Clinical trial NCT03591874
Conditions: Graft Versus Host Disease Ocular Surface Disease oGVHD Ocular Graft vs Host Disease Brimonidine Tartrate Lubricant Eye Drops Ophthalmic Solutions Graft vs Host Disease
Keywords: ogvhd ocular graft vs host Ocular Surface Disease Ocular Graft vs Host Disease Brimonidine Tartrate Lubricant Eye Drops Ophthalmic Solutions Graft vs Host Disease
Sponsor: Ocugen
Start date: 2018-12-23; Completion date: 2020-04-30
Enrollment: 59 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study evaluates the use of Brimonidine tartrate nanoemulsion eye drop solution in the treatment of ocular Graft Verses Host Disease (oGVHD). Two thirds of participants will receive Brimonidine and one third will receive ophthalmic buffered saline (placebo).

Detailed description:
Ocular GVHD (oGVHD) is a common complication that occurs in 40-60% of patients who have undergone allogeneic bone marrow transplants. Driven by inflammation, oGVHD can result in damage to the ocular surface and tear-producing glands, which over time significantly diminishes quality of life and restricts daily activities due to visual impairment.

Early studies in animals and humans indicate that Brimonidine nano-emulsion, also known as OCU300, may relieve the signs and symptoms of oGVHD. These symptoms include blurry vision, foreign body sensation, burning sensation, severe light sensitivity, chronic conjunctivitis (pink or red eye), dry eyes and eye pain.

This study will be a randomized, placebo-controlled, double-masked, multicenter phase 3 study in the United States conducted at approximately 15 centers. Upon meeting the eligibility criteria, enrolled subjects with a diagnosis of definite oGVHD will be randomly assigned in a 2:1 (test: control) fashion to receive either Brimonidine Nanoemulsion Eye Drops 0.18% investigational product (test) or ophthalmic buffered saline (placebo).

Arms: arm 1: Brimonidine Tartrate Nanoemulsion Eye Drops 0.18% given 2 times a day for 12 weeks. arm 2: Placebo - Ophthalmic buffered saline Eye Drops given 2 times a day for 12 weeks.
Interventions: intervention 1: Brimonidine Tartrate intervention 2: Placebos
Intervention descriptions: intervention 1: Brimonidine Tartrate Nanoemulsion Eye Drops given 2 times a day for 12 weeks. intervention 2: Opthalmic buffered saline solution Eye Drops given 2 times a day for 12 weeks.

Protocol documents:
Prot_000.pdf: 
Ocugen, Inc. 
OCU-300-301 
Amendment 1 
07 Dec 2018 
1 
CLINICAL STUDY PROTOCOL 
Title: A Phase 3 Randomized, Placebo-Controlled, Double-Masked, Multicenter, Safety and Efficacy 
Study of Brimonidine Tartrate Nanoemulsion Eye Drops in Patients with ocular Graft-vs-Host Disease 
(oGVHD) 
Protocol Number: 
OCU-300-301 
Investigational: 
OCU300 (Brimonidine Tartrate Ophthalmic 
Nanoemulsion 0.18%) 
Version: 
Amendment 1 (07 Dec 2018) 
IND Applicant/Product Sponsor: 
Ocugen, Inc. 
5 Great Valley Parkway, Suite 160 
Malvern, PA 19355 USA 
Authorized Signatory: 
 
Ocugen, Inc. 
5 Great Valley Parkway, Suite 160 
Malvern, PA 19355 USA 
Telephone: 
 
Fax: 
 
E-mail: 
NCT #NCT03591874


Ocugen, Inc. 
OCU-300-301 
Amendment 1 
07 Dec 2018 
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Table 1. Administrative Structure 
 
 
Medical Monitor: 
(24-hour emergency contact) 
 
 
 - Office 
 – Cellular 
 
24-hour contact: 
 
Email:
 
 
Biostatistician: 
 
Brightech International LLC 
285 Davidson Ave., Suite 504 
Somerset, NJ 08873 
Email: 
 
 
 
Serious Adverse Event Reporting: 
 
G2 BioPharma Services, Inc. 
3637 Brunswick Pike 
Princeton, NJ 08540 
Email:
 
Phone: 
 
 
 
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. 


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OCU-300-301 
Amendment 1 
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PRINCIPAL INVESTIGATOR’S SIGNATURE 
 
I have received and read the Investigator’s Brochure for Brimonidine. I have read protocol OCU-300-301 
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 Principal Investigator 
 
 
 
Title of Principal Investigator 
 
 
 
Signature of Principal Investigator 
 
 
 
Date 


Ocugen, Inc. 
OCU-300-301 
Amendment 1 
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SPONSOR'S SIGNATURE 
 
 
Approved by: 
 
 
 
 
O  1 l>elen1ber ;;/6 / 
Date 


Ocugen, Inc. 
OCU-300-301 
Amendment 1 
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PROTOCOL REVISION HISTORY 
 
 
 
 
Table 2. Revision History 
 
Version 
Number 
Version date 
Summary of Revisions Made 
Major 
Administrative 
Version 1.0 
25 May 2018 
Amendment 1 
07 Dec 2018 
The Diagnosis of Definite oGVHD 
using the International Chronic 
Ocular GVHD Consensus Group 
revised diagnostic criteria was 
adapted for use in this protocol 
(Appendix 1, Section 18.1) 
The Diagnosis of Definite oGVHD, 
using the International Chronic 
Ocular GVHD Consensus Group 
revised diagnostic criteria language 
has been clarified to indicate “in at 
least one eye”. 
The protocol schedule of events was 
updated to clarify that screening 
procedures that are also to be done at 
the baseline D1 visit do not need to 
be duplicated if the screening visit 
and baseline D1 visit occur on the 
same day. 
“Change from baseline in corneal 
lissamine green (LG) staining at 12 
weeks (Day 84)” added as 
exploratory endpoint. 
“Received corticosteroid-containing 
eye drops within 14 days prior to 
Screening visit or planned use during 
study” has been added to exclusion 
criteria. 
“Validated Bulbar Redness score ≥ 
40” inclusion criteria language has 
been updated to indicate in both eyes 
All page numbers have been 
updated to reflect the updated 
protocol. 
The list of abbreviations was 
updated to include additional 
items. 
The sponsor medical monitor 
and corresponding contact 
information were updated. 
The sponsor safety representative 
and corresponding contact 
information were updated. 
The previously listed medical 
writer and corresponding contact 
information were removed from 
the protocol. 


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Use of contact lenses exclusion 
criteria has been updated to exclude 
use within 14 days of screening visit 
and any time during the study. 
For subject-level assessments (e.g. 
ocular discomfort), the unit of 
analysis for the efficacy measures 
will be the subject 
ITT population simplified to “all 
randomized subjects” 
Section 4.5 was updated to include 
additional information regarding 
which assessments are to be 
completed at the subject early 
termination/discontinuation visit. 
Exclusion #2 was updated to exclude 
all Glaucoma management 
treatments. 
The study procedure 
schedule/schedule of events was 
updated to show that a review of prior 
and concomitant medications will 
take place at all in-clinic visits. 
The study procedure 
schedule/schedule of events was 
updated to show that a urine 
pregnancy test will be collected at all 
in-clinic visits. 
Section 18.9 (Appendix 9) Visual 
Acuity was simplified 


Ocugen, Inc. 
OCU-300-301 
Amendment 1 
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Synopsis 
 
Protocol Title: 
A Phase 3 Randomized, Placebo-Controlled, Double-Masked, Multicenter, Safety and Efficacy Study 
of Brimonidine Tartrate Nanoemulsion Eye Drops in Patients with ocular Graft-vs-Host Disease 
(oGVHD) 
Protocol Number: 
OCU-300-301 
Clinical Phase: 
Phase 3 
IND Applicant/Product Sponsor: 
Ocugen, Inc. 
5 Great Valley Parkway, Suite 160 
Malvern, PA 19355 USA 
Telephone: 
 
Fax: 
 
Authorized Signatory: 
 
 
Regulatory IND Number: 
136917 
Indication: 
Treatment of ocular redness and ocular discomfort in patients with oGVHD 
Investigational Drug: 
Brimonidine Tartrate Nanoemulsion 0.18% Ophthalmic Solution (OCU300). 
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 ocular Graft-vs-Host Disease (oGVHD) 
Primary Efficacy Endpoint(s): 
• Ocular redness based on a 100-point Validated Bulbar Redness (VBR) scale measuring change 
in appearance from baseline to Day 84 
• Ocular discomfort based on a 10-point Visual Analog Scale (VAS) measuring change in 
intensity from baseline to Day 84 


Ocugen, Inc. 
OCU-300-301 
Amendment 1 
07 Dec 2018 
8 
 
 
 
Secondary Efficacy Endpoint(s): 
• Change in Symptom Assessment iN Dry Eye (SANDE) questionnaire scores from baseline to 
Day 84 
Safety Endpoint(s): 
• Rate of ocular adverse events (AEs) 
Exploratory Endpoint(s): 
• 
Change from baseline in in Validated Bulbar Redness (VBR) score at Days 28 and 56 
• 
Change from baseline in in Ocular Discomfort Score at Days 28 and 56 
• 
Change from baseline in OSDI at 12 weeks (Day 84) 
• 
Change from baseline in corneal fluorescein staining at 12 weeks (Day 84) 
• 
Change from baseline in corneal lissamine green (LG) staining at 12 weeks (Day 84) 
• 
Change from baseline in conjunctival lissamine green (LG) staining at 12 weeks (Day 84) 
• 
Change from baseline in tear secretion as measured by Schirmer’s test 
• 
Clinical global impression of change in signs and symptoms from baseline (physician’s rating) 
• 
Subject global assessment of overall change from baseline (subject’s rating) 
Investigational Products 
Investigational Drug Dosage: 
One drop of Brimonidine Tartrate Nanoemulsion 0.18% administered in each eye, two times/day (bid) 
Control Dosage: 
One drop of ophthalmic buffered saline administered in each eye, two times/day (bid) 


