Conditions: Dry Eye
Keywords: Dry Eye Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 252
Healthy volunteers: no

Brief summary:
This study evaluates the use of Brimonidine tartrate nanoemulsion eye drop solution in the treatment of Dry Eye Disease (DED). Half of participants will receive Brimonidine and half will receive ophthalmic buffered saline (placebo).

Detailed description:
Dry eye disease (DED) is a common ocular disorder involving the aberrant production and instability of tear film, which results in damage to the ocular surface and is correlated with symptoms of ocular discomfort.

This study will be a randomized, placebo-controlled, double-masked, multicenter phase 3 study in the United States conducted at approximately 25 centers. Upon meeting the eligibility criteria, enrolled subjects will be randomly assigned in a 1:1 (test:control) fashion to receive either Brimonidine Nanoemulsion Eye Drops 0.20% investigational product (test) or ophthalmic buffered saline (placebo).

Arms:
arm 1: Brimonidine Tartrate Nanoemulsion Eye Drops 0.20% given 2 times a day for 4 weeks arm 2: Ophthalmic buffered saline Eye Drops given 2 times a day for 4 weeks

Interventions: intervention 1: Brimonidine Tartrate intervention 2: Placebos
Intervention descriptions: intervention 1: Brimonidine Tartrate Nanoemulsion Eye Drops 0.20% given 2 times a day for 4 weeks. intervention 2: Ophthalmic buffered saline Eye Drops given 2 times a day for 4 weeks.

Protocol document:
Prot_SAP_ICF_000.pdf: 
Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
1 
 
 
CLINICAL STUDY PROTOCOL 
 
Title: A Phase 3 Randomized, Placebo-Controlled, Double-Masked, Multicenter, Safety and Efficacy 
Study of Brimonidine Tartrate 0.2% Nanoemulsion Eye Drops in Patients with Dry Eye Disease (DED) 
 
Protocol Number:  
 
OCU-310-301 
Investigational Product: 
OCU310 (Brimonidine Tartrate Ophthalmic 
Nanoemulsion 0.20%) 
Version: 
v. 1.0 (12 Aug 2018) 
 
IND Applicant/Product Sponsor: 
Ocugen, Inc. 
5 Great Valley Parkway, Suite 160 
Malvern, PA 19355 USA  
 
Authorized Signatory: 
Daniel Jorgensen, MD, MPH 
Chief Medical Officer 
Ocugen, Inc. 
5 Great Valley Parkway, Suite 160 
Malvern, PA 19355 USA 
Telephone: (484) 328-4702  
Fax: 610-644-4005 
E-mail: dan.jorgensen@ocugen.com 
 
 
 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
2 
 
Table 1. Administrative Structure 
 
 
Medical Monitor: 
(24-hour emergency contact)  
Barbara Wirostko, MD 
Trial Runners 
116 W. Villard 
Dickinson, ND  58601 
Phone:  24-hour contact :  347-453-1521 
Email: barbarawirostko@trialrunners.com 
 
Biostatistician: 
 
 
Steve Crockett, PhD 
Design and Analysis of Trials Associates, Inc 
10053 Border Drive, East 
Grand Bay, AL  36541 
Email: scrocket@iglou.com 
 
Serious Adverse Event Reporting: 
Barbara Wirostko, MD 
Medical Monitor 
Trial Runners 
116 W. Villard 
Dickinson, ND  58601 
Email: barbarawirostko@trialrunners.com 
Phone: 347-453-1521 
General Fax:  
SAE Fax Number (US):  
SAE Hot Line Number (US): 
 
 
Confidentiality Statement 
The confidential information in this document is provided to you as an Investigator or consultant for review by you, your staff, 
and the applicable Institutional Review Board. Your acceptance of this document constitutes agreement that you will not disclose 
the information contained herein to others without written authorization from the sponsor. 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
3 
 
INVESTIGATOR’S SIGNATURE 
 
I have received and read the Investigator’s brochure for Brimonidine (OCU310). I have read protocol 
OCU-310-301 and agree to conduct the study as outlined. I agree to maintain the confidentiality of all 
information received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Title of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
4 
 
SPONSOR’S SIGNATURE 
 
Approved by: 
 
 
 
 
 
 
 
Daniel Jorgensen, MD, MPH 
Chief Medical Officer 
Ocugen, Inc.  
 
Date 
 
 
 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
5 
 
PROTOCOL REVISION HISTORY 
 
 
Table 2. Revision History 
Version  
Number 
Version date 
Summary of Revisions Made 
Major 
Administrative 
Version 1.0 
12 August 2018 
 
 
 
 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
6 
 
SYNOPSIS 
Protocol Title: 
A Phase 3 Randomized, Placebo-Controlled, Double-Masked, Multicenter, Safety and Efficacy Study of 
Brimonidine Tartrate 0.2% Nanoemulsion Eye Drops in Patients with Dry Eye Disease (DED) 
Protocol Number: 
OCU-310-301  
Clinical Phase: 
Phase 3 
IND Applicant/Product Sponsor: 
Ocugen, Inc. 
5 Great Valley Parkway, Suite 160 
Malvern, PA  19355 USA 
Telephone: 484-328-4701 
Fax: 610-644-4005 
Authorized Signatory: 
Daniel Jorgensen, MD, MPH  
Chief Medical Officer 
Regulatory IND Number: 
136132 
Indication: 
Relief of signs and symptoms of dry eye disease  
Investigational Drug:  
Brimonidine Tartrate Nanoemulsion 0.20% Ophthalmic Solution (OCU310).  
Control:  
Placebo (ophthalmic buffered saline; OBS, pH 6-8)  
Primary Objective(s): 
• To evaluate the safety, tolerability, and efficacy of Brimonidine Nanoemulsion Eye Drops in 
Patients with Dry Eye Disease (DED) 
 
Primary Efficacy Endpoint(s): 
1. Change from baseline to 4 weeks (Day 28) in SANDE score 
2. Change from baseline to 4 weeks (Day 28) in Lissamine Green conjunctival staining scores  
Note: This endpoint would be considered in a hierarchical fashion if statistical success is first 
demonstrated for SANDE at Day 28.   
Secondary Efficacy Endpoint(s): 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
7 
 
3. Change from baseline to 2 weeks (Day 14) in SANDE score 
4. Change from baseline to 2 weeks (Day 14) in Lissamine Green conjunctival staining scores  
Note: The above endpoints (Primary and Secondary) will be tested in a fixed sequence (1-4) 
proceeding to the next endpoint until a p-value >0.05 is found.  
 
Safety Endpoint(s): 
• Rate of ocular adverse events (AEs) 
Exploratory Endpoint(s): 
• Change from baseline to 4 weeks (Day 28) in Lissamine Green corneal staining scores 
• Change from baseline to 2 weeks (Day 14) in Lissamine Green corneal staining scores 
• Change from baseline to 4 weeks (Day 28) in Schirmers scores 
• Change in appearance from baseline to 4 weeks (Day 28) in Validated Bulbar Redness (VBR) 
scale 
• Change in appearance from baseline to 4 weeks (Day 14) in Validated Bulbar Redness (VBR) 
scale 
• Clinical Global Impression (CGI) of change in symptoms from baseline (physician’s rating) to 4 
weeks (Day 28) 
• Subject Global Assessment (SGA) of overall change from baseline (subject’s rating) to 4 weeks 
(Day 28) 
 
Investigational Products 
Investigational Drug Dosage: 
One drop of Brimonidine Tartrate Nanoemulsion 0.20% administered in each eye, two times a day (bid)  
Control Dosage: 
One drop of OBS administered in each eye, two times a day (bid) 
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 for >6 months 
4. Demonstrate the following 2 signs of DED in the same eye at Screening and Baseline (Day 
1): 
a. Conjunctival staining at >3 (out of a possible score of 6 per eye), and 
b. Schirmer test (with anesthesia) at >1 to <7mm in 5 minutes 
5. Symptomatic evidence of DED by having a global symptom score (Overall SANDE) >40 
mm at Screening and Baseline (Day 1) visit  
6. Intraocular pressure (IOP) > 5 mmHg and <22 mmHg in each eye 
7. Women who satisfy one of the following:  


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
8 
 
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 28), OR 
b. Are post-menopausal or have undergone a sterilization procedure  
 
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 or any similar products, or excipients of brimonidine or loteprednol 
2. Use of contact lenses within 14 days prior to Screening visit or planned use 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, or others who may be considered 
vulnerable populations 
13. Received corticosteroid-containing eye drops within 14 days prior to Screening visit or 
planned use during study 
14. Any change in systemic corticosteroids/immunosuppressives, cyclosporine ophthalmic 
emulsion 0.05% (Restasis®), or lifitegrast ophthalmic solution 5% (Xiidra™) within 30 
days prior to Screening visit or planned change during study 
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 
 
Note: Subjects will be permitted to continue all their ocular treatments, including the use of artificial 
tears, eyelid massage, or warm compresses, if they commit to using the same brand/regimen throughout 
the study. None of the ocular treatments, whether OTC or prescription (e.g. Restasis or Xiidra) or study 
medication, should be used within 5 minutes of another ocular treatment during the study. Study 
medication should not be used within 2 hours prior to any study visit.  


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
9 
 
General Statistical Methods and Types of Analysis  
 
The primary analysis is a test of superiority of topical OCU300 vs OBS drops with a set of ordered 
endpoints to be tested in a fixed sequence. 
 
Tests will be conducted using two-sided alpha = .05 in a fixed sequence. 
 
Unit of Analysis 
The unit of analysis for variables measured at the individual eye level 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 Lissamine Green conjunctival staining score will be 
the study eye and the other eye will be considered the qualified fellow eye; (iii) if both eyes have the same 
Lissamine Green conjunctival staining score, then the eye with the lower Schirmer score will be the study 
eye and the other eye will be considered the qualified fellow eye; (iv) if both eyes have same Schirmer  
score, the right eye will be the study eye and the other eye will be considered the qualified fellow eye. 
Analysis of safety and efficacy variables measured at the eye level will be primarily performed on the 
study eyes and secondarily on the qualified fellow eyes (for efficacy) and all fellow eyes (for safety).   
 
The unit of analyses for variables measured at the subject level will be the subject. 
 
Power and Sample Size 
One-hundred eight subjects in each of the OCU 310 and placebo arms yields 99% power to reject the null 
hypothesis and conclude superiority of OCU 310 over placebo in the mean change from baseline SANDE 
score at 4 weeks assuming the mean changes from baseline in OCU 310 and placebo are -20.0 and -3.5 
respectively, a common standard deviation of 25.0, and a two-sided alpha = 0.05.  
Additionally, 108 study eyes in each of the OCU 310 and placebo arms yields 90% power to reject the 
null hypothesis and conclude superiority of OCU 310 over placebo in the mean change from baseline 
Lissamine Green conjunctival staining score in the study eye at 4 weeks assuming the mean changes from 
baseline in OCU 310 and placebo are -0.4 and 0.2 respectively, a common standard deviation of 1.35, and 
a two-sided alpha = 0.05.  For the secondary endpoints (Day 14), there are not enough data to make a 
power/sample size statement.   
 
For the primary analysis, with 108 subjects per arm, the study will have approximately 90% power to 
reject both H01 and H02, assuming independence between endpoints (with higher power should the 
endpoints be positively correlated), and conclude the OCU 310 to be superior to placebo in both the mean 
change from baseline SANDE score at 4 weeks and the mean change from baseline Lissamine Green 
conjunctival staining score in the study eye at 4 weeks. 
 
Accounting for 10% subject discontinuations, 240 total subjects will be enrolled (120 per arm). 
 
 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
10 
 
Analysis Populations 
Safety Population 
The safety set will be the primary analysis set for the safety endpoints and will include all subjects who 
have signed informed consent forms, were randomized into the study, and who took at least one dose of 
study drug. The safety set will be analyzed according to the treatment actually received. 
Intent-to-treat (ITT) Population 
The ITT set will be the primary analysis set for the efficacy endpoints and will include all randomized 
subjects who have at least one post-baseline efficacy measurement. The ITT population will be analyzed 
according to the planned treatment. 
Per-protocol (PP) Population 
The PP population set will be tested to confirm the robustness of the primary analysis and will include 
all ITT subjects who have no major protocol deviations. The PP population will be analyzed according 
to the treatment actually received. 
 
Hypotheses  
The following type of hypothesis will be tested: 
H0: 
The difference (OCU 310 minus placebo), between subjects treated with the OCU 310 
and subjects treated with placebo in the mean change from baseline = 0. 
HA: 
The difference (OCU 310 minus placebo), between subjects treated with the OCU 310 
and subjects treated with placebo in the mean change from baseline ≠ 0, with superiority 
claimed if the difference < 0. 
Fixed sequence testing will be employed to maintain the type I error rate. 
 
General Considerations 
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). Categorical study assessments will be summarized by treatment and visit (as 
applicable) using frequency counts and percentages. 
 
Efficacy Analysis 
Four endpoints (two primary and two secondary) will be tested in a fixed sequence proceeding to the next 
endpoint until a p-value >0.05 is found. The analysis of the four outcomes will employ a repeated 
measures mixed model with mean change from baseline score at the stated time point as the response with 
baseline score as a covariate and treatment, visit, and their interaction as fixed effects. The least squares 
mean difference (OCU 310 – placebo) at the stated time point will be tested. The 2-sided p-values and 
associated 95% confidence intervals will be presented. 
 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
11 
 
The primary efficacy analyses will be conducted on the ITT population. The same set of efficacy 
analyses will also be performed on the per-protocol population.  
 
Safety Analysis 
Safety analyses will be performed on the Safety set. Safety parameters include ocular examinations, 
vital signs, AEs, and slit lamp examinations. Safety data will be reported for all patients that have signed 
informed consent forms. 
 
Full details of the statistical analysis method used for the primary and secondary endpoints will be 
described in the Statistical Analysis Plan (SAP). 
Date of Protocol: 12 August 2018 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
12 
 
TABLE OF CONTENTS 
 
  
TABLE OF CONTENTS ............................................................................................................................ 12 
LIST OF TABLES ...................................................................................................................................... 17 
LIST OF FIGURES .................................................................................................................................... 17 
LIST OF ABBREVIATIONS ..................................................................................................................... 18 
 
INTRODUCTION ................................................................................................................. 20 
 
Dry Eye Disease ..................................................................................................................... 20 
 
Dry Eye Disease: Clinical Signs and Symptoms ................................................................... 21 
 
Dry Eye Disease: Diagnostic Testing .................................................................................... 21 
 
Dry Eye Disease: Current Management ................................................................................. 21 
 
Scientific Rationale for Brimonidine Therapy in Dry Eye Disease ....................................... 22 
 
Preclinical Data Supporting Use of Brimonidine in DED ..................................................... 22 
 
Clinical Data Supporting Use of Brimonidine in DED .......................................................... 23 
 
Product Rationale ................................................................................................................... 23 
 
Summary of Known and Potential Risks and Benefits to Human Subjects ........................... 24 
 
STUDY DESIGN ................................................................................................................... 24 
 
Study Objectives .................................................................................................................... 24 
 
Primary Objective(s) .............................................................................................................. 24 
 
Study Endpoints ..................................................................................................................... 24 
 
Primary Endpoints .................................................................................................................. 24 
 
Secondary Endpoints .............................................................................................................. 25 
 
Exploratory Endpoints ........................................................................................................... 25 
 
INVESTIGATIONAL PLAN ................................................................................................ 25 
 
Overall Study Design ............................................................................................................. 25 
 
Rationale for the Study Design .............................................................................................. 26 
 
SELECTION AND WITHDRAWAL OF SUBJECTS ......................................................... 26 
 
Number of Subjects ................................................................................................................ 26 
 
Subject Inclusion Criteria ....................................................................................................... 26 
 
Subject Exclusion Criteria...................................................................................................... 26 
 
Randomization Criteria .......................................................................................................... 27 
 
Subject Withdrawal Criteria ................................................................................................... 27 
 
Study Termination .................................................................................................................. 28 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
13 
 
 
STUDY SCHEDULE AND PROCEDURES ........................................................................ 28 
 
Study Schedule ....................................................................................................................... 28 
 
Study Visits ............................................................................................................................ 30 
 
Unscheduled Study Visits ...................................................................................................... 30 
 
Screening (Day -7 ± 1 day) .................................................................................................... 30 
 
Day 1 (Baseline, Randomization, and First Treatment Visit) ................................................ 31 
 
Day 14 (± 3 days) ................................................................................................................... 31 
 
Day 28 (± 7 days) ................................................................................................................... 32 
 
ASSESSMENTS .................................................................................................................... 33 
 
Demographic/Ocular and Medical History ............................................................................ 33 
 
Prior & Concomitant Medications/Therapies ........................................................................ 33 
 
Pregnancy Screen ................................................................................................................... 33 
 
Efficacy Assessments ............................................................................................................. 33 
 
Primary Efficacy Assessment ................................................................................................ 33 
6.4.1.1 
Symptom Assessment iN Dry Eye (SANDE) at Day 28 ....................................................... 33 
6.4.1.2 
Conjunctival Staining Score with Lissamine Green at Day 28 .............................................. 33 
 
Secondary Efficacy Assessment ............................................................................................ 34 
6.4.2.1 
Symptom Assessment iN Dry Eye (SANDE) at Day 14 ....................................................... 34 
6.4.2.2 
Conjunctival Staining Score with Lissamine Green at Day 14 .............................................. 34 
 
Exploratory Efficacy Assessments ......................................................................................... 34 
6.4.3.1 
Corneal Staining Score with Lissamine Green at Day 28 ...................................................... 35 
6.4.3.2 
Corneal Staining Score with Lissamine Green at Day 14 ...................................................... 35 
6.4.3.3 
Schirmers Test (with anesthesia) at Day 28 ........................................................................... 35 
6.4.3.4 
Validated Bulbar Redness grading scale (VBR) at Day 28 ................................................... 35 
6.4.3.5 
Clinical Global Impression (CGI) at Day 28 ......................................................................... 35 
6.4.3.6 
Subject Global Assessment (SGA) at Day 28 ........................................................................ 36 
 
Safety Assessments ................................................................................................................ 36 
 
Adverse Events ...................................................................................................................... 36 
 
Visual Acuity (logMAR) ....................................................................................................... 37 
 
IOP - Goldmann Applanation ................................................................................................ 37 
 
Ophthalmic Examination (Slit Lamp) .................................................................................... 37 
 
Vital Signs .............................................................................................................................. 37 
 
INVESTIGATIONAL DRUG INFORMATION AND MANAGEMENT ........................... 37 
 
Investigational Drug Dose Regimen ...................................................................................... 37 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
14 
 
 
Dose Rationale ....................................................................................................................... 37 
 
Investigational Drug Packaging and Labeling ....................................................................... 38 
 
Investigational Drug Storage.................................................................................................. 38 
 
Investigational Drug Preparation ........................................................................................... 38 
 
Investigational Drug Administration ...................................................................................... 38 
 
Investigational Drug Accountability ...................................................................................... 39 
 
Investigational Drug Handling and Disposal ......................................................................... 39 
 
TREATMENT OF SUBJECTS ............................................................................................. 39 
 
Rescue Medication ................................................................................................................. 39 
 
Prohibited Medications or Treatment ..................................................................................... 40 
 
Other Study Restrictions ........................................................................................................ 40 
 
Treatment Compliance ........................................................................................................... 40 
 
RANDOMIZATION AND MASKING PROCEDURES...................................................... 40 
 
Method of Assigning Subjects to Treatment Groups ............................................................. 40 
 
Masking and Unmasking of Treatment Assignment .............................................................. 40 
 
Emergency Unmasking .......................................................................................................... 41 
 
ADVERSE EVENTS ............................................................................................................. 42 
 
Adverse Events and Serious Adverse Events ......................................................................... 42 
 
Definitions of Adverse Events ............................................................................................... 42 
10.1.1.1 
Adverse Event (AE) ............................................................................................................... 42 
10.1.1.2 
Serious Adverse Event (SAE) ................................................................................................ 42 
10.1.1.3 
Adverse Drug Reaction (ADR) and Suspected Adverse Reaction (SAR) ............................. 43 
10.1.1.4 
Unexpected Adverse Reaction (UAR) ................................................................................... 44 
10.1.1.5 
Adverse Events of Interest (AEIs) ......................................................................................... 44 
 
Severity of AEs/SAEs ............................................................................................................ 44 
 
Relationship to Investigational Drug Treatment .................................................................... 44 
 
Collecting and Recording Adverse Events ............................................................................ 45 
10.1.4.1 
Period of Collection ............................................................................................................... 45 
10.1.4.2 
Methods of Collection ............................................................................................................ 45 
10.1.4.3 
Recording Method .................................................................................................................. 46 
 
Reporting Adverse Events...................................................................................................... 46 
10.1.5.1 
Reporting SAEs to the Sponsor.............................................................................................. 46 
10.1.5.2 
Reporting Serious Adverse Events to FDA ........................................................................... 47 
 
Reporting Pregnancy .............................................................................................................. 48 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
15 
 
 
STATISTICAL ANALYSIS PLAN ...................................................................................... 49 
 
General Statistical Methods and Types of Analysis ............................................................... 49 
 
Unit of Analysis ..................................................................................................................... 49 
 
Power and Sample Size Determination .................................................................................. 49 
 
Analysis Populations .............................................................................................................. 51 
 
Background and Demographic Characteristics ...................................................................... 51 
 
Efficacy Analyses .................................................................................................................. 51 
11.4.2.1 
Primary Efficacy Analyses ..................................................................................................... 51 
11.4.2.2 
Efficacy Analyses—General Considerations ......................................................................... 52 
11.4.2.3 
Safety Analyses ...................................................................................................................... 52 
11.4.2.4 
Adverse Events ...................................................................................................................... 52 
11.4.2.5 
Concomitant Medications and Concomitant Therapies ......................................................... 52 
11.4.2.6 
Pharmacokinetic Analyses ..................................................................................................... 52 
 
Other Statistical Considerations ............................................................................................. 52 
11.4.3.1 
Significance Levels ................................................................................................................ 52 
11.4.3.2 
Multiple Comparisons ............................................................................................................ 52 
11.4.3.3 
Missing Data .......................................................................................................................... 53 
11.4.3.4 
Visit Windows........................................................................................................................ 53 
 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................................... 53 
 
Study Monitoring ................................................................................................................... 53 
 
Data Collection and Management .......................................................................................... 54 
 
QUALITY CONTROL AND QUALITY ASSURANCE ..................................................... 54 
 
ETHICS .................................................................................................................................. 54 
 
Ethics Review ........................................................................................................................ 54 
 
Ethical Conduct of the Study ................................................................................................. 55 
 
Written Informed Consent...................................................................................................... 55 
 
Subject Information and Informed Consent ........................................................................... 55 
 
Provision of New and Important Information Influencing Subject’s Consent and 
Revision of the Written Information ...................................................................................... 55 
 
Subject Confidentiality .......................................................................................................... 55 
 
ADMINISTRATIVE PROCEDURES ................................................................................... 56 
 
Publications of the Clinical Study .......................................................................................... 56 
 
Protocol Amendments and Deviations ................................................................................... 56 
 
DATA HANDLING AND RECORD KEEPING .................................................................. 56 
 
Inspection of Records ............................................................................................................. 56 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
16 
 
 
Retention of Records .............................................................................................................. 57 
 
Sample Retention ................................................................................................................... 57 
 
REFERENCES....................................................................................................................... 58 
 
APPENDICES ....................................................................................................................... 62 
 
Appendix 1. Validated Bulbar Redness Grading Scales (VBR) ............................................ 62 
 
Appendix 2. Symptom Assessment iN Dry Eye (SANDE) ................................................... 63 
 
Appendix 3. Ocular Surface Staining: Lissamine Green ....................................................... 64 
 
Lissamine Solution ................................................................................................................. 64 
 
Instillation of Lissamine Green .............................................................................................. 64 
 
Evaluating Lissamine Green Staining .................................................................................... 64 
 
Appendix 4. LogMAR Visual Acuity .................................................................................... 67 
 
Visual Acuity Testing ............................................................................................................ 67 
 
Standard ETDRS Visual Acuity Protocol .............................................................................. 67 
 
Illumination of Visual Acuity Charts and Room ................................................................... 67 
 
Uncorrected (UCVA) and Best-Corrected VA (BCVA) ........................................................ 68 
 
Recording and Scoring VA .................................................................................................... 68 
 
Calculating LogMar from VA Score ...................................................................................... 69 
 
Appendix 5. Intraocular Pressure (IOP) ................................................................................. 70 
 
Calibration of Tonometer ....................................................................................................... 70 
 
IOP Measurement .................................................................................................................. 70 
 
Appendix 6. Slit-Lamp Examination ..................................................................................... 71 
 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
17 
 
LIST OF TABLES 
Table 1. Administrative Structure ......................................................................................................... 2 
Table 2. Revision History ....................................................................................................................... 5 
Table 3. Abbreviations ......................................................................................................................... 18 
Table 4. Study Schedule of Events ....................................................................................................... 29 
Table 5. Attribution of Adverse Events ............................................................................................... 45 
Table 6. Corneal and Conjunctival Lissamine Green Scoring ............................................................. 66 
Table 7. Calculation of logMAR from Visual Acuity Worksheet .......................................................... 69 
Table 8. Evaluation of Slit-Lamp Assessments ................................................................................... 71 
 
LIST OF FIGURES 
Figure 1. Validated Bulbar Redness Scale........................................................................................... 62 
Figure 2. SANDE Questionnaire ......................................................................................................... 63 
Figure 3. Lissamine Green Corneal Staining Pattern and Grade (NEI Scale) ................................... 65 
Figure 4. Lissamine Green Conjunctival Staining Pattern and Grade (NEI Scale) ............................ 65 
Figure 5. Visual Acuity logMAR .......................................................................................................... 68 
 
 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
18 
 
LIST OF ABBREVIATIONS 
The following abbreviations are used in this study protocol. 
Table 3. Abbreviations 
Abbreviation or specialist term 
Explanation 
ADL 
Activities of daily living 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AEI 
Adverse events of interest 
BCVA 
Best corrected visual acuity 
BID 
Twice daily 
CFR 
Code of Federal Regulations 
CFS  
Corneal fluorescein staining 
CGI 
Clinical Global Impression 
CI 
Confidence interval 
CMH 
Cochran–Mantel–Haenszel test 
CRF 
Case report form 
DBP 
Diastolic blood pressure 
DED 
Dry Eye Disease  
ECM 
Extracellular matrix 
eCRF 
Electronic case report form 
EDTRS 
Early Treatment Diabetic Retinopathy Study  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HR 
Heart rate 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug Application 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IWRS 
Interactive Web Response System 
LG 
Lissamine Green 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
19 
 
logMAR 
Logarithm of the Minimum Angle of Resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
mm 
Millimeter 
MMRM 
Mixed model of repeated measurements 
NEI 
National Eye Institute 
NIH 
National Institute of Health 
OBS 
Ophthalmic Buffered Saline 
ODD 
Orphan Drug Designation 
OS 
Left eye 
OSDI 
Ocular Surface Disease Index 
OTC 
Over-the-counter 
OU 
Both eyes 
PI 
Principal Investigator 
PP  
Per-protocol 
PRO 
Patient-reported outcomes 
QSR 
Quality System Regulations 
SAE 
Serious adverse event 
SANDE 
Symptom Assessment iN Dry Eye 
SAP 
Statistical Analysis Plan 
SAR 
Suspected adverse reaction 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SGA 
Subject Global Assessment 
SOP 
Standard Operating Procedure 
SUSAR 
Serious and unexpected suspected adverse reaction 
TEAE 
Treatment-emergent adverse event 
UAR 
Unexpected Adverse Reaction 
UCVA 
Uncorrected Visual Acuity 
USA 
United States of America 
VAS 
Visual Analog Scale 
VBR 
Validated Bulbar Redness 
WHO 
World Health Organization 
WOCP 
Women of child-bearing potential 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
20 
 
 
 INTRODUCTION 
Ocugen Inc. is developing a proprietary novel product (OCU310) consisting of brimonidine tartrate 
(0.2%) as an ophthalmic nanoemulsion eye drops for the relief of signs and symptoms of Dry Eye Disease 
(DED). Brimonidine is an imidazoline compound that acts as a specific alpha 2 adrenergic receptor 
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 
 
 Dry Eye Disease 
Dry eye disease (DED) is a common ocular disorder involving the aberrant production and instability 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 
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).   
 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
21 
 
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).  
 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) 
 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).) 
 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 
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 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
22 
 
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 early relief and long-term daily use. 
 Scientific Rationale for Brimonidine Therapy in Dry Eye Disease  
As mentioned, brimonidine tartrate is a selective alpha-2 adrenergic receptor agonist and is currently 
available as an ophthalmic solution at different concentrations and is indicated for the reduction of 
intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension 
 
 Preclinical Data Supporting Use of Brimonidine in DED 
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 and inflammation 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 by its action on pain receptors (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 corneal surface inflammation: In the mouse dry eye model, ocular staining data 
comparing brimonidine to other treatments showed a reduction in fluorescein staining scores 
over a 2-week period, indicating an overall decrease in ocular surface inflammation. This 
effect was further enhanced in OCU300 relative to marketed brimonidine. 
 
In summary, brimonidine, through its ability to vasoconstrict and reduce inflammation, has the potential 
to reduce redness of the ocular surface. In addition, by attenuating chronic inflammation, brimonidine 
tartrate allows the ocular surface and tear film producing glands to heal and 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.  Finally, 
brimonidine tartrate is an FDA approved product that has demonstrated a robust safety profile via topical 
ocular delivery for the chronic treatment of open-angle glaucoma.  


