Clinical trial NCT03418727
Conditions: Dry Eye
Sponsor: Ocugen
Start date: 2017-09-06; Completion date: 2018-03-29
Enrollment: 84 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the tolerability and preliminary efficacy of Brimonidine eye drops (with and without corticosteroid eye drops) for the treatment of Dry Eye Disease (DED).

Detailed description:
Subjects will assess their tolerance to the administration of the study drug, utilizing a Visual Analog Scale (VAS). The VAS is a 100-mm horizontal line with verbal descriptors at either end. The VAS ratings will be completed after administration of the study drug on Day 1 (post-dose), Day 28, Day 56, Day 84, and Day 105. Subjects will place a single slash mark across the horizontal line between the end labeled "completely intolerable" (0 mm) and "easily tolerable" (100mm).

Arms: arm 1: Combination Therapy: brimonidine (0.2%) administered as eye drops, followed by corticosteroid eye drops, two times a day (BID) for 12 weeks arm 2: Monotherapy: brimonidine (0.2%) administered as eye drops followed by placebo, two times a day (BID) for 12 weeks arm 3: Placebo: sodium carboxymethylcellulose (0.25%) administered as eye drops followed by a second application, two time a day (BID) for 12 weeks
Interventions: intervention 1: Brimonidine intervention 2: Brimonidine Mono Therapy intervention 3: sodium carboxymethylcellulose intervention 4: Corticosteroid Eye Drop
Intervention descriptions: intervention 1: Two products delivered in sequence twice daily. intervention 2: Brimonidine given twice daily along with placebo drops intervention 3: Placebo given twice daily. intervention 4: Eye drop to be administered after Brimonidine in treatment arm 1

Protocol documents:
Prot_000.pdf: 
Brimonidine for DED 
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CONFIDENTIAL 
CLINICAL RESEARCH PROTOCOL 
CLINICAL STUDY PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Multicenter, Proof-of-Concept 
Study of Brimonidine Eye Drops for the Treatment of Dry Eye Disease (DED) 
Sponsor: 
Ocugen, Inc. 
5 Great Valley Parkway, Suite 160 
Malvern, PA 19355 
Sponsor Contact: 
 
 
Ocugen, Inc. 
5 Great Valley Parkway, Suite 160 
Malvern, PA 19355 
Study Products: 
Brimonidine 0.2% 
Brimonidine 0.2% plus Loteprednol 0.2% 
Sodium carboxymethylcellulose 0.25%(placebo) 
Protocol Number: 
OCU-310-DED-2017 
Version: 
2.0 (25 October 2017) 
DOCUMENT HISTORY 
Version Date 
Version Number 
Description 
21 July 2017 
1.0 
Original Version 
25 October 2017 
2.0 
Amendment 1 
NCT #NCT03418727


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CONFIDENTIAL 
 
 
ABBREVIATIONS ..................................................................................................................................................... 6 
STUDY SUMMARY .................................................................................................................................................. 7 
1 
BACKGROUND & RATIONALE .......................................................................................................................... 9 
1.1 
INTRODUCTION ...................................................................................................................................................................................... 9 
1.2 
DRY EYE DISEASE: DEFINITION AND PATHOGENESIS ........................................................................................................................... 9 
1.3 
DRY EYE DISEASE: CLINICAL SIGNS AND SYMPTOMS ........................................................................................................................ 10 
1.4 
DRY EYE DISEASE: DIAGNOSTIC TESTING .......................................................................................................................................... 10 
1.5 
DRY EYE DISEASE: CURRENT MANAGEMENT .................................................................................................................................... 10 
1.6 
SCIENTIFIC RATIONALE FOR BRIMONIDINE THERAPY IN DRY EYE DISEASE ...................................................................................... 11 
1.7 
SCIENTIFIC RATIONALE FOR BRIMONIDINE COMBINATION THERAPY IN DRY EYE DISEASE ............................................................. 12 
1.8 
SPECIFIC AGENTS IN THIS STUDY ........................................................................................................................................................ 12 
1.9 
BRIMONIDINE PRECLINICAL DATA ..................................................................................................................................................... 13 
1.9.1 
Published Literature: In Vitro Studies .................................................................................................... 13 
1.9.2 
Published Literature: In Vivo Animal Studies ........................................................................................ 14 
1.10 
BRIMONIDINE CLINICAL DATA TO DATE ............................................................................................................................................ 15 
1.11 
DOSE RATIONALE AND RISK/BENEFITS .............................................................................................................................................. 16 
2 
STUDY OBJECTIVES ....................................................................................................................................... 16 
3 
STUDY DESIGN .............................................................................................................................................. 17 
3.1 
GENERAL DESIGN ............................................................................................................................................................................... 17 
3.1.1 
Primary Tolerability Endpoint: Test Substance Tolerance (Visual Analogue Scale) ............................... 17 
3.2 
SECONDARY STUDY ENDPOINTS ........................................................................................................................................................ 18 
3.3 
EXPLORATORY STUDY ENDPOINTS ..................................................................................................................................................... 18 
3.3.1 
Exploratory Efficacy Endpoint: Symptom Assessment iN Dry Eye (SANDE) ........................................... 18 
3.3.2 
Exploratory Efficacy Endpoint: Ocular Surface Lissamine Green Dye Staining Score (via Slit Lamp) ..... 19 
3.3.3 
Exploratory Efficacy Endpoint: Schirmer I Test ...................................................................................... 19 
3.3.4 
Exploratory Efficacy Endpoint: Ocular Redness Score (ORS) (via Keratograph) .................................... 20 
3.3.5 
Exploratory Efficacy Endpoint: Validated Bulbar Redness (VBR) Grading Scale (via Slit Lamp) ............ 20 
3.3.6 
Exploratory Efficacy Endpoint: Clinical Global Impression (CGI) ........................................................... 21 
3.3.7 
Exploratory Efficacy Endpoint: Subject Global Assessment (SGA) ......................................................... 21 
3.4 
SAFETY ENDPOINTS ............................................................................................................................................................................ 21 
3.4.1 
Vital Signs ............................................................................................................................................. 22 
3.4.2 
Ophthalmic Examination ...................................................................................................................... 22 
4 
SUBJECT SELECTION AND WITHDRAWAL ...................................................................................................... 22 
4.1 
INCLUSION CRITERIA .......................................................................................................................................................................... 22 
4.2 
EXCLUSION CRITERIA .......................................................................................................................................................................... 23 
4.3 
SUBJECT RECRUITMENT AND SCREENING .......................................................................................................................................... 24 
4.4 
EARLY WITHDRAWAL OF SUBJECTS ................................................................................................................................................... 24 
4.4.1 
When and How to Withdraw Subjects .................................................................................................. 24 
4.4.2 
Data Collection and Follow-Up for Withdrawn Subjects ....................................................................... 24 
5 
STUDY DRUG ................................................................................................................................................ 24 
5.1 
DESCRIPTION ...................................................................................................................................................................................... 24 
5.2 
TREATMENT REGIMEN ....................................................................................................................................................................... 25 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ........................................................................................................ 25 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ................................................................................................................... 25 
5.5 
SUBJECT COMPLIANCE MONITORING ................................................................................................................................................ 26 
5.6 
PRIOR AND CONCOMITANT THERAPY ................................................................................................................................................ 26 
5.7 
RESCUE PLAN ..................................................................................................................................................................................... 27 
5.8 
PACKAGING ........................................................................................................................................................................................ 27 


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5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN ............................................................................................................................ 27 
5.9.1 
Receipt of Drug Supplies ....................................................................................................................... 27 
5.9.2 
Storage ................................................................................................................................................. 27 
5.9.3 
Dispensing of Study Drug ...................................................................................................................... 28 
5.9.4 
Return or Destruction of Study Drug ..................................................................................................... 28 
6 
STUDY PROCEDURES ...................................................................................................................................... 28 
6.1 
ASSIGNMENT OF SUBJECT IDENTIFICATION ....................................................................................................................................... 28 
6.2 
SCREEN FAILURE ................................................................................................................................................................................. 28 
6.3 
STUDY ASSESSMENTS ......................................................................................................................................................................... 28 
6.3.1 
Day -7 to 0 (Screening Visit) ................................................................................................................. 28 
6.3.2 
Day 1 (Baseline, Randomization, and First Treatment Visit) ................................................................. 29 
6.3.3 
Day 28 (± 7 days) .................................................................................................................................. 29 
6.3.4 
Day 56 (± 7 days) .................................................................................................................................. 30 
6.3.5 
Day 84 (± 7 days) .................................................................................................................................. 30 
6.3.6 
Day 105 (± 7 days) ................................................................................................................................ 30 
7 
STATISTICAL PLAN......................................................................................................................................... 31 
7.1 
SAMPLE SIZE DETERMINATION .......................................................................................................................................................... 31 
7.2 
STATISTICAL METHODS ...................................................................................................................................................................... 31 
7.2.1 
Unit of Analysis ..................................................................................................................................... 31 
7.2.2 
Analysis Populations ............................................................................................................................. 31 
7.2.3 
General Considerations ......................................................................................................................... 32 
7.2.4 
Safety Analysis ...................................................................................................................................... 32 
7.2.5 
Efficacy Analysis ................................................................................................................................... 32 
7.2.6 
Missing Data ........................................................................................................................................ 33 
7.2.7 
Multiplicity Considerations ................................................................................................................... 33 
8 
SAFETY AND ADVERSE EVENTS ..................................................................................................................... 33 
8.1 
DEFINITION OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS (SAES) ..................................................................... 33 
8.2 
CLASSIFICATION OF ADVERSE EVENTS BY SEVERITY .......................................................................................................................... 34 
8.3 
CLASSIFICATION OF ADVERSE EVENTS BY RELATIONSHIP TO STUDY TREATMENT ............................................................................ 34 
8.4 
ACTION(S) TAKEN .............................................................................................................................................................................. 34 
8.5 
OUTCOME .......................................................................................................................................................................................... 35 
8.6 
ADVERSE EVENT REPORTING ............................................................................................................................................................. 35 
8.7 
SERIOUS ADVERSE EVENT REPORTING .............................................................................................................................................. 35 
8.8 
MEDICAL EMERGENCIES .................................................................................................................................................................... 36 
8.9 
STUDY OVERSIGHT ............................................................................................................................................................................. 36 
9 
CONFIDENTIALITY ......................................................................................................................................... 36 
10 
SOURCE DOCUMENTS ............................................................................................................................... 36 
10.1 
RECORDS RETENTION ......................................................................................................................................................................... 37 
11 
ETHICAL CONSIDERATIONS ....................................................................................................................... 37 
12 
REFERENCES .............................................................................................................................................. 38 


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CONFIDENTIAL 
 
 
SCHEDULE OF VISITS AND PROCEDURES 
 
Day -7-0 
(Screening)* 
Day 1* 
Day 28 
(+/- 7 days) 
Day 56 
(+/- 7 days) 
Day 84 
(+/- 7 days) 
Day 105 
(+/- 7 days) 
Informed consent 
X 
Demographic information 
X 
Medical history 
X 
Ocular/ Dry Eye history 
X 
Symptom Assessment iN Dry Eye 
(SANDE) questionnaire 
X 
X 
X 
X 
X 
X 
Diary Review 
X 
X 
X 
Vital signs 
X 
X 
X 
Visual Acuity (via Snellen) 
X 
X 
X 
X 
X 
Ocular Redness Score (ORS) (via 
Keratograph) 
X 
X 
X 
X 
X 
Noninvasive Tear Breakup Time (NITBUT) 
(via Keratograph) 
X 
X 
X 
Validated Bulbar Redness (VBR) Scale (via 
Slit Lamp) 
X 
X 
X 
X 
X 
Ophthalmic examination (via Slit lamp) 
X 
X 
X 
X 
X 
X 
Lissamine Green staining (Corneal and 
Conjunctival) (via Slit Lamp) 
X 
X 
X 
Schirmer I test 
X 
X 
X 
Intraocular Pressure (IOP) via Goldmann 
X 
X 
X 
X 
X 
Clinical Global Impression (CGI) 
X 
X 
X 
X 
Subject Global Assessment (SGA) 
X 
X 
X 
X 
First study medication 
X 
Drug dispensation, with instruction on 
study medication self-administration 
Xa 
Xb 
Xb 
Adverse Events (AEs) 
Xc 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Tolerability Visual Analogue Scale (VAS) 
Xd 
X 
X 
X 
*Day 1, by definition, is when the first dose of study drug is administered. The Screening Visit and Day 1 Visit may be combined into 
a single visit; in this case, do not duplicate any of the Screening/Day 1 procedures. Subjects taking steroid-containing eye drops at 
the Screening Visit must discontinue those drops and wait a full 7 days before attending the Day 1 Visit. 
a After administration of the first dose of study medication, subjects will be trained on how to self-administer the eyedrops and will be 
given a 1-month supply 


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CONFIDENTIAL 
 
 
b If required 
c AE collection begins after the first dose of study medication on Day 1 
d Tolerability VAS should be completed after the first dose of study medication on Day 1 


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CONFIDENTIAL 
 
 
ABBREVIATIONS 
AE 
Adverse Event 
APC 
Antigen-presenting cells 
BAK 
Benzalkonium chloride 
BID 
Two times per day 
CNL 
Corneal Neurobiology Laboratory 
CRF 
Case Report Form 
CGI 
Clinical Global Impression 
DED 
Dry Eye Disease 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
KCS 
Keratoconjunctivitis sicca 
LLT 
Lipid Layer Thickness 
MAO 
Monoamine Oxidase 
MGD 
Meibomian Gland Disease 
NEI 
National Eye Institute 
NIKBUT 
Non-invasive Keratograph Tear Film Break-Up Time 
ORS 
Ocular Redness Score (ORS) 
OSDI 
Ocular Surface Disease Index 
OTC 
Over the counter 
SANDE 
Symptom Assessment iN Dry Eye 
SAE 
Serious Adverse Event 
SGA 
Subject Global Assessment 
SP 
Substance P 
TCA 
Tricyclic Anti-depressant 
TMH 
Tear Meniscus Height 
VA 
Visual Acuity 
VBR 
Validated Bulbar Redness 
VAS 
Visual Analog Scale 


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CONFIDENTIAL 
 
 
 
Study Summary 
Title 
A Randomized, Placebo-Controlled, Double-Blind, Multicenter, Proof- 
of-Concept Study of Brimonidine Eye Drops for the Treatment of Dry 
Eye Disease (DED) 
Short Title 
Brimonidine treatment for Dry Eye Disease (DED) 
Protocol Number 
OCU-310-DED-2017 
Phase 
Proof-of-Concept 
Methodology 
Double-blind, placebo controlled, with 1:1:1 randomization 
Study Duration 
15 weeks (105 days) 
Study Center(s) 
Multicenter 
Objectives 
To evaluate the tolerability and preliminary efficacy of Brimonidine eye 
drops (with and without loteprednol ophthalmic suspension) for the 
treatment of DED. 
Number of Subjects 
90 (30 per arm) 
Diagnosis and Main 
Inclusion Criteria 
Men and women ≥ 18 years of age with a diagnosis of DED 
Study Product, 
Dose, Route, 
Regimen 
Study Drug Arm #1 (combination therapy): Brimonidine (0.2%) 
administered as eye drops, followed by loteprednol ophthalmic 
suspension (0.2%), two times a day (BID) for 12 weeks 
Study Drug Arm #2 (monotherapy): Brimonidine (0.2%) administered 
as eye drops, followed by placebo, two times a day (BID) for 12 weeks 
Control Arm (placebo): Lubricant Eye Drops (sodium 
carboxymethylcellulose, 0.25%) followed by a second application, two 
times a day (BID) for 12 weeks 
All treatment arms will contain benzalkonium chloride (BAK) 
preservative. 
Duration of 
administration 
12 weeks of double-blind randomized treatment. An additional End of 
Study visit will be performed at 15 weeks (Day 105), to provide post- 
treatment follow-up data. 


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Statistical 
Methodology 
Unit of Analysis 
The unit of analysis for efficacy will be the study eye. Each subject will 
have a single eye identified as the study eye as follows: (i) if only 1 eye 
meets inclusion criteria, this eye will be the study eye and the other eye 
will be considered the non-qualified fellow eye; (ii) if both eyes meet 
inclusion criteria, the eye with the higher Ocular Redness Score (ORS) 
will be the study eye and the other eye will be considered the qualified 
fellow eye; (iii) if both eyes have the same Ocular Redness Score 
(ORS), then the eye with the lower Schirmer I score will be the study 
eye and the other eye will be considered the qualified fellow eye; (iv) if 
both eyes have same Schirmer 1 score, the right eye will be the study 
eye and the other eye will be considered the qualified fellow eye. Safety 
and Efficacy analyses will be primarily performed on the study eyes and 
secondarily on the qualified fellow eyes (for efficacy) and all fellow eyes 
(for safety). 
General Considerations 
The sample size was not calculated to have pre-determined power for 
efficacy in this proof of concept study. All continuous study 
assessments will be summarized by treatment and visit (as applicable) 
and change from baseline to each post-baseline visit using descriptive 
statistics (n, mean, median, standard deviation, minimum, and 
maximum). All categorical study assessments will be summarized by 
treatment and visit (as applicable) using frequency counts and 
percentages. 
Safety 
Tolerability will be summarized by treatment group at each visit using 
continuous summary statistics; p-values from pairwise two-sample t- 
tests and 90% and 95% CIs will be presented to test the difference in 
mean tolerability among the three treatment groups 
Efficacy 
The efficacy parameters, SANDE, CGI, SGA, Lissamine Green corneal 
and conjunctival staining, Schirmer’s Test I, Keratograph Ocular 
Redness Score (ORS), and validated bulbar redness (VBR) scales will 
be summarized by treatment group at each visit and for change from 
baseline to each visit using continuous and discrete summary statistics 
as appropriate and using pairwise two-sample t-tests or Pearson’s chi- 
squared test (or Fisher’s exact test if expected cell count is <5) and 
corresponding asymptotic 90% and 95% CI around the difference in 
means or proportions. 
Lissamine Green corneal and conjunctival staining will be summarized 
by region and overall. 


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1 Background & Rationale 
1.1 Introduction 
Ocugen Inc. is developing brimonidine tartrate 0.2% eye drops (with or without loteprednol etabonate) 
for the treatment of Dry Eye Disease (DED). Brimonidine is an imizadoline compound that acts as a 
specific alpha 2 adrenergic agonist. Brimonidine tartrate ophthalmic solution is currently an FDA 
approved product and is available at different concentrations and is indicated for the reduction of 
intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. Loteprednol 
etabonate ophthalmic suspension (0.2%) is a topical anti-inflammatory corticosteroid. The compound is 
FDA approved for the temporary relief of the signs and symptoms of seasonal allergic conjunctivitis. 
 
This document is a protocol for a human research study. This study is to be conducted according to US 
and international standards of Good Clinical Practice (FDA CFR Title 21 part 312 and International 
Conference on Harmonization guidelines), applicable government regulations and Institutional research 
policies and procedures. 
 
1.2 
Dry Eye Disease: Definition and Pathogenesis 
Dry eye disease (DED) is a common ocular disorder involving the aberrant production and stability of 
tear film, which results in damage to the ocular surface and is correlated with symptoms of ocular 
discomfort. DED is also recognized as keratoconjunctivitis sicca (KCS), sicca syndrome, keratitis sicca, 
xerophthalmia, dry eye syndrome (DES), dysfunctional tear syndrome (DTS), ocular surface disease 
(OSD) or dry eye. DED is caused by chronic instability of preocular tear film. Tear film instability can be 
triggered by insufficient tear production, or by poor tear film quality that results in increased tear 
evaporation (Phadatare et al 2015). Furthermore, dry eye is typically categorized into two groups: 
 
1) Aqueous tear deficient dry eye disease 
2) Evaporative dry eye disease 
 
DED is a result of changes to the lacrimal functional unit (LFU). The LFU is composed of the lacrimal 
glands, cornea, eyelids, meibomian glands, conjunctiva, goblet cells, and ocular nerves. The LFU is 
responsible for the sustained production of adequate tear film to consistently lubricate the ocular 
surface. Structural changes to the LFU can induce tear film instability and insufficiency, which in turn 
can lead to tear hyperosmolarity. Chronic osmotic stress from tear film can activate stress associated 
pathways in ocular surface epithelial cells, thereby triggering a pro-inflammatory response that involves 
a mix of chemokines, cytokines, and matrix metalloproteinases. The subsequent maturation of antigen- 
presenting cells (APC’s) on the ocular surface leads to the migration, activation, and expansion of 
autoreactive T cell lymphocytes as well as other leukocytic classes in the LFU. The constant 
recruitment of pro-inflammatory leukocytes onto the ocular surface inflicts epithelium damage in the 
form of small abrasions and epithelium barrier defects (Pflugfelder et al 2008; Stevenson et al 2012). 
These abrasions can eventually progress to superficial punctuate keratitis, squamous metaplasia, 
extracellular matrix deposits, decreased goblet cell differentiation, increased epithelial cell turnover 
(epitheliopathy), and significant ocular surface nerve damage and neuropathy. 
 
As DED progresses, lacrimal gland obstruction, meibomian gland orifice obstruction, thickened eyelid 
margins, cloudy, solid, or granular meibum secretion, eyelid telangiectasia, and meibomian gland 
dysfunction become common clinical features. In advanced cases, dry eye can cause fibrotic thickening 
of the cornea and conjunctiva, filamentous keratitis, mucoid clumping, trichiasis, symblepharon, 
keratinization of the eyelids and meibomian glands, corneal and conjunctival erosion and thinning, 
corneal and conjunctival neovascularization, corneal and conjunctival scarring, corneal ulceration, and 


Brimonidine for DED 
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CONFIDENTIAL 
 
 
corneal perforation. In addition, prolonged ocular surface inflammation can lead to moderate or 
absolute loss/atrophy of the meibomian glands, lacrimal glands, and conjunctival goblet cells, and 
subsequently a dramatic reduction in tear film production and the onset of permanent DED (Messmer et 
al 2015). 
 
DED prevalence increases with age. The most common causes of dry eye are contact lens usage, 
autoimmune disorders, systemic drug effects, and refractive surgeries, particularly in middle-aged and 
older adults. DED also occurs in a higher percentage of women than men, especially in women 
entering menopause or pregnancy; hormone imbalances during menopause or pregnancy can cause 
lacrimal gland and ocular surface inflammation and tear film abnormalities (Phadatare et al 2015). 
 
1.3 Dry Eye Disease: Clinical Signs and Symptoms 
Common signs and symptoms of DED include: eye redness, ocular pain, burning and stinging 
sensation, foreign body sensation, pruritus, itchy or scratchy eye sensation, tired eyes, enhanced eye 
pressure, photophobia, painful mucous discharge, and in some cases epiphora. DED typically affects 
eyes bilaterally. Dry eye can heavily impact visual function especially during visually intensive activities 
and can overall decrease quality of life. (Phadatare et al 2015; Messmer et al 2015). 
 
1.4 Dry Eye Disease: Diagnostic Testing 
Clinicians use several diagnostic tests to diagnose DED and to assess disease severity. These tests 
fall into two groups: signs (objective) and symptoms (subjective). For DED signs, there are several 
quantitative tests, including: Schirmer Test, Schirmer I Test, Schirmer II test, tear film breakup time 
(TBUT), non-invasive tear film breakup time (NITBUT) epithelial staining scores (rose bengal, lissamine 
green, fluorescein) via slit-lamp examination, tear function index (TFI), tear fluid protein immunoassays, 
fluorophotometry, meibography, meibometry, meiboscopy, meniscometry, lacrimal gland biopsy, 
impression cytology, hypolysozyme measurement, hyperosmolarity measurement, and lipid layer 
analysis, ocular redness scoring, automated blink analysis, and meniscus evaluation utilizing Lipiview 
II, Keratograph 5M, or OCT equipment (Phadatare et al 2015). 
 
Symptom measurements utilizing physician and/or patient disease scoring include: extensive dry eye 
questionnaire (DEQ), visual analog scale (VAS), ocular surface disease index (OSDI), national eye 
institute visual function questionnaire (NEI-VFQ-25), symptom assessment in dry eye questionnaire 
(SANDE), and standardized patient evaluation of eye dryness questionnaire (SPEED). While most 
physicians use OSDI as the primary diagnostic questionnaire for dry eye, the SANDE visual analog 
scale-based questionnaire offers significant advantages, such as simplicity and brevity, while 
maintaining a high degree of diagnostic accuracy. In addition, in two recent review articles, the SANDE 
questionnaire showed a significant correlation to OSDI in terms of DED scoring (Amparo, et al, 2015; 
Saboo, et al, 2015).). 
 
Many of the above tests have been used in recent DED studies. In this proof-of-concept study, there 
will be multiple exploratory endpoints based on conventional dry eye assessments, subjective and 
objective. Each study site will use the Oculos Keratograph 5M to assess the Ocular Redness Score 
(ORS), and these results will be compared to the Validated Bulbar Redness (VBR) scale (Section 3.4.5. 
Based on the results of this study, Ocugen will decide which sign and/or symptom to be used as the 
primary (or co-primary) endpoint(s) in later stage studies. 
 
