Clinical trial NCT04498182
Conditions: Dry Eye Disease
Sponsor: Aerie Pharmaceuticals
Start date: 2020-10-26; Completion date: 2021-07-17
Enrollment: 369 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2b, multicenter, vehicle-controlled, double-masked, randomized study. All subjects enrolled will have dry eye disease. The study consists of Screening and Baseline visits to determine eligibility, followed by efficacy assessments at Day 14 (Visit 3), 28 (Visit 4) and 84 (Visit 5/Study Exit). Safety will be assessed at all study visits.

Detailed description:
At the end of the Screening Visit, all qualified subjects will be assigned to administer AR-15512 vehicle twice a day to both eyes for 14 days (vehicle run-in period). After the vehicle run-in period, subjects will be re-evaluated for signs and symptoms of Dry Eye Disease (DED). Subjects who requalify based on inclusion/exclusion criteria will be randomized in a 1:1:1 ratio to receive AR-15512 0.0014% (lower dose), AR-15512 0.003% (higher dose) or AR-15512 vehicle administered as 1 drop in each eye twice daily for 84 days.

This study will utilize a Controlled Adverse Environment (CAE) chamber, which serves to (1) minimize the factors that could impact the evaluation (temperature, humidity, and airflow) and (2) stress the ocular surface in a safe, standardized, controlled, and reproducible manner. Subjects will be exposed to the CAE for approximately 90 minutes during each CAE visit. Subjects will be exposed to the CAE at the Screening and Baseline visits as well as on Day 28 (Visit 4) and Day 84 (Visit 5). Efficacy endpoints will be evaluated pre- and post- exposure to the CAE.

Aerie Pharmaceuticals was acquired by Alcon on November 22, 2022.

Arms: arm 1: AR-15512 Ophthalmic Solution 0.003%, one drop in each eye twice daily for 84 days. Both eyes will be treated. arm 2: AR-15512 Ophthalmic Solution 0.0014%, one drop in each eye twice daily for 84 days. Both eyes will be treated. arm 3: AR-15512 Ophthalmic Solution Vehicle, one drop in each eye twice daily for 84 days. Both eyes will be treated.
Interventions: intervention 1: AR-15512 Ophthalmic Solution intervention 2: AR-15512 Ophthalmic Solution Vehicle
Intervention descriptions: intervention 1: Ophthalmic solution administered via topical ocular instillation in one of two dose concentrations: 0.0014% (lower dose) or 0.003% (higher dose) intervention 2: Ophthalmic solution vehicle administered via topical ocular instillation

Protocol documents:
Prot_000.pdf: 














 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 


 
 





























































































































































































SAP_001.pdf: 
 
 
 
 
 
A Phase 2b Study Evaluating the Safety and Efficacy of 
AR‐15512 Ophthalmic Solution for the Treatment of Dry 
Eye Disease ( COMET‐1 ) 
 
 
STUDY ID: 
AR‐15512‐CS201 
 
Statistical Analysis Plan v1 
August 12, 2021 
 
 
NCT04498182 


Aerie Pharmaceuticals, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AR-15512-CS201
12Aug2021
Version 1.0 
 
Page 1 of 42 
  
STATISTICAL ANALYSIS PLAN 
Version 1.0 
 
August 12,  2021  
 
 
 
 
 A Phase 2b Study Evaluating the Safety and Efficacy of AR-15512 
Ophthalmic Solution for the Treatment of Dry Eye Disease (COMET-1) 
 
 
PROTOCOL NUMBER AR-15512-CS201 
 
 
SPONSORED BY 
 
Aerie Pharmaceuticals, Inc. 
550 Hills Drive, 3rd Floor 
Bedminster, NJ 07921 
 
 
 
 
PREPARED BY 
 
Statistics & Data Corporation 
63 South Rockford Drive, Suite 240 
Tempe, AZ 85281 
Telephone: (480) 632-5468 
Fax: (480) 632-5469 
 
 
 
 
 This document contains Aerie Pharmaceutic
proprietary in nature. It is loaned to you for your confidential use on behalf of Aerie and is not to be photocopied, 
disclosed or transmitted to any other person or party who is not covered by a Confidential Disclosure Agreement 
with Aerie. 