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
23 
 
In short, brimonidine may address the signs and symptoms of DED through several mechanistic 
pathways. In contrast, the available treatments for dry eye disease have limited mechanisms of action, and 
this may explain their inability to completely resolve the signs and symptoms of DED.   
 
 Clinical Data Supporting Use of Brimonidine in DED  
Brimonidine tartrate is an FDA approved product that has demonstrated a robust safety profile via 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. Given that preservative-
free OCU310 nanoemulsion was not yet available for clinical trials in late 2017, an IND-opening phase 2 
proof-of-concept study was conducted, using commercially available brimonidine.    
The main objective of the study was to establish whether subjects with DED can tolerate receiving 
Brimonidine 0.2% eye drops, alone or in combination with loteprednol 0.2%, two times a day for twelve 
weeks (84 days). The other objective was to investigate the preliminary efficacy of Brimonidine 0.2% 
topical eye drop solution, alone or in combination with loteprednol 0.2%, in treating DED, and to use this 
information, if possible, to select the appropriate brimonidine treatment regimen (with or without 
loteprednol) and the appropriate efficacy endpoints for phase 3 studies. This was a randomized, placebo-
controlled, double-blind study, in which 84 subjects were enrolled at three clinical sites. The primary 
endpoint was tolerability at Day 84, using a visual analog scale (VAS). There were several pre-specified 
exploratory efficacy endpoints.    
In summary, the phase 2 study showed that both brimonidine combination therapy (with loteprednol) and 
brimonidine monotherapy (without loteprednol) are safe and well tolerated, and both were consistently 
better than placebo for key exploratory efficacy endpoints, particularly at early post-baseline visits. The 
most promising symptom endpoint was SANDE, for which both brimonidine regimens (combination and 
monotherapy), were statistically superior to placebo at the Day 28 visit, and only the monotherapy arm 
was statistically superior at Day 84, the primary assessment visit. The most promising sign endpoint was 
Lissamine Green Staining of either the conjunctivae or the cornea, for which both brimonidine regimens 
(combination and monotherapy) were better than placebo at the Day 84 visit, and the differences bordered 
on statistical significance. Given the results of this study, and given the mechanism of action of 
brimonidine, these endpoints have been selected as primary endpoints in phase 3.  
Further, based on the results of this study, there is no significant incremental benefit in adding loteprednol 
to brimonidine, when compared to using brimonidine alone, in treating patients with DED.  Given that 
ocular steroids, such as loteprednol, have their own associated adverse effects, it makes sense to proceed to 
phase 3 with the brimonidine monotherapy product: brimonidine tartrate 0.2% without loteprednol in a 
nanoemulsion formulation, also known as OCU310.  
 
 Product Rationale 
Brimonidine tartrate ophthalmic solution, 0.2% is an FDA approved product that has demonstrated a 
robust safety profile via topical ocular delivery in patients with open-angle glaucoma or ocular 
hypertension, with low occurrence of adverse events (AEs). This product was also shown to be safe and 
tolerable, while demonstrating preliminary efficacy, in a phase 2 proof-of-concept study conducted in 
2017. 
OCU 310 is a sterile, preservative-free solution of brimonidine tartrate 0.2% in an ophthalmic 
nanoemulsion. It was developed to provide relief of the signs and symptoms of dry eye disease for topical 
instillation in the eye.  The proposed dose is one drop of OCU310 (0.2% brimonidine tartrate ophthalmic 
nanoemulsion) twice daily (approximately 12 hours apart) into each eye using a single-use container.  


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
24 
 
 
  Summary of Known and Potential Risks and Benefits to Human 
Subjects 
In this study, one drop of OCU310 (brimonidine tartrate nanoemulsion 0.2%) will be administered into 
each eye, two times a day (bid) for 28 days. The brimonidine tartrate concentration (0.2%) is similar to 
the concentration of the currently marketed brimonidine tartrate (0.2%) used for chronic dosing in 
glaucoma patients.  
Several studies have reported the overall safety and efficacy of marketed brimonidine 0.2% and 0.15% 
after 1, 3, and 4 years. (Katz 2002, Mundorf 2003, Adkins 1998, Chew 2014, Melamed 2000, LeBlanc 
1998, Schuman 1996, Schuman 1997, Nguyen 2013, Rahman 2010) Based on the current evidence, 
related serious adverse events are not expected with the dose in the current study (0.2%). One study 
demonstrated a reduction in adverse effects with brimonidine 0.15%, relative to 0.2% (Katz 2002), but 
another has shown no difference between brimonidine 0.2% and 0.15% (Mundorf 2003). The most 
common systemic side effects include dysgeusia, 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 in 9.0 – 12.7% of patients (Schuman 1997, Katz 1999, Schuman 
1996), follicular conjunctivitis in 7.8 – 12.7% of patients (Schuman 1997, Katz 1999), and conjunctival 
hyperemia in 5.0 - 30.3% of patients (Nguyen 2013, Rahman 2010). 
Given the long-term safety profile of marketed brimonidine tartrate (0.15%-0.20%), the positive 
tolerability and efficacy signals in a phase 2 study of dry eye disease, the added benefits of a preservative-
free nanoemulsion, and the high medical need in this patient population, the risk/benefit profile supports 
the use of OCU 310 for the relief of signs and symptoms of dry eye disease.  
 STUDY DESIGN 
 Study Objectives 
 Primary Objective(s) 
The primary objective of this study is to evaluate the safety, tolerability, and efficacy of Brimonidine 
Nanoemulsion Eye Drops in Patients with Dry Eye Disease (DED) 
 
 Study Endpoints 
 Primary Endpoints 
Two primary efficacy endpoints will be tested:  
1. Change from baseline to 4 weeks (Day 28) in SANDE score 
2. Change from baseline to 4 weeks (Day 28) in Lissamine Green conjunctival staining scores  
Note: This endpoint would be considered in a hierarchical fashion if statistical success is first 
demonstrated for SANDE at Day 28 (Section 11).   
 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
25 
 
 Secondary Endpoints 
3. Change from baseline to 2 weeks (Day 14) in SANDE score 
4. Change from baseline to 2 weeks (Day 14) in Lissamine Green conjunctival staining scores 
   
Note: The above endpoints (Primary and Secondary) will be tested in a fixed sequence (1-4) 
proceeding to the next endpoint until a p-value >0.05 is found (Section 11) 
 
 Exploratory Endpoints 
• 
Change from baseline to 4 weeks (Day 28) in Lissamine Green corneal staining scores 
• 
Change from baseline to 2 weeks (Day 14) in Lissamine Green corneal staining scores  
• 
Change from baseline to 4 weeks (Day 28) in Schirmers scores 
• 
Change in appearance from baseline to 4 weeks (Day 28) in Validated Bulbar Redness (VBR) 
scale 
• 
Change in appearance from baseline to 4 weeks (Day 14) in Validated Bulbar Redness (VBR) 
scale 
• 
Clinical Global Impression (CGI) of change in symptoms from baseline (physician’s rating) to 4 
weeks (Day 28) 
• 
Subject Global Assessment (SGA) of overall change from baseline (subject’s rating) to 4 weeks 
(Day 28) 
 INVESTIGATIONAL PLAN 
 Overall Study Design 
This will be a randomized, placebo-controlled, double-masked, multicenter phase 3 study in the United 
States conducted in approximately 15 centers. Upon meeting the eligibility criteria, enrolled subjects with 
a history of DED will be randomly assigned in a 1:1 fashion to receive either Brimonidine Nanoemulsion 
Eye Drops 0.2% investigational product or ophthalmic buffered saline (placebo).  
Four  study visits are planned: Day -7± 1day (screening visit), Day 1 (randomization), Day 14 ± 3 days, 
and Day 28 ± 7 days (See Table 4). An informed consent form (ICF) must be obtained from each subject 
prior to the commencement of any study procedures. All subjects must be given ample time to review the 
ICF and ask questions regarding the study prior to participation in the study. The subject will be provided 
a copy of the signed ICF. 
Subjects will receive the first dose of medication on Day 1 at the study site. Study medication will be 
dispensed to subjects at each study visit (except the Day 28 visit) for self-administration during the study, 
beginning with the Day1 Visit. 
Subjects will be provided with diaries to record twice daily dosing. Doses should be administered 
approximately 12 hours apart. In addition, subjects will be asked to make note of any missed doses 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
26 
 
together with the reason for the missed dosage. The intent is to capture missed doses, per se, rather than a 
shifted dosing schedule.  
 Rationale for the Study Design 
Given the long-term safety profile of marketed brimonidine tartrate (0.15%-0.20%), the positive 
tolerability and efficacy signals in a phase 2 study of dry eye disease, the added benefits of a preservative-
free nanoemulsion, and the high medical need in this patient population, the risk/benefit profile supports 
the use of OCU 310 for the relief of signs and symptoms of dry eye disease (Section 1.7).  The medical 
need, in part, may be due to the limited mechanisms of action of existing dry eye products (Section 1.5.1).  
To support the proposed indication, efficacy in both a sign and a symptom of DED are expected to be 
demonstrated in phase 3 studies. In phase 2, positive efficacy signals were observed across multiple 
endpoints, consistent with the hypothesis that brimonidine works through multiple mechanistic pathways. 
The strongest signals observed for “sign” (Lissamine Green staining of the conjunctivae) and for 
“symptom” (SANDE score) were selected as primary endpoints in phase 3. Moreover, in phase 2, efficacy 
signals were observed as early as the first post-baseline study visit (Day 28), which supports the selection 
of Day 28 as the primary timepoint for endpoint assessments in phase 3.  
 SELECTION AND WITHDRAWAL OF SUBJECTS 
 Number of Subjects 
At least 240 participants will be randomly assigned to the study treatment such that approximately 120 
evaluable subjects per active arm (OCU310) and 120 per placebo arm (OBS) complete the study (1:1 
randomization). 
 Subject Inclusion Criteria 
Subjects must meet all the following inclusion criteria to be eligible to enroll in the clinical trial: 
1. Aged 18 years or older.  
2. Sign and date informed consent form approved by the IRB   
3. History of Dry Eye Disease for >6 months 
4. Demonstrate the following 2 signs of DED in the same eye at Screening and Baseline (Day 1): 
a. Conjunctival staining at > 1 (out of a possible score of 6 per eye), and 
b. Schirmer test (with anesthesia) at > 1 to < 7 mm in 5 minutes 
5. Symptomatic evidence of DED by having a global symptom score (Overall SANDE) >40 mm at 
Screening and Baseline (Day 1) visit  
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 28), OR 
b. Are post-menopausal or have undergone a sterilization procedure  
 
 Subject Exclusion Criteria 
The presence of any of the following exclusion criteria excludes a subject from study enrollment: 
1. Allergic to brimonidine or any similar products, or excipients of brimonidine or loteprednol 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
27 
 
2. Use of contact lenses within 14 days prior to Screening visit or planned use 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, or others who may be considered vulnerable 
populations 
13. Received corticosteroid-containing eye drops within the past 14 days prior to Screening visit or 
planned use during study 
14. Any change in systemic corticosteroids/immunosuppressives, cyclosporine ophthalmic emulsion 
0.05% (Restasis®) or lifitegrast ophthalmic solution 5% (Xiidra™) within 30 days prior to 
Screening visit or planned change during study 
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 
 
Note: Subjects will be permitted to continue all their ocular treatments, including the use of artificial 
tears, eyelid massage, or warm compresses, if they commit to using the same brand/regimen 
throughout the study. None of the ocular treatments, whether OTC or prescription (e.g. Restasis or 
Xiidra) or study medication should be used within 5 minutes of another ocular treatment during the 
study. Study medication should not be used within 2 hours prior to any study visit.  
 Randomization Criteria 
Not applicable. 
 Subject Withdrawal Criteria 
Subjects may withdraw consent at any time for any reason without effect on subsequent care. Subjects 
will be encouraged to adhere to the protocol and complete all required assessments prior to exiting the 
study.    
If study medication use has been discontinued, subjects should continue to attend all scheduled visits. A 
subject will be discontinued from study medication for any of the following reasons: 
• 
Pregnancy 
• 
At the discretion of the Investigator at any time 
• 
At the subject’s request (voluntary discontinuation) 
• 
Occurrence of a treatment-emergent adverse event (TEAE) or considerable worsening of an AE 
that, in the opinion of the Investigator in consultation with the Medical Monitor and Sponsor, 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
28 
 
represents an unacceptable risk to the subject if he/she continues to receive study medication. The 
Investigator must follow the subject until the AE resolves or satisfactorily stabilizes. 
• 
Progression of disease that, in the opinion of the Investigator, precludes further study drug 
treatment 
• 
Lack of tolerability to the study drug  
Subject participation in the study is purely voluntary. Subjects who withdraw from the study outside of 
any scheduled visit will be encouraged to complete a final study visit at the time of discontinuation. 
Subjects who are discontinued during a scheduled visit will be encouraged to complete all unique 
assessments for that study visit at the time of discontinuation.  
The reason for study withdrawal is to be documented in the subject’s source documents and CRFs, as 
follows: 
1. Adverse event 
2. Subject voluntary withdrawal (with explanation) 
3. Investigator withdrawal of subject (with explanation and after discussion with MM and 
Sponsor) 
4. Lost-to follow-up  
5. Study termination 
6. Other (with explanation) 
 
 Study Termination  
This study may be terminated at any time if, in the opinion of the Investigator or the Sponsor, 
continuation of the study represents a significant medical risk to participating subjects. Appropriate 
consultation between the Sponsor and Investigator must take place prior to termination of the study. 
 STUDY SCHEDULE AND PROCEDURES 
 Study Schedule  
The study schedule can be found in Table 4. Detailed information on study assessments is provided in 
Section 6.   


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
29 
 
 
Table 4. Study Schedule of Events 
 
Screening and Baseline 
Visit  
Dosing and Evaluation 
Visit number  
 
 
Day (Time) 
 
Day -7± 1d 
(Screening) 
 
Day 1 
(Baseline) 
Day 14 ± 3d 
(Week 2) 
Day 28 ± 7d 
(Week 4) 
Informed consent 
X 
 
 
 
Eligibility criteria 
X 
X 
 
 
Demographic Information 
X 
 
 
 
Medical/surgical/ocular history1 
X 
X 
 
 
Vitals signs2 
 
X 
X 
X 
Review of prior and concomitant medications3 
X 
X 
X 
X 
Urine collection and Pregnancy test (females of 
childbearing capacity only; hCG dipstick)4 
X 
        X 
 
 
Visual acuity ([logMar])5 
 
X 
X 
X 
Symptom Assessment in Dry eye (SANDE)6 
X 
X 
X 
X 
Ocular redness 100 -point VBR scale via slit lamp7 
 
X 
X 
X 
Slit lamp ophthalmic exam 
X 
X 
X 
X 
Corneal Lissamine green stain8 
 
X 
X 
X 
Conjunctival Lissamine green stain9 
X 
X 
X 
X 
Schirmer’s test with anesthesia (mm,)10 
X 
X 
 
X 
Intraocular pressure11 
X 
X 
X 
X 
Clinical Global Impression (CGI) 
 
 
X 
X 
Subject Global Assessment (SGA) 
 
 
X 
X 
Randomization 
 
X 
 
 
Dispense/Instill Investigative Product12 
 
X 
 
 
Adverse event surveillance 
X 
X 
X 
X 
Diary recording and review13 
 
X 
X 
X 
 
1. 
The ocular history will include any previously diagnosed ophthalmic abnormalities and ocular surgeries (including 
laser procedures). Ocular history at baseline (day 1) will cover the time from the screening visit.  
2. 
Baseline Vital signs on Day 1 to be completed at least 30 ± 10 mins before dose on Day 1. All othervitals to be 
completed before ocular assessments on Days 14 and 28. 
3. 
Corticosteroid-containing eye drops are not allowed within 14 days prior to Screening or during the study. Review of 
prior and concomitant medications and regimens will occur at all study visits. Subjects will be permitted to continue all 
their ocular treatments, including the use of artificial tears, eyelid massage, or warm compresses if they commit to the 
same brand/regimen throughout the study. None of the ocular treatments, whether over-the counter or prescription (e.g. 
Restasis® or Xiidra®) or study medication should be used within 5 minutes of another ocular treatment during the 
study. Study medication should not be used within 2 hours prior to any study visit.  
4. 
hCG = human chorionic gonadotrophin. A urine pregnancy test is required at screening and baseline (Day 1).. A urine 
pregnancy test may be performed at any time during study participation if pregnancy is suspected. 
5. 
Subjects should use the most recent correction to attain their best-corrected visual acuity (BCVA). 
6. 
The SANDE questionnaire measures symptom frequency (“rarely” to “all of the time”) and symptom severity (“very 
mild” to “very severe.”) on a visual analogue scale (VAS). Subjects will complete this scale at Screening and on Day 1 
prior to first dose (Baseline), Day 14, and Day 28. 
7. 
Injection in the bulbar conjunctiva (nasal and temporal; OS and OD) of the subject’s eyes will be evaluated via slit-
lamp examination and compared to the reference images in the VBR and graded accordingly. The same grader should 
assess each time at the slit lamp and use identical lighting conditions. 
8. 
Corneal lissamine green staining using a solution made from Lissamine Green Ophthalmic Strips. Corneal staining will 
be graded in 5 zones in each eye. Each zone will be graded from 0 to 3 based on the density of punctate staining 
(maximum score/eye =15) 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
30 
 
9. 
Conjunctiva lissamine green staining will be performed using a solution made from Lissamine Green Ophthalmic 
Strips. 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/eye = 6). 
10. Anesthetize each eye (OS and OD) with a drop of proparacaine. Insert Schirmer strips into lower lid for 5 min.  
11. Measure intraocular pressure using Goldman applanation tonometry. 
12. Subjects will receive the first dose of medication on Day 1 at the study site and will instill the dose into both eyes 
before leaving the clinic, with oversight/training by site staff. Study medication will be dispensed to subjects at the 
baseline (Day 1) visit for self-administration during the study. 
13. Subject diaries must be reviewed by the study staff at each visit prior to the subject’s leaving the clinic. 
 
 Study Visits 
 
  Unscheduled Study Visits 
If an unscheduled visit is necessary to follow an intercurrent event, any untoward findings related to that 
event should be captured as adverse events and/or as concomitant therapies on source documents and 
relevant pages of the CRF. If the event meets the requirement for an SAE, please record on the SAE page 
of  the CRF and follow all SAE-related procedures (see  Section 10, Adverse Events).   
  Screening (Day -7 ± 1 day)  
An ICF must be obtained from each subject before initiation of any study-related procedures.  
The following assessments should be completed at the Screening Visit: 
• 
Informed Consent 
• 
Inclusion and Exclusion criteria check 
• 
Demographic information   
• 
Medical history including prior procedures and conditions 
• 
Ophthalmic history including: date when the DED began, medications used by the subject to treat 
DED, previous procedures to treat DED.  
• 
Review of prior and concomitant medications: medications used by the subject to treat DED, 
previous procedures to treat DED; OTC ocular medications; medications for chronic diseases 
• 
Urine collection and dipstick test for pregnancy in women of child bearing capacity 
• 
Symptom Assessment iN Dry Eye (SANDE) 
• 
Slit-lamp ophthalmic exam 
• 
Conjunctival Lissamine Green 
• 
Schirmer’s test with anesthesia  
• 
Intraocular pressure (IOP) 
• 
Adverse event surveillance 
 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
31 
 
  Day 1 (Baseline, Randomization, and First Treatment Visit) 
Baseline: The following should be completed prior to the first dose  
• 
Inclusion and Exclusion criteria check 
o Note: Eligibility criteria must be fulfilled at both the Screening and Baseline (Day 1) 
visits. Except for Informed Consent and Demographic Information, all activities at the 
Screening visit are repeated at the Baseline (Day 1) visit, as detailed below.   
• 
Medical/surgical ocular history (update since Screening visit) 
• 
Review of prior and concomitant medications 
• 
Urine collection and dipstick test for pregnancy in women of child bearing capacity 
• 
Visual Acuity (LogMar) 
• 
Symptom Assessment iN Dry Eye (SANDE) 
• 
Ocular Redness 100-point VBR scale 
• 
Slit-lamp ophthalmic exam 
• 
Corneal Lissamine Green 
• 
Conjunctival Lissamine Green 
• 
Schirmer’s test with anesthesia  
• 
Intraocular pressure (IOP) 
• 
Vital signs: body temperature, heart rate, blood pressure, respiratory rate  (done at least 30 ± 10 
minutes before dose on Day 1) 
• 
Randomization 
• 
Instill investigative product (Instruct subject on how to self-administer the study eye drops and 
when to take the next dose)  
 
 
Post-Dose: The following assessments should be completed during / after administration of the first dose:  
• 
Dispense the investigational product kit (provide the subject with a sufficient supply to last for 
approximately 4 weeks, to take home) 
• 
Post-dose evaluation for any adverse effects 
• 
Provide subject with a study diary (study staff should instruct the patient on use and responsibility 
for the study diary) 
• 
Make appointment for next visit 
 
  Day 14 (± 3 days) 
• 
Review of prior and concomitant medications 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
32 
 
• 
Vital signs: body temperature, heart rate, blood pressure, respiratory rate   
• 
Visual acuity (LogMar) 
• 
Symptom Assessment iN Dry Eye (SANDE) 
• 
Ocular Redness 100-point VBR scale 
• 
Slit-lamp ophthalmic exam 
• 
Corneal lissamine green 
• 
Conjunctival lissamine green 
• 
Intraocular pressure (IOP) 
• 
Clinical Global Impression 
• 
Subject Global Assessment 
• 
Adverse event surveillance 
• 
Diary recording and review 
 
 Day 28 (± 7 days) 
• 
Review of prior and concomitant medications 
• 
Vital signs: body temperature, heart rate, blood pressure, respiratory rate   
• 
Visual acuity (LogMar) 
• 
Symptom Assessment iN Dry Eye (SANDE) 
• 
Ocular Redness 100-point VBR scale 
• 
Slit-lamp ophthalmic exam 
• 
Corneal lissamine green 
• 
Conjunctival lissamine green 
• 
Schirmer’s test with anesthesia  
• 
Intraocular pressure (IOP) 
• 
Clinical Global Impression 
• 
Subject Global Assessment  
• 
Collect used investigative products 
• 
Adverse event surveillance 
• 
Diary recording and review 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
33 
 
 ASSESSMENTS 
 Demographic/Ocular and Medical History 
Information relating to the subject’s sex, age, race, height, and weight will be recorded at the Screening Visit 
on the appropriate case report form (CRF) page. Ocular and medical history of each subject will be collected 
at the Screening and Baseline (Day 1) Visits and recorded on the appropriate CRF. 
 Prior & Concomitant Medications/Therapies 
All prior and concomitant medications/therapies taken by subjects within 30 days prior to enrollment and 
throughout the study must be recorded on the appropriate CRFs.  
 Pregnancy Screen 
At the Screening and Baseline (Day 1) Visits, a urine dipstick pregnancy test will be performed for all female 
subjects of child-bearing potential. 
 Efficacy Assessments 
 
 Primary Efficacy Assessment 
 
There are two primary efficacy endpoints in this study: 
1. Change from baseline to 4 weeks (Day 28) in SANDE score 
2. Change from baseline to 4 weeks (Day 28) in Lissamine Green conjunctival staining scores  
 
Note: This endpoint would be considered in a hierarchical fashion if statistical success is first demonstrated 
for SANDE at Day 28 (Section 11) 
 
6.4.1.1 Symptom Assessment iN Dry Eye (SANDE) at Day 28 
The SANDE questionnaire is a short visual analog assessment scale that quantifies both severity and 
frequency of current dry eye symptoms. The SANDE is comprised of two questions, and each question 
employs a 100-mm horizontal linear VAS (Figure 2). 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 at Screening, Day 1 prior to first dose, Day 14, and Day 28. Data collected from the 
SANDE questionnaire will be calculated by multiplying the frequency score by the severity score and 
obtaining the square root. The result is the Overall SANDE score (see Section 18.4).  
 
6.4.1.2 Conjunctival Staining Score with Lissamine Green at Day 28 
Conjunctival staining with Lissamine Green dye (1%; LG) staining in each eye (OS and OD) will be 
conducted using the slit lamp at Screening, Day 1 prior to first dose, Day 14, and Day 28. A single drop of 
1% Lissamine Green dye will applied to the inferior conjunctival fornix of both eyes. The conjunctivae will 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
34 
 
be examined with the slit lamp at ×10 magnification, using a neutral-density filter. Conjunctival staining will 
be graded in two zones, as per the methods described in Section 18.3 (Table 6)(Figure 3)(Figure 4). 
 
 Secondary Efficacy Assessment 
  
There are two secondary efficacy endpoints in this study: 
3. Change from baseline to 2 weeks (Day 14) in SANDE score 
4. Change from baseline to 2 weeks (Day 14) in Lissamine Green conjunctival staining scores 
 
Note: The above endpoints (Primary and Secondary) will be tested in a fixed sequence (1-4) proceeding to 
the next endpoint until a p-value >0.05 is found (Section 11).  
 
  
6.4.2.1 Symptom Assessment iN Dry Eye (SANDE) at Day 14 
See 6.4.1.1 above. 
 
6.4.2.2 Conjunctival Staining Score with Lissamine Green at Day 14 
See 6.4.1.2 above. 
 
 Exploratory Efficacy Assessments 
 
There are seven exploratory efficacy endpoints in this study: 
• 
Change from baseline to 4 weeks (Day 28) in Lissamine Green corneal staining scores 
• 
Change from baseline to 2 weeks (Day 14) in Lissamine Green corneal staining scores  
• 
Change from baseline to 4 weeks (Day 28) in Schirmers scores 
• 
Change in appearance from baseline to 4 weeks (Day 28) in Validated Bulbar Redness (VBR) 
scale 
• 
Change in appearance from baseline to 4 weeks (Day 14) in Validated Bulbar Redness (VBR) 
scale 
• 
Clinical Global Impression (CGI) of change in symptoms from baseline (physician’s rating) to 4 
weeks (Day 28) 
• 
Subject Global Assessment (SGA) of overall change from baseline (subject’s rating) to 4 weeks 
(Day 28) 
 
 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
35 
 
6.4.3.1 Corneal Staining Score with Lissamine Green at Day 28 
 
Corneal staining will be graded in 5 zones, as per the methods described in Section 18.3 (Table 6)(Figure 
3)(Figure 4). 
 
6.4.3.2 Corneal Staining Score with Lissamine Green at Day 14 
 
Corneal staining will be graded in 5 zones, as per the methods described in Section 18.3 (Table 6)(Figure 
3)(Figure 4). 
 
6.4.3.3 Schirmers Test (with anesthesia) at Day 28 
A Schirmer’s test will be conducted at Screening, Day 1 (prior to first dose), and Day 28 to access tear 
production. After instilling one drop of a topical anesthetic (e.g., proparacaine) to each eye, wait 
approximately 30 seconds, then blot the inferior cul-de-sac with a tissue. The test is conducted by application 
of standardized Schirmer strips over the lower lid margin, toward the temporal angle of the lids in both eye 
as possible. The subject should be instructed to keep her/his eyelids closed during the test. Strips should 
remain in place in both eyes for 5 min, or until completely saturated with tears. After 5 min, wetting of the 
strips will be measured using the millimeter scale on each strip.  
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 (Ogawa, 2013), as follows:     
1. Normal is >15 mm 
2. Mild dry eye is 11-15 mm 
3. Moderate dry eye is 6-10 mm 
4. Severe dry eye is ≤5 mm 
 
6.4.3.4 Validated Bulbar Redness grading scale (VBR) at Day 28 
Ocular surface redness (OR; nasal or temporal) will be assessed using the VBR grading scale (Schulze 2007) 
at Day 1 prior to first dose, Day 14, and Day 28. The VBR consists of a set of ten images illustrating 
different degrees of OR, ranging from normal to severe, and each image is assigned a value in an order of 
ascending severity (see Section 18.1; Figure 1). The VBR will be completed at each clinic visit. The bulbar 
conjunctival injection of the subject’s eye (nasal and temporal) will be examined via slit-lamp examination 
and compared to the reference images in the VBR and graded accordingly. To maintain uniformity, the same 
physician (PI) will perform the VBR assessments for each subject, and under constant illumination 
conditions.  
6.4.3.5 Clinical Global Impression (CGI) at Day 28 
At Day 14 and Day 28, the PI will use their clinical evaluation (all signs and symptoms taken together) to 
provide a global assessment of the subjects’ change in symptoms and signs. The CGI is assessed as follows 
(Miller 2010):  


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
36 
 
Question (to physician): In general, compared with the subjects’ symptoms and signs at baseline, how 
would you characterize his/her overall signs and symptoms now? 
The responses will be categorized on a 7-point scale as follows: 
- 
Marked worsening 
- 
Moderate worsening 
- 
Minimal worsening 
- 
Unchanged 
- 
Minimal improvement 
- 
Moderate improvement 
- 
Marked improvement 
 
6.4.3.6 Subject Global Assessment (SGA) at Day 28 
At Day 14 and Day 28, the subjects will be asked to assess their overall change from baseline. The SGA is 
assessed as follows (Miller 2010): 
Question 1 (to subject): Compared with your first visit, how are your eye symptoms now? 
The responses will be categorized on a 5-point scale as follows:  
- 
Much worse 
- 
Worse 
- 
About the same 
- 
Improved 
- 
Much improved 
 
 Safety Assessments 
All subjects who enter the study will be assessed for safety. Safety will be monitored by observation of and 
direct inquiry regarding AEs at each visit. Safety assessments include vital signs, recording of adverse 
events, as well as ophthalmic exam findings. All ocular and non-ocular adverse events will be assessed for 
severity and relationship to the investigational product. The following analyses will be performed: 
o The proportion of subjects at Day 28 who were able to successfully complete a full 28 days of therapy 
with topical ophthalmic administration  
o All adverse events reported, whether deemed related to treatment or not 
o Clinically significant changes in vital signs or ophthalmic examinations from baseline 
 Adverse Events 
All AEs will be collected from the time of informed consent completion through the completion of the study 
for each subject. Details regarding AE definitions, collection, recording, and reporting are found in Section 
10.1.  