Ocugen, Inc. 
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Amendment 1 
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Study Population 
Inclusion Criteria: 
Subjects must meet all the following criteria to participate in the study: 
1. Men and women ≥ 18 years of age 
2. Diagnosis of ‘definite’ oGVHD using the International Chronic Ocular GVHD Consensus Group 
revised diagnostic criteria (see Appendix I) in at least one eye 
3. Ocular Discomfort Score > 3 
4. Validated Bulbar Redness score ≥ 40 in both eyes 
5. Subjects who are capable and willing to provide informed consent and follow study instructions 
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 at the screening 
visit; and who are either abstinent or sexually active on an acceptable method of birth 
control (oral contraceptive pills, birth control implants/shots or patches, barrier methods) 
for at least 4 weeks prior to baseline visit (Day 1) and throughout the study, 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: 
1. Allergic to brimonidine or any similar products, or excipients of brimonidine 
2. Currently receiving brimonidine or other treatment for glaucoma 
3. Receiving or have received any experimental or investigational drug or device within 30 days 
prior to Screening visit 
4. Use of contact lenses within 14 days prior to Screening visit or planned use during study 
5. Active ocular infection or ocular allergies 
6. Any history of eyelid surgery or ocular surgery within the past 3 months 
2 
7. Corneal epithelial defect larger than 1 mm in either eye 
8. Received corticosteroid-containing eye drops within 14 days prior to Screening visit or planned 
use during study 
9. Any change in systemic corticosteroids/immunosuppressives, topical ocular antibiotics, 
cyclosporine ophthalmic emulsion 0.05% (Restasis®), cyclosporine ophthalmic solution 0.09% 
(Cequa™), lifitegrast ophthalmic solution 5% (Xiidra®), or autologous serum tears within 30 days 
prior to Screening visit or planned change during study 
Note: Subjects will be permitted to continue all their current ocular treatments, including the use of 
artificial tears, eyelid massage, punctal plugs, or warmcompresses, if they commit to using the same 
brand/regimen throughout the study. None of the ocular treatments, whether OTC or prescription (e.g. 
Restasis® ,Xiidra® or Cequa™) 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. 
If a punctal plug is lost during the study, it may be replaced. 


Ocugen, Inc. 
OCU-300-301 
Amendment 1 
07 Dec 2018 
10 
 
 
 
General Statistical Methods and Types of Analysis 
The primary analysis is a test of superiority of topical OCU300 vs OBS drops with co-primary 
endpoints. Tests will be conducted using two-sided alpha = .05. 
Unit of Analysis 
For eye-specific assessments (e.g., ocular redness), the unit of analysis for the efficacy measures will 
be the average of study-eligible eyes in each subject. Efficacy measures will be summarized using the 
average value between the two eyes within a subject and within a visit. For subject-level assessments 
(e.g. ocular discomfort), the unit of analysis for the efficacy measures will be the subject. Safety 
analyses will be performed on each eye separately (OD and OS) with the exception of adverse events, 
which will be presented at the subject level, where ocular adverse events will be considered as 
occurring if either eye had the adverse event. Safety measures captured at the subject level will be 
summarized at the subject level. 
Power and Sample Size 
The sample size is calculated based on limited data (
, May 24, 2017) on OSDI/SGA 
(as proxy endpoints to ocular discomfort), and ocular redness score (as a proxy endpoint for VBR). 
With a two-sided alpha of 0.05, a sample size of 60 patients in a 2:1 randomization (40 in OCU300, 20 
in control) would provide more than 90% power to detect a difference of 0.47 (SD 0.39) in the mean 
difference in change from baseline in the validated bulbar redness score (VBR). This sample size 
provides about 85% of power to detect a clinically meaningful difference in ocular discomfort as 
measured by the ocular discomfort score (ODS). Since the sample size is calculated using indirect 
information, a sample size re-estimation is planned at an interim analysis when data from 50% of 
patients are available. If the conditional power is less than 90%, the sample size will be increased to 
provide sufficient power. To control type I error, a two-sided alpha of 0.0002 will be spent at the 
interim analysis, and the two-sided alpha for the final analysis will be 0.0498. If sample size is 
modified, the final critical value of 0.0498 will be adjusted to control type I error. The details of the 
interim analysis will be provided in the Statistical Analysis Plan (SAP). 
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. 
Intent-to-treat (ITT) Population 
The ITT set will be the primary analysis set for the efficacy endpoints and will include all randomized 
subjects. 
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. 


Ocugen, Inc. 
OCU-300-301 
Amendment 1 
07 Dec 2018 
11 
 
 
 
Hypothesis and Power 
Because there are two co-primary endpoints, a composite hypothesis testing framework will be defined 
as following: 
Hypothesis 
The statistical hypotheses for the primary endpoint of the mean change from baseline bulbar redness 
score (VBR) at 12 weeks (Day 84) are as follows: 
H01:  The difference (OCU 300 minus placebo), between study eyes treated with the OCU 300 
and study eyes treated with placebo (OBS) in the mean change from baseline VBR score 
at 12 weeks (Day 84) = 0. 
HA1:  The difference (OCU 300 minus placebo), between study eyes treated with the OCU 300 
and study eyes treated with placebo (OBS) in the mean change from baseline VBR score 
at 12 weeks (Day 84) ≠ 0. 
The statistical hypotheses for the primary endpoint of the mean change from baseline ocular discomfort 
score (ODS) at 12 weeks (Day 84) are as follows: 
H02:  The difference (OCU 300 minus placebo), between subjects treated with the OCU 300 
and subjects treated with placebo (OBS) in the mean change from baseline ODS at 12 
weeks (Day 84) = 0. 
HA2:  The difference (OCU 300 minus placebo), between subjects treated with the OCU 300 
and subjects treated with placebo (OBS) in the mean change from baseline ODS at 12 
weeks (Day 84) ≠ 0. 
To control family-wise type I error, the primary endpoints will be tested with the Hochberg procedure: 
o If the p-values for both VBR and ODS are less or equal to 0.05, then both null 
hypotheses will be rejected, and alternative hypotheses claimed; 
o If the p-value for either parameter VBR or ODS is greater than 0.05, then a p-value 
of 0.025 will be required to reject the null hypothesis for the test on the other 
parameter; 
In general, continuous variables will be presented as number of non-missing values, mean, standard 
deviation, median, minimum, maximum, and quartiles. For categorical variables, descriptive statistics 
will include counts and percentages per category. Confidence intervals (CI) will be computed when 
appropriate, usually as 95% intervals. 
In general, data will not be imputed with the exception of the primary and key secondary efficacy 
endpoints. 


Ocugen, Inc. 
OCU-300-301 
Amendment 1 
07 Dec 2018 
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Efficacy Analysis 
The primary efficacy analyses will be conducted on the ITT population and the comparison will be 
made based on the randomized treatment. The same set of efficacy analyses will also be performed on 
the per-protocol population. For efficacy endpoints where measurements from both eyes are available, 
a single mean will be calculated for the analyses. For continuous endpoints, the change from baseline 
will be summarized with descriptive statistics for the values at baseline, values at each time point (Days 
28, 56 and 84), 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. The percent change from baseline may also be 
summarized in a similar manner. 
Primary and key secondary continuous endpoints will be analyzed using a mixed model of repeated 
measurements (MMRM) under a missing at random (MAR) assumption. The model will use an 
unstructured covariance matrix and include treatment, visit, and visit-by-treatment interaction as fixed 
terms. From this model, the by-visit results will be presented. A sensitivity analysis using pattern- 
mixture model with control- based pattern imputation will be performed to compare with the results of 
the primary analysis. 
For categoric endpoints, such as the severity scores, the analysis will be performed by using the 
Cochran–Mantel–Haenszel test (CMH) method controlling for baseline scores. The null hypothesis for 
categorical endpoints is that there is no association between the treatment assignment and the outcomes 
for each category; the alternative hypothesis is that there is an association. 
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: 15 September, 2018 


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Amendment 1
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TABLE OF CONTENTS
TABLE OF CONTENTS............................................................................................................................ 13
LIST OF TABLES ...................................................................................................................................... 18
LIST OF FIGURES..................................................................................................................................... 18
LIST OF ABBREVIATIONS ..................................................................................................................... 19
INTRODUCTION.................................................................................................................. 22
Ocular Graft vs Host Disease ................................................................................................. 22
Product Rationale ................................................................................................................... 22
Trial Rationale........................................................................................................................ 22
Summary of Known and Potential Risks and Benefits to Human Subjects............................ 23
STUDY DESIGN................................................................................................................... 24
Study Objectives..................................................................................................................... 24
Primary Objective(s)................................................................................................................ 24
Study Endpoints ...................................................................................................................... 24
Co-primary Efficacy Endpoints.............................................................................................. 24
Secondary Efficacy Endpoints ................................................................................................ 24
Exploratory Endpoints............................................................................................................ 24
INVESTIGATIONAL PLAN................................................................................................. 25
Overall Study Design ............................................................................................................. 25
Rationale for the Study Design............................................................................................... 25
SELECTION AND WITHDRAWAL OF SUBJECTS.......................................................... 25
Number of Subjects................................................................................................................ 25
Subject Inclusion Criteria....................................................................................................... 26
Subject Exclusion Criteria...................................................................................................... 26
Randomization Criteria .......................................................................................................... 27
Subject Withdrawal Criteria.................................................................................................... 27
Study Termination................................................................................................................... 28
STUDY SCHEDULE AND PROCEDURES......................................................................... 28
Study Schedule........................................................................................................................ 28
Study Visits ............................................................................................................................ 30
Unscheduled Study Visits....................................................................................................... 30
Screening................................................................................................................................ 30


