best Corrected Visual Acuity 
Twice daily 
CNI 
CRA 
Calcineurin inhibitor 
Clinical Research Associate 
CRO 
Contract Research Organization 
CsA 
DED 
Cyclosporine A 
Dry Eye Disease 
 
EC 
eCRF 
 
Ethics Committee 
Electronic case report form 
EDC 
Electronic data capture 
ERG 
ETDRS 
FCS 
FDA 
Electroretinography 
Early Treatment of Diabetic Retinopathy Study 
Fluorescein Corneal Staining 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 


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IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IUD 
KCS 
LogMAR 
NEI 
NFAT 
NOAEL 
NSAID 
NZW 
OD 
OS 
OSDI 
Intrauterine device 
Keratoconjunctivitis sicca 
Logarithm of the Minimum Angle of Resolution 
National Eye Institute 
Nuclear Factor of Activated T-cells 
No observed adverse event level 
Nonsteroidal Anti-Inflammatory Drug 
New Zealand White 
Right eye 
Left eye 
Ocular Surface Disease Index 
OTC 
Over the counter 
OU 
Both eyes 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
SAE 
SANDE 
Serious adverse event 
Symptom Assessment in Dry Eye 
SAP 
SAR 
Statistical Analysis Plan 
Serious adverse reaction 
STT 
Schirmer Tear Test 
SUSAR 
Suspected unexpected serious adverse reaction 


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TEAE 
UPT 
VAS 
VOS 
Treatment-emergent adverse event 
Urine pregnancy test 
Visual Analog Scale 
Voclosporin ophthalmic solution 
WHO 
WOCBP 
World Health Organization 
Women of childbearing potential 


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1. INTRODUCTION AND BACKGROUND 
1.1 
Background of the Disease and Treatment Options  
Dry Eye Disease (DED), also called keratoconjunctivitis sicca (KCS), is a common clinical 
problem as over 7 million people in the United States experience dry eye symptoms.  
Symptoms of DED include a sensation of dry eyes, foreign body sensation, irritation, burning, 
tearing, ocular pain, and itching, among others.  DED affects quality of life and work 
productivity, and patients with moderate to severe DED may experience reduced visual 
function in addition to ocular dysfunction.  
DED is a multi-factorial disease, defined by a loss of homeostasis of the tear film and 
accompanied by ocular symptoms, in which tear film instability and hyper-osmolarity, ocular 
surface inflammation and damage, and neuro-sensory abnormalities play etiological roles [1].  
DED patients are classified by the overlapping etiologies of aqueous deficient and evaporative 
dry eye.  Evaporative dry eye tends to be more prevalent than aqueous deficient; however, as 
the disease progresses, both components become apparent [1].  The common pathway for both 
groups is that desiccating stress leads to ocular surface inflammation [7,10,12]  
1.1.1 Limitations of Current Treatment 
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 [1]. There are currently two FDA-approved 
prescription medications used for DED, topical cyclosporine (Restasis®) and lifitigrast 
(Xiidra®).  A significant number of patients using Restasis® experience the following 
problems: ocular irritation upon instillation, slow onset of response, and limited efficacy 
(Restasis® Package Insert, see Appendix 8).  Problems with Xiidra® include instillation 
irritation, dysgeusia and reduced visual acuity which occurred in 5-25% of subjects in clinical 
trials (Xiidra® Package Insert). There is a clear unmet clinical need for improved therapeutic 
options for patients with moderate to severe DED. 
1.2 
Rationale for the Use of Calcineurin Inhibitors in Dry Eye Disease 
In patients with DED, tear production has been shown to be increased with the use of topical 
immunosuppressants, including cyclosporine. It is believed T-lymphocyte infiltration and 
activation in the lacrimal gland represents an underlying pathogenesis for DED. Calcineurin 
inhibitors 
(CNIs) 
reversibly 
inhibit 
immunocompetent 
lymphocytes, 
particularly 


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T-lymphocytes, in the G0 or G1 phase of the cell cycle and also reversibly inhibit the 
production and release of lymphokines [9].  Calcineurin is a calcium- and 
calmodulin-dependent serine-threonine phosphatase. 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 (e.g., interleukin-2, interleukin-4, tumor necrosis factor-α, granulocyte-macrophage 
colony stimulating factor, and interferon-γ,[11,13]). 
Voclosporin is a 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 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 as compared to CsA. The combination of increased 
potency and decreased metabolite exposure, for voclosporin as compared to CsA, has led to 
better pharmacokinetic (PK)/pharmacodynamic (PD) predictability. 
1.2.1 Non-Clinical Studies of Voclosporin in Dry Eye 
Two Good Laboratory Practice toxicology studies [3,4] 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 evaluation, 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 Day 1 and Day 13 at pre-dose, 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 


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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 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 [5], 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 is >0.56 mg/eye/day.  
In summary, the two repeated-dose ocular toxicology studies [3,4] 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 
the S08711 study.  


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In addition to the three repeated dose toxicology studies, the safety and efficacy of VOS 0.2% 
has been evaluated in dogs with naturally occurring KCS [6], 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 twice daily (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 both safe and effective in 
treating KCS in dogs. 
In order to determine potential melanin binding of 
14C-LX214, ocular tissue 
14C-LX214-derived radioactivity concentrations were compared between data obtained from 
albino NZW rabbits given a single bilateral instillation in a separate study and similarly treated 
pigmented Dutch-Belted rabbits. 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.  
1.2.2 Clinical Studies of Voclosporin in Dry Eye 
VOS 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 5 subjects with DED. In that study, 
both 0.02% and 0.2% concentrations were found to be safe and well tolerated following 
multiple instillations in healthy subjects. Adverse events (AEs) and ocular findings were mild 
and similar between VOS and placebo groups. Although the sample size was small, results 
from the 5 subjects with DED suggest VOS may be beneficial in the treatment of DED and is 
supported by the Ocular Surface Disease Index (OSDI) 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. 


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These factors form the basis for the rationale to investigate the safety and efficacy of 
voclosporin in subjects with DED.  Study AUR-VOS-2017-01 will evaluate the tolerability 
and efficacy of VOS versus Restasis® in subjects with DED.  


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2. RATIONALE 
2.1 
Dose Rationale 
Based on Phase 1 studies in healthy subjects and all clinical trials to date in the clinical 
development program in other indications, oral voclosporin is generally well tolerated at doses 
up to 0.8 mg/kg BID with no unexpected safety concerns compared to the profile expected for 
CNIs.  
VOS was evaluated in a Phase 1 parallel, randomized, double-masked, placebo-controlled, 
dose-escalation (0.02% and 0.2%) study assessing the safety and tolerability of VOS in healthy 
volunteers, followed by an open-label evaluation of VOS (0.2%) BID in subjects with DED 
(see voclosporin Investigator’s Brochure (IB)). Although the sample size was small, results 
from the five subjects with DED suggest VOS may be beneficial in the treatment of DED and 
is supported by the OSDI scores which were improved in all subjects at all timepoints while 
on study drug. The mean improvement in STT scores between baseline and the end of treatment 
provides further evidence of efficacy. It is anticipated that 0.2% VOS BID will be an effective 
dose in the treatment of immune-mediated ocular surface disease. 


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3. STUDY OBJECTIVES 
3.1 
Primary Objective 
• To assess the ocular tolerability of VOS compared to cyclosporine ophthalmic 
emulsion (Restasis®) in subjects with DED.   
3.2 
Secondary Objective 
• To assess the safety and efficacy of VOS in subjects with DED. 
3.3 
Endpoints 
3.3.1 Primary Endpoint 
• Change from baseline in Drop Discomfort Visual Analogue Scale (VAS) score 
1-minute post Dose 1 instillation.  
3.3.2 Secondary Endpoints 
3.3.2.1 Key Secondary Endpoints 
• Change from baseline in Drop Discomfort VAS score 
• Change from baseline in each of the 6 Individual Symptom Severity Assessments 
(VAS) scores  
• Change from baseline in the sum of the Individual Symptom Severity Assessments 
score (VAS Total Symptom Summary Score)  
• Change from baseline in Symptom Assessment in Dry Eye (SANDE) score  
• Change from baseline in unanesthetized STT score  
• Change from baseline in Fluorescein Corneal Staining (FCS) total score (National Eye 
Institute (NEI)/Industry Workshop 0-15 scale)   
3.3.2.2 Other Secondary Safety Endpoints 
• Treatment-emergent adverse events (TEAEs) 
• Change from screening in Best Corrected Visual Acuity (BCVA) 


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• Changes from baseline in Slit-Lamp Biomicroscopy  
• Changes from screening in Dilated Ophthalmoscopy 


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4. INVESTIGATIONAL PLAN 
4.1 
Overall Study Design 
This is a Phase 2, multi-center, Investigator-masked, randomized, parallel-group study to 
evaluate the tolerability, efficacy and safety of VOS versus Restasis® over a 28-day treatment 
period in subjects with mild to moderate DED.  Approximately 60 subjects will be randomized 
to either VOS or Restasis® at approximately 5 centers located in the US.   
At Visit 1 (screening), informed consent will be obtained from subjects and eligibility will be 
determined.  A STT will be performed at this visit. The score will be used for eligibility and 
baseline.  During this visit, all subjects will self-administer an OTC ocular lubricant, Refresh 
Plus®, OU to assess ability to self-administer study product. 
At Visit 2 (Randomization), continued eligibility will be confirmed.  During this visit, all 
subjects will self-administer an OTC ocular lubricant, Refresh Plus®, in both eyes to evaluate 
ability to tolerate ocular drops.  Individuals who are unable to successfully instill the drops or 
who rate OTC ocular lubricant as uncomfortable, based on a post-instillation Drop Discomfort 
VAS score, will not be eligible for participation in the study.  (Note:  For subjects meeting the 
Screening and Randomization Criteria, the Visit 2 Drop Discomfort VAS score will be used 
as the baseline value.)   
Eligible subjects will be randomly assigned in a 1:1 ratio to one of the two treatment groups:  
VOS BID or Restasis® BID.  The first instillation of Investigational Product (IP) will be 
administered, at least 2 hours following administration of Refresh Plus® and by clinic personnel 
to OU during Visit 2.  IP will be administered to the subject by a dedicated dosing coordinator 
(the subject and the Investigator will be masked to study treatment for the first post 
randomization instillation). Tolerability, safety and efficacy assessments will be performed at 
this visit. 
At Treatment Visits 3 and 4, tolerability, safety and efficacy evaluations will be performed.  At 
the End of Treatment, Visit 5, tolerability, safety and efficacy evaluations will be performed.  
Subjects who discontinue before Visit 5 will undergo all Visit 5 evaluations (early 
termination).  IP will be administered to the subject by a dedicated dosing coordinator at the 
clinic visits (single masked: the Investigator and study staff will remain masked to study 
treatment). A Drop Discomfort VAS will be administered in the clinic at 1 and 5 minutes 
following instillation of IP at Visits 2 through 5.  With the exception of clinic day visits, 
subjects will self-administer IP twice a day OU over the 4-week treatment period.  On the 


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evening of Visits 2 through 4 and in the evening prior to Visit 5, site staff will contact the 
subject by phone to prompt administration of IP followed by completion of the dosing diary 
(See Appendix 9) and the Drop Discomfort VAS (1- and 5-minutes post-instillation). 
At Visit 6, there will be a 3-day post-treatment Follow-Up, in which safety assessments are 
performed and all remaining study materials are collected.  The subjects will be instructed to 
continue to withhold all other concomitant topical medications as outlined by the protocol for 
the duration of their participation (through Visit 6). 
Serious adverse events (SAEs) ongoing as of Visit 6 will be followed until they have resolved, 
stabilized in the opinion of the Investigator, or returned to baseline. 
This study will be conducted per the schedule shown in the Schedule of Events (Table 1) and 
the Study Schematic (Figure 1). 
4.2 
Duration of Subject Participation and Study 
The expected duration of subject participation is approximately 5 weeks. The treatment 
duration is 28 days with a follow-up visit 3 days after last dose (completion or early 
termination).  