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
37 
 
 Visual Acuity (logMAR) 
Monocular and binocular visual acuity will be completed with the subject’s best correction vision in place 
using a logMAR ETDRS chart, at Day 1 prior to the first dose , Day 14, and Day 28. Procedures for BCVA 
are outlined in Section 18.4 (Figure 5)(Table 7).  
 IOP - Goldmann Applanation 
IOP will be assessed in both eyes, at each clinic visit, using the Goldmann applanation tonometry method 
(see Section 18.5).  
 Ophthalmic Examination (Slit Lamp) 
Biomicroscopic examination will be completed at each clinic visit (see Section 18.6)(Table 8). The 
conjunctiva, cornea, anterior chamber, lens and anterior vitreous of each eye will be examined.  
 Vital Signs 
Vital signs will be assessed at the Day 1, Day 14, and Day 28 visits.  Diastolic and systolic blood pressure 
(DBP/SBP) and heart rate (HR) will be assessed via oscillometer method using an automated 
sphygmomanometer. At each visit, 3 consecutive readings (at least 2 minutes apart) will be taken by the 
study staff and recorded in the subject’s source documents. The average DBP and SBP will be documented 
in the CRFs. Subjects should be comfortably seated for 5 minutes prior to blood pressure readings. Study 
staff must take care to select the appropriate cuff size for each subject.  
Heart rate will be assessed for at least 1 minute and recorded as beats per minute (bpm), and body 
temperature (forehead) will be recorded in degrees Celsius (˚C).   
 
Clinically significant negative changes from baseline will be recorded as adverse events. 
 INVESTIGATIONAL DRUG INFORMATION AND MANAGEMENT 
 Investigational Drug Dose Regimen 
The proposed dose is one drop of OCU310 in each eye (OU) approximately every 12 hours. The proposed 
dosing regimen is twice daily (bid). 
 Dose Rationale  
OCU310 has a dosage strength of 0.2% brimonidine tartrate applied as a single drop to each eye, twice daily. 
This dose was selected based on results of the Phase 2 proof-of-concept study and the data available from 
marketed brimonidine ophthalmic products, accounting for the improved pharmaceutical attributes of an oil-
in-water proprietary nanoemulsion of brimonidine tartrate (sterile filtered) formulation compared to the 
solution formulation. The nanoemulsion formulation, with a pH buffered to maintain the optimum range for 
ocular delivery, is expected to decrease drainage rate and prolong precorneal residence time, without 
increasing the drug peak concentration. Based on these pharmaceutical attributes, as well as preliminary 
clinical data, it is suggested that a 0.2% concentration of brimonidine in the OCU310 ophthalmic 
nanoemulsion formulation with twice daily application will be able to exert therapeutic effects.  
Moreover, the potential protective effect of OCU310 brimonidine tartrate against corneal epithelial damage 
is assumed to be similar to that of OCU300, which Ocugen is developing for patients with chronic ocular 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
38 
 
graft-vs-host disease oGVHD). OCU 300, in comparison to a placebo nanoemulsion, commercially available 
brimonidine tartrate ophthalmic solution (0.2 %), and marketed products (Restasis ®- Cyclosporine; 
Xiidra®- Lifitegrast) demonstrated a protective effect in a mouse dry-eye disease model.  These results infer 
that OCU310 could provide better protection for corneal epithelial damage than the reference product 
brimonidine tartrate ophthalmic solution 0.2 %, and placebo nanoemulsion. 
In addition, brimonidine tartrate solution is considered safe based on the long history of over 20 years for 
ophthalmic chronic use (Allergan 2010; Serle 1996). Brimonidine tartrate 0.2% is currently used topically as 
eye drops, 3 times a day, for the lowering of intra-ocular pressure (IOP) in patients with open-angle 
glaucoma or ocular hypertension. The brimonidine tartrate concentration (0.2%) and frequency of 
administration > bid may provide a greater exposure, and hence, a greater probability of adverse events, than 
the proposed OCU310 dosing regimen.  
 Investigational Drug Packaging and Labeling 
All investigational drugs used in this study will be prepared, packaged, and labeled in accordance with the 
standard operating procedures (SOPs) of Good Manufacturing Practice (GMP) guidelines, International 
Conference on Harmonization (ICH) guidelines for GCP, guidelines for Quality System Regulations (QSR), 
and applicable regulations. 
To maintain the double-masking, the investigational product and placebo will be provided in packaging that 
will be similar in appearance and labeling. A label with “OCU310 Investigational Drug Product” will be 
affixed to each pouch containing eye dropper vials and will include the appropriate instructions for storage. 
The label will also include a statement that the drug is “for investigational use.” 
 Investigational Drug Storage 
The study drug will be stored in a designated and secure area, with access given to only authorized study 
personnel. The recommended storage temperature is 15°-25° C/ 59°-77°F. Other storage conditions will be 
observed as per the labeling instructions of the study drug. 
 Investigational Drug Preparation 
Not applicable. The study drugs will be supplied in a form that is ready for instillation in the eye. 
 Investigational Drug Administration 
At the first treatment visit on Day1, the first study medication dose will be administered by the patient under 
the supervision of the study staff, after which the patient will be given a 35-day supply (final visit at Day 28 
28 plus 7-day visit window) of eye-dropper vials for self-administration at home. At the site level, drug 
dispensation should only be performed by the pharmacist or designee, and not by the PI or other personnel 
involved in patient assessments.    
Subjects will be instructed on the use of the study medication, for each eye, as follows: 
Instructions for Drug Use: 
1. Wash your hands thoroughly with soap and water. 
2. Remove the vial from its pouch. 
3. Check the dropper tip to make sure that it is not chipped or cracked. 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
39 
 
4. Avoid touching the dropper tip against your eye or anything else – eye drops and droppers must be 
kept clean. 
5. While tilting your head back, pull down the lower lid of your eye with your index finger to form a 
pocket. 
6. Hold the dropper (tip down) with the other hand, as close to the eye as possible without touching it. 
7. 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. 
8. Close your eye for 2 to 3 minutes and tip your head down as though looking at the floor. Try not to 
blink or squeeze your eyelids. 
9. Place your finger on the tear duct and apply gentle pressure. 
10. Repeat the above listed steps for eye #2. 
 
11. This sequence of steps should be followed twice a day; once in the morning and once in the evening 
(approximately 12 hours apart). 
 
 Investigational Drug Accountability 
The investigational products will be shipped to each Investigative site by the Sponsor’s designee. The PI is 
responsible for the receiving, handling, and reconciliation of the received study drug to shipment records. 
Any discrepancy should be documented, and the appropriate individual at the Sponsor or designee must be 
notified immediately. Dispensing of the study medication to subjects must be accounted for and properly 
documented in the subject or the site’s records. Subjects will be instructed to return all dosing vials, used or 
unused, to the site at each post-baseline visit, for which compliance will be assessed by the Investigator or 
designee, utilizing the subject’s dose diary. The investigational product(s) must only be dispensed to subjects 
participating in this study by the pharmacist or designee, and not by the PI or other personnel involved in 
patient assessments. A Drug Accountability Log will be kept at the clinical site. 
 Investigational Drug Handling and Disposal 
At the completion of the study, all unused investigational products will be returned by the Investigator to the 
Sponsor or designee. Any discrepancies or missing study drug bottles will be investigated, resolved, and 
documented as appropriate.  
 TREATMENT OF SUBJECTS 
 Rescue Medication 
Subjects will be monitored by the PI at each study visit for any worsening of ocular conditions or other AEs. 
Any clinical worsening of the subject’s condition will be evaluated and properly treated as based on the 
Investigator’s clinical judgment. Treatment may involve use of other medications and/or discontinuation of 
study drug.  


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
40 
 
 Prohibited Medications or Treatment 
Subjects will be allowed to remain on current concomitant ocular therapies during the study, given that no 
changes are made to the dose and frequency of the medication within 30 days prior to enrollment and 
throughout the study, with the exception of corticosteroid containing eyedrops, which are prohibited within 7 
days prior to enrollment and during the study. Accordingly, subjects will be permitted to continue all their 
ocular treatments, including the use of artificial tears, eyelid massage, or warm compresses, , and over-the-
counter (OTC) remedies if they commit to using the same brand/regimen throughout the study. None of the 
ocular treatments, whether OTC, prescription (e.g. Restasis® or Xiidra®) or investigational product should 
be used within 5 minutes of another ocular treatment during the study. Study medication should not be used 
within 4 hours prior to any study visit.  
Any changes in concomitant medication from the previous visit should be assessed by the Investigator for 
AEs and documented as appropriate. 
 Other Study Restrictions 
The use of scleral contacts is restricted from Day 1 (baseline) to Day 28 (last study day) in this study. 
 Treatment Compliance 
Treatment compliance will be documented by way of subject diaries. Subjects will be dispensed diaries at the 
Day 1 Visit and will be instructed to record portion of day (a.m. or p.m.) during which bid dosing occurred.  
Subject diaries must be reviewed by the study staff at each visit prior to the subjects’ leaving the clinic.  
 RANDOMIZATION AND MASKING PROCEDURES 
 
Method of Assigning Subjects to Treatment Groups 
In this parallel-group randomized study, subjects who meet study entry criteria will be randomly assigned in 
a 1:1 ratio to OCU310 or placebo. The randomization schedule will be computer generated using a permuted 
block algorithm and will randomly allocate IP to randomization numbers. The randomization numbers will 
be assigned sequentially through a central Interactive Web Response System (IWRS) as subjects are entered 
into the study, with a goal of maintaining balance across the overall study and not necessarily within a study 
site. 
 
The randomization schedule will be prepared by xxxxx before the start of the study. No one involved in the 
conduct of the study will have access to the randomization schedule before official unmasking of treatment  
assignment. No subject will be randomized into this study more than once. 
 
 Masking and Unmasking of Treatment Assignment 
All subjects, investigators, and study personnel involved in the conduct of the study, including data 
management and statistics, will be masked to treatment assignment except for a specified partially 
unmasked staff member personnel from the designated packaging vendor who will do the package 
labeling. This person will know the scramble kit numbers and associated drug groups. The partially 


Ocugen, Inc. 
 
Protocol version 1.0 
OCU-310-301 
 
12 Aug 2018 
41 
 
unmasked study personnel will not otherwise participate in study procedures or data analysis prior to 
unmasking the study data to all study related personnel. 
Study personnel will endeavor to safeguard the integrity of the study masking to minimize bias in the 
conduct of the study. Treatment unmasking is discouraged if knowledge of the treatment assignment will 
not materially change the planned management of a medical emergency. Unmasking will be permitted in a 
medical emergency that requires immediate knowledge of the subject’s treatment assignment. Unmasking 
should be discussed in advance with the medical monitor, if possible.  
 
 Emergency Unmasking 
For emergency unmasking, study personnel will use the IWRS. Access to the IWRS unmasking module 
requires a special password that may be obtained from the medical monitor or other designated team 
member. If the investigator is not able to discuss treatment unmasking in advance, then he/she must notify 
the medical monitor as soon as possible about the unmasking incident without revealing the subject’s 
treatment assignment. The investigator or designee must record the date and reason for study discontinuation 
on the appropriate CRF for that subject. In all cases that are not emergencies, the investigator must discuss 
the event with the medical monitor prior to unmasking the subject’s treatment assignment. 
If treatment assignment is unmasked for an individual subject, study personnel will be notified of that 
subject’s treatment assignment without unmasking the treatment assignments for the remaining subjects in 
the study. Thus, the overall study mask will not be compromised. If a subject’s treatment assignment is 
unmasked, he/she may or may not be asked to withdraw from the study. The investigator will make this 
decision after consultation with the medical monitor. 


Ocugen 
 
Protocol version 1.0 
OCU-300-301 
 
12 July2018 
42 
 
 ADVERSE EVENTS 
 Adverse Events and Serious Adverse Events 
This section defines the types of AEs and outlines the procedures for appropriately collecting, grading, 
recording, and reporting them. Information in this section complies with 21 Code of Federal Regulations 
(CFR) 312, ICH Guideline E2A: Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting, and ICH Guideline E-6: Guidelines for Good Clinical Practice. 
Adverse events will be recorded from the time of informed consent completion, throughout the study, and 
at early termination; AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  
The Investigator is responsible for the detection and documentation of AEs, regardless of treatment group 
or suspected causal relationship to the investigational product. For all AEs, the Investigator must pursue 
and obtain information adequate to determine the outcome of the AE and to assess whether the AE meets 
the criteria for classification as an SAE, requiring immediate notification to the Sponsor or its designated 
representative. 
 Definitions of Adverse Events 
10.1.1.1 Adverse Event (AE) 
An AE is defined as any untoward or unfavorable medical occurrence associated with the subject’s 
participation in the research, whether or not considered related to the subject’s participation in the 
research (ICH E6 Guidelines for GCP). Any medical condition that is present at the time that the subject 
is screened will be considered as medical history and not recorded as an AE; however, if the condition 
worsens at any time during the study, it will be recorded and reported as an AE. 
10.1.1.2 Serious Adverse Event (SAE) 
An AE is considered “serious” if, in the view of either the Investigator or the Sponsor, it results in any of 
the following outcomes (21 CFR 312.32(a)): 
• 
Death: A death that occurs during the study or that comes to the attention of the Investigator 
during the protocol-defined follow-up period must be reported to the Sponsor whether it is 
considered treatment related or not. 
• 
A life-threatening event: An AE or suspected adverse reaction (SAR) is considered “life-
threatening” if, in the view of either the Investigator or the Sponsor, its occurrence places the 
participant at immediate risk of death. It does not include an AE or SAR that, had it occurred 
in a more severe form, might have caused death. 
• 
In-patient hospitalization or prolongation of existing hospitalization. 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions. 


Ocugen 
 
Protocol version 1.0 
OCU-300-301 
 
12 July2018 
43 
 
• 
An important medical event that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based on appropriate medical judgment, it 
may jeopardize the participant and may require medical or surgical intervention to prevent 
one of the outcomes listed above. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in in-patient hospitalization, or the development 
of investigational product dependency or abuse. 
• 
Congenital anomaly or birth defect. 
If an event meets any of the above definitions, regardless of the severity or relationship of the event to the 
study product, the event must be reported to the Sponsor, as described in Section 10.1.5. 
Adverse events reported from clinical studies associated with hospitalization or prolongation of 
hospitalization are considered serious. Any hospitalization except observational admissions of less than 
24 hours meets these criteria. This category also includes transfer within the hospital to an acute/intensive 
care unit (e.g., from a standard of care unit to an acute/intensive care unit). 
Hospitalization does not include the following: 
• 
Rehabilitation facilities, hospice facilities or respite care (e.g. caregiver relief) 
• 
Nursing homes or skilled nursing facilities 
• 
Emergency room visits 
• 
Same day surgeries (as outpatient/same day/ambulatory procedures) 
• 
<24-hour admissions for observation or evaluation 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical AE is not in 
itself an SAE. Examples include: 
• 
Admission for treatment of a preexisting condition that did not worsen 
• 
Protocol-specified admission (e.g. for a procedure required by the study protocol) 
• 
Hospitalizations for cosmetic elective surgery, social, and/or convenience admissions 
• 
Pre-planned treatments or surgical procedures should be noted in the baseline documentation 
for the individual subject. 
• 
Diagnostic and therapeutic procedures, such as surgery, should not be reported as AEs; 
however, the medical condition for which the procedure was performed should be reported if 
it occurs during the reporting period and meets the definition of an AE. For example, an acute 
appendicitis attack that begins during the AE reporting period should be reported as an AE, 
and the resulting appendectomy should be recorded as treatment of the AE. 
10.1.1.3 Adverse Drug Reaction (ADR) and Suspected Adverse Reaction (SAR) 
An adverse drug reaction (ADR) refers to any AE caused by a drug.   


Ocugen 
 
Protocol version 1.0 
OCU-300-301 
 
12 July2018 
44 
 
Suspected adverse reaction (SAR) refers to any AE for which there is a reasonable possibility that the 
drug caused the AE. For the purposes of safety reporting, “reasonable possibility” indicates that there is 
evidence to suggest a causal relationship between the drug and the AE. An SAR implies a lesser degree of 
certainty about causality than an ADR (21 CFR 312.32(a)).  
10.1.1.4 Unexpected Adverse Reaction (UAR) 
The Sponsor is responsible for assessing AEs for expectedness. With regards to reporting to the FDA, an 
AE is considered “unexpected” when its nature (specificity), severity, or rate of occurrence is not 
consistent with applicable product information as described in the safety information provided in the 
protocol/package insert/Investigator’s brochure/prescribing information for brimonidine tartrate. 
"Unexpected," as used in this definition, also refers to AEs or SARs that are mentioned in the 
Investigator’s brochure as occurring with a class of drugs or as anticipated from the pharmacological 
properties of the drug but are not specifically mentioned as occurring with the particular drug under 
investigation (21 CFR 312.32(a)).  
10.1.1.5 Adverse Events of Interest (AEIs) 
Not applicable. 
 Severity of AEs/SAEs 
The study site will grade the clinical severity of AEs experienced by study participants as either: 
• 
Mild: Causes no limitation of usual activities  
• 
Moderate: Causes some limitation of usual activities  
• 
Severe: Prevents or severely limits usual activities 
Note: The terms serious and severe are not synonymous. Serious criteria as defined in Section 10.1.1.2 
above serve as a guide for defining regulatory reporting obligations. The term severe is often used to 
describe the intensity (severity) of a specific event (as in mild, moderate, or severe headache); the event 
itself, however, may be of relatively minor medical significance. This is not the same as serious, which is 
based on patient/adverse outcome. Therefore, an AE of severe headache might not be considered serious, 
but a moderate infection for which a subject is hospitalized should be reported as an SAE. 
 Relationship to Investigational Drug Treatment 
An Investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE and must be provided for all 
AEs (serious and non-serious).  
The Sponsor’s determination of attribution will be used for reporting to the appropriate health authorities. 
The relation of an AE to study participation will be determined using the descriptors and definitions 
provided in Table 5.  


Ocugen 
 
Protocol version 1.0 
OCU-300-301 
 
12 July2018 
45 
 
 
Table 5. Attribution of Adverse Events 
Unrelated 
 
 
 
Possibly 
Related 
The AE is clearly/most probably caused by other etiologies such as participant’s 
underlying condition, therapeutic intervention or concomitant therapy, or the delay 
between administration and the onset of the AE is incompatible with a causal relation, 
or the AE started before administration (screening phase). Therefore, there is not a 
reasonable possibility that the AE was caused by the investigational drug. 
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 
Related 
There is a reasonable possibility that the AE was caused by the investigational drug. 
The expression “reasonable possibility” is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship (21 CFR 312.32(a)).   
The Investigator should decide whether, in his or her medical judgment, there is a reasonable possibility 
that the event may have been caused by the investigational product. Any AE that is suspected to be 
related to the investigational product will be classified as an ADR.  
 Collecting and Recording Adverse Events 
10.1.4.1 Period of Collection 
All AEs will be collected from the time of informed consent through the subject’s final study visit. All 
AEs and SAEs should be treated as medically appropriate and followed until event resolution.   
The investigator will follow unresolved AEs to resolution until the subject is lost to follow-up or until the 
AE is otherwise classified. Resolution means the subject has returned to baseline state of health or the 
investigator does not expect any further improvement or worsening of the AE. If the subject is lost to 
follow-up, the investigator should make 3 reasonable attempts to contact the subject via telephone, post, 
or certified mail. All follow-up will be documented in the subject’s source document. Non-serious AEs 
identified on the last scheduled contact must be recorded on the AE CRF with the status noted. 
10.1.4.2 Methods of Collection 
Adverse events may be collected as follows: 
• 
Observing the participant 
• 
Questioning the participant in an unbiased and non-leading manner 
• 
Receiving an unsolicited complaint from the participant 
An abnormal value or result from a clinical or laboratory evaluation can also indicate an AE if it is 
determined by the Investigator to be clinically significant. If this is the case, it must be recorded in the 
source document and as an AE on the appropriate AE form(s). The evaluation that produced the value or 


Ocugen 
 
Protocol version 1.0 
OCU-300-301 
 
12 July2018 
46 
 
result should be repeated until that value or result returns to normal or is stabilized and the participant’s 
safety is not at risk. Note: In this study, there are no planned laboratory evaluations.  
10.1.4.3 Recording Method 
10.1.4.3.1 Adverse Events 
All AEs occurring during this clinical study will be recorded by the Investigator on the appropriate CRF 
in precise medical terms, along with the date and time of onset and the date and time of resolution. To 
avoid vague, ambiguous, or colloquial expressions, the AE should be recorded in standard medical 
terminology rather than the subject’s own words. Whenever possible, the Investigator should combine 
signs and symptoms into a single term that constitutes a single diagnosis. Each AE is to be evaluated for 
duration, severity, seriousness, and relatedness to study drug. The severity of the AE and its relationship 
to the study drug will be assessed by the Investigator. 
The Investigator will treat participants experiencing AEs appropriately and observe them at suitable 
intervals until their symptoms resolve or their status stabilizes. If any medication is administered in 
response to the AE, this medication should be noted on the concomitant medication CRF as a concomitant 
medication administered. If possible, medications administered in response to an AE would not constitute 
a change in the patient’s ongoing DED regimen. As noted, a significant change in the over-the-counter 
DED regimen (e.g., artificial tears, eyelid massage, warm compresses), or in cyclosporine ophthalmic 
emulsion 0.05% (Restasis®), or lifitegrast ophthalmic solution, 5% (Xiidra®) during the study should be 
avoided, if possible. In addition, corticosteroid containing eyedrops are prohibited within 14 days prior to 
enrollment and during the study. 
The action taken, and the outcome must also be recorded. The Investigator will follow a non-serious AE 
until resolution, stabilization of the Follow-up Visit. The Investigator will follow an SAE (regardless of 
relationship to study drug until the event resolves, stabilizes, or becomes non-serious. The terms of AE 
resolution (i.e., recovered/resolved, not recovered/not resolved, recovered/resolved with sequelae, 
recovering/resolving, fatal, unknown) should also be recorded.   
10.1.4.3.2 Serious Adverse Events 
Serious adverse events will be recorded on the AE CRF and on the SAE CRF, and health authorities will 
be notified as outlined in Section 10.1.5.2. 
 Reporting Adverse Events 
10.1.5.1 Reporting SAEs to the Sponsor 
The following process for reporting an SAE ensures compliance with 21 CFR 312 and ICH guidelines. 
After learning that a participant has experienced an SAE, the Investigator or designee is responsible for 
reporting the SAE to the Sponsor, regardless of relationship or expectedness, within 24 hours of 
becoming aware of the event. The initial SAE report should include as much information as possible, but 
at a minimum must include the following: 
• 
Reporter 
• 
Subject ID 
• 
Study product or intervention 
• 
Serious AE term 


Ocugen 
 
Protocol version 1.0 
OCU-300-301 
 
12 July2018 
47 
 
• 
Relationship to study medication(s) 
• 
Reason why the event is serious 
Supplemental CRF pages should be current at the time of SAE reporting: medical history, concomitant 
medications, demographics, study drug administration, and death, as applicable.  
Unavailable details of the event should not delay submission of the known information. As additional 
details become available, the SAE CRF should be updated and re-submitted. 
All SAEs, regardless of relationship to the study treatment, must be reported to the Sponsor (or designee) 
within 24 hours of the Investigators’ becoming aware of the event. An initial written SAE report should 
be faxed to Trial Runners/TFS Fax Number:  .  This instruction pertains to initial SAE reports and to any 
follow-up reports.  
The SAE report should provide a detailed description of the SAE and supporting medical documents 
should be included with the report. Follow-up SAE reports must be submitted by the Investigator as new 
information becomes available. 
The Safety Associate will forward the SAE reports and documents to the Medical Monitor and the 
Sponsor for review. 
For additional information regarding SAE reporting, contact: 
 
 
Medical Monitor 
Dr. Barbara Wirotsko 
Trial Runners 
116 W. Villard 
Dickinson, ND  58601 
Phone:  347-453-1521 
24-hour contact : 347-453-1521 
Email: barbarawirostko@trialrunners.com 
 
SAE Fax Number (US): 
SAE Hotline Number (US):  
 
The SAE Hotline is available 24/7 to report an SAE when unable to successfully fax an SAE Report or 
for reporting after normal business hours (Monday-Friday 8:00 AM to 5:00 PM (CST). For all SAE 
Hotline calls, the investigator and site personnel must also follow-up with the Safety Associate by phone 
or email and ensure the SAE Report is received by Trial Runners/TFS Safety.   
10.1.5.2 Reporting Serious Adverse Events to FDA 
The Sponsor will report Investigational New Drug (IND) Safety Reports to the FDA and Investigators, in 
accordance with the FDA regulations detailed in the 21 CFR 312.32.  
After the SAE has been reported by the site Investigator and assessed by the IND Sponsor, there are 2 
options for the IND Sponsor to report an event to the appropriate health authorities: 


Ocugen 
 
Protocol version 1.0 
OCU-300-301 
 
12 July2018 
48 
 
Standard reporting (report in the IND annual report) is required. This option applies if the AE is 
classified as one of the following: 
• 
Serious, SAR per the definitions section (Section 10.1.1) 
• 
Serious and not an SAR per the definitions section (Section 10.1.1) 
Expedited reporting is required. This option applies if the AE/safety finding is classified as one of the 
following: 
• 
Serious and unexpected suspected adverse reaction (SUSAR) per the definitions section 
(Section 10.1.1) 
The Sponsor must report any SAR that is both serious and unexpected. The Sponsor must report AE as an 
SAR only if there is evidence to suggest a causal relationship between the study product and the AE, such 
as: 
• 
A single occurrence of an event that is uncommon and known to be strongly associated with 
the product treatment (e.g. bradycardia, iritis). 
• 
One or more occurrences of an event that is not commonly associated with product treatment 
but is otherwise uncommon in the population exposed to the product.  
• 
An aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other events that 
commonly occur in the study population independent of investigational product therapy) that 
indicates those events occur more frequently in the treatment group than in a concurrent or 
historical control group. 
• 
Any safety findings from other studies: The Sponsor must report any findings from other 
epidemiological studies, pooled analysis of multiple studies, or clinical or nonclinical studies 
that suggest a significant risk in humans exposed to the investigational product that would 
result in a safety-related change in the protocol, informed consent, Investigator’s brochure, or 
other aspects of the overall conduct of the study. 
These events, which require unmasking, must be reported by the Sponsor to the appropriate health 
authorities within 15 calendar days; fatal or life-threatening events must be reported within 7 calendar 
days. 
 Reporting Pregnancy 
During the study, all subjects should be instructed to contact the Investigator immediately if they suspect 
they might be pregnant (e.g., missed or late menstrual period). If pregnancy is confirmed, the subject will 
be withdrawn from the study and followed until the pregnancy comes to term.   
The Investigator is responsible for reporting all available pregnancy information on the Pregnancy 
Questionnaire Form (provided by the Sponsor) within 24 hours of becoming aware of the event, although 
pregnancy itself if not considered an AE. Study treatment must be discontinued immediately in the event 
of a pregnancy. The patient should be referred to an obstetrician/gynecologist experienced in reproductive 
toxicity for further evaluation and counseling. Monitoring of the participant should continue until the 
conclusion of the pregnancy. The Investigator is responsible for reporting the outcome of the pregnancy 


Ocugen 
 
Protocol version 1.0 
OCU-300-301 
 
12 July2018 
49 
 
and the health of the newborn on the Pregnancy Outcome Form (provided by the Sponsor) as it becomes 
available. Partner pregnancies of a male subject do not need to be reported.  
Any pregnancy complication or premature terminations including miscarriage, spontaneous abortion or 
elective termination of a pregnancy for medical reasons will be reported as an SAE, as described in 
Section 10.1.5. If the pregnancy results in a congenital abnormality or birth defect, a separate SAE report 
must be submitted. Furthermore, all neonatal deaths that occur within 30 days of the birth should be 
reported as SAEs, without regard to causality. In addition, any infant death that occurs after the 30-day 
reporting period that the Investigator suspects is related to the in-utero exposure to the study treatment 
should also be reported.  
 STATISTICAL ANALYSIS PLAN 
 General Statistical Methods and Types of Analysis 
 
The primary analysis is a test of superiority of topical OCU310 vs OBS drops with a set of ordered 
endpoints to be tested in a fixed sequence. 
 
Tests will be conducted using two-sided alpha = .05 in a fixed sequence. 
 