Aerie Pharmaceuticals, Inc. 
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Statistical Analysis Plan 
Protocol No. AR-15512-CS201
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Protocol No. AR-15512-CS201
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ....................................................................................................... 5 
1. 
PURPOSE OF THE ANALYSES ......................................................................................... 6 
2. 
PROTOCOL SUMMARY ..................................................................................................... 7 
2.1 Study Objectives .............................................................................................................. 7 
2.2 Overall Study Design and Plan ........................................................................................ 7 
2.3 Study Population .............................................................................................................. 8 
2.4 Treatment Regimens ........................................................................................................ 8 
2.5 Treatment Group Assignments or Randomization ........................................................... 8 
2.6 Sample Size Determination .............................................................................................. 9 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS ..................................... 10 
4. 
ANALYSIS POPULATIONS .............................................................................................. 11 
4.1 Intent-to-Treat Population (ITT) .................................................................................... 11 
4.2 Per-Protocol Population (PP) ......................................................................................... 11 
4.3 Safety Population ........................................................................................................... 11 
4.4 Vehicle Run-in Population ............................................................................................. 11 
5. 
STUDY SUBJECTS ............................................................................................................. 12 
5.1 Disposition of Subjects ................................................................................................... 12 
5.2 Protocol Deviations ........................................................................................................ 12 
6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .......................... 13 
6.1 Demographics and Baseline Characteristics .................................................................. 13 
6.2 Prior and Concomitant Medications ............................................................................... 13 
6.3 Medical and Ocular History ........................................................................................... 13 
7. 
MEASUREMENTS OF TREATMENT COMPLIANCE ................................................ 14 
8. 
EFFICACY EVALUATION ............................................................................................... 15 
8.1 Efficacy and Tolerability Assessments .......................................................................... 15 
8.1.1 
Symptom Questionnaire (Visual Analog Scale (VAS)) .................................... 15 
8.1.2 
Symptom Assessment in Dry Eye (SANDE) Questionnaire ............................. 15 
8.1.6 
Anesthetized Schirmer Test .............................................................................. 16 
8.2 Efficacy Variables and Primary Hypotheses .................................................................. 20 
8.3 Overview of Efficacy Analysis Issues ............................................................................ 27 


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8.3.1 
Handling of Dropouts or Missing Data ............................................................. 27 
 
 
9. 
SAFETY EVALUATION .................................................................................................... 33 
9.1 Overview of Safety Analysis Methods ........................................................................... 33 
9.2 Extent of Study Treatment Exposure ............................................................................. 33 
9.3 Adverse Events ............................................................................................................... 33 
9.4 Intraocular Pressure ........................................................................................................ 34 
9.5 Best Correct Visual Acuity............................................................................................. 34 
9.6 Dilated Fundus Examination .......................................................................................... 34 
9.7 Slit-Lamp Biomicroscopy .............................................................................................. 35 
 
11. INTERIM ANALYSES AND DATA MONITORING ..................................................... 37 
12. CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL ........................... 38 
13. REFERENCES ..................................................................................................................... 39 
14. APPENDICES ...................................................................................................................... 40 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
ATC 
Anatomical Therapeutic Chemical 
BCVA 
Best Corrected Visual Acuity 
BID 
Twice Daily 
CAE 
Controlled Adverse Environment  
CI 
Confidence Interval 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
DED 
Dry Eye Disease 
EDS 
Eye Dryness Score 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IOP 
Intraocular Pressure 
ITT 
Intent-to-Treat 
IWRS 
Interactive Web Response System 
LOCF 
Last Observation Carried Forward 
logMAR 
Logarithm of the Minimum Angle of Resolution 
 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
NEI 
National Eye Institute 
OCT 
Optical Coherence Topography 
ODS
Ocular Discomfort Score 
PDF
Portable Document Format 
PP
Per-Protocol
PT
Preferred Term
RTF
Rich Text Format
SANDE
Symptoms Assessment in Dry Eye
SAP
Statistical Analysis Plan
SD
Standard Deviation
SDC
Statistics & Data Corporation
SOC
System Organ Class 
 
TEAE
Treatment-Emergent Adverse Event
 
 
VAS
Visual Analogue Scale
WHO
World Health Organization


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1. PURPOSE OF THE ANALYSES 
This statistical analysis plan (SAP) is in support of the Aerie Pharmaceuticals, Inc., protocol 
number AR-15512-CS201 (Amendment 4 dated 2 April 2021 and, if applicable, any subsequent 
amendments prior to study completion), finalized before any analyses of the data.  The SAP 
contains detailed information to aid in the performance of the statistical analysis and reporting of 
the study data for use in the final clinical study report (CSR).  This SAP was written with due 
consideration of the recommendations outlined in the most recent International Conference on 
Harmonization (ICH) E9 Guideline entitled: Statistical Principles for Clinical Trials and the most 
recent ICH E3 Guideline entitled: Structure and Content of Clinical Study Reports. 
This SAP describes the data that will be analyzed and the subject characteristics, efficacy, and 
safety assessments that will be evaluated.  This SAP provides details of the specific statistical 
methods that will be used.  If additional analyses are required to supplement the planned analyses 
described in this SAP, they may be completed and will be identified in the CSR. 
 


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2. PROTOCOL SUMMARY 
2.1 
Study Objectives 
The primary objective of this study is to evaluate the safety, tolerability and efficacy of 2 doses 
(0.0014% and 0.003%) of topical ophthalmic AR-15512 compared to its vehicle dosed twice 
daily (BID) in subjects with dry eye disease (DED).  
  
2.2 
Overall Study Design and Plan 
This will be a Phase 2b, multicenter, vehicle-controlled, double-masked, randomized study 
conducted at approximately 15 sites in the United States. All subjects enrolled will have DED. 
The study will consist of Screening and Baseline visits as well as follow-up visits at Day 14 
(Visit 3), 28 (Visit 4) and 84 (Visit 5 / Study Exit). All subjects will be exposed to the Controlled 
Adverse Environment (CAE®) at the Screening, Baseline, Day 28 and Day 84 visits. A summary 
of the overall study design is found in Figure 1.  
 