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5. SELECTION, WITHDRAWAL OF SUBJECTS AND PERMANENT 
DISCONTINUATION OF DRUG 
5.1 
Number of Subjects 
Approximately 60 subjects will be randomized to either VOS or Restasis®.  Approximately 30 
subjects will be assigned to each treatment group. 
5.2 
Inclusion Criteria 
At Visit 1 and Visit 2 (as specified in the Schedule of Events), subjects may be eligible for 
participation if they:  
1. Provide written informed consent before any study-specific procedures are performed. 
2. Are male or female subjects with a minimum age of 18 (or legal age of consent if >18 years) 
years, at the time of screening (Visit 1). 
3. Are willing and able to follow instructions and can be present for the required study visits 
for the duration of the study. 
4. 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.  
5. Have a documented history of DED in both eyes supported by a previous clinical diagnosis 
at Visit 1. 
6. Have ongoing DED, as defined by at least one eye (if one eye, the same eye) meeting all 
the following criteria:  
− 
A symptom severity score of ≥ 30 for Eye Dryness on a VAS (0-100) at Visit 2 
− 
An unanesthetized STT score of ≥ 1 mm and ≤ 10 mm per 5 minutes (Note:  
STT Score obtained at Visit 1) 
− 
Evidence of ocular surface staining (total fluorescein staining score of at least 
3 [0-15 scale]) at Visit 2 
7. Have normal lid anatomy at Visit 1. 


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5.3 
Exclusion Criteria 
In order for subjects to be eligible at Visit 1 and Visit 2 (as specified in the Schedule of Events), 
subjects must not: 
1. Be unable or unwilling to give written informed consent and/or to comply with study 
procedures. 
2. Have any known hypersensitivity or contraindication to study treatments (including 
excipients), topical anesthetics or vital dyes. 
3. Be unable to demonstrate correct instillation of OTC ocular lubricant during Visit 1. 
4. Report discomfort from instillation of OTC ocular lubricant during Visit 2 (based on score 
of ≥ 30 on the Drop Discomfort VAS).  
5. Have used Restasis® (cyclosporine ophthalmic solution) within 30 days prior to Visit 1. 
6. Have used Restasis® for more than 1 month (if prior use is reported). 
7. Have used Xiidra® (lifitegrast ophthalmic solution) within 14 days prior to Visit 1. 
8. Have had corneal graft surgery in either eye within 1 year of Visit 1.  
9. Have recent or current evidence of ocular infection or inflammation in either eye. 
10. Have current evidence of clinically significant blepharitis (defined as requiring lid hygiene 
therapy), conjunctivitis, or a history of herpes simplex or zoster keratitis in either eye. 
11. Have clinically significant ocular disease in either eye (e.g., corneal edema, uveitis, severe 
KCS) which might interfere with study procedures or assessments. 
12. Have any abnormality in either eye preventing reliable applanation tonometry.  
13. Be taking or known need for any of the known treatment therapies listed in Section 7.7, 
Prohibited Therapy and Concomitant Treatment at Visit 1 or during the study. This 
includes prohibited medications prior to Visit 1 as specified in Section 7.7, Prohibited 
Therapy and Concomitant Treatment. 
14. Have any known hypersensitivity or contraindication to CNIs.  


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15. Have clinically significant systemic disease (e.g., uncontrolled diabetes, hepatic, renal, 
endocrine or cardiovascular disorders) which might interfere with the study.  
16. Have participated in any investigational clinical study within 30 days prior to Visit 1. 
17. Have altered systemic medication that could have an effect on dry eye signs or symptoms 
within 30 days prior to Visit 1 or anticipated during the study.  
18. Be women of childbearing potential (WOCBP) who are pregnant, nursing, planning a 
pregnancy, or not using a medically acceptable form of birth control.  
5.4 
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 WOCBP must have a negative 
urine pregnancy test (UPT) 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 (IUD) in place for at least 4 weeks prior to Visit 1 through Visit 5 or 
last administration of IP or until completion of the subject’s first menstrual cycle following 
last administration of the IP, whichever period of time is longer. 
2. Barrier method (condom or diaphragm) with spermicide for at least 4 weeks prior to Visit 
1 through Visit 5 or last administration of the IP or until completion of the subject’s first 
menstrual cycle following last administration of the IP, whichever period of time is longer. 
3. Stable hormonal contraceptive for at least 3 months prior to Visit 1 through Visit 5 or last 
administration of the IP or until completion of the subject’s first menstrual cycle following 
administration of the IP, whichever period of time is longer.  
NOTE: For Depo-Provera injection contraceptives, the statement regarding first menstrual 
cycle following administration of the IP is not applicable as females receiving this form of 
contraception will not have menses. 
4. In a monogamous relationship with a surgically sterilized (i.e., vasectomized) partner at 
least 6 months prior to Visit 1 through Visit 5 or last administration of the IP or until 
completion of the subject’s first menstrual cycle following administration of the IP, 
whichever period of time is longer. 


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5.5 
Withdrawal of Subjects 
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 5), if possible. If 
possible, the subject should also be advised to come for the Follow-up Visit, 3 days after last 
dose (Visit 6). If a subject refuses end of study procedures, the reason for refusal should be 
fully documented in the subject’s source document and recorded in the study specific electronic 
case report form (eCRF). It is the subject’s right to withdraw from the study without providing 
a reason. In this case, the source documents and the eCRF should document the reason for 
discontinuation as “withdrawal of consent.” Withdrawn subjects will not be replaced. 
5.6 
Discontinuation of Study Treatment 
If any subject is discontinued from study treatment, the reason for discontinuation will be 
documented in the eCRF. If the reason for discontinuing study treatment is an AE, the specific 
event or test will be recorded in the eCRF. The subject should also be advised to come for the 
Safety Follow-up Visit, 3 days after last dose.  
Subjects who are permanently discontinued from study treatment will be treated as deemed 
appropriate by the Investigator. 
5.6.1 Discontinuation of Study Treatment Due to an Adverse Event 
Subjects may be permanently discontinued from study treatment because of the appearance of 
an unacceptable AE. It is vital to obtain follow-up data on any subject withdrawn because of 
an AE. In any case, every effort must be made to evaluate protocol-specified safety follow-up 
procedures (see Section 9.3, Reporting Procedure for AEs, SAEs, and Pregnancy). If a subject 
is withdrawn due to an AE, the event should be followed by the Investigator through contact 
with the subject until resolution or stabilization has occurred. All AEs should be followed until 
resolution, stabilization or the subject is lost to follow-up and cannot be contacted. 


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6. RANDOMIZATION, MASKING AND UNMASKING PROCEDURES 
6.1 
Randomization 
A computer-generated randomization schedule will be used to assign subjects into treatment 
groups.  The randomization ratio will be maintained within each study center.  A randomization 
list will be generated and provided by an unmasked statistician.  
The Sponsor, the project teams at the designated Contract Research Organizations (CROs), 
and investigative staff responsible for assessments of study endpoints will be masked to study 
product assignments. There will be an unmasked dedicated dosing coordinator who will 
dispense the IP to the subject and who will perform drug accountability on the returned IP.  
This individual will be otherwise uninvolved in the study operations.  Furthermore, there will 
be a Clinical Research Associate (CRA) dedicated to drug accountability who will be 
unmasked to the treatment assignment by default but will be uninvolved in review of the 
clinical trial data beyond the scope of IP accountability.  In case of medical emergency, or 
occurrence of an SAE, the randomization code may be unmasked and made available to the 
Investigator, Sponsor, and/or other personnel involved in the monitoring or conduct of this 
study. In the absence of medical need, the randomization code will not be available to the 
above individuals until after the study is completed and the database is locked.   
In the event of a medical need, the Investigator will treat each subject as needed. Since there 
is no specific antidote to VOS, immediate emergency unmasking is not necessary. If the 
Investigator feels it is necessary to unmask a subject’s assignment after an emergency situation, 
the Investigator may call the Medical Monitor and notify the Sponsor. The IP assignment will 
be revealed on a subject-by-subject basis with the approval of the medical monitor and 
Sponsor, thus leaving the masking of the remaining subjects intact. 
A randomization schedule will be generated by an unmasked statistician who will also be 
responsible for loading the schedule into the electronic data capture (EDC) system.  No other 
 or Aurinia Pharmaceuticals Inc. (Aurinia) staff will have access 
to the schedule. 
Randomization team members will work independently of other team members at the CRO. 
With the exception of the dedicated dosing coordinator and drug accountability CRA, all other 
study personnel, the Sponsor, and project teams at the CROs involved in the study will be 
masked to study product assignments.   
 