 Unit of Analysis 
 
The unit of analysis for variables measured at the individual eye level 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 Lissamine Green conjunctival staining score will be the 
study eye and the other eye will be considered the qualified fellow eye; (iii) if both eyes have the same 
Lissamine Green conjunctival staining score, then the eye with the lower Schirmer score will be the study 
eye and the other eye will be considered the qualified fellow eye; (iv) if both eyes have same Schirmer  
score, the right eye will be the study eye and the other eye will be considered the qualified fellow eye. 
Analysis of safety and efficacy variables measured at the eye level will be primarily performed on the study 
eyes and secondarily on the qualified fellow eyes (for efficacy) and all fellow eyes (for safety).   
 
The unit of analyses for variables measured at the subject level will be the subject. 
 
 Power and Sample Size Determination 
 
One-hundred eight subjects in each of the OCU 310 and placebo arms yields 99% power to reject H01 and 
conclude superiority of OCU 310 over placebo in the mean change from baseline SANDE score at 4 weeks 
assuming the mean changes from baseline in OCU 310 and placebo are -20.0 and -3.5 respectively, a 
common standard deviation of 25.0, and a two-sided alpha = 0.05.  


Ocugen 
 
Protocol version 1.0 
OCU-300-301 
 
12 July2018 
50 
 
 
Additionally, 108 study eyes in each of the OCU 310 and placebo arms yields 90% power to reject H02 and 
conclude superiority of OCU 310 over placebo in the mean change from baseline Lissamine Green 
conjunctival staining score in the study eye at 4 weeks assuming the mean changes from baseline in OCU 
310 and placebo are -0.4 and 0.2 respectively, a common standard deviation of 1.35, and a two-sided alpha 
= 0.05.   
 
For the secondary endpoints, change from baseline in SANDE score at Day 14 and change from baseline 
in Lissamine Green conjunctival staining scores at Day 14, there are not enough data to make a 
power/sample size statement. 
 
For the primary analyses, with 108 subjects per arm, the study will have approximately 90% power to reject 
both H01 and H02, assuming independence between endpoints (with higher power should the endpoints be 
positively correlated), and conclude the OCU 310 to be superior to placebo in both the mean change from 
baseline SANDE score at 4 weeks and the mean change from baseline Lissamine Green conjunctival 
staining score in the study eye at 4 weeks. 
 
Accounting for 10% subject discontinuations, 240 total subjects will be enrolled (120 per arm). 
 
Primary and Secondary Efficacy Endpoints (in fixed sequence): 
 
1. Change from baseline to 4 weeks (Day 28) in SANDE score 
2. Change from baseline to 4 weeks (Day 28) in Lissamine Green conjunctival staining scores  
3. Change from baseline to 2 weeks (Day 14) in SANDE score 
4. Change from baseline to 2 weeks (Day 14) in Lissamine Green conjunctival staining scores 
 
These endpoints will be tested in a fixed sequence proceeding to the next endpoint until a p-value >0.05 is 
found. 
 
Exploratory Endpoint(s): 
• 
Change from baseline to 4 weeks (Day 28) in Lissamine Green corneal staining scores 
• 
Change from baseline to 2 weeks (Day 14) in Lissamine Green corneal staining scores using a 
standard grading scale, such as NEI or Oxford Schema   
• 
Change from baseline to 4 weeks (Day 28) in Schirmers scores 
• 
Change in appearance from baseline to 4 weeks (Day 28) in Validated Bulbar Redness (VBR) 
scale 
• 
Change in appearance from baseline to 4 weeks (Day 14) in Validated Bulbar Redness (VBR) 
scale 
• 
Clinical Global Impression (CGI) of change in symptoms from baseline (physician’s rating) to 4 
weeks (Day 28) 


Ocugen 
 
Protocol version 1.0 
OCU-300-301 
 
12 July2018 
51 
 
• 
Subject Global Assessment (SGA) of overall change from baseline (subject’s rating) to 4 weeks 
(Day 28) 
 
 Analysis Populations 
 
Safety Population 
The safety set will be the primary analysis set for the safety endpoints and will include all subjects who 
have signed informed consent forms, were randomized into the study, and who took at least one dose of 
study drug. The safety set will be analyzed according to the treatment actually received. 
Intent-to-treat (ITT) Population 
The ITT set will be the primary analysis set for the efficacy endpoints and will include all randomized 
subjects who have at least one post-baseline efficacy measurement. The ITT population will be analyzed 
according to the planned treatment. 
Per-protocol (PP) Population 
The PP population set will be tested to confirm the robustness of the primary analysis and will include all 
ITT subjects who have no major protocol deviations. The PP population will be analyzed according to the 
treatment actually received. Efficacy and Safety Analyses 
 
 Background and Demographic Characteristics 
Demographics and baseline characteristics including sex, age, race, height, weight, and ocular and 
medical history will be summarized for the safety population overall and for the ITT population by 
treatment group.  
 Efficacy Analyses 
11.4.2.1 Primary Efficacy Analyses 
The primary efficacy analyses will be conducted on the ITT population. The same set of efficacy analyses 
will also be performed on the per-protocol population.  
Four endpoints (two primary and two secondary) will be tested in a fixed sequence proceeding to the next 
endpoint until a p-value >0.05 is found (Section 11.3). The analysis of the four outcomes will employ a 
repeated measures mixed model with mean change from baseline score at the stated time point as the 
response with baseline score as a covariate and treatment, visit, and their interaction as fixed effects. The 
least squares mean difference (OCU 310 – placebo) at the stated time point will be tested. The 2-sided p-
values and associated 95% confidence intervals will be presented. 
 
The following type of hypothesis will be tested: 
H01: 
The difference (OCU 310 minus placebo), between subjects treated with the OCU 310 and 
subjects treated with placebo in the mean change from baseline = 0. 


Ocugen 
 
Protocol version 1.0 
OCU-300-301 
 
12 July2018 
52 
 
HA1: 
The difference (OCU 310 minus placebo), between subjects treated with the OCU 310 and 
subjects treated with placebo in the mean change from baseline ≠ 0, with superiority 
claimed if the difference < 0. 
 
11.4.2.2 Efficacy Analyses—General Considerations 
Efficacy analyses will be conducted primarily on the ITT population. The same set of efficacy analyses 
will also be performed on per-protocol population. For efficacy endpoints where measurements from 
both eyes are available, the study eye will be used for the analyses.  
For continuous endpoints, the change from baseline will be summarized with descriptive statistics for the 
values at baseline, values at each post-baseline time point (Day14 and Day 28), and for the change from 
baseline at each time point for the set of patients who have data at both the baseline and the time point being 
assessed. Categorical study assessments will be summarized by treatment and visit (as applicable) using 
frequency counts and percentages. 
11.4.2.3 Safety Analyses 
Safety analyses will be performed on the Safety set. Safety parameters include ocular examinations, vital 
signs, AEs, and slit-lamp examinations. Safety data will be reported for all patients that have signed 
informed consent documents. 
11.4.2.4 Adverse Events  
Adverse events will be coded using the MedDRA dictionary. Frequencies and percentages of subjects 
with treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs causing premature 
discontinuation will be provided by treatment group. An AE is treatment emergent if it occurs or worsens 
after the first dose of study treatment. Furthermore, frequencies will be given of subjects with TEAEs by 
system organ class, by system organ class and preferred term, by system organ class, preferred term and 
maximal severity, by system organ class, preferred term and strongest relationship, and by system organ 
class preferred term, maximal severity, and strongest relationship. Separate summaries will be performed 
for ocular and non-ocular AEs. The treatment groups will be compared with respect to safety 
endpoints descriptively. No inferential comparison will be conducted.  
11.4.2.5 Concomitant Medications and Concomitant Therapies 
Concomitant medications will be coded using the most recent version of World Health Organization 
(WHO)-Drug and summarized by treatment group. 
11.4.2.6 Pharmacokinetic Analyses 
None in this study 
 Other Statistical Considerations 
11.4.3.1 Significance Levels 
Tests will be conducted using two-sided alpha = .05.  
11.4.3.2 Multiple Comparisons 
To control for inflation of type 1 error rate due to multiple hypotheses, the analysis will be conducted in a 
hierarchical manner. 


Ocugen 
 
Protocol version 1.0 
OCU-300-301 
 
12 July2018 
53 
 
11.4.3.3 Missing Data 
The primary efficacy analyses will be performed using the ITT population, and using a repeated measures 
model without any imputation for missing observations. Sensitivity analyses using different analysis 
populations and methods for handling missing data may be further detailed in the Statistical Analysis Plan 
(SAP). 
Secondary analyses will also be based on observed data. Missing data handling techniques for secondary 
endpoints may also be detailed in the SAP. 
11.4.3.4 Visit Windows 
All data collected during study follow-up will be displayed and analyzed according to the actual visit data 
in the CRF. Assessments taken outside of windows described in the protocol will be displayed according 
to the CRF assessment recorded by the Investigator. 
  DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
 Study Monitoring 
According to ICH GCP guidelines, the Sponsor of the study is responsible for ensuring the proper 
conduct of the study regarding protocol adherence and validity of data recorded on the CRFs. The 
Sponsor is responsible for assigning the study monitor(s) to this study. The study monitor’s duties are to 
aid the Investigator and the CRO in the maintenance of complete, accurate, legible, well-organized, and 
easily retrievable data. The study monitor will advise the Investigator of the regulatory necessity for 
study-related monitoring, audits, IRB(s) review, and inspection by providing direct access to the source 
data/documents. In addition, the study monitor will explain to and interpret for the Investigator all 
regulations applicable to the clinical evaluation of an investigational drug as documented in ICH 
guidelines. 
It is the study monitor’s responsibility to inspect the CRFs and source documentation throughout the 
study to protect the rights of the subjects; to verify adherence to the protocol; to verify completeness, 
accuracy, and consistency of the data; and to confirm adherence of study conduct to any local regulations. 
Details will be outlined in the clinical monitoring plan.  
The Sponsor requires that the Investigator prepare and maintain adequate and accurate records for each 
subject treated with the investigational drug. Source documents such as any hospital, clinic, or office 
charts and the signed informed consent forms are to be included in the Investigator’s files with the 
subject’s study records. 
Study data will be captured on paper source documents and ultimately electronic case files Study site 
personnel will record CRF data from source documents. Subjects will record selected study assessments 
directly into the CRF. If any data are first recorded onto documents such as laboratory reports, these 
documents will be considered source.  


Ocugen 
 
Protocol version 1.0 
OCU-300-301 
 
12 July2018 
54 
 
 Data Collection and Management 
This study will be conducted in compliance with the ICH document “Guidance for Industry-E6 Good 
Clinical Practice: Consolidated Guidance,” dated April 1996. This study will also be conducted in 
accordance with the Declaration of Helsinki (2013).  
This study will use (TR/TFS/vendor) for data collection and data management. The Investigator is 
responsible for ensuring that all sections of each CRF are completed promptly and correctly and that 
entries can be verified against any source data.   
Study monitors will perform 100% source document verification to ensure there are no inconsistencies 
between the CRFs and source documents. Discrepancies will be resolved in accordance with the 
principles of GCP. Detailed study monitoring procedures are provided in the clinical monitoring plan. 
At intervals throughout the study and upon completion, data will be exported from the database into SAS 
datasets. 
Data management will be coordinated by the data managers  (TR/TFS/vendor)  in accordance with their 
SOPs for data management and a formal study data management plan.  
Adverse events will be coded with MedDRA. Concomitant medications will be coded using the World 
Health Organization – Drug Reference List.  
 QUALITY CONTROL AND QUALITY ASSURANCE 
Quality assurance includes all the planned and systematic actions that are established to ensure that the 
clinical study is performed, and the data are generated, documented (recorded), and reported according to 
ICH GCP and local/regional regulatory standards. 
A quality assurance representative from the Sponsor, who is independent of and separated from routine 
monitoring, may periodically arrange inspections/audits of the clinical study by reviewing the data 
obtained and procedural aspects. These inspections may include on-site inspections/audits and source data 
checks. Direct access to source documents is required for these periodic inspections/audits. 
 ETHICS 
 Ethics Review 
The Investigator will not start this study, nor will investigational devices be shipped to the Investigator’s 
site, before providing the Sponsor with evidence of the IRB(s) approval. The Investigator will promptly 
report to the IRB all changes in the research activity and all unanticipated problems involving risks to 
subjects. The Investigator will not make any changes in the research without the IRB(s) approval, except 
where necessary to eliminate apparent immediate hazards to the subjects. The Investigator will provide 
progress reports to the IRB(s) as required by the IRB(s). The Investigator will provide a final report to the 
IRB(s) after completion of participation in the study.  


Ocugen 
 
Protocol version 1.0 
OCU-300-301 
 
12 July2018 
55 
 
 Ethical Conduct of the Study 
The Investigator should conduct the study in accordance with this protocol, the Declaration of Helsinki, 
and ICH GCP guidelines. The Investigator and Sponsor will sign the protocol and study contract to 
confirm agreement. The Investigator will not implement any amendment (deviation or changes of the 
protocol) without agreement by the Sponsor and the IRB(s) approval/information, except where necessary 
to eliminate immediate hazards to study subjects or when changes involve only logistical or 
administrative aspects of the study.  
 Written Informed Consent 
 Subject Information and Informed Consent 
The informed consent form will be approved by the IRB that is appropriate for each study site. The 
Investigator is responsible for ensuring that the subject fully understands the nature and purpose of the 
study. Information should be given in both oral and written form whenever possible. No subject should be 
obliged to participate in the study. Subjects, their relatives, guardians, or (if applicable) legal 
representatives must be given ample opportunity to inquire about details of the study. The information 
must make clear that refusal to participate in the study or withdrawal from the study at any stage is 
without any prejudice to the subject’s subsequent care. Subjects must be allowed sufficient time to decide 
whether they wish to participate.  
The subject must be made aware of and give consent to direct access to his/her source medical records by 
study monitors, auditors, the IRB(s), and regulatory authorities. The subject should be informed that such 
access will not violate subject confidentiality or any applicable regulations. The subject should also be 
informed that he/she is authorizing such access by signing the informed consent form. 
Each subject will be given a signed copy of the informed consent form to keep for his/her records.   
 Provision of New and Important Information Influencing Subject’s Consent and 
Revision of the Written Information 
When any new and important information that may be relevant to the subject’s consent is obtained, the 
Investigator and Sponsor will consult with each other on how to deal with the information. When the 
Sponsor and a responsible Investigator judge it necessary, the Investigator must immediately provide the 
subjects with such information, revise the written information and other explanatory documents based on 
the new information, and obtain approval from the IRB(s). In this instance, the Investigator should also 
immediately inform subjects currently participating in the clinical study of such information, confirm 
their intention to continue participation, re-explain the study to them using the revised written information 
and other explanatory documents, and obtain written consent to continue participation based on their 
voluntary decision.  
 Subject Confidentiality 
Individual subject medical information obtained as a result of this study is considered confidential, and 
disclosure to third parties is prohibited. Information will be accessible to authorized parties or personnel 
only. Medical information may be given to the subject’s physician or to other appropriate medical 
personnel responsible for the subject’s well-being. Each subject will be asked to complete a form 


Ocugen 
 
Protocol version 1.0 
OCU-300-301 
 
12 July2018 
56 
 
allowing the Investigator to notify the subject’s primary health care provider of his/her participation in 
this study. 
 ADMINISTRATIVE PROCEDURES 
 Publications of the Clinical Study 
The clinical study plan and the results of the study will be published on www.ClinicalTrials.gov in 
accordance with 21 CFR 50.25(c). The results of and data from this study belong to the Sponsor.  
 Protocol Amendments and Deviations 
No change or amendment to this protocol may be made by the Investigator after the protocol has been 
agreed to and signed by all parties unless such change(s) or amendment(s) has (have) been agreed upon 
by the Investigator and Sponsor. Any change agreed upon will be recorded in writing, and the written 
amendment will be signed by the Investigator and Sponsor. Institutional review board approval is 
required prior to the implementation of an amendment, unless overriding safety reasons warrant 
immediate action, in which case the IRB(s) will be promptly notified. 
No deviation from the protocol or investigational plan will be made except to protect the life or physical 
well-being of a subject in an emergency. Except in such emergencies, prior approval of the sponsor, and 
the regulatory authorities (e.g., FDA) or the IRB(s) if applicable, is required before deviations from the 
planned protocol. All protocol deviations that occur during the study will be documented and reported to 
Sponsor and to the IRB(s), if applicable, according to regulations. Further details about the 
documentation, evaluation, and follow-up of protocol deviations are detailed in this study’s clinical 
monitoring plan. 
No waivers to inclusion/exclusion criteria will be granted; subjects need to meet all criteria, exactly as 
specified, to be enrolled. Additionally, prospective deviations from the protocol or investigational plan are 
not permitted except to protect the life or physical well-being of a subject in an emergency. Deviations 
that occur unintentionally or are the result of action by the subject must be documented and reported to 
the Study Sponsor and to the IRB(s), if applicable, according to regulations. Further details about the 
documentation, evaluation, and follow-up of protocol deviations are detailed in this study’s clinical 
monitoring plan. 
 DATA HANDLING AND RECORD KEEPING 
 Inspection of Records 
The Sponsor, their designee(s), the IRB(s), or regulatory authorities will be allowed to conduct site visits 
to the investigational facilities for monitoring or inspecting any aspect of the study. The Investigator 
agrees to allow the Sponsor, their designee(s), the IRB(s), or regulatory authorities to inspect the 
investigational drug storage area, investigational drug stocks, investigational drug records, subject charts 
and study source documents, and other records relative to study conduct.  


Ocugen 
 
Protocol version 1.0 
OCU-300-301 
 
12 July2018 
57 
 
 Retention of Records 
The principal Investigator must retain all documentation relating to the study for a period of at least 
2 years after the last marketing application approval or, if not approved, 2 years following the 
discontinuance of the test article for investigation. If this requirement differs from any local regulations, 
the local regulations will take precedence unless the local retention policy is less than 2 years.  
 
 Sample Retention 
No blood or tissue samples will be obtained during this study. 
 
 


Ocugen 
 
Protocol version 1.0 
OCU-300-301 
 
12 July2018 
58 
 
 
 REFERENCES 
Adkins JC, Balfour JA. Brimonidine. A review of its pharmacological properties and clinical potential in 
the management of open-angle glaucoma and ocular hypertension. Drugs Aging 1998;12(3):225-241. 
Ban Y, Ogawa Y, Goto E, Uchino M, Terauchi N, Seki M, et al. Tear function and lipid layer alterations 
in dry eye patients with chronic graft-vs-host disease. Eye (Lond) 2009; 23:202-208. 
Ban Y, Ogawa Y, Ibrahim OM, Tatematsu Y, Kamoi M, Uchino M, et al. Morphologic evaluation of 
meibomian glands in chronic graft-versus-host disease using in vivo laser confocal microscopy. Mol Vis 
2011; 17:2533-2543. 
Blazar BR, Murphy WJ, Abedi M. Advances in graft-versus-host disease biology and therapy. Nat Rev 
Immunol 2012; 12(6):443-458. 
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. 
Caraceni A, Cherny N, Fainsinger R, Kaasa S, Poulain P, Radbruch L, et al. Pain measurement tools and 
methods in clinical research in palliative care: recommendations of an Expert Working Group of the 
European Association of Palliative Care. J Pain Symptom Manage 2002;23(3):239-255. 
Chew SK, Skalicky SE, Goldberg I. Brinzolamide plus brimonidine for the treatment of glaucoma: an 
update. Expert Opin Pharmacother 2014;15(16):2461-2471. 
Curtis LM, Datiles MB, III, Steinberg SM, Mitchell SA, Bishop RJ, Cowen EW, et al. Predictive models 
for ocular chronic graft-versus-host disease diagnosis and disease activity in transplant clinical practice. 
Haematologica 2015; 100(9):1228-1236. 
Dworkin RH, Turk DC, Farrar JT, Haythornthwaite JA, Jensen MP, Katz NP, et al. Core outcome 
measures for chronic pain clinical trials: IMMPACT recommendations. Pain 2005;113(1-2):9-19. 
Farrar JT, Young JP, Jr., LaMoreaux L, Werth JL, Poole RM. Clinical importance of changes in chronic 
pain intensity measured on an 11-point numerical pain rating scale. Pain 2001;94(2):149-158. 
Ferreira-Valente MA, Pais-Ribeiro JL, Jensen MP. Validity of four pain intensity rating scales. Pain 
2011;152(10):2399-2404. 
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. 
Genetic and Rare Diseases Information Center. Acute Graft Versus Host Disease. 
https://rarediseases.info.nih.gov/diseases/6544/acute-graft-versus-host-disease. 2016a. 10-31-2016a.  


Ocugen 
 
Protocol version 1.0 
OCU-300-301 
 
12 July2018 
59 
 
Genetic and Rare Diseases Information Center. Chronic Graft Versus Host Disease. 
https://rarediseases.info.nih.gov/diseases/10964/chronic-graft-versus-host-disease. 2016b. 10-31-2016b.  
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. 
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. 
Katz LJ. Twelve-month evaluation of brimonidine-purite versus brimonidine in patients with glaucoma or 
ocular hypertension. J Glaucoma 2002;11(2):119-126. 
LeBlanc RP. Twelve-month results of an ongoing randomized trial comparing brimonidine tartrate 0.2% 
and timolol 0.5% given twice daily in patients with glaucoma or ocular hypertension. Brimonidine Study 
Group 2. Ophthalmology 1998;105(10):1960-1967. 
Lee SJ, Wolff D, Kitko C, Koreth J, Inamoto Y, Jagasia M, et al. Measuring therapeutic response in 
chronic graft-versus-host disease. National Institutes of Health consensus development project on criteria 
for clinical trials in chronic graft-versus-host disease: IV. The 2014 Response Criteria Working Group 
report. Biol Blood Marrow Transplant 2015; 21(6):984-999. 
Lemp MA. Report of the National Eye Institute/Industry workshop on Clinical Trials in Dry Eyes. CLAO 
J. 1995;21: 221–232. 
Martin PJ, Lee SJ, Przepiorka D, Horowitz MM, Koreth J, Vogelsang GB, et al. National Institutes of 
Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host 
Disease: VI. The 2014 Clinical Trial Design Working Group Report. Biol Blood Marrow Transplant 
2015;21(8):1343-1359. 
Melamed S, David R. Ongoing clinical assessment of the safety profile and efficacy of brimonidine 
compared with timolol: year-three results. Brimonidine Study Group II. Clin Ther 2000;22(1):103-111. 
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. 
Mundorf T, Williams R, Whitcup S, Felix C, Batoosingh A. A 3-month comparison of efficacy and safety 
of brimonidine-purite 0.15% and brimonidine 0.2% in patients with glaucoma or ocular hypertension. J 
Ocul Pharmacol Ther 2003;19(1):37-44. 
Nassar A, Tabbara KF, Aljurf M. Ocular manifestations of graft-versus-host disease. Saudi J Ophthalmol 
2013; 27(3):215-222. 
Nassiri N, Eslani M, Panahi N, Mehravaran S, Ziaei A, Djalilian AR. Ocular graft versus host disease 
following allogeneic stem cell transplantation: a review of current knowledge and recommendations. J 
Ophthalmic Vis Res 2013; 8(4):351-358. 


Ocugen 
 
Protocol version 1.0 
OCU-300-301 
 
12 July2018 
60 
 
National Organization for Rare Disorders. Graft versus Host Disease. https://rarediseases.org/rare-
diseases/graft-versus-host-disease/. 2016. 10-31-2016.  
Nguyen QH, McMenemy MG, Realini T, Whitson JT, Goode SM. Phase 3 randomized 3-month trial with 
an ongoing 3-month safety extension of fixed-combination brinzolamide 1%/brimonidine 0.2%. J Ocul 
Pharmacol Ther 2013;29(3):290-297. 
Ogawa Y, Kim SK, Dana R, Clayton J, Jain S, Rosenblatt MI, et al. International Chronic Ocular Graft-
vs-Host-Disease (GVHD) Consensus Group: proposed diagnostic criteria for chronic GVHD (Part I). Sci 
Rep 2013; 3:3419. 
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. 
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. 
Rahman MQ, Ramaesh K, Montgomery DM. Brimonidine for glaucoma. Expert Opin Drug Saf 
2010;9(3):483-491. 
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. 
Satitpitakul V, Kheirkhah A, Crnej A, Hamrah P, Dana R. Determinants of ocular pain severity in patients 
with dry eye disease. Am J Ophthalmol 2017;179:198-204. 
Schuman JS. Clinical experience with brimonidine 0.2% and timolol 0.5% in glaucoma and ocular 
hypertension. Surv Ophthalmol 1996;41 Suppl 1:S27-37. 
Schuman JS, Horwitz B, Choplin NT, David R, Albracht D, Chen K. A 1-year study of brimonidine twice 
daily in glaucoma and ocular hypertension. A controlled, randomized, multicenter clinical trial. Chronic 
Brimonidine Study Group. Arch Ophthalmol 1997;115(7):847-852. 
Shikari H, Amparo F, Saboo U, Dana R. Onset of ocular graft-versus-host disease symptoms after 
allogeneic hematopoietic stem cell transplantation. Cornea 2015; 34(3):243-247. 
Sun YC, Chai X, Inamoto Y, Pidala J, Martin PJ, Flowers ME, et al. Impact of ocular chronic graft-
versus-host disease on quality of life. Biol Blood Marrow Transplant 2015; 21(9):1687-1691. 


Ocugen 
 
Protocol version 1.0 
OCU-300-301 
 
12 July2018 
61 
 
Wang Y, Ogawa Y, Dogru M, Tatematsu Y, Uchino M, Kamoi M, et al. Baseline profiles of ocular 
surface and tear dynamics after allogeneic hematopoietic stem cell transplantation in patients with or 
without chronic GVHD-related dry eye. Bone Marrow Transplant 2010; 45(6):1077-1083. 
Westeneng AC, Hettinga Y, Lokhorst H, Verdonck L, van DS, Rothova A. Ocular graft-versus-host 
disease after allogeneic stem cell transplantation. Cornea 2010; 29(7):758-763. 
 
 


Ocugen 
 
Protocol version 1.0 
OCU-300-301 
 
12 July2018 
62 
 
 APPENDICES 
 
 Appendix 1. Validated Bulbar Redness Grading Scales (VBR) 
To evaluate ocular redness, the same physician (PI) must assess the subject at all examinations, and under 
consistent illumination. Examinations must be completed 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). 
A set of colored reference images will be provided at high resolution (with one image per page) (Figure 
1). To maintain the integrity of the original image, the photos should not be photocopied or reproduced in 
any way by site personnel. Multiple sets of images will be provided to each site, corresponding with the 
number of examination rooms. If a set of images is lost or damaged, a new one will be supplied to the 
site.   
During the examination, ask the subject to look at nasal or temporal fixation marks while the temporal or 
nasal bulbar conjunctivae, respectively are examined by the physician. Compare the physician’s 
assessment of the bulbar conjunctival injection of the subject’s eye (nasal and temporal) to the reference 
images in the VBR, and grade accordingly in the subject’s source documents and CRFs. 
Using the 10-picture photographic grading scale select a number (e.g. 10, 20,… 80, 90, or  100) that best 
approximates but does not overestimate the average level of bulbar redness observed in each eye (OD, 
OS). There is no image representing an absolute grade 0, because the bulbar conjunctiva usually exhibits 
some level of redness. Therefore, a white eye would be scored as a 10.  
Figure 1. Validated Bulbar Redness Scale 
Source: Shulze, 2007 
This manner of testing with increments of 10 as chosen because this assessment yields a slightly higher 
level of repeatability than continuous scales (e.g. 1, 1.1, 1.2…9.8, 9.9, 10) and a strong linear association 
between test and retest. 
The above scale will be measured at Screening and at each study visit: Baseline (prior to first dose), Day 
14± 3d, and Day 28 ± 7d. 
 
 


Ocugen 
 
Protocol version 1.0 
OCU-300-301 
 
12 July2018 
63 
 
 
 Appendix 2. Symptom Assessment iN Dry Eye (SANDE)  
Administer the questionnaire at Screening, Day 1 (prior to dosing), and again at Day 14 ± 3d, and Day 28 
± 7d. 
At each visit, ask the subject to place a mark on each of the “frequency” and “severity” lines below based 
on the extent of their current dry eye symptoms (Figure 2).  
Measure the locations of the marks made by the subject in millimeters, from left to right on the 100 mm 
horizontal lines; record the results in the subject’s source documents and CRFs. 
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).  
Figure 2. SANDE Questionnaire 
 
 
 
 


Ocugen 
Protocol version 1.0 
OCU-300-301 
12 July2018 
64 
 Appendix 3. Ocular Surface Staining: Lissamine Green 
Lissamine Green dye (approximately 5 µL of 1% solution) will be applied over the surface of both eyes. 
A solution shall be made from Lissamine Green Ophthalmic Strips.  
 Lissamine Solution 
Materials Supplied: 
1.
Lissamine Green (LG) Ophthalmic Strips (NDC 17238-920-11) impregnated with 1.5 mg of
LG/strip
2.
Sterile Saline (0.9 %) solution (supplied as syringe filled normal saline)
3.
Sterile microfuge tubes (1.5 mL)
4.
Sterile pipette tips (5 µL (microliter) and 200 µL volume dispensing)
5.
Fixed Volume Pipettes (5 µL and 200 µL)
Lissamine Green Ophthalmic Strips (NDC 17238-920-11) impregnated with 1.5 mg of LG dye will be 
used to prepare LG solution. Dispense saline (about 0.5 to I mL) from the pre-filled syringe to an empty 
sterile microfuge tube. From the microfuge tube, dispense 200 µL of saline solution to an empty 
microfuge tube using 200 µL pipette. Dip 2 LG strips into the microfuge tube containing 200 µL of 
saline. Make sure the impregnated portion of the LG is immersed in the saline solution and leave for 5 
minutes at room temperature for the LG dye to dissolve from strips and enter in the saline solution. 
Afterwards, discard the strips and use the LG solution for staining. Mix the LG solution by finger tapping 
the bottom of the tube.  
Instillation of Lissamine Green 
Take out 5 µL of LG solution from microfuge tube using 5 µL fixed volume pipette attached with sterile 
tip and apply in the lower conjunctival cul-de-sac (inferior conjunctival fornix) by pulling the lower lid to 
make a pocket and instilling the dye. Instruct the subject to blink 5 times and avoid closing eyelids tightly 
or squeezing eyelids after dye instillation and ask to move the eyes in all directions (left, right, up and 
down) while blinking gently to spread the dye.  
Ocular surface staining is recorded 1-2 minutes after dye instillation (within 4 minutes) as the staining 
fades variably after 4 minutes. After slightly pulling down the lower eye lid of the patient, Lissamine 
Green dye will be released into the lower conjunctival sac. The right eye will be evaluated first, and the 
process will be repeated in the left eye.  
Evaluating Lissamine Green Staining 
Using the slit lamp (white light of moderate intensity and a Hoya 25A red barrier filter or Kodak Wratten 
92 filter), corneal and conjunctival staining will be graded using the grading system described below 
modified from the NEI Scale (Lempe 1995).  
The scoring pattern is represented below in Figures 3 and 4. The dots are ordered on a log scale. 