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Day 1 (Baseline, Randomization, and First Treatment Visit)................................................. 31
Day 28 (± 7 days)................................................................................................................... 32
Day 56 (± 7 days)................................................................................................................... 33
Day 84 (± 7 days)................................................................................................................... 33
ASSESSMENTS .................................................................................................................... 35
Demographic/Ocular and Medical History............................................................................. 35
Prior & Concomitant Medications/Therapies ......................................................................... 35
Pregnancy Screen ................................................................................................................... 35
Efficacy Assessments............................................................................................................. 35
Primary Efficacy Assessment................................................................................................. 35
6.4.1.1
Validated Bulbar Redness (VBR) grading scale..................................................................... 35
6.4.1.2
Ocular Discomfort (VAS)....................................................................................................... 35
Secondary Efficacy Assessment............................................................................................. 36
6.4.2.1
Symptom Assessment iN Dry Eye (SANDE)......................................................................... 36
Exploratory Efficacy Assessments ......................................................................................... 36
6.4.3.1
Ocular Surface Disease Index (OSDI).................................................................................... 36
6.4.3.2
Corneal Staining Score with Fluorescein................................................................................ 36
6.4.3.3
Corneal and Conjunctival Staining Score with Lissamine Green ........................................... 36
6.4.3.4
Schirmer’s test....................................................................................................................... 36
6.4.3.5
Clinical Global Impression (CGI)........................................................................................... 37
6.4.3.6
Subject Global Assessment (SGA)......................................................................................... 37
Safety Assessments................................................................................................................. 38
Adverse Events....................................................................................................................... 38
Visual Acuity.......................................................................................................................... 38
IOP - Goldmann Applanation................................................................................................. 38
Ophthalmic Examination (Slit Lamp)..................................................................................... 38
Vital Signs.............................................................................................................................. 38
INVESTIGATIONAL DRUG INFORMATION AND MANAGEMENT............................ 39
Investigational Drug Dose Regimen....................................................................................... 39
Dose Rationale ....................................................................................................................... 39
Investigational Drug Packaging and Labeling........................................................................ 39
Investigational Drug Storage................................................................................................... 39
Investigational Drug Preparation............................................................................................ 40
Investigational Drug Administration ...................................................................................... 40


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Investigational Drug Accountability....................................................................................... 40
Investigational Drug Handling and Disposal.......................................................................... 41
TREATMENT OF SUBJECTS.............................................................................................. 41
Rescue Medication ................................................................................................................. 41
Prohibited Medications or Treatment ..................................................................................... 41
Other Study Restrictions......................................................................................................... 41
Treatment Compliance ........................................................................................................... 41
RANDOMIZATION AND MASKING PROCEDURES ...................................................... 42
Method of Assigning Subjects to Treatment Groups.............................................................. 42
Masking and Unmasking of Treatment Assignment .............................................................. 42
Emergency Unmasking........................................................................................................... 42
ADVERSE EVENTS ............................................................................................................. 43
Adverse and Serious Adverse Events..................................................................................... 43
Definitions of Adverse Events................................................................................................ 43
10.1.1.1
Adverse Event (AE) ............................................................................................................... 43
10.1.1.2
Serious Adverse Event (SAE) ................................................................................................ 43
10.1.1.3
Adverse Drug Reaction (ADR) and Suspected Adverse Reaction (SAR).............................. 44
10.1.1.4
Unexpected Adverse Reaction (UAR).................................................................................... 45
10.1.1.5
Adverse Events of Interest (AEIs).......................................................................................... 45
Severity of AEs/SAEs ............................................................................................................ 45
Relationship to Investigational Drug Treatment..................................................................... 46
Collecting and Recording Adverse Events............................................................................. 46
10.1.4.1
Period of Collection................................................................................................................ 46
10.1.4.2
Methods of Collection............................................................................................................ 47
10.1.4.3
Recording Method.................................................................................................................. 47
Reporting Adverse Events...................................................................................................... 48
10.1.5.1
Reporting SAEs to the Sponsor.............................................................................................. 48
10.1.5.2
Reporting Serious Adverse Events to FDA............................................................................ 49
Reporting Pregnancy .............................................................................................................. 50
STATISTICAL ANALYSIS PLAN....................................................................................... 50
General Statistical Methods and Types of Analysis ............................................................... 50
Power and Sample Size Determination .................................................................................. 51
Analysis Populations .............................................................................................................. 52
Efficacy and Safety Analyses................................................................................................. 52


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Background and Demographic Characteristics....................................................................... 52
Efficacy Analyses................................................................................................................... 52
11.4.2.1
Primary Efficacy Analyses..................................................................................................... 52
11.4.2.2
Efficacy Analyses—General Considerations.......................................................................... 53
11.4.2.3
Safety Analyses...................................................................................................................... 54
11.4.2.4
Adverse Events....................................................................................................................... 54
11.4.2.5
Concomitant Medications and Concomitant Therapies.......................................................... 54
11.4.2.6
Pharmacokinetic Analyses...................................................................................................... 54
Other Statistical Considerations.............................................................................................. 54
11.4.3.1
Significance Levels ................................................................................................................ 54
11.4.3.2
Multiple Comparisons ............................................................................................................ 54
11.4.3.3
Missing Data........................................................................................................................... 54
11.4.3.4
Visit Windows........................................................................................................................ 54
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS..................................................... 55
Study Monitoring .................................................................................................................... 55
Data Collection and Management .......................................................................................... 55
QUALITY CONTROL AND QUALITY ASSURANCE....................................................... 56
ETHICS.................................................................................................................................. 56
Ethics Review......................................................................................................................... 56
Ethical Conduct of the Study.................................................................................................. 56
Written Informed Consent...................................................................................................... 56
Subject Information and Informed Consent............................................................................ 56
Provision of New and Important Information Influencing Subject’s Consent and
Revision of the Written Information....................................................................................... 57
Subject Confidentiality........................................................................................................... 57
ADMINISTRATIVE PROCEDURES ................................................................................... 57
Publications of the Clinical Study .......................................................................................... 57
Protocol Amendments and Deviations ................................................................................... 57
DATA HANDLING AND RECORD KEEPING .................................................................. 58
Inspection of Records............................................................................................................. 58
Retention of Records............................................................................................................... 58
Sample Retention.................................................................................................................... 58
REFERENCES....................................................................................................................... 58
APPENDICES........................................................................................................................ 62
Appendix 1 Diagnosis of Definite oGVHD............................................................................ 62


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18.2
Appendix 2 Ocular Discomfort Scale..................................................................................... 64
Appendix 3 Validated Bulbar Redness Grading Scales (VBR).............................................. 64
Appendix 4 Symptom Assessment iN Dry Eye (SANDE)..................................................... 66
Appendix 5 Ocular Surface Disease Index (OSDI)................................................................ 67
Appendix 6. Ocular Surface Staining: Lissamine Green........................................................ 69
Lissamine Solution................................................................................................................. 69
Instillation of Lissamine Green .............................................................................................. 69
Evaluating Lissamine Green Staining .................................................................................... 70
Appendix 7 Ocular Surface Staining: Fluorescein.................................................................. 71
Fluorescein solution................................................................................................................ 71
Corneal Fluorescein Staining (CFS) with Severity Points...................................................... 71
Corneal Fluorescein Staining without Severity Points (NEI scale) ........................................ 72
Appendix 8. Conjunctival Injection with Severity Points....................................................... 73
Appendix 9. Visual Acuity..................................................................................................... 75
Visual Acuity Testing............................................................................................................. 75
18.9.1.1
Best-Corrected Visual Acuity (BCVA).................................................................................. 75
Appendix 10. Intraocular Pressure (IOP)................................................................................ 76
Calibration of Tonometer ....................................................................................................... 76
IOP Measurement................................................................................................................... 76
Appendix 11. Slit-Lamp Examination..................................................................................... 77


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LIST OF TABLES 
Table 1. Administrative Structure .......................................................................................................... 2 
Table 2. Revision History ....................................................................................................................... 5 
Table 3. Abbreviations .......................................................................................................................... 19 
Table 4. Study Schedule of Events ....................................................................................................... 28 
Table 5. Attribution of Adverse Events ................................................................................................ 46 
Table 6. International Chronic Ocular GVHD Consensus Group Severity Scale for oGVHD .............. 62 
Table 7. Diagnosis of Chronic oGVHD .................................................................................................. 63 
Table 8. Corneal and Conjunctival Lissamine Green Scoring .............................................................. 71 
Table 9. Corneal Fluorescein Staining (CFS) with Severity Points ...................................................... 72 
Table 10. Corneal Fluorescein Scoring (NEI Scale) .............................................................................. 73 
Table 11. Conjunctival Injection Scoring .............................................................................................. 74 
Table 13. Evaluation of Slit-Lamp Assessments .................................................................................. 77 
 
 
 