Figure 1 Study Design 
 
 
 
At the end of the Screening Visit, all qualified subjects will be assigned to administer study 
vehicle BID to both eyes for 14 days (vehicle run-in period). After the vehicle run-in period, 


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subjects will be re-evaluated for signs and symptoms of DED. Only subjects who requalify, 
based on inclusion/exclusion criteria, will be enrolled in the study and randomized at a 1:1:1 
ratio within each site, to receive AR-15512 0.0014%, AR-15512 0.003% or AR-15512 vehicle to 
be administered as 1 drop in each eye twice daily for 84 days. Efficacy will be assessed on 
Visit 3 without use of the CAE and at Visits 4 and 5 pre-, during and post- use of the CAE. 
Safety assessments will be conducted at each study visit. At the end of Study Visit 5, the subject 
will exit the study. A summary of all study assessments per visit can be found in Appendix 1 
(Schedule of Visits and Procedures). 
 
2.3 
Study Population 
This study is anticipated to enroll approximately 360 subjects with DED as defined in Protocol 
Sections 4.2 and 4.3 so that approximately 324 subjects complete Day 84. The anticipated 
dropout rate is 10%. To achieve this goal, approximately 1500 subjects may be screened.  
 
2.4 
Treatment Regimens 
There will be 3 treatments in this study: 
 AR-15512 ophthalmic solution, 0.0014%   
 AR-15512 ophthalmic solution, 0.003% 
 Vehicle (Placebo)  
 
Subjects who qualify at the Screening visit will be instructed on proper administration procedure to 
administer 1 drop of AR-15512 vehicle BID to both eyes on Days -14 to -1 (vehicle run-in period). 
Note: If absolutely necessary, the vehicle run-in period may be extended to a maximum of 21 days 
per protocol.   
 
Subjects will be re-instructed on proper administration procedures at the Baseline Visit. Subjects 
will be instructed to administer their randomized study treatment BID to both eyes as follows: 1 
drop in each eye in the morning (from approximately 7:00h to 10:00h) and 1 drop in each eye in 
the evening (from approximately 19:00h to 22:00h).  
 
2.5 
Treatment Group Assignments or Randomization 
A randomization code for allocating the treatments was prepared by an independent 
biostatistician, who was not involved in the day-to-day conduct of the study and provided in 
confidence to the unmasked clinical supply manager at Aerie and the Interactive Response 
Technology personnel.   
All subjects will be centrally assigned to randomized study treatment using an interactive web 
response system (IWRS). Before the study is initiated, the log-in information and directions for 
the IWRS will be provided to qualified personnel at each site.  


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All qualified subjects will be assigned to receive AR-15512 vehicle BID to both eyes for 14 days 
(vehicle run-in period). Following the run-in period, all subjects who requalify at the Baseline 
visit (Day 1 [Visit 2]), will be randomized in a 1:1:1 ratio, within each site, to receive AR-15512 
0.0014% : AR-15512 0.003% : Vehicle. The IWRS will provide the site with the specific packer 
number(s) for each randomized subject at the time of randomization. Sites will dispense the 
study treatment according to the IWRS instructions. 
2.6 
Sample Size Determination 
One hundred and eight (108) subjects (study eyes) per treatment group yields 90% power to 
reject H01 in favor of H11 and H03 in favor of H13 and conclude superiority of AR-15512 (0.003% 
or 0.0014%) over vehicle in the mean change from baseline in pre-CAE Ocular Discomfort score 
(ODS) Visual Analog Scale (VAS) at Day 28, assuming a true difference (AR-15512 minus 
vehicle) of -8.5, a common standard deviation (SD) of 19.0, and a two-sided alpha = 0.05.  
Additionally, 108 subjects (study eyes) per treatment group yields 90% power to reject H02 in 
favor of H12 and H04 in favor of H14 and conclude superiority of AR-15512 (0.003% or 0.0014%) 
over vehicle in the mean change from baseline in pre-CAE anesthetized Schirmer score at Day 
28 assuming a true difference (AR-15512 minus vehicle) of 1.4 mm, a common SD of 3.15 mm, 
and a two-sided alpha = 0.05.  
Accounting for subject discontinuations, approximately 360 total subjects (120 per treatment 
arm) will be randomized assuming a dropout rate of 10%.  