Ocugen 
Protocol version 1.0 
OCU-300-301 
12 July2018 
65 
Figure 3. Lissamine Green Corneal Staining Pattern and Grade (NEI Scale) 
Corneal staining will be graded in 5 zones (Central (3mm), Superior, Inferior, Nasal, and Temporal).  
Each zone will be graded from 0 to 3 based on the density of punctate staining (maximum score = 15). 
Similarly, the 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) (Figure 4). Instruct 
the subject to look toward the midline (nasally) to grade the temporal zone. Likewise, instruct the subject 
to look temporally to grade the nasal conjunctiva. 
Figure 4. Lissamine Green Conjunctival Staining Pattern and Grade (NEI Scale) 
Because Lissamine Green dye can fade variably within 4-5 minutes, results should be recorded within 
approximately 1-2 minutes of application to the eye surface. Scoring is demonstrated in Table 6. 


Ocugen 
 
Protocol version 1.0 
OCU-300-301 
 
12 July2018 
66 
 
  
 
 
Table 6. Corneal and Conjunctival Lissamine Green Scoring 
 
Lissamine 
Green 
Staining 
 
Grade 
Zones 
Maximum Score/Eye  
(all zones) 
 
Cornea 
0-3 
Central (3mm)  
 Superior 
 Inferior 
Nasal 
Temporal   
15 OD 
15 OS 
Conjunctiva 
0-3 
Nasal bulbar 
Temporal bulbar 
6 OS 
6 OD 
The above staining/scale will be measured at each study visit: Screening (conjunctival staining only), Day 
1 Baseline (prior to first dose), Day 14 ± 3d, and Day 28 ± 7d. 
 
 


Ocugen 
 
Protocol version 1.0 
OCU-300-301 
 
12 July2018 
67 
 
 
 Appendix 4. LogMAR Visual Acuity 
 
 Visual Acuity Testing 
It is essential that a standard procedure be used to obtain VA measurements. The VA measurements 
should be obtained by a qualified ophthalmologist, optometrist or trained ophthalmic technician using the 
standard ETDRS charts with light box that will be supplied by the Sponsor. The right eye (OD) 
should be tested first 
 Standard ETDRS Visual Acuity Protocol 
The ETDRS visual acuity charts 1 and 2 are used for standardized measurement of visual acuity. Acuity 
testing of all subjects, regardless of visual acuity, begins at four meters. Two ETDRS Visual Acuity 
Charts are used for the measurement of visual acuity, each with a different letter sequence. The right eye 
will always be tested with Chart 1 and the left eye with Chart 2. Each clinic will have/use an ETDRS light 
box for the ETDRS visual acuity charts during any study acuity testing if the EVA is non-functional. The 
light box should be hung on the wall or placed on a stand at a height such that the top of the 3rd row of 
letters (0.8 LogMAR) is 49 + 2 inches (124.5 + 5.1 cm) from the floor. The distance from the outer 
canthus of the subject’s eye to the front of the ETDRS chart should be 4.0 meters and should be measured 
with a tape measure, tautly held, or a rigid measuring stick. 
To maintain the ETDRS charts in good condition, vision examiners are advised to slide the charts into the 
front slot of the light box, rather than bending the charts, when changing charts in the front compartment 
of the light box. To maintain the high contrast of the white background the ETDRS charts, examiners 
should refrain from touching the front of the charts with their fingers, pens, pencils, etc. If the ETDRS 
charts become permanently damaged or yellowed, they should be replaced. The ETDRS vision testing 
equipment (illuminator cabinet, floor stand with casters, Original Series ETDRS charts, and replacement 
tubes with aluminum sleeves) can be ordered from Precision Vision, 944 First Avenue, La Salle, IL, 
61301, 800-772-9211 (phone). 
 Illumination of Visual Acuity Charts and Room  
Room lighting should be uniform between the subject and the light box.  
The two 20-watt (Cool Daylight) fluorescent tubes in the ETDRS light box must be changed annually; a 
sticker must be affixed to the side or back of the light box with the date that the bulbs were changed. Cool 
Daylight (20-watt) fluorescent tubes can be purchased from a local hardware store. When changing the 
fluorescent tubes, the aluminum fenestrated sleeves must be saved and centered on the new light tubes 
with the opening of the sleeves pointing towards the back of the light box. If the aluminum sleeves are 
discarded, they must be replaced. (Precision Vision, 944 First Avenue, La Salle, IL, 61301, 800-772-
9211 (phone). Furthermore, when changing the fluorescent light tubes, the new tubes must be “burned 
in” (i.e., left on continuously for 4 days or 96 hours) before using the ETDRS light box. 


Ocugen 
 
Protocol version 1.0 
OCU-300-301 
 
12 July2018 
68 
 
 Uncorrected (UCVA) and Best-Corrected VA (BCVA) 
For BCVA, the subject will be fitted with a half eye trial frame provided by the Sponsor, containing the 
manifest subjective refraction result, adjusted for optical infinity.  
 Recording and Scoring VA  
Using the Sponsor supplied recording/scoring sheet, an example of which is shown below, the tester will 
CIRCLE ALL CORRECT RESPONSES, PUT AN “X” THROUGH THE MISSED LETTERS, 
AND INSTRUCT THE SUBJECT TO FINISH READING THE ENTIRE LINE. 
THE SPONSOR-SUPPLIED SCORING SHEET MUST BE KEPT IN THE SUBJECT SOURCE 
RECORD. 
Each line on the ETDRS chart has 5 letters and the number of CORRECT letters will be recorded on the 
recording/scoring sheet in the far-right box on the corresponding line. The lines will then be added up and 
the “TOTAL” number of letters correctly identified will be recorded on the recording/scoring sheet. The 
“TOTAL” is the number that will be entered onto the CRF. For subjects who are unable to see ANY 
letters, or for subjects whose best VA could be recorded as finger count, hand movement, light perception 
or no light perception, a score of “0” will be recorded on both the source document and on the CRF. 
Example: 
For instance, all lines were read correctly through line 7, line 8 had 2 correct responses, and VA 
testing was completed. The total letters correctly identified would be 17 and it would be recorded 
in the space marked “TOTAL” (see Figure 5) 
Figure 5. Visual Acuity logMAR 
 
 
The linked image cannot be displayed.  The file may have been moved, renamed, or deleted. Verify that the link points to the correct file and location.


Ocugen 
 
Protocol version 1.0 
OCU-300-301 
 
12 July2018 
69 
 
 Calculating LogMar from VA Score 
The last line in which a letter is read correctly will be taken as the base logMAR reading. 
To this value will be added the number "N x 0.02" where 'N' represents the total number of 
letters missed up to and including in the last line read. This total sum represents the logMAR 
visual acuity for that eye. 
In the example above: Subject correctly reads 5 of 5 letters on the 0.7 line, and 2 of 5 
letters on the 0.6 line (see Table 7 below). The correct logMar is 0.66 
 
Table 7. Calculation of logMAR from Visual Acuity Worksheet 
Base logMar (The last line in which a letter 
is read correctly) 
0.6 
N (total number of letters incorrect on line 
0.6 as well as 0.7) 
3 
N x T (T = 0.02) 
0.06 
Base logMAR + (N x T) 
0.6 + 0.06 
logMAR VA 
0.66 
Instruct the subject to read the ENTIRE top line, from left to right, to the end of that line, even if letters 
are missed. Circle correct responses and place an "X" through incorrect responses. Have the subject 
continue to read each ENTIRE line down the chart, from left to right, until they miss 3 or more letters on 
one line (even with guessing); or they read the entire chart. 
NOTE: The ENTIRE line must be attempted (even with guessing) even if letters are missed, as the subject 
will get credit for all correct letters on that line. 
The above scale will be measured at Baseline (Day 1, prior to first dose), Day 14 ± 3d, and Day 28 ± 7d. 
 
 


Ocugen 
 
Protocol version 1.0 
OCU-300-301 
 
12 July2018 
70 
 
 
 Appendix 5. Intraocular Pressure (IOP) 
 
Intraocular Pressure (IOP) will be measured in both eyes. IOP will be measured at Screening and at each 
study visit: Day 1 (prior to first dose), Day 14 ± 3d, and Day 28 ± 7d. 
  Calibration of Tonometer 
The Goldmann tonometer shall be used for IOP measurements. The tonometer must be calibrated before 
first use and calibration will be checked by the Investigator prior to measuring IOP for each subject, with 
the weight system at 0, 2, and 6 grams as supplied by the manufacturer. When the calibration steps 
provide readings within ± 0.5 mmHg of the target value for each weight, the tonometer is considered 
adequately calibrated. The investigator must maintain written documentation (e.g., unit model or serial 
number, calibration date, name/initial of person performing calibration, indication of pass or fail) of the 
calibration of each tonometer throughout the study period. 
 
 IOP Measurement 
IOP will be taken as follows: 
1. Anaesthetize the selected eye of the subject. 
2. Stain with sodium fluorescein.  
NOTE – step may be combined by using an anesthetic to which sodium fluorescein has already 
been added. 
3. Set the tonometer drum to a force corresponding to an IOP of 10 mmHg. Wherever possible, do 
not touch the eyelid with the fingers to open the palpebral aperture. If the palpebral aperture is not 
wide enough to allow the tonometer cone to make contact, instruct the subject to open their eyes 
wider. 
4. Direct the subject to view a distance fixation point.  
NOTE – If distance fixation cannot be maintained and near fixation is used, this fact should be 
recorded. 
5. Measure the IOP for the mean of the ocular pulse and remove the tonometer from the eye.  
6. Repeat steps if the measurement was not valid due to the following reasons;  
• 
The patient felt a sensation 
• 
The eyelid was touched 
• 
The fluorescein ring was too broad or too small 
• 
Any other circumstances suggesting that the measurement may have been inaccurate 
7. If there is any evidence that the anesthetic is no longer fully effective, then re-administer 
anesthetic. 
8. Record the IOP, as the mean of 3 valid measures. Measure and record means for OS and OD. 


Ocugen 
 
Protocol version 1.0 
OCU-300-301 
 
12 July2018 
71 
 
 Appendix 6. Slit-Lamp Examination 
Slit-lamp ophthalmic examination will be performed at each clinic visit. The subject should be seated 
with their chin and forehead rested against the chin rest and head support during the examination. 
Fluorescein dye should be instilled into the ocular cul-de-sac to facilitate the examination. The lid, lashes, 
tear film, conjunctiva, sclera, cornea, anterior chamber, iris, lens, and anterior vitreous of the eye will be 
examined and graded as follows in Table 8: 
Table 8. Evaluation of Slit-Lamp Assessments 
Assessment 
Observation 
Evaluation 
External Eyelid Examination  
• 
Eyelid position and character,  
• 
Lashes, lacrimal apparatus and tear function;  
• 
Globe position; and 
• 
Pertinent facial features 
 
Normal 
Abnormal (CS, 
not CS) 
 
Iris 
• 
Pigmentation 
• 
Atrophy/erosion, peaking 
• 
Other 
Normal 
Abnormal (CS, 
not CS) 
 
Cornea 
• 
No Edema / Edema  
• 
Staining  
• 
Erosion 
• 
Fluorescein staining  
Normal: None  
 
Abnormal CS 
 
Abnormal NCS 


Ocugen 
 
Protocol version 1.0 
OCU-300-301 
 
12 July2018 
72 
 
Assessment 
Observation 
Evaluation 
Anterior Chamber Cells  
Grade Aqueous Cells 
Per 1x1 mm slit 
Global 
evaluation 
0 
< 1 cell 
Normal 
0.5+ 
1-5 cells seen in 45 
seconds or 1 minute 
Abnormal  
(CS/NCS) 
 
 
1+ 
6-15 cells seen at once 
2+ 
16-25 cells scattered 
throughout beam 
3+ 
26-50 (Dense 
scattering of cells; too 
many to count) 
4+ 
> 50 or hypopyon 
Grade Flare (Slit Beam) 
Per 1x1 mm slit 
Global 
evaluation 
0 
None; Optically 
empty, compared 
bilaterally 
Normal 
1+ 
Faint haze (any 
appreciable light in 
slit beam) or not equal 
bilaterally 
Abnormal 
CS/NCS 
 
 
2+ 
Moderate: but iris 
details are clear 
through slit beam 
3+ 
Marked: iris and lens 
details hazy 
4+ 
Severe dense haze: 
obvious plasmoid 
aqueous or fibrin 
present in anterior 
chamber 
 
Posterior Segment 
Vitreous, Retina, Macular, Blood Vessels, Optic 
Nerve 
 
Normal: None  
 
Abnormal CS 
 
Abnormal NCS 
 *CS = clinically significant; NCS = not clinically significant 
For any abnormal case, the investigator will determine whether it is clinically significant or not. 


IND # 136132 
OCU310 Brimonidine Tartrate 0.2% Nanoemulsion Annual Report (August 
2018 – July 2019); April 20, 2020 
 
 
 
 
One new clinical study was undertaken during this reporting period (August 
2018 to July 2019). 
The study has been completed.  
Title:  A Phase 3 Randomized, Placebo-Controlled, Double-Masked, Multicenter, 
Safety and Efficacy Study of Brimonidine Tartrate 0.2% Nanoemulsion Eye Drops 
in Patients with Dry Eye Disease (DED) 
 
 
Phase 3 
Name and Address of the Clinical 
Centre 
There were 19 study sites, all in US:  
Chicago Cornea Consultants; Abrams Eye Center; Advanced Laser 
Vision & Surgical Institute; Aesthetic Eye Care Institute/David Wirta, 
MD and Associates; Apex Eye, Apex Eye Clinical Research;  Toyos 
Clinic; Cornea Consultants of Albany:  Heart of America Eye Care, 
P.A.;  Midtown Eye Physicians & Associates; Kannarr Eye Care; 
Martel Medical Eye Group;  Ophthalmology Associates; Rand Eye 
Institute; Revolution Research, Inc; Lake Travis Eye and Laser Center;  
Scott and Christie Eyecare Associates; Shettle Eye Research, Inc.; 
Total Eye Care;  The Eye Institute of Utah. 
For names of Investigators and site addresses, see Appendix 16.1.4 of 
CSR 
Name and Address of the Clinical 
Data Management Centre 
CONTRACT RESEARCH ORGANISATION (CRO) 
Name: 
TFS 
Address: 
Consell de Cent, 334-336 
ES-08009 Barcelona, Spain 
Phone: 
+34 931850200 
Fax: 
     +34 931850257 
CLINICAL DATA MANAGER (TFS) 
Name: 
Eric Fritz  
A. Individual Clinical Study Information 


IND # 136132 
OCU310 Brimonidine Tartrate 0.2% Nanoemulsion Annual Report (August 
2018 – July 2019); April 20, 2020 
 
Address: 
212 Carnegie Center 
Suite 208, Princeton, NJ 08540 
Phone: 
+1 609-455-9219 
E-mail:       Eric.Fritz@tfscro.com 
Name and Address of the Bio- 
analytical Laboratory 
NA 
Name and Address of the Clinical 
Laboratory 
Not Applicable 
(No clinical specimens were required in this study) 
 
The details of studies completed in 2018-19 are 
provided below.  
 
 


IND # 136132 
OCU310 Brimonidine Tartrate 0.2% Nanoemulsion Annual Report (August 
2018 – July 2019); April 20, 2020 
 
 
Title of Study: A Phase 3 Randomized, Placebo-Controlled, Double-Masked, Multicenter, Safety 
and Efficacy Study of Brimonidine Tartrate 0.2% Nanoemulsion Eye Drops in Patients with Dry 
Eye Disease (DED) 
Protocol No.: OCU-310-301 
US IND Number: 136132 
Investigational Product: Brimonidine Tartrate Nanoemulsion, 0.2% Ophthalmic Solution 
(OCU310). 
Control: Placebo (Ophthalmic Buffered Saline; OBS, pH 6-8) 
Purpose of study: To evaluate the safety, tolerability and efficacy of Brimonidine Nanoemulsion 
eye drops (OCU 310) in subjects with Dry Eye Disease (DED) 
Research subject population: Men and women > 18 years of age with a history of DED for at least 
6 months who: 
Demonstrate the following 2 signs of DED in the same eye at screening and baseline (Day 1): 
Conjunctival staining of ≥3 (out of a possible score of 6 per eye) 
Schirmer’s test (with anesthesia) of ≥1 to ≤7 mm in 5 minutes 
Symptomatic evidence of DED by having a global symptom score (overall SANDE) of ≥40 mm 
at screening and baseline (Day 1) 
Current status of study: Completed 
Total number of subjects initially planned for inclusion in the study:  240 subjects in a 1:1 
randomization (120 per study arm).   
Total number of subjects entered into the study to date and demographics:  252 subjects in a 1:1 
randomization (126 per study arm).   
The age (central tendency), gender and race are given in Table 1below. 
 
 
 
 
 
 
 


IND # 136132 
OCU310 Brimonidine Tartrate 0.2% Nanoemulsion Annual Report (August 
2018 – July 2019); April 20, 2020 
Table 1. Demographic characteristics – Randomized set 
OCU 310 
(N=126) 
Placebo 
(N=126) 
Total 
(N=252) 
Age (years) 
na 
126 
126 
252 
Mean (SD) 
61.7 (11.8) 
62.1 (11.6) 
61.9 (11.7) 
Median 
63.0 
63.0 
63.0 
Min, Max 
27, 85 
24, 85 
24, 85 
Gender n (%) 
na 
126 
126 
252 
Male 
20 (15.9) 
21 (16.7) 
41 (16.3) 
Female 
106 (84.1) 
105 (83.3) 
211 (83.7) 
Race n (%) 
na 
126 
126 
252 
White 
101 (80.2) 
111 (88.1) 
212 (84.1) 
Black or African American 
19 (15.1) 
11 (8.7) 
30 (11.9) 
Asian 
4 (3.2) 
3 (2.4) 
7 (2.8) 
American Indian or Alaska Native 
1 (0.8) 
0 (0.0) 
1 (0.4) 
Multipleb 
1 (0.8) 
1 (0.8) 
2 (0.8) 
Ethnicity n (%) 
na 
126 
126 
252 
Hispanic or Latino 
12 (9.5) 
11 (8.7) 
23 (9.1) 
Not Hispanic or Latino 
114 (90.5) 
115 (91.3) 
229 (90.9) 
Source: Table 14.1.4 (Clinical Study Report) 
a Number of subjects with non-missing data. 
b One subject filled in both Asian and Black or African American and one subject filled in both White and Black or African American 
in CRF 
CRF: Case report form; Max: Maximum; Min: Minimum; SD: Standard deviation 
•
Number of subjects whose participation in the study was completed as planned:
•
Of the 252 randomized subjects, 249 completed the study (123 in the OCU 310 group and 126
in the Placebo group).
•
Number of subjects who dropped out of the study early for any reason:
•
Only 3 subjects, all randomized to the OCU 310 group, withdrew from the study. Specifically,
Subjects 305-015 and 322-0009 were lost to follow-up after baseline and were excluded from
the ITT and PP populations, and Subject 314-008 discontinued the study due to two AEs and
was included in the ITT but excluded from the PP population.


IND # 136132 
OCU310 Brimonidine Tartrate 0.2% Nanoemulsion Annual Report (August 
2018 – July 2019); April 20, 2020 
•
Pharmacokinetic (PK) Results:   Not applicable (N/A). No clinical specimens were required in
this study 
Brief description of final or interim study results: 
NOTE:  Efficacy data will be presented in this section (Section A), while safety data will be 
presented in the following section (Section B: Summary Investigational Drug Information).  
Synopsis of the Clinical Study Report (CSR) is included with this IND Annual Report in  
Exhibit I. 
Full clinical study report with Appendices will be submitted later as an information amendment 
to the IND.  


Ocugen, Inc. / Protocol Number OCU-310-301 
Page 1 of 12   
 
«PiFullName» 
XXXX IRB Approved Version xxxxxxxxxxx 
Revised «PIApprovalDate» 
 
 
INFORMED CONSENT  
And AUTHORIZATION to be a RESEARCH SUBJECT FORM 
 
Sponsor / Study Title: 
  
Ocugen, Inc. / “A Phase 3 Randomized, Placebo-Controlled, Double-
Masked, Multicenter, Safety and Efficacy Study of Brimonidine 
Tartrate 0.2% Nanoemulsion Eye Drops in Patients with Dry Eye 
Disease (DED)” 
 
Protocol Number: 
 
OCU-310-301 
Principal Investigator: 
(Study Doctor) 
 
«PiFullName» 
 
Telephone: 
 
«IcfPhoneNumber» 
 
Additional Contact(s): 
(Study Staff) 
 
«AdditionalStaffMemberContacts» 
 
Address: 
«PiLocations» 
 
The study doctor wants to know if you would like to be part of a research study. This form describes the 
study to help you decide whether you want to participate. This form will tell you what you will have to 
do during the study and the risks and benefits of the study.  If you have any questions about, or do not 
understand something in this form, you should ask the study doctor.  Do not sign and date this form 
unless the study doctor or study staff has answered your questions and you decide that you want to be 
part of this study.  When you have completed reading this form, if you would like to take part in this 
study, you will sign the form on the last page, initial and date each page, and hand it back to your study 
doctor.  You should also remember that being in this study does not replace your regular medical care.   
 
WHAT IS THIS STUDY ABOUT? 
You are invited to take part in a research study because your medical history indicates you have Dry Eye 
Disease (DED).  This study is being done to see how safe and effective an investigational product is in the 
treatment of your eye disease. 
 
By participating in this study, you will be helping the study Sponsor evaluate a new therapy for this 
condition.  This investigational drug is an eye drop containing Brimonidine, a drug that has already been 
approved by the FDA for use in patients with glaucoma, but in the form of a nano-emulsion, which 
increases the time that the eye drop can stay on the surface of your eye.  Early studies in animals and 
humans indicate that brimonidine nano-emulsion, also known as OCU310, can relieve the signs and 
symptoms of DED.    This eye drop is being studied to see if it can help you better manage your DED 
symptoms, which may include ocular pain or discomfort, and DED signs, which may include redness. 
 
Your study doctor can explain how this investigational drug is intended to work. Your medical history 
will be reviewed, and you will receive certain standard eye tests to assess the severity of your DED. You 
must be honest with the study doctor about your medical health history or it may not be safe to 
participate in the study. 
 


Ocugen, Inc. / Protocol Number OCU-310-301 
Page 2 of 12   
 
«PiFullName» 
XXXX IRB Approved Version xxxxxxxxxxx 
Revised «PIApprovalDate» 
 
This is a randomized, double-masked study. This means that you will be randomly assigned to receive 
either OCU310 or PLACEBO (inactive substance) study drug. Neither you nor the study doctor will know 
to which study drug you have been assigned. The study is designed in a way that you have a 50/50 
chance of being assigned OCU310.  
 
HOW DO I KNOW IF I CAN BE IN THIS STUDY? 
The first part of the study is called a Screening visit.  You will be required to read, sign and date this 
INFORMED CONSENT and AUTHORIZATION to be a RESEARCH SUBJECT before the Screening visit can 
begin.  The Screening visit will occur 7 days prior to the first day of the study (Day 1). During the 
Screening visit, the study doctor will decide if you qualify to be in the study based on a list of criteria that 
he/she will discuss with you.  Your selection in part will be determined by your age, the condition of 
your current DED, your medical history, health status, your current medications, and your ability to 
participate in all visits and follow-up exams.  You cannot be in this study if you are in another research 
study or if you have been in any other research study in the last 30 days.  You cannot be in this study if 
you are pregnant, or plan on becoming pregnant. A urine test will be performed to check for pregnancy.  
Following your completion of the Screening visit you will be informed of whether you have met the 
eligibility criteria to participate in this study, at which time you can decide again whether to participate 
or not participate.   
 
HOW MANY SUBJECTS IN TOTAL WILL BE ENROLLED AT HOW MANY STUDY CENTERS? 
Approximately two hundred and forty (240) subjects will be enrolled in this study.  This study will be 
conducted at approximately 15 US clinical sites/centers.   
WHAT WILL HAPPEN DURING THIS STUDY? 
The study will involve 4 visits over a period of 5 weeks. The length of each visit will likely take 2 to 4 
hours.   
Subject Responsibilities: 
While participating in this research study, your responsibilities are to: 
• 
Be willing and able to follow the study directions and procedures. 
• 
Tell the study staff about any side effects or problems. 
• 
Ask questions as you think of them. 
• 
Tell the investigator or the study staff if you change your mind about staying in the study. 
• 
Administer your study in drug in both eyes, 2 times a day approximately 12 hours apart. 
• 
Maintain your same lifestyle and routine such as work, exercise and recreation activities, and diet. 
Do not take any new, or change any of your current, eye treatments, vitamins, herbs or supplements 
during the study without first discussing with your study doctor. 
• 
Attend all study visits  
• 
Remain in the clinic for at least 2 to 3 hours after your first drop of study medication 
 
Before the first examination, or before any information can be requested of you, you will have a 
thorough discussion with your doctor about this study.  Following a careful discussion, you will be asked 


Ocugen, Inc. / Protocol Number OCU-310-301 
Page 3 of 12   
 
«PiFullName» 
XXXX IRB Approved Version xxxxxxxxxxx 
Revised «PIApprovalDate» 
 
to sign this INFORMED CONSENT and AUTHORIZATION to be a RESEARCH SUBJECT form.  Your decision 
to be a candidate participant and the signing of this FORM are totally voluntary and up to you.  If you 
agree to be a candidate participant and sign this FORM, the four (4) study visits will involve the 
following:     
 
Screening Visit: 
Before the study starts, you will be asked to sign and date this consent form, give your health 
history, and tell study staff if you have taken any over-the-counter or prescription medicines, 
vitamins, probiotics, herbs or nutritional supplements, or eye-drops.  Your screening examination 
visit will last approximately 2 to 3 hours and must occur 7 days prior to the actual start of the study.  
The study doctor will do some tests to find out if you can be in the study.  These tests are often used 
in the eye clinic and include: 
 
• 
Informed Consent 
• 
Eligibility Criteria 
• 
Demographic Information  
• 
Medical/Surgical/Ocular History 
• 
Review of Prior and Concomitant Medications 
• 
Urine Collection and Pregnancy Test (if applicable) 
• 
Symptom Assessment in Dry Eye (SANDE) 
• 
Slit Lamp Ophthalmic Exam  
• 
Conjunctival Lissamine Green Stain 
• 
Schirmer’s Test with Anesthesia (mm) 
• 
Intraocular Pressure 
• 
Adverse Event Surveillance  
 
Baseline (Day 1) Visit:  During this exam, your current medications and changes in your medical 
history will be discussed and you will receive several routine eye tests. If you continue to meet study 
inclusion criteria you will be given a 28-35 day supply of the study drug and your subject diary. You 
will be instructed on how to administer your first dose of study drug in the clinic, and the staff will 
instruct you on proper methods to place a single drop in each eye, how to record use of the eye 
drops in your diary, storage of your study drugs, and timing of your daily doses.   
 
Before the first dose of medication is given in the clinic, the study doctor will do some tests.  These 
tests include: 
 
• 
Eligibility Criteria  
• 
Medical/Surgical/Ocular History 
• 
Vital Signs 
• 
Review of Prior and Concomitant Medications 
• 
Urine Collection and Pregnancy Test 
• 
Visual Acuity (logMar) 
• 
Symptom Assessment in Dry Eye (SANDE) 
• 
Ocular Redness 100-point VBR Scale via Slit Lamp 
• 
Slit Lamp Opthalmic Exam  
• 
Corneal Lissamine Green Stain 
• 
Conjunctival Lissamine Green Stain  
• 
Schirmer’s Test with Anesthesia (mm) 


Ocugen, Inc. / Protocol Number OCU-310-301 
Page 4 of 12   
 
«PiFullName» 
XXXX IRB Approved Version xxxxxxxxxxx 
Revised «PIApprovalDate» 
 
• 
Intraocular Pressure 
• 
Randomization 
• 
Dispense/Instill IP 
• 
Adverse Event Surveillance  
• 
Diary Recording and Review 
 
There is the possibility that during your screening and baseline (Day 1) visits (Day 1) visit that your 
study doctor could decide that you are ineligible to participate further in the study for a variety of 
reasons. If this happens, you will be dismissed from the study.  
 