LIST OF FIGURES 
Figure 1. Ocular Discomfort Scale ........................................................................................................ 64 
Figure 2. Validated Bulbar Redness Scale ........................................................................................... 65 
Figure 3. SANDE Questionnaire .......................................................................................................... 66 
Figure 4. OSDI Questionnaire .............................................................................................................. 67 
Figure 5. Lissamine Green Corneal Staining Pattern and Grade (NEI Scale) ..................................... 70 
Figure 6. Lissamine Green Conjunctival Staining Pattern and Grade (NEI Scale) ............................. 70 


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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 
BPM 
Beats Per Minute 
CD34+ 
Transmembrane phosphoglycoprotein; protein encoded by the 
CD34 gene 
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 
CRO 
Contract Research Organization 
DBP 
Diastolic blood pressure 
ECM 
Extracellular matrix 
eCRF 
Electronic case report form 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
FGF2 
Fibroblast growth factor 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GVHD 
Graft-vs-Host Disease 
HR 
Heart rate 
ICD 
Informed consent document 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug Application 


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IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IWRS 
Interactive Web Response System 
LG 
Lissamine Green 
MedDRA 
Medical Dictionary for Regulatory Activities 
mm 
Millimeter 
MMRM 
Mixed model of repeated measurements 
NCI-CTCAE 
National Cancer Institute’s Common Terminology Criteria for 
Adverse Events 
NEI 
National Eye Institute 
NIH 
National Institute of Health 
OBS 
Ophthalmic Buffered Saline 
OD 
Right Eye 
ODD 
Orphan Drug Designation 
ODS 
Ocular Discomfort Score 
oGVHD 
Ocular Graft-vs-Host Disease 
OR 
Ocular surface redness 
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 


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SUSAR 
Serious and unexpected suspected adverse reaction 
TEAE 
Treatment-emergent adverse event 
TGF-β 
Transformed growth factor-beta 
UAR 
Unexpected Adverse Reaction 
UCVA 
Uncorrected Visual Acuity 
USA 
United States of America 
VAS 
Visual Analog Scale 
VA 
Visual Acuity 
VBR 
Validated Bulbar Redness 
WHO 
World Health Organization 
WOCP 
Women of child-bearing potential 


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INTRODUCTION
Ocular Graft vs Host Disease
Graft-vs-Host Disease (GVHD) is an autoimmune disorder that can occur in patients receiving allogeneic 
or, in rare instances, autologous hematopoietic stem cell transplantation (allo-HSCT and auto-HSCT) 
(Blazar 2012). Both acute GVHD and chronic GVHD are recognized as rare diseases (Genetic and Rare 
Diseases Information Center 2016a; Genetic and Rare Diseases Information Center 2016b; National 
Organization for Rare Disorders 2016). It is estimated that 60%-90% of GVHD patients experience 
oGVHD symptoms (Curtis 2015, Nassiri 2013, Shikari 2015; Sun 2015).
Ocular GVHD (oGVHD) is characterized as a chronic autoimmune ocular disorder in patients who suffer 
from GVHD. Pathologically, the disease is driven by the invasion of HSCT derived leukocytes onto the 
ocular surface of HSCT recipients, fibrosis, and excessive production of extracellular matrix (ECM) 
proteins. The donor leukocytes subsequently launch an autoimmune assault on the tear producing glands, 
cornea, conjunctiva, and eyelid of the eye, resulting in decreased tear production. Dry eye, pain and 
redness can develop any time from a few weeks up to 100 months after transplantation, and the median 
time is usually around 6 months (Nassiri 2013). In the chronic setting, oGVHD is commonly associated 
with severe dry eye symptoms including visual hazing, reduction in visual acuity, photophobia, excessive 
ocular redness (caused by hyperemia and telangiectasia), foreign body sensation, heightened ocular pain, 
and corneal perforation, melting, and ulceration (Curtis 2015; Westeneng 2010). The lack of tear film 
secretion from the damaged tear glands induces severe thinning, fibrosis, opacification, and atrophy of the 
ocular surface, particularly in the conjunctiva and cornea (Ban 2009; Ban 2011; Ogawa 2010; Wang 
2010). Punctuate keratopathy, filamentous keratitis, and high tear film osmolarity are also common signs 
of oGVHD (Nassar 2013; Wang 2010). Other notable oGVHD signs/symptoms in chronic patients 
include: severe eyelid inflammation (hyperemia and telangiectasia), severe blepharitis, lagophthalmos, 
eyelid dermatitis/perioribital hyperpigmentation, ectropion, poliosis, madarosis, and vitiligo (Nassar 
2013). If left untreated, oGVHD can cause significant vision loss and irreparable damage to the 
aforementioned tissues.
Product Rationale
OCU 300 is a sterile, preservative-free solution of brimonidine tartrate 0.18% in an ophthalmic 
nanoemulsion. It was developed to treat the signs and symptoms associated with oGVHD as defined by 
the International Chronic Ocular GVHD Consensus Group revised diagnostic criteria (see Appendix I) .
There is currently no FDA approved drug product for the treatment of oGVHD. Therefore, there is a 
significant clinical need for oGVHD treatment options that can be administered as topical ophthalmic 
formulations.
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). Brimonidine tartrate, the active component in 
OCU300, is an alpha-adrenergic receptor agonist that also mediates autoimmune leukocyte inflammation 
and down-regulates fibrosis formation, which are hallmarks of oGVHD (Piwnica, 2014).
Trial Rationale
OCU-300 may provide a clinical benefit to patients with oGVHD. The scientific rationale to establish a 
medically plausible basis for the use of OCU300 for the treatment of oGVHD include the following 
potential mechanisms:


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1.
Reduction of ocular surface blood flow: As an α agonist, brimonidine tartrate can significantly 
cause vasoconstriction leading to the reduction of blood flow to the ocular surface by reducing 
local pressure, edema, and inflammation (Piwnica 2014).
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 studied 
with brimonidine tartrate, activation of α2 receptors (with another α2 agonist) has been shown to 
suppress the reactivation of T lymphocytes (Felsner 1995). However, induction of neutrophil 
apoptosis with brimonidine has been reported in acute inflammation (Herrera-Garcia 2014).
4.
Analgesic properties: Brimonidine antagonizes or suppresses the excitatory response of 
phenylephrine and noradrenaline (Bradshaw 1984). As an α agonist, brimonidine may attenuate 
pro-inflammatory cytokine release from leukocytes, which in turn attenuates neuritis-induced 
pain (Romero-Sandoval 2007; Romero-Sandoval 2005).
5.
Reduction of fibrosis and suppression of excessive ECM formation: Fibrosis in oGVHD is 
characterized by an excessive number of CD34+ fibroblasts, excessive fibrosis, and over 
accumulation of ECM in the lacrimal glands leading to the dysfunction of this exocrine gland 
(Ogawa 2010). Brimonidine has been shown to attenuate the TGF-β1-induced production of 
ECM proteins, which in turn leads to the decrease in the synthesis of fibronectin and collagens in 
human fibroblasts (Hong 2015).
By attenuating autoimmune activity and inflammation, brimonidine tartrate helps the ocular surface and 
tear film producing glands to avoid further atrophy and to heal from damage sustained during an HSCT 
pre-conditioning regimen. In addition, brimonidine tartrate can alleviate elevated ocular pain through its 
analgesic and anti-inflammatory properties. This, in turn, makes the drug highly tolerable when 
administered directly to the ocular surface.
Summary of Known and Potential Risks and Benefits to Human 
Subjects
In this study, one drop of OCU300 (brimonidine tartrate nanoemulsion 0.18%) will be administered into 
each eye, two times a day (bid) for 84 days. The brimonidine tartrate concentration (0.18%) is less than 
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 (0.18%). 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


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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 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 300 for the relief treatment of ocular redness and ocular discomfort in 
patients with oGVHD.
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 for the treatment of ocular redness and ocular discomfort in patients with ocular 
oGVHD.
Study Endpoints
Co-primary Efficacy Endpoints
Two primary efficacy endpoints will be tested:
•
Ocular Redness based on a 100-point Validated Bulbar Redness (VBR) scale measuring change 
in appearance (pre-dose) from baseline to Day 84
•
Ocular discomfort based on a 10-point Visual Analog Scale (VAS) measuring change in intensity 
(pre-dose) from baseline to Day 84
Secondary Efficacy Endpoints
•
Change in Symptom Assessment iN Dry Eye (SANDE) questionnaire scores from baseline to 
Day 84
Exploratory Endpoints
•
Change from baseline in Validated Bulbar Redness (VBR) score at Days 28 and 56
•
Change from baseline in Ocular Discomfort Score at Days 28 and 56
•
Change from baseline in OSDI at 12 weeks (Day 84)
•
Change from baseline in corneal fluorescein staining at 12 weeks (Day 84)
•
Change from baseline in corneal lissamine green (LG) staining at 12 weeks (Day 84)
•
Change from baseline in conjunctival lissamine green (LG) staining at 12 weeks (Day 84)
•
Change from baseline in tear secretion as measured by Schirmer’s test
•
Clinical global impression of change in signs and symptoms from baseline (physician’s rating)
•
Subject global assessment of overall change from baseline (subject’s rating)