1.5 Dry Eye Disease: Current Management 
Typically, clinicians prescribe artificial tear eyedrops and topical corticosteroids for short-term relief of 
DED. Antibiotics (tetracyclines and macrolides), non-steroidal anti-inflammatory agents, autologous 
serum drops, omega fatty acids, mucin secretagogues, and anti-inflammatory agents are also used to 


Brimonidine for DED 
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CONFIDENTIAL 
 
 
combat DED symptoms. In addition, prosthetic scleral lenses (i.e. PROSE) that also serve as 
supplemental tear reservoirs are increasingly being prescribed to enhance ocular surface hydration in 
patients with chronic DED. Hot eyelid compresses are often utilized to treat meibomian gland 
dysfunction, a primary driver of evaporative dry eye disease. In advanced cases of DED, punctual plugs 
can be installed to block tear drainage. In severe cases of dry eye, tarsorrhaphy surgery, tear duct 
cauterization, or amniotic membrane transplant might be required to reduce tear evaporation 
(Phadatare et al 2015; Lin et al 2014). 
 
Currently there are only two pharmaceutical agents that are FDA approved for the treatment of dry eye: 
cylcosporine A ophthalmic emulsion (Restasis®) and lifitegrast ophthalmic solution (Xiidra™). 
Restasis® 0.05% is a topical immunomodulator indicated to increase tear production in patients whose 
tear production is presumed to be suppressed due to ocular inflammation associated with 
keratoconjunctivitis sicca (Restasis® Prescribing Information). Xiidra™ 5% is a lymphocyte function- 
associated antigen (LFA-1) antagonist indicated for the treatment of signs and symptoms of dry eye 
disease (Xiidra™ Prescribing Information). Given the complexity, severity, and frequency of DED, and 
given the limited modes of action by which these two compounds treat dry eyes, there is a medical 
need for other dry eye therapies, particularly those with multiple modes of action that target the wider 
dry eye population and are effective and safe for long-term daily use. 
 
1.6 Scientific Rationale for Brimonidine Therapy in Dry Eye Disease 
The scientific rationale to establish a medically plausible basis for the use of local brimonidine tartrate 
for the treatment of DED include the potential following mechanisms: 
1. 
Reduction of ocular surface blood flow: As an alpha agonist, brimonidine tartrate can 
significantly cause vasoconstriction leading to the reduction of blood flow to the ocular surface, which, 
in turn, reduces local pressure, edema and inflammation (Piwnica, 2014). In this manner, brimonidine 
has the potential to reduce redness of the ocular surface. 
2. 
Disruption of leukocyte extravasation to the ocular tissue: brimonidine can inhibit the 
infiltration of activated leukocytes by modulating endothelial cell activity (Herrera-Garcia, 2014). 
3. 
Suppression of leukocytes activation: Although inhibition of T lymphocytes has not been 
directly studied with brimonidine tartrate, activation of alpha 2 receptors (with another alpha 2 agonist) 
has been shown to suppress the reactivation of T lymphocytes (Felsner, 1995). In addition, induction of 
neutrophil apoptosis with brimonidine has been reported in acute inflammation (Herrera-Garcia, 2014). 
4. 
Analgesic properties: Brimonidine antagonizes or suppresses the excitatory response of 
phenylephrine and noradrenaline (Bradshaw, 1984). As an alpha agonist, brimonidine may attenuate 
pro-inflammatory cytokine release from leukocytes, which in turn, attenuates neuritis-induced pain 
(Romero-Sandoval, 2007; Romero-Sandoval, 2005). 
5. 
Reduction of fibrosis and suppression of excessive extracellular matrix (ECM) formation: 
Fibrosis is observed in ocular Graft-vs. Host Disease (oGVHD), and this is associated with severe dry 
eye. oGVHD is characterized by excessive number of CD34+ fibroblasts, excessive fibrosis, and over 
accumulation of ECM in the lacrimal glands leading to dysfunction (Ogawa, 2010). Brimonidine has 
been shown to attenuate the TGF-β1-induced production of ECM proteins, which in turn leads to the 
decrease in the synthesis of fibronectin and collagens in human fibroblasts (Hong, 2015). 
 
In summary, brimonidine, through its ability to vasoconstrict, has the potential to reduce redness of the 
ocular surface. In addition, by attenuating chronic inflammation and excessive fibrosis, brimonidine 
tartrate allows the ocular surface and tear film producing glands to avoid further damage from DED. 
Moreover, brimonidine tartrate can alleviate heightened ocular pain through its analgesic and anti- 
inflammatory properties, which maximizes tolerability when delivered to the surface of the eye. 
Brimonidine tartrate is an FDA approved product that has demonstrated a robust safety profile via 


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topical ocular delivery for the treatment of open-angle glaucoma. Brimonidine tartrate 0.2%, which 
includes the preservative benzalkonium chloride (BAK), is generally safe and well tolerated. 
 
1.7 Scientific Rationale for Brimonidine Combination Therapy in Dry Eye Disease 
As mentioned, loteprednol etabonate ophthalmic suspension (0.2%) is a topical anti-inflammatory 
corticosteroid that is FDA approved for the temporary relief of the signs and symptoms of seasonal 
allergic conjunctivitis when given as eye drops 4 times a day. In addition, loteprednol, as both an 
ophthalmic suspension and gel, has been used to relieve some signs and symptoms of DED, though 
without specific FDA approval for this indication. Currently, a new formulation of loteprednol etabonate, 
designated KPI-121 0.25% ophthalmic suspension, is being assessed in two phase 3 studies in 
subjects who have a documented clinical diagnosis of DED (NCT02813265; NCT02819284). 
 
Loteprednol, like other ophthalmic steroids, has the potential to raise intra-ocular pressure (IOP). 
Among the patients studied in the development program for loteprednol etabonate ophthalmic 
suspension, 0.2% (Alrex™), the incidence of clinically significant increases in IOP (> 10mmHg) was 1% 
(1/133) and 1% (1/135) with placebo (Alrex™ Prescribing Information). Data from published literature 
indicate that topical loteprednol has a minimal effect on IOP when used for a variety of ocular surface 
and intraocular inflammatory disorders, including DED, ocular allergies, anterior uveitis, keratoplasty, 
and postoperative pain/inflammation following cataract surgery (Sheppard, 2016). Nevertheless, for 
safety purposes, IOP will be measured at Screening, and only subjects with an IOP >5 mmHg and < 
22mmHg are eligible for this study. In addition, IOP will be measured at Days 28, 84, and 105. Finally, 
loteprednol will be given twice per day (not 4 times per day) in this study, and only to subjects on the 
combination arm, who will also be receiving brimonidine. 
 
As described, brimonidine and loteprednol, when given together, may enhance efficacy in treating DED, 
relative to either product alone, given their different modes of action. Moreover, these two compounds 
may act in synergy to enhance the safety profile compared to either product alone. For example, 
brimonidine is FDA approved to reduce IOP in patients with glaucoma. Therefore, when used in 
combination, brimonidine, which can lower IOP, can counteract loteprednol, which can elevate IOP. 
Conversely, loteprednol, like other corticosteroids, can treat allergic reactions, including those caused 
by other eye drops. Indeed, allergic reactions have occurred in patients receiving brimonidine, and 
these reactions could be treated (or prevented) by loteprednol. 
 
In summary, the combination of brimonidine and loteprednol makes sense from both an efficacy and 
safety standpoint. Accordingly, in one arm of this study, loteprednol etabonate ophthalmic suspension 
(0.2%) will be given 5-10 minutes after brimonidine tartrate ophthalmic solution (0.2%). If the results are 
positive, a true combination formulation may be developed for use in subsequent clinical trials. 
 
1.8 Specific Agents in this Study 
The primary agent used in this study is a commercial alpha-2 adrenergic receptor agonist, brimonidine 
0.2%, applied as eye drops in subjects with DED. Brimonidine tartrate ophthalmic solution is a relatively 
selective alpha-2 adrenergic agonist for ophthalmic use. The chemical name of brimonidine tartrate is 
5-bromo-6-(2-imidazolidinylideneamino) quinoxaline L-tartrate. 
 
The other active agent is a commercial topical anti-inflammatory corticosteroid, loteprednol etabonate 
ophthalmic suspension (0.2%), approved for the temporary relief of the signs and symptoms of 
seasonal allergic conjunctivitis. Loteprednol etabonate is structurally similar to other ester-based 
corticosteroids except that the position 20 ketone group is absent. It is lipid soluble, which enhances 
cell penetration, and undergoes extensive metabolism to inactive carboxylic acid metabolites. It has a 


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potent anti-inflammatory effect but decreased potential to raise IOP relative to other corticosteroids, 
(Alrex™ Prescribing Information). 
 
The placebo in this study is Lubricant Eye Drops (sodium carboxymethylcellulose, 0.25%). 
 
All three agents in this study are commercially available and preserved with benzalkonium chloride 
(BAK). 
 
1.9 Brimonidine Preclinical Data 
 
1.9.1 Published Literature: In Vitro Studies 
 
1.9.1.1 
Vasoconstriction Properties 
Brimonidine is a potent vasoconstrictor. In an ex vivo human skin biopsy neural inflammation model, 
brimonidine significantly inhibited vasodilation of human blood vessels exposed to capsaicin. Further, in 
an ex vivo model, brimonidine has been shown to attenuate the vasodilation of subcutaneous vessels 
with a diameter of less than 200 micrometers (Piwnica, 2014) that is approximately 13-fold larger than 
typical capillaries of the conjunctiva, suggesting brimonidine has vasoconstriction effects on conjunctiva 
vessels (Shahidi, 2010). Supowit et al 1998 determined in a separate study that brimonidine attenuates 
the release of calcitonin gene-related peptide (CGRP, a key neurotransmitter) in adult rat dorsal root 
ganglia neurons that in turn mediates inflammation and vasodilation (Supowit, 1998). 
 
 
1.9.1.2 
Inhibition of Activated Leukocyte Migration 
Alpha 2 adrenergic agonists disrupt leukocyte extravasation into inflamed tissue by modulating 
endothelial cell activity. Herrera-Garcia et al 2014 demonstrated that brimonidine significantly 
decreased neutrophil trans-endothelial migration by restricting macromolecular and ion transport in 
HUVEC endothelial cells (Herrera-Garcia, 2014). Herrera-Garcia et al also noted that brimonidine 
decreased ICAM 1- VE-cadherin phosphorylation on HUVEC cells; ICAM1 and VE-Cadherin play 
crucial roles in leukocyte extravasation via the destabilization of endothelial cell adherens junctions. 
The authors additionally proved that brimonidine restricted L-selectin shedding and CD11b up- 
regulation, both critical steps in neutrophil extravasation into inflamed tissue (Herrera-Garcia, 2014). 
 
 
1.9.1.3 
Alpha 2 Adrenergic Agonists Potently Disrupt Leukocyte Activation 
Bao et al proved that alpha -2 adrenergic agonists (e.g., clonidine) markedly diminished rat leukocyte 
proliferation, specifically T lymphocytes, and interfered with the production of pro-inflammatory 
cytokines IFN-gamma and IL-4. Clonidine is an adrenergic agonist that binds with nanomolar affinity to 
alpha 2a receptor subtypes (analogous to brimonidine’s binding affinity to alpha-2 adrenergic receptors; 
Bao, 2007), suggesting that both brimonidine and clonidine can inhibit the activation of leukocytes. 
 
 
1.9.1.4 
Mediation of Fibroblast Activity and Production of Extracellular Matrix Proteins 
Brimonidine can potentially alleviate ocular surface fibrosis and stimulate corneal wound healing. Hong 
et al demonstrated that brimonidine down-regulated TGF-beta activity in human Tenon’s fibroblasts 
suggesting that brimonidine acts an anti-fibrotic compound (Hong, 2015). It is possible that brimonidine 
can alleviate hyperkeratinization and fibrotic conditions found in the meibomian glands, lacrimal glands, 
conjunctiva, and cornea. It has also been shown that fibroblasts, excessive fibrosis, and over 
accumulation of ECM in the lacrimal glands can lead to dysfunction of the lacrimal gland (Ogawa, 
2010). 


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1.9.2 Published Literature: In Vivo Animal Studies 
 
1.9.2.1 
Potential Ocular Analgesic Activity 
Brimonidine is believed to act as an ocular analgesic via its antagonistic effects on nociceptive receptor 
signaling. The compound has been shown to significantly suppress the stimulation of nociceptive 
receptors in the murine cerebral cortex by antagonizing the pro-inflammatory effects of norepinephrine 
and phenylephrine (Bradshaw, 1984). Nociceptive neuron activation in ocular surface tissue is linked to 
elevated ocular pain, photophobia, ocular discomfort, and ocular surface inflammation (Belmonte, 
2004). CGRP and substance P are two neuropeptides linked to chronic ocular surface inflammation 
and hyperemia; nociceptive corneal nerves release CGRP and substance P when the cornea is 
wounded. The neural inflammatory peptides spur the recruitment of immune cells onto the ocular 
surface and induce up-regulation of pro-inflammatory cytokines and hyperalgesia (Belmonte, 2004). 
Nociceptive neurons that release CGRP are found in the conjunctiva and eyelid, including the 
meibomian glands (Luhtala, 1991; Simons, 1994). An immunohistochemical study on primate 
meibomian tissue confirmed the presence of CGRP and substance P releasing nociceptive nerves 
(Seifert, 1996). 
 
Moreover, a study in guinea pig demonstrated that brimonidine counteracts the bronchoconstriction 
effects of CGRP as well as the release of key peptides under inflammatory conditions (Lou, 1992). 
Therefore, it is likely that brimonidine’s inhibition of nociceptive receptors prevents the release of 
neural-inflammatory peptides, including CGRP, on the ocular surface and reduces ocular surface pain 
sensitivity. Furthermore, recent evidence has suggested that tear film hyperosmolarity increases ocular 
surface nociceptive sensitivity to pain. Tear film hyperosmolarity is a key pathological sign of ocular 
surface disease and severe dry eye (Hirata, 2014). Brimonidine’s analgesic properties may prevent the 
hyper-activation of ocular nociceptive neurons to inflammatory stimuli. In addition, alpha 2 adrenergic 
agonists, including brimonidine and clonidine, lower pro-inflammatory cytokine release from leukocytes, 
which in turn attenuate neuritis-induced pain (Romero-Sandoval, 2005). 
 
 
1.9.2.2 
Potential Suppression of Activated Leukocytes 
Alpha 2 adrenergic agonists suppress leukocyte reactivity and activation, and can cause leukocyte 
apoptosis at high concentrations. This effect is particularly seen with T cell lymphocytes and 
neutrophils. Notably, clonidine (an alpha agonist) markedly diminishes leukocyte proliferation and 
interferes with the release of TNF alpha, IFN-gamma, IL-1a, IL-1beta, IL-4 and IL-6. Clonidine shifts 
leukocyte cytokine activity to an anti-inflammatory profile (Felsner, 1995; Romero-Sandoval, 2007; 
Romero-Sandoval, 2005). Herrera-Garcia et al (2014) demonstrated that brimonidine significantly 
lowered the recruitment and activation of neutrophils in an acute inflammation mouse model, 
suggesting that suppression of activated leukocytes may be one of the key modes of action of 
brimonidine. 
 
 
1.9.2.3 
In Vivo Inhibition of Local Edema 
In an in vivo mouse ear inflammation model, brimonidine inhibited ear edema by up to 76% (Piwnica, 
2014). 


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1.10 Brimonidine Clinical Data to Date 
 
In two small studies, brimonidine has been used to treat ocular Graft-vs-Host Disease (oGVHD), which 
shares some of the features of severe Dry Eye Disease (DED). 
 
In an exploratory retrospective investigator-led study of meibomian gland dysfunction (MGD) in 18 
patients with chronic oGVHD, one drop of brimonidine tartrate ophthalmic solution, 0.15% (Alphagon® 
P) was instilled twice per day in each eye for at least 6 months. A beneficial effect was observed in 
16/18 (89%) of patients, who in turn showed no progression of disease and no significant side effects. 
Of the 18 patients, 15 (83%) had moderate to marked improvement in the physician’s clinical evaluation 
(Sponsor data, unpublished). After this hypothesis-generating study, plans were made for a small 
prospective, controlled study using objective endpoints. 
 
A phase I/II randomized, placebo-controlled, double-blind, single-center, tolerability and preliminary 
efficacy study of use of brimonidine eye drops (0.075% and 0.15%) for treatment of ocular Graft-vs- 
Host Disease (oGVHD) was conducted at the University of Illinois (Chicago). Given the slow pace of 
identifying and recruiting oGVHD patients, the study was paused after 40% enrollment. An interim 
analysis was performed to access tolerability to avoid any unethical continuation of this trial, if any harm 
was found. The scope of this analysis was limited to tolerability only and imposed p-value adjustments 
on the analysis to alleviate inflated type I error. Specifically, the study evaluated if the categorical type 
of tolerability measure was different between control (Artificial Tears) and intervention (Brimonidine, 
including both 0.15% and 0.075% dose groups), by using Fisher’s exact test. The type I error was 
adjusted by using an alpha spending function approach with O'Brien-Fleming type boundaries. There 
was inadequate power to assess an efficacy benefit. 
 
In this tolerability analysis, the valid sample size was 11 patients at 12 weeks. The table below showed 
the frequency/distribution of tolerability at week 12 by randomization group. The numbers indicated that 
the distributions of two groups were similar, where most participants [4 out of 6 (67%) in Artificial Tears, 
and 4 out of 5 (80%) in Brimonidine group] had 100% tolerability. The other two tolerability categories, 
95% and 90%, only had 1 or 2 responses. The investigator then grouped 90% and 95% tolerability 
together, and conducted a Fisher’s exact test to see if statistically there was a distribution difference 
between the two groups. The result was negative with a p-value =1, meaning no statistical difference 
was found. Overall, the results showed similar tolerability between the Brimonidine and Artificial Tears 
groups. In summary, there was no specific tolerability concern for brimonidine (Sponsor data, 
unpublished). 
 
Table 1. Distribution of Tolerability by Randomization 
 
Artificial Tears 
(N=6) 
Brimonidine: low+high 
(N=5) 
Total 
(N=11) 
Tolerability (%): 
100 
67% (4) 
80% (4) 
73% (8) 
95 
17% (1) 
0% (0) 
9% (1) 
90 
17% (1) 
20% (1) 
18% (2) 


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1.11 Dose Rationale and Risk/Benefits 
 
Brimonidine 0.2% is currently used topically as eye drops, 2-3 times a day, for the lowering of 
intraocular pressure in patients with open-angle glaucoma or ocular hypertension. The other active 
agent is a commercial topical anti-inflammatory corticosteroid, loteprednol ophthalmic suspension 
(0.2%), used topically as eye drops 4 times a day, for the temporary relief of the signs and symptoms of 
seasonal allergic conjunctivitis. The placebo control group is Lubricant Eye Drops (sodium 
carboxymethylcellulose, 0.25%) eye drops. All three agents are considered safe and well tolerated 
when used multiple times per day over extended time periods. In this proof of concept study, all three 
agents will be preserved with benzalkonium chloride (BAK). 
 
Regardless of study arm, a total of two drops will be applied to each eye, two times a day in a double 
blinded fashion over 12 weeks. An End of Study visit will be performed at 15 weeks (day 105) for post- 
treatment evaluation. 
 
Several studies of brimonidine for the treatment of glaucoma have reported the overall long-term safety 
and efficacy of brimonidine 0.2% and 0.15% after 1, 3 and 4 years. One study demonstrated a 
reduction in adverse effects with brimonidine 0.15% (Katz, 2002), but another has shown no difference 
between brimonidine 0.2% and 0.15% (Mundorf, 2003). The most common systemic side effects 
include dysguesia, fatigue, eye pain, dry mouth and headache (Adkins, 1998; Chew, 2014; Melamed, 
2000; LeBlanc, 1998; Schuman, 1997). The incidence of blepharitis and blepharoconjunctivitis has 
been reported as 9 – 12.7% (Schuman, 1997; Katz, 1999; Schuman, 1996); follicular conjunctivitis has 
been found in 7.8 – 12.7% of patients (Schuman, 1997; Katz, 1999); and conjunctival hyperemia has a 
reported incidence of 5 – 30.3% (Nguyen, 2013; Rahman, 2010). 
 
Brimonidine tartrate ophthalmic solution 0.2% is contraindicated in patients with hypersensitivity to any 
component of this medication, and in neonates and infants under the age of 2 years in whom side 
effects associated with CNS depression have been observed (Carlsen, 1999; Korsch, 1999; Soto- 
Perez-de-Celis, 2007; Vanhaesebrouck, 2009). These effects may occur because children have a less 
mature blood-brain barrier (BBB), and hence, a limited capacity to impede brimonidine uptake and 
prevent CNS effects. In addition, there is laboratory evidence that alpha-2-adrenoceptor agonists may 
potentiate smooth muscle vasoconstriction in arteries (Chotani, 2000), and brimonidine is, therefore, 
contraindicated in cerebral or coronary insufficiency, orthostatic hypotension, thromboangitis obliterans 
and Raynaud's phenomenon (Alphagan® and Alphagan® P Prescribing Information). 
 
An allergic reaction to brimonidine cannot be predicted beforehand. In event of an allergic reaction, the 
drug will be stopped immediately, and symptoms will be managed appropriately depending on the 
severity of the reaction. As mentioned, in the combination arm of the study, loteprednol could prevent or 
attenuate hypersensitivity reactions and is approved for the treatment of allergic conjunctivitis. 
 
No psychological, social, legal, or financial risk is expected from participating in the research. 
 
 
2 Study Objectives 
 
The main objective of this study is to establish whether subjects with dry eye disease (DED) can 
tolerate receiving Brimonidine 0.2% eye drops, alone or in combination with loteprednol, two times a 
day for twelve weeks (primary tolerability objective). The other objective is to investigate the preliminary 
efficacy of Brimonidine 0.2% topical eye drop solution, alone or in combination with loteprednol 0.2%, in 
treating DED. 


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3 Study Design 
3.1 General Design 
 
This will be a randomized, placebo-controlled, double-blind study, in which 90 subjects will be enrolled 
at up to four clinical sites. Subjects will be randomly assigned to one of three groups, with 30 subjects 
per group, as follows: 
 
Study Drug Arm #1 (combination therapy): Brimonidine (0.2%) administered as eye drops, 
followed by loteprednol ophthalmic suspension (0.2%), two times a day (BID) for 12 weeks 
 
Study Drug Arm #2 (monotherapy): Brimonidine (0.2%) administered as eye drops, followed by 
placebo, two times a day (BID) for 12 weeks 
 
Control Arm (placebo): Lubricant Eye Drops (sodium carboxymethylcellulose, 0.25%), followed 
by a second application, two times a day (BID) for 12 weeks 
 
Enrolled subjects will receive the study treatment for 12 weeks and will be asked to return for a final 
visit at 15 weeks to evaluate safety and efficacy post-treatment. 
 
Patients with DED will be approached by a member of the research staff to determine if the patient 
might be interested in participating in this study. If the patient is interested, the research staff member 
will describe the study, and thereafter the patient will be asked to sign the informed consent form. 
Screening procedures include documentation of DED using currently accepted criteria. Eligible patients 
who are willing to participate and meet study criteria will be enrolled in the study. 
 
All enrolled subjects will receive their first dose of the test medication (Brimonidine 0.2% with or without 
loteprednol ophthalmic suspension 0.2%), or placebo (sodium carboxymethylcellulose, 0.25%) on study 
Day 1 in the doctor’s office, and will self-administer all subsequent doses. See Section 5.4 Preparation 
and Administration of Study Drug for details. 
 
Subjects will be given diaries to record the time of each dose. In addition, they will be asked to make a 
note of any missed doses together with the reason for the omission. Subjects will return four weeks 
later (Day 28) for further study assessments, and thereafter at Day 56 and Day 84 (primary endpoint 
assessment visit), and finally at Day 105 after three weeks (or 21 days) of no study drug treatment. 
 
There is no primary efficacy endpoint in this study. Instead several exploratory efficacy endpoints will 
be assessed. 
The primary tolerability endpoint is the change in the test substance tolerance between Day 1 (post- 
dose) and 12 weeks (84 days). 
 
3.1.1  Primary Tolerability Endpoint: Test Substance Tolerance (Visual Analogue Scale) 
Subjects will assess their tolerance to the administration of the study drug, utilizing a Visual Analogue 
Scale (VAS). The VAS is a 100-mm horizontal line with verbal descriptors at either end. The VAS 
ratings will be completed after administration of the study drug on Day 1 (post-dose), Day 28, Day 56, 
and Day 84,. Subjects will place a single slash mark across the horizontal line between the end labeled 
“completely intolerable” (0 mm) and “easily tolerable” (100mm). 


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Completely 
Easily 
The VAS rating is as follows: 
 
Visual Analogue 
 
 
On the scale of 0 to 100 seen below, please mark where you would rate your 
tolerability to administration of the study drug. 
 
 
 
 
 
3.2 Secondary Study Endpoints 
There are no secondary endpoints in this study 
 
3.3 
Exploratory Study Endpoints 
The exploratory study endpoints will include: 
1. Symptom Assessment Questionnaire iN Dry Eye (SANDE) 
2. Change in corneal and conjunctival staining scores by Lissamine Green dye staining 
3. Change in tear secretion as measured by Schirmer I test 
4. Change in Keratograph Ocular Redness Score (ORS) 
5. Change in Validated Bulbar Redness (VBR) grading scale 
6. Clinical Global Impression (CGI) of change in symptoms from baseline (physician’s rating) 
7. Subject Global Assessment (SGA) of overall change from baseline (subject’s rating) 
 
Note: In these exploratory analyses, endpoint values will be compared to baseline values, where 
“baseline” is defined as the measurement done on Day 1 before initial study drug is administered. 
 