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6.2 
Masking 
On Day 1 Dose 1, this study is double-masked. The IP allocation (VOS versus Restasis®) will 
be masked to the Sponsor, the subject and the investigative staff with the exception of a 
dedicated dosing coordinator and unmasked CRA.  The dosing coordinator will be responsible 
for dispensing and retrieving IP to/from subjects, instructing subjects regarding dosing of the 
IP, addressing study subjects’ questions regarding IP, and reviewing daily dosing diaries.  As 
a consequence of these interactions, the dosing coordinator will be unmasked to the study 
treatment for each subject. In order to ensure subject masking, at Visit 2, first dose, the dosing 
coordinator will not provide any IP related information prior to instilling the IP. The IP will be 
instilled in a masked manner.  Instructions regarding storage and dosing will be provided after 
this first instillation.   
On Days 2-28, subjects will not have visibility to the study product assignment; however, as 
VOS and Restasis® have different storage conditions and appearance, it may be possible that 
the subjects who have previously used Restasis®, may know that those differ from their prior 
experience. Therefore, the study will be considered Investigator-masked during this timeframe. 
The randomization schedule will be generated by the Randomization Statistician (who is not 
on the project team) or designee and maintained in a secure and limited-access location 
separate from the study Investigator and members of the project team. 
6.3 
Unmasking 
The treatment assignment for an individual subject may be obtained in the case of a medical 
emergency when knowledge of the IP identity is essential for the clinical management of the 
subject. The Investigator must make every effort to contact the study medical monitor or the 
Clinical Study Manager before unmasking the treatment assignment.  
In the event of emergency unmasking, the Investigator must inform the Sponsor immediately, 
without revealing to the Sponsor personnel the treatment assignment.  
If unmasking is required for emergency subject management, the Investigator must document 
the medical rationale for unmasking and forward the information to the Sponsor within 
24 hours of unmasking. 
If an SAE is assessed as unexpected and related to the IP, and therefore meets the requirement 
for expedited regulatory submission, the Sponsor’s Drug Safety Surveillance department will 
unmask the treatment assignment for the individual subject. Expedited reports will be 
submitted to Regulatory Authorities in accordance with applicable regulations. Expedited 


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reports will be distributed to Investigators without revealing the treatment assignment and will 
be submitted to Institutional Review Boards (IRBs). 
If emergency unmasking is required, withdrawal of the subject from the study is not mandatory 
unless there are other circumstances that require the subject’s discontinuation.  At the 
Sponsor’s discretion, the subject may remain in the study without continued use of the IP.   
In the event of accidental unmasking, the event would be reported as a protocol deviation and 
escalation to the Sponsor.  The subject may remain in the study.  If identified by the study 
center, a Sub-Investigator may be asked to assume clinical study assessments for a subject if 
the PI was inadvertently unmasked.  
 




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7.2.2 Dosing Guidelines 
7.2.2.1 VOS/Restasis®– Study Treatment 
7.3 
Package and Labeling 
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 
Good Clinical Practice (GCP). 
7.4 
Study Treatment Allocation 
Subjects will be randomized to receive either VOS or Restasis® in a 1:1 ratio. Subjects will be 
allocated a kit number for the duration of the study.  Subjects will be assigned to treatment 
groups using the randomization module within the EDC system.  As eligible subjects are 
enrolled and the corresponding Randomization eCRF completed, a kit number will be 
assigned. 
7.5 
Site Supply, Storage, Accountability 
7.5.1 Site Supply 
Once a site has been approved for study initiation, the site will be supplied with an initial stock 
of IP. Each site will receive one shipment of both Restasis® and VOS prior to study enrollment.  
Additional shipments of both Restasis® and VOS will be provided to each site as needed. 
7.5.2 Storage 
VOS should be stored refrigerated between 2º C and 8º C (35º F to 49º F) but may be brought 
to room temperature prior to use. Subjects should be consistent in their use of VOS IP.  
Opened ampules must not be stored for re-use as the formulation does not contain 
preservatives. 
STUDY DRUG SHOULD NOT BE FROZEN. DO NOT USE IF THE VIAL CONTENT 
DOES NOT APPEAR CLEAR. 
Restasis® should be stored at room temperature (15-25°C/59-77°F). 
Each site should have a thermometer that records minimum and maximum temperatures daily. 
Maintenance of a temperature log is mandatory. The log should be updated by site personnel 


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during normal working hours. This log must be available for review by the Site Monitor during 
on-site monitoring visits. 
7.5.3 Accountability 
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 designee for the central study file. The original will be kept in the site files. 
After completion of the study, or if it is prematurely terminated, all undispensed IP will be 
returned to Aurinia. The decision to destroy IP at a site must be made by Aurinia. If the 
dispensed/returned IP is destroyed at a site, the Investigator must receive Aurinia approval of 
the site’s standard operating procedure addressing the destruction process and forward 
documentation of destruction to Aurinia. 
7.6 
Procedures for Overdose 
Preclinical findings suggest that systemic effects from an overdose are unlikely, as the peak 
blood levels after ocular instillation are below those achieved with oral doses of voclosporin. 
Based on clinical experience with voclosporin, symptomatic treatment of AEs is indicated. In 
the event of overdose, discontinuation of treatment should be considered. 
7.7 
Prohibited Therapy and Concomitant Treatment 
Any concomitant treatment given for any reason during the study must be recorded in the eCRF 
and in the subject’s source documents, including dosage, start and stop dates, and reason for 
use. 
Any class of medications not mentioned in Section 7.7.1, Prohibited Medications and with the 
potential to interfere with evaluation of the study treatment must be discussed and documented 
with the Medical Monitor. 


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7.7.1 Prohibited Medications 
The following drugs/therapies shall be prohibited during the study and for the timeframes 
specified below:  A subject should not have received  
• any investigational drug or device within 30 days prior to the Screening Visit (Visit 1) 
and may not receive any investigational drug or device during the entire study except 
that which is allowed by the protocol 
• Ophthalmic drugs (any topical eye medications) including prescription medication and 
OTC agents, except IP, from Visit 1 to Visit 6. 
• Contact lenses during the period from the Screening Visit (Visit 1) to the end of the 
study (Visit 6) 
• Prohibited Medications:   
o Any prior use of amiodarone 
o Within 14 days prior to study and for the duration of the study: 
 Xiidra® (lifitigrast) 
o Within 30 days prior to study and for the duration of the study:   
 Restasis® (cyclosporin ophthalmic emulsion); NOTE:  Any prior use of 
Restasis® may not have exceeded 1 month of continuous use 
 Topical ocular antihistamines 
 Ocular, inhaled or intranasal corticosteroids 
 Topical or oral mast cell stabilizers  
 Oral antihistamines 
 Topical or nasal vasoconstrictors 
 Topical ocular nonsteroidal anti-inflammatory drugs (NSAIDs) 


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 Topical ocular antibiotics 
o 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 
o 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 
o Within 90 days prior to the screening visit (Visit 1) or during the study, in the 
study eye has had cauterization of the punctum or alternations to (insertion or 
removal) punctal plug(s) or nasolacrimal surgery. Note:  If a Punctal Pug in 
place at screening visit (Visit 1) and it is dislodged during the study, the plug 
should be replaced as soon as possible 
o At screening visit (Visit 1) or any time throughout the study: 
 Chronic oral anti-viral medications for ocular herpetic disease 


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8. STUDY PROCEDURES 
8.1 
Description of Study Assessments 
8.1.1 Dry Eye Disease Activity Assessments 
The following assessments will occur as part of the evaluation of DED (See Appendix 2).  
8.1.1.1 Symptom Assessment in Dry Eye (SANDE)  
Subjects will be asked to subjectively rate the frequency and severity of their dry eye symptoms 
at Visits 2, 3, 4 and 5 using the SANDE.  The total length of the line from “rarely” to “all the 
time” (frequency of symptoms) and from “very mild” to “very severe” (severity of symptoms) 
is 100 mm. Subjects will be asked to subjectively rate the frequency and severity of their 
symptoms (OU) by placing an “X” on the relevant horizontal line. The length of the line 
between the “rarely” or “very mild” starting point and the first point where the subject’s mark 
crosses each line will be measured and recorded 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 prior to assessing for AEs and prior to any other invasive visit assessment 
(See Appendix 3).  
8.1.1.2 Visual Analogue Scale (VAS) Symptom Assessments  
Individual Symptom Severity Assessments using VAS: 
Subjects will be asked to rate their current symptoms (unrelated to study drug instillation) at 
Visits 2, 3, 4 and 5.   The following six symptoms will be evaluated:  Burning/Stinging, Foreign 
Body Sensation, Photophobia, Eye Pain, Eye Dryness, and Itching. 
The subject will be asked to subjectively rate each of six ocular symptom (OU) by placing a 
vertical mark on the horizontal line to indicate their level of discomfort. 0 corresponds to “No 
Symptoms” and 100 corresponds to “Severe Symptoms.” 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 (See Appendix 
4).  
8.1.1.3 Fluorescein Corneal Staining  
Corneal staining will be performed at Visit 2, 3, 4 and 5.  Corneal staining assessment will be 
performed using methods developed by the NEI Dry Eye Workshop (See Appendix 7). 


 
 
 
 
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Evaluation Technique 
NOTE: All steps in this procedure should be completed for the right eye (OD) prior to 
repeating the procedure for the left eye (OS). 
• Place Slit-Lamp magnification at 10x (it is acceptable to use 16x if no reticle is used) 
• Use a yellow barrier filter (Wratten or Tiffen #11 or #12)  
• Place 5 µL of non-preserved, 2% fluorescein into eye, gently touching the drop at the 
tip to the lower palpebral conjunctiva of the eye 
• In order to thoroughly mix the fluorescein with the tear film, ask the subject to blink 
several times and move his/her eye around 
• Wait 2.5 minutes to assess cornea 
• Measure staining under Cobalt blue light (465 nm to 490 nm) 
• Compare staining with the standard with scoring in each of 5 areas of the 5 corneal 
sections 
Scoring system 
• Grade each of 5 sections of cornea (superior, inferior, nasal, temporal, central) 
• Provide grades for each of the 5 sections: 
o Grade by NEI scale (definition in Appendix 7) as 0, 1 (mild), 2 (moderate), or 3 
(severe) 
• Total score is obtained by summing each of the 5 sections of the cornea 
o NEI score will be from 0-15  
(See Appendix 7). 
8.1.1.4 Unanesthetized Schirmer Test (STT) 
Schirmer Tear Test (without anesthesia) will be conducted at Visit 1 and Visit 5.  This 
procedure should be conducted 1 hour following administration of IP and at least 20 minutes 
following FCS at Visit 5: 


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Identical Schirmer strips will be supplied to each site.  When conducting assessments room 
temperature and humidity should be relatively consistent throughout each visit and throughout 
the study.  
• While still in the plastic sheath, fold the notched end of the Schirmer strip at the apex 
of the “v.”  Additionally, make a partial second fold at the halfway point of the strip so 
that the strip does not lie directly in the subject’s line of sight 
• Remove the right eye strip from the sheath 
• Ask the subject to look up and gently draw the right lower lid in a downward and 
temporal direction  
• Place the rounded end of the strip toward the temporal one-third of the lower eyelid  
• Repeat this procedure in the left eye 
• Darken the room but ensure that the largest letter(s) of a Snellen or ETDRS chart is 
visible 
• Instruct the subject to relax and look at the chart while blinking normally or have 
patients gently close eyes 
• Remove the strips after 5 minutes 
• After removing the strips, with a sharp pencil draw a horizontal line across the leading 
edge of moisture and a second horizontal line across the lowest point of moisture 
• Using a ruler and/or the millimeters recorded on the strips, measure a point halfway 
between the two lines and record this as the amount of wetting 
8.1.2 Post-Instillation Tolerability Assessments 
8.1.2.1 Drop Discomfort Assessment  
Drop discomfort will be assessed by the subject through a Drop Discomfort VAS (0-100 mm) 
where 0 corresponds to “no discomfort” and 100 corresponds to “maximal discomfort.” (See 
Appendix 1). 
At Visit 2, prior to randomization, in order to evaluate the subject’s ability to tolerate ocular 
drops, all subjects will self-administer an OTC ocular lubricant, Refresh Plus®, in both eyes. 
Upon instillation of the ocular lubricant in both eyes, subjects will be instructed by the site 
staff to rate their eye discomfort at 1- and 5- minutes post-instillation by placing a mark on the 