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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 15-20 centers. Upon meeting the eligibility criteria, enrolled subjects 
with a diagnosis of definite oGVHD will be randomly assigned in a 2:1 (test: control) fashion to receive 
either Brimonidine Nanoemulsion Eye Drops 0.18% investigational product (test) or ophthalmic buffered 
saline (placebo).
Up to 5 study visits are planned: including a screening period (Day -7 to 0), and 4 on-therapy visits at
Day 1, Day 28 ± 7 days (Week 4), Day 56 ± 7 days (Week 8), and Day 84 ± 7 days (Week 12) (See Table 
1). An informed consent document (ICD) must be obtained from each subject prior to the commencement 
of any study procedures. All subjects must be given ample time to review the ICD and ask questions 
regarding the study prior to participation in the study. The subject will be provided a copy of the signed 
ICD.
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 84 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 
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
oGVHD is an orphan disease with no ophthalmic drug products approved for its treatment. There is a 
significant therapeutic need for an oGVHD ophthalmic formulation that mediates autoimmune leukocyte 
inflammation and fibrosis, with low occurrence of long-term ocular AEs. An Orphan Drug Designation 
(ODD) was granted for brimonidine tartrate for the treatment of oGVHD (Designation request #16-5640) 
on 03 August 2017.
The criteria for evaluation, study assessments, and follow-up period are consistent with the standard of 
care for the treatment of oGVHD. The National Institutes of Health (NIH) suggests using patient-reported 
outcomes (PRO) for the response of oGVHD to treatments (Martin 2015, Lee 2015). Therefore, ocular 
discomfort (a measure of ocular pain), a subjective score, and ocular redness, an objective score, are the 
co-primary endpoints. Additional subjective scores, SANDE and SGA, will also be evaluated.
SELECTION AND WITHDRAWAL OF SUBJECTS
Number of Subjects
At least 60 participants will be randomly assigned to the study treatment such that approximately 40 
evaluable subjects per active arm (OCU300) and 20 per placebo arm (OBS) complete the study (2:1 
randomization).


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Subject Inclusion Criteria
Subjects must meet all the following inclusion criteria to be eligible to enroll in the clinical trial:
1.
Men or women ≥ 18 years of age
2.
Diagnosis of “definite oGVHD” in at least one eye
The diagnosis of ‘definite’ oGVHD will be made using the International Chronic Ocular 
GVHD Consensus Group Revised Diagnostic criteria. The Consensus Group Severity Scale 
is based on the cumulative grading of 4 individual scores (See Appendix I):
•
Schirmer’s Test (tear film secretion levels)
•
Corneal staining score
•
Conjunctival Injection
•
OSDI score
3. Ocular Discomfort Score ≥ 3 
4. Validated Bulbar Redness score ≥ 40 in both eyes
5. Subjects who are capable and willing to provide informed consent and follow study instructions
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 at the screening 
visit; and who are either abstinent or sexually active on an acceptable method of birth control 
(oral contraceptive pills, birth control implants/shots or patches, barrier methods) for at least 
4 weeks prior to baseline visit (Day 1) and throughout the study, 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
2.
Currently receiving brimonidine or other treatment for glaucoma.
3.
Receiving or have received any experimental or investigational drug or device within 30 days 
prior to screening visit. 
4.
Use of contact lenses within 14 days prior to Screening visit or planned use during the study.
5.
Active ocular infection or ocular allergies
6.
Any history of eyelid surgery or ocular surgery within the past 3 months
7.
Corneal epithelial defect larger than 1 mm2 in either eye
8.
Received corticosteroid-containing eye drops within 14 days prior to Screening visit or


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planned use during the study.
9.
Any change in systemic corticosteroids/immunosuppressive, topic ocular antibiotics, 
cyclosporine ophthalmic emulsion 0.05% (Restasis®), cyclosporine ophthalmic solution 
0.09% (Cequa™), lifitegrast ophthalmic solution 5% (Xiidra®), or autologous serum tears 
within 30 days prior to Screening visit or planned change during study. 
Note: Subjects will be permitted to continue all their current ocular treatments, including the use of 
artificial tears, eyelid massage, punctal plugs, or warmcompresses, if they commit to using the same 
brand/regimen throughout the study. None of the ocular treatments, whether OTC or prescription (e.g. 
Restasis®, Xiidra® or Cequa™) 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. If 
a punctal plug is lost during the study, it may be replaced. 
Not applicable.
Randomization Criteria
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. A subject will be discontinued from the study for any of the following reasons: 
•
Pregnancy
•
At the discretion of the Investigator at any time
•
At the subject’s request (voluntary withdrawal)
•
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, 
represents an unacceptable risk to the subject if he/she continues in the study. 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 are discontinued outside of any 
scheduled visit will be encouraged to return to the clinic to complete a final study visit, which will consist 
of all day 84 assessments. 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, including the 
completion of the Validated Bulbar Redness Scale (VBR), the Visual Analog Scale (VAS), and the 
Symptom Assessment iN Dry Eye (SANDE) Questionnaire. Subjects who discontinue following study 
drug administration will not be replaced. 
The reason for study withdrawal is to be documented in the subject’s source documents and CRFs, as 
follows:


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1. Adverse event
2. Subject voluntary withdrawal
3. Investigator withdrawal of subject
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. 
Table 4. Study Schedule of Events
Screening and Baseline 
Visit*
Dosing and Evaluation
Visit number
Day (Time)
Day –7 to
Day –0
Day 1
(Baseline)
Day 28 ± 7d
(Week 4)
Day 56 ± 7d
(Week 8)
Day 84 ± 7d
(Week 12)
Informed consent
X
Eligibility criteria
X
X
Demographic Information
X
Medical/surgical/ocular history1
X
Body weight and height2
X
Vital signs (body temperature, 
heart rate, blood pressure,
respiratory rate)3
X
X
X
X
Review of prior and concomitant 
medications4
X
X
X
X
X
Urine collection and Pregnancy
test (females of childbearing 
capacity only; hCG dipstick)5
X
X
X
X
X
Ocular 
Exam
Ocular Discomfort 
10-point VAS6
X
X
X
X
X
OSDI; ocular 
surface disease
index (points)7
X
X
X
X
X


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Visual acuity8 
X 
X 
X 
X 
Symptom 
Assessment in Dry 
eye (SANDE)9 
X 
X 
X 
X 
Ocular redness 100 
-point VBR scale 
via slit lamp10 
X 
X 
X 
X 
X 
Conjunctival 
Injection (points)11 
X 
Slit lamp 
ophthalmic exam 
X 
X 
X 
X 
X 
Corneal fluorescein 
stain (CFS; 
points)12 
X 
Corneal fluorescein 
stain (NEI scale)13 
X 
X 
X 
X 
Corneal Lissamine 
green14 
X 
X 
X 
X 
Conjunctival 
Lissamine green 
stain15 
X 
X 
X 
X 
Schirmer’s test 
with anesthesia 
(mm, points)16 
X 
X 
X 
X 
X 
Intraocular 
pressure17 
X 
X 
X 
X 
X 
Clinical Global 
Impression (CGI) 
X 
X 
X 
Subject Global 
Assessment (SGA) 
X 
X 
X 
Randomization 
X 
Dispense/Instill Investigative 
Product 
X18 
X 
X 
Adverse event surveillance 
X 
X 
X 
X 
X 
Diary recording and review19 
X 
X 
X 
X 
*Maximum 7-day screening period prior to randomization. Duplication of assessments during this period is not 
required; however, results of some assessments (e.g. corneal fluorescein staining) will be used for both screening and 
baseline purposes. 
 
1. 
The ocular history will include any previously diagnosed ophthalmic abnormalities and ocular surgeries (including 
laser procedures). 
2. 
BMI to be auto-calculated from weight and height using the BMI formula; BMI= (Weight in pounds/ (Height in inches 
X Height in inches)) x 703 
3. 
Baseline Vital signs on Day 1 to be completed at least 30 ± 10 mins before dose on Day 1. All other vitals to be 
completed before ocular assessments on Days 28, 56, and 84 
4. 
Review of prior and concomitant medications and regimens will occur at all study visits. Corticosteroid-containing eye 
drops are not allowed within 14 days prior to Screening or during the study. Subjects will be permitted to continue all 
their current ocular treatments, including the use of artificial tears, eyelid massage, punctal plugs, or warmcompresses, 
if they commit to using the same brand/regimen throughout the study. None of the ocular treatments, whether OTC or 
prescription (e.g. Restasis®, Xiidra® or Cequa™) 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. If a punctal 
plug is lost during the study, it may be replaced. 
5. 
hCG = human chorionic gonadotrophin. A urine pregnancy test is required at screening. A urine pregnancy test may be 
performed at any time during study participation if pregnancy is suspected. 
6. 
To evaluate intensity of Ocular Discomfort, patients will be asked to rate their worst ocular pain/discomfort in the 
preceding 24 hours using a 10-point scale ranging from “None” (score 0 to “Unbearable/Excruciating” (score 10). 
7. 
OSDI will be completed at all visits and is assessed on a scale of 0 to 100, with higher scores representing greater 
disability. In determining subject eligibility, 0-3 points will be assessed based on the score. (Ogawa, 2013) 
8. 
Subjects should use the most recent correction to attain their best-corrected visual acuity (BCVA). 