3.3.1 Exploratory Efficacy Endpoint: Symptom Assessment iN Dry Eye (SANDE) 
The Symptom Assessment Questionnaire iN Dry Eye (SANDE) is a short questionnaire based on a 
visual analog scale that quantifies both severity and frequency of dry eye symptoms. The SANDE is 
comprised of two questions, and each question employs a 100mm horizontal linear visual analog scale. 
The measurement of symptom frequency ranges from “rarely” to “all of the time,” and the symptom 
severity from “very mild” to “very severe.” Subjects will complete this scale on Day 1 prior to first dose 
(Baseline), Day 28, Day 56, Day 84, and Day 105. At each visit, subjects will be asked to place a mark 
on the two given lines based on the extent of their symptoms. The locations of the marks made by the 
subjects on the 100 mm horizontal lines will be measured in mm from left to right and recorded. The 
overall SANDE score will be calculated by multiplying the frequency score by the severity score and 
obtaining the square root (Amparo, 2015; Saboo, 2015). The questions and scoring system are shown 
below: 


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3.3.2
Exploratory Efficacy Endpoint: Ocular Surface Lissamine Green Dye Staining Score (via 
Slit Lamp)
Lissamine Green dye (approximately 5uL of 1% solution) will be applied over the surface of both eyes. 
Using the slit lamp, Corneal and Conjunctival Staining will be graded using the grading system 
described below. Corneal staining will be graded in 5 zones. Each zone will be graded from 0 to 3 
based on the density of punctate staining (maximum score =15). Similarly, conjunctiva will be graded
for each eye from 0 to 3 based on the density of punctate staining in the nasal-bulbar and temporal- 
bulbar zones staining (maximum score =6). Because Lissamine Green dye can fade variably within 4-5 
minutes, results should be recorded within approximately 1 minute of application to the eye surface.
The scoring pattern is represented below:
3.3.3
Exploratory Efficacy Endpoint: Schirmer I Test
Schirmer's test uses paper strips inserted into the eye for several minutes to measure the production of 
tears. After instilling one drop of a topical anesthetic (e.g., proparacaine) to each eye, wait


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approximately 30 seconds, then blot the inferior cul-de-sac with a tissue. Place a small strip of filter 
paper inside the lower eyelid (inferior fornix). The eyes are closed for 5 minutes. The paper is then 
removed and the amount of moisture is measured. The study site will capture the actual measurement 
in millimeters (mm) and the Sponsor will convert to categories based on the number of mm of wetting of 
the paper after 5 minutes, as follows: 
 
1. Normal is ≥15 mm. 
2. Mild dry eye is 11-14 mm 
3. Moderate dry eye is 6-10mm 
4. Severe dry eye is <5 mm 
 
3.3.4 Exploratory Efficacy Endpoint: Ocular Redness Score (ORS) (via Keratograph) 
Keratograph is FDA approved and is used in clinical care of patients in the US. The Oculus 
Keratograph 5M performs a non-invasive tear film analysis. It uses a Placido bowl with a camera 
aperture that has a fixation mark in the center. The device provides consistent illumination, allowing 
scanning of the exposed bulbar conjunctiva to take place. The keratograph then analyzes the scanned 
area. This system generates an ocular redness score (ORS) automatically, which is based on the area 
percentage ratio between the vessels and the rest of the analyzed area. For instance, if the ratio is 
16%, then the score is 1.6. The maximum ratio, according to the manufacturer, is 40%; therefore, the 
ocular redness scores that the machine generates range between 0.0 and 4.0. 
Note: The Keratograph 5M will also be used for measurement of average NITBUT, although this is not 
considered an Exploratory Efficacy Endpoint in this study. 
 
3.3.5 Exploratory Efficacy Endpoint: Validated Bulbar Redness (VBR) Grading Scale (via Slit 
Lamp) 
Ocular surface redness (nasal or temporal) will be assessed using the Validated Bulbar Redness 
grading scale (VBR) (Schulze, 2007). The VBR consists of a set of ten images illustrating different 
degrees of ocular surface redness (OR), ranging from normal to severe, and each image is assigned a 
value in an order of ascending severity. Colored copies of these images will be made and put up in all 
the examination rooms. Subjects will be examined by a slit-lamp at 10X magnification using direct 
diffuse illumination (slit fully opened, angled at 30°- 50° approximately; at half illumination intensity with 
rheostat set to maximum voltage) and the bulbar conjunctival injection of the subject’s eye (nasal and 
temporal) will be compared to the reference images and graded accordingly. To maintain uniformity, all 
subjects will be graded by a single physician (Principal Investigator) at each study site under constant 
illumination conditions. The subjects will be asked to look at nasal or temporal fixation marks while the 
physician will examine the temporal or nasal bulbar conjunctivae, respectively. 
 
Photographic anchors and their respective grades for ocular surface redness are shown below: 


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3.3.6 Exploratory Efficacy Endpoint: Clinical Global Impression (CGI) 
At each visit after Day 1, the Principal Investigator will use his/her clinical judgement of all signs and 
symptoms to provide a global assessment of each subject’s change in signs and symptoms from Day 1. 
 
The CGI is as follows (Miller, 2010): Question (to physician): In general, compared with the subject’s 
symptoms and signs on Day 1, how would you characterize his/her overall signs and symptoms now? 
 
The responses will be categorized on a seven-point scale as follows: 
 
• 
Marked worsening 
• 
Moderate worsening 
• 
Minimal worsening 
• 
Unchanged 
• 
Minimal improvement 
• 
Moderate improvement 
• 
Marked improvement 
 
3.3.7 Exploratory Efficacy Endpoint: Subject Global Assessment (SGA) 
At each visit after Day 1, subjects will be asked to assess their overall change from Day 1. The SGA is 
as follows (Miller, 2010): 
 
Question 1 (to subject): Compared to when you first received the study medication (Day 1 visit), how 
are your eye symptoms now? 
 
The responses will be categorized on a five-point scale as follows: 
 
• 
Much worse 
• 
Worse 
• 
About the same 
• 
Improved 
• 
Much improved 
 
3.4 Safety Endpoints 


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Safety assessments include Vital Signs, adverse events, and findings from ophthalmic examinations. 
All ocular and non-ocular adverse events will be assessed for severity and relationship to the 
investigational product. 
 
In addition to the primary tolerability endpoint (Section 3.1.1), the following safety endpoints will be 
assessed: 
 
• 
The proportion of subjects at Day 84 who successfully complete (i.e., tolerate) a full twelve weeks 
(i.e., 84 days) of therapy with topical administration two times per day (BID). 
• 
All reported adverse events, classified by frequency, severity, and relatedness, from baseline (Day 
1) through the last study visit (Day 105). 
• 
Clinically significant changes in vital signs or ophthalmic examination from baseline. 
 
3.4.1 Vital Signs 
Vital signs will be obtained and recorded at the Day 1 Visit, prior to the first administration of the study 
drug, and on Day 84 and Day 105. The following vital signs will be measured: 1) blood pressure 
measurements (mm Hg) will be taken while the subject is relaxed in a sitting position for at least 3 
minutes with the arm at heart level. 2) Heart rate will be recorded as beats per minute (bpm). 3) Body 
temperature (forehead) will be recorded in degrees Celsius (0C). 
 
Clinically significant changes (worsening) from baseline (Day 1) will be recorded on the adverse event 
forms. 
 
3.4.2 Ophthalmic Examination 
At all visits, the Investigator will conduct a complete undilated examination of the eyes using a binocular 
slit lamp. The Investigator will examine the tear film, eye lids, lashes, bulbar and palpebral conjunctiva, 
upper and lower lid puncta, cornea, anterior chamber, iris, lens, and anterior vitreous. Conjunctival 
hyperemia (ocular surface redness) will be graded at each visit using the VBR grading system as 
explained in Section 3.3.5. Also, measurement of visual acuity (via Snellen, with eyeglasses if 
applicable), and intraocular pressure (via Goldmann tonometry) will be performed. Clinically significant 
changes (worsening) from the baseline examination (Day 1) will be recorded on the adverse event 
forms. 
 
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
 
Subjects will be eligible for the study if all the following criteria are met: 
 
1. Aged 18 years or older. 
2. Sign and date informed consent form approved by the IRB 
3. History of Dry Eye Disease 
4. Objective evidence of DED in at least one eye by having 2 or more of the following 4 signs 
in the same eye at Screening and Baseline (Day 1) visits (same qualifying signs must be 
present at both visits): 
 
i. Conjunctival staining at > 1 (out of a possible score of 6 per eye) 
ii. Corneal staining at >2 (out of a possible score of 15 per eye) 
iii. Noninvasive Tear Break-Up Time (NITBUT) at < 7 seconds 


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iv. Schirmer test at <10mm in 5 minutes 
 
Note: For those subjects undergoing a combined Screening/Baseline visit, these criteria 
need only be met during that one visit. 
 
5. Symptomatic evidence of DED by having a global symptom score (SANDE) >25 mm at both 
Screening and Baseline (Day 1) visits 
6. Intraocular pressure (IOP) > 5 mmHg and <22 mmHg in each eye 
7. Women who satisfy one of the following: 
a. Are of child-bearing potential (WOCP) who are not pregnant or lactating and who are 
either abstinent or sexually active on an acceptable method of birth control for at 
least 4 weeks prior to Visit 1 and throughout the study (i.e., until Day 105), OR 
b. Are post-menopausal or have undergone a sterilization procedure 
 
 
4.2 Exclusion Criteria 
 
Subjects will not be eligible for the study if any of the following criteria are met prior to initial dosing: 
 
1. Allergic to brimonidine, loteprednol or any similar products, or excipients of brimonidine 
or loteprednol, including benzalkonium chloride (BAK) 
2. Use of contact lenses within 2 weeks prior to Screening visit or during study 
3. Currently receiving brimonidine or other treatment for glaucoma or ocular hypertension 
or history of glaucoma surgery. 
4. Receiving or have received any experimental or investigational drug or device within 30 
days prior to Screening visit 
5. Intraocular pressure <5 mmHg or >22 mmHg in either eye 
6. Active ocular infection or history of ocular herpetic keratitis 
7. History of neurotrophic keratitis or ocular neuropathic pain 
8. Any history of eyelid surgery or intraocular/ocular surgery within the past 3 months 
9. Punctal occlusion within 3 months prior to Screening visit or during study 
10. Corneal epithelial defect larger than 1 mm2 in either eye 
11. Have active drug/alcohol dependence or abuse history 
12. Are neonates, pregnant/lactating women, children, institutionalized individuals, or others 
who may be considered vulnerable populations 
13. Received corticosteroid-containing eye drops within the past 7 days, or a change in 
systemic corticosteroids/immunosuppressives within the past 30 days 
14. A change in cyclosporine ophthalmic emulsion 0.05% (Restasis®) or lifitegrast 
ophthalmic solution 5% (Xiidra™) within 30 days prior to Screening visit 
15. In the opinion of Investigator or Study Coordinator, be unwilling or unable to comply with 
study protocol or unable to successfully instill eye drops 
16. Disease, condition, or disorder that in the judgement of Investigator could confound 
study assessments or limit compliance to study protocol 
 
Subjects will be permitted to continue all their over-the-counter dry eye treatments, including the use of 
artificial tears, eyelid massage, or warm compresses, if they commit to the same brand/regimen 
throughout the study. In addition, they can continue their use of cyclosporine ophthalmic emulsion 
0.05% 
(Restasis®) 
or 
lifitegrast 
ophthalmic 
solution 
5% 
(Xiidra™) 
or 
systemic 
corticosteroids/immunosuppressives as long as the dosing regimen has not changed within the 30 days 
prior to Screening. None of the dry eye treatments, whether over-the-counter or prescription (e.g., 


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Restasis® or Xiidra™), should be used within 2 hours of instilling study medication or within 2 hours 
prior to a study visit. 
 
4.3 Subject Recruitment and Screening 
 
Potential subjects will be recruited from the clinical practice of the Investigator at the time of their 
routine eye examination visit. Subjects will include patients who have been diagnosed with DED in the 
Investigator’s eye clinic. All subjects will be screened, recruited, and will attend all study related visits 
only at their Investigator’s clinic. 
 
Patients with diagnosed DED and annoying or activity limiting visual symptoms will be approached by a 
member of the research staff to determine if the subject might be interested in participating in a 
research study. If the patient is interested, the research staff member will describe the study. If the 
patient is willing to enter the study, the study will be discussed and the patient will be asked to sign the 
Informed Consent form. Screening procedures include documentation of DED as well as other 
assessments as detailed in Section 6.3.1. Eligible subjects will be enrolled in the study. 
 
 
4.4 Early Withdrawal of Subjects 
 
4.4.1 When and How to Withdraw Subjects 
Subjects have the right to withdraw from the study at any time, for any reason, without jeopardizing 
their medical care. Where possible, subjects will be followed for safety and encouraged to return for 
follow-up visits for any unresolved safety events. 
 
The IRB and Investigator also have the right to withdraw subjects from the study for the following 
reasons: when continuation may jeopardize the health of the subject, protocol violations, adverse 
events or concurrent conditions that affect the patient’s well-being, and administrative or other reasons. 
 
4.4.2 Data Collection and Follow-Up for Withdrawn Subjects 
If a subject withdraws from the study prior to 12 weeks (84 days), the subject will be asked to complete 
the procedures outlined in the Day 84 visit as soon as possible. Subjects who voluntarily withdraw from 
the study between Day 84 and Day 105 will be asked to complete procedures outlined in the Day 105 
visit as soon as possible. Subjects who are withdrawn due to adverse events will be followed at least 
until resolution or stabilization of the adverse event. 
 
If the subject remains in the study for safety evaluation, follow-up visits will be scheduled according to 
the schedule of visits and procedures. 
 
5 Study Drug 
5.1 Description 
The assigned study treatment will be provided to subjects in two bottles. In the brimonidine + 
loteprednol combination arm, brimonidine 0.2% will be supplied as an ophthalmic solution in Bottle #1 
for administration as a single eye drop, followed by a loteprednol ophthalmic suspension (0.2%) 
application from Bottle #2 approximately 5-10 minutes later in each eye two times a day (BID) for 
twelve weeks (84 days). In the brimonidine monotherapy arm, each subject will receive the study drug 
as a single eye drop from Bottle #1(brimonidine) followed by an application from Bottle #2 (placebo) 
approximately 5-10 minutes later in each eye two times a day (BID) for twelve weeks (84 days). 


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Similarly, the control group will receive placebo (sodium carboxymethylcellulose, 0.25%) as a single 
eye drop from Bottle #1 followed by another application from Bottle #2 approximately 5-10 minutes later 
in each eye two times a day (BID) for twelve weeks (84 days). Except for the first dose during the clinic 
visit on Day 1, subjects will self-administer the study eye drops at home. Study drug will be blinded to 
both patient and Investigator. To maintain the blind, commercial dropper vials of approximately the 
same size (minimum 10mL) will be used for all study medication, and the original labels will be covered, 
obscured, or removed. There will be a uniform-appearing study-specific label for all study medication. 
 
In summary, regardless of study arm, subjects will administer a single drop from Bottle #1 in each eye 
and wait 5-10 minutes before administering a single drop from Bottle #2 in each eye. This regimen will 
be conducted two times each day (BID) for twelve weeks (84 days). 
 
Subjects will not be charged for the study drug in any way (neither the cost of the medication nor its 
dispensing cost). 
 
5.2 Treatment Regimen 
After Day 1, the subject will be instructed to instill the first dose of the study medication in the morning 
at approximately 8 a.m., and the next dose at approximately a 12-hour interval. Therefore, doses will be 
scheduled at approximately 8 a.m. and 8 p.m. During the treatment period, on days in which the patient 
will be in the clinic for evaluation (Days 1, 28, 56, and 84), patients should still receive both doses of 
study medication, on or close to their usual schedule, approximately 12 hours apart. However, no eye 
treatment (whether study medication or other eye drops/products) should be used within 2 hours prior 
to the clinic evaluation 
 
 
5.3 Method for Assigning Subjects to Treatment Groups 
This placebo-controlled, double-blind study will have three treatment groups utilizing a 1:1:1 
randomization. One group will receive the study drug combination (brimonidine 0.2% then loteprednol 
ophthalmic suspension 0.2% separated by 5-10 minutes), one group will receive study drug 
monotherapy (brimonidine 0.2% then placebo separated by 5-10 minutes), and the third group will 
receive placebo (sodium carboxymethylcellulose, 0.25% x 2 applications separated by 5-10 minutes). 
Randomization/treatment assignment will be stratified by site and performed by an unblinded study 
team member. 
 
To maintain confidentiality, the subject’s name will not be recorded on any study document other than 
the informed consent form. A subject identification number will be created and linked to the drug vial 
number in a way that maintains the blind. Commercial dropper vials of approximately the same size 
(minimum 10mL) will be used for all study medication, and the original labels will be covered, obscured, 
or removed. There will be a uniform-appearing study-specific label for all study medication. 
 
 
5.4 Preparation and Administration of Study Drug 
The study drug will be procured, packaged, labeled, and coded by an outside vendor. One 
concentration of brimonidine tartrate ophthalmic solution will be used (0.2%), one concentration of 
loteprednol etabonate ophthalmic suspension will be used (0.2%), and one concentration of sodium 
carboxymethylcellulose, eye drops will be used (0.25%). All three agents will contain benzalkonium 
chloride. The eye droppers will be used by subjects as multiple-dose applications. The agents are 
regularly stored at room temperature (15°-25° C/ 59-77°F). 


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Instructions for Drug Administration (for clinic staff on Day 1): 
1. Wash your hands thoroughly with soap and water 
2. Check the dropper tip to make sure that it is not chipped or cracked. 
3. Avoid touching the dropper tip against the subject’s eye or anything else – eye drops and 
droppers must be kept clean 
4. Have the subject tilt their head back and pull down the lower lid of his/her eye with your 
index finger to form a pocket 
5. Hold the dropper (tip down) with the other hand, as close to the eye as possible without 
touching it 
6. While looking up, gently squeeze the dropper so that a single drop falls into the pocket 
made by the lower eyelid. Remove your index finger from the lower eyelid 
7. Ask the subject to close the eye for 2 to 3 minutes and tip his/her head down as though 
looking at the floor. Ask them to try not to blink or squeeze their eyelids 
8. Place a finger on the tear duct and apply gentle pressure 
 
Subjects should repeat the above procedures for the other eye in the clinic to demonstrate to the 
Investigator or designee that they are able to perform the drug administration satisfactorily. Subjects will 
be instructed to perform these steps on each subsequent administration of the study medication. 
Instructions for use will be provided to the subjects with the study drug. 
 
5.5 Subject Compliance Monitoring 
Subjects will receive their first dose of study drug on study Day 1 in the clinic, consistent with the 
treatment arm to which they were randomized. All subsequent doses will be self-administered. 
Subjects will be given diaries to record each dose. In addition, they will be asked to make a note of any 
missed doses together with the reason for the omission. Subjects will be asked to bring their diaries, 
along with any used and unused dropper vials, with them to the Day 28, 56, and Day 84 visits to aid in 
determining study drug compliance. Enough study drug to last until the next visit will be given to the 
subject at each visit, starting with Day 1 (Baseline visit). No study drug will be given at the Screening 
visit (if separate from the Day 1 visit), Day 84, and Day 105 visits. 
 
5.6 Prior and Concomitant Therapy 
All eye medication (prescription and over-the-counter), steroids, antibiotics, blood pressure medication, 
anti-inflammatory medication, or immunosuppressive medication, whether topical or systemic, should 
be recorded if taken within 30 days prior to Day 1, whether there is continued use or not. All 
concomitant medications must be identified in the subject’s medical record, including all eye treatments 
administered for DED. These medications will be recorded in the case report form (CRF). 
 
For each medication taken, the following information will be collected: 
 
1. Medication trade name 
2. Eye that was treated, if applicable 
3. Indication for which the medication was given 
4. Date started 
5. Date stopped 
6. Dose, frequency and route of administration of the medication 
 
Subjects will be permitted to continue all their over-the-counter dry eye treatments, including the use of 
artificial tears, eyelid massage, or warm compresses, if they commit to the same brand/regimen 
throughout the study. In addition, they can continue their use of cyclosporine ophthalmic emulsion 
0.05%  (Restasis®)  or  lifitegrast  ophthalmic  solution  5%  (Xiidra™)  or  systemic 


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corticosteroids/immunosuppressives as long as the dosing regimen has not changed within the 30 days 
prior to Screening. None of the dry eye treatments, whether over-the-counter or prescription (e.g., 
Restasis® or Xiidra™), should be used within 2 hours of instilling study medication or within 2 hours 
prior to a study visit. 
 
The use of any investigational agent during the 30 days prior to enrollment is prohibited. 
 
 
5.7 Rescue Plan 
Subjects will be monitored by the Principal Investigator and/or Sub-Investigator or designee at each 
study visit (approximately every 4 weeks). Subjects will also be encouraged to contact the research 
team in case they experience any ocular discomfort during the study. Any worsening of DED or any 
adverse event (AE) will be recorded, and in the case of AEs, followed to resolution. Based on the 
individual subject’s clinical condition, one or more of the following therapeutic decisions may be 
implemented: 
(1) Increasing the frequency of artificial tears or other over-the-counter dry eye treatments, 
and/or 
(2) Discontinuing the study drug. 
The decision will be made by the Principal Investigator based on his/her clinical judgment and the 
individual subject’s clinical condition. The subject shall receive the treatment required for his/ her eye 
condition as per established clinical guidelines. Such treatment, and reason for administration, will be 
recorded in the case report form. In this situation, the subject will be followed closely (at least weekly) 
until complete resolution of symptoms and return to the subject’s previous baseline. 
 
5.8 Packaging 
The study drug will be procured, packaged, labeled, and coded by an outside vendor. To maintain the 
blind, commercial dropper vials of approximately the same size (minimum 10mL) will be used for all 
study medication, and the original labels will be covered, obscured, or removed. There will be a 
uniform-appearing study-specific label for all study medication. The two bottles of study drug for the 
assigned arm will be packaged together in a plastic bag with a label that will be customized with the 
subject’s identifiers. The bag label will also include the study protocol number, guidance for product 
storage, and a statement that the drug is “New Drug – Limited by Federal Law to Investigational Use 
Only”. Instructions on medication self-administration will be included in each medication bag distributed 
to the subject. The dispensing of medication to subjects will be done at each study site. The eye 
dropper bottles will be used by subjects as multiple-dose applications. 
 
The first dose will be administered to the subject by the researcher at the first treatment visit (Day 1). 
 
5.9 Receiving, Storage, Dispensing and Return 
 
5.9.1 Receipt of Drug Supplies 
Each Investigator will receive a standard shipment of study materials and will order additional study 
drug as required. The study drug will be stored in a controlled environment and dispensed to subjects 
as needed. 
 
5.9.2 Storage 
Study drug will be stored at each site at room temperature (15°-25° C/ 59-77°F). The study drug will be 
directly dispensed to the subject from the site on each treatment visit. 


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5.9.3 Dispensing of Study Drug 
At the first treatment visit (Day 1), the first study medication dose will be administered to subjects in the 
clinic and the eyedropper bottle containing sufficient drug to last for 4 weeks will be given to them to 
take home. The subjects will be asked to return the used eyedropper bottle at the follow-up visits. The 
designated study team member will then retrieve the previously dispensed eyedropper bottle and a 
fresh 4-week supply will be dispensed by the site. 
 
5.9.4 Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of drug ordered/received, drug 
consumed, and drug remaining. Any discrepancies will be investigated, resolved, and documented. 
The used drug eyedroppers will be disposed by the study staff according to the site’s standard 
protocols. 
 
 
6 
Study Procedures 
6.1 Assignment of Subject Identification 
Subjects meeting the enrollment criteria (see Sections 4.1 and 4.2) will be eligible for the study. To 
maintain confidentiality, the subject’s name will not be recorded on any study document other than the 
informed consent. At the time of Screening, each subject will be assigned a five-digit site-specific 
subject number, and for subjects who qualify for the study, a unique 6-digit randomization number will 
be assigned. All data submitted to the sponsor will be de-identified. 
 
6.2 Screen Failure 
A record of screen failures and the reasons for non-eligibility will be maintained. 
 
6.3 Study Assessments 
The following detailed procedures are performed at the designated clinic visit. All results will be 
documented on the subject’s medical/research charts, source documents, and CRFs as required. All 
ophthalmic procedures will be performed on both eyes. In general, assessments may be performed by 
the Principal Investigator, a Sub-investigator, a research coordinator, nursing staff, or other members of 
the research team. However, all tear film and ocular surface parameters are to be measured by the 
same investigator within each study site. 
 
 
6.3.1 Day -7 to 0 (Screening Visit) 
The Screening Visit and Day 1 Visit may be combined into a single visit. In this case, do not duplicate 
any of the Screening/Day 1 procedures. Subjects taking steroid-containing eye drops at the Screening 
Visit must discontinue those drops and wait a full 7 days before attending the Day 1 Visit. 
 