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3. GENERAL ANALYSIS AND REPORTING CONVENTIONS 
This section discusses general policies to be employed in the analysis and reporting of the data 
from the study.  Departures from these general policies may be given in the specific detailed 
sections of this SAP.  When this situation occurs, the rules set forth in the specific section take 
precedence over the general policies. 
All continuous study assessments will be summarized by treatment and time point (as applicable) 
using descriptive statistics (n, mean, median, SD, minimum, and maximum).  All categorical 
study assessments will be summarized by treatment and time point (as applicable) using 
frequency counts and percentages.   
Hypothesis testing, unless otherwise indicated, will be performed at a two-sided 0.05 
significance level. Where applicable, two-sided 95% confidence intervals (CIs) will be reported.  
All p-values will be displayed to four decimal places, with p-values less than 0.0001 presented as 
<0.0001  and p-values greater than 0.9999 presented as >0.9999    
Differences between AR-15512 and vehicle will be calculated as AR-15512  vehicle.
Baseline is defined as the last measurement prior to the first dose of investigational product (after 
randomization). Change from baseline will be calculated as follow-up visit  baseline visit. 
The unit of analysis for efficacy will be the study eye. 
All study data will be listed by subject, treatment, and time point (as applicable).  In the listings, 
individual subjects will be identified by a combination of site number and subject number, e.g., 
XXX-YYY, where XXX is the site number and YYY is the subject number.  
All data analysis will be performed by Statistics & Data Corporation (SDC) after the study is 
completed and the database has been locked and released for un-masking.  Statistical 
programming and analyses will be performed using SAS  Version 9.4 or higher.  Output will be 
provided in rich text format (RTF) for tables and portable document format (PDF) for tables, 
listings, and figures.   
Study Eye Criteria 
 
Safety endpoints will be analyzed for both eyes. For efficacy endpoints, the unit of analysis will 
 (where applicable) as defined by the following: 
 
The study subject must have one eye (the same eye) meeting all the inclusion criteria (Protocol 
Section 4.2) and none of the exclusion criteria (Protocol Section 4.3). Study subjects will be 
dosed in both eyes. If both eyes are eligible at the time of randomization, the study eye will be 
defined as the eye with the higher pre-CAE Ora Calibra® ODS at the Baseline visit. If both eyes 
qualify and have the same pre-CAE Ora Calibra® ODS, then study eye will be defined as the eye 
with the lowest anesthetized Schirmer score at the Baseline visit. If both eyes still qualify, the 
right eye will be designated as the study eye. 
 


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4. ANALYSIS POPULATIONS 
4.1 
Intent-to-Treat Population (ITT) 
The ITT population will include all randomized subjects. Subjects in the ITT population will be 
analyzed as randomized. The primary efficacy analysis will be performed on the ITT population. 
 
4.2 
Per-Protocol Population (PP) 
The PP population is a subset of the ITT population that do not have significant protocol 
deviations and who complete the trial through Day 28. Protocol deviations will be assessed prior 
to database lock and unmasking. The PP population will be analyzed using observed data only 
for efficacy variables. Subjects in the PP population will be analyzed as treated. 
 
4.3 
Safety Population 
The Safety population will include all randomized subjects who have received at least one dose 
of the investigational product (after randomization).  This population will be used to summarize 
safety variables. Subjects in the Safety population will be analyzed as treated. 
 
4.4 
Vehicle Run-in Population   
The vehicle run-in population will include all subjects who have received at least one dose of 
vehicle in the run-in period.  


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5. STUDY SUBJECTS 
5.1 
Disposition of Subjects 
Screen failures, subjects enrolled (i.e. subjects who entered the vehicle run-in period), subjects 
randomized, analysis populations, study completion, and withdrawal from the study will be 
summarized.  The summary table will include screen failures, the number of subjects enrolled, 
the number of subjects randomized and included in the analysis populations by randomized 
treatment group for the ITT population and by actual treatment group for the PP and Safety 
populations.  It will also include the numbers of subjects who completed and discontinued from 
the study.  The reasons for subject discontinuation and test agent discontinuation will be 
summarized for the applicable subjects.  Reasons for subject discontinuation will include adverse 
event (AE), withdrawal of consent, non-compliant, lost to follow-up, lack of efficacy, disallowed 
concurrent medication, investigator decision, protocol violation, death, and other.  
5.2 
Protocol Deviations 
Protocol deviations will be evaluated for all subjects. Major protocol violations will be judged by 
a masked evaluation prior to the unmasking of the study treatment, for the purpose of selecting 
the PP population. All protocol deviations will be in a subject data listing. The number and 
percentage of subjects with any deviations, any major or minor deviations, related to COVID-19 
will be summarized by treatment group along with the disposition data. A separate data listing 
for COVID-19 related protocol deviations will be provided. 