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9.
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 on Day 1 prior to first dose 
(Baseline), Day 28, Day 56, and Day 84.
10. 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.
11. In determining subject eligibility, conjunctival injection grading of each eye, OS and OD, will be assessed, with Grade 
0 = none [0 points]; Grade 1 = mild/moderate injection [1 point]; and Grade 2 = severe injection [2 points]. (Ogawa, 
2013)
12. In determining subject eligibility, corneal fluorescein stain (CFS) grading of each eye, OS and OD, will be assessed, 
with Grade 0 = no staining [0 points], Grade 1 = minimal staining [1 point], Grade 2 = mild/moderate staining [2 
points], Grade 3 = severe staining [3 points] (Ogawa, 2013)
13. Each eye (OS and OD) CFS=corneal fluorescein stain grading. Corneal staining will be graded in 5 zones in each eye 
using the NEI scale. Each zone will be graded from 0 to 3 based on the density of punctate staining (maximum 
score/eye =15)
14. Corneal lissamine green staining using a solution made from Lissamine Green Ophthalmic Strips. Corneal staining will 
be graded in 5 zones in each eye using the NEI scale. Each zone will be graded from 0 to 3 based on the density of 
punctate staining (maximum score/eye =15)
15. 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 using the NEI scale (maximum score/eye = 6).
16. Anesthetize each eye (OS and OD) with a drop of proparacaine. Insert Schirmer strips into lower lid for 5 min. If 
tearing exceeds 15 mm [0 points]; 11-15 min [1 point]; 6-10 mm [2 points]; <5 mm [3 points] (Ogawa, 2013).
17. Measure intraocular pressure using Goldman applanation tonometry.
18. 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 each 
study visit (except the Day 84 visit) for self-administration during the study.
19. Subject diaries must be reviewed by the study staff at each visit prior to the subject leaving the clinic.
. 
Study Visits
Unscheduled Study Visits
Unscheduled visits may be completed between the scheduled follow-up periods, at the Investigator’s 
discretion, or if subjects experience AEs that necessitate an unscheduled visit. Subsequent unscheduled 
visits may be necessary following the report of an AE. Additional examinations may be conducted at 
these visits as necessary to ensure the safety and well-being of subjects during the study. Case report 
forms (CRFs) should be completed for each unscheduled visit.
Screening
There is a maximum 7-day period for completing all screening tests prior to randomization. Therefore, the 
Screening Visit and Day 1 Visit may be combined into a single visit lasting up to 7 days. In this case, 
there is no need to duplicate any of the Screening/Day 1 procedures. An ICD must be obtained from each 
subject before initiation of any study-related procedures.
The following procedures and assessments should be completed at the Screening Visit:
•
Informed Consent
•
Diagnosis of definite chronic oGVHD using points for Schirmer’s, CFS, OSDI, Conjunctival 
injection (see Appendix 1)(Table 6)(Table 7)(Table 11) 
•
Inclusion and Exclusion criteria check
•
Demographic information including: birth date, gender, race, and ethnic origin


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•
Medical history including prior procedures and conditions
•
Ophthalmic history including: date when the oGVHD began, medications used by the subject to 
treat oGVHD, previous procedures to treat oGVHD. 
•
Review of prior and concomitant medications: medications used by the subject to treat oGVHD, 
previous procedures to treat oGVHD; OTC medications; medications for chronic diseases
•
Urine collection and dipstick test for pregnancy in women of child bearing capacity
•
Ocular Discomfort 10-point VAS
•
Ocular surface disease index (OSDI) (severity points, for diagnosis of oGVHD)
•
Ocular Redness 100-point VBR scale
•
Conjunctival injection (severity points, for diagnosis of oGVHD)
•
Slit-lamp ophthalmic exam
•
Corneal fluorescein (CFS) (severity points, for diagnosis of oGVHD)
•
Schirmer’s test with anesthesia (severity points, for diagnosis of oGVHD)
•
Intraocular pressure (IOP)
•
Adverse event surveillance
Day 1 (Baseline, Randomization, and First Treatment Visit)
Baseline: The following should be completed prior to the first dose
•
Inclusion and Exclusion criteria confirmation
•
Body weight (pounds) and height (inches)
•
Vital Signs: body temperature, heart rate, blood pressure, respiratory rate (measured after the 
subject has been sitting for approximately 3-5 minutes) 
•
Urine collection and dipstick test for pregnancy in women of child bearing capacity
•
Review of prior and concomitant medications
•
Ocular Discomfort 10-point VAS
•
Ocular surface disease index (OSDI)
•
Visual Acuity
•
Symptom Assessment iN Dry Eye (SANDE)
•
Ocular Redness 100-point VBR scale
•
Slit-lamp ophthalmic exam
•
Corneal fluorescein(CFS) (NEI scale)
•
Corneal lissamine green
•
Conjunctival lissamine green


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•
Schirmer’s test with anesthesia
•
Intraocular pressure (IOP)
•
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) and record first dose. 
•
Make appointment for next visit
Day 28 (± 7 days)
•
Vital Signs: body temperature, heart rate, blood pressure, respiratory rate (measured after the 
subject has been sitting for approximately 3-5 minutes) 
•
Urine collection and dipstick test for Pregnancy in women of child bearing capacity
•
Review of prior and concomitant medications
•
Ocular Discomfort 10-point VAS
•
Ocular surface disease index (OSDI)
•
Visual acuity
•
Symptom Assessment iN Dry Eye (SANDE)
•
Ocular Redness 100-point VBR scale
•
Slit-lamp ophthalmic exam
•
Corneal fluorescein (CFS) (NEI scale)
•
Corneal lissamine green
•
Conjunctival lissamine green
•
Schirmer’s test with anesthesia
•
Intraocular pressure (IOP)
•
Clinical Global Impression
•
Subject Global Assessment
•
Collect used investigative products
•
Dispense investigative product kit


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•
Adverse event surveillance
•
Diary collection and review
Day 56 (± 7 days)
•
Vital Signs: body temperature, heart rate, blood pressure, respiratory rate (measured after the 
subject has been sitting for approximately 3-5 minutes)
•
Urine collection and dipstick test for pregnancy in women of child bearing capacity
•
Review of prior and concomitant medications
•
Ocular Discomfort 10-point VAS
•
Ocular surface disease index (OSDI)
•
Visual acuity
•
Symptom Assessment iN Dry Eye (SANDE)
•
Ocular Redness 100-point VBR scale
•
Slit-lamp ophthalmic exam
•
Corneal fluorescein (CFS) (NEI scale)
•
Corneal lissamine green
•
Conjunctival lissamine green
•
Schirmer’s test with anesthesia
•
Intraocular pressure (IOP)
•
Clinical Global Impression
•
Subject Global Assessment
•
Collect used investigative products
•
Dispense investigative product kit
•
Adverse event surveillance
•
Diary collection and review
Day 84 (± 7 days)
•
Vital Signs: body temperature, heart rate, blood pressure, respiratory rate (measured after the 
subject has been sitting for approximately 3-5 minutes)
•
Urine collection and dipstick test for pregnancy in women of child bearing capacity
•
Ocular Discomfort 10-point VAS
•
OSDI
•
Visual acuity


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• 
Symptom Assessment iN Dry Eye (SANDE) 
• 
Ocular Redness 100-point VBR scale 
• 
Slit lamp ophthalmic exam 
• 
Corneal fluorescein (CFS) (NEI scale) 
• 
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 collection and review 


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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 Visit 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 Visit, a urine dipstick pregnancy test will be performed for all female subjects of 
child-bearing potential. Additionally, a urine pregnancy test may be performed at any time during study 
participation if pregnancy is suspected. 
Efficacy Assessments
Primary Efficacy Assessment
There are two co-primary efficacy endpoints.
•
Ocular Redness based on a 100-point Validated Bulbar Redness (VBR) scale measuring 
change in appearance from baseline to Day 84
•
Ocular Discomfort based on a 10-point Visual Analog Scale (VAS) measuring change in 
intensity from baseline to Day 84 
6.4.1.1
Validated Bulbar Redness (VBR) grading scale
Ocular surface redness (OR; nasal or temporal) will be assessed using the VBR grading scale (Schulze 
2007). 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 18.3; Figure
2). 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.
6.4.1.2
Ocular Discomfort (VAS)
Symptom scales often measure both intensity and frequency. In this study, the intensity of ocular 
discomfort in oGVHD has been selected as a co-primary endpoint and this will be reflected in the visual 
analogue scale. The term ocular discomfort is meant to capture the ocular surface pain and discomfort 
experienced by oGVHD patients, often described as “pain”, “burning”, “grittiness”, and “photophobia”, 
or a combination thereof. Because the ocular discomfort associated with oGVHD is chronic in nature, the


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frequency of episodic pain will not be captured by the pain VAS. (see Section 18.2, Figure 1) Ocular 
discomfort (VAS) will be assessed at each clinic visit.
Secondary Efficacy Assessment
6.4.2.1
Symptom Assessment iN Dry Eye (SANDE)
The SANDE questionnaire is a short visual analog assessment scale that quantifies both severity and 
frequency of dry eye symptoms. The SANDE is comprised of two questions, and each question employs a 
100-mm horizontal linear VAS (Figure 3). The measurement of symptom frequency ranges from “rarely” 
to “all of the time,” and the symptom severity from “very mild” to “very severe.” Subjects will complete 
this scale on Day 1 prior to first dose (Baseline), Day 28, Day 56, and Day 84. 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).
Exploratory Efficacy Assessments
6.4.3.1
Ocular Surface Disease Index (OSDI)
The OSDI© is a validated and reliable instrument for measuring dry eye disease (normal, mild to 
moderate, and severe) and effect on vision-related function (Figure 4). The OSDI will be completed at 
each clinic visit and is assessed on a scale of 0 to 100, with higher scores representing greater disability. 
The index demonstrates sensitivity and specificity in distinguishing between normal subjects and patients
with dry eye disease (see Section 18.5). The OSDI will be used as part of the Chronic Ocular GVHD 
Consensus Group criteria for diagnosing oGVHD (Ogawa, 2013). The OSDI will be completed at all 
follow-up visits. 
6.4.3.2
Corneal Staining Score with Fluorescein
Staining of the corneas in each eye (OS and OD) will be conducted using the slit lamp at each clinic visit. 
At Screening, central corneal fluorescence staining (CFS) will be evaluated as per the methods described 
in Ogawa, 2013and adapted for this trial (Table 9)(Table 10). (See section 18.7), and for baseline and 
subsequent measurements, the NEI scale will be used.
6.4.3.3
Corneal and Conjunctival Staining Score with Lissamine Green
Corneal and conjunctival staining with Lissamine Green dye (1%; LG) staining in each eye (OS and OD) 
will be conducted using the slit lamp on Day 1 prior to first dose (Baseline), Day 28, Day 56, and Day 84 
and evaluated using the NEI scale. A single drop of 1% Lissamine Green dye will be applied to the 
inferior conjunctival fornix of both eyes. The conjunctivae will be examined with the slit lamp at ×10 
magnification, using a neutral-density filter, graded in two zones. Corneal staining will be graded in 5 
zones, as per the methods described in Section 18.6 (Table 8)(Figure 5)(Figure 6). 
6.4.3.4
Schirmer’s test
At each clinic visit, a Schirmer’s test will be conducted 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 