After obtaining Informed Consent, the following assessments will be performed within 7 days prior to 
the subject receiving the first dose of study medication: 
• Demographic information, including: birth date, gender, race and ethnic origin 
• Medical History, including a review of the following systems: cardiovascular, dermatologic, 
gastrointestinal, genitourinary, musculoskeletal, neurologic and respiratory. Any history of 
cerebral or coronary insufficiency, postural hypotension or Raynaud's disease will be noted. An 
allergic history (including medications and food) will also be obtained. A history of prior and 


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concomitant medication use (including prescription, OTC, and herbal products) during the past 
30 days will also be completed 
 
• Ocular History, including: date when the subject began treatment for DED, as well as 
medications and procedures for DED. 
• SANDE Questionnaire (Section 3.3.1) to quantify ocular symptoms due to Dry Eye Disease 
 
• Keratograph Noninvasive Tear Breakup Time (NIBUT). The Keratograph 5M will automatically 
record NITBUT values based on manufacturer’s guidelines 
• Ophthalmic Examination (slit lamp examination, Lissamine Green staining, and a Schirmer I 
test). Eyelid margins and meibomian gland openings will be evaluated during a slit lamp 
examination by the physician, and changes such as lid margin vascularization (including 
telangiectasia) will be recorded 
• IOP (Goldmann tonometry) assessment 
 
6.3.2 Day 1 (Baseline, Randomization, and First Treatment Visit) 
Note: Day 1, by definition, is when the first dose of study drug is administered. Endpoint 
assessments done at subsequent visits will be compared to baseline assessments done at the 
Day 1 visit. For this reason, the Day 1 Visit is also known as the Baseline visit. 
 
-Prior to first dose of study drug (Baseline): 
• 
SANDE Questionnaire 
• 
Vital Signs (blood pressure taken while subject is relaxed in a sitting position for at least 
3 minutes, pulse, and temperature) 
• 
Visual Acuity (Snellen chart) 
• 
Keratograph Ocular Redness Score (ORS) 
• 
Keratograph Noninvasive Tear Breakup Time (NIBUT) 
• 
Baseline Ophthalmic Examination (slit lamp examination, VBR scale and Lissamine 
Green staining) 
• 
Schirmer I test 
• 
IOP (Goldmann tonometry) assessment 
• 
Record changes in concomitant medication 
• 
Adverse events since screening visit. 
 
-Randomization and administration of first dose of study drug by clinic staff 
 
-After first dose of study drug: 
• 
Subjects will be trained on how to self-administer the study eye drops and be given a 
sufficient supply to last for 4 weeks 
• 
Subjects will receive a study diary on which to record the day/time of the first dose and 
each subsequent dose 
• 
Post-dose evaluation for any adverse effects 
• 
Tolerability Visual Analog Scale (VAS) 
 
6.3.3 Day 28 (± 7 days) 
Treatment Visit 
• 
SANDE Questionnaire 


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• 
Review the subject’s diary 
• 
Visual Acuity (Snellen chart) 
• 
Keratograph Ocular Redness Score (ORS) 
• 
Ophthalmic Examination (slit lamp examination, VBR scale) 
• 
IOP (Goldmann tonometry) assessment 
• 
Clinical Global Impression, Subject Global Assessment 
• 
Subjects will be given study medication refill 
• 
Tolerability VAS 
• 
Record changes in concomitant medication and adverse events 
 
6.3.4 Day 56 (± 7 days) 
Treatment Visit 
• 
SANDE Questionnaire 
• 
Review the subject’s diary 
• 
Visual Acuity (Snellen chart) 
• 
Keratograph Ocular Redness Score (ORS) 
• 
Ophthalmic Examination (slit lamp examination, VBR score) 
• 
Clinical Global Impression, Subject Global Assessment 
• 
Subjects will be given study medication refill 
• 
Tolerability VAS 
• 
Record changes in concomitant medication and adverse events 
 
6.3.5 
Day 84 (± 7 days) 
Primary Endpoint Assessment Visit 
 
• 
SANDE Questionnaire 
• 
Review the subject’s diary 
• 
Vital Signs 
• 
Visual Acuity (Snellen chart) 
• 
Keratograph Ocular Redness Score (ORS) 
• 
Keratograph Noninvasive Tear Breakup Time (NIBUT) 
• 
Ophthalmic Examination (slit lamp examination, VBR scale, Lissamine Green staining) 
• 
Schirmer I test 
• 
IOP (Goldmann tonometry) assessment 
• 
Clinical Global Impression, Subject Global Assessment 
• 
Tolerability VAS 
• 
Record changes in concomitant medication and adverse events 
 
6.3.6 Day 105 (± 7 days) 
End-of-Study Visit 
 
• 
SANDE Questionnaire 
• 
Vital Signs 
• 
Visual Acuity (Snellen chart) 
• 
Keratograph Ocular Redness Score (ORS) 
• 
Ophthalmic Examination (slit lamp examination, VBR scale) 
• 
IOP (Goldmann tonometry) assessment 
• 
Clinical Global Impression, Subject Global Assessment 
• 
Record changes in concomitant medication and adverse events 


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7 Statistical Plan 
7.1 Sample Size Determination 
Thirty (30) subjects per treatment group and a common standard deviation of 20 mm yields precision 
(half-width) of the point estimate of pairwise difference (active – placebo) in tolerability of +/- 10.3 mm 
for a two-sided 95% confidence interval (CI) and +/- 8.6 mm for a two-sided 90% CI. Therefore, if the 
observed mean difference in tolerability is 5.0 mm, the true mean difference in tolerability will be within 
(-5.3, 15.3) with 95% confidence and (-3.6, 13.6) with 90% confidence. 
 
Additionally, with a sample size of 30 subjects within a treatment group, adverse events that are not 
observed will be concluded to occur at a true rate of <10% with 95% confidence within that treatment 
group. For example, if headache is not seen within the combination treatment group, then with 95% 
confidence, headache would be concluded to occur at a true rate of <10%. 
 
The sample size was not calculated to have pre-determined power for efficacy in this proof-of-concept 
study. 
 
 
7.2 Statistical Methods 
 
7.2.1 Unit of Analysis 
The unit of analysis for efficacy will be the study eye. Each subject will have a single eye identified as 
the study eye as follows: (i) if only 1 eye meets inclusion criteria, this eye will be the study eye and the 
other eye will be considered the non-qualified fellow eye; (ii) if both eyes meet inclusion criteria, the eye 
with the higher Ocular Redness Score (ORS) will be the study eye and the other eye will be considered 
the qualified fellow eye; (iii) if both eyes have the same Ocular Redness Score (ORS), then the eye with 
the lower Schirmer I score will be the study eye and the other eye will be considered the qualified fellow 
eye; (iv) if both eyes have same Schirmer 1 score, the right eye will be the study eye and the other eye 
will be considered the qualified fellow eye. Safety and Efficacy analyses will be primarily performed on 
the study eyes and secondarily on the qualified fellow eyes (for efficacy) and all fellow eyes (for safety). 
 
7.2.2 Analysis Populations 
Randomized Population: The randomized population will include all subjects who were randomized to 
treatment. Baseline variables and demographic characteristics will be summarized for this population. 
 
Safety Population: The safety population will include all randomized subjects who have received at 
least one dose of study medication. This population will be used to summarize safety variables and will 
summarize subjects as treated. 
 
Intent-to-Treat Population (ITT): The ITT population will include all randomized subjects who have 
received at least one dose of study medication. This population will be the primary population for 
efficacy analyses and will be used to summarize all efficacy variables and will summarize subjects as 
randomized. 
 
Per-protocol population (PP): The PP population is a subset of the ITT population, which will include 
those subjects who do not have major protocol violations likely to seriously affect the primary outcome 
of the study as judged by a masked evaluation prior to the unmasking of the study treatment. This 
population will be the secondary population for efficacy analyses and will be used to summarize a 
subset of efficacy variables. If the PP and ITT populations are exactly the same, then additional efficacy 


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analyses on the PP population will not be performed. The PP population will summarize subjects as 
treated. 
 
7.2.3 General Considerations 
All continuous study assessments will be summarized by treatment and visit (as applicable) and 
change from baseline to each post-baseline visit using descriptive statistics (n, mean, median, standard 
deviation, minimum, and maximum). All categorical study assessments will be summarized by 
treatment and visit (as applicable) using frequency counts and percentages. 
 
Baseline is defined as the last measurement prior to the first dose of study medication. 
 
Missing values of less than 25% will be imputed by using multiple imputations; otherwise will not be 
included in the analysis. Descriptive statistics will be utilized before the modeling to describe the 
sample. Assumptions behind each statistical method will be examined. Two-sided P-value less than 
0.05 would be considered as statistical significance. All the analyses will be conducted by using SAS 
9.2 (SAS Inst., Cary, NC). 
 
7.2.4 Safety Analysis 
Tolerability will be summarized by treatment group at each visit using continuous summary statistics; p- 
values from pairwise two-sample t-tests and 90% and 95% CIs will be presented to test the difference 
in mean tolerability among the three treatment groups. 
 
Verbatim descriptions of AEs will be mapped to MedDRA thesaurus terms. Treatment emergent AEs 
(TEAEs), those that occur after the first dose of study medication, will be summarized by treatment 
group using frequency and percent for each system organ class (SOC) and preferred term (PT) within 
each SOC. Summaries will be presented at the subject level for both ocular and non-ocular TEAEs. 
Summaries will also be presented for serious TEAEs, TEAEs related to Investigational Product, TEAEs 
by severity, and TEAEs leading to discontinuation. 
 
Slit lamp biomicroscopy measures will be summarized by treatment group at each visit using discrete 
summary statistics. 
 
Visual acuity data will be summarized by treatment group at each visit and for change from baseline to 
each visit using discrete summaries including change from baseline in the number of lines and the 
proportion of subjects with a worsening of ≥ 3 lines from baseline. 
 
Intraocular pressure will be summarized by treatment group at each visit and for change from baseline 
to each visit using both continuous and discrete summaries. 
 
Vital signs will be summarized by treatment group at each visit and for change from baseline to each 
visit using continuous summary statistics. 
 
7.2.5 Efficacy Analysis 
The efficacy parameters, SANDE, CGI, SGA, Lissamine Green corneal and conjunctival staining, 
Schirmer’s Test I, Keratograph Ocular Redness Score (ORS), and Validated Bulbar Redness (VBR) 
scores will be summarized by treatment group at each visit and for change from baseline to each visit 
using continuous and discrete summary statistics as appropriate and using pairwise two-sample t-tests 
or Pearson’s chi-squared test (or Fisher’s exact test if expected cell count is <5) and corresponding 
asymptotic 90% and 95% CI around the difference in means or proportions. 


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Lissamine Green corneal and conjunctival staining will be summarized by region and overall. 
 
7.2.6 Missing Data 
Efficacy analyses will be performed using the ITT (primary) and PP (secondarily) populations and will 
summarize both observed data only and with missing data imputed using: multiple imputation 
techniques, trimmed mean analyses, and last observation carried forward (for endpoints as detailed in 
the formal statistical analysis plan; additionally, the statistical analysis plan will detail which imputation 
or observed data only will be considered primary and which imputations or observed data only will be 
considered secondary). 
 
 
7.2.7 Multiplicity Considerations 
As this is a proof of concept study for which there is no pre-determined power for a specific endpoint 
measure, there will be no multiplicity adjustments to account for the testing of the multiple endpoints 
and for the testing of both the combination arm and monotherapy arm to placebo. 
 
 
8 Safety and Adverse Events 
8.1 Definition of Adverse Events and Serious Adverse Events (SAEs) 
The following are specific definitions of terms guided by the International Conference on Harmonization 
(ICH) Guidelines for Good Clinical Practice (GCP) and the U.S. Code of Federal Regulations that apply 
to this section: 
 
Adverse Event: Any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. An adverse event can be any unfavorable sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of the investigational 
product, whether considered related or not related to the investigational product. 
 
Subjects will be reminded to inform the study staff of any adverse effects that they have experienced or 
are experiencing after the first administration of study drug. All reports of adverse events during the 
study will be recorded on an Adverse Event Case Report Form (CRF). The subject should not be 
prompted about any adverse events that may occur during this trial. 
 
The study staff should instruct the subject to notify the research facility should any adverse event occur 
within 7 days of study completion. Subjects who withdraw due to an adverse event may be replaced. 
 
Serious Adverse Event (SAE): An Adverse Event should be considered a Serious Adverse Event 
(SAE) if any of the following criteria are met: 
• 
results in death 
• 
is life-threatening* 
• 
requires inpatient hospitalization or prolongs existing hospitalization 
• 
results in persistent or significant disability/incapacity 
• 
is a congenital anomaly/ birth defect 
• 
requires medical or surgical intervention to prevent any of the occurrences noted above 
 
*Life-Threatening: Any adverse drug experience in which the subject was at risk of death at the time of 
the event. It does not refer to an event which hypothetically might have caused death if it were more 
severe. 


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If a subject experiences an SAE, the study staff should notify the Sponsor within 24 hours of the staff 
becoming aware of the event. 
 
Unexpected Adverse Event: Any adverse event, the specificity or severity of which is not consistent 
with the current Package Insert. 
 
 
8.2 Classification of Adverse Events by Severity 
All toxicities/adverse events will be graded according to the following definitions to code the intensity of 
the event. 
 
Mild: Usually transient, requiring no special treatment, and does not interfere with the subject’s daily 
activities. 
Moderate: Traditionally introduces a low level of inconvenience or concern to the subject and may 
interfere with daily activities, but are usually relieved by simple therapeutic measures. 
Severe: Causes an interruption of the subject’s usual daily activity and traditionally required systemic 
drug therapy or other treatment. 
Note: If the intensity of an adverse event changes, the event will be reentered as a separate event. 
 
There is a distinction between the severity and the seriousness of an adverse event. Severity is a 
measurement of intensity; thus, a severe reaction is not necessarily a serious adverse event. For 
example, a headache may be severe in intensity, but would not be serious unless it met one of the 
criteria for serious adverse events listed previously. 
 
 
8.3 Classification of Adverse Events by Relationship to Study Treatment 
The relationship or association of the study medication to an adverse event, as causing or contributing 
to the adverse event, will be characterized as defined below: 
 
Probably/Definitely Related: Either a direct association can be demonstrated or the adverse event 
follows a reasonable temporal sequence from administration of the drug (including the course after 
withdrawal of the drug) and the possibilities of factors other than the drug, such as underlying disease, 
concomitant drugs or concurrent treatment, can be excluded. 
 
Possibly Related: The adverse event follows a reasonable temporal sequence from administration of 
the drug (including the course after withdrawal of the drug) and the possibility that drug involvement 
cannot be excluded, e.g. existence of similar reports attributable to the suspected drug, its analog or its 
pharmacological effect. However, other factors such as underlying disease, concomitant drugs or 
concurrent treatment are presumable. 
 
Not Related: The adverse event has no temporal sequence from administration of the drug, or it can be 
explained by other factors, including underlying disease, concomitant drugs or concurrent treatment. 
 
 
8.4 Action(s) Taken 
The investigator will select one or more of the following choices in the CRF for each adverse event: 


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Action taken with the study drug: 
• 
Dose not changed 
• 
Drug Interrupted 
• 
Drug Discontinued 
• 
Unknown 
• 
Not Applicable 
 
Action taken for subject: 
• 
None 
• 
Subject Withdrawn 
• 
Administered Therapy 
• 
Hospitalized Subject 
• 
Other 
 
8.5 Outcome 
The outcome for each adverse event documented will also be recorded in the CRF. The selection of 
options include the following: 
 
• 
Recovered/Resolved 
• 
Not Recovered/Not Resolved 
• 
Recovered/Resolved with Sequelae 
• 
Fatal 
• 
Unknown 
 
8.6 Adverse Event Reporting 
All subjects who have been exposed to study drug will be evaluated for adverse events. Adverse 
events will be recorded starting after the first dose of study drug and continuing until the end of the 
study. All adverse events will be evaluated beginning with onset, and evaluation will continue until 
resolution is noted, or until the Investigator determines that the subject’s condition is stable, whichever 
is earlier. The Investigator will take all appropriate and necessary therapeutic measures required for 
resolution of the adverse event. Any medication necessary for the treatment of an adverse event must 
be recorded on the Concomitant Medication case report form. If more than one distinct adverse event 
occurs, each event should be recorded separately. Procedures such as surgery should not be recorded 
as adverse events. However, the medical condition for which the procedure was performed should be 
reported if it meets the definition of adverse event as described previously. 
 
8.7 Serious Adverse Event Reporting 
All SAEs (as defined in Section 8.1) that occur during the study will be reported to the Sponsor within 
24 hours of the study staff becoming aware of the event. SAEs will be recorded starting after first dose 
of study drug and continuing until the end of the study. A copy of the report will be sent to the FDA. 
 
In cases where an event is both Serious and Unexpected, the study Sponsor is responsible for 
submitting an IND Safety Report to the FDA and all participating investigators. Any adverse events or 
IND Safety reports that require a change to this protocol or the associated Informed Consent document 
will be reported to the IRB within 5 days. 


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8.8 Medical Emergencies 
In medical emergencies, the Investigator should use medical judgment and remove the subject from 
immediate hazard. The IRB should be notified as to the type of emergency and the course of action 
taken. In case of an Emergency, a code list will be accessible to one member of the study team for the 
purpose of emergency unblinding, if required. 
 
8.9 Study Oversight 
The Study PI has primary oversight responsibility for this study. The Principal Investigator and his/her 
research team are responsible for identifying adverse events. Safety monitoring will include careful 
assessment and appropriate reporting of adverse events. Subjects will be reminded to inform the study 
staff of any adverse effects that they have experienced or are experiencing after the first administration 
of study drug. All reports of adverse events during the study will be recorded on an Adverse Event 
Case Report Form (CRF). In addition, subjects will be asked to make a note of any missed doses 
together with the reason for the omission. A member of the research staff will review diary entries with 
the subject at each study visit. Subjects will be asked to bring back the leftover drug at each study visit. 
The amount of drug remaining in the used vial will also give an estimate of the compliance. 
 
It is the responsibility of each Investigator and the study Sponsor, Ocugen Inc. to conduct this study in 
compliance with all aspects of the protocol, IRB requirements, Declaration of Helsinki, all applicable 
Federal Regulations (21 CFR Parts 812, 50, 54 and 56) and general Good Clinical Practice (GCP). In 
the event of a protocol deviation, the Sponsor should be notified, as should the IRB if the deviation 
meets their stated requirements for deviation reporting. As necessary, corrective action should be taken 
to ensure the subject’s safety and to maintain the integrity of the clinical investigation. 
 
 
9 Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements 
of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Those regulations require a 
signed subject authorization informing the subject of the following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI. 
 
If a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains the ability 
to use all information collected prior to the revocation of subject authorization. For subjects that have 
revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect at 
least vital status (i.e. that the subject is alive) at the end of their scheduled study period. 
 
 
10 Source Documents 
Source data are all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in 
source documents. Examples of these original documents, and data records include: hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the 
laboratories, and at medical-technical departments involved in the clinical trial. 


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10.1 Records Retention 
It is the investigator’s responsibility to retain study essential documents for the full duration of the study. 
This includes, but is not limited to, the following: completed Informed Consent forms, Case Report 
Forms, AE/SAE report forms, all study correspondence and associated documentation. Per regulations, 
these records should be maintained for a period of two years following a marketing approval for the 
study drug or two years following shipment and delivery of the drug for investigational use is 
discontinued. In the event the site is not able to store records for the full 2-year duration, the study 
Sponsor should be informed so that alternative retention and storage plans can be confirmed. 
 
 
11 Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical Practice 
(FDA Title 21 part 312 and International Conference on Harmonization guidelines), applicable 
government regulations and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the study 
conduct. The decision of the IRB concerning the conduct of the study will be made in writing to the 
investigator. The study may not commence until IRB approval is granted. 
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study. This 
consent form will be submitted with the protocol for review and approval by the IRB for the study. The 
formal consent of a subject, using the IRB-approved consent form, must be obtained before that subject 
undergoes any study procedure. The consent form must be signed by the subject (or legally authorized 
representative) and the investigator-designated research professional obtaining the consent. 


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12 References 
 
Allergan. Approved Labeling for Alphlagan P 
AlrexTM [package insert]. Bausch and Lomb Pharmaceuticals, Inc. Tampa, FL; 1998 
 
Amparo F, Schaumberg DA, and Dana R. Comparison of Two Questionnaires for Dry Eye Symptom Assessment: 
The Ocular Surface Disease Index and the Symptom Assessment in Dry Eye. Ophthalmology (2015) Jul; 122(7): 
1498-1503. 
 
Bao JY, Huang Y, Wang F, Peng YP, Qiu YH. Expression of alpha-AR subtypes in T lymphocytes and role of the 
alpha-ARs in mediating modulation of T cell function. Neuroimmunomodulation 2007; 14(6):344-353. 
Belmonte C, Acosta MC, Gallar J. Neural basis of sensation in intact and injured corneas. Exp Eye Res 2004; 
78(3):513-525. 
Bradshaw CM, Sheridan RD, Szabadi E. Neuronal responses to noradrenaline in the cerebral cortex: evidence 
against the involvement of alpha 2-adrenoceptors. Br J Pharmacol 1984; 82(2):453-458. 
Felsner P, Hofer D, Rinner I, Porta S, Korsatko W, Schauenstein K. Adrenergic suppression of peripheral blood T 
cell reactivity in the rat is due to activation of peripheral alpha 2-receptors. J Neuroimmunol 1995; 57(1-2):27-34. 
Herrera-Garcia AM, Dominguez-Luis MJ, Arce-Franco M, Armas-Gonzalez E, Alvarez de La RD, Machado JD et 
al. Prevention of neutrophil extravasation by alpha2-adrenoceptor-mediated endothelial stabilization. J Immunol 
2014; 193(6):3023-3035. 
Hirata H, Rosenblatt MI. Hyperosmolar tears enhance cooling sensitivity of the corneal nerves in rats: possible 
neural basis for cold-induced dry eye pain. Invest Ophthalmol Vis Sci 2014; 55(9):5821-5833. 
Hong S, Han SH, Kim CY, Kim KY, Song YK, Seong GJ. Brimonidine reduces TGF-beta-induced extracellular 
matrix synthesis in human Tenon's fibroblasts. BMC Ophthalmol 2015; 15:54. 
Lin H, Yiu SC. Dry eye disease: a review of diagnostic approaches and treatments. Saudi Journal of 
Ophthalmology (2014) Jul-Sep; 28 (3): 173-181. 
Lou YP, Franco-Cereceda A, Lundberg JM. Variable alpha 2-adrenoceptor-mediated inhibition of 
bronchoconstriction and peptide release upon activation of pulmonary afferents. Eur J Pharmacol 1992; 
210(2):173-181. 
Luhtala J, Palkama A, Uusitalo H. Calcitonin gene-related peptide immunoreactive nerve fibers in the rat 
conjunctiva. Invest Ophthalmol Vis Sci 1991; 32(3):640-645. 
Messmer EM. The Pathophysiology, Diagnosis, and Treatment of Dry Eye Disease. Dtsch Arztebl Int (2015) Jan; 
112(5): 71-82. 
 
Miller KL, Walt JG, Mink DR, Satram-Hoang S, Wilson SE, Perry HD et al. Minimal clinically important difference 
for the ocular surface disease index. Arch Ophthalmol 2010; 128(1):94-101. 
Ogawa Y, Shimmura S, Dogru M, Tsubota K. Immune processes and pathogenic fibrosis in ocular chronic graft- 
versus-host disease and clinical manifestations after allogeneic hematopoietic stem cell transplantation. Cornea 
2010; 29 Suppl 1:S68-S77. 
Pflugfelder SC, Paiva CS, Li DQ, Stern ME. Epithelial-Immune Cell Interaction in Dry Eye. Cornea (2008) Sep; 
27(01): S9-11. 


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Phadatare SP, Monin M, Nighojkar P, Askarkar S, Singh KK. A Comprehensive Review on Dry Eye Disease: 
Diagnosis, Medical Management, Recent Developments, and Future Challenges. Advances in Pharmaceutics 
(2015); Vol 2015, Article ID 704946. 
 
Piwnica D, Rosignoli C, de Menonville ST, Alvarez T, Schuppli NM, Roye O et al. Vasoconstriction and anti- 
inflammatory properties of the selective alpha-adrenergic receptor agonist brimonidine. J Dermatol Sci 2014; 
75(1):49-54. 
Research in dry eye: report of the Research Subcommittee of the International Dry Eye WorkShop (2007). Ocul 
Surf 2007;5(2):179–93. 
Restasis® [package insert]. Allergan Inc., Irvine, CA; 2014. 
Romero-Sandoval A, Eisenach JC. Clonidine reduces hypersensitivity and alters the balance of pro- and anti- 
inflammatory leukocytes after local injection at the site of inflammatory neuritis. Brain Behav Immun 2007; 
21(5):569-580. 
Romero-Sandoval EA, McCall C, Eisenach JC. Alpha2-adrenoceptor stimulation transforms immune responses in 
neuritis and blocks neuritis-induced pain. J Neurosci 2005; 25(39):8988-8994. 
Saboo US, Amparo F, Abud TB, Schaumberg DA, Dana R. Vision-Related Quality of Life in Patients with Ocular 
Graft-versus-host disease. Ophthalmology (2015) Aug’ 122 (8): 1669-1674. 
Sheppard JD, Comstock TL, Cavet ME. Impact of the Topical Ophthalmic Corticosteroid Loteprednol Etabonate 
on Intraocular Pressure. Adv Ther (2016) 33:532–552. 
 