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6. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
6.1 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by treatment group for the safety 
population and listed for all subjects.  Demographic parameters will include sex assigned at birth, 
iris color, age in years at signing of informed consent form (ICF), race, and ethnicity.  Baseline 
characteristics will include pre-CAE assessments scores of ODS-VAS, eye dryness (EDS) VAS, 
ocular pain-VAS and global SANDE as well as study eye scores for anesthetized Schirmer score 
   
6.2 
Prior and Concomitant Medications 
All prior and concomitant medications will be coded to preferred drug names and therapeutic 
drug class using the World Health Organization (WHO) Drug Dictionary (B3, March 2020). 
Prior medications are defined as medications used in the 90 days prior to first dose date of the 
investigational product (i.e. prior to randomization). Concomitant medications are defined as 
medications used on or after the first dose date of the investigational product (i.e. after 
randomization).  Use of prior and concomitant medications will be summarized by Anatomical 
Therapeutic Chemical (ATC) level 4 drug class, preferred drug name, and treatment group for 
the safety population.  Subjects will be counted only once under each drug class and preferred 
term for which they have used at least one concomitant medication. All prior and concomitant 
medication data will also be listed.   
6.3 
Medical and Ocular History 
All medical history and ocular history data will be presented in a by-subject listing.  Medical and 
ocular history will be coded to preferred term (PT) and system organ class (SOC) using the 
Medical Dictionary for Regulatory Activities (MedDRA) Dictionary (Version 23.0).  Medical 
and ocular histories will be summarized for each SOC and each PT by treatment group for the 
safety population.  Subjects will be counted only once under each SOC and PT for which they 
have at least one medical/ocular history.  


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7. MEASUREMENTS OF TREATMENT COMPLIANCE 
For Visit 1, the morning dose will be administered in clinic by the subject under supervision 
from site personnel. For Visits 2, 3 and 4, the second dose will be administered by designated 
site personnel; all other doses will be administered by the subject. 
In-between office visits, study compliance will be monitored by counting the number of used and 
l be 
collected at each visit from Visit 2 up to and including Visit 5 to assess dosing compliance. 
Dosing compliance will be based off the used and unused vial count. If the subject is less than 
80% or more than 125% compliant with dosing based on the expected number of used and 
unused vials, then the subject will be deemed non-compliant and a deviation should be recorded. 
Treatment compliance will be reported on the electronic case report form (eCRF) and listed in a 
subject data listing.  


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8. EFFICACY EVALUATION 
8.1 
Efficacy and Tolerability Assessments 
8.1.1 
Symptom Questionnaire (Visual Analog Scale (VAS)) 
Subjects will be asked to rate each of the following DED symptoms (both eyes together), 
over the last 24 hours (pre-
-CAE), each on a separate 
VAS: ocular discomfort (ODS), eye dryness (EDS), ocular pain (OP). For each VAS, 
subjects will be asked to place a vertical mark on the horizontal line to indicate the level 
 to 
 of the scale will be 100 mm and will be 
similar to the following depiction for ocular discomfort. 
While in the CAE, subjects will be reassessed at 5-minute intervals on only the ODS-
VAS based on how they fe
 
8.1.2 
Symptom Assessment in Dry Eye (SANDE) Questionnaire 
The SANDE questionnaire (Schaumberg 2007) is comprised of 2 unique VAS scales to 
assess the frequency and severity of DED symptoms, with each scale being 100 mm. 
Higher scores indicate greater frequency or severity.  
The Global SANDE score will be calculated by multiplying the frequency score by the 
severity score and obtaining the square root. The final value must be rounded to the 
nearest whole number.  


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8.1.6 
Anesthetized Schirmer Test 
Topical anesthetic drops such as 0.5% proparacaine hydrochloride or equivalent should 
be instilled in both eyes of the subject. The subject will be instructed to keep the eyes 
gently closed for 1 minute. After opening the eyes and allowing the eyes to recover for 
approximately 1 additional minute, excess moisture in the inferior fornix can be gently 
middle and lateral thirds of the lower eye lid. Under ambient light, the subject will be 
instructed to look forward and to blink normally during the course of the test. The timer 
ips should 
remain in place until 5 minutes have elapsed or both strips have reached maximum score. 
After 5 minutes, strips will be removed from both eyes and the amount of wetting will be 
recorded. As the tear front may continue advancing a few millimeters after it has been 
removed from the eyes, it is important to read the tear front immediately after removal. 
Only whole numbers are to be recorded, rounding up to the nearest whole number if the 
tear front is at or greater than the half millimeter mark. 


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8.2 
Efficacy Variables and Primary Hypotheses 
1. 
The co-primary efficacy endpoints will be the comparisons of AR-15512 0.003% to 
vehicle and AR-15512 0.014% to vehicle for: 
 Change from baseline in pre-CAE ODS-VAS at Day 28 
 Change from baseline in pre-CAE anesthetized Schirmer score at Day 28 
 
2. 
Secondary efficacy endpoints will include the comparisons of AR-15512 0.003% to 
vehicle and AR-15512 0.014% to vehicle for:  
1. Mean pre-CAE ODS-VAS at Day 28 
2. Change from baseline in pre-CAE ODS-VAS at Day 84 
3. Mean pre-CAE ODS-VAS at Day 84 
4. Change from baseline in pre-CAE anesthetized Schirmer score in study eyes at Day 
84 
5. Mean pre-CAE anesthetized Schirmer score in study eyes at Day 84 
6. Mean pre-CAE anesthetized Schirmer score in study eyes at Day 28 
7. Change from baseline in pre-CAE Pain VAS at Day 84 
8. Mean pre-CAE Pain-VAS at Day 84 
9. Change from baseline in pre-CAE Pain-VAS at Day 28 
10. Mean pre-CAE Pain-VAS at Day 28 