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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, at the Screening visit, the 
Sponsor will convert to categories consistent with the chronic oGVHD Consensus Group criteria 
(Appendix 1; Ogawa, 2013), based on the number of mm of wetting of the paper after 5 minutes, as 
follows: 
1. Normal is >15 mm 
2. Mild dry eye is 11-15 mm 
3. Moderate dry eye is 6-10 mm 
4. Severe dry eye is ≤5 mm 
6.4.3.5 Clinical Global Impression (CGI) 
At Day 28, Day 56, and Day 84, 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): 
 
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, Day 56, and Day 84, the subjects will be asked to assess their overall change from baseline. 
The SGA is assessed as follows (Miller 2010): 
 
Question (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 


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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 week 12 who were able to successfully complete a full 12 weeks 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. 
Visual Acuity
Monocular visual acuity will be completed with the subject’s best correction vision in place using 
standard of care ETDRS chart, at Day 1 prior to the first dose (Baseline), Day 28, Day 56, and Day 84. 
Procedures for BCVA are outlined in Section 18.9 (Figure 7)(Table 12). 
IOP - Goldmann Applanation
IOP will be assessed in both eyes, at each clinic visit, using the Goldmann applanation tonometry method 
(see Section 18.10). 
Ophthalmic Examination (Slit Lamp)
Biomicroscopic examination will be completed at each clinic visit (see Section 18.11)(Table 13). The 
conjunctiva, cornea, anterior chamber, lens and anterior vitreous of each eye will be examined. 
Vital Signs
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) at Day 1, Day 28, Day 56, and Day 84 by 
the study staff. 
Clinically significant negative changes from baseline will be recorded as adverse events.


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INVESTIGATIONAL DRUG INFORMATION AND MANAGEMENT
Investigational Drug Dose Regimen
The proposed dose is one drop of OCU300 in each eye (OU) every 12 hours. The proposed dosing 
regimen is twice daily (bid).
Dose Rationale
Brimonidine 0.2% is currently used topically as eye drops, 2-3 times a day, for the lowering of intraocular 
pressure in patients with open-angle glaucoma or ocular hypertension. 
OCU300 has a dosage strength of 0.18% brimonidine tartrate in a preservative-free nanoemulsion and is 
applied as a single drop to each eye, twice daily. This proposed dose of OCU300 is selected based on data 
available from the listed drug (LD) and associated Alphagan® ophthalmic products. The emulsion 
formulation, with a pH buffered to maintain the optimum range for ocular delivery, is expected to prolong 
the precorneal residence time, and increase aqueous humor drug levels. Based on these pharmaceutical 
attributes as well as preliminary clinical data, it is suggested that a 0.18% concentration of brimonidine in 
the proposed OCU300 ophthalmic emulsion formulation with twice-daily application will be able to exert 
therapeutic effects. The potential protective effect of OCU300 brimonidine tartrate (0.18%) against 
corneal epithelial damage in comparison to a placebo nanoemulsion and a marketed product was 
demonstrated in a mouse dry-eye disease model, supporting the selection of OCU300 proposed dose 
(Arumugham 2018). These results infer that OCU300 provided better protection for corneal epithelial 
damage than the reference product Restasis® and Placebo (vehicle).
Moreover, 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 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 OCU300 
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 “OCU300 Brimonidine Tartrate Ophthalmic 
Nanoemolusion 0.18% or Placebo”, or similar language, 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. 


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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 (28 days 
between visits plus 7-day visit window) of eye-dropper vials for self-administration at home. A similar 
supply will be given to the patient upon completion of the Day 28 and Day 56 visits. 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.
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


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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 bottle/vials 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.
Prohibited Medications or Treatment
Corticosteroid-containing eye drops are not permitted within 14 days prior to Screening or during the 
study. Subjects will be allowed to remain on current concomitant 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.
Specifically, subjects will be permitted to continue all their current ocular treatments, including the use of 
artificial tears, eyelid massage, punctal plugs, or warmcompresses, if they commit to using the same 
brand/regimen throughout the study. None of the ocular treatments, whether OTC or prescription (e.g.
Restasis® ,Xiidra® or Cequa™) 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. If 
a punctal plug is lost during the study, it may be replaced.
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 84 (last study day) in this study.
Treatment Compliance
Treatment compliance will be documented with subject diaries. Subjects will be dispensed diaries at the 
Day 1 Visit and will be instructed to record the time(s) (a.m. or p.m.) at which bid dosing occurred.
Subject diaries must be reviewed by the study staff at each visit prior to the subjects’ leaving the clinic.


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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 2:1 ratio to OCU300 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 Brightech International, LLC (Somerset, NJ) 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 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 
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.


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ADVERSE EVENTS
Adverse 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 Title 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(R2): 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 E6R2 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.
•
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


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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. 
 
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)). 


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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 severity of AEs experienced by study participants according to the criteria
set forth in the National Cancer Institute’s Common Terminology Criteria for Adverse Events Version 5.0. 
This document (referred to herein as the “NCI-CTCAE manual”) provides a common language to
describe levels of severity, to analyze and interpret data, and to articulate the clinical significance of AEs. 
Please refer to the NCI-CTCAE manual for the desired event and specific grading for that event. 
If the event is not listed in the NCI-CTCAE manual, please refer to the following standards in the 
NCI-CTCAE manual:
•
Grade 1 = mild; asymptomatic or mild symptoms, clinical or diagnostic observations only, 
intervention not indicated
•
Grade 2 = moderate minimal, local or noninvasive intervention indicated, limiting
age-appropriate instrumental activities of daily living (ADL), e.g. preparing meals, shopping 
for groceries or clothes, using the telephone, managing money 
•
Grade 3 = severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL 
(e.g. bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden) 
•
Grade 4 = life-threatening consequences; urgent intervention indicated
•
Grade 5 = death related to AE
For additional information and a printable version of the NCI-CTCAE manual, go to 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
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


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Note: The terms serious and severe are not synonymous. Serious criteria as defined in Section 10.1.5.2 
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. 
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


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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 
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 oGVHD regimen or confound the assessment of the patient’s signs or 
symptoms of oGVHD.. 
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. 


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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
•
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 G2 BioPharma SAE 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 Project Manager 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
 - Office
 – Cellular
Email:
24-Hour Contact: 
G2 BioPharma Safety Project Manager


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G2 BioPharma Services, Inc. 
3637 Brunswick Pike 
Princeton, NJ 08540 
Email: 
 
Phone: 
 
 
 
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 G2 BioPharma Services. 
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: 
 
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. 


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•
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 
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 OCU300 vs OBS eyedrops with co-primary 
endpoints. Tests will be conducted using two-sided alpha = .05.
Unit of Analysis
For eye-specific assessments (e.g., ocular redness), the unit of analysis for the efficacy measures will be 
the average of study-eligible eyes in each subject. Efficacy measures will be summarized using the 
average value between the two eyes within a subject and within a visit. For subject-level assessments (e.g. 
ocular discomfort), the unit of analysis for the efficacy measures will be the subject. Safety analyses will


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be performed on each eye separately (OD and OS) with the exception of adverse events, which will be 
presented at the subject level, where ocular adverse events will be considered as occurring if either eye 
had the adverse event. Safety measures captured at the subject level will be summarized at the subject 
level.
Power and Sample Size Determination
The sample size is calculated based on limited data (
, May 24, 2017) on OSDI/SGA (as 
proxy endpoints to ocular discomfort), and ocular redness score (as a proxy endpoint for VBR). With a 
two-sided alpha of 0.05, a sample size of 60 patients in a 2:1 randomization (40 in OCU300, 20 in 
control) would provide more than 90% power to detect a difference of 0.47 (SD 0.39) in the mean 
difference in change from baseline in the validated bulbar redness score (VBR). This sample size provides 
about 85% of power to detect a clinically meaningful difference in ocular discomfort as measured by the 
ocular discomfort score (ODS). Since the sample size is calculated using indirect information, a sample 
size re-estimation is planned at an interim analysis when data from 50% of patients are available. If the 
conditional power is less than 90%, the sample size will be increased to provide sufficient power. To 
control type I error, a two-sided alpha of 0.0002 will be spent at the interim analysis, and the two-sided 
alpha for the final analysis will be 0.0498. If sample size is modified, the final critical value of 0.0498 
will be adjusted to control type I error. The details of the interim analysis will be provided in the 
Statistical Analysis Plan (SAP).
Primary Efficacy Endpoint(s):
• Ocular redness based on a 100-point Validated Bulbar Redness (VBR) scale measuring change in 
appearance from baseline to Day 84
• Ocular discomfort based on a 10-point Visual Analog Scale (VAS) measuring change in intensity 
from baseline to Day 84 
Secondary Efficacy Endpoint(s):
• Change in Symptom Assessment iN Dry Eye (SANDE) questionnaire scores from baseline to Day 
84
Exploratory Endpoint(s):
•
Change from baseline in in Validated Bulbar Redness (VBR) score at Days 28 and 56
•
Change from baseline in in Ocular Discomfort Score at Days 28 and 56
•
Change from baseline in OSDI at 12 weeks (Day 84)
•
Change from baseline in corneal fluorescein staining at 12 weeks (Day 84)
•
Change from baseline in corneal lissamine green (LG) staining at 12 weeks (Day 84)
•
Change from baseline in conjunctival lissamine green (LG) staining (Oxford scale) at 12 weeks 
(Day 84) 
•
Change from baseline in tear secretion as measured by Schirmer’s test