Study Day 14 Visit:  This visit occurs approximately 14 days after your first dose of the study drug 
and lasts 2- 4 hours.  During this visit, you will bring your diary to the clinic and it will be reviewed by 
the clinic staff. The study doctor will do some tests to find out how you are progressing in the study.  
These tests include: 
 
• 
Vital Signs 
• 
Review of Prior and Concomitant Medications 
• 
Visual Acuity (logMar) 
• 
Symptom Assessment in Dry Eye (SANDE) 
• 
Ocular Redness 100-point VBR Scale via Slit Lamp 
• 
Slit Lamp Ophthalmic Exam  
• 
Corneal Lissamine Green Stain 
• 
Conjunctival Lissamine Green Stain 
• 
Intraocular Pressure 
• 
Clinical Global Impression (CGI) 
• 
Subject Global Assessment (SGA) 
• 
Adverse Event Surveillance  
• 
Diary Recording and Review 
 
At the end of this visit you will continue to use the initial study drug that was supplied at the Day 1 
Visit.  You will continue to record your use of your eye drops in your diary.  
Study Day 28 Visit:  This visit occurs approximately 28 days after your first dose of the study drug 
and lasts 2- 4 hours.  The assessments are the same as the Day 14 Visit, except there is one more 
test, the Schirmer’s test.  During this visit, you will bring your diary to the clinic and it will be 
reviewed by the clinic staff.   Your current medications, daily dose diary and changes in your medical 
history will be reviewed. Your doctor will conduct tests to see how well you have progressed in the 
study.  These tests include: 
 
• 
Vital Signs 
• 
Review of Prior and Concomitant Medications 
• 
Visual Acuity (LogMar) 
• 
Symptom Assessment in Dry Eye (SANDE) 
• 
Ocular Redness 100-point VBR Scale via Slit Lamp 
• 
Slit Lamp Ophthalmic Exam  
• 
Corneal Lissamine Green Stain 
• 
Conjunctival Lissamine Green Stain 
• 
Schirmer’s Test with Anesthesia (mm) 
• 
Intraocular Pressure 
• 
Clinical Global Impression (CGI) 


Ocugen, Inc. / Protocol Number OCU-310-301 
Page 5 of 12   
 
«PiFullName» 
XXXX IRB Approved Version xxxxxxxxxxx 
Revised «PIApprovalDate» 
 
• 
Subject Global Assessment (SGA) 
• 
Adverse Event Surveillance  
• 
Diary Recording and Review 
 
At the end of the visit you will be DISMISSED from the study. 
 
ARE THERE RISKS TO ME IF I AM IN THIS STUDY? 
Any time you are enrolled in a clinical study, there may be risks, discomfort, and side effects that are not 
yet known.   
As mentioned earlier, this is a randomized, double-masked study. This means that you will be randomly 
assigned to receive either OCU310 or PLACEBO study drug. Neither you nor the study doctor will know 
to which study medication you have been assigned. The study is designed in a way that you have a 
50/50 chance of being assigned OCU310. Neither treatment (OCU310 or Placebo) has a preservative. 
 
The placebo in this study is called “ophthalmic buffered saline” or OBS.  This is similar to “normal saline 
eye drops” or “normal saline solution”.  Normal saline is another name for the kind of saltwater found in 
your body, including tear drops. Some brands of “artificial tears” contain normal saline. Therefore, some 
subjects receiving OBS in this study may experience some temporary relief from their DED symptoms. 
OBS is safe and widely used and no side effects are expected. Like most eye drops, there may be some 
temporary blurring of vision immediately after application, so wait until the blurring clears before 
operating your vehicle or heavy machinery.   
 
The active drug in this study is “Brimonidine Nanoemulsion” or OCU310.  You are encouraged to discuss 
the safety aspects of Brimonidine Nanoemulsion (OCU310) eye drops with your doctor.  
 
Brimonidine is currently approved for use as a treatment for glaucoma.  The FDA approval for 
brimonidine (Alphagan and Alphagan-P) includes data from three clinical studies in a total of 1214 
subjects. Additional safety information is available from 300 peer-reviewed articles involving 
13,983 subjects. In summary, brimonidine tartrate ophthalmic solution of up to 0.2% is considered safe, 
based on the long history of chronic use and data available in the published literature. 
 
In clinical studies on its use for treating glaucoma, the following possible side effects have been reported 
in the approved product label: 
 
• 
10-30% of subjects experienced (in order of frequency):  
o Dry mouth,  
o Red eyes,  
o Burning/stinging in eyes,  
o Headache,  
o Blurring, 
o Eye allergic reactions. 
• 
3-9% of subjects experienced (in order of frequency):  
o Corneal staining,  
o Sensitivity to light,  
o Eyelid redness,  
o Eye pain/irritation. 


Ocugen, Inc. / Protocol Number OCU-310-301 
Page 6 of 12   
 
«PiFullName» 
XXXX IRB Approved Version xxxxxxxxxxx 
Revised «PIApprovalDate» 
 
 
Less commonly, some of the following conditions have been reported: 
• 
Swelling of the eyelid with associated burning and dryness of the eye.  
• 
Swelling of the eyelid along with pink eye. The symptoms of pink eye include a reddening of the 
whites of the eyes, itchy eyes, and thick discharge around the eye, often after sleep. 
Because approved brimonidine (e.g., Alphagan and Alphagan-P) has a preservative, it is possible that 
some of the adverse events listed above are caused by the preservative. Of course, should you have any 
questions about changes in your health and/or vision, you should contact the study doctor or study staff 
immediately.  Please tell the study doctor or study staff right away if you experience any changes in your 
normal routine.  Also, please tell them if you experience any other problems with your health or the way 
you feel during the study 
 
WHAT ARE THE POTENTIAL RISKS AND THEIR LIKELIHOOD FROM USING THIS NEW STUDY DRUG? 
You and your study doctor will discuss the potential risks and likelihood of these risks from the use of 
this new study drug.  This new drug, OCU310, has “brimonidine” as its active ingredient, so the adverse 
events listed above could potentially occur.  Because the new drug, OCUI310, does not have a 
preservative, there will be no adverse events related to preservative. 
The Sponsor has also uncovered the following risks that have been described with eyedrops, in general, 
when used for DED: 
• 
Skin rash on the eyelids 
• 
Pink eye 
• 
Fungal infection from incorrect use of the eye drop 
 
ARE THERE RISKS IF I AM PREGNANT DURING THE STUDY?  
 
Because the effect of this study medication on babies is unknown, you may not participate if you are a 
woman who is pregnant or planning to become pregnant. You may not participate if breast feeding.  
Please inform your study doctor immediately if you become pregnant during the study. If you do 
become pregnant the sponsor will want to follow you to term or termination to collect information 
about your pregnancy and birth.  If you are a female who is able to become pregnant you are required 
to use an acceptable method of birth control (oral contraceptive pills, birth control implants/shots or 
patches, barrier methods) throughout the study.   
WILL BEING IN THIS STUDY HELP ME? 
This new eye drop therapy may help you better manage your DED symptoms, such as eye pain, or signs, 
such as redness, but there is no guarantee that this will occur.  Although being a research subject in this 
study may or may not help you personally, information from this study will help the study Sponsor, 
study doctors and researchers come up with new tests or therapies to help others in the future. 
 


Ocugen, Inc. / Protocol Number OCU-310-301 
Page 7 of 12   
 
«PiFullName» 
XXXX IRB Approved Version xxxxxxxxxxx 
Revised «PIApprovalDate» 
 
NEW FINDINGS: 
If the study doctor learns any new information about the study treatment or your condition that might 
change your mind about continuing in the study, the study doctor or study staff will tell you about it.  
WILL I GET PAID?  
You will be paid up to a total of $xx.xx if you complete this study. You will be paid for the visits you 
complete according to the following schedule: 
• 
$xx.xx for Visits xxx.  
• 
$xx.xx for Visits xxx.   
• 
$xx.xx for Visits xxx.   
 
If you do not complete the study, for any reason, you will be paid for each study visit you do complete.   
 
You will be paid ___________ after each visit 
 
If you have any questions regarding your compensation for participation, please contact the study staff.     
 
WILL I GET PAYMENT IF THE SPONSOR INVENTS NEW TESTS OR THERAPIES?  
No.  If the Sponsor invents new tests or therapies as a result of this study, you will not receive any 
money for these tests or therapies.  The Sponsor will own any new tests or therapies that are developed 
using the data from this study.  
WHAT IF I GET HURT OR SICK WHILE I AM IN THIS STUDY?  
If you become ill or are physically injured as a result of participation in this study, please contact the 
study doctor right away. The study doctor will treat you or refer you for treatment. 
 
The reasonable costs of such treatment beyond that provided by your insurance will be covered by the 
sponsor, Ocugen: 
 
• If you followed instructions, 
• If the injury is related to the study drug or to properly performed study procedures that are 
not part of your usual medical care, 
• If the injury is not the result of the natural course of any underlying disease and/or pre-
existing disease process present prior to the proper administration of the study drug. 
 
In no way does signing this consent form waive your legal rights nor does it relieve the investigators, 
sponsor or involved institutions from their legal and professional responsibilities. 
 
You do not give up any of your legal rights by signing this form. 
 
Be aware that your health care payer/insurer might not cover the costs of study-related injuries or 
illnesses 
 
 


Ocugen, Inc. / Protocol Number OCU-310-301 
Page 8 of 12   
 
«PiFullName» 
XXXX IRB Approved Version xxxxxxxxxxx 
Revised «PIApprovalDate» 
 
DO I HAVE TO BE IN THIS STUDY?  
Your decision to be in this study is totally voluntary.  You do not have to be in this study if you don’t 
want to, and you can change your mind at any time.  If you decide to withdraw before your eye(s) are 
treated then you don’t have to have your eye(s) examined.  If you withdraw from the study after your 
eye(s) have been treated, for your safety, you will be asked to come in for a follow-up visit.  If you 
decide not to participate or decide to participate and then later change your mind, there will be no 
penalty to you, and you won’t lose any benefits to which you are otherwise entitled.  Your regular 
medical care at this study center will not change if you decide not to be in the study or withdraw from it 
after you have agreed to participate.  
WHOM TO CONTACT ABOUT THIS STUDY 
 
During the study, if you experience any medical problems, suffer a research-related injury, or have 
questions, concerns or complaints about the study, please contact the Investigator at the telephone 
number listed on the first page of this consent document.  If you seek emergency care, or hospitalization 
is required, alert the treating physician that you are participating in this research study.   
 
An institutional review board (IRB) is an independent committee established to help protect the rights of 
research subjects.  If you have any questions about your rights as a research subject, and/or concerns or 
complaints regarding this research study, contact: 
 
Study Subject Adviser 
• 
By mail:  
• 
or call toll free:         
• 
or by email:               
 
Please reference the following number when contacting the Study Subject Adviser: XXXXXXX. 
 
ARE THERE OTHER ALTERNATIVE TREATMENTS TO HELP TREAT THE SYMPTOMS OF DED?  
The US FDA has approved treatment for DED. Other current treatments include Restasis, Xiidra, punctal 
plugs, and combinations thereof.  There are also over-the-counter eyedrops, often called “artificial 
tears”. You should talk with the study doctor about other treatments that might help you. 
 
WHO IS PAYING FOR THIS STUDY?  
The Sponsor, Ocugen, Inc. is paying for this study.   
WILL IT COST ANYTHING TO BE IN THIS STUDY?  
You will not be charged for your participation in this study. All study-related procedures and tests, as 
well as study drug, will be given to you free of charge during the time you will be participating in this 
study.  
While you are in the study, if you need to get regular medical care, you (and/or your health care payer) 
will still have to pay for the costs of your regular medical care that are not a part of this study. 


Ocugen, Inc. / Protocol Number OCU-310-301 
Page 9 of 12   
 
«PiFullName» 
XXXX IRB Approved Version xxxxxxxxxxx 
Revised «PIApprovalDate» 
 
WILL INFORMATION ABOUT ME BEING IN THIS STUDY BE USED AND SHARED?  
Yes, selectively as follows: 
• 
Mandatory www.ClinicalTrials.gov Reporting:  A description of this clinical trial will be 
available on http://www.ClinicalTrials.gov, as required by U.S. Law.  This Web site will not 
include information that can identify you.  At most the Web site will include a summary of the 
results.  You are free to search this Web site at any time.   
 
• 
Confidentiality and Protected Health Information (PHI): Protected health information (PHI) 
includes identifying information and any information about your health.  Research personnel 
who are conducting the study may have access to your PHI.   People other than those doing the 
study may look at both medical charts and study records.  These include agencies, your study 
doctor, departments and committees that make rules and policy about how research is done, 
and the sponsors of this study.  Some specific examples include the US FDA, the Office for 
Human Research Protections, the Institutional Review Board, the institution’s Office of 
Research Compliance, and the Clinical Trials Office.  Ocugen the company that will pay for this 
study also will have the right to look at your records.  In addition, records can be opened by 
court order or produced in response to a subpoena or a request for production of documents.  
We will keep any records that we produce private to the extent we are required to do so by 
law.  We will use a study number rather than your name on study records where we can.  Your 
name and other facts that might point to you will not appear when we present this study or 
publish its results.  
 
If you are or have been a patient at one of the study sites, then you will have a medical record at that 
site.  Your medical records and the study records will be maintained separately.  If you are not, and 
never have been, a patient at any of the study sites, then no medical record will be created at that site 
for you just because you are participating in a research study.  
We will put a copy of your signed Informed Consent Form for the Research Study and your signed HIPAA 
Authorization form into any medical record that you may have with any of the research sites.  
Laboratory results and other test results obtained as part of this study may be placed in your medical 
records, if they exist, at the research site. 
 
 
 
 
 
 
 
 


Ocugen, Inc. / Protocol Number OCU-310-301 
Page 10 of 12   
 
«PiFullName» 
XXXX IRB Approved Version xxxxxxxxxxx 
Revised «PIApprovalDate» 
 
 
DO YOU WANT TO BE IN THIS STUDY?  
You have read this form, and you have been able to ask questions about this study.  The study doctor or 
study staff has talked with you about this study.  They have answered all your questions.  You voluntarily 
agree to be in this study.  By signing this form, you have not given up any of your legal rights as a 
research participant.  I understand there will be no penalty to me for making this decision. 
 
 
 
_____________________________________________________________________________________ 
 
SIGNATURE--ORIGINAL STUDY 
 
Subject’s Signature: ______________________________   
 
______________________________ 
Subject’s PRINTED NAME (*as above) 
 
Date(dd/mmm/yyyy)/Time: ____________________ 
 
 
Signature of Person Obtaining Consent: ______________________________ 
 
Person Obtaining Consent – PRINTED NAME: (*as above):  ______________________________ 
 
Date(dd/mmm/yyyy)/Time: _________________


Ocugen, Inc. / Protocol Number OCU-310-301 
Page 11 of 12   
 
«PiFullName» 
XXXX IRB Approved Version xxxxxxxxxxx 
Revised «PIApprovalDate» 
 
AUTHORIZATION TO USE AND DISCLOSE 
PROTECTED HEALTH INFORMATION 
 
If you decide to be in this study, the study doctor and research team will use and share health data 
about you to conduct the study.  Health data may include: 
• 
Your name 
• 
Address 
• 
Phone number 
• 
Date of birth 
• 
Medical history 
• 
Information from your study visits, including all test results  
 
Health data may come from your study records or from existing records kept by your doctor or other 
health care workers.   
 
For this study, the research team may share health data about you with authorized users.  Authorized 
users may include 
• 
Representatives of Ocugen, Inc.  
• 
Representatives of XXXX (an Institutional Review Board, or IRB, that reviews this study). 
• 
The Food and Drug Administration (FDA) and other US federal and state agencies. 
• 
Government agencies to whom certain diseases (like HIV, hepatitis, and STDs) must be reported. 
• 
Governmental agencies of other countries. 
• 
Outside individuals and companies, such as laboratories and data storage companies, that work 
with the researchers and sponsor and need to access your information to conduct this study. 
• 
Other research doctors and medical centers participating in this research, if applicable.  
• 
A data safety monitoring board which oversees this research, if applicable. 
 
Your health data will be used to conduct and oversee the research, including for instance: 
• 
To see if the study drug works and is safe. 
• 
To compare the study drug to other drugs. 
• 
For other research activities related to the study drug. 
 
Once your health data has been shared with authorized users, it may no longer be protected by federal 
privacy law and could possibly be used or disclosed in ways other than those listed here.   
 
Your permission to use and share health data about you will end in 50 years unless you revoke it (take it 
back) sooner.  
 
You may revoke (take back) your permission to use and share health data about you at any time by 
writing to the study doctor at the address listed on the first page of this form.  If you do this, you will not 
be able to stay in this study.  No new health data that identifies you will be gathered after your written 
request is received.  However, health data about you that has already been gathered may still be used 
and given to others as described in this form.   
 
Your right to access your health data in the study records will be suspended during the study to keep 
from changing the study results.  When the study is over, you can access your study health data. 
 
If you decide not to sign this form, you will not be able to take part in the study. 
 


Ocugen, Inc. / Protocol Number OCU-310-301 
Page 12 of 12   
 
«PiFullName» 
XXXX IRB Approved Version xxxxxxxxxxx 
Revised «PIApprovalDate» 
 
STATEMENT OF AUTHORIZATION 
I have read this form and its contents were explained.  My questions have been answered.  I voluntarily 
agree to allow study staff to collect, use and share my health data as specified in this form.  I will receive 
a signed and dated copy of this form for my records.  I am not giving up any of my legal rights by signing 
this form.   
 
____________________________________ 
Printed Name of Subject 
 
____________________________________ 
 
__________ 
Signature of Subject 
 
 
 
 
Date 
 
____________________________________ 
Printed Name of the Person Obtaining the  
Authorization 
 
____________________________________ 
 
__________ 
Signature of the Person Obtaining the  
 
Date 
Authorization  


IND # 136132 
OCU310 Brimonidine Tartrate 0.2% Nanoemulsion Annual Report (August 
2018 – July 2019); April 20, 2020 
 
 
EFFICACY RESULTS:  
Demographic and Baseline Information 
Demographic and other baseline characteristics were comparable between the OCU 310 and 
placebo groups. Demographic and baseline characteristics were well balanced between the two 
treatment groups. Briefly, overall mean (SD) age was 62 (12) year, and the majority of subjects 
were females (84%), and Caucasian (84%). Overall mean time since first DED diagnosis was 
5 years. Compliance to the study treatment was ≥ 80%-≤ 100% for the majority (99%) of subjects, 
and the median number of received doses was the same in the two treatment groups (55). 
Primary Efficacy Endpoints  
Change from baseline to Day 28 in SANDE score 
In the ITT set, both study treatments resulted in a reduction (i.e. improvement) from baseline to 
Day 28 in SANDE overall, and in frequency of symptoms and severity of symptoms scores. None 
of the comparisons of OCU 310 vs. placebo were statistically significant, with estimated mean 
differences between the two treatments (OCU 310 - placebo) of -0.8 mm (p= 0.739) for the overall 
score, -2.7 mm (p= 0.297) for the frequency of symptoms score, and 0.7 mm (p= 0.803) for the 
severity of symptoms score. Results were confirmed in the PP set and, overall, in the subgroups 
(ITT set) analysis for the SANDE overall score with improver subjects, non-improver subjects, as 
well as subjects with SANDE ≥ 60 at baseline, SANDE ≥ median at baseline, VBR ≥ 40 at baseline, 
VBR ≥ 50 at baseline and VBR ≥ median at baseline. 
Change from baseline to Day 28 in lissamine green total conjunctival staining scores 
In the ITT set, both study treatments resulted in a reduction (i.e. improvement) from baseline to 
Day 28 in lissamine green total conjunctival staining scores in both the study eye and qualified 
fellow eye. For the study eye, the comparison OCU 310 vs. placebo was not statistically 
significant, with an estimated mean difference between the two treatments (OCU 310 - placebo) 
of 0.26 (p= 0.097). Results were confirmed in the PP set, and in the subgroups (ITT set) of 
improver and non-improver subjects.  
Secondary and Exploratory Efficacy Endpoints  
None of the secondary or exploratory endpoints demonstrated a statistically significant difference 
in OCU310 vs. control, except for the Validated Bulbar Redness scale (VBR). 
With OCU 310, VBR scores (overall area) for the study eye and the qualified fellow eye decreased 


IND # 136132 
OCU310 Brimonidine Tartrate 0.2% Nanoemulsion Annual Report (August 
2018 – July 2019); April 20, 2020 
 
(i.e. improved) from Baseline. With placebo, mean VBR scores (overall area) remained stable at 
all time points. In the ITT set, mean reductions from baseline in VBR score (overall area) were 
greater with OCU 310 than with placebo at both Day 14 and Day 28, with estimated mean 
differences between treatments (OCU 310 - placebo) of -2.8 (p= 0.006) and -2.6 (p= 0.020), 
respectively. These results were confirmed in the PP set and, in the subgroups, (ITT set) of subjects 
with SANDE ≥ 60 at baseline, VBR ≥ 40 at baseline and VBR ≥ median at baseline.  
 
CONCLUSIONS:  
This study showed that OCU 310 is generally safe and well-tolerated, though it did not meet its 
co-primary endpoints for DED symptom and sign. Importantly, OCU 310 was better than placebo 
in reducing ocular redness, an exploratory sign endpoint, at both Day 14 and Day 28.  
 
 
 
 
1. Safety Data Summary 
 
Only one clinical study (OCU310-301) has been conducted thus far using the investigational drug 
(OCU310): 
 
Title of Study: A Phase 3 Randomized, Placebo-Controlled, Double-Masked, Multicenter, Safety 
and Efficacy Study of Brimonidine Tartrate 0.2% Nanoemulsion Eye Drops in Patients with Dry 
Eye Disease (DED) 
 
This study has been completed. 
 
SAFETY RESULTS:  
Brief Summary of Adverse Events 
All AEs were reported after the first dose of study treatment and therefore, all AEs were TEAEs 
(Table 2). Forty TEAEs (39 unique TEAEs) were reported in 34 (14%) subjects. In the OCU 310 
group, 27 TEAEs were reported in 23 (18%) subjects while 12 TEAEs were reported in 11 (8.7%) 
B. Summary Investigational Drug Information   


IND # 136132 
OCU310 Brimonidine Tartrate 0.2% Nanoemulsion Annual Report (August 
2018 – July 2019); April 20, 2020 
subjects in the placebo group. Regarding treatment related TEAEs, 15 TEAEs were reported in 
12 (9.5%) subjects in the OCU 310 group and 5 TEAEs were reported in 4 (3.2%) subjects in the 
placebo group. TEAEs leading to study treatment discontinuation were reported only in the 
OCU 310 group, 2 TEAEs in 1 (0.8%) subject. The majority of TEAEs reported during the study 
treatment were of mild nature, and none were of severe nature. There were no serious TEAEs, 
including TEAEs leading to death. 
Table 2 Summary of AEs – Safety set 
OCU 310 
(n=126) 
Placebo 
(n=126) 
Total 
(n=252) 
Number of AEs 
27 
13 
40 
Number of unique AEsa 
27 
12 
39 
Number of subjects with at least one AE 
23 (18.3%) 
11 (8.7%) 
34 (13.5%) 
Number of AEs leading to death 
0 
0 
0 
Number of SAEsb 
0 
0 
0 
Number of unique SAEsa 
0 
0 
0 
Number of subjects with at least one SAE 
0 
0 
0 
Number of TEAEs 
27 
13 
40 
Number of unique TEAEs 
27 
12 
39 
Number of subjects with at least one TEAE 
23 (18.3%) 
11 (8.7%) 
34 (13.5%) 
Number of AEs where action taken is Drug discontinued 
2 
0 
2 
Number of subjects with at least one AE where action taken is Drug 
discontinued 
1 (0.8%) 
0 
1 (0.4%) 
Number of related AEsc 
15 
5 
20 
Number of subjects with at least one related AEc 
12 (9.5%) 
4 (3.2%) 
16 (6.3%) 
Source: Table 14.3.1.1 (Clinical Study Report) 
a Unique adverse event = adverse event of a certain PT, counted only once within each subject 
b Including deaths 
c Adverse event with Relationship to study drug 'Definitely Related' or 'Possibly Related' 
AE: Adverse event; PT: Preferred term; SAE: Serious adverse event; TEAE: Treatment-emergent adverse event
As expected, the most common ocular SOC reported during the study treatment was eye disorders, 
17 events in 13 subjects (5.2%). Eye irritation (SOC: eye disorders) and instillation site irritation 
(SOC: general disorders and administration site conditions) were the most common ocular TEAEs, 
4 events in 4 subjects (1.6%) in each TEAE. Amongst the non-ocular TEAEs, the most common 
SOC reported was infections and infestations, 8 events in 8 subjects (3.2%). Three events of 
sinusitis were reported in 3 subjects (1.2%) (Table 3). 


IND # 136132 
OCU310 Brimonidine Tartrate 0.2% Nanoemulsion Annual Report (August 
2018 – July 2019); April 20, 2020 
 
Table 3 TEAEs by SOC and PT – Safety set 
 
Ocular TEAEs 
Non-ocular TEAEs 
 
OCU 310 (n=126) Placebo (n=126) OCU 310 (n=126) Placebo (n=126) 
Total (n=252) 
SOC  
PTa 
No. (%)  
subjects 
No.  
eventsb 
No. (%)  
subjects 
No.  
eventsb 
No. (%)  
subjects 
No.  
eventsb 
No. (%)  
subjects 
No.  
eventsb 
No. (%)  
subjects 
No.  
eventsb 
Blood and lymphatic system disorders 
 
 
 
 
1 (0.8%) 
1 
 
 
1 (0.4%) 
1 
 
Anemia 
 
 
 
 
1 (0.8%) 
1 
 
 
1 (0.4%) 
1 
Eye disorders 
8 (6.3%) 
11 
5 (4.0%) 
6 
 
 
 
 
13 
(5.2%) 
17 
 
Conjunctival hemorrhages 
 
 
1 (0.8%) 
1 
 
 
 
 
1 (0.4%) 
1 
 
Corneal disorder 
1 (0.8%) 
1 
 
 
 
 
 
 
1 (0.4%) 
1 
 
Dry eye 
2 (1.6%) 
2 
 
 
 
 
 
 
2 (0.8%) 
2 
 
Episcleritis 
1 (0.8%) 
1 
 
 
 
 
 
 
1 (0.4%) 
1 
 
Eye irritation 
3 (2.4%) 
3 
1 (0.8%) 
1 
 
 
 
 
4 (1.6%) 
4 
 
Eye pruritus 
1 (0.8%) 
1 
1 (0.8%) 
1 
 
 
 
 
2 (0.8%) 
2 
 
Lacrimation increased 
1 (0.8%) 
1 
1 (0.8%) 
1 
 
 
 
 
2 (0.8%) 
2 
 
Photophobia 
1 (0.8%) 
1 
 
 
 
 
 
 
1 (0.4%) 
1 
 
Vision blurred 
1 (0.8%) 
1 
2 (1.6%) 
2 
 
 
 
 
3 (1.2%) 
3 
Gastrointestinal disorders 
 
 
 
 
2 (1.6%) 
2 
 
 
2 (0.8%) 
2 
 
Dry mouth 
 
 
 
 
1 (0.8%) 
1 
 
 
1 (0.4%) 
1 
 
Gastroesophageal reflux 
disease 
 
 
 
 
1 (0.8%) 
1 
 
 
1 (0.4%) 
1 
General disorders and administration 
site conditions 
3 (2.4%) 
3 
1 (0.8%) 
1 
1 (0.8%) 
1 
 
 
5 (2.0%) 
5 
 
Instillation site irritation 
3 (2.4%) 
3 
1 (0.8%) 
1 
 
 
 
 
4 (1.6%) 
4 
 
Pain 
 
 
 
 
1 (0.8%) 
1 
 
 
1 (0.4%) 
1 
Immune system disorders 
 
 
 
 
1 (0.8%) 
1 
 
 
1 (0.4%) 
1 
 
Rubber sensitivity 
 
 
 
 
1 (0.8%) 
1 
 
 
1 (0.4%) 
1 
Infections and infestations 
 
 
 
 
4 (3.2%) 
4 
4 (3.2%) 
4 
8 (3.2%) 
8 
 
Bronchitis 
 
 
 
 
1 (0.8%) 
1 
 
 
1 (0.4%) 
1 
 
Gastroenteritis viral 
 
 
 
 
 
 
1 (0.8%) 
1 
1 (0.4%) 
1 
 
Pneumonia 
 
 
 
 
1 (0.8%) 
1 
 
 
1 (0.4%) 
1 
 
Sinusitis 
 
 
 
 
1 (0.8%) 
1 
2 (1.6%) 
2 
3 (1.2%) 
3 
 
Upper respiratory tract 
infection 
 
 
 
 
1 (0.8%) 
1 
1 (0.8%) 
1 
2 (0.8%) 
2 
Musculoskeletal and connective tissue 
disorders 
 
 
 
 
1 (0.8%) 
1 
 
 
1 (0.4%) 
1 
 
Costochondritis 
 
 
 
 
1 (0.8%) 
1 
 
 
1 (0.4%) 
1 
Nervous system disorders 
 
 
 
 
2 (1.6%) 
2 
 
 
2 (0.8%) 
2 
 
Dizziness 
 
 
 
 
1 (0.8%) 
1 
 
 
1 (0.4%) 
1 
 
Hypoaesthesia 
 
 
 
 
1 (0.8%) 
1 
 
 
1 (0.4%) 
1 
Respiratory, thoracic, and mediastinal 
disorders 
 
 
 
 
1 (0.8%) 
1 
 
 
1 (0.4%) 
1 


IND # 136132 
OCU310 Brimonidine Tartrate 0.2% Nanoemulsion Annual Report (August 
2018 – July 2019); April 20, 2020 
Ocular TEAEs 
Non-ocular TEAEs 
OCU 310 (n=126) Placebo (n=126) OCU 310 (n=126) Placebo (n=126) 
Total (n=252) 
SOC 
PTa 
No. (%) 
subjects 
No. 
eventsb 
No. (%) 
subjects 
No. 
eventsb 
No. (%) 
subjects 
No. 
eventsb 
No. (%) 
subjects 
No. 
eventsb 
No. (%) 
subjects 
No. 
eventsb 
Cough 
1 (0.8%) 
1 
1 (0.4%) 
1 
Skin and subcutaneous tissue disorders 
1 (0.8%) 
1 
1 (0.4%) 
1 
Rash 
1 (0.8%) 
1 
1 (0.4%) 
1 
Source: Table 14.3.1.6 (Clinical Study Report) 
Subjects are counted once for each PT, and once for each SOC this preferred term belongs to. Thus, one subject can have 
one or more PT reported under a given SOC. Consequently, the total number of subjects by PT can be higher than the total 
number of subjects in that specific SOC. 
aText from MedDRA version 21.1 
bAEs are counted once per subject and PT. 
AE: Adverse event; MedDRA: Medical Dictionary for Regulatory Activities; PT: Preferred term; SOC: System organ class; 
TEAE: Treatment-emergent adverse event 
Treatment-related TEAEs were reported in 9.5% of subjects in the OCU 310 group and in 3.2% of 
subjects in the placebo group. In the OCU 310 group, treatment-related TEAEs reported in > 1 
subject were of ocular nature: “dry eye” and “instillation site irritation” (in 1.6% and 2.4% of 
subjects, respectively). In the placebo group, treatment related TEAEs were reported at most in 1 
subject.  
Most treatment-related TEAEs were of mild intensity (OCU310: 12 out of 15; Placebo: 5 out of 
5), and none were severe. Notably, two treatment-related ocular TEAEs of moderate intensity 
(PTs: lacrimation increased and eye irritation) in the OCU 310 group led to study treatment 
discontinuation of one subject (Subject 314-008), and accounted for all TEAEs leading to study 
treatment discontinuation of the study. Both events resolved by the end of the study without 
corrective treatment. 
Overall, no safety concerns were identified in this study. 
2. Summary of all IND Safety Reports submitted during the previous year:
No IND safety reports have been submitted during this reporting period.
3. List of research subjects who died during participation in clinical studies of the
investigational drug (i.e., inclusive of all clinical studies conducted under the IND)
No subject died during participation in clinical studies of the investigational drug under
the IND.
4. List of research subjects whose participation in clinical studies of the investigational
drug was terminated in association with an adverse experience (i.e., inclusive of all


IND # 136132 
OCU310 Brimonidine Tartrate 0.2% Nanoemulsion Annual Report (August 
2018 – July 2019); April 20, 2020 
 
clinical studies conducted under the IND):  
 
There were no deaths and no Serious Adverse Events (SAEs).  
As mentioned, two (2) treatment-related ocular TEAEs of moderate intensity (PTs: lacrimation 
increased and eye irritation) in the OCU 310 group led to study treatment discontinuation of one 
subject (Subject 314-008), and accounted for all TEAEs leading to study treatment 
discontinuation of the study. Both events resolved by the end of the study without corrective 
treatment. 
 