Stevenson W, Chauhan SK, Dana R. Dry eye disease: an immune-mediated ocular surface disorder. Arch 
Ophthalmol (2012) Jan; 130(1): 90-100. 
 
Seifert P, Spitznas M. Immunocytochemical and ultrastructural evaluation of the distribution of nervous tissue and 
neuropeptides in the meibomian gland. Graefes Arch Clin Exp Ophthalmol 1996; 234(10):648-656. 
Shahidi M, Wanek J, Gaynes B, Wu T. Quantitative assessment of conjunctival microvascular circulation of the 
human eye. Microvasc Res 2010; 79(2):109-113. 
Simons E, Smith PG. Sensory and autonomic innervation of the rat eyelid: neuronal origins and peptide 
phenotypes. J Chem Neuroanat 1994; 7(1-2):35-47. 
Supowit SC, Hallman DM, Zhao H, DiPette DJ. Alpha 2-adrenergic receptor activation inhibits calcitonin gene- 
related peptide expression in cultured dorsal root ganglia neurons. Brain Res 1998; 782(1-2):184-193. 
Xiidra® [package insert]. Shire, Lexington, MA; 2016. 

SAP_001.pdf: 
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OCUGEN, Inc. 
Statistical Analysis Plan 
Version: Final 1.1 
Protocol No: OCU-310-DED-2017
Date: MAY 23, 2018 
 A Randomized, Placebo-Controlled, Double-Blind, Multicenter, Proof-of-Concept Study 
of Brimonidine Eye Drops for the Treatment of Dry Eye Disease (DED) 
Study Statistician 
Statistical Analysis CRO     
Quartesian 
Date (MMM DD, 
YYYY) 
Sponsor Representative 
Date (MMM DD, 
YYYY) 
NCT #NCT03418727


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TABLE OF CONTENTS 
PAGE 
 
TITLE PAGE .......................................................................................................... 1 
TABLE OF CONTENTS ........................................................................................ 2 
REVISION HISTORY ............................................................................................ 4 
LIST OF ABBREVIATIONS ................................................................................. 7 
1 
INTRODUCTION ................................................................................................... 8 
2 
STUDY DETAILS .................................................................................................. 8 
2.1 
Study Objectives...................................................................................................... 8 
2.2 
Study Design ........................................................................................................... 9 
2.3 
Determination of Sample Size:.............................................................................. 11 
2.4 
Randomization....................................................................................................... 11 
2.5 
Blinding ................................................................................................................. 11 
2.6 
STATISTICAL AND DATA ANALYSIS CONSIDERATION .......................... 12 
2.7 
Definition............................................................................................................... 16 
3 
PRIMARY, SECONDARY AND EXPLORATORY ENDPOINTS ................... 16 
3.1 
Primary Tolerability Endpoint............................................................................... 16 
3.2 
Secondary Endpoints ............................................................................................. 17 
3.3 
Exploratory Endpoints ........................................................................................... 17 
3.4 
Safety Endpoints.................................................................................................... 17 
4 
STATISTICAL METHODOLOGY...................................................................... 17 
4.1 
Analysis Populations ............................................................................................. 17 
4.2 
Coding Dictionaries Used ..................................................................................... 18 
4.3 
Statistical Methods and Data Analysis .................................................................. 18 
4.3.1 
Disposition............................................................................................................. 18 
4.3.2 
Demographics and Baseline Characteristics ......................................................... 18 
4.3.3 
Protocol Deviation ................................................................................................. 19 
4.3.4 
Study Drug Administration and Accountability .................................................... 19 
4.3.5 
Medical and Allergic History ................................................................................ 19 
4.3.6 
Prior and Concomitant Medications ...................................................................... 20 
4.3.7 
Concomitant Non-drug treatment/therapies .......................................................... 20 
4.3.8 
Table 2: Summary of Analysis Strategy................................................................ 21 
4.3.9 
Primary Endpoints ................................................................................................. 23 
4.3.10 
Secondary endpoint: .............................................................................................. 23 
4.3.11 
Exploratory endpoint: ............................................................................................ 23 


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4.3.12 
Safety Endpoints: .................................................................................................. 29 
4.4 
INTERIM ANALYSES AND DATA MONITORING ........................................ 33 
4.5 
CHANGES OF ANALYSIS FROM PROTOCOL ............................................... 33 
4.6 
REFERENCES ...................................................................................................... 33 
4.7 
APPENDICES ....................................................................................................... 33 
5 
LIST OF TABLES, LISTINGS AND FIGURES ................................................. 38 
5.1 
Summary Tables .................................................................................................... 38 
5.2 
Listings .................................................................................................................. 43 
5.3 
Figures ................................................................................................................... 44 
 


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REVISION HISTORY 
Version 
Date 
Author 
Reasons 
1.1 
MAY 23, 
2018 
 
 
The below points have been updated/added to the SAP 
version 1.1 based on client request 
 
Section 4.3.9: Updated the below text to present line plot 
mono vs placebo and combo vs placebo separately. 
“line plot of the vas score will be presented separately for 
brimonidine mono therapy vs placebo and brimonidine 
combination therapy vs. placebo by visits for safety and pp 
population.” 
 
Section 4.3.9: Added below text to include forest plot 
for tolerability VAS score to be displayed with 
summary table. 
“A forest plot of VAS score will be presented along 
with summary table for placebo and Brimonidine mono 
and combination therapy treatment groups for baseline 
and post baseline visits for the safety population.”  
 
 
 
Section 4.3.11: Updated/Added the below paragraphs for 
SANDE 
“Mean change from baseline plot of frequency of 
symptoms, severity of symptoms and overall SANDE 
score without 95% CI will be presented for each three 
treatment groups and study visit using the ITT 
population. 
 
“A forest plot of overall SANDE VAS score will be 
presented along with summary table for placebo and 
Brimonidine mono and combination therapy treatment 
groups for baseline and post baseline visits for the 
safety population.” 
 
 
 
Section 4.3.11: Updated/Added the below text for Change 
in corneal and conjunctival staining scores by 
Lissamine Green dye staining 
 
“Mean change from baseline plot of frequency of 
symptoms, severity of symptoms and overall SANDE 
score without 95% CI will be presented for each three 
treatment groups and study visit using the ITT 
population. 
 
A forest plot of overall SANDE VAS score will be 
presented along with summary table for placebo and 
Brimonidine mono and combination therapy treatment 


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groups for baseline and post baseline visits for the safety 
population. 
” 
 
 
 
Section 4.3.11: Added the below text for change in 
keratograph ocular redness score (ORS): 
“Also, a subgroup analysis of patients with baseline 
ORS-Bulbar Redness category score >=1.5 (i.e. Baseline 
Bulbar Redness score >= 1.5) will be summarized for 
observed ORS score by treatment arm and by eye (study 
eye and qualified fellow eye) for the ITT and PP 
population using descriptive statistics and analysis 
change from baseline of ORS score by treatment arm and 
study eye using ITT and PP population in addition with 
MI for ITT population as described above.” 
 
“Also, a subgroup analysis of patients with baseline 
ORS-Bulbar Redness category score >=1.5 (i.e. Baseline 
Bulbar Redness score >= 1.5) or VBR-Overall Score 
>=25 (i.e. Baseline Total VBR Score >= 25) will be 
summarized for observed ORS score by treatment arm 
and by eye (study eye and qualified fellow eye) for the 
ITT and PP population using descriptive statistics and 
analysis change from baseline of ORS score by treatment 
arm and study eye using ITT, ITT (MI) and PP 
population as described above.”    
 
 
 
 
Section 4.3.11 Updated/added the below text for Change 
in Validated Bulbar Redness (VBR) grading scale 
“Also, a subgroup analysis of patients with baseline 
VBR-Overall Score >=25 (i.e. Baseline Total VBR 
Score >=25) will be summarized for observed VBR 
score by treatment arm and by eye (study eye and 
qualified fellow eye) for the ITT and PP population 
using descriptive statistics and analysis change from 
baseline of VBR score by treatment arm and study eye 
using ITT, ITT (MI) and PP population as described 
above.”  
A subgroup analysis of patients with baseline VBR-
Overall Score >=25 (i.e. Baseline Total VBR Score >= 
25) will be summarized for derived overall worsening in 
VBR scale (category given below) using frequency and 
percentage by Eye (study eye, qualified fellow eye), 


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treatment arm and study visit using the ITT and PP 
population.  
“The above described subgroup analysis for worsening 
in VBR scale will also be summarized for patients with 
baseline ORS-Bulbar Redness category score >=1.5 (i.e. 
Baseline Bulbar Redness >=1.5) or VBR-Overall Score 
>=25 (i.e. Baseline Total VBR Score>=25) using 
frequency and percentage by Eye (study eye, qualified 
fellow eye), treatment arm and study visit using the ITT 
and PP population.” 
“Also, a subgroup analysis of patients with baseline 
ORS-Bulbar Redness category score >=1.5 (i.e. 
Baseline Bulbar Redness >=1.5) or VBR-Overall Score 
>=25 (i.e. Baseline Total VBR Score>=25) will be 
summarized for observed VBR score by treatment arm 
and by eye (study eye and qualified fellow eye) for the 
ITT and PP population using descriptive statistics and 
analysis change from baseline of VBR score by 
treatment arm and study eye using ITT, ITT (MI) and 
PP population as described above.” 
 
 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation or 
special term 
Explanation 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical  
BID  
Two Times a Day 
CGI 
Clinical Global Impression 
CI 
Confidence Intervals 
DED 
Dry Eye Disease 
IMP 
Investigational Medicinal Product 
IOP 
Intraocular Pressure 
ITT 
Intent-to-Treat 
LOCF 
Last Observation Carried Forward 
MAR 
MAgnification Requirement 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
N/A 
Not Applicable 
NC 
Not Computable 
NITBUT 
Noninvasive Tear Breakup Time 
ORS 
Ocular Redness Score 
PD 
Protocol Deviation 
PP 
Per Protocol  
PT 
Preferred Terms 
SANDE 
Symptom Assessment in Dry Eye 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SGA 
Subject Global Assessment 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
VAS 
Visual Analogue Scale 
VBR 
Validated Bulbar Redness 
WHO 
World Health Organization 
 
 
 
 


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1 
INTRODUCTION 
This statistical analysis plan (SAP) provides the explicit guidance and describes the planned statistical and 
data handling methods to be followed during the final reporting and analyses for the study protocol OCU-
310-DED-2017.  
This SAP should be read in conjunction with the study protocol (OCU-310-DED-2017, Version 2.0 
(25OCT2017)) and electronic case report form (eCRF) (OCUGEN_OCU-310-DED-2017, Version Final 
4.0 (DEC 01, 2017)).  
As per the Clinical Study Protocol OCU-310-DED-2017, Ocugen Inc. is evaluating the use of brimonidine 
tartrate 0.2% eye drops (with or without loteprednol etabonate 0.2% ophthalmic suspension) for the 
treatment of Dry Eye Disease (DED). Dry eye disease (DED) is a common ocular disorder involving the 
aberrant production and stability of tear film, which results in damage to the ocular surface and is 
correlated with symptoms of ocular discomfort. 
2 
STUDY DETAILS 
2.1 
Study Objectives 
 
Objective: To evaluate the tolerability and preliminary efficacy of Brimonidine eye drops (with and 
without loteprednol ophthalmic suspension) for the treatment of DED.  
 
The main study objective is to establish whether subjects with dry eye disease (DED) can tolerate 
receiving Brimonidine 0.2% eye drops, alone or in combination with loteprednol 0.2% ophthalmic 
suspension, two times a day for twelve weeks.  
 
The other objective is to investigate the preliminary efficacy of Brimonidine 0.2% topical eye drop 
solution, alone or in combination with loteprednol 0.2% ophthalmic suspension, in treating DED. 


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2.2 
Study Design 
This will be a randomized, placebo-controlled, double-blind study, in which 90 subjects will be enrolled 
at up to four clinical sites. Subjects will be randomly assigned to one of three groups, with 30 subjects per 
group, as follows: 
  
Study Drug Arm #1 (combination therapy): Brimonidine (0.2%) administered as eye drops, followed by 
loteprednol ophthalmic suspension (0.2%), two times a day (BID) for 12 weeks. 
  
Study Drug Arm #2 (monotherapy): Brimonidine (0.2%) administered as eye drops followed by placebo, 
two times a day (BID) for 12 weeks. 
  
Control Arm (placebo): Lubricant Eye Drops (sodium carboxymethylcellulose, 0.25%), followed by a second 
application, two times a day (BID) for 12 weeks. 
  
Enrolled subjects will receive the study treatment for 12 weeks and will be asked to return for a final visit 
at 15 weeks to evaluate safety and efficacy post-treatment.  
 
All enrolled subjects will receive their first dose of the test medication (Brimonidine 0.2% with or without 
loteprednol ophthalmic suspension 0.2%), or placebo (sodium carboxymethylcellulose, 0.25%), on study Day 
1 in the doctor’s office, and will self-administer all subsequent doses.  
 
Subjects will be given diaries to record the approximate time of each dose. In addition, they will be asked 
to make a note of any missed doses together with the reason for the omission. Subjects will return four 
weeks later (Day 28) for further study assessments, and thereafter at Day 56 and Day 84 (primary endpoint 
assessment visit), and finally at Day 105 after three weeks (or 21 days) of no study drug treatment. 
 
  
 


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Table 1: Schedule of Visits and Procedure 
  
*Day 1, by definition, is when the first dose of study drug is administered. The Screening Visit and Day 1 Visit may be combined into a single visit; in this case, do not duplicate any of the 
Screening/Day 1 procedures. Subjects taking steroid-containing eye drops at the Screening Visit must discontinue those drops and wait a full 7 days before attending the Day 1 Visit.  
 
a After administration of the first dose of study medication, subjects will be trained on how to self-administer the eyedrops and will be given a 1-month supply b If required  
c AE collection begins after the first dose of study medication on Day 1  
d Tolerability VAS should be completed after the first dose of study medication on Day 1  
 
 
Day -7 to 0 
(Screening*) 
Day 1* 
Day 28  
(+/- 7 days) 
Day 56 
(+/- 7 days) 
Day 84 
(+/- 7 days) 
Day 105 
(+/- 7 days) 
Informed consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Ocular/Dry Eye History 
X 
 
 
 
 
 
Symptom Assessment iN Dry Eye (SANDE) 
questionnaire  
X 
X 
X 
X 
X 
X 
Diary Review 
 
 
X 
X 
X 
 
Vital Signs 
 
X 
 
 
X 
X 
Visual Acuity (via Snellen) 
 
X 
X 
X 
X 
X 
Ocular Redness Score (ORS) (via keratography) 
 
X 
X 
X 
X 
X 
Noninvasive Tear Breakup Time (NITBUT) (via 
Keratograph)  
X 
X 
 
 
X 
 
Validated Bulbar Redness (VBR) Scale (via Slit 
Lamp)  
 
X 
X 
X 
X 
X 
Ophthalmic examination (via Slit lamp)  
X 
X 
X 
X 
X 
X 
Lissamine Green staining (Corneal and Conjunctival) 
(via Slit Lamp)  
X 
X 
 
 
X 
 
Schirmer I test  
X 
X 
 
 
X 
 
Intraocular Pressure (IOP) via Goldmann  
X 
X 
X 
 
X 
X 
Clinical Global Impression (CGI)  
 
 
X 
X 
X 
X 
Subject Global Assessment (SGA)  
 
 
X 
X 
X 
X 
First study medication  
 
X 
 
 
 
 
Drug dispensation, with instruction on study 
medication self-administration  
 
Xa 
Xb 
Xb 
 
 
Adverse Events (AEs)  
 
Xc 
X 
X 
X 
X 
Concomitant medications  
X 
X 
X 
X 
X 
X 
Tolerability Visual Analogue Scale (VAS)  
 
Xd 
X 
X 
X 
 


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2.3 
Determination of Sample Size:  
Thirty (30) subjects per treatment group and a common standard deviation of 20 mm yields precision 
(half-width) of the point estimate of pairwise difference (active – placebo) in tolerability of +/- 10.3 mm 
for a two-sided 95% confidence interval (CI) and +/- 8.6 mm for a two-sided 90% CI. Therefore, if the 
observed mean difference in tolerability is 5.0 mm, the true mean difference in tolerability will be within 
(-5.3, 15.3) with 95% confidence and (-3.6, 13.6) with 90% confidence.  
 
Additionally, with a sample size of 30 subjects within a treatment group, adverse events that are not 
observed will be concluded to occur at a true rate of <10% with 95% confidence within that treatment 
group. For example, if headache is not seen within the combination treatment group, then with 95% 
confidence, headache would be concluded to occur at a true rate of <10%. 
  
The sample size was not calculated to have pre-determined power for efficacy in this proof-of-concept 
study.   
2.4 
Randomization 
This placebo-controlled, double-blind study will have three treatment groups utilizing a 1:1:1 
randomization.  
 
One group will receive the study drug combination (brimonidine 0.2% then loteprednol ophthalmic 
suspension 0.2% separated by 5-10 minutes), one group will receive the study drug alone (brimonidine 
0.2%, followed by placebo separated by 5-10 minutes), and the third group will receive placebo (sodium 
carboxymethylcellulose, 0.25%), x 2 applications separated by 5-10 minutes).  
 
Randomization/treatment assignment will be stratified by site and performed by an unblinded study team 
member. 
 
2.5 
Blinding 
This is a placebo-controlled, double-blind study and the study drug will be blinded to both patient and 
Investigator.  
 
Blinding Process: 
 
The person dispensing medication at the site level will be partially unblinded and does not perform subject 
assessments. 
 
Any person performing subject assessments at the site level will be blinded. In addition, the person doing 
assessments will not enter or “sign-off” on EDC until after the final visit and all data were entered, 
monitored, and cleaned; i.e., just before database lock. 
 
In this study, the randomization was partially masked, as assignment to masked randomization groups A, 
B or C was recorded in the database. 
 
 


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2.6 
STATISTICAL AND DATA ANALYSIS CONSIDERATION 
The statistical analyses will be performed by Quartesian Clinical Research, using SAS Version 9.2 (or 
higher). All tables, figures and listings will be produced in landscape format. In general, all data will be 
listed by the subject and visit/time point where appropriate. 
For measures collected at the individual eye level, the unit of analysis will be the study eye. Each subject 
will have a single eye identified as the study eye as follows:  
(i) 
if only 1 eye meets inclusion criteria, this eye will be the study eye and the other eye will be 
considered the non-qualified fellow eye;  
(ii) 
if both eyes meet inclusion criteria, the eye with the higher Ocular Redness Score (ORS) will 
be the study eye and the other eye will be considered the qualified fellow eye;  
(iii) 
if both eyes have the same Ocular Redness Score (ORS), then the eye with the lower Schirmer 
I score will be the study eye and the other eye will be considered the qualified fellow eye;  
(iv) 
if both eyes have same Schirmer 1 score, the right eye will be the study eye and the other eye 
will be considered the qualified fellow eye. 
Safety and Efficacy analyses will be primarily performed on the study eyes and secondarily on the 
qualified fellow eyes (for efficacy) and all fellow eyes (for safety). For measures collected at the 
subject level, the unit of analysis will be the subject. 
Data will be summarized by time-point where appropriate. The total number of subjects in the study group 
(N) under the stated population will be displayed in the header of summary tables. 
Data will be summarized using descriptive statistics for continuous variables. Unless otherwise stated, 
descriptive statistics will include number of subjects, mean, standard deviation, minimum, median and 
maximum and 90% CI & 95% CI for tolerability endpoint and exploratory efficacy endpoints In case of 
n<2, where n indicates the number of evaluable subjects at the particular time point, only n, mean, 
minimum and maximum will be displayed. The statistic “Missing” will also be evaluated by enumerating 
the number of missing entries/subjects, if any at that visit, and presented along with summary statistic. 
Display NC if any value is not computable.  
Decimal Precision Convention: The minimum and maximum statistics will be presented to the same 
number of decimal places as the original data. The mean and median will be presented to one more decimal 
place than the original data, whereas the standard deviation will be presented to two more decimal places 
than the original data.  
For categorical variables, counts and percentages will be used. The count [n] indicates the actual number 
of subjects with non-missing value at particular visit or actual number of subjects with that event or 
category, which should always be less than or equal to the total number of subjects in the respective study 
group [N]. 
M is the number of subjects with non-missing data of a variable at particular visit. 
Percentages will be calculated as per applicable summary are listed below:  
(i) For non-by visit summary, percentage will be calculated as % = (n/N)*100. 
(ii) For by visit summary, percentage will be calculated as % = (n/M)*100 (summary of observed data) 
(iii)For by visit summary, percentage will be calculated as % = (n/N)*100 (Summary of data with 
imputation) 
 Unless otherwise stated, all percentages will be expressed to one decimal place. 


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 Also the distributions for continuous variables will be examined for normality using Shapiro-Wilk tests 
and Q-Q plot. If any deviation in the normality assumption is judged, then the data will be analyzed 
using appropriate non-parametric tests. Results of such tests will be presented in SAS LST file as an 
appendix to that analysis.  
 
As this is a proof of concept study for which there is no pre-determined power for a specific efficacy 
endpoint measure, there will be no multiplicity adjustments to account for the testing of the multiple 
endpoints and for the testing of both the combination arm and monotherapy arms relative to placebo. 
The following conventions will be applied to analyses/data presentation: 
All dates will be displayed in DDMMMYYYY format. 
Unscheduled visit data will be presented in Listings, but not in Tables and Figures with by-visit 
summaries.  
For Listings, data will be presented by Subject, parameter, assessment date in chronological order. 
Protocol Deviations: 
Both manual and programmable Protocol deviations (PDs) will be summarized. Programmable PDs will 
be derived programmatically. Additional deviations identified during monitoring will be classified as 
major or minor and will be included in the study report. 
Subjects with major protocol deviations, i.e. deviations deemed to have an impact on treatment evaluation 
will be excluded from the Per Protocol population. The list of protocol deviations which lead to exclusion 
of subjects from the PP population will be finalized prior to the first analysis of unmasked data and updated 
as needed prior to database lock for the final analysis. 
Programmable deviations will be defined as follows: 
1. Inclusion/Exclusion Criteria Not Met (major) 
2. Use of prohibited medication (major). Prohibited medications will be identified through a manual 
review of prior and concomitant medications taken during the study. 
3. Treatment compliance <80% or >120% (major). 
4. Missed instillations: subject missed at least one scheduled instillation, but compliance is still 
within the range 80%-120% (minor). 
5. Unblinding (major). 
6. Visit out of window: visits occurring outside of protocol specified +/- 7 day range (minor). 
7. Missing tolerability assessment at Day 84 visit (major) 
8. Missing tolerability assessment at Day 1, Day 28 or Day 54 visit (minor) 
 
 
 
 
 
Handling of Missing Data: 


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Missing values for primary tolerability endpoint and exploratory efficacy endpoints will be imputed by 
using LOCF or Multiple imputation; otherwise subjects missing values for each parameter wise will not 
be included in the respective analysis. Imputed exploratory efficacy endpoints will be primarily analyzed 
using ITT population.  
 
Efficacy analyses will be performed using the ITT (primary) and PP (secondarily) populations and will 
summarize both observed data only and with missing data imputed.  
 
Multiple imputation methods will be used to impute missing data for the exploratory efficacy endpoints, 
assuming missing completely at random and missing not at random mechanism.  Details of the imputation 
methods to be used are provided in Appendix 1 
 
To handle missing or partial AE and concomitant medication dates, the following rules will be 
applied. 
 
For partial start dates: 
 
1. If the year is unknown, then do not impute the date but assign a missing value. 
2. If the month is unknown, then: 
a. If the year matches the year of the dose date, then impute the month and day of the dose date. 
b. Otherwise, assign “January.” 
3. If the day is unknown, then: 
a. If the month and year match the month and year of the first dose date, then impute the day of    
    the dose date. 
b. Otherwise, assign “01.” 
 
For partial end dates: 
 
1. If the year is unknown, then do not impute the date but assign a missing value. 
2. If the month is unknown, then assign “December.” 
3. If the day is unknown, then assign the last day of the month. 
 
After implementing the rules above, to determine whether AEs (or medications) with missing start or stop 
dates 
are 
pretreatment 
or 
on/after 
treatment, 
the 
following 
strategy 
will 
be 
used: 
 
1. If the start date and stop date are both missing, then the most conservative approach is taken and the 
AE (or medication) is considered to be treatment emergent (or concomitant medication). 
 
2. If the start date is missing but the stop date is not missing and is on or after the day of study dose 
administration, then the most conservative approach is taken and the AE (or 
medication) is considered to be treatment emergent (or concomitant medication). 
 
3. If the start date is missing but the stop date is not missing and is before the day of study dose and after 
the date of signed informed consent, then the AE (or medication) is considered to be before treatment (or 
prior medication). 
 