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11. Change from baseline in post-CAE Pain VAS at Day 84 
12. Mean post-CAE Pain-VAS at Day 84 
13. Change from baseline in post-CAE Pain VAS at Day 28 
14. Mean post-CAE Pain-VAS at Day 28 
15. Change from baseline in pre-CAE Global SANDE at Day 28 
16. Mean pre-CAE Global SANDE at Day 28 
17. Change from baseline in pre-CAE Global SANDE at Day 84 
18. Mean pre-CAE Global SANDE at Day 84 
19. Change from baseline in pre-CAE Eye Dryness (EDS)-VAS at Day 28 
20. Mean pre-CAE EDS-VAS at Day 28 
21. Change from baseline in pre-CAE Eye Dryness (EDS)-VAS at Day 84 
22. Mean pre-CAE EDS-VAS at Day 84 
23. Change from baseline in pre-CAE ODS-VAS at Day 14 
24. Change from baseline in pre-CAE Ora Calibra® ODS in study eyes at Day 28 
25. Change from baseline in pre-CAE Ora Calibra® ODS in study eyes at Day 84 
26. Mean pre-CAE ODS-VAS at Day 14 
27. Change from baseline in pre-CAE Pain VAS at Day 14 
28. Mean pre-CAE Pain-VAS at Day 14 
29. Change from baseline in pre-CAE Global SANDE at Day 14 
30. Mean pre-CAE Global SANDE at Day 14 
31. Change from baseline in pre-CAE EDS VAS at Day 14 
32. Mean pre-CAE EDS-VAS at Day 14 
33. Proportion of subjects wi
in study eyes at Day 84 
34. Proportion of subjects with baseline a
in study eyes at Day 28 
35. Proportion of subjects that achieved at least a 10 mm increase in pre-CAE 
anesthetized Schirmer score relative to baseline in study eyes at Day 28 
36. Proportion of subjects that achieved at least a 10 mm increase in pre-CAE 
anesthetized Schirmer score relative to baseline in study eyes at Day 84  


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8.3 
Overview of Efficacy Analysis Issues 
8.3.1 Handling of Dropouts or Missing Data 
The primary analysis will be completed with available data per subject from the ITT population, 
assuming the overall study discontinuation rate is <5%. If the overall study discontinuation rate is 
 the primary multiple imputation methodology and 
the available data analyses will become robustness analyses. 


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8.3.2 Assessment Time Windows 
In general, it is intended that all safety and efficacy data (with some exceptions) will be 
summarized at each scheduled time point collected regardless of assessment time windows.  
Because subjects may have an early termination visit at any time or may have unscheduled visits, 
the following conventions will be implemented. 
For all by-visit statistical summaries, safety and efficacy data collected at early termination visits 
will be windowed into a scheduled study visit if the early termination visit falls within a protocol 
specified visit window. Visit 2 (Day 1) has to be on Day 1. Visit 3 (Day 14) and Visit 4 (Day 28) 
have a ± 2-day window. Visit 5 (Day 84) has -5/+2 day window. Unscheduled visits and early 
termination visits falling out of protocol specified scheduled visit windows will be excluded 
from summaries.   


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8.4 
Analysis Methods 
8.4.1 Primary Efficacy Analyses 
The primary comparisons in this trial will be between AR-15512 (0.003%) and vehicle with 
hierarchical analyses between AR-15512 (0.0014%) and vehicle at Day 28 in the ITT population 
 Population: subjects with DED defined through enrollment criteria  
 Endpoint:  
o Change from baseline in pre-CAE ODS-VAS at Day 28 
o Change from baseline in pre-CAE anesthetized Schirmer score at Day 28 


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The primary efficacy endpoints (e.g., change from baseline in pre-CAE ODS-VAS and change 
from baseline pre-CAE anesthetized Schirmer score) will be summarized using continuous 
summary statistics and analyzed separately using analysis of covariance (ANCOVA) models 
with terms for baseline value, treatment, and analysis center. In addition, the analysis center by 
treatment interaction will be explored in a separate model to evaluate how the treatment effect 
may differ across analysis centers for the ITT population using available data. 
 
Least squares mean for each treatment group and for the difference between treatment groups 
will be presented from the model together with two-sided p-values and 95% CIs.  


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8.4.2 Secondary Efficacy Analyses 
The secondary efficacy endpoints are listed in Section 8.2. The summaries and analyses of 
secondary efficacy endpoints will be conducted for the ITT population.  
 
Summarization and analysis of secondary endpoints #1-30 (please refer to Section 8.2) will be 
completed using a similar strategy as for the primary endpoints. 
 
Testing of the proportion of subjects with baseline ane
 mm at Day 84 and Day 28 (#31 and #32, 
respectively) will be completed using logistic regression modes with fixed effects of treatment, 
corresponding baseline measure, and analysis center using available data, missing data imputed 
using LOCF, trimmed means, and MCMC multiple imputation methodology under assumption 
of missing (at random and not at random). The adjusted odds ratios and marginal proportions and 
difference in proportions along with corresponding two-sided 95% CIs and p-values will be 
presented. Treatment comparisons will also be made using Pe
-
exact test if any of the cell counts are less than five as a sensitivity analysis to the primary model 
above and p-values will be provided. 