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•
Clinical global impression of change in signs and symptoms from baseline (physician’s rating)
•
Subject global assessment of overall change from baseline (subject’s rating)
Analysis Populations
The analysis populations are defined as follows:
•
The safety population is defined as all subjects all subjects who have signed informed consent 
were randomized into the study and took at least one dose of study drug.
•
The intent-to-treat (ITT) population is defined as all randomized subjects.
•
The per-protocol (PP) population is defined as all ITT subjects who have no major protocol 
deviations. The PP population will be identified prior to database lock and treatment unmasking.
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 evaluation of efficacy will be a co-primary endpoint of bulbar redness as measured by VBR 
and ocular discomfort as measured by the ODS after 12 weeks dosing (Day 84). The primary efficacy 
analysis will be performed on the Intent-to-Treat population.
The following two sets of hypotheses will be tested as the primary hypotheses of the study:
Hypothesis
The statistical hypotheses for the primary endpoint of the mean change from baseline bulbar redness score 
(VBR) at 12 weeks (Day 84) are as follows:
H01:  The difference (OCU 300 minus placebo), between study eyes treated with the OCU 300 
and study eyes treated with placebo (OBS) in the mean change from baseline VBR score 
at 12 weeks (Day 84) = 0.
HA1:  The difference (OCU 300 minus placebo), between study eyes treated with the OCU 300 
and study eyes treated with placebo in the mean change from baseline VBR score at 12 
weeks (Day 84) ≠ 0.
The statistical hypotheses for the primary endpoint of the mean change from baseline ocular discomfort
score (ODS) at 12 weeks (Day 84) are as follows:


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H02:  The difference (OCU 300 minus placebo), between subjects treated with the OCU 300 and 
subjects treated with placebo (OBS) in the mean change from baseline ODS at 12 weeks 
(Day 84) = 0. 
 
HA2:  The difference (OCU 300 minus placebo), between subjects treated with the OCU 300 and 
subjects treated with placebo (OBS) in the mean change from baseline ODS at 12 weeks 
(Day 84) ≠ 0. 
 
To control family-wise type I error, the primary endpoints will be tested with the Hochberg procedure: 
o If the p-values for both VBR and ODS are less or equal to 0.05, then both null 
hypotheses will be rejected, and alternative hypotheses claimed; 
o If the p-value for either parameter VBR or ODS is greater than 0.05, then a p-value 
of 0.025 will be required to reject the null hypothesis for the test on the other 
parameter; 
In general, continuous variables will be presented as the number of non-missing values, mean, standard 
deviation, median, minimum, maximum, and quartiles. For categorical variables, descriptive statistics will 
include counts and percentages per category. Confidence intervals (CI) will be computed when 
appropriate, usually as 95% intervals. 
11.4.2.2 Efficacy Analyses—General Considerations 
The primary efficacy analyses will be conducted on the ITT population and the comparison will be made 
based on the randomized treatment. The same set of efficacy analyses will also be performed on per- 
protocol population. For efficacy endpoints where measurements from both eyes are available, a single 
mean will be calculated for the analyses. For continuous endpoints, the change from baseline will be 
summarized with descriptive statistics for the values at baseline, values at each time point (Days 28, 56 
and 84), 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. Percent change from baseline may also be summarized in a 
similar manner. 
 
Primary and key secondary continuous endpoints will be analyzed using a mixed model of repeated 
measurements (MMRM) under a missing at random (MAR) assumption. The model will use an 
unstructured covariance matrix and include treatment, visit, and visit-by-treatment interaction as fixed 
terms. A sensitivity analysis using pattern-mixture model with control- based pattern imputation will be 
performed to compare with the results of the primary analysis. 
 
For categoric endpoints, such as the severity scores, the analysis will be performed by using the Cochran– 
Mantel–Haenszel test (CMH) method controlling for baseline scores. The null hypothesis for categorical 
endpoints is that there is no association between the treatment assignment and the outcomes for each 
category; the alternative hypothesis is that there is an association. 


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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 family-wise type I error, the primary endpoints will be tested with the Hochberg procedure
11.4.3.3 Missing Data
Primary and key secondary continuous endpoints will be analyzed using a mixed model of repeated 
measurements (MMRM) under a missing at random (MAR) assumption. A sensitivity analysis using 
pattern-mixture model with control- based pattern imputation will be performed to compare with the 
results of the primary analysis.
Exploratory analyses will be based on observed data. Missing data will not be imputed.
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.


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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.
Data Collection and Management
This study will be conducted in compliance with the ICH document E6(R2) Good Clinical Practice: 
Integrated Addendum to ICH E6(R1). This study will also be conducted in accordance with the 
Declaration of Helsinki (2013).
This study will use Brightech International’s Clinical Information Management Suite (CIMS) 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 of Brightech International in accordance with 
their SOPs for data management and a formal study data management plan.


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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.
Ethical Conduct of the Study
The Investigator is to 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 document 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. Verbal consent will 
be accepted for subjects who are unable to read or write. 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


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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 
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.


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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.
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.
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OCU300 Nanoemulsion for the Treatment of Ocular Graft Versus Host Disease oGVHD. Invest.
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Adkins JC, Balfour JA. Brimonidine. A review of its pharmacological properties and clinical potential in 
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Ban Y, Ogawa Y, Goto E, Uchino M, Terauchi N, Seki M, et al. Tear function and lipid layer alterations 
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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 
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Blazar BR, Murphy WJ, Abedi M. Advances in graft-versus-host disease biology and therapy. Nat Rev 
Immunol 2012; 12(6):443-458. 
 
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Caraceni A, Cherny N, Fainsinger R, Kaasa S, Poulain P, Radbruch L, et al. Pain measurement tools and 
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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. 
 
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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. 
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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. 


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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. 
 
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. 


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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. 
 
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. 


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APPENDICES
Appendix 1 Diagnosis of Definite oGVHD
The diagnosis of ‘definite’ oGVHD shall be made using the International Chronic Ocular GVHD 
Consensus Group revised diagnostic criteria. The Consensus Group Severity Scale is based on the 
cumulative grading of 4 individual scores (see Table 6):
1.
Schirmer’s Test,
2.
Corneal staining score,
3.
Conjunctival Injection, and
4.
OSDI score.
Assign a severity score from 0 to 3 to each of the assessments below, except for conjunctival injection, 
which should be scored from 0 to 2 points. The sum of the 4 severity scores (in points) gives a total, or 
aggregate, score for each eye. 
Table 6. International Chronic Ocular GVHD Consensus Group Severity Scale for oGVHD
Severity score 
(points)
Schirmer’s test 
(mm)
CFS*
(Grade)
OSDI
(Score)
Conjunctival 
Injection 
(Description)
0 
>15
None 
(Grade 0) 
<13
None
1 
11-15
Minimal 
(Grade 1)
13-22
Mild/Moderate
2 
6-10
Mild/Mod 
erate 
(Grade 2)
23-32
Severe
3 
<5 
Severe 
(Grade 3) 
>33
CFS = Corneal fluorescein staining, OSDI = Ocular Surface Disease Index 
Source: Table adapted from Ogawa, 2013; *For CFS, see appendix 18.7
Based on the aggregate score and the presence or absence of systemic GVHD, a diagnosis of oGVHD 
will be made for each eye. For example, in the presence of systemic GVHD, aggregate score 0-3 indicates 
absence of oGVHD (i.e., “none”), aggregate score 4-5 indicates “probable” oGVHD, and aggregate score
>6 indicates “definite” oGVHD. In the absence of systemic GVHD, aggregate score 0–5 indicates 
absence of oGVHD (i.e., “none”), aggregate score 6–7 indicates “probable” oGVHD, and aggregate score
≥ 8 indicates “definite” oGVHD. (see Table 7) 


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Table 7. Diagnosis of Chronic oGVHD 
 
Systemic GVHD 
No oGVHD 
(points*) 
Probable oGVHD (points*) 
Definite oGVHD 
(points*) 
Absent 
0-5 
6-7 
≥8 
Present 
0-3 
4-5 
≥6 
GVHD = graft versus host disease 
Source: Adapted from Ogawa 2013. Refer to Appendix 18.7 
* Points are aggregate severity scores from 4 diagnostic tests (see Table 6 above). 
 
The above assessment will be measured independently on each eye at the Screening visit. Subjects who 
meet the diagnosis of “definite oGVHD” in at least one eye satisfy Inclusion Criterion #2. 


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18.2
Appendix 2 Ocular Discomfort Scale
To evaluate intensity of Ocular Discomfort, patients will be asked to rate their worst ocular 
pain/discomfort in the preceding 24 hours using a 10-point scale ranging from “None (score 0” to 
“Unbearable