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Discomfort VAS. Subjects who rate OTC ocular lubricant as uncomfortable, defined as a VAS 
score ≥ 30 mm, will not be eligible for participation in the study.  These Drop Discomfort VAS 
scores will be used as the baseline values.  
At Visit 2, after randomization, a dosing coordinator will instill the IP in both eyes. Subjects 
will be instructed by a masked site staff to rate their eye discomfort at 1- and 5-minutes post-
instillation of IP as described above.   
Subjects will complete this assessment in the clinic following the AM dose of IP at Visits 2, 3, 
4 and 5 and again at home following the PM dose on the evenings of Visits 2, 3, 4 and the 
evening prior to Visit 5.   
8.1.3 Safety Assessments 
The following assessments will occur as part of the safety evaluation of the subjects: 
8.1.3.1 Best Corrected Visual Acuity (BCVA)  
BCVA will be conducted at Visit 1 and Visit 6.  Visual acuity testing should precede any 
examination requiring contact with the eye or instillation of study dyes.  LogMAR visual acuity 
must be assessed using an ETDRS or modified ETDRS chart.  Visual acuity testing should be 
performed with best correction using subject’s own corrective lenses (spectacles only) or 
pinhole refraction. 
An ETDRS or modified ETDRS chart may be used, and charts may be reflectance or 
retro-illuminated.  If a 24.5” by 25” chart is used, the subject must view the chart from exactly 
4 meters (13.1 feet).  If smaller reproductions (18” by 18”, e.g., Prevent Blindness) are used, 
the subject viewing distance should be exactly 10 feet.  Reflectance wall charts should be 
frontally illuminated (60-watt bulb or a well-lit room). 
The subject should be positioned per the elevation of the chart (either seated or standing) so 
that the chart is at a comfortable viewing angle.  The right eye should be tested first.  The 
subject should attempt to read each letter, line-by-line, left to right, beginning with line 1 at the 
top of the chart.  The subject should be told that the chart has letters only, no numbers.  If the 
subject reads a number, he or she should be reminded that the chart contains no numbers, and 
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to read slowly, about 1 letter per second, to achieve the best identification of each letter.  He/she 
is not to proceed to the next letter until he/she has given a definite response.  If the subject 
changes a response before he has read aloud the next letter, then the change must be accepted. 
Maximum effort should be made to identify each letter on the chart encouraging the subject to 
guess.  When it becomes evident that no further meaningful readings can be made, the 
examiner should stop the test.  The number of letters missed or read incorrectly should be 
noted.  (See Appendix 6). 
8.1.3.2 Ophthalmoscopy  
Dilated ophthalmoscopy exam will be performed per the Investigator’s standard procedure at 
Visit 1 and Visit 6.   
The Investigator will determine if findings are within normal limits or are abnormal.  For 
abnormal findings at Visit 1, the Investigator will determine whether the abnormality would 
exclude subject from study participation.  A clinically significant change from baseline may 
indicate an AE. 
8.1.3.3 Slit-Lamp Biomicroscopy  
The biomicroscopy exam will be performed at Visit 2 and Visit 5.  It should be performed with 
the Slit-Lamp using a beam of width and intensity to provide optimal evaluation of anterior 
segment. 
This procedure will be performed in the same manner for all subjects observed at the 
Investigator’s site (See Appendix 5). 
8.2 
Schedule of Assessments 
A detailed schedule of assessments (including all protocol-required assessments, visits, and 
visit windows) is located on the Schedule of Events (Table 1). No study-related assessments 
will be performed (including changes to current medications to meet study eligibility) until the 
subject has provided signed and dated informed consent. Every effort will be made to keep the 
subject within the requested visit schedule. If a subject is seen outside of the visit window 
listed on the Schedule of Events, the reason must be clearly documented in the source notes.  


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8.2.1 Screening Procedures 
8.2.1.1 Visit 1  
The screening visit will take place within 3 days prior to Visit 2. After obtaining informed 
consent, site staff will perform/assess the following procedures in the order below. There will 
be a collection of information including:   
• Demographics 
• Prior documented DED diagnosis 
• Ocular, general medical and surgical history 
• Concomitant medication history 
• UPT for all eligible WOCBP 
• BCVA assessment 
• Dilated ophthalmoscopy 
• Unanesthetized STT  
• Assessment of ocular lubricant self-instillation  
• Inclusion and exclusion criteria assessment: Subjects who do not meet the evaluated 
criteria will not continue participation in the study. Any subject who does not meet 
eligibility requirements will be considered a Screen Failure. 
Subjects should be reminded not to use artificial tears or any other OTC or prescription or any 
other topical eye medication except for the IP for the duration of their participation in the study. 
Subject will be scheduled to return for Visit 2 in one to three days. 
8.2.2 Treatment Procedures 
8.2.2.1 Visit 2  
Pre-Randomization 


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The site staff will perform/assess the following procedures:  
• SANDE  
• Individual Symptom Severity Assessments (VAS) 
• Concomitant medication review 
• AE assessment since last visit 
• Self-instillation of ocular lubricant and Drop Discomfort assessment (VAS) 
• Slit-Lamp biomicroscopy  
• FCS  
• Inclusion and exclusion criteria assessment. Any subject who does not meet eligibility 
requirements will be designated as Visit 2 Screen Failure and discontinued from the 
study 
Upon verification of study eligibility, subjects will be randomized to receive either VOS or 
Restasis®.   
Post-Randomization  
The following procedures will be performed after randomization:   
• IP administration: the unmasked dedicated dosing coordinator will administer the first 
dose of IP to the subject in both eyes 
Note: IP administration should not take place until at least 2 hours after administration 
of ocular lubricant. 
• Drop Discomfort assessment: A masked site staff will administer the Drop Discomfort 
VAS to the subject and instruct the subject to complete the Drop Discomfort VAS at 
1-minute and 5-minutes post-dose 
• Assess for occurrence of any AEs 
• IP dispensation: The dedicated Dosing Coordinator will dispense the IP, provide 
instructions for IP administration and storage conditions  
• Dosing Diary and VAS scales dispensation:  Train the subjects on the completion of 
the daily dosing diary and VAS scales  


 
 
 
 
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• Evening contact scheduling: Masked site staff will schedule and contact the subject in 
the evening of the clinic visit to prompt administration of the next dose and completion 
the Drop Discomfort VAS  
• Subjects should be reminded to withhold AM dose of IP on morning of next clinic visit 
and to return all used and unused IP 
Subject will be scheduled to return for Visit 3 on Day 7 ±2 days. 
PM Contact with Patient: 
• Masked site staff will call subject to prompt IP administration and will remain on call 
to facilitate completion of the Drop Discomfort VAS at 1-minute and 5-minutes post-
dose 
8.2.2.2 VISIT 3 (Treatment Day 7 ±2) 
The site staff will perform/assess the following procedures:  
• SANDE 
• Individual Symptom Severity Assessments (VAS) 
• Query the subject regarding AEs 
• Update concomitant medication use 
• AE assessment since last visit 
• Dedicated dosing coordinator will collect returned carton containing used and 
unused IP ampules 
• Dedicated dosing coordinator will collect Dosing Diary, Drop Comfort VAS and 
dispense new Dosing Diary and Drop Comfort VAS 
• Masked site staff will query the subject regarding compliance with dosing and the 
protocol. If the subject has not been compliant with the dosing regimen, record this in 
the source document and eCRF and discuss proper compliance with the subject 
• FCS 
• IP Administration:   
o The dedicated dosing coordinator will administer the AM dose of IP in the 
clinic 
• Drop Discomfort VAS: 


 
 
 
 
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o The masked site staff will administer the Drop Discomfort VAS at 1-minute 
and 5-minutes post-dose 
• Assess for occurrence of any AEs following instillation 
• Dedicated dosing coordinator will dispense IP to the subject  
• Evening contact scheduling: Masked site staff will schedule and contact the subject 
in the evening of the clinic visit to prompt administration of the next dose and 
completion the Drop Discomfort VAS   
• Remind subject to withhold AM dose of IP on morning of next clinic visit and to return 
all used and unused IP 
Schedule the subject to return in 1 week for Visit 4 on Day 14 ±2 days. 
 
PM Contact with Patient: 
• Masked site staff will call subject to prompt IP administration and will remain on 
call to facilitate completion of the Drop Discomfort VAS at 1-minute and 5-minutes 
post-dose 
 
8.2.2.3 VISIT 4 (Treatment Day 14 ±2) 
The site staff will perform/assess the following procedures: 
• SANDE 
• Individual Symptom Severity Assessments (VAS) 
• Query the subject regarding AEs 
• Update concomitant medication use 
• Dedicated dosing coordinator will collect returned carton containing used and 
unused IP ampules 
• Dedicated dosing coordinator will collect Dosing Diary, Drop Comfort VAS and 
dispense new Dosing Diary and Drop Comfort VAS. 
• Masked site staff will query the subject regarding compliance with dosing and the 
protocol. If the subject has not been compliant with the dosing regimen, record this in 
the source document and eCRF and discuss proper compliance with the subject 


 
 
 
 
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• FCS 
• IP Administration:   
o The dedicated dosing coordinator will administer the AM dose of IP in the 
clinic.  
• Drop Discomfort VAS: 
o The masked site staff will administer the Drop Discomfort VAS at 1-minute 
and 5-minutes post-dose 
• Assess for occurrence of any AEs following instillation 
• Dedicated dosing coordinator will dispense IP to the subject 
• Evening contact scheduling: Masked site staff will schedule and contact the subject 
in the evening of the clinic visit to prompt administration of the next dose and 
completion the Drop Discomfort VAS 
• Remind subject to withhold AM dose of IP on morning of next clinic visit and to return 
all used and unused IP 
Schedule the subject to return in 1 week for Visit 5 on Day 28 ±2 days.  
 
PM Contact with Patient: 
• Masked site staff will call subject to prompt IP administration and will remain on 
call to facilitate completion of the Drop Discomfort VAS at 1-minute and 5-minutes 
post-dose. 
 