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4. If the start date is not missing but the stop date is missing, then the most conservative approach is 
taken and medication is considered to be concomitant while the AE is defined by start date. 
 
If the Adverse Event Relationship flag is missing, the relationship for adverse event will be imputed and 
will be considered as definitely related. If the Adverse Event Severity flag is missing, the severity will be 
imputed and will be considered as severe. 
 
 
 


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Treatment Group Labelling in TFLs:  
The treatment groups will be labelled as 
Study drug Arm-1 
Study Drug Arm-2 
Control Arm 
Brimonidine  
Combination therapy 
Brimonidine  
Monotherapy 
Placebo  
  
2.7 
Definition 
Baseline: Baseline is defined as the latest non-missing assessment (whether from scheduled or 
unscheduled) prior to the first dose administration of the study drug, unless otherwise stated.  
The Post-baseline values are defined as measurements taken after the first administration of study drug. 
Change from Baseline: The change from baseline values will be calculated as post baseline value minus 
the baseline value. 
An Adverse Event is any untoward medical occurrence in a subject or clinical investigation in a subject 
administered a pharmaceutical product and which does not necessarily have to have a causal relationship 
with this treatment. An adverse event can be any unfavorable sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of the investigational product, whether 
considered related or not related to the investigational product. 
 
A Pre-Treatment AE is any AE in a clinical study subject that occurs after he/she signed the Informed 
Consent Form (ICF) up until the first administration of Investigational Medicinal Product (IMP). 
 
A Treatment Emergent AE (TEAE): TEAE is any AE not present prior to the initiation of IMP 
administration or any event already present that worsens in either intensity or frequency following 
exposure to the IMP. 
 
An SAE is any AE that results in death, is life-threatening (this refers to an event in which the subject 
was at risk of death at the time of the event; it does not refer to an event that hypothetically might have 
caused death had it been more severe), requires inpatient hospitalization or prolongation of existing 
hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth 
defect, requires medical or surgical intervention to prevent any of the occurrences noted above.  
 
Unexpected Adverse Event: Any adverse event, the specificity or severity of which is not consistent with 
the current Package Insert. 
3 
PRIMARY, SECONDARY AND EXPLORATORY ENDPOINTS 
3.1 
Primary Tolerability Endpoint 
The primary tolerability evaluation parameters are: 
 
 Test Substance Tolerance (Visual Analogue Scale)  
 


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Subjects will assess their tolerance to the administration of the study drug, utilizing a Visual 
Analog Scale (VAS). The VAS is a 100-mm horizontal line with verbal descriptors at either end.  
 
The VAS ratings will be completed after administration of the study drug on Day 1 (post-dose), 
Day 28, Day 56 and Day 84. Subjects will place a single slash mark across the horizontal line 
between the end labeled “completely intolerable” (0 mm) and “easily tolerable” (100mm). 
3.2 
Secondary Endpoints 
 N/A 
 
3.3 
Exploratory Endpoints 
The exploratory study endpoints are: 
  
 Symptom Assessment Questionnaire iN Dry Eye (SANDE)  
 Change in corneal and conjunctival staining scores by Lissamine Green dye staining  
 Change in tear secretion as measured by Schirmer I test  
 Change in Keratograph Ocular Redness Score (ORS)  
 Change in Validated Bulbar Redness (VBR) grading scale  
 Clinical Global Impression (CGI) of change in symptoms from baseline (physician’s rating)  
 Subject Global Assessment (SGA) of overall change from baseline (subject’s rating)  
 
3.4 
Safety Endpoints 
The safety endpoints are: 
 
 Treatment emergent adverse events, classified by frequency, severity, and relatedness, from 
baseline (Day 1) through the last study visit (Day 105).  
 Vital signs 
 Findings from ophthalmic examinations 
 The proportion of subjects at Day 84 who successfully complete (i.e., tolerate) a full twelve 
weeks (i.e.,84 days) of therapy with topical administration two times per day (BID).  
4 
STATISTICAL METHODOLOGY 
4.1 
Analysis Populations  
 
All Subjects: All subjects will include the subjects who signed the informed consent form and who meet 
all inclusion criteria and none of the exclusion criteria and eligible to be randomized. 
Randomized Population: The randomized population will include all subjects who were randomized to 
treatment.  


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Safety Population: The safety population will include all randomized subjects who have received at least 
one dose of study medication. This population will be used to summarize safety variables and will 
summarize subjects as treated.  
Intent-to-Treat Population (ITT): The ITT population will include all randomized subjects who have 
received at least one dose of study medication. This population will be the primary population for efficacy 
analyses and will be used to summarize all efficacy variables and will summarize subjects as randomized.  
Per-protocol population (PP): The PP population is a subset of the ITT population.  The PP population 
will include those subjects who do not have major protocol violations likely to seriously affect the primary 
outcome of the study as judged by a masked evaluation prior to the unmasking of the study treatment.  
 
(This population will be the secondary population for efficacy analyses and will be used to summarize a 
subset of efficacy variables. If the PP and ITT populations are exactly the same, then additional efficacy 
analyses on the PP population will not be performed. The PP population will summarize subjects as 
randomized.)  
4.2 
Coding Dictionaries Used 
Adverse events and Medical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) version 20.0 
Prior & concomitant medication will be coded using World Health Organization-Drug Reference List 
(WHO-DRL) (Version: WHO DRUG Enhanced Sep-2016 B2) and by Anatomical Therapeutic Chemical 
(ATC) level 4. 
4.3 
Statistical Methods and Data Analysis 
4.3.1 Disposition 
The number and percentage of subjects who entered the study, and those who completed the study will be 
presented, together with the number and percentage of subjects who prematurely discontinued from the 
study along with reasons for study discontinuation. Additionally, subjects included in the Randomized 
population, Safety Population, Intent-to-treat population and per-protocol population will be summarized 
by treatment groups using all subjects.  
A listing of each subject’s analysis population (Randomized Population, Safety Population, Intent-To-
Treat population and Per-Protocol population), disposition and reason for discontinuation will be listed. 
4.3.2 Demographics and Baseline Characteristics 
Demographic and baseline characteristics (gender, ethnicity, race, age [years] will be summarized by 
treatment groups using descriptive statistics for subjects in the Randomized population, ITT population 
and PP population.  Qualitative variables (Gender, ethnicity, race, Age <65 years vs >=65 years) will be 
summarized using frequencies while quantitative variables (age) will be summarized using mean, SD, 
median, minimum, and maximum.   
Demographic and baseline data will also be listed using Randomized population. The screening test such 
as ocular and dry eye history will be listed using All Subjects. 


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4.3.3 Protocol Deviation 
A summary of Protocol Deviations for the Randomized Population will be summarized.  
A listing of subjects with protocol deviations (PD) will be provided.  
4.3.4 Study Drug Administration and Accountability  
Duration of Exposure will be defined as [Date of Last Dose] – [Date of First Dose] + 1 
Treatment Compliance (%) will be defined as [Number of Actual Instillations] / [Number of Planned 
Instillations] * 100%. Treatment Compliance would be categorized as <80%, 80% - 120% and >120%. 
Number of Actual Instillations will be counted from the subject diaries and first study drug administration 
CRF form. For all treatment arms, both instillations will be counted.  
Number of Planned Instillations will be 336 (84 days of BID dosing & each dose will have two bottles). 
Number of Actual Instillations, Treatment Compliance % and Duration of Exposure will be summarized 
descriptively by treatment group for the Safety population. 
The proportion of subjects at Day 84 who successfully complete a full twelve weeks (i.e.,84 days) of 
therapy with topical administration two times per day (BID) will be summarized by treatment arm and 
will be presented as total numbers and percentage. 
The subjects are said to be a successful completer if the subject exposure to study drug is >77 days. 
A listing will be provided for study drug administration information including date and approximate time 
of dosing (am vs. pm), dose administered from bottles #1 and #2 and any comments regarding doses that 
were not administered. 
Also, a listing of exposure, treatment compliance, drug accountability and diary accountability will be 
provided for the Safety Population. 
4.3.5 Medical and Allergic History 
Medical history for the Safety Population will be summarized both by each individual treatment group 
and for the study overall as the number and percentage of subjects in each system organ class (SOC) and 
sub-categorized by preferred term (PT).  Subjects will be counted only once at the preferred term (PT), 
only once at the system organ class (SOC), and only once at subject level for the counting of total number 
of subjects with a medical history term. Counts will be presented in descending frequency of SOC term 
for the overall column unless otherwise specified.  
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) version 
20.0 
Listings of medical and allergy history events will be provided separately for all Subjects. 


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4.3.6 Prior and Concomitant Medications 
Prior medication will be summarize by treatment groups for Randomized population, whereas 
concomitant medication will be summarized by treatment group for Safety population.  
 
Prior and Concomitant Medications will be coded using World Health Organization-Drug Reference List 
(WHO DRUG Enhanced Sep-2016 B2) and will be categorized by preferred name and ATC level 4 class 
per WHO. 
 
A prior medication is one taken only prior to the first dose of the study drug, i.e. stopped prior to the first 
dose of the study drug. All other medications are concomitant (including those taken both prior to and 
continued after the first dose and those started after first dose). 
 
All prior and concomitant medications (ocular and other medications) will be listed for the Safety 
Population. 
4.3.7 Concomitant Non-drug treatment/therapies 
The concomitant non-drug treatment and therapy will be listed using all subjects. 
 
 
 
 
 
 
 
 
 


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4.3.8 Table 2: Summary of Analysis Strategy 
Endpoint 
Statistical 
Method / 
Test 
Analysis 
Population 
Missing 
Data 
Imputation 
Approach 
Parameters/Variables 
in the analysis (Stat. 
test/Model) 
  Analysis 
Time point 
Primary Safety Endpoint 
Test Substance 
Tolerance 
(Visual 
Analogue 
Scale) 
Pairwise 
Two Sample 
t-test 
Safety and 
Per Protocol 
*ITT (if N 
differs from 
Safety) 
LOCF 
VAS 
Day 1, Day 28, 
Day 56 & Day 
84. 
Exploratory Endpoint(s) 
Symptom 
Assessment 
Questionnaire 
iN Dry Eye 
(SANDE) 
Pairwise 
Two Sample 
t-test 
ITT and Per 
Protocol 
Multiple 
Imputation 
Change from 
baseline SANDE 
Baseline, Post 
baseline 
assessments: 
Day 28, Day 
56, Day 84 & 
Day 105. 
Change in 
corneal and 
conjunctival 
staining scores 
by Lissamine 
Green dye 
staining 
Pairwise 
Two Sample 
t-test 
ITT and Per 
Protocol 
NA 
Change from 
Baseline Corneal and 
Conjunctival 
Staining zone wise 
and Overall Score 
Baseline & 
Post baseline 
assessments: 
Day 84. 
Change in tear 
secretion as 
measured by 
Schirmer I test 
Pairwise 
Two Sample 
t-test 
ITT and Per 
Protocol 
NA 
Change from 
baseline in tear 
secretion as 
measured by 
Schirmer I test 
Baseline & 
Post baseline 
assessments:  
Day 84. 
Change in 
Keratograph 
Ocular Redness 
Score (ORS) 
Pairwise 
Two Sample 
t-test 
ITT and Per 
Protocol 
Multiple 
Imputation 
Change from 
baseline in 
Keratograph Ocular 
Redness Score 
(ORS) 
Baseline, Post 
baseline 
assessments: 
Day 28, Day 
56, Day 84 & 
Day 105). 


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Endpoint 
Statistical 
Method / 
Test 
Analysis 
Population 
Missing 
Data 
Imputation 
Approach 
Parameters/Variables 
in the analysis (Stat. 
test/Model) 
  Analysis 
Time point 
Change in 
Validated 
Bulbar Redness 
(VBR) grading 
scale 
Pairwise 
Two Sample 
t-test 
ITT and Per 
Protocol 
Multiple 
Imputation 
Change from 
baseline in Validated 
Bulbar Redness 
(VBR) grading scale. 
Baseline, Post 
baseline 
assessments: 
Day 28, Day 
56, Day 84 & 
Day 105. 
Clinical Global 
Impression 
(CGI)  
 
Fisher exact 
test 
comparison 
of 
proportions 
ITT and Per 
Protocol 
LOCF 
CGI Categories 
Day 28, Day 
56, Day 84 & 
Day 105. 
Subject Global 
Assessment 
(SGA)  
 
Fisher exact 
test 
comparison 
of 
proportions 
ITT and Per 
Protocol 
LOCF 
SGA Categories 
Day 28, Day 
56, Day 84 & 
Day 105. 
Additional Endpoints 
The proportion 
of subjects with 
grade 
improvement in 
Tear secretion 
Fisher exact 
test 
comparison 
of 
proportions 
ITT & PP 
NA 
Proportion of 
subjects with grade 
improvement of 
1,2,3 
Day 84 
Intraocular 
pressure (via 
Goldmann 
tonometry) 
Pairwise 
Two Sample 
t-test 
Safety and 
Per Protocol 
Multiple 
Imputation 
Change from 
baseline in 
Intraocular pressure 
Baseline, Post 
baseline 
assessments: 
Day 28, Day 
84 & Day 105 
Intraocular 
pressure 
category  
 
Fisher exact 
test 
comparison 
of 
proportions 
Safety and 
Per Protocol 
NA 
Intraocular pressure 
categories 
Baseline, Post 
baseline 
assessments: 
Day 28, Day 
84 & Day 105 
As per the above table if any data is imputed, the imputed data will be presented in corresponding listing 
with a flag and footnote. (e.g. * - imputed using LOCF). 


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4.3.9 Primary Endpoints 
Primary tolerability endpoint: 
 
The primary tolerability endpoint will be evaluated from subject responses to the Tolerability Visual 
Analogue Scale (VAS), which will be collected on day 1 post-dose, day 28, day 56 and day 84. The 
descriptive statistics will be presented for this VAS by treatment arm and study visit using the Safety  
and PP population. Treatment groups will be compared at each post dose visit by pairwise two sample t-
tests and corresponding p-value along with 90% and 95% Confidence Interval (CI) for mean will be 
presented. Pairwise comparisons in mean among the three treatment groups (i.e. Brimonidine 
Monotherapy vs. placebo, Brimonidine Combination therapy vs. placebo, Brimonidine Monotherapy vs. 
Combination therapy). This analysis will performed for both Safety and PP Population for observed data 
(without LOCF) and only for Safety population for imputed data (with LOCF). 
 
Two-sided P-value less than 0.05 would be considered as statistical significance. 
 
Line plot of the VAS score will be presented separately for Brimonidine mono therapy vs placebo and 
Brimonidine Combination therapy vs. placebo by visits for Safety and PP population.  
 
A forest plot of VAS score will be presented along with summary table for placebo and Brimonidine 
mono and combination therapy treatment groups for baseline and post baseline visits for the safety 
population.  
 
If the ITT population “N” differs from Safety Population “N”, then the above analysis will be produced 
for ITT population along with safety and PP population (for both tables and figures).  
 
The listing of the VAS scores for the Safety Population will be provided.  
 
LOCF imputations will be applied to missing assessments at Days 56 and 84. The last available post-Day 
1 assessment will be carried forward to impute the missing assessments at later visits. Day 1 assessment 
will not be carried forward, since Day 1 tolerability assessment is performed immediately after dosing, 
while on other visits these assessments are performed at least 2 hours after dosing. 
 
 
4.3.10 Secondary endpoint: 
There are no secondary endpoints in this study. 
 
4.3.11 Exploratory endpoint: 
 
The exploratory study endpoints will be analysed using the ITT and PP Population for both for observed 
and imputed data; If ITT and PP population are same then ITT alone will be used to summarize and plot 
the exploratory endpoints data.  
  
• Symptom Assessment Questionnaire in Dry Eye (SANDE): The SANDE data will be 
summarized by treatment group and study visit for the ITT and PP Populations.  These data 
will be summarized using descriptive statistics for the observed values and change from 
baseline values for “frequency of symptoms”, “severity of symptoms” and an overall 


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SANDE VAS score. The overall SANDE score will be calculated by multiplying the 
frequency score by the severity score and obtaining the square root. 
 
Change from baseline of Frequency of Symptoms, Severity of Symptoms and Overall 
SANDE VAS score will be compared between the treatment groups for study eye using 
the ITT and PP population for observed data (without MI) and only ITT population for 
imputed data (with MI)  at each visit by pairwise two sample t-tests and corresponding p-
value along with 90% and 95% Confidence Interval (CI)  for mean will be presented. 
Pairwise comparison in mean among the three treatment groups (Brimonidine 
Monotherapy vs. placebo, Brimonidine Combination therapy vs. placebo, Brimonidine 
Monotherapy vs. Combination therapy) 
  
Two-sided P-value less than 0.05 would be considered as statistical significance.  
 
Mean change from baseline plot of SANDE with 95% CI will be presented for each all 
three treatment groups and study visit using the ITT and PP populations.  
 
Mean change from baseline plot of frequency of symptoms, severity of symptoms and 
overall SANDE score without 95% CI will be presented for each three treatment groups 
and study visit using the ITT population. 
 
A forest plot of overall SANDE VAS score will be presented along with summary table 
for placebo and Brimonidine mono and combination therapy treatment groups for baseline 
and post baseline visits for the safety population. 
 
The SANDE will also be listed using the Randomized population.  
 
Subjects with missing values will be imputed using the Multiple Imputation(MI) method. 
See section 4.7 Appendices for Multiple Imputation methodology.   
 
• Change in corneal and conjunctival staining scores by Lissamine Green dye staining 
- Corneal staining will be graded in 5 eye zones. Each eye zone will be graded from 0 to 3 
based on the density of punctate staining (for an overall maximum score =15). Similarly, 
conjunctiva will be graded for each eye from 0 to 3 based on the density of punctate staining 
in the nasal-bulbar and temporal-bulbar zones staining (maximum score =6). 
  
The graded scores for corneal and conjunctiva staining will be summarized by eye zone 
using the descriptive statistics for observed values and change from baseline values and 
present by treatment arm, study visit and eye (study eye, qualified fellow eye) for the ITT 
and PP population. 
 
Change from baseline of corneal and conjunctival score (by eye zone and overall) will be 
compared between the treatment groups for study eye using the ITT and PP population at 
each visit by pairwise two sample t-tests and corresponding p-value along with 90% and 
95% Confidence Interval (CI) for mean will be presented. Pairwise comparisons in mean 
among the three treatment groups (Brimonidine Monotherapy vs. placebo, Brimonidine 
Combination therapy vs. placebo, Brimonidine Monotherapy vs. Combination therapy) 


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Two-sided P-value less than 0.05 would be considered as statistical significance.  
 
Mean change from baseline plot of Lissamine Green dye staining scores (by eye zone and 
overall) with 95% CI for both corneal and conjunctival staining will be presented for all 
three treatment groups and study visit for study eye for the ITT and PP populations. 
 
Mean change from baseline plot of Overall Lissamine Green dye staining scores for study 
eye will be plotted without the 95% CI for the ITT populations. 
 
A forest plot of mean change from baseline of Overall Conjunctival and Overall Corneal 
Lissamine Green dye score will be presented along with summary table for treatment 
groups for study eye at baseline and post baseline visits for the ITT population.   
 
The corneal and conjunctival staining scores will also be listed using the Randomized 
population. Also missing values will not be imputed for corneal and conjunctival staining 
scores. 
  
• Change in tear secretion as measured by Schirmer I test – The data for the change in 
tear secretion will be summarized by treatment arm and study eye designation (study eye 
or qualified fellow eye) for the ITT and PP populations.  These data will be summarized 
using descriptive statistics for the observed values and change from baseline values. The 
Change in tear secretion values are determined from the measured amount of moisture (in 
mm) collected from the Schirmer procedures. 
 
Change from baseline of tear secretion will be compared between the treatment groups for 
study eye using the ITT and PP population by pairwise two sample t-tests and 
corresponding p-value along with 90% and 95% Confidence Interval (CI) for mean will be 
presented. Pairwise comparison in mean among the three treatment groups (Brimonidine 
Monotherapy vs. placebo, Brimonidine Combination therapy vs. placebo, Brimonidine 
Monotherapy vs. Combination therapy). 
 
Two-sided P-value less than 0.05 would be considered as statistical significance. 
Also, the measured moisture in mm will be summarized using frequency and percentage 
by treatment arm, study visit and by eye (study eye, qualified fellow eye) using the ITT 
and PP population according to the following categories: 
 
1. Normal is ≥15 mm.  
2. Mild dry eye is 11-14 mm  
3. Moderate dry eye is 6-10mm  
4. Severe dry eye is ≤5 mm  
 
The proportion of subjects with 1, 2, 3 grade improvement will be summarized by treatment 
groups for both ITT and PP population.  
 


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The proportion of subject with improvement among treatment groups will be compared 
using Fisher’s exact test for both ITT and PP population. 
 
Also shift table will be provided to compare the category shift from baseline to post 
baseline visit for the ITT and PP population. 
 
Mean change from baseline plot of tear secretion as measured by Schirmer I test with 95% 
CI will be presented for all three treatment groups and for study eye using ITT and PP 
population.  
 
The Change in tear secretion as measured in mm and categorized by grade will also be 
listed using the Randomized population. Also missing values will not be imputed for tear 
secretion scores. 
 
• Change in Keratograph Ocular Redness Score (ORS): The data for the ORS score 
(range between 0.0-4.0) will be summarized by treatment arm and study eye (study eye or 
qualified fellow eye) for the ITT and PP populations. These data will be summarized using 
the descriptive statistics for observed values and change from baseline values by treatment 
and by eye (study eye and qualified fellow eye) using the ITT and PP population.  
 
Change from baseline of ORS score will be compared between the treatment groups for 
study eye using the ITT and PP population for observed (without MI) and only ITT 
population for imputed data (with MI) at each visit by pairwise two sample t-tests and 
corresponding p-value along with 90% and 95% Confidence Interval (CI) for mean will be 
presented. Pairwise comparison in mean among the three treatment groups (Brimonidine 
Monotherapy vs. placebo, Brimonidine Combination therapy vs. placebo, Brimonidine 
Monotherapy vs. Combination therapy) 
 
Also, a subgroup analysis of patients with baseline ORS-Bulbar Redness category score 
>=1.5 (i.e. Baseline Bulbar Redness score >= 1.5), will be summarized for observed ORS 
score by treatment arm and by eye (study eye and qualified fellow eye) for the ITT and PP 
population using descriptive statistics and analysis change from baseline of ORS score by 
treatment arm and study eye using ITT and PP population in addition with MI for ITT 
population as described above. 
 
Also, a subgroup analysis of patients with baseline ORS-Bulbar Redness category score 
>=1.5 (i.e. Baseline Bulbar Redness score >= 1.5) or VBR-Overall Score >=25 (i.e. 
Baseline Total VBR Score >= 25) will be summarized for observed ORS score by treatment 
arm and by eye (study eye and qualified fellow eye) for the ITT and PP population using 
descriptive statistics and analysis change from baseline of ORS score by treatment arm and 
study eye using ITT, ITT (MI) and PP population as described above.    
 
Two-sided P-value less than 0.05 would be considered as statistical significance.  
 
Mean change from baseline plot of the Ocular Redness score with 95% CI will be presented 
for all three treatment groups and study visit for study eye using ITT and PP population.  
 


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The ORS will also be listed using the Randomized population.  
 
Subjects with missing values will be imputed using the Multiple Imputation(MI) method. 
See section 4.7 Appendices for Multiple Imputation methodology. 
 
• Change in Noninvasive Tear Breakup Time (NITBUT): The data for the NITBUT will 
be summarized by treatment arm and study eye (study eye or qualified fellow eye) for the 
ITT and PP populations. These data will be summarized using the descriptive statistics for 
observed values and change from baseline values by treatment and by eye (study eye and 
qualified fellow eye) using the ITT and PP population.  
 
Change from baseline of NITBUT will be compared between the treatment groups for 
study eye using the ITT and PP population by pairwise two sample t-tests and 
corresponding p-value along with 90% and 95% Confidence Interval (CI) for mean will be 
presented. Pairwise comparison in mean among the three treatment groups (Brimonidine 
Monotherapy vs. placebo, Brimonidine Combination therapy vs. placebo, Brimonidine 
Monotherapy vs. Combination therapy). 
 
Mean change from baseline plot of the NITBUT with 95% CI will be presented for all three 
treatment groups and for study eye using ITT and PP population. 
 
Also, Non-invasive Tear Breakup Time (NITBUT) will be listed using the Randomized 
population. 
 
No imputation will be done for NITBUT. 
 
 
• Change in Validated Bulbar Redness (VBR) grading scale: The VBR will be 
summarized using descriptive statistics for observed values and change from baseline 
values for graded scores for the temporal, nasal regions and for overall score by treatment 
arm, study visit and eye (study eye or qualified fellow eye).  The overall score of VBR 
would be arrived by averaging the Nasal and temporal score. 
 
Change from baseline of VBR (nasal, temporal and overall VBR score) will be compared 
between the treatment groups for study eye using the ITT and PP population for observed 
(without MI) and only ITT population for imputed data (with MI) by pairwise two sample 
t-tests and corresponding p-value along with 90% and 95% Confidence Interval (CI) for 
mean will be presented. Pairwise comparison in mean among the three treatment groups 
(Brimonidine Monotherapy vs. placebo, Brimonidine Combination therapy vs. placebo, 
Brimonidine Monotherapy vs. Combination therapy). 
 