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9. SAFETY EVALUATION 
9.1 
Overview of Safety Analysis Methods 
All safety analyses will be carried out using the Safety Population and will include the study eye 
and fellow eye separately, where applicable.  
The assessment of safety will be evaluated by: 
 Adverse events 
 Slit-lamp biomicroscopy 
 Dilated fundus exam  
 Best Corrected Visual Acuity (BCVA) 
 Intraocular pressure (IOP) 
 
All safety variables will be descriptively summarized by treatment group at each assessment time 
and for relevant changes from baseline, where applicable. 
For complete inclusion of subjects who withdraw from the study early, the End of Study visit for 
safety outcomes will be defined as either Visit 5 (Day 84) or Early Discontinuation.   
9.2 
Extent of Study Treatment Exposure 
Summary statistics will be presented for treatment exposure.  Treatment exposure will be defined 
as the number of days that the subject was exposed to study treatment as calculated using the 
formula:  
Treatment exposure = Date of Last Dose  Date of First Dose + 1. 
9.3 
Adverse Events 
Adverse events will be coded to SOC and PT using MedDRA, Version 23.0.  
Treatment-emergent adverse events (TEAEs), those that occur on/after the first dose of assigned 
study treatment (i.e. during the randomized treatment period) at subject level, will be 
summarized by treatment group using frequencies and proportions for each SOC and each PT 
within a SOC.  
Adverse events occurring during the vehicle run-in period will also be summarized.  
The number and percentages of subjects with TEAEs (with onset during the randomized 
treatment period) listed below will be summarized by SOC, PT, and treatment separately. An 
overall summary table will be also developed to report the number of events and the incidence of 
subjects having at least one event in the categories below.   
 TEAEs 
 Serious TEAEs  


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 Treatment-Related SAEs (reported as possibly related or related to the investigational 
product) 
 TEAEs by strongest relationship 
 TEAEs by maximum severity 
 TEAEs leading to investigational product discontinuation 
 TEAEs resulting in death 
While the overall summary of TEAEs with onset during randomized treatment period will 
present both the number of TEAEs and the incidence of TEAEs, the other summaries will only 
report the incidence of TEAEs.  When reporting the number of TEAEs, if the same TEAE occurs 
for a subject on multiple occasions the event will be counted once for each occurrence.  When 
reporting the incidence, a subject will only be counted once if they ever experience an event 
within the SOC and ever experience the individual PT.  Summaries will be performed using the 
actual treatment received. Separate summaries will be performed for ocular and non-ocular AEs. 
AEs that occurred during the vehicle run-in period will also be summarized by SOC and PT for 
the vehicle run-in population. 
All AEs, serious AEs, and AEs leading to investigational product discontinuation will be listed in 
subject data listings separately.  
 
9.4 
Intraocular Pressure 
Intraocular pressure will be presented in data listings. Intraocular pressure data will be 
summarized at each visit using continuous summaries, including change from baseline, for both 
the study eye and the fellow eye.  
9.5 
Best Correct Visual Acuity 
The BCVA logarithm of the minimum angle of resolution (logMAR) score will be presented in 
data listings. BCVA data will be summarized at each visit using continuous summaries, 
including change from baseline, for both the study eye and the fellow eye. Additionally, discrete 
summaries of the worst change from baseline will be presented for both the study eye and the 
fellow eye with the following groupings based on the logMAR scores: 0 or less, >0 to +0.09, 
+0.10 to +0.19, +0.20 to 0.29, +0.30 or more.   
9.6 
Dilated Fundus Examination 
Dilated fundus exam results at each visit will be presented in data listings. A separate listing will 
 
 
 
Clinically Significant.  
Frequencies and percentages of normal and abnormal results will be created for the following 
fields: Vitreous, Retina, Macula, Choroid, and Optic Nerve. Abnormal results will further be 


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broken down by clinical significance and non-clinical significance. A shift from baseline in the 
results for study eyes and fellow eyes will also be summarized by treatment group.   
9.7 
Slit-Lamp Biomicroscopy 
Biomicroscopy results will be listed at each visit. A separate listing will be created for those 
subjects with a criterion change, defined as a change 
 
 Clinically Significant.  
Frequencies and percentages of normal, abnormal results will be created for the following fields: 
Cornea, Conjunctiva, Anterior Chamber, Iris, Lens, and Lid. Abnormal results will further be 
broken down by clinical significance and non-clinical significance.  A shift from baseline in the 
results for study eyes and fellow eyes will also be summarized by treatment group.   
 
 


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11. INTERIM ANALYSES AND DATA MONITORING 
This section is not applicable for this study.  
 
 


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12. CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
No changes to the analyses that are planned in the protocol. 
 