8.2.2.4 VISIT 5 (End of Treatment Day 28 ± 2) 
PM Contact with Patient: (Evening Prior to Visit 5) 
• Masked site staff will call subject to prompt IP administration and will remain on 
call to facilitate completion of the Drop Discomfort VAS at 1-minute and 5-minutes 
post-dose 
 
During the visit the site staff will perform/assess the following procedures: 
• SANDE 


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• Individual Symptom Severity Assessments (VAS) 
• Query the subject regarding AEs 
• Update concomitant medication use 
• Dedicated dosing coordinator will collect returned carton containing used and 
unused IP ampules 
• Dedicated dosing coordinator will collect Dosing Diary and Drop Comfort VAS. 
• Masked site staff will query the subject regarding compliance with dosing and the 
protocol. If the subject has not been compliant with the dosing regimen, record this in 
the source document and eCRF and discuss proper compliance with the subject 
• Slit-Lamp biomicroscopy 
• FCS 
• IP Administration:   
o The dedicated dosing coordinator will administer the AM dose of IP in the 
clinic 
• Drop Discomfort VAS: 
o The masked site staff will administer the Drop Discomfort VAS at 1-minute 
and 5-minutes post-dose 
• Unanesthetized STT.  This should be performed no less than 1-hour following the 
administration of IP and at least 20 minutes following FCS 
Schedule the subject to return in 3 days for the post-treatment follow-up visit. 
8.2.3 End of Study (or Early Discontinuation) Procedures 
On completion of treatment at Day 28 or earlier if subject is discontinued/withdrawn early, all 
assessments for Visit 5 (end of study or early termination) will be completed per the 
Schedule of Events. See also Section 5.5, Withdrawal of Subjects, for further information on 
withdrawal procedures and criteria. 


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8.2.4 Follow-up Procedures 
8.2.4.1 VISIT 6 (Post-Treatment Follow-Up Day 31 ±2) 
During the visit, the site staff will perform/assess the following procedures: 
• Query the subject regarding AEs 
• Update concomitant medication use 
• UPT for WOCBP 
• BCVA 
• Dilated ophthalmoscopy 
Subjects are discharged from the study and instructed to resume their normal prior ocular 
therapy. 
 


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9. EVALUATION, RECORDING AND REPORTING OF AES AND 
SAES 
9.1 
Definitions 
9.1.1 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. 
9.1.2 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. 
9.1.3 Suspected Adverse Reaction (SAR) 
A Suspect Adverse Reaction (SAR) is any AE for which there is reasonable possibility that the 
drug caused the AE. For purposes of Investigational New Drug (IND) safety reporting, 
“reasonable possibility” means there is evidence to suggest causal relationship between the 
drug and the AE.  
9.1.4 Unexpected 
An AE or SAR is considered “unexpected” if it is not listed in the IB or is not listed at the 
specificity or severity that has been observed. 
9.1.5 Life-threatening 
An AE/SAR is considered “life-threatening” if, in the view of either the Investigator or 
Sponsor, its occurrence places the patient or subject at immediate risk of death.  It does not 
include an AE or SAR that, had it occurred in a more severe form, might have caused death. 


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9.1.6 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 which 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. 
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 informed consent form (ICF).  
9.1.7 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 suspected unexpected serious adverse reaction (SUSAR). 


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9.2 
Adverse Event Descriptors 
9.2.1 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. 
9.2.2 Causal Relationship Categorization 
An Investigator who is qualified in medicine must make the determination of relationship to 
the study treatment 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: 
 
 


 
 
 
 
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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. 
9.2.3 Outcome Categorization 
Outcome may be classified as recovered without sequelae; recovered with sequelae; improved; 
worsened; ongoing; ongoing at end of study; 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 SAE reporting form. SAEs that are ongoing at the time of death will have an outcome of 
“unknown” recorded. SAEs resulting in a fatal outcome will have an outcome of “fatal” 
recorded. 
9.2.4 Symptoms of the Disease Under Study 
Symptoms and fluctuations in laboratory parameters related to the disease under study will not 
be classed 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 or laboratory parameters, however, will be recorded as an AE and 
clearly marked as worsening or by the subject’s worst observed intensity. The Investigator will 
be required to assess the relationship to disease under study for each AE as related or not 
related. An AE will not be able to be assessed as related to both disease under study and related 
to study treatment. 
9.2.5 Abuse, Misuse, Overdose and Medication Error 
All AEs of special interest such as study treatment abuse, misuse, overdose, and medication 
error must be documented in the subject’s eCRF and source documentation. If any occurrence 


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of abuse, misuse, overdose, or medication errors leads to any event that fulfils any seriousness 
criteria, the event has to be reported as an SAE. 
9.3 
Reporting Procedure for AEs, SAEs, and Pregnancy 
9.3.1 Adverse Events 
All AEs observed from time of signing of the ICF will be recorded in the subject's source 
documentation. This applies to all AEs regardless of presumed relationship to the study drug. 
For screen failure subjects, any AEs and SAEs occurring during the screening period (after 
informed consent) will be recorded in the subject’s source documentation only and will not be 
collected on the eCRF. Adverse events leading to discontinuation of study drug must be 
collected. 
If any AE is reported, the date of onset, relationship to disease under study, relationship to 
study treatment, 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 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. 
The AE reporting period begins at the time the ICF is signed by the subject. For screen failure 
subjects, any AEs and SAEs occurring during the screening period will be recorded in the 
subject’s source documentation only. For enrolled subjects (i.e., those who successfully 
complete screening), the AE reporting period ends at the Follow-Up visit (Visit 6). 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 documents. 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 




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All SAEs, regardless of causality, will be reported from the time the ICF is signed until 30 days 
following the last study visit or 30 days after last study treatment administration in subjects 
who withdraw or discontinue prior to study completion. No formal study visit is required but 
Investigators must report any SAEs that occur during this 30-day period on the eCRF. 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. 
All recorded SAEs, regardless of relationship to disease under study or relationship to study 
treatment, 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. 
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. A rationale for the 
assessment of a causal relationship must be provided by the Investigator. The Investigator will 
also be required to assess the relationship to 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. Any safety information that is obtained after the follow-up visit 
(Visit 6) will be documented in the safety database only. 
A death occurring during the study or which comes to the attention of the Investigator within 
30 days after the last study visit (including the follow-up visit) or until 30 days after the last 
study treatment administration, whichever is longer, whether considered treatment related or 
not, must be reported to Aurinia. If the subject died, the SAE report should include the cause 
of death as the event term and whether or not the death was related to study treatment, 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. 
Additional follow-up information must be reported in the eCRF 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 
 by the reporting procedures described above. 
The Investigator is encouraged to discuss with the study Medical Monitor when the issue of 
seriousness is unclear or questionable. 


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An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAE) from the Sponsor will file it along with 
the IB and will notify the IRB/Independent Ethics Committee (IEC) if appropriate, according 
to local requirements. 
The Sponsor or its representative will be responsible for determining and, in turn, reporting 
SAEs to Regulatory Authorities according to the applicable regulatory requirements. 
9.3.3 Pregnancy 
Pregnancy occurring in a female subject or in the partner of a male subject should be reported 
to 
 within 24 hours of becoming aware of the event using the pregnancy eCRF. The 
Investigator should counsel the subject, and in the case of a male subject, the subject’s partner, 
discuss the risks of continuing with the pregnancy and the possible effects on the fetus. A 
female subject must immediately inform the Investigator if she becomes pregnant during the 
study. Monitoring of the pregnancy in a female subject should continue until conclusion of the 
pregnancy. In case of a pregnancy in the partner of a male subject, the Investigator should 
obtain informed consent of the pregnant partner prior to monitoring of the pregnancy. 
Women 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). 
All pregnancies, subject or partner of a subject, that occur during the study or come to the 
attention of the Investigator within 30 days after the last study visit (including the Follow-up 
Visit) or until 30 days after last study treatment administration, whichever is longer, must be 
reported to 
 by the reporting procedures described above. 
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 9.3.2, Serious Adverse Events.  


 
 
 
 
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In the event that the site experiences a temporary disruption of the EDC system, a back-up 
paper Pregnancy Reporting Form will be available for site staff to complete. The Investigator 
must complete, sign and date the Pregnancy form and verify the accuracy of the information 
recorded on the form with the corresponding source documents. 
• Site staff will complete the paper Pregnancy report form and e-mail it within 24 hours 
to the following address, Email: 
 
• Only in cases where the email system is unavailable, site staff will send the Pregnancy 
form by fax to: 
 
If notification is made via email or fax, site staff must enter the Pregnancy information into the 
EDC system as soon as the system becomes available. 
 


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10. STATISTICAL ANALYSIS 
10.1 Statistical Methods 
Complete details of the statistical and analytical methods will be provided in a formal 
Statistical Analysis Plan (SAP) which will be finalized prior to the database lock. A general 
description of the planned methods is provided below. Any deviation from the SAP will be 
noted and explained in the Clinical Study Report. 
All statistical analyses will be undertaken at study closure and will incorporate all endpoints. 
10.2 Sample Size and Power Calculations 
The study will include approximately 60 male or female subjects. 
The primary analysis will assess the difference in change from baseline in Drop Discomfort 
VAS scores (range 0 to 100 mm) 1-minute post-Dose 1 instillation between the two treatment 
groups.   
A sample size of 26 subjects per group (52 in total) will provide at least 90% power 
assuming: 
• A mean change from baseline Drop Discomfort VAS score of +30 mm for subjects 
randomized to Restasis® 
• A mean change from baseline Drop Discomfort VAS score of +10 mm for those 
randomized to VOS 
• A common standard deviation of 21 mm 
• A 2-sided alpha of 5% 
Under the same assumptions, the study will have at least 80% power if the common standard 
deviation for the discomfort score were to be 25. 
The study also provides 80% power should the treatment difference in discomfort scores be 
16 (common standard deviation=20). 
To allow for 15% dropouts, approximately 60 subjects will be randomized. 


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10.3 Populations 
10.3.1 Intent-to-Treat Set 
The tolerability and efficacy analysis will be based on the intent-to-treat (ITT) principles and 
will consist of all randomized subjects who receive at least 1 dose of study treatment.  
10.3.2 Per Protocol  
The per-protocol set will be a subset of subjects in the ITT population who do not have any 
major protocol violations (to be defined prior to unmasking). 
10.3.3 Safety Set 
The safety analysis will consist of all randomized subjects who receive at least 1 dose of study 
treatment. The subjects in this group will be analyzed based on the treatment they received. 
 