Also, a subgroup analysis of patients with baseline VBR-Overall Score >=25 (i.e. Baseline 
Total VBR Score >=25) will be summarized for observed VBR score by treatment arm and 
by eye (study eye and qualified fellow eye) for the ITT and PP population using descriptive 
statistics and analysis change from baseline of VBR score by treatment arm and study eye 
using ITT, ITT (MI) and PP population as described above.  
 


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Mean change from baseline plot of VBR (nasal, temporal and overall score) with 95% CI 
will be presented for all three treatment groups and for study eye using ITT and PP 
population. 
 
Subjects with missing values will be imputed using the Multiple Imputation(MI) method. 
See section 4.7 Appendices for Multiple Imputation methodology. 
 
The overall improvement/worsening in VBR scale (category given below) will be derived 
and summarized as frequency and percentage by treatment arm and study visit using the 
ITT and PP population. 
 
A subgroup analysis of patients with baseline VBR-Overall Score >=25 (i.e. Baseline Total 
VBR Score >= 25) will be summarized for derived overall worsening in VBR scale 
(category given below) using frequency and percentage by Eye (study eye, qualified fellow 
eye), treatment arm and study visit using the ITT and PP population.  
 
The above described subgroup analysis for worsening in VBR scale will also be 
summarized for patients with baseline ORS-Bulbar Redness category score >=1.5 (i.e. 
Baseline Bulbar Redness >=1.5) or VBR-Overall Score >=25 (i.e. Baseline Total VBR 
Score>=25) using frequency and percentage by Eye (study eye, qualified fellow eye), 
treatment arm and study visit using the ITT and PP population. 
 
Also, a subgroup analysis of patients with baseline ORS-Bulbar Redness category score 
>=1.5 (i.e. Baseline Bulbar Redness >=1.5) or VBR-Overall Score >=25 (i.e. Baseline 
Total VBR Score>=25) will be summarized for observed VBR score by treatment arm and 
by eye (study eye and qualified fellow eye) for the ITT and PP population using descriptive 
statistics and analysis change from baseline of VBR score by treatment arm and study eye 
using ITT, ITT (MI) and PP population as described above.    
 
i. 
Marked worsening (increase > 40) 
ii. 
Moderate worsening (increase  >20 and <40) 
iii. 
Minimal worsening (increase >0 and <20) 
iv. 
Unchanged (difference of 0) 
v. 
Minimal improvement (reduction >0 and <20) 
vi. 
Moderate improvement (reduction  >20 and <40) 
vii. 
Marked improvement (reduction > 40) 
 
The VBR and overall improvement/worsening in VBR scale category will also be listed 
using the Randomized population. 
  
No imputation will be done for overall improvement/worsening in VBR scale response 
category. 
 
• Clinical Global Impression (CGI) of change in symptoms from baseline (physician’s 
rating) – The CGI response category (as response category given below) will be 
summarized as frequency and percentage by treatment arm and study visit using the ITT 
and PP population. 


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I. 
Marked worsening 
II. 
Moderate worsening 
III. 
Minimal worsening 
IV. 
Unchanged 
V. 
Minimal improvement 
VI. 
Moderate improvement 
VII. 
Marked improvement 
 
The proportion of subjects with improvements (Minimal improvement, Moderate 
improvement, Marked improvement) at the day 84 and 105 will be summarized and 
compared among pairwise treatment groups (Brimonidine Monotherapy vs. placebo, 
Brimonidine Combination therapy vs. placebo, Brimonidine Monotherapy vs. 
Combination therapy) using Fisher’s exact test for ITT and PP population for observed 
(without LOCF) and ITT population for imputed data (with LOCF).  
 
The CGI response category will also be listed using the Randomized population. 
  
The missing values of post dose CGI score will be imputed using LOCF (Last Observation 
Carried Forward) method, expect for the first post dose assessment. 
 
•  Subject Global Assessment (SGA) of overall change from baseline (subject’s rating) 
– The SGA response category (as response category given below) will be summarized as 
frequency and percentage by treatment arm and study visit using the ITT and PP 
population. 
i. 
Much worse 
ii. 
Worse 
iii. 
About the same 
iv. 
Improved 
v. 
Much improved 
 
The proportion of subjects with improvement (Improved and Much Improved) at the day 
84 and 105 will be summarized and compared among pairwise treatment groups 
(Brimonidine Monotherapy vs. placebo, Brimonidine Combination therapy vs. placebo, 
Brimonidine Monotherapy vs. Combination therapy) using Fisher’s exact test for ITT and 
PP population for observed (without LOCF) and only ITT population for imputed data 
(with LOCF).  
 
 The SGA response category will also be listed using the Randomized population. 
  
The missing values of post dose SGA score will be imputed using LOCF (Last Observation 
Carried Forward) method, expect for the first post dose assessment. 
 
 
4.3.12 Safety Endpoints: 
Adverse Events:  


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AEs will be coded to system organ class (SOC) and preferred term (PT) using MedDRA (version 20.0). 
An overall summary of number and percentage of subjects with at least one AE, TEAE, serious TEAE, 
treatment-related TEAE, serious treatment-related TEAE, and TEAE leading to treatment discontinuation, 
TEAE leading to study discontinuation will be presented by treatment arm and also by Ocular (by study 
eye and fellow eye) and Non-Ocular AEs using safety population. 
 
TEAE will also be summarized using frequency and percentage by overall, AE type (Ocular AE (study 
eye, fellow eye), Non-Ocular AE) and by treatment with SOC and PT using safety population. Each 
subject can have AEs of all types. Therefore, the percentage base is the number of subjects in the safety 
population under each treatment. 
 
Number and percentage of patients with TEAEs will be tabulated by MedDRA system organ class, and 
preferred term by Treatment. TEAEs (MedDRA system organ class and preferred term) will also be 
summarized by relationship to study drug (by ocular (study eye, fellow eye) and non-ocular AE), severity 
grade - mild, moderate or severe (by ocular (study eye, fellow eye) and non-ocular AE). Related events 
will include those with, possibly related, definitely related captured on the CRF.  
 
In calculating the number of subjects who have TEAEs, if a subject has the same event occur more than 
once, the TEAE with the highest degree of relatedness (Probable, Possible) and the event with the highest 
severity (from low to high – Mild, Moderate, Severe) will be summarized. In case of missing relatedness 
or severity, the highest value will be assumed. A summary table for Death due to TEAE will be 
summarized. All the above tables will be summarized using safety population.  
 
All adverse events (AEs) reported during the study will be present in a by-subject listing using the All 
Subjects.  Separate by-subject listings will be generated to present Serious TEAEs and AEs leading to 
discontinuation from the study using safety population. 
 
Vital signs: 
Vital signs (systolic and diastolic blood pressure, pulse rate and body temperature) will be summarized 
using the descriptive statistics for each vital sign measurement and change from baseline by treatment arm 
and study visit using the safety population. Also overall interpretation of vital signs will be summarized 
with frequency and percentage using the safety population. 
Vital Sign data will be listed by individual time course for each parameter and subject using the safety 
population. 
 
Findings from ophthalmic examinations (via Slit Lamp): 
The ophthalmic examinations such as tear film, eye lids, lashes, bulbar and palpebral conjunctiva, upper 
and lower lid puncta, cornea, anterior chamber, iris, lens, and anterior vitreous will be summarized by 
categories such as Normal, Abnormal (NCS) and Abnormal (CS) using frequency and percentage for 
treatment and by eye using safety population. 
A separate listing will be presented for the each of the ophthalmic examination findings noted above using 
the safety population. 


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Visual acuity collected in CRF is in US notation i.e. Snellen Numerator and Snellen Denominator. Change 
from baseline will be derived based on transformed decimal notation and line worsening will be 
categorised using derived logMAR values.  
The Visual acuity derivation of Decimal notation, MAR and logMAR are explained below with example.  
Visual acuity values are understood best by the following simple rule.  On a Snellen chart we determine 
the line that the person can just recognize.  If that line is twice as large as the reference standard (20/20), 
we state that that person’s MAgnification Requirement (MAR) is 2x.  If the MAgnification Requirement 
is 2x, the visual acuity is 1/2 (20/40).  Similarly, if the MAgnification Requirement (MAR) is 5x, the 
visual acuity is 1/5 (20/100); if MAR = 10, visual acuity = 1/10 (20/200), and so on. 
LogMAR = log10 (MAR) 
Snellen Chart Lines 
US 
notation 
Decimal 
notation 
MAR 
LogMAR 
Super Normal 
20/10 
2.0 
0.5 
-0.3 
Super Normal 
20/15 
1.33 
0.75 
-0.1 
Line 10 (normal vision) 
20/20 
1.0 
1.0 
0.0 
Line 9 
20/25 
0.8 
1.25 
0.1 
Line 8 
20/30 
0.67 
1.67 
0.2 
Line 7 
20/40 
0.50 
2.0 
0.3 
Line 6 
20/50 
0.40 
2.5 
0.4 
Line 5 
20/60 
0.33 
3.03 
0.5 
Line 4 
20/70 
0.28 
3.57 
0.6 
Line 3 
20/80 
0.25 
4 
0.6 
Line 2 
20/100 
0.2 
5 
0.7 
Line 1 (worst vision) 
20/200 
0.1 
10 
1 
 
LogMAR values will be rounded to 1-digit precision. 1 line change is defined as increase in LogMAR 
value by 0.1. 
Measurement of visual acuity (via Snellen, with eyeglasses if applicable) data will be summarized by 
treatment group and by eye at each visit and for change from baseline to each visit using discrete 
summaries including change from baseline in the number of lines and the proportion of subjects with ≥ 3 
line change (worsening) from baseline will be summarized by Eye and Visit. 
A listing of visual acuity include Snellen individual measurements and abnormal values (≥ 3 line change 
from Baseline) will be presented using the safety population. 
Intraocular pressure (via Goldmann tonometry) will be summarized for Safety and PP population by 
treatment group and by eye at each visit and for change from baseline to each visit using descriptive 
statistics. 
Change from baseline of Intraocular pressure will be compared between the treatment groups for study 
eye using the Safety and PP population for observed (without MI) and only Safety population for imputed 
data (with MI) at each visit by pairwise two sample t-tests and corresponding p-value along with 90% and 


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95% Confidence Interval (CI)  for mean will be presented. Pairwise comparison in mean among the three 
treatment groups (Brimonidine Monotherapy vs. placebo, Brimonidine Combination therapy vs. placebo, 
Brimonidine Monotherapy vs. Combination therapy) will be assessed. 
Two-sided P-value less than 0.05 would be considered as statistical significance.  
Clinical significant changes (worsening) from baseline (% change from baseline) in Intraocular Pressure 
of study eye will be categorised as IOP increase >= 20% vs. Baseline; IOP decrease >= 20% vs. Baseline; 
and No significant change (change value of -19 to 19%) vs. Baseline; and summarized using frequency 
and percentage by  visits and treatment arm. 
Mean change from baseline plot of Intraocular pressure with 95% CI will be presented for all three 
treatment groups and study visit using the Safety and PP populations. 
Subjects with missing values will be imputed using the Multiple Imputation (MI) method. See section 4.7 
Appendices for Multiple Imputation methodology. 
The Intraocular pressure (category given below) will be derived and summarized as frequency and 
percentage by treatment arm and study visit for both eyes using the Safety and PP population. 
i. 
Normal (>5 =mmHg or <=22 mmHg) 
ii. 
Abnormal (<5 mmHg or >22 mmHg) 
The proportion of subjects with Intraocular pressure category (Normal & Abnormal) at the day 84 and 
105 will be summarized and compared among pairwise treatment groups (Brimonidine Monotherapy vs. 
placebo, Brimonidine Combination therapy vs. placebo, Brimonidine Monotherapy vs. Combination 
therapy) using Fisher’s exact test for Safety and PP. 
A listing of Intraocular pressure with category will be presented using the Safety population. 
No imputation will be done for Intraocular pressure category. 
.  
 
 


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4.4 
INTERIM ANALYSES AND DATA MONITORING 
Interim analysis will be performed by the unblinded team for data through Day 84 for regulatory 
submission. As a part of this interim analysis, the applicable TLFs for the following end points 
will be submitted for data up to day 84.  As this will be the primary analysis for efficacy, no 
alpha adjustment will be made. 
 
1. Disposition & Demographics  
2. Primary Tolerability Endpoint: Test Substance Tolerance (Visual Analogue Scale).  
3. Adverse Events - ocular and non-ocular  
4. Intraocular pressure 
5. Efficacy endpoints as per Section 3.3 
• Symptom Assessment Questionnaire iN Dry Eye (SANDE)  
• Change in corneal and conjunctival staining scores by Lissamine Green dye 
staining  
• Change in tear secretion as measured by Schirmer I test  
• Change in Keratograph Ocular Redness Score (ORS)  
• Change in Validated Bulbar Redness (VBR) grading scale  
• Clinical Global Impression (CGI) of change in symptoms from baseline 
(physician’s rating)  
• Subject Global Assessment (SGA) of overall change from baseline (subject’s 
rating)  
 
4.5 
CHANGES OF ANALYSIS FROM PROTOCOL 
Included a summary and analysis for Change in Noninvasive Tear Breakup Time (NITBUT) 
along with plot. 
Interim analysis for Day 84 will be performed for regulatory submission as per Sponsor request.     
4.6 
REFERENCES 
NA 
4.7 
APPENDICES 
Appendix 1- Multiple Imputation Method for the Exploratory Efficacy Endpoint 
The missing data pattern of the exploratory efficacy parameters, SANDE VAS, Keratograph Ocular 
Redness Score (ORS), Validated Bulbar Redness (VBR) scores, and Intraocular Pressure(IOP) will be 
analyzed by using the Multiple Imputation (MI) method.  
Imputation of missing data will be conducted under a working assumption of Missing Completely At 
Random (MCAR). Missing Completely At Random means that the missing data mechanism is assumed 
not to depend on observed or unobserved missing values. These assumptions will be assessed in the 
sensitivity analyses described later in this Appendix.  


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Multiple Imputation replaces each missing value with a set of m=5 plausible possibilities. The set of these 
possibilities represent the uncertainty about the unobserved ‘true’ value that was imputed. The imputation 
model uses observed data to assist in the prediction of the missing data. Then, the m full datasets (with the 
imputation) are analyzed by the selected inferential statistical model separately. The inference is 
conducted by combining the m point estimates and their variance into a single test as described below.  
The exploratory efficacy endpoints, SANDE VAS Score, Keratograph Ocular Redness Score (ORS), 
Validated Bulbar Redness (VBR) scores, and Intraocular Pressure(IOP) outcome will then be derived out 
of their respective imputed data set as follows.   
The 5 datasets will be summarized to one data set that includes the exploratory efficacy endpoint score 
average across all datasets for each patient and each time point separately. On the summarized dataset, a 
change from baseline will be calculated. Finally, the inferential model of the exploratory efficacy 
endpoints will be applied according to the SAP section 4.3.11.  
At a minimum, the set of covariates that will be incorporated into the imputation model is treatment group. 
The MI will be conducted in three steps: 
Step I: Imputation of Intermediate Missing Data 
/**Pseudo code to perform Multiple Imputation, with example of SANDE VAS parameter**/ 
*Format for visit;  
PROC FORMAT;  
 VALUE vis 1.5 = 'BL'  
 2 = 'DAY 28'  
 3= 'Day 56'  
 4= 'Day 84'  
 5= 'Day 105';  
RUN;  
 
*Filter data of SANDE VAS parameter and post baseline scheduled visits; 
*Transpose to horizontal structure for the parameter SANDE VAS;  
PROC TRANSPOSE DATA=sande OUT=onepersub PREFIX=sande;  
 
BY subjid trt01p paramcd param;  
 
ID avisitn;  
 
VAR aval;  
RUN;  
 
* Step 1a: Imputation of Intermediate Missing Data; 
proc mi data=onepersub out=outds  
        nimpute=5 seed=3102017 /*Seed number was based on protocl ID*/ 
        minimum = 0 0 0 0 /*This will be based on the range of the analysis variable*/ 
 
  maximum =  100 100 100 100 /*This will be based on the range of the analysis variable*/ 
 
 ROUND =  0.1 0.1 0.1 0.1; /*This will vary bsaed on the analysis variable*/; 
var  sande2 sande3 sande4 sande5; 
mcmc chain=multiple impute=monotone; /*To impute the intermediate missing data and 
make the remaining missingness as monotone*/ 
run;     


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Step II: Imputation of Withdrawal Missing Data 
* Step 1b: Imputation of Withdrawal Missing Data; 
proc mi data=outds OUT = outds2  
nimpute=1 /*Since we already have the 5 imputations from previous step, imputing only once here*/ 
minimum =. 0 0 0 0 /*This will be based on the range of the analysis variable*/ 
maximum = . 100 100 100 100 /*This will be based on the range of the analysis variable*/ 
ROUND = . 0.1 0.1 0.1 0.1; /*This will vary bsaed on the analysis variable*/ 
class trt01p; 
var trt01p sande2 sande3 sande4 sande5; 
monotone reg(sande2 sande3 sande4 sande5/ details); 
run; 
 
*Step 2a - transpose back to vertical structure;  
PROC TRANSPOSE DATA=outds2 OUT=back;  
 
BY _imputation_ subjid trt01p paramcd param;  
 
VAR sande2 sande3 sande4 sande5;  
RUN;  
 
*Clean up;  
DATA _mi;  
 
SET back;  
 
*Rederive avist/avisitn;  
 
avisitn=INPUT(COMPRESS(_name_, 'sande'), BEST.);  
 
avisit=PUT(avisitn, VIS.); 
 
DROP _name_; 
RUN;  
 
*Sort for merge with original data;  
PROC SORT DATA=_mi;  
 
BY subjid avisitn aval;  
RUN;  
 
*Flag imputed records;  
DATA mi (RENAME=(_imputation_=imputeno));  
 
MERGE _mi(IN=mi) sande (IN=observed KEEP=subjid avisitn aval);  
 
BY subjid avisitn aval;  
 
IF mi AND NOT observed THEN dtype='MI';  
RUN; 
Step III: Inference 
*Sort for analysis step;  
PROC SORT DATA=mi;  
 BY imputeno avisitn subjid;  
RUN;  
 
*Step 2b - Analysis step;  
/*ods trace on;*/ 
PROC TTEST DATA=mi ci=equal; 
  class trt01p; 
  where trt01p in ("COMBO","MONO"); /*selecting only two for pairwise comparison, for 
other comparisons change the values*/ 
  VAR aval; 
  BY imputeno avisitn; 
  ODS OUTPUT statistics=diffbyvis2; 
RUN; 


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/*ods trace off;*/ 
DATA formianalyze2;  
 
SET diffbyvis2;  
 
where upcase(class) eq "DIFF (1-2)"; 
 
keep imputeno avisitn mean stderr; 
RUN;  
 
*Step 3 – Pooling step;  
PROC SORT DATA=formianalyze2;  
  
BY avisitn imputeno;  
RUN;  
 
ODS OUTPUT PARAMETERESTIMATES=diffestvisi2;  
PROC MIANALYZE DATA=formianalyze2;  
 
BY avisitn;  
 
MODELEFFECTS mean;  
 
STDERR stderr;  
RUN;  
ODS OUTPUT CLOSE; 
/****the following estimates to be presented in the outputs based on MI**********/ 
*Point estimate, StdErr, Confidence interval, Minimum, Maximum, p-value; 
/*********************************************************************************/ 
Step IV: Sensitivity analysis for the exploratory efficacy endpoints 
*For Sensitivity Analyses, Follow above procedure until step 1a and from Step 1b 
onwards till Step 3 follow below code; 
 
* Step 1b: Imputation of Withdrawal Missing Data with MNAR; 
proc mi data=outds OUT = outsense  
nimpute=1 /*Since we already have the 5 imputations from previous step, imputing only once here*/ 
minimum =. 0 0 0 0 /*This will be based on the range of the analysis variable*/ 
maximum = . 100 100 100 100 /*This will be based on the range of the analysis variable*/ 
ROUND = . 0.1 0.1 0.1 0.1; /*This will vary bsaed on the analysis variable*/ 
class trt01p; 
monotone reg(sande2 sande3 sande4 sande5 /details ); 
mnar  adjust (sande2  /scale=0.9 ); 
mnar  adjust (sande3  /scale=0.9 ); 
mnar  adjust (sande4  /scale=0.9 ); 
mnar  adjust (sande5  /scale=0.9 ); 
var trt01p sande2 sande3 sande4 sande5; 
run; 
 
PROC SORT DATA= outsense;  
  
BY _imputation_ subjid trt01p paramcd param;  
RUN;  
 
 
 
 
*Step 2a - transpose back to vertical structure;  
PROC TRANSPOSE DATA=outsense OUT=back2;  
 
BY _imputation_ subjid trt01p paramcd param;  
 
VAR sande2 sande3 sande4 sande5;  
RUN;  
 


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*Clean up;  
DATA _mi2;  
 
SET back2;  
 
*Rederive avist/avisitn;  
 
avisitn=INPUT(COMPRESS(_name_, 'sande'), BEST.);  
 
avisit=PUT(avisitn, VIS.); 
 
DROP _name_; 
RUN;  
 
*Sort for merge with original data;  
PROC SORT DATA=_mi2;  
 
BY subjid avisitn aval;  
RUN;  
 
*Flag imputed records;  
DATA mi2 (RENAME=(_imputation_=imputeno));  
 
MERGE _mi2(IN=mi) sande (IN=observed KEEP=subjid avisitn aval);  
 
BY subjid avisitn aval;  
 
IF mi AND NOT observed THEN dtype='MI';  
RUN;  
 
*Sort for analysis step;  
PROC SORT DATA=mi2;  
 BY imputeno avisitn subjid;  
RUN;  
 
*Step 2b - Analysis step;  
/*ods trace on;*/ 
PROC TTEST DATA=mi2 ci=equal; 
  class trt01p; 
  where trt01p in ("COMBO","MONO"); /*selecting only two for pairwise comparison, 
for other comparisons change the values*/ 
  VAR aval; 
  BY imputeno avisitn; 
  ODS OUTPUT statistics=diffbyvis3; 
RUN; 
 
/*ods trace off;*/ 
DATA formianalyze3;  
 
SET diffbyvis3;  
 
where upcase(class) eq "DIFF (1-2)"; 
 
keep imputeno avisitn mean stderr; 
RUN;  
 
*Step 3 – Pooling step;  
PROC SORT DATA=formianalyze3;  
  
BY avisitn imputeno;  
RUN;  
 
ODS OUTPUT PARAMETERESTIMATES=diffestvisi3;  
PROC MIANALYZE DATA=formianalyze3;  
 
BY avisitn;  
 
MODELEFFECTS mean;  
 
STDERR stderr;  
RUN;  
ODS OUTPUT CLOSE; 


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/****the following estimates to be presented in the outputs based on MI**********/ 
*Point estimate, StdErr, Confidence interval, Minimum, Maximum, p-value; 
/*********************************************************************************/ 
The results of this sensitivity analysis will then be compared with the results of the MCAR analyses.  If 
the results agree, then one can say that the result is robust for the choice of difference in parameter values.  
All the results of sensitivity analysis of the efficacy and safety parameters will be presented in the 
supplemental Tables of the respective parameter analysis. Results (Estimates) from the SAS LST output 
will be presented in the supplemental table outputs. No formal Table shell is required to report the results 
of sensitivity analysis. 
5 
LIST OF TABLES, LISTINGS AND FIGURES 
5.1 
Summary Tables 
Number 
Title 
Table 14.1.1.1 
Summary of Subject Disposition – All Subjects 
Table 14.1.1.2 
Summary of Demographic and Baseline Characteristics – Randomized 
Population 
Table 14.1.1.3 
Summary of Demographic and Baseline Characteristics – ITT Population 
Table 14.1.1.4 
Summary of Demographic and Baseline Characteristics – PP Population 
Table 14.1.2.1 
Summary of Protocol Deviation – Randomized Population 
Table 14.1.3.1 
Summary of Study Drug Exposure – Safety Population 
Table 14.1.4.1 
Summary of Medical History – Safety Population 
Table 14.1.4.2 
Summary of Prior Medications – Randomized Population 
Table 14.1.4.3 
Summary of Concomitant Medications – Safety Population 
Table 14.2.1.1.1 
Summary of SANDE VAS Score – ITT Population 
Table 14.2.1.1.2 
Analysis of SANDE VAS Score Change from Baseline – ITT Population 
Table 14.2.1.2.1 
Summary of SANDE VAS Score – PP Population 
Table 14.2.1.2.2 
Analysis of SANDE VAS Score Change from Baseline – PP Population 
Table 14.2.1.3.1 
Summary of SANDE VAS Score (MI) – ITT Population 
Table S14.2.1.3.1 
Sensitivity Analysis of Multiple Imputation of SANDE VAS Score – ITT 
Population 
Table 14.2.1.3.2 
Analysis of SANDE VAS Score Change from Baseline (MI) – ITT Population 
Table 14.2.2.1.1 
Summary of Corneal Lissamine Green Staining by Zone and Overall– ITT 
Population 
Table 14.2.2.1.2 
Summary of Corneal Lissamine Green Staining by Zone and Overall– PP 
Population 
Table 14.2.2.2.1 
Analysis of Corneal Lissamine Green Staining Overall Score Change from 
Baseline for Study Eye – ITT Population 
Table 14.2.2.2.2 
Analysis of Corneal Lissamine Green Staining Overall Score Change from 
Baseline for Study Eye – PP Population 
Table 14.2.2.3.1 
Summary of Conjunctival Lissamine Green Staining by Zone and Overall – ITT 
Population 