5. Description of new information pertinent to understanding the actions of the 
investigational drug: 
 
None. 
 
6. List of preclinical studies (including in-vitro and animal studies) completed or in 
progress during the past year, and a summary of major preclinical findings:  
In IND application, Ocugen submitted result of a GLP-compliant ocular irritation study 
conducted in rabbits to assess local tolerability of 0.18% brimonidine tartrate formulation 
(OCU300) to establish overall tolerance of “OCU310”-similar formulation with 0.2% 
brimonidine tartrate. In addition, data from single and 14-day repeat dose biodistribution and 
toxicokinetic studies of 0.18% brimonidine tartrate nanoemulsion were included with original 
IND submission, which provides a comparative outlook of pharmacokinetic and toxicokinetic 
profile of brimonidine in nanoemulsion formulation. Results for above studies submitted with 
OCU310 IND application. No additional preclinical study was conducted during reporting 
period (August 2018 – July 2019).


IND # 136132 
OCU310 Brimonidine Tartrate 0.2% Nanoemulsion Annual Report (August 
2018 – July 2019); April 20, 2020 
 
 
 
7. Summary of any significant manufacturing or microbiological changes made during 
the past year:  
No significant manufacturing or microbiological changes are made during the past year. All 
the stability results for OCU310 Clinical Drug Product Batch and Ophthalmic Buffered 
Saline (placebo) are satisfactory.  
The following stability tables are included in Exhibit II: 
 
• OCU310 Clinical Drug Product Batch (18E38) at Long Term Storage Condition 
(25°C ± 2C/40% RH ± 5%) for 12 months 
• OCU310 Clinical Drug Product Batch (18E38) at Accelerated Storage Condition 
(40°C ± 2C/NMT25% RH) for 12 months 
• Ophthalmic Buffered Saline Batch (18CL8) at Long Term Storage Condition 
(25°C ± 2C/60% RH ± 5%) for 18 months 
• Ophthalmic Buffered Saline Batch (18CL8) at Long Term Storage Condition 
(25°C ± 2C/40% RH ± 5%) for 18 months 
• Ophthalmic Buffered Saline Batch (18CL8) at Accelerated Storage Condition 
(40°C ± 2°C/NMT25% RH) for 6 months 
 
 
 
 


IND # 136132 
OCU310 Brimonidine Tartrate 0.2% Nanoemulsion Annual Report (August 
2018 – July 2019); April 20, 2020 
 
 
 
1. Rationale for the investigational drug or the research study (studies): 
The proposed studies are conducted to support the submission of 505(b) (2) New Drug 
Application for OCU310. This Annual Report covers the only clinical study the Sponsor has 
conducted thus far using OCU310:  
A Phase 3 Randomized, Placebo-Controlled, Double-Masked, Multicenter, Safety and Efficacy 
Study of Brimonidine Tartrate 0.2% Nanoemulsion Eye Drops in Patients with Dry Eye 
Disease (DED) 
Currently, the only FDA-approved pharmaceutical agents for the treatment of DED are 
Restasis®, Cequa™ and Xiidra®. Given the complexity, severity and frequency of DED, and 
the limited modes of action by which these three products treat DED, there is a medical need for 
other DED therapies, particularly those with multiple modes of action that target the wider DED 
population and are effective and safe for early relief and long-term daily use. 
Brimonidine tartrate ophthalmic solution 0.2% is an FDA-approved product that has 
demonstrated a robust safety profile via topical ocular delivery in subjects with open-angle 
glaucoma or ocular hypertension, with a low occurrence of adverse events (AEs). It was also 
shown to be safe and tolerable, while demonstrating preliminary efficacy, in a Phase 2 
proof-of-concept study in subjects with DED conducted in 2017. 
OCU 310 is a sterile, preservative-free solution of brimonidine tartrate 0.2% in an ophthalmic 
nanoemulsion. It was developed for topical instillation in the eye to provide relief of the signs 
and symptoms of DED. To support the proposed indication, efficacy in both a sign and a 
symptom of DED are expected to be demonstrated in phase 3 studies. In the above-mentioned 
Phase 2 study of DED, positive efficacy signals were observed across multiple endpoints, 
consistent with the hypothesis that brimonidine works through multiple mechanistic pathways. 
The present study is further supported by the long-term safety profile of marketed brimonidine 
tartrate, the tolerability of brimonidine 0.2% in the Phase 2 study of DED and the added 
pharmaceutical benefits of the preservative-free nanoemulsion.  
2. 
Indication(s) to be studied:  
Relief of signs and symptoms of dry eye disease 
3. 
General approach to be followed in evaluating the investigational drug: 
C. General investigational plan  


IND # 136132 
OCU310 Brimonidine Tartrate 0.2% Nanoemulsion Annual Report (August 
2018 – July 2019); April 20, 2020 
 
The General Investigational Plan for evaluating the investigational drug remains same as 
submitted in the original IND submission.  
4. 
Types of clinical studies to be conducted in the following year: 
The clinical studies proposed to be conducted are as follows:  
None 
5. 
Estimated number of patients or subjects who will be administered the 
investigational drug under these studies during the following year: 
Number of subjects: None 
6. 
Anticipated significant risks of study participation: 
OCU310 was safe and well tolerated in the above-mentioned phase 3 study. No additional 
OCU310 studies are planned in the upcoming year. If a future OCU310 study is conducted, 
Ocugen does not anticipate any significant risks to the subjects enrolling in that study, based on 
the prior history of the drug and known clinical experience.  
 
 
 
 
 
 


IND # 136132 
OCU310 Brimonidine Tartrate 0.2% Nanoemulsion Annual Report (August 
2018 – July 2019); April 20, 2020 
 
 
The Investigator’s Brochure is the same as the one submitted in the IND. No revision planned 
at this time and if any revisions are made, will be submitted at subsequent annual status update.  
 
 
D. Investigator Brochure Revisions 


IND # 136132 
OCU310 Brimonidine Tartrate 0.2% Nanoemulsion Annual Report (August 
2018 – July 2019); April 20, 2020 
 
 
None 
 
 
None. 
E. Protocol Modifications 
F. Foreign Market Developments 


IND # 136132 
OCU310 Brimonidine Tartrate 0.2% Nanoemulsion Annual Report (August 
2018 – July 2019); April 20, 2020 
 
 
None. 
G. Outstanding business with respect to IND 


 
This study was performed in compliance with Good Clinical Practice (ICH E6). 
 
This Clinical Study Report contains privileged or confidential information which is the property of the 
Sponsor. Information may not be disclosed to a third party without written authorisation from the Sponsor. 
 
1 
TITLE PAGE 
CONFIDENTIAL 
CLINICAL STUDY REPORT 
SYNOPSIS 
 
 
A Phase 3 Randomized, Placebo-Controlled, Double-Masked, Multicenter, Safety 
and Efficacy Study of Brimonidine Tartrate 0.2% Nanoemulsion Eye Drops in 
Patients with Dry Eye Disease (DED) 
 
Study code: 
OCU-310-301 
Study 
development 
phase: 
Phase 3 
IND number: 
136132 
Investigational 
medicinal product: 
OCU 310 (Brimonidine 
Tartrate 
Ophthalmic 
Nanoemulsion 0.20%) 
Indication: 
Relief of signs and symptoms of dry eye disease 
First subject first visit: 
December 4th, 2018 
Last subject last visit: 
February 25th, 2019 
Version: 
Final 
Date: 
January 24th, 2020 
 
 
 
 
 
 


Clinical Study Report 
Sponsor: Ocugen, Inc. 
Version: Final 
Study Code: OCU-310-301 
Date: January 24th, 2020 
IND No.: 136132 
Confidential 
Page 2 of 11 
2 
SYNOPSIS 
Name of the Sponsor/Company: 
Ocugen, Inc. 
Individual Study Table 
Referring to Module 5 of the 
Dossier 
 
Volume:  
Page:  
Study No.:  
(For National Authority Use only) 
 
Name of Finished Product: 
OCU 310 
Name of Active Ingredient: 
Brimonidine tartrate 0.2% 
STUDY CODE: OCU-310-301 
TITLE OF STUDY: 
A Phase 3 Randomized, Placebo-Controlled, Double-Masked, Multicenter, Safety and Efficacy Study of 
Brimonidine Tartrate 0.2% Nanoemulsion Eye Drops in Patients with Dry Eye Disease (DED) 
INVESTIGATORS:  
Dr. Parag Majmudar, Dr. Marc Abrams, Dr. William Lipsky, Dr. David Wirta, Dr. Robert Benza, Dr. Karen 
Klugo, Dr. Melissa Toyos, Dr. Robert Schultze, Dr. Brenda Edwards, Dr. Emelike Agomo, Dr. Shane 
Kannarr, Dr. Joseph Martel, Dr. Ranjan Malhotra, Dr. William Rand, Dr. Kyle Rhodes, Dr. Daniel Zimmer, 
Dr. Lee Shettle, Dr. David Evans, Dr. Darcy Wolsey. 
STUDY SITES:  
Chicago Cornea Consultants, Abrams Eye Center, Advanced Laser Vision & Surgical Institute, Aesthetic 
Eye Care Institute/David Wirta, MD and Associates, Apex Eye, Apex Eye Clinical Research, Toyos 
Clinic, Cornea Consultants of Albany, Heart of America Eye Care, P.A., Midtown Eye Physicans & 
Associates, Kannarr Eye Care, Martel Medical Eye Group, Ophthalmology Associates, Rand Eye 
Institute, Revolution Research, Inc ; Lake Travis Eye and Laser Center, Scott and Christie Eyecare 
Associates, Shettle Eye Research, Inc., Total Eye Care, The Eye Institute of Utah. 
PUBLICATION (REFERENCE):  
Not applicable at the date of this report 
STUDY PERIOD (YEARS):  
Date of first subject first visit: December 4th, 2018 
Date of last subject last visit: February 25th, 2019 
PHASE OF DEVELOPMENT:  
Phase 3 
OBJECTIVES: 
The primary objective of this study was to evaluate the safety, tolerability and efficacy of Brimonidine 
Nanoemulsion eye drops (OCU 310) in subjects with DED. 
Endpoints: 
Primary and secondary endpoints were evaluated in a hierarchical fashion 
Two primary efficacy endpoints were to be tested: 
1. Change from baseline to 4 weeks (Day 28) in Symptom Assessment iN Dry Eye (SANDE) score 
2. Change from baseline to 4 weeks (Day 28) in lissamine green conjunctival staining scores 
Four secondary efficacy endpoints were also to be tested: 
3. Change from baseline to 2 weeks (Day 14) in SANDE score 
4. Change from baseline to 2 weeks (Day 14) in lissamine green conjunctival staining scores 
5. Change from baseline to 4 weeks (Day 28) in lissamine green corneal staining scores 
6. Change from baseline to 2 weeks (Day 14) in lissamine green corneal staining scores 


Clinical Study Report 
Sponsor: Ocugen, Inc. 
Version: Final 
Study Code: OCU-310-301 
Date: January 24th, 2020 
IND No.: 136132 
Confidential 
Page 3 of 11 
Name of the Sponsor/Company: 
Ocugen, Inc. 
Individual Study Table 
Referring to Module 5 of the 
Dossier 
 
Volume:  
Page:  
Study No.:  
(For National Authority Use only) 
 
Name of Finished Product: 
OCU 310 
Name of Active Ingredient: 
Brimonidine tartrate 0.2% 
Exploratory efficacy endpoints: 
• Change from baseline to 4 weeks (Day 28) in Schirmer’s scores 
• Change in appearance from baseline to 4 weeks (Day 28) on the Validated Bulbar Redness (VBR) scale 
• Change in appearance from baseline to 2 weeks (Day 14) on the VBR scale 
• Clinical Global Impression (CGI) of change in symptoms from baseline (physician’s rating) to 4 weeks 
(Day 28) 
• Subject Global Assessment (SGA) of overall change from baseline (subject’s rating) to 4 weeks (Day 
28) 
• Change from baseline to 2 weeks (Day 14) and 4 weeks (Day 28) in temporal bulbar lissamine green 
conjunctival staining scores 
• Change from baseline to 2 weeks (Day 14) and 4 weeks (Day 28) in nasal bulbar lissamine green 
conjunctival staining scores 
Safety endpoints: 
• Vital Signs (systolic and diastolic blood pressure, temperature, pulse and respiration rates) 
• Best Corrected Visual Acuity 
• Ophthalmic Examination (Slit Lamp) 
• Intraocular Pressure (IOP) 
• Rate of serious adverse events (SAEs), adverse events (AEs) and treatment-emergent adverse 
event (TEAEs) (ocular/non-ocular) 
METHODOLOGY:  
This was a randomized, placebo-controlled, double-masked, multicenter phase 3 study in the United 
States. Upon meeting the eligibility criteria, enrolled subjects with a history of DED were randomly 
assigned in a 1:1 fashion to receive either OCU 310 (brimonidine tartrate 0.2% nanoemulsion eye drops) 
or ophthalmic buffered saline (placebo). 
Four study visits were planned: Day -7 ±1 day (screening visit), Day 1 (randomization/baseline), Day 14 
± 3 days and Day 28 ± 7 days. An attempt was to be made to schedule subject visits for approximately 
the same time during the day. Signed informed consent was obtained from each subject prior to the 
commencement of any study procedures.  
Subjects received the first dose of medication on Day 1 at the study site. Study treatment was dispensed 
to subjects on Day 1 for self-administration during the study. 
Subjects were provided with diaries to record twice daily dosing. Doses were to be administered 
approximately 12 hours apart. In addition, subjects were asked to make note of any missed doses 
together with the reason for missing the dose. 


Clinical Study Report 
Sponsor: Ocugen, Inc. 
Version: Final 
Study Code: OCU-310-301 
Date: January 24th, 2020 
IND No.: 136132 
Confidential 
Page 4 of 11 
Name of the Sponsor/Company: 
Ocugen, Inc. 
Individual Study Table 
Referring to Module 5 of the 
Dossier 
 
Volume:  
Page:  
Study No.:  
(For National Authority Use only) 
 
Name of Finished Product: 
OCU 310 
Name of Active Ingredient: 
Brimonidine tartrate 0.2% 
NUMBER OF SUBJECTS (planned and analysed): 
 
OCU 310 
Placebo 
Total 
No. planned: 
120 
120 
240 
No. screened: 
 
 
401 
No. randomized and treated: 
126 
126 
252 
Males/females: 
20 (16%)/106 (84%) 
21 (17%)/105 (83%) 
41 (16%)/211 (84%) 
Mean age (range), years: 
62 (28) 
62 (25)  
62 (25) 
No. analyzed for efficacy 
(ITT/PP): 
124/123 
124/124 
248/247 
No. analyzed for safety:  
126 
126 
252 
No. who completed the study: 
123 
126 
249 
DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION:  
Subjects had to meet all the following inclusion criteria to be eligible to enroll in the clinical trial: 
1) Aged 18 years or older 
2) Sign and date informed consent form approved by the institutional review board (IRB) 
3) History of DED for ≥6 months 
4) Demonstrate the following 2 signs of DED in the same eye at screening and baseline (Day 1): 
a) Conjunctival staining of ≥3 (out of a possible score of 6 per eye) 
b) Schirmer’s test (with anesthesia) of ≥1 to ≤7 mm in 5 minutes 
5) Symptomatic evidence of DED by having a global symptom score (overall SANDE) of ≥40 mm at 
screening and baseline (Day 1) 
6) Intraocular pressure (IOP) ≥5 mmHg and ≤22 mmHg in each eye 
7) Women who satisfied one of the following: 
a) Were women of child-bearing potential (WOCP) who were not pregnant or lactating and who 
were 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 28) 
b) Were post-menopausal or had undergone a sterilization procedure 
The subjects did not meet any of the following criteria: 
1. Allergic to brimonidine or any similar products, or excipients of brimonidine 
2. Use of contact lenses within 14 days prior to the screening visit or planned use during the 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 the screening visit 
5. IOP <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 


Clinical Study Report 
Sponsor: Ocugen, Inc. 
Version: Final 
Study Code: OCU-310-301 
Date: January 24th, 2020 
IND No.: 136132 
Confidential 
Page 5 of 11 
Name of the Sponsor/Company: 
Ocugen, Inc. 
Individual Study Table 
Referring to Module 5 of the 
Dossier 
 
Volume:  
Page:  
Study No.:  
(For National Authority Use only) 
 
Name of Finished Product: 
OCU 310 
Name of Active Ingredient: 
Brimonidine tartrate 0.2% 
9. Punctal occlusion within 3 months prior to the screening visit or during the 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, or others who could be considered vulnerable 
populations 
13. Received corticosteroid-containing eye drops within the past 14 days prior to the screening visit or 
planned use during the study 
14. Any change in systemic corticosteroids/immunosuppressives, cyclosporine A 0.05% ophthalmic 
emulsion (Restasis®), cyclosporine 0.09% ophthalmic solution (Cequa™) or lifitegrast 5% ophthalmic 
solution (Xiidra®) within 30 days prior to the screening visit or planned change during study 
15. In the opinion of the Investigator or Study Coordinator, unwilling or unable to comply with the study 
protocol or unable to successfully instill eye drops 
16. Disease, condition or disorder that in the judgement of the Investigator could confound study 
assessments or limit compliance with the study protocol 
Note: Subjects were permitted to continue all their current ocular treatments, including the use of artificial tears, eyelid massage or 
warm compresses, if they committed to using the same brand/regimen throughout the study. No ocular treatment, including 
Restasis®, Cequa™, Xiidra® and study treatment, was to be used within 5 minutes of another ocular treatment during the study. 
Study treatment was not to be used within 2 hours prior to any study visit. 
TEST PRODUCTS, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBER: 
OCU 310, one drop per eye every ~12 hours (i.e. twice daily dosing). OCU 310 contains 0.2% 
brimonidine tartrate. It was self-administered by participating subjects using an eye dropper. Batch 
numbers were 18R0040 and 18R0054. Average drop size was 35µL (typical range: 20-70 µL). 
DURATION OF TREATMENT: 28 days 
REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBER:  
Placebo eye drops containing ophthalmic buffered saline (OBS), one drop per eye every ~12 hours (i.e. 
twice daily dosing). Placebo eye drops were self-administered by participating subjects using an eye 
dropper. Batch numbers were 18R0040 and 18R0054. Drop size of reference therapy presumed to be 
similar to that of test product, given identical dosing vials and near equivalent drop density. 
CRITERIA FOR EVALUATION: 
EFFICACY:  
• SANDE score 
• Lissamine green conjunctival and corneal staining score 
• Schirmer’s score 
• VBR scale 
• CGI 
• SGA 
SAFETY:  
• AEs (from the time of informed consent completion through the completion of the study) 
• Monocular visual acuity (Early Treatment Diabetic Retinopathy Study chart) 
• IOP (Goldmann applanation tonometry) 
• Slit Lamp examination of the conjunctiva, cornea, anterior chamber, lens and anterior vitreous 


Clinical Study Report 
Sponsor: Ocugen, Inc. 
Version: Final 
Study Code: OCU-310-301 
Date: January 24th, 2020 
IND No.: 136132 
Confidential 
Page 6 of 11 
Name of the Sponsor/Company: 
Ocugen, Inc. 
Individual Study Table 
Referring to Module 5 of the 
Dossier 
 
Volume:  
Page:  
Study No.:  
(For National Authority Use only) 
 
Name of Finished Product: 
OCU 310 
Name of Active Ingredient: 
Brimonidine tartrate 0.2% 
• Vital signs: diastolic blood pressure (DBP), systolic blood pressure (SBP), heart rate (HR), respiratory 
rate and body temperature (forehead) 
STATISTICAL METHODS:  
The following analysis sets were defined: 
• Randomized set: All randomized subjects who previously signed the informed consent. 
• Safety set: All subjects in the Randomized set who received at least one dose of the Investigational 
Medicinal Product. 
• Intention-To-Treat (ITT) set: All subjects in the Safety set with at least one post-baseline efficacy 
measurement.  
• Per protocol (PP) set: All subjects in the ITT set who fulfilled the study protocol requirements with no 
major deviations that may affect study results. 
Unit of Analysis 
The unit of analysis for variables measured at the individual eye level was the study eye. Each subject 
had a single eye identified as the study eye as follows: (i) if only 1 eye met inclusion criteria, this eye 
was the study eye and the other eye was considered the non-qualified fellow eye; (ii) if both eyes met 
inclusion criteria, the eye with the higher lissamine green conjunctival staining score was the study eye 
and the other eye was considered the qualified fellow eye; (iii) if both eyes had the same lissamine green 
conjunctival staining score, then the eye with the lower Schirmer’s score was the study eye and the 
other eye was considered the qualified fellow eye; (iv) if both eyes had same Schirmer’s score, the right 
eye was the study eye and the other eye was considered the qualified fellow eye.  
Analysis of primary and secondary endpoints 
The analysis of the six primary/secondary outcomes employed a Mixed Model for Repeated 
Measurements (MMRM) with mean change from baseline score (Day 28 for Primary, Day 28 and 14 for 
Secondary) as the response (dependent variable) with baseline value as a covariate and treatment, 
visit, and treatment-by-visit interaction as fixed effects (independent variables).  
The treatment comparisons (OCU 310 vs. Placebo) were carried out by means of the contrasts on the 
treatment factor by visit effect in SAS® Software, using proc mixed. Treatment effects were estimated 
by means of Least Square Means and 95% confidence interval (CI). Differences between treatments 
were estimated and resulting 2-sided p-values and associated 95% CI were presented. 
Primary and Secondary efficacy analyses were conducted primarily on the ITT set and repeated in the 
PP set for sensitivity purposes. For efficacy endpoints where measurements from both eyes were 
available, the study eye was used for the analyses. 
Results of all primary and secondary analyses are graphically displayed as Forest Plots. 
Sites with low enrollment were collapsed into pseudo sites for the primary efficacy analysis. Sites with 
the smallest number of enrolled subjects were combined until a minimum of 10 subjects per pseudo site 
was achieved, with the restriction that no pseudo site created by pooling exceeded the average number 
of subjects in the set of original sites with 10 or more subjects enrolled. 
For key efficacy endpoints (SANDE, lissamine green conjunctival staining, CGI and SGA) two sub-groups 
were compared: Improvers vs. Non-Improvers. While all subjects enrolled were to satisfy eligibility criteria 
at both Screening and Baseline Visits, some study-eligible subjects (Improvers) may have clinically 
improved from the Screening Visit to the Baseline Visit, and this may dilute the overall treatment effect. 


Clinical Study Report 
Sponsor: Ocugen, Inc. 
Version: Final 
Study Code: OCU-310-301 
Date: January 24th, 2020 
IND No.: 136132 
Confidential 
Page 7 of 11 
Name of the Sponsor/Company: 
Ocugen, Inc. 
Individual Study Table 
Referring to Module 5 of the 
Dossier 
 
Volume:  
Page:  
Study No.:  
(For National Authority Use only) 
 
Name of Finished Product: 
OCU 310 
Name of Active Ingredient: 
Brimonidine tartrate 0.2% 
The definitions of Improver and Non-Improver were pre-specified in the Statistical Analysis Plan.  
Post hoc subgroup analyses were also done, based on several baseline cut-off values for SANDE and VBR 
Analysis of exploratory endpoints 
• Changes from baseline to Day 28 in Schirmer’s score were summarized descriptively. A shift table 
was presented as well.  
• Changes from baseline to Day 14 and Day 28 in VBR scale were summarized descriptively, analyzed 
in both the ITT and PP sets, and graphically displayed as a Forest plots. 
• Change from baseline to Day 14 and Day 28 in temporal bulbar and and nasal bulbar lissamine green 
conjunctival staining scores were presented in shift tables. 
• Changes in CGI and SGA from baseline to Day 14 and Day 28 were summarized descriptively. 
For CGI and SGA, results were also collapsed into two categories (Responder vs. Non-Responder). 
Other efficacy analyses 
Time to improvement was investigated graphically through Kaplan-Meier curves. 
Post hoc subgroup analyses for three key endpoints (SANDE, VBR and SGA) were also done, based 
on the following cut-off values: SANDE ≥60 at baseline, SANDE ≥median at baseline, VBR ≥40 at 
baseline, VBR ≥50 at baseline and VBR ≥median at baseline) 
Safety analyses 
Most safety data were summarized descriptively.  
SUMMARY AND CONCLUSIONS:  
EFFICACY RESULTS:  
Demographic and other baseline characteristics were comparable between the OCU 310 and placebo 
groups. Demographic and baseline characteristics were well balanced between the two treatment 
groups. Briefly, overall mean (SD) age was 62 (12) year, and the majority of subjects were females 
(84%), and Caucasian (84%). Overall mean time since first DED diagnosis was 5 years. Compliance to 
the study treatment was ≥ 80%-≤ 100% for the majority (99%) of subjects, and the median number of 
received doses was the same in the two treatment groups (55). 
Primary efficacy endpoints  
Change from baseline to Day 28 in SANDE score 
In the ITT set, both study treatments resulted in a reduction (i.e. improvement) from baseline to Day 28 
in SANDE overall, and in frequency of symptoms and severity of symptoms scores. None of the 
comparisons of OCU 310 vs. placebo were statistically significant, with estimated mean differences 
between the two treatments (OCU 310 - placebo) of -0.8 mm (p= 0.739) for the overall score, -2.7 mm 
(p= 0.297) for the frequency of symptoms score, and 0.7 mm (p= 0.803) for the severity of symptoms 
score. Results were confirmed in the PP set and, overall, in the subgroups (ITT set) analysis for the 
SANDE overall score with improver subjects, non-improver subjects, as well as subjects with SANDE ≥ 
60 at baseline, SANDE ≥ median at baseline, VBR ≥ 40 at baseline, VBR ≥ 50 at baseline and VBR ≥ 
median at baseline. 