 


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13. REFERENCES 
US Federal Register. (1998) International Conference on Harmonization; Guidance for Industry: 
Statistical Principles for Clinical Trials. Department of Health and Human Services: Food and 
Drug Administration.  Federal Register, Vol. 63, No. 179, September 16, 1998, page 49583. (E9) 
 
US Federal Register. (1996) International Conference on Harmonization; Guidance for Industry: 
Structure and Content of Clinical Study Reports. Department of Health and Human Services: 
Food and Drug Administration.  Federal Register Vol. 61, July 17, 1996, page 37320. (E3) 
 
 
 


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14. APPENDICES 
Appendix 1 Schedule of Visits and Procedures  
Study Day 
Start of 
2 Week Run-In 
(AR-15512 Vehicle) 
Treatment Period 
(BID-OU, 1:1:1 Randomization  
0.0014% AR-15512: 0.003% AR-15512: AR-15512 Vehicle) 
Early 
Termination 
 
Visit 1 
Screening 
Visit 2 
Baseline 
Visit 3 
Visit 4 
Visit 5 
Study Exit 
 
 
Day -14 
(+3)a 
Day 1 
Day 14 
(±2) 
Day 28 
(±2) 
Day 84 
(-5/+2) 
 
 
Pre-CAE 
Post-CAE 
Pre-CAE 
Post-CAEf 
n/a 
Pre-CAE 
Post-CAEf 
Pre-CAE 
Post-CAEf 
n/a 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
X 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Collection of used / unused 
study treatment 
 
 
X 
 
X 
X 
 
X 
 
X 
Medical, ophthalmic, and 
surgical history 
X 
 
 
 
 
 
 
 
 
 
Prior or concomitant 
medication review 
X 
 
X 
 
X 
X 
 
X 
 
X 
AE review 
X 
 
X 
 
X 
X 
 
X 
 
X 
Vital signs (heart rate and 
blood pressure) 
X 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
(WOCBP only) 
X 
 
X 
 
 
 
 
X 
 
X 
Symptom questionnaire 
(VAS) (Ocular 
Discomforta i(1)(a)(i)1 b, Eye 
Dryness and Ocular Pain) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SANDE questionnaire (VAS) 
X 
 
X 
 
X 
X 
 
X 
 
X 
Ora Calibra Ocular 
Discomfort Scale 
(ODS)a i(1)(a)(i)1 b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Best-corrected visual acuity  
X 
 
X 
 
X 
X 
 
X 
X 
X 


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Study Day 
Start of 
2 Week Run-In 
(AR-15512 Vehicle) 
Treatment Period 
(BID-OU, 1:1:1 Randomization  
0.0014% AR-15512: 0.003% AR-15512: AR-15512 Vehicle) 
Early 
Termination 
 
Visit 1 
Screening 
Visit 2 
Baseline 
Visit 3 
Visit 4 
Visit 5 
Study Exit 
 
 
Day -14 
(+3)a 
Day 1 
Day 14 
(±2) 
Day 28 
(±2) 
Day 84 
(-5/+2) 
 
 
Pre-CAE 
Post-CAE 
Pre-CAE 
Post-CAEf 
n/a 
Pre-CAE 
Post-CAEf 
Pre-CAE 
Post-CAEf 
n/a 
Slit-lamp biomicroscopy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anesthetized Schirmer test 
X 
 
X 
 
 
X 
 
X 
 
 
CAE exposure 
X 
Xd 
 
Xd,e 
Xd 
 
Review of qualification 
 
X 
 
X 
 
 
 
 
 
 
Hematology, chemistry, and 
urinalysis 
 
X 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
 
 
Intraocular pressure 
 
X 
 
 
 
 
 
 
X 
X 
Dilated fundus exam 
 
X 
 
 
 
 
 
 
X 
X 
Dispensing of study 
treatment  
 
X 
 
X 
X 
 
X 
 
 
 


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Study Day 
Start of 
2 Week Run-In 
(AR-15512 Vehicle) 
Treatment Period 
(BID-OU, 1:1:1 Randomization  
0.0014% AR-15512: 0.003% AR-15512: AR-15512 Vehicle) 
Early 
Termination 
 
Visit 1 
Screening 
Visit 2 
Baseline 
Visit 3 
Visit 4 
Visit 5 
Study Exit 
 
 
Day -14 
(+3)a 
Day 1 
Day 14 
(±2) 
Day 28 
(±2) 
Day 84 
(-5/+2) 
 
 
Pre-CAE 
Post-CAE 
Pre-CAE 
Post-CAEf 
n/a 
Pre-CAE 
Post-CAEf 
Pre-CAE 
Post-CAEf 
n/a 
In office administration of 
study treatment 
 
X 
 
X 
X 
 
X 
 
 
 
AE Review 
 
X 
 
X 
X 
 
X 
 
X 
 
Study exit 
 
 
 
 
 
 
 
 
X 
X 
a. 
Visit 1 should be scheduled between 11 and 14 days before Visit 2. If absolutely necessary, Visit 2 may be delayed up to 7 days (extending the run-in period 
to a maximum of 21 days).