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10.4 Concomitant Therapy 
All concomitant medications will be coded by the World Health Organization (WHO) 
Anatomical Therapeutic Chemical Drug Reference List classification. The version used will 
be provided in the Clinical Study Report. 
10.5 Endpoint Evaluations 
10.5.1 Primary Endpoint 
The primary endpoint is the change from baseline to 1-minute post-instillation of IP in Drop 
Discomfort VAS score at Visit 2.  The baseline measure will be taken 1-minute following 
Refresh Plus® administration at least 2 hours prior to IP administration. 
10.5.2 Secondary Endpoints 
10.5.2.1 
Key Secondary/Efficacy Endpoints 
• Change from baseline in Drop Discomfort VAS score 
• Change from baseline in each of the 6 Individual Symptom Severity Assessments 
(VAS) 
• Change from baseline of the sum of the Individual Symptom Severity Assessments 
(VAS Total Symptom Summary Score)  
• Change from baseline in SANDE score  
• Change in unanesthetized STT score  
• Change from baseline in FCS total score (NEI/Industry Workshop 0-15 scale) Safety 
Endpoints 
10.5.2.2 
Safety Endpoints 
• Treatment-emergent adverse events (TEAEs) 
• Change from screening in BCVA 
• Changes from baseline in Slit-Lamp Biomicroscopy  
• Changes from screening in Dilated Ophthalmoscopy 


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10.6 Statistical and Analytical Methods 
10.6.1 Primary Analysis 
The primary endpoint is measured on a VAS and will be summarized and analyzed as 
continuous data.  Summaries of VAS scores (absolute and change from baseline) by treatment 
group will be displayed for each VAS assessment (minutes 1, 5 and overall mean) at each visit.  
Should the data meet the necessary assumptions (normality and equal variance in both 
treatment groups), then the treatment groups will be compared using a t-test.  If assumptions 
are violated, the Wilcoxon rank sum test will be used.  If needed, transformations will be 
considered in order to meet the necessary assumptions. 
10.6.2 Secondary Efficacy Analysis 
Descriptive statistical summary (sample size, mean, standard deviation, median, minimum and 
maximum) will be presented by treatment group for each endpoint.  Changes from 
randomization/baseline will be compared between VOS and Restasis® using a two-sample t-
test or the Wilcoxon rank sum test.  Further details will be addressed in the SAP. 
10.6.3 Safety Analysis 
Adverse events will be aggregated by System Organ Class and preferred term and presented 
as summary tables.  Other safety endpoints will be summarized by visit as absolute values and 
changes from baseline (as appropriate).  Endpoints with specific ranges will have counts of 
values falling outside of the range summarized by visit and overall.   
10.7 Safety Evaluations 
Safety evaluations include: 
• Treatment-emergent adverse events (TEAEs) 
• BCVA 
• Slit-Lamp Biomicroscopy  
• Dilated Ophthalmoscopy 
10.8 Interim Analyses 
No interim analyses are planned for this study. 


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10.9 Other Evaluations 
N/A 


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11. ETHICAL CONDUCT OF THE STUDY 
The study will be conducted according to the principles of the World Medical Association’s 
Declaration of Helsinki and the ICH guidelines for GCP. Aurinia will ensure that the study 
complies with all local, federal, and country regulatory requirements. 
The Investigator must ensure the confidentiality of all subjects participating in the study. 
All anonymous data remains the property of Aurinia. 
11.1 Informed Consent 
The ICF used for the study must comply with the Declaration of Helsinki, federal regulations, 
and ICH guidelines; and must have been approved by the IRB/Ethics Committee (EC)/IEC 
prior to use. The Investigator or an authorized associate must explain the nature of the study 
and the treatment in such a manner that the subject is aware of potential benefits and risks. 
Subjects must also be informed that participation is voluntary and that they may withdraw from 
the study at any time without prejudice. Subjects must be provided sufficient time to consider 
participation, including discussion with family members prior to signing the ICF. 
Documentation of the discussion and the date of informed consent must be recorded in the 
source documentation. After signing the ICF, subjects will be enrolled into the study and 
assigned a subject identification number that will be used on all subject documentation. 
11.2 Institutional Review Board or EC/IEC 
The protocol, any protocol amendments and consent form for the proposed clinical study and 
any other documents required by the local IRB/EC/IEC must be submitted by the Investigator 
for review and approval to the IRB/EC/IEC. The Investigator must also ensure that the 
IRB/EC/IEC reviews the progress of the study on a regular basis and, if necessary, renews its 
approval of the study per local requirements. 


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12. QUALITY CONTROL AND QUALITY ASSURANCE 
The Investigator must ensure that all study-related site source data, study-related documents, 
and reports will be available, and that the provision of direct access for monitoring and auditing 
by Aurinia or its designees will be permitted. In addition, the Investigator must ensure that all 
study-related site source data, study-related documents, and reports will be made available for 
inspection by the appropriate Regulatory Authority and review by the IRB/EC/IEC. 
The Investigator is responsible for notifying Aurinia in advance of an impending regulatory 
inspection. He/she may request that Aurinia provide support for preparation, if necessary. The 
Investigator is required to provide updates to Aurinia on the ongoing activities during the 
inspection, respond to any citations/objectionable findings (i.e., U.S. Food and Drug 
Administration Form 483) and to share any follow-up responses from the Regulatory 
Authority. 
Accurate and reliable data collection will be assured by verification and cross-check of the 
eCRFs against the Investigator’s records by the Study Monitor (source document verification). 
An unmasked Monitor will also review the Investigator’s drug accountability records to ensure 
that the drug supplies are stored and dispensed appropriately. A comprehensive validation 
program will verify the data and queries will be generated for resolution by the Investigator. 
Throughout the study, Aurinia or its designee may review data as deemed necessary. 


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13. ADMINISTRATIVE PROCEDURES 
13.1 Sponsor’s Responsibilities 
13.1.1 Study Supplies 
Sites will be provided with all supplies required to manage this study. This will include but not 
be limited to the following: 
• Investigator file(s) (for filing of all study-related documentation) 
• Contact list of all relevant study personnel 
• eCRF and completion guidelines (or equivalent EDC system) 
• Study reference manual 
• All study forms (e.g., SAE, Pregnancy, Drug Accountability, etc.) 
13.1.2 Insurance 
Aurinia confirms that it carries liability insurance which protects nonemployee physicians or 
Investigators/study staff against claims for which they may become liable as a result of 
damages caused by Aurinia products used in clinical studies. Insurance coverage is not 
extended to damages that the Investigators or third parties may suffer by reason of acts of 
commission or omission on the part of such Investigators or third parties and that are not in 
accordance with accepted common medical practices (lege artis procedures). Aurinia will 
reimburse the subject for all study-related injuries provided that the injury does not arise from 
the subject’s misuse of the IP or failure to follow the Investigator’s instructions. 
13.1.3 Study Monitoring 
The study will be monitored by representatives of Aurinia (or designee, which may include a 
CRO). If not monitored by Aurinia, documentation of delegation will be described in the 
Clinical Trial Agreement. It is understood that the responsible Monitor will contact and visit 
the Investigator regularly and will be allowed, on request, to inspect the various records of the 
study (eCRFs and other pertinent data) provided that subject confidentiality is maintained in 
accordance with local requirements. 
It will be the Monitor's responsibility to inspect the eCRFs at regular intervals throughout the 
study (frequency outlined in a separate procedural document), to verify the adherence to the 


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protocol and the completeness, consistency, and accuracy of the data being entered on them. 
The Monitor must have access to subject records needed to verify the entries on the eCRF. The 
Investigator (or his/her deputy) agrees to co-operate with the Monitor to ensure that any 
problems detected in the course of these monitoring visits are resolved. 
13.2 Investigator’s Responsibilities 
13.2.1 Reporting and Recording of Data 
All required study data must be entered in the eCRF created for the study. Training on the 
system will be provided to all sites, including instructions on how to address missing data, 
corrections, query procedures, and electronic signatures. Only individuals who are identified 
on the authorized signature page may enter/correct data in the eCRF. For those subjects who 
withdraw before completion of the study, all available efficacy and safety data must be entered 
in the eCRF. Incomplete or inconsistent data on the eCRF will result in data queries addressed 
to the Investigator for resolution. 
13.2.2 Investigator Training 
All Investigators and their study personnel will receive training regarding the study procedures, 
study treatments, and GCP/regulations specific to the conduct of clinical studies. This training 
will take place prior to enrollment of the first subject at the study site and must be documented 
and filed in the Investigator’s Study Site File. 
13.2.3 Source Documentation 
The Investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. 
Subject clinical source documents would include subject hospital/clinic records, physician’s 
and nurse’s notes, appointment book, original laboratory reports, signed ICFs, consultant 
letters, and subject enrollment logs. These are to be separate and distinct from eCRFs. All data 
for the study must be available in source documentation, including oral and written 
communication with the subject regarding the study treatment (including the risks and benefits 
of the study). The date of informed consent must be recorded in the source documentation. 
The Investigator must arrange for the retention of all study documentation (such as eCRFs, 
research files, and master files) for the duration specified in their respective site contract. The 
Investigator must keep these documents on file after completion or discontinuation of the study 


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according to local governing guidelines. Archived data may be held electronically, provided 
that a back-up copy exists and that a hard copy can be generated if required. 
The Investigator must inform Aurinia immediately if any documents are lost, to be transferred 
to a different facility, or to be transferred to a different owner. 


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14. PROCEDURE FOR MODIFICATION OF PROTOCOL OR 
PREMATURE TERMINATION OF THE STUDY 
14.1 Protocol Waivers, Deviations and Violations 
Protocol waivers shall not be permitted. 
The Investigator should not implement any deviation from, or changes of the protocol without 
written agreement from Aurinia and prior documented approval/favorable opinion from the 
IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) to 
study subjects, or when change(s) involves only logistical or administrative aspects of the 
study. If the Investigator must implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to study subjects without prior written approval, the 
implemented deviation or change and the reasons for it should be submitted in a timely manner 
to Aurinia and to the IRB/IEC as required by applicable local requirements. 
The Investigator, or person designated by the Investigator, will document and record the 
preventative and/or corrective measures for any deviation from the approved protocol. 
Accidental deviations from the protocol including violations of inclusion/exclusion criteria 
will be assessed as minor or major on a case-by-case basis. The criteria describing the 
deviation(s) and how they will be handled will be documented in the SAP. 
Any amendment to the protocol requires written approval/favorable opinion by the IRB/IEC 
prior to its implementation unless there are overriding safety reasons. 
In some instances, an amendment may require a change to the ICF. The Investigator must 
receive an IRB/IEC approval/favorable opinion concerning the reviewed document prior to 
administering to study subjects. 
14.2 Study Termination 
Aurinia reserves the right to terminate the study in its entirety or at a site at any time. Reasons 
for termination may include but are not limited to the following: unsatisfactory subject 
enrollment with respect to quality and/or quantity, site is unable to comply with the 
requirements of the protocol or GCP, or data recording is inaccurate and/or incomplete. 


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In terminating the study, Aurinia and the Investigator will assure that adequate consideration 
is given to the protection of the subjects. Both parties will arrange the procedures on an 
individual basis after review and consultation and in accordance with the study contract. 