Clinical Study Report 
Sponsor: Ocugen, Inc. 
Version: Final 
Study Code: OCU-310-301 
Date: January 24th, 2020 
IND No.: 136132 
Confidential 
Page 8 of 11 
Name of the Sponsor/Company: 
Ocugen, Inc. 
Individual Study Table 
Referring to Module 5 of the 
Dossier 
 
Volume:  
Page:  
Study No.:  
(For National Authority Use only) 
 
Name of Finished Product: 
OCU 310 
Name of Active Ingredient: 
Brimonidine tartrate 0.2% 
Change from baseline to Day 28 in lissamine green total conjunctival staining scores 
In the ITT set, both study treatments resulted in a reduction (i.e. improvement) from baseline to Day 28 
in lissamine green total conjunctival staining scores in both the study eye and qualified fellow eye. For 
the study eye, the comparison OCU 310 vs. placebo was not statistically significant, with an estimated 
mean difference between the two treatments (OCU 310 - placebo) of 0.26 (p= 0.097). Results were 
confirmed in the PP set, and in the subgroups (ITT set) of improver and non-improver subjects.  
Secondary efficacy endpoints 
Change from baseline to Day 14 in SANDE score 
In the ITT set, both study treatments resulted in a reduction from baseline to Day 14 in SANDE overall, 
and in frequency of symptoms and severity of symptoms scores. None of the comparisons of OCU 310 
vs. placebo were statistically significant, with estimated mean differences between the two treatments 
(OCU 310 - placebo) of 2.4 (p= 0.257) for the overall score, 2.8 (p= 0.210) for the frequency of symptoms 
score, and 2.1 (p= 0.354) for the severity of symptoms score. Results were confirmed in the PP set and 
in the subgroups (ITT set) of subjects with SANDE ≥ 60 at baseline, SANDE ≥ median at baseline, VBR 
≥ 40 at baseline, VBR ≥ 50 at baseline and VBR ≥ median at baseline.  
Change from baseline to Day 14 in lissamine green total conjunctival staining scores 
In the ITT set, both study treatments resulted in a reduction from baseline to Day 14 in lissamine green 
total conjunctival staining scores in both the study eye and qualified fellow eye. For the study eye, the 
comparison OCU 310 vs. placebo favored placebo, with an estimated mean difference between the two 
treatments (OCU 310 - placebo) of 0.29 (p = 0.034). Results were confirmed in the PP set. 
Change from baseline to Day 14 and Day 28 in lissamine green total corneal staining scores 
In the ITT set, both study treatments resulted in a reduction from baseline to Day 14 and Day 28 in 
lissamine green total corneal staining scores in both the study eye and qualified fellow eye at Day 14 
and Day 28. For the study eye, the comparison OCU 310 vs. placebo favored placebo at Day 14, with 
an estimated mean difference between the two treatments (OCU 310 - placebo) of 0.6 (p= 0.016). At 
Day 28, the comparison OCU 310 vs. placebo was not statistically significant, with an estimated mean 
difference between the two treatments of 0.53 in favor of placebo (p= 0.063). Results were confirmed in 
the PP set. 
Exploratory efficacy endpoints 
Schirmer’s score 
Both study treatments resulted in an increase (i.e. improvement) of Schirmer’s score at Day 28. Mean 
(SD) changes from baseline was 1.9 (3.9) mm for OCU 310 and 2.5 (4.5) mm for the placebo group in 
the study eye, and for the qualified fellow eye was 1.6 (4.2) and 1.5 (3.0), respectively. 
Most study eyes and qualified fellow eyes had severe Schirmer’s score at baseline. Overall, the 
proportion of eyes with scores that improved from baseline were similar between groups in both the 
study eye and the qualified fellow eyes. Similarly, the proportion of study eyes and qualified fellow eyes 


Clinical Study Report 
Sponsor: Ocugen, Inc. 
Version: Final 
Study Code: OCU-310-301 
Date: January 24th, 2020 
IND No.: 136132 
Confidential 
Page 9 of 11 
Name of the Sponsor/Company: 
Ocugen, Inc. 
Individual Study Table 
Referring to Module 5 of the 
Dossier 
 
Volume:  
Page:  
Study No.:  
(For National Authority Use only) 
 
Name of Finished Product: 
OCU 310 
Name of Active Ingredient: 
Brimonidine tartrate 0.2% 
that deteriorated from baseline was similar in the two treatment groups in both study eye and qualified 
fellow eye. In a post hoc analysis on 124 study eyes (ITT), 14 (11%) of OCU310 subjects and 20 (16%) 
of placebo subjects went from having a Schirmer’s score ≤10 mm at baseline to a Schirmer’s score 
>10 mm (tear production) at Day 28.  
VBR scale 
With OCU 310, VBR scores (overall area) for the study eye and the qualified fellow eye decreased (i.e. 
improved) from baseline. With placebo, mean VBR scores (overall area) remained stable at all time 
points. Results obtained for VBR scores for the nasal and temporal areas confirmed those obtained for 
the overall area in both the study eye and qualified fellow eye. In the ITT set, mean reductions from 
baseline in VBR score (overall area) were greater with OCU 310 than with placebo at both Day 14 and 
Day 28, with estimated mean differences between treatments (OCU 310 - placebo) of -2.8 (p= 0.006) 
and -2.6 (p= 0.020), respectively. These results were confirmed in the PP set and in the subgroups (ITT 
set) of subjects with SANDE ≥ 60 at baseline, VBR ≥ 40 at baseline and VBR ≥ median at baseline. For 
the subgroups of subjects with SANDE ≥ median at baseline and VBR ≥ 50 at baseline non-significant 
differences were observed between groups at either time points. 
Temporal bulbar and nasal bulbar lissamine green conjunctival staining scores 
Temporal bulbar lissamine green conjunctival staining scores 
Overall, the number of study eyes and qualified fellow eyes that improved from baseline to Day 14 and 
Day 28 were similar with OCU 310 and with placebo. Similarly, deteriorations from baseline were similar 
between groups. 
Nasal bulbar lissamine green conjunctival staining scores 
Improvements from baseline to Day 14 were observed in a similar number of study eyes with OCU 310 
and placebo and in a smaller number of qualified fellow eyes with OCU 310 than with placebo (19% vs. 
34%). Improvements from baseline to Day 28 were observed in a similar number of study and qualified 
fellow eyes. 
The number of study eyes and qualified fellow eyes that deteriorated from baseline to Day 14 were 
similar between OCU 310 and placebo groups. Deterioration from baseline to Day 28 was similar 
between OCU 310 and placebo groups in qualified fellow eyes but greater with OCU 310 than with 
placebo at Day 28 in the study eyes (15% vs. 7%). 
CGI scale 
Responder analysis (dichotomized) 
Although a higher percentage of CGI responders relative to Baseline was observed in the placebo arm 
at Day 14 (46% vs. 39%), the percentage was identical at Day 28 (48% vs. 48%). The proportion of 
subjects worsening from baseline was higher in OCU 310 than in placebo at Day 14 (20% vs. 8.1%), 
but more similar at Day 28 (13% vs. 4.8%, respectively).   
 


Clinical Study Report 
Sponsor: Ocugen, Inc. 
Version: Final 
Study Code: OCU-310-301 
Date: January 24th, 2020 
IND No.: 136132 
Confidential 
Page 10 of 11 
Name of the Sponsor/Company: 
Ocugen, Inc. 
Individual Study Table 
Referring to Module 5 of the 
Dossier 
 
Volume:  
Page:  
Study No.:  
(For National Authority Use only) 
 
Name of Finished Product: 
OCU 310 
Name of Active Ingredient: 
Brimonidine tartrate 0.2% 
Subgroup Analysis 
This analysis was also performed in non-improver and improver subjects and the results are similar to 
the responder analysis. For the subgroup of non-improvers, the percentage of subjects with an 
improvement in CGI from Baseline to Day 14 was higher for the placebo arm (51%) than for the OCU310 
arm (39%). However, by Day 28, the percentage was identical (48% vs. 48% respectively). 
SGA scale 
Responder analysis (dichotomized) 
At Day 14 the percentage of SGA responders relative to Baseline was slightly higher for the placebo 
arm (45%) than for the OCU310 arm (42%). However, by Day 28, there is a higher percentage of SGA 
responders in the OCU310 arm (50%) relative to the placebo arm (44%).  
Subgroup analysis 
This analysis was also performed in non-improver and improver subjects and the results are similar to 
the responder analysis. For the subgroup of non-improvers, the percentage of subjects with an 
improvement in SGA from Baseline to Day 14 was higher for the placebo arm (47%) than for the 
OCU310 arm (43%). However, by Day 28, there was a higher percentage of OCU310 subjects with 
improvement relative to Baseline (54%) vs. placebo (43%).   
The SANDE, VBR and SGA analyses in subgroups of subjects (SANDE ≥60 at baseline, SANDE 
≥median at baseline, VBR ≥40 at baseline, VBR ≥50 at baseline and VBR ≥median at baseline) were also 
consistent with those obtained in the ITT set.  
Multicenter Studies 
The pooling analysis, whereby data from 6 low-enrolling sites were combined into 1 pseudo sites, did 
not change the interpretation of the efficacy data. 
SAFETY RESULTS:  
Subjects in the two treatment groups received a similar median number of doses of study treatment in 
the OCU 310 and placebo groups; 55 doses. 
TEAEs 
Overall, a total of 40 TEAEs (39 unique TEAEs) were reported in 34 (14%) subjects. In the OCU 310 
group 27 TEAEs were reported in 18% of subjects while 12 TEAEs were reported in 8.7% subjects in 
the placebo group. The majority of TEAEs reported during the study treatment were of mild nature, and 
none were of severe nature. There were no serious TEAEs, including TEAEs leading to death. 
As expected, the most common TEAEs were of ocular nature and were reported equally between 
groups. Amongst ocular TEAEs, those reported in >1 subject in any group were dry eye, eye irritation, 
vision blurred and instillation site irritation. Among the non-ocular TEAEs, sinusitis was the only one 
reported in >1 subject. 


Clinical Study Report 
Sponsor: Ocugen, Inc. 
Version: Final 
Study Code: OCU-310-301 
Date: January 24th, 2020 
IND No.: 136132 
Confidential 
Page 11 of 11 
Name of the Sponsor/Company: 
Ocugen, Inc. 
Individual Study Table 
Referring to Module 5 of the 
Dossier 
 
Volume:  
Page:  
Study No.:  
(For National Authority Use only) 
 
Name of Finished Product: 
OCU 310 
Name of Active Ingredient: 
Brimonidine tartrate 0.2% 
Treatment related TEAEs were reported in 9.5% of subjects in the OCU 310 group and in 3.2% of 
subjects in the placebo group. In the OCU 310 group, treatment related TEAEs reported in > 1 subject 
were of ocular nature: “dry eye” and “instillation site irritation” (in 1.6% and 2.4% of subjects, 
respectively). In the placebo group, treatment related TEAEs were reported at most in 1 subject.  
Notably, two treatment related ocular TEAEs of moderate intensity (PTs: lacrimation increased and eye 
irritation) in the OCU 310 group led to study treatment discontinuation of one subject, and accounted for 
all TEAEs leading to study treatment discontinuation of the study. Both events resolved by the end of 
the study without corrective treatment. 
Vital signs 
Mean changes from baseline in SBP, DBP, HR, respiratory rate and body temperature were minimal at 
both Day 14 and Day 28 in both treatment groups. Vital signs were considered as normal or non-
significant abnormal by Investigators. 
Best corrected visual acuity 
Overall, mean best corrected visual acuity of the study eye, qualified fellow eye and non-qualified fellow 
eye were stable at all time points, with very small and similar mean changes from baseline in both 
treatment groups. 
Intraocular pressure (IOP) 
IOP decreased from baseline in both groups at Day 14 and Day 28, with mean changes greater with 
OCU 310 than with placebo at both time points for the study eye, qualified fellow eye and non-qualified 
fellow eye. The comparison of OCU 310 vs. placebo for change in IOP from baseline favored OCU 310 
at both Day 14 and Day 28, with estimated mean differences between the two treatments (OCU 310 - 
placebo) of -0.752 mmHg (p= 0.003) at Day 14 and -0.515 mmHg (p= 0.040) at Day 28. Of note, no 
subject had an IOP measurement outside of the normal range. 
Ophthalmic examination 
Clinically significant abnormalities were observed for the study eye and qualified fellow eye only for the 
area “tear film” and were reported in 3 and 2 subjects in the OCU 310 and placebo groups, respectively, 
from the Baseline visit  
CONCLUSIONS:  
This study showed that OCU 310 is generally safe and well-tolerated, though it did not meet its co-
primary endpoints for DED symptom and sign. Importantly, OCU 310 was better than placebo in 
reducing ocular redness, an exploratory sign endpoint, at both Day 14 and Day 28. In addition, a 
numerical, but not statistical, improvement was noted at Day 28 in SGA, an exploratory symptom 
endpoint, for OCU 310 relative to placebo.  
 
 


IND # 136132 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OCU310 Brimonidine Tartrate 0.2% Nanoemulsion Annual Report (August 2018 – July 2019); April 20, 2020 
 
 
Exhibit II 
 
Stability Data for OCU310 Clinical Drug Product Batch (18E38) at Long Term Storage Condition (25°C ± 2°C/40%RH ± 5%RH) 
 
Test 
Acceptance 
Criteria 
Test 
Method 
Time Points (M) 
0 
2 
3 
6 
Appearance 
of Product 
White-to-yellowish or 
brownish cloudy 
emulsion 
ATM-1095 
Yellowish cloudy 
emulsion 
Yellowish cloudy 
emulsion 
Yellowish cloudy 
emulsion 
Yellowish cloudy 
emulsion 
Assay 
(HPLC) 
80 – 120% of label 
claim 
ATM-1704 
100% 
100% 
100% 
100% 
Impurities 
(HPLC) 
Impurity A: NMT 
1.0%  
Each Impurity: NMT 
1.0% 
Total Impurities 
(known and 
unknown): NMT 5.0% 
ATM-1705 
Imp. A: Not detected 
RRT 0.82: 0.09%  
Total: 0.1% 
Imp A: Not detected 
RRT 0.83: 0.06% 
Total: 0.1% 
Imp A: Not detected 
RRT 0.83: 0.05% 
Total: 0.1% 
Imp A: Not detected 
RRT 0.75: <0.05% (LOQ) 
RRT 0.83: 0.07% 
RRT 1.25:< 0.05% (LOQ) 
RRT 1.31: <0.05% (LOQ) 
Total: 0.1% 
pH 
6.0 – 7.0 
USP <791> 
6.6 
6.6 
6.5 
6.2 
Globule Size 
(Mastersizer 
3000) 
Mean Dv (50): NMT 
0.150 µm; 
Dv (10) and Dv (90): 
For information only 
ATM-1707 
Dv (10): 0.0256 µm 
 
Dv (50): 0.0585 µm 
 
Dv (90): 0.128 µm 
Dv (10): 0.0220 µm 
 
Dv (50): 0.0539 µm 
 
Dv (90): 0.128 µm 
Dv (10): 0.0245 µm 
 
Dv (50): 0.0551 µm 
 
Dv (90): 0.120 µm 
Dv (10): 0.0222 µm 
 
Dv (50): 0.0538 µm 
 
Dv (90): 0.126 µm 
Particulate 
Matter 
(Visual) 
Uniform emulsion free 
from visible 
particulate 
matter 
USP <790> 
Uniform emulsion free 
from particulate matter 
Uniform emulsion free 
from particulate matter 
Uniform emulsion free 
from particulate matter 
Uniform emulsion free 
from particulate matter 
Sterility 
Meets compendial 
requirements 
USP <71> 
Meets compendial 
requirements 
Not tested per protocol 
Not tested per protocol 
Not tested per protocol 
Bacterial 
Endotoxin 
≤ 10 EU/mL 
USP <85> 
< 0.5 EU/mL 
Not tested per protocol 
Not tested per protocol 
Not tested per protocol 
 
 
 
 
 
 
 


IND # 136132 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OCU310 Brimonidine Tartrate 0.2% Nanoemulsion Annual Report (August 2018 – July 2019); April 20, 2020 
 
 
 
 
 
Stability Data for OCU310 Clinical Drug Product Batch (18E38) at Long Term Storage Condition (25°C ± 2°C/40%RH ± 5%RH) 
(continued) 
 
Test 
Acceptance Criteria 
Test Method 
Time Points (M) 
9 
12 
 
 
Appearance of 
Product 
White-to-yellowish 
or brownish cloudy 
emulsion 
ATM-1095 
Yellowish cloudy 
emulsion 
Yellowish cloudy 
emulsion 
 
 
Assay (HPLC) 
80 – 120% of label 
claim 
ATM-1704 
100% 
101% 
 
 
Impurities 
(HPLC) 
Impurity A: NMT 
1.0%  
Each Impurity: NMT 
1.0% 
Total Impurities 
(known and 
unknown): NMT 
5.0% 
ATM-1705 
Imp A: <0.05% (LOQ) 
RRT 0.75: <0.05% (LOQ) 
RRT 0.83: 0.06% 
IAQ1: <0.05% (LOQ) 
RRT 1.31: <0.05% (LOQ)  
Total: 0.1% 
Imp A: <0.05% (LOQ) 
RRT 0.75: <0.05% (LOQ) 
RRT 0.83: 0.07% 
RRT 1.31:0.06%  
Total: 0.1% 
 
 
pH 
6.0 – 7.0 
USP <791> 
6.5 
6.6 
 
 
Globule Size 
(Mastersizer 
3000) 
Mean Dv (50): NMT 
0.150 µm; 
Dv (10) and Dv (90): 
For information only 
ATM-1707 
Dv (10): 0.0280 µm 
 
Dv (50): 0.0535 µm 
 
Dv (90): 0.0991 µm 
Dv (10): 0.0256 µm 
 
Dv (50): 0.0548 µm 
 
Dv (90): 0.113 µm 
 
 
Particulate 
Matter 
(Visual) 
Uniform emulsion 
free from visible 
particulate 
matter 
USP <790> 
Uniform emulsion free 
from particulate matter 
Uniform emulsion free 
from particulate matter 
 
 
Sterility 
Meets compendial 
requirements 
USP <71> 
Not tested per protocol 
Meets compendial 
requirements 
 
 
Bacterial 
Endotoxin 
≤ 10 EU/mL 
USP <85> 
Not tested per protocol 
<0.5 EU/ml 
 
 
1 6-(2-Imidazolin-2-ylamino) quinoxaline 
 
 
 
 


IND # 136132 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OCU310 Brimonidine Tartrate 0.2% Nanoemulsion Annual Report (August 2018 – July 2019); April 20, 2020 
 
 
 
Stability Data for OCU310 Clinical Drug Product Batch (18E38) at Accelerated Storage Condition (40°C ± 2°C/NMT 25%RH) 
 
Test 
Acceptance Criteria 
Test Method 
Time Points (M) 
0 
2 
3 
Appearance of 
Product 
White-to-yellowish 
or brownish cloudy 
emulsion 
ATM-1095 
Yellowish cloudy emulsion 
Yellowish cloudy emulsion 
Yellowish cloudy emulsion 
Assay (HPLC) 
80 – 120% of label 
claim 
ATM-1704 
100% 
100% 
100% 
Impurities 
(HPLC) 
Impurity A: NMT 
1.0%  
Each Impurity: NMT 
1.0% 
Total Impurities 
(known and 
unknown): NMT 
5.0% 
ATM-1705 
Imp A: Not detected 
RRT 0.82: 0.09% 
Total: 0.1% 
Imp A: Not detected 
RRT 0.83: 0.08% 
RRT 1.31: 0.09%  
Total: 0.2% 
Imp A: Not detected 
RRT 0.83: 0.06% 
RRT 1.31: 0.12%  
Total: 0.2% 
pH 
6.0 – 7.0 
USP <791> 
6.6 
6.6 
6.5 
Globule Size 
(Mastersizer 
3000) 
Mean Dv (50): NMT 
0.150 µm; 
Dv (10) and Dv (90): 
For information only 
ATM-1707 
Dv (10): 0.0256 µm 
 
Dv (50): 0.0585 µm 
 
Dv (90): 0.128 µm 
Dv (10): 0.0216 µm 
 
Dv (50): 0.0528 µm 
 
Dv (90): 0.126 µm 
Dv (10): 0.0243 µm 
 
Dv (50): 0.0552 µm 
 
Dv (90): 0.121 µm 
Particulate 
Matter 
(Visual) 
Uniform emulsion 
free from visible 
particulate 
matter 
USP <790> 
Uniform emulsion free from 
particulate matter 
Uniform emulsion free from 
particulate matter 
Uniform emulsion free from 
particulate matter 
Sterility 
Meets compendial 
requirements 
USP <71> 
Meets compendial requirements 
Not tested per protocol 
Not tested per protocol 
Bacterial 
Endotoxin 
≤ 10 EU/mL 
USP <85> 
<0.5 EU/ml 
Not tested per protocol 
Not tested per protocol 
 
 
 
 
 
 
 
 


IND # 136132 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OCU310 Brimonidine Tartrate 0.2% Nanoemulsion Annual Report (August 2018 – July 2019); April 20, 2020 
 
 
 
Stability Data for OCU310 Clinical Drug Product Batch (18E38) at Accelerated Storage Condition (40°C ± 2°C/NMT 25%RH) –(Continued) 
  
1 6-(2-Imidazolin-2-ylamino) quinoxaline 
 
 
 
 
Test 
Acceptance Criteria 
Test Method 
Time Points (M) 
6 
9 
12 
Appearance 
of Product 
White-to-yellowish or 
brownish cloudy 
emulsion 
ATM-1095 
Yellowish cloudy emulsion 
Yellowish cloudy emulsion 
Yellowish cloudy emulsion 
Assay 
(HPLC) 
80 – 120% of label 
claim 
ATM-1704 
101% 
96% 
97% 
Impurities 
(HPLC) 
Impurity A: NMT 
1.0%  
Each Impurity: NMT 
1.0% 
Total Impurities 
(known and 
unknown): NMT 5.0% 
ATM-1705 
Imp A: 0.08%  
RRT 0.75: <0.05%(LOQ) 
RRT 0.83: 0.08% 
IAQ1: <0.05% (LOQ) 
RRT 1.25: 0.06% 
RRT 1.31: 0.18% 
RRT 2.15: <0.05% (LOQ) 
RRT 2.36: <0.05% (LOQ) 
Total: 0.4% 
 
Imp A: 0.15%  
RRT 0.75: 0.07% 
RRT 0.83: 0.08% 
RRT 1.16: <0.05%(LOQ) 
RRT 1.25: 0.08% 
RRT 1.31: 0.21% 
RRT 1.38: <0.05%(LOQ) 
RRT 2.15: <0.05% (LOQ) 
RRT 2.36: 0.05%  
Total: 0.6% 
Imp A: 0.24%  
RRT 0.75: 0.08% 
RRT 0.83: 0.09% 
RRT 1.25: 0.08% 
RRT 1.31: 0.23% 
RRT 2.05: <0.05%(LOQ) 
RRT 2.15: <0.05% (LOQ) 
RRT 2.36: 0.08%  
Total: 0.8% 
pH 
6.0 – 7.0 
USP <791> 
6.3 
6.4 
6.4 
Globule Size 
(Mastersizer 
3000) 
Mean Dv (50): NMT 
0.150 µm; 
Dv (10) and Dv (90): 
For information only 
ATM-1707 
Dv (10): 0.0202 µm 
 
Dv (50): 0.0475 µm 
 
Dv (90): 0.112 µm 
Dv (10): 0.0235 µm 
 
Dv (50): 0.0550 µm 
 
Dv (90): 0.124 µm 
 
 
Dv (10): 0.0247 µm 
 
Dv (50): 0.0553 µm 
 
Dv (90): 0.120 µm 
 
 
Particulate 
Matter 
(Visual) 
Uniform emulsion free 
from visible 
particulate 
matter 
USP <790> 
Uniform emulsion free from 
particulate matter 
Uniform emulsion free from 
particulate matter 
Uniform emulsion free from 
particulate matter 
Sterility 
Meets compendial 
requirements 
USP <71> 
Not tested per protocol 
Not tested per protocol 
Meets compendial requirements 
Bacterial 
Endotoxin 
≤ 10 EU/mL 
USP <85> 
Not tested per protocol 
Not tested per protocol 
< 0.5 EU/ml 


IND # 136132 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OCU310 Brimonidine Tartrate 0.2% Nanoemulsion Annual Report (August 2018 – July 2019); April 20, 2020 
 
 
 
Stability Data for Ophthalmic Buffered Saline (18CL8) at Long Term Storage Condition (25°C ± 2°C/60%RH ± 5% RH) 
 
Test 
Acceptance 
Criteria 
Test 
Method 
Time Points (M) 
0 
1 
3 
6 
9 
12 
18 
Appearance  
Clear, Colorless 
Solution 
TRC-SOP-
1032 
Pass 
Pass 
Pass 
Pass 
Pass 
Pass 
Pass 
pH 
6.0 – 8.0 
USP <791> 
7.0 
6.9 
7.0 
7.0 
6.9 
6.9 
6.9 
Assay for 
Sodium 
Chloride 
90.0 – 110.0% of 
Label Claim 
USP 
Monograph 
101.7% 
101.8% 
100.9% 
100.9% 
101.1% 
101.7% 
100.5% 
Sterility 
No growth after 14 
days 
USP <71> 
Pass 
Not tested per 
protocol 
Not tested per 
protocol 
Not tested per 
protocol 
Not tested per 
protocol 
Pass 
Not tested per 
protocol 
Particulate 
Matter  
NMT 50 particles/mL 
≥ 10 µm 
NMT 5 particles/mL ≥ 
25 µm 
NMT 2 particles/mL ≥ 
50 µm 
USP <789> 
1 particle/mL 
≥ 10 µm 
 
0 particle/mL 
≥ 25 µm 
 
0 particle/mL 
≥ 50 µm 
Not tested per 
protocol 
Not tested per 
protocol 
Not tested per 
protocol 
Not tested per 
protocol 
19 
particles/mL 
≥ 10 µm 
 
0 particle/mL 
≥ 25 µm 
 
0 particle/mL 
  ≥ 50 µm 
Not tested per 
protocol 
 
 
 
 


IND # 136132 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OCU310 Brimonidine Tartrate 0.2% Nanoemulsion Annual Report (August 2018 – July 2019); April 20, 2020 
 
 
Stability Data for Ophthalmic Buffered Saline (18CL8) at Long Term Storage Condition (25°C ± 2°C/40%RH ± 5% RH) 
 
Test 
Acceptance 
Criteria 
Test 
Method 
Time Points (M) 
0 
1 
3 
6 
9 
12 
18 
Appearance  
Clear, Colorless 
Solution 
TRC-SOP-
1032 
Pass 
Pass 
Pass 
Pass 
Pass 
Pass 
Pass 
pH 
6.0 – 8.0 
USP <791> 
7.0 
6.9 
7.0 
6.9 
6.8 
6.9 
6.9 
Assay for 
Sodium 
Chloride 
90.0 – 110.0% of 
Label Claim 
USP 
Monograph 
101.7% 
101.9% 
101.3% 
100.9% 
101.8% 
101.4% 
102.2% 
Sterility 
No growth after 14 
days 
USP <71> 
Pass 
Not tested per 
protocol 
Not tested per 
protocol 
Not tested per 
protocol 
Not tested per 
protocol 
Pass 
Not tested per 
protocol 
Particulate 
Matter  
NMT 50 particles/mL 
≥ 10 µm 
NMT 5 particles/mL ≥ 
25 µm 
NMT 2 particles/mL ≥ 
50 µm 
USP <789> 
1 particle/mL 
≥ 10 µm 
 
0 particle/mL 
≥ 25 µm 
 
0 particle/mL 
≥ 50 µm 
Not tested per 
protocol 
Not tested per 
protocol 
Not tested per 
protocol 
Not tested per 
protocol 
28 
particles/mL 
≥ 10 µm 
 
1 particle/mL 
≥ 25 µm 
 
0 particle/mL 
  ≥ 50 µm 
Not tested per 
protocol 
 
 
 


IND # 136132 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OCU310 Brimonidine Tartrate 0.2% Nanoemulsion Annual Report (August 2018 – July 2019); April 20, 2020 
 
 
Stability Data for Ophthalmic Buffered Saline (18CL8) at Accelerated Storage Condition (40°C ± 2°C/NMT 25%RH) 
 
Test 
Acceptance 
Criteria 
Test 
Method 
Time Points (M) 
0  
1 
3 
6 
Appearance  
Clear, Colorless 
Solution 
TRC-SOP-
1032 
Pass 
Pass 
Pass 
Pass 
pH 
6.0 – 8.0 
USP <791> 
7.0 
6.9 
6.9 
6.7 
Assay for 
Sodium 
Chloride 
90.0 – 110.0% of 
Label Claim 
USP 
Monograph 
101.7% 
101.5% 
102.2% 
102.8% 
Sterility 
No growth after 14 
days 
USP <71> 
Pass 
Not tested per protocol 
Not tested per protocol 
Pass 
Particulate 
Matter  
NMT 50 particles/mL 
≥ 10 µm 
NMT 5 particles/mL ≥ 
25 µm 
NMT 2 particles/mL ≥ 
50 µm 
USP <789> 
1 particle/mL ≥ 10 µm 
 
0 particle/mL ≥ 25 µm 
 
0 particle/mL ≥ 50 µm 
Not tested per protocol 
Not tested per protocol 
6 particles/mL ≥ 10 µm 
 
0 particle/mL ≥ 25 µm 
 
0 particle/mL ≥ 50 µm