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Number 
Title 
Table 14.2.2.3.2 
Summary of Conjunctival Lissamine Green Staining by Zone and Overall – PP 
Population 
Table 14.2.2.4.1 
Analysis of Conjunctival Lissamine Green Staining Overall Score Change from 
Baseline for Study Eye – ITT Population 
Table 14.2.2.4.2 
Analysis of Conjunctival Lissamine Green Staining Overall Score Change from 
Baseline for Study Eye – PP Population 
Table 14.2.3.1.1 
Summary of Tear Secretion (Schirmer I Test) – ITT Population 
Table 14.2.3.1.2 
Summary of Tear Secretion (Schirmer I Test) – PP Population 
Table 14.2.3.2.1 
Analysis of Tear Secretion (Schirmer I Test) Change from Baseline for Study 
Eye – ITT Population 
Table 14.2.3.2.2 
Analysis of Tear Secretion (Schirmer I Test) Change from Baseline for Study 
Eye – PP Population 
Table 14.2.3.3.1 
Summary of Tear Secretion (Categorical) – ITT Population 
Table 14.2.3.3.2 
Summary of Tear Secretion (Categorical) – PP Population 
Table 14.2.3.4.1 
Summary of grade improvement in Tear Secretion (Categorical) – ITT 
Population 
Table 14.2.3.4.2 
Summary of grade improvement in Tear Secretion (Categorical) – PP Population 
Table 14.2.3.5.1 
Summary of Shift from Baseline in Tear Secretion (Categorical) – ITT 
Population 
Table 14.2.3.5.2 
Summary of Shift from Baseline in Tear Secretion (Categorical) – PP Population 
Table 14.2.4.1.1 
Summary of Keratograph Ocular Redness Score for Study Eye – ITT Population 
Table 14.2.4.1.1.1 
Summary of Keratograph Ocular Redness Score for Study Eye - ITT Population - 
Patients with Baseline ORS-Bulbar Redness Score >=1.5 
Table 14.2.4.1.1.2 
Summary of Keratograph Ocular Redness Score for Study Eye - ITT Population - 
Patients with Baseline ORS-Bulbar Redness Score >=1.5 or Baseline VBR-
Overall Score >=25 
Table 14.2.4.1.2 
Summary of Keratograph Ocular Redness Score for Qualified Fellow Eye – ITT 
Population 
Table 14.2.4.1.2.1 
Summary of Keratograph Ocular Redness Score for Qualified Fellow Eye - ITT 
Population – Patients with Baseline ORS-Bulbar Redness Score >=1.5 
Table 14.2.4.1.2.2 
Summary of Keratograph Ocular Redness Score for Qualified Fellow Eye - ITT 
Population – Patients with Baseline ORS-Bulbar Redness Score >=1.5 or 
Baseline VBR-Overall Score >=25 
Table 14.2.4.2.1 
Summary of Keratograph Ocular Redness Score for Study Eye – PP Population 
Table 14.2.4.2.1.1 
Summary of Keratograph Ocular Redness Score for Study Eye - PP Population - 
Patients with Baseline ORS-Bulbar Redness Score >=1.5 
Table 14.2.4.2.1.2 
Summary of Keratograph Ocular Redness Score for Study Eye - PP Population - 
Patients with Baseline ORS-Bulbar Redness Score >=1.5 or Baseline VBR-
Overall Score >=25 
Table 14.2.4.2.2 
Summary of Keratograph Ocular Redness Score for Qualified Fellow Eye - PP 
Population 
Table 14.2.4.2.2.1 
Summary of Keratograph Ocular Redness Score for Qualified Fellow Eye - PP 
Population - Patients with Baseline ORS-Bulbar Redness Score >=1.5 


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Number 
Title 
Table 14.2.4.2.2.2 
Summary of Keratograph Ocular Redness Score for Qualified Fellow Eye - PP 
Population - Patients with Baseline ORS-Bulbar Redness Score >=1.5 or 
Baseline VBR-Overall Score >=25 
Table 14.2.4.3.1 
Analysis of Keratograph Ocular Redness Score Change from Baseline for Study 
Eye – ITT Population 
Table 14.2.4.3.1.1 
Analysis of Keratograph Ocular Redness Score Change from Baseline for Study 
Eye - ITT Population - Patients with Baseline ORS-Bulbar Redness Score >=1.5 
Table 14.2.4.3.1.2 
Analysis of Keratograph Ocular Redness Score Change from Baseline for Study 
Eye - ITT Population - Patients with Baseline ORS-Bulbar Redness Score >=1.5 
or Baseline VBR-Overall Score >=25 
Table 14.2.4.3.2 
Analysis of Keratograph Ocular Redness Score Change from Baseline for Study 
Eye – PP Population 
Table 14.2.4.3.2.1 
Analysis of Keratograph Ocular Redness Score Change from Baseline for Study 
Eye - PP Population - Patients with Baseline ORS-Bulbar Redness Score >=1.5 
Table 14.2.4.3.2.2 
Analysis of Keratograph Ocular Redness Score Change from Baseline for Study 
Eye - PP Population - Patients with Baseline ORS-Bulbar Redness Score >=1.5 
or Baseline VBR-Overall Score >=25 
Table 14.2.4.3.3 
Analysis of Keratograph Ocular Redness Score Change from Baseline for Study 
Eye (MI) – ITT Population 
Table 14.2.4.3.3.1 
Analysis of Keratograph Ocular Redness Score Change from Baseline for Study 
Eye (MI) - ITT Population - Patients with Baseline ORS-Bulbar Redness Score 
>=1.5 
Table 14.2.4.3.3.2 
Analysis of Keratograph Ocular Redness Score Change from Baseline for Study 
Eye (MI) - ITT Population - Patients with Baseline ORS-Bulbar Redness Score 
>=1.5 or Baseline VBR-Overall Score >=25 
Table S14.2.4.3.3 
Sensitivity Analysis of Multiple Imputation of Ocular Redness Score – ITT 
Population 
Table 14.2.5.1.1 
Summary of Validated Bulbar Redness (VBR) for Study Eye – ITT Population 
Table 14.2.5.1.1.1 
Summary of Validated Bulbar Redness (VBR) for Study Eye - ITT Population – 
Patients with Baseline VBR-Overall Score >= 25 
Table 14.2.5.1.1.2 
Summary of Validated Bulbar Redness (VBR) for Study Eye - ITT Population – 
Patients with Baseline ORS-Bulbar Redness Score >=1.5 or Baseline VBR-
Overall Score >= 25 
Table 14.2.5.1.2 
Summary of Validated Bulbar Redness (VBR) for Qualified Fellow Eye – ITT 
Population 
Table 14.2.5.1.2.1 
Summary of Validated Bulbar Redness (VBR) for Qualified Fellow Eye - ITT 
Population - Patients with Baseline VBR-Overall Score >= 25 
Table 14.2.5.1.2.2 
Summary of Validated Bulbar Redness (VBR) for Qualified Fellow Eye - ITT 
Population - Patients with Baseline ORS-Bulbar Redness Score >=1.5 or 
Baseline VBR-Overall Score >= 25 
Table 14.2.5.2.1 
Summary of Validated Bulbar Redness (VBR) for Study Eye – PP Population 
Table 14.2.5.2.1.1 
Summary of Validated Bulbar Redness (VBR) for Study Eye – PP Population - 
Patients with Baseline VBR-Overall Score >= 25 


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Number 
Title 
Table 14.2.5.2.1.2 
Summary of Validated Bulbar Redness (VBR) for Study Eye – PP Population - 
Patients with Baseline ORS-Bulbar Redness Score >=1.5 or Baseline VBR-
Overall Score >= 25 
Table 14.2.5.2.2 
Summary of Validated Bulbar Redness (VBR) for Qualified Fellow Eye – PP 
Population 
Table 14.2.5.2.2.1 
Summary of Validated Bulbar Redness (VBR) for Qualified Fellow Eye - PP 
Population - Patients with Baseline VBR-Overall Score >= 25 
Table 14.2.5.2.2.2 
Summary of Validated Bulbar Redness (VBR) for Qualified Fellow Eye - PP 
Population - Patients with Baseline ORS-Bulbar Redness Score >=1.5 or 
Baseline VBR-Overall Score >= 25 
Table 14.2.5.3.1 
Analysis of Validated Bulbar Redness (VBR) Change from Baseline for Study 
Eye – ITT Population 
Table 14.2.5.3.1.1 
Analysis of Validated Bulbar Redness (VBR) Change from Baseline for Study 
Eye - PP Population - Patients with Baseline VBR-Overall Score >= 25 
Table 14.2.5.3.1.2 
Analysis of Validated Bulbar Redness (VBR) Change from Baseline for Study 
Eye - PP Population - Patients with Baseline ORS-Bulbar Redness Score >=1.5 
or Baseline VBR-Overall Score >= 25 
Table 14.2.5.3.2 
Analysis of Validated Bulbar Redness (VBR) Change from Baseline for Study 
Eye – PP Population 
Table 14.2.5.3.2.1 
Analysis of Validated Bulbar Redness (VBR) Change from Baseline for Study 
Eye - PP Population - Patients with Baseline VBR-Overall Score >= 25 
Table 14.2.5.3.2.2 
Analysis of Validated Bulbar Redness (VBR) Change from Baseline for Study 
Eye - PP Population - Patients with Baseline ORS-Bulbar Redness Score >=1.5 
or Baseline VBR-Overall Score >= 25 
Table 14.2.5.3.3 
Analysis of Validated Bulbar Redness (VBR) Change from Baseline for Study 
Eye – MI – ITT Population 
Table 14.2.5.3.3.1 
Analysis of Validated Bulbar Redness (VBR) Change from Baseline for Study 
Eye – MI - ITT Population - Patients with Baseline VBR-Overall Score >= 25 
Table 14.2.5.3.3.2 
Analysis of Validated Bulbar Redness (VBR) Change from Baseline for Study 
Eye – MI - ITT Population - Patients with Baseline ORS-Bulbar Redness Score 
>=1.5 or Baseline VBR-Overall Score >= 25 
Table S14.2.5.3.3 
Sensitivity Analysis of Multiple Imputation of Validated Bulbar Redness (VBR) 
Grading Scale – ITT Population 
Table 14.2.5.4.1 
Summary of overall worsening in VBR scale – ITT Population 
Table 14.2.5.4.1.1 
Summary of Overall Worsening in Validated Bulbar Redness (VBR)Scale - ITT 
Population - Patients with Baseline VBR-Overall Score >= 25 
Table 14.2.5.4.2 
Summary of overall worsening in VBR scale – PP Population 
Table 14.2.5.4.2.1 
Summary of Overall Worsening in Validated Bulbar Redness (VBR)Scale - PP 
Population - Patients with Baseline VBR-Overall Score >= 25 
Table 14.2.5.4.3.1 
Summary of Overall Worsening in Validated Bulbar Redness (VBR)Scale - ITT 
Population - Patients with Baseline ORS-Bulbar Redness Score >=1.5 or 
Baseline VBR-Overall Score >= 25 
Table 14.2.5.4.3.2 
Summary of Overall Worsening in Validated Bulbar Redness (VBR)Scale - PP 
Population - Patients with Baseline ORS-Bulbar Redness Score >=1.5 or 
Baseline VBR-Overall Score >= 25 


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Number 
Title 
Table 14.2.6.1.1 
Summary of Clinical Global Impression – ITT Population 
Table 14.2.6.1.2 
Summary of Clinical Global Impression – PP Population 
Table 14.2.6.2.1 
Improvement of Clinical Global Impression – ITT Population 
Table 14.2.6.2.2 
Improvement of Clinical Global Impression – PP Population 
Table 14.2.6.2.3 
Improvement of Clinical Global Impression (LOCF) – ITT Population 
Table 14.2.7.1.1 
Summary of Subject Global Assessment – ITT Population 
Table 14.2.7.1.2 
Summary of Subject Global Assessment – PP Population 
Table 14.2.7.2.1 
Improvement of Subject Global Assessment – ITT Population 
Table 14.2.7.2.2 
Improvement of Subject Global Assessment – PP Population 
Table 14.2.7.2.3 
Improvement of Subject Global Assessment (LOCF) – ITT Population 
Table 14.2.8.1.1 
Summary of Noninvasive Tear Breakup Time (NITBUT) for Study Eye– ITT 
Population 
Table 14.2.8.1.2 
Summary of Noninvasive Tear Breakup Time (NITBUT) for Qualified Fellow 
Eye – ITT Population 
Table 14.2.8.2.1 
Summary of Noninvasive Tear Breakup Time (NITBUT) for Study Eye– PP 
Population 
Table 14.2.8.2.2 
Summary of Noninvasive Tear Breakup Time (NITBUT) for Qualified Fellow 
Eye – PP Population 
Table 14.2.8.3.1 
Analysis of Noninvasive Tear Breakup Time (NITBUT) Change from Baseline 
for Study Eye – ITT Population 
Table 14.2.8.3.2 
Analysis of Noninvasive Tear Breakup Time (NITBUT) Change from Baseline 
for Study Eye – PP Population 
Table 14.3.1.1 
Overall Summary of Adverse Events – Safety Population 
Table 14.3.1.2 
Summary of Treatment-Emergent Adverse Events by MedDRA System Organ 
Class and Preferred Term – Safety Population 
Table 14.3.1.3 
Summary of Ocular Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term – Safety Population 
Table 14.3.1.4 
Summary of Non-Ocular Treatment-Emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term – Safety Population 
Table 14.3.1.5 
Summary of Serious Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term – Safety Population 
Table 14.3.1.6.1 
Summary of Ocular Treatment-Emergent Adverse Events by Maximum Severity, 
MedDRA System Organ Class and Preferred Term – Safety Population 
Table 14.3.1.6.2 
Summary of Non-Ocular Treatment-Emergent Adverse Events by Maximum 
Severity, MedDRA System Organ Class and Preferred Term – Safety Population 
Table 14.3.1.7.1 
Summary of Ocular Treatment-Emergent Adverse Events by Highest 
Relationship, MedDRA System Organ Class and Preferred Term – Safety 
Population 
Table 14.3.1.7.2 
Summary of Non-Ocular Treatment-Emergent Adverse Events by Highest 
Relationship, MedDRA System Organ Class and Preferred Term – Safety 
Population 
Table 14.3.1.8 
Summary of Deaths due to TEAE – Safety Population 
Table 14.3.2.1 
Summary and Analysis of VAS Score (Tolerance of Substance) – Safety 
Population 


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Number 
Title 
Table 14.3.2.2 
Summary and Analysis of VAS Score (Tolerance of Substance) – PP Population 
Table 14.3.2.3 
Summary and Analysis of VAS Score - LOCF (Tolerance of Substance) – Safety 
Population 
Table 14.3.2.4 
Summary and Analysis of VAS Score (Tolerance of Substance) – ITT Population 
Table 14.3.3.1 
Summary and Analysis of Intraocular pressure (via Goldmann tonometry) – 
Safety Population 
Table 14.3.3.2 
Summary and Analysis of Intraocular pressure (via Goldmann tonometry) – PP 
Population 
Table 14.3.3.3 
Summary and Analysis of Intraocular pressure - MI (via Goldmann tonometry) – 
Safety Population 
Table S14.3.3.3 
Sensitivity Analysis of Multiple Imputation of Intraocular Pressure 
measurements – Safety Population 
Table 14.3.3.4 
Summary of Intraocular pressure category – Safety Population 
Table 14.3.3.5 
Summary of Intraocular pressure category – PP Population 
Table 14.3.3.6 
Analysis of Intraocular pressure category – Safety Population 
Table 14.3.3.7 
Analysis of Intraocular pressure category – PP Population 
Table 14.3.3.8 
Summary of Clinical Significant Change (worsening) from baseline in 
Intraocular Pressure – Safety Population 
Table 14.3.4.1 
Summary of Vital Signs Observed and Change from Baseline – Safety 
Population 
Table 14.3.4.2 
Summary of Vital Signs Overall Interpretation – Safety Population 
Table 14.3.5.1 
Summary of Ophthalmic Examination – Safety Population 
Table 14.3.6.1 
Summary of Visual Acuity (Snellen) – Safety population 
Table 14.3.6.2 
Summary of Visual Acuity (Snellen Chart) Change from Baseline in Number of 
Lines - Safety Population 
Table 14.3.6.3 
Summary of Proportion of Subjects with >=3 line change (worsening) from 
baseline in visual Acuity – Safety Population 
 
5.2 
Listings 
Number 
Title 
Listing 16.2.1.1 
Listing of Subject Disposition – All Subjects 
Listing 16.2.1.2 
Listing of Study Population – All Subjects 
Listing 16.2.2.1 
Listing of Subjects with Protocol Deviation – Randomized Population 
Listing 16.2.3.1.1 
Listing of Prior and Concomitant Medication – Safety Population 
Listing 16.2.3.1.2 
Listing of Concomitant Non-Drug Treatment and Therapy – All Subjects 
Listing 16.2.4.1 
Listing of Subject Demographic and Baseline Characteristics – Randomized 
Population 
Listing 16.2.4.2.1 
Listing of Medical History – All Subjects 
Listing 16.2.4.2.2 
Listing of Allergy History – All Subjects 
Listing 16.2.4.2.3 
Listing of Dry Eye History – All Subjects 
Listing 16.2.4.2.4 
Listing of Ocular history – All Subjects 
Listing 16.2.4.2.5 
Listing of Study Eye Identification – All Subjects 
Listing 16.2.5.1.1 
Listing of Study Drug Administration – Safety Population 


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Number 
Title 
Listing 16.2.5.1.2 
Listing of Drug Accountability and Diary Accountability at Day 1 – Safety 
Population 
Listing 16.2.5.1.3 
Listing of Study Exposure and Compliance – Safety Population 
Listing 16.2.6.1 
Listing of VAS Score (Tolerance of Substance) – Safety Population 
Listing 16.2.6.2 
Listing of Symptom Assessment Questionnaire in Dry Eye (SANDE) – 
Randomized Population 
Listing 16.2.6.3.1 
Listing of Corneal Lissamine Green Dye Staining – Randomized Population 
Listing 16.2.6.3.2 
Listing of Conjunctival Lissamine Green Dye Staining – Randomized Population 
Listing 16.2.6.4 
Listing of Change in Tear Secretion as Measured by Schirmer I test – 
Randomized Population 
Listing 16.2.6.5 
Listing of Change in Keratograph Ocular Redness Score (ORS) – Randomized 
Population 
Listing 16.2.6.6 
Listing of Change in Validated Bulbar Redness (VBR) Grading Scale – 
Randomized Population 
Listing 16.2.6.7 
Listing of Subjects with Clinical Global Impression – Randomized Population 
Listing 16.2.6.8 
Listing of Subjects with Subject Global Assessment – Randomized Population 
Listing 16.2.6.9 
Listing of Noninvasive Tear Break up Time (NITBUT) – Randomized Population 
Listing 16.2.7.1 
Listing of Subjects with Adverse Events – All Subjects 
Listing 16.2.7.2 
Listing of Subjects with Serious Treatment Emergent Adverse Events – Safety 
Population 
Listing 16.2.8.1 
Listing of Subjects with Vital Signs – Safety Population 
Listing 16.2.9.1 
Listing of Subjects with Ophthalmic Examination – Safety Population 
 
 
Listing 16.2.10.1 
Listing of Visual Acuity – Safety Population 
Listing 16.2.11.1 
Listing of Intraocular Pressure with category – Safety Population 
Listing 16.2.12.1 
Listing of Subject Drug and Diary Accountability during follow up visits – Safety 
Population 
Listing 16.2.13.1 
Listing of Subject Diary – Safety Population 
 
5.3 
Figures 
Number 
Title 
Figure 14.2.1.1.2.1 
Mean Change from Baseline Plot of SANDE by Treatment and Visit – ITT 
Population 
Figure 14.2.1.1.2.2 
Forest Plot of Mean Change from Baseline of Overall SANDE VAS Score by 
Treatment and Visit - ITT Population 
Figure 14.2.1.2.2 
Mean Change from Baseline Plot of SANDE by Treatment and Visit – PP 
Population 
Figure 14.2.1.3.2 
Mean Change from Baseline Plot of SANDE by Treatment and Visit (MI) – ITT 
Population 
Figure 14.2.2.2.1 
Mean Change from Baseline Plot of Overall Corneal Lissamine Green Staining 
by Treatment for Study Eye – ITT Population 
Figure 14.2.2.2.2 
Forest Plot of Mean Change from Baseline of Overall Corneal Lissamine Green 
Staining by Zone Treatment and by Visit for Study Eye - ITT Population 


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Figure 14.2.2.2.3 
Mean Change from Baseline Plot of Overall Corneal Lissamine Green Staining 
by Treatment for Study Eye – PP Population 
Figure 14.2.2.4.1 
Mean Change from Baseline Plot of Conjunctival Lissamine Green Staining by 
Treatment for Study Eye – ITT Population 
Figure 14.2.2.4.2 
Mean Change from Baseline Plot of Conjunctival Lissamine Green Staining by 
Treatment for Study Eye – PP Population 
Figure 14.2.2.4.3 
Forest Plot of Mean Change from Baseline of Overall Conjunctival Lissamine 
Green Staining by Treatment and Visit for Study Eye - ITT Population 
Figure 14.2.3.2.1 
Mean Change from Baseline Plot of Tear Secretion by Schirmer I Test by 
Treatment for Study Eye – ITT Population 
Figure 14.2.3.2.2 
Mean Change from Baseline Plot of Tear Secretion by Schirmer I Test by 
Treatment for Study Eye – PP Population 
Figure 14.2.4.3.1 
Mean Change from Baseline Plot of Ocular Redness Score by Treatment for 
Study Eye – ITT Population 
Figure 14.2.4.3.2 
Mean Change from Baseline Plot of Ocular Redness Score by Treatment for 
Study Eye – PP Population 
Figure 14.2.4.3.3 
Mean Change from Baseline Plot of Ocular Redness Score by Treatment for 
Study Eye (MI) – ITT Population 
Figure 14.2.5.3.1 
Mean Change from Baseline Plot of Validated Bulbar Redness (VBR) by 
Treatment for Study Eye – ITT Population 
Figure 14.2.5.3.2 
Mean Change from Baseline Plot of Validated Bulbar Redness (VBR) by 
Treatment for Study Eye – PP Population 
Figure 14.2.5.3.3 
Mean Change from Baseline Plot of Validated Bulbar Redness (VBR) by 
Treatment for Study Eye (MI) – ITT Population 
Figure 14.2.8.3.1 
Mean Change from Baseline Plot of Noninvasive Tear Breakup Time (NITBUT) 
by Treatment for Study Eye – ITT Population 
Figure 14.2.8.3.2 
Mean Change from Baseline Plot of Noninvasive Tear Breakup Time (NITBUT) 
by Treatment for Study Eye – PP Population 
Figure 14.3.2.1.1 
Line Plot of VAS score (Tolerance of Substance) for Brimonidine Monotherapy 
vs. Placebo by Visit – Safety Population  
Figure 14.3.2.1.2 
Line Plot of VAS score (Tolerance of Substance) for Brimonidine Combination 
Therapy vs Placebo by Visit Safety Population 
Figure 14.3.2.2.1 
Line Plot of VAS score (Tolerance of Substance) for Brimonidine Monotherapy 
vs Placebo by Visit – PP Population 
Figure 14.3.2.2.2 
Line Plot of VAS score (Tolerance of Substance) for Brimonidine Combination 
Therapy vs Placebo by Visit PP Population 
Figure 14.3.2.3.1 
Line Plot of VAS score (Tolerance of Substance) for Brimonidine Monotherapy 
vs Placebo by Visit (LOCF) – Safety Population 
Figure 14.3.2.3.2 
Line Plot of VAS score (Tolerance of Substance) for Brimonidine Combination 
Therapy vs Placebo by Visit (LOCF) Safety Population 
Figure 14.3.2.4.1 
Line Plot of VAS score (Tolerance of Substance) for Brimonidine Monotherapy 
vs Placebo by Visit – ITT Population 
Figure 14.3.2.4.2 
Line Plot of VAS score (Tolerance of Substance) for Brimonidine Combination 
Therapy vs Placebo by Visit ITT Population 


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Figure 14.3.2.5.1 
Forest Plot of VAS score (Tolerance of Substance) by Treatment and Visit 
Safety Population 
Figure 14.3.3.1 
Mean Change from Baseline Plot of Intraocular pressure (via Goldmann 
tonometry) by Treatment – Safety Population 
Figure 14.3.3.2 
Mean Change from Baseline Plot of Intraocular pressure (via Goldmann 
tonometry) by Treatment – PP Population 
Figure 14.3.3.3 
Mean Change from Baseline Plot of Intraocular pressure – MI (via Goldmann 
tonometry) Treatment – Saftey Population