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15. POLICY FOR PUBLICATION AND PRESENTATION OF DATA 
Aurinia is committed to the timely communication of data from clinical research trials, 
following the Pharmaceutical Research and Manufacturers of America principles (The 
Pharmaceutical Research and Manufacturers of America (PhrMa), Principals on Conduct of 
Clinical Trials/Communication of Clinical Trials; December 2014).  Where possible, 
authorship will be agreed at the beginning of the study. The authors will form a publication 
committee and this committee will propose and develop appropriate scientific manuscripts or 
abstracts from the study data. Investigators may not present or publish partial or complete study 
results individually. Any manuscript or abstract proposed by the Investigators must be 
reviewed and approved in writing by Aurinia before submission for publication. Names of all 
Investigators participating in the study will be included in the publication. 
The publication committee for a study will comprise of authors selected in adherence with the 
International Committee of Medical Journal Editors criteria (International Committee of 
Medical Journal Editors criteria; ICMJE.org) for authorship. If studies are multicenter, it may 
be appropriate to assign group authorship. 
In addition, certain Aurinia employees involved in the design and conception of the protocol, 
study management and data analysis and interpretation are qualified authors and will be 
included in the publication committee. 


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16. REFERENCES  
1. TFOS DEWS II Definition and Classification Report; The Ocular Surface. 2017: 276-
281.  Available at http://sx.doi.org. 
2. Aurinia Pharmaceuticals Inc. Investigator Brochure, Version 1.0  
3. S07654 – 14-Day ocular tolerability and toxicity of LX214 in New Zealand whit rabbits 
with 14-Day recovery period. Lux Biosciences, Inc.; 2009 Apr 3. Report No.: S07654. 
4. S07655 – 14-Day ocular tolerability and toxicity of LX214 in beagle dogs with 14-day 
recovery period. Lux Biosciences, Inc.; 2009 Apr 8. Report No.: S07655 
5. S08661 – Ocular tissue distribution of 14C-LX214 following a single or multiple 
ophthalmic administration to New Zealand White Rabbit. Lux Biosciences, Inc 23 Mar 
2009. Report No.: S08661. 
6. S15389-00 – To evaluate the efficacy of Voclosporin Ophthalmic Solution (0.2% 
voclosporin) in naturally occurring keratoconjunctivitis sicca in client owned dogs with 
twice-daily administration. Intervet Inc (d/b/a Merck Animal Health), 28 Apr 2017. 
Report No.: S15389-00. 
7. Chauhan S, Dana R. Role of Th17 Cells in the Immunopathogenesis of Dry Eye 
Disease. Mucosal Immunol (2009) 2(4): 375–376. 
8. DEWS Report. The definition and classification of dry eye disease.; Ocular Surface.  
2007:75-92.  Available at: 
http://www.sciencedirect.com/science/article/pii/S1542012412700812. 
9. Granelli-Piperno A, Andrus L, Steinman RM. Lymphokine and nonlymphokine mRNA 
levels in stimulated human cells: kinetics, mitogen requirements, and effects of 
cyclosporine A. J Exp Med. 1986 Apr;163:922-37 
10. Pflugfelder et al., 2008: The diagnosis and management of dry eye: a twenty-five-year 
review 
11. Stepkowski S.M. Molecular targets for existing and novel immunosuppressive drugs. 
Expert Rev Mol Med. 2000. p. 1-6. 


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12. Stevenson W, Chauhan SK, Dana R. Dry eye disease: An immune-mediated ocular 
surface disorder. Arch Ophthalmol. 2012;130(1):90-100. 
doi:10.1001/archophthalmol.2011.364. 
13. Wiseman AC. Immunosuppressive medications. Clin J Am Soc Nephrol. 2016 
Feb;11:332-43. 
14.  Xiidra® Package Insert 
 


 
 
 
 
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17. APPENDICES 
Appendix  1 Tolerability Assessment 
Drop Discomfort Assessment (Tolerability Assessment): 
Subject will rate Drop Discomfort using a VAS. Subject will complete this assessment in the 
clinic following dosing of OTC ocular lubricant at Visit 2 and in the clinic following the AM 
dose of IP at Visits 2, 3, 4 and 5 and again at home following the PM dose of IP on the evenings 
of Visits 2, 3, 4 and the evening prior to Visit 5. The assessment will be completed at 1- and 
5-minutes post-instillation of OTC ocular lubricant or IP. 
Subject Instructions:  Please rate how your eyes feel following instillation of the study drug by placing a vertical 
mark on the horizontal line. 0 corresponds to “no discomfort” and 100 corresponds to “maximal discomfort” 
You will rate your Drop Discomfort at 1 and 5 minutes following instillation of the study drug.  
 
 
Eye Discomfort 
 
0                                                                                                  100 
|                                                                                                     |        
 
 
 
 
 
 
 
 
 


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Appendix  2 EYE DRYNESS ASSESSMENTS 
The following assessments are included as a part of the overall assessment of the presence and 
severity of DED: 
• Fluorescein Corneal Staining (FCS) 
• Unanaesthetized STT 
• SANDE 
• Individual Symptom Severity Assessments  
o VAS assessments of six symptoms:  Burning/Stinging, Foreign Body 
Sensation, Photophobia, Eye Pain, Eye Dryness, Itching 
 


 
 
 
 
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Appendix  3  SANDE 
 
 
 
 


 
 
 
 
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Appendix  4  Individual Symptom Severity Assessments using VAS 
 
 
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 
|                                                                                                     |        
 
Foreign Body 
Sensation (grain of 
sand/grittiness) 
 
  0                                                                                               100 
|                                                                                                     |        
 
Photophobia 
 
  0                                                                                               100 
|                                                                                                     |        
 
Eye Pain 
 
  0                                                                                               100 
|                                                                                                     |        
 
Eye Dryness 
 
  0                                                                                               100 
|                                                                                                     |        
 
Itching 
 
  0                                                                                               100 
|                                                                                                     |        
 
 
 
 
 


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Appendix  5  Slit-Lamp Biomicroscopy 
This procedure will be the performed in the same manner for all subjects observed at the 
Investigator’s site.   
Lashes  
             
0 = Normal 
 
1 = Abnormal 
Eyelid Erythema 
 
 
0 = Normal, without any redness 
 
1 = Abnormal 
Edema  
 
  
 
  0 = Normal, no swelling of the lid tissue 
 
  1 = Abnormal 
Conjunctiva Edema 
  
  
 
  0 = Normal, no swelling of the conjunctiva 
 
  1 = Abnormal 
Cornea Infiltrates 
 
 0 = Absent 
 
 1 = Present 
Endothelial Changes 
 
 0 = Normal, None 
 
 1 = Abnormal, pigment, keratoprecipitates, guttata 
Edema 
  
 
 0 = Normal None, transparent and clear 
 
 1 = Abnormal 
Anterior Chamber Cells 
  
 0 = Normal, No cells seen 
  
 1 = Abnormal (+ to +++ cells) 


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Flare 
  
 0 = Normal, No Tyndall effect 
  
  
 1 = Abnormal, Tyndall beam in the anterior chamber 
Lens Pathology 
 
0 = Normal; no opacity in the lens 
1 = Abnormal; existing opacity in the lens; aphakic or pseudophakic eyes or 
other abnormal findings. 
Sclera Injection 
 
0 = Normal, without any redness  
 
1 = Abnormal 
 


 
 
 
 
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Appendix  6  Best Corrected Visual Acuity 
 
BCVA will be conducted at Visit 1 and Visit 6 using ETDRS.   
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 
 
 
 


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Appendix  7  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. 
 
 
 


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Appendix  8  Restasis® Package Insert 
 
 
 


 
 
HIGHLIGHTS OF PRESCRIBING INFORMATION 
These highlights do not include all the information needed to use 
RESTASIS® 0.05% safely and effectively. See full prescribing 
information for RESTASIS®. 
 
RESTASIS® (cyclosporine ophthalmic emulsion) 0.05% 
For topical ophthalmic use 
Initial U.S. Approval: 1983 
 
 
____________________________INDICATIONS AND USAGE_______________________________ 
RESTASIS® is a calcineurin inhibitor immunosuppressant indicated to 
increase tear production in patients whose tear production is presumed to be 
suppressed due to ocular inflammation associated with keratoconjunctivitis 
sicca. Increased tear production was not seen in patients currently taking 
topical anti-inflammatory drugs or using punctal plugs. (1) 
 
________________________DOSAGE AND ADMINISTRATION_________________________ 
Instill one drop of RESTASIS® ophthalmic emulsion twice a day in each eye 
approximately 12 hours apart. (2) 
 
 
 
 
 
_______________________DOSAGE FORMS AND STRENGTHS_______________________ 
Cyclosporine ophthalmic emulsion 0.5 mg/mL (3) 
 
_________________________________CONTRAINDICATIONS________________________________ 
• 
Hypersensitivity (4) 
 
_________________________WARNINGS AND PRECAUTIONS__________________________ 
• 
To avoid the potential for eye injury and contamination, be careful not to 
touch the vial tip to your eye or other surfaces. (5.1) 
 
______________________________ADVERSE REACTIONS___________________________________ 
The most common adverse reaction following the use of RESTASIS® was 
ocular burning (17%). (6.1) 
 
To report SUSPECTED ADVERSE REACTIONS, contact Allergan at 1-
800-433-8871 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 
 
 
See 17 for PATIENT COUNSELING INFORMATION. 
 
Revised: 07/2017 
 
 
FULL PRESCRIBING INFORMATION: CONTENTS* 
 
1 INDICATIONS AND USAGE 
2 DOSAGE AND ADMINISTRATION 
3 DOSAGE FORMS AND STRENGTHS 
4 CONTRAINDICATIONS 
5 WARNINGS AND PRECAUTIONS 
    5.1 Potential for Eye Injury and Contamination  
    5.2 Use with Contact Lenses  
6 ADVERSE REACTIONS 
    6.1 Clinical Trials Experience 
    6.2 Post-marketing Experience 
8 USE IN SPECIFIC POPULATIONS 
    8.1 Pregnancy 
    8.2 Lactation 
    8.4 Pediatric Use 
    8.5 Geriatric Use 
 
 
 
     
11 DESCRIPTION 
12 CLINICAL PHARMACOLOGY 
    12.1 Mechanism of Action 
    12.3 Pharmacokinetics  
13 NONCLINICAL TOXICOLOGY 
    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 
14 CLINICAL STUDIES 
16 HOW SUPPLIED/STORAGE AND HANDLING 
17 PATIENT COUNSELING INFORMATION 
 
* Sections or subsections omitted from the full prescribing information are not 
listed. 
 


 
 
FULL PRESCRIBING INFORMATION 
 
1 
INDICATIONS AND USAGE 
RESTASIS® ophthalmic emulsion is indicated to increase tear production in patients whose tear production is 
presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca. Increased tear 
production was not seen in patients currently taking topical anti-inflammatory drugs or using punctal plugs. 
 
2 
DOSAGE AND ADMINISTRATION 
Invert the unit dose vial a few times to obtain a uniform, white, opaque emulsion before using. Instill one drop 
of RESTASIS® ophthalmic emulsion twice a day in each eye approximately 12 hours apart. RESTASIS® can 
be used concomitantly with lubricant eye drops, allowing a 15-minute interval between products. Discard vial 
immediately after use. 
 
3 
DOSAGE FORMS AND STRENGTHS 
Ophthalmic emulsion containing cyclosporine 0.5 mg/mL 
 
4 
CONTRAINDICATIONS 
RESTASIS® is contraindicated in patients with known or suspected hypersensitivity to any of the ingredients in 
the formulation. 
 
5 
WARNINGS AND PRECAUTIONS 
 
5.1  
 
Potential for Eye Injury and Contamination 
Be careful not to touch the vial tip to your eye or other surfaces to avoid potential for eye injury and 
contamination. 
 
5.2  
 
Use with Contact Lenses 
RESTASIS® should not be administered while wearing contact lenses. Patients with decreased tear production 
typically should not wear contact lenses. If contact lenses are worn, they should be removed prior to the 
administration of the emulsion. Lenses may be reinserted 15 minutes following administration of RESTASIS® 
ophthalmic emulsion. 
6 
ADVERSE REACTIONS 
The following serious adverse reactions are described elsewhere in the labeling:  
• Potential for Eye Injury and Contamination [see Warnings and Precautions (5.1)] 
6.1 
Clinical Trials Experience  
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the 
clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not 
reflect the rates observed in practice. 
In clinical trials, the most common adverse reaction following the use of RESTASIS® was ocular burning 
(17%). 
 
Other reactions reported in 1% to 5% of patients included conjunctival hyperemia, discharge, epiphora, eye 
pain, foreign body sensation, pruritus, stinging, and visual disturbance (most often blurring). 
 


 
 
6.2 
Post-marketing Experience 
The following adverse reactions have been identified during post approval use of RESTASIS®. Because these 
reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably 
estimate their frequency or establish a causal relationship to drug exposure.  
 
Reported reactions have included: hypersensitivity (including eye swelling, urticaria, rare cases of severe 
angioedema, face swelling, tongue swelling, pharyngeal edema, and dyspnea); and superficial injury of the eye 
(from the vial tip touching the eye during administration).  
 
8 
USE IN SPECIFIC POPULATIONS 
 
8.1  
 
Pregnancy 
Risk Summary 
Clinical administration of cyclosporine ophthalmic emulsion 0.05% is not detected systemically following 
topical ocular administration [see Clinical Pharmacology (12.3)], and maternal use is not expected to result in 
fetal exposure to the drug. Oral administration of cyclosporine to pregnant rats or rabbits did not produce 
teratogenicity at clinically relevant doses [see Data]. 
Data 
Animal Data 
At maternally toxic doses (30 mg/kg/day in rats and 100 mg/kg/day in rabbits), cyclosporine oral solution 
(USP) was teratogenic as indicated by increased pre- and postnatal mortality, reduced fetal weight and skeletal 
retardations. These doses (normalized to body surface area) are 5,000 and 32,000 times greater, respectively, 
than the daily recommended human dose of one drop (approximately 28 mcL) of cyclosporine ophthalmic 
emulsion 0.05% twice daily into each eye of a 60 kg person (0.001 mg/kg/day), assuming that the entire dose is 
absorbed. No evidence of embryofetal toxicity was observed in rats or rabbits receiving cyclosporine during 
organogenesis at oral doses up to 17 mg/kg/day or 30 mg/kg/day, respectively. These doses in rats and rabbits 
are approximately 3,000 and 10,000 times greater, respectively, than the daily recommended human dose. 
An oral dose of 45 mg/kg/day cyclosporine administered to rats from Day 15 of pregnancy until Day 21 
postpartum produced maternal toxicity and an increase in postnatal mortality in offspring. This dose is 7,000 
times greater than the daily recommended human dose. No adverse effects in dams or offspring were observed 
at oral doses up to 15 mg/kg/day (2,000 times greater than the daily recommended human dose). 
 
8.2  
 
Lactation 
Risk Summary 
Cyclosporine is known to appear in human milk following systemic administration, but its presence in human 
milk following topical treatment has not been investigated. Although blood concentrations are undetectable 
following topical administration of RESTASIS® ophthalmic emulsion [see Clinical Pharmacology (12.3)], 
caution should be exercised when RESTASIS® is administered to a nursing woman. The developmental and 
health benefits of breastfeeding should be considered along with the mother’s clinical need for RESTASIS® and 
any potential adverse effects on the breast-fed child from cyclosporine. 
 
8.4  
 
Pediatric Use 
Safety and efficacy have not been established in pediatric patients below the age of 16. 
 


 
 
8.5  
 
Geriatric Use 
No overall difference in safety or effectiveness has been observed between elderly and younger patients. 
 
11 
DESCRIPTION 
RESTASIS® (cyclosporine ophthalmic emulsion) 0.05% contains a topical calcineurin inhibitor 
immunosuppressant with anti-inflammatory effects. Cyclosporine’s chemical name is Cyclo[[(E)-(2S,3R,4R)-3-
hydroxy-4-methyl-2-(methylamino)-6-octenoyl]-L-2-aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-
N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl] and it has the 
following structure: 
 
Structural Formula 
 
                                                
Formula: C62H111N11O12        Mol. Wt.: 1202.6 
 
Cyclosporine is a fine white powder. RESTASIS® appears as a white opaque to slightly translucent 
homogeneous emulsion. It has an osmolality of 230 to 320 mOsmol/kg and a pH of 6.5-8.0. Each mL of 
RESTASIS® ophthalmic emulsion contains: Active: cyclosporine 0.05%. Inactives: glycerin; castor oil; 
polysorbate 80; carbomer copolymer type A; purified water; and sodium hydroxide to adjust pH. 
 
12 
CLINICAL PHARMACOLOGY 
 
12.1 
 
Mechanism of Action 
Cyclosporine is an immunosuppressive agent when administered systemically. 
 
In patients whose tear production is presumed to be suppressed due to ocular inflammation associated with 
keratoconjunctivitis sicca, cyclosporine emulsion is thought to act as a partial immunomodulator. The exact 
mechanism of action is not known. 
 
12.3 
 
Pharmacokinetics 
Blood cyclosporine A concentrations were measured using a specific high pressure liquid chromatography-mass 
spectrometry assay. Blood concentrations of cyclosporine, in all the samples collected, after topical 
administration of RESTASIS® 0.05%, twice daily, in humans for up to 12 months, were below the quantitation 
limit of 0.1 ng/mL. There was no detectable drug accumulation in blood during 12 months of treatment with 
RESTASIS® ophthalmic emulsion. 
 


 
 
13 
NONCLINICAL TOXICOLOGY 
 
13.1 
 
Carcinogenesis, Mutagenesis, Impairment of Fertility  
Carcinogenesis 
Systemic carcinogenicity studies were conducted in male and female mice and rats. In the 78-week oral (diet) 
mouse study, at doses of 1, 4, and 16 mg/kg/day, evidence of a statistically significant trend was found for 
lymphocytic lymphomas in females, and the incidence of hepatocellular carcinomas in mid-dose males 
significantly exceeded the control value. 
 
In the 24-month oral (diet) rat study, conducted at 0.5, 2, and 8 mg/kg/day, pancreatic islet cell adenomas 
significantly exceeded the control rate in the low dose level. The hepatocellular carcinomas and pancreatic islet 
cell adenomas were not dose related. The low doses in mice and rats are approximately 80 times greater 
(normalized to body surface area) than the daily recommended human dose of one drop (approximately 28 
mcL) of 0.05% RESTASIS® twice daily into each eye of a 60 kg person (0.001 mg/kg/day), assuming that the 
entire dose is absorbed.  
 
Mutagenesis 
Cyclosporine has not been found to be mutagenic/genotoxic in the Ames Test, the V79-HGPRT Test, the 
micronucleus test in mice and Chinese hamsters, the chromosome-aberration tests in Chinese hamster bone-
marrow, the mouse dominant lethal assay, and the DNA-repair test in sperm from treated mice. A study 
analyzing sister chromatid exchange (SCE) induction by cyclosporine using human lymphocytes in vitro gave 
indication of a positive effect (i.e., induction of SCE). 
 
Impairment of Fertility 
No impairment in fertility was demonstrated in studies in male and female rats receiving oral doses of 
cyclosporine up to 15 mg/kg/day (approximately 2,000 times the human daily dose of 0.001 mg/kg/day 
normalized to body surface area) for 9 weeks (male) and 2 weeks (female) prior to mating. 
 
14 
CLINICAL STUDIES  
 
Four multicenter, randomized, adequate and well-controlled clinical studies were performed in approximately 
1,200 patients with moderate to severe keratoconjunctivitis sicca. RESTASIS® demonstrated statistically 
significant increases in Schirmer wetting of 10 mm versus vehicle at six months in patients whose tear 
production was presumed to be suppressed due to ocular inflammation. This effect was seen in approximately 
15% of RESTASIS® ophthalmic emulsion-treated patients versus approximately 5% of vehicle-treated patients. 
Increased tear production was not seen in patients currently taking topical anti-inflammatory drugs or using 
punctal plugs. 
 
No increase in bacterial or fungal ocular infections was reported following administration of RESTASIS®. 
 
16 
HOW SUPPLIED/STORAGE AND HANDLING 
 
RESTASIS® ophthalmic emulsion is packaged in sterile, preservative-free single-use vials. Each vial contains 
0.4 mL fill in a 0.9 mL LDPE vial; 30 or 60 vials are packaged in a polypropylene tray with an aluminum 
peelable lid. The entire contents of each tray (30 vials or 60 vials) must be dispensed intact. 
 
30 Vials 0.4 mL each - NDC 0023-9163-30 
60 Vials 0.4 mL each - NDC 0023-9163-60 
 
Storage: Store at 15°-25 °C (59°-77 °F). 


 
 
 
17 
PATIENT COUNSELING INFORMATION 
 
Handling the Container 
Advise patients to not allow the tip of the vial to touch the eye or any surface, as this may contaminate the 
emulsion. Advise patients to not touch the vial tip to their eye to avoid the potential for injury to the eye [see 
Warnings and Precautions (5.1)]. 
 
Use with Contact Lenses 
RESTASIS® should not be administered while wearing contact lenses. Patients with decreased tear production 
typically should not wear contact lenses. Advise patients that if contact lenses are worn, they should be removed 
prior to the administration of the emulsion. Lenses may be reinserted 15 minutes following administration of 
RESTASIS® ophthalmic emulsion [see Warnings and Precautions (5.2)]. 
 
Administration 
Advise patients that the emulsion from one individual single-use vial is to be used immediately after opening 
for administration to one or both eyes, and the remaining contents should be discarded immediately after 
administration. 
 
© 2017 Allergan. All rights reserved. 
All trademarks are the property of their respective owners.  
 
 
 
 
 
Patented. See www.allergan.com/patents 
Irvine, CA 92612 
Made in the U.S.A. 
 
 
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AUR-VOS-2017-01, Version 1.0 
Confidential 
12 March 2018 
Page 95 of 95 
Appendix  9  Daily Dosing Diary 
Subjects will be asked to record each day the following information related to administration 
of study drug: 
• Date 
• Time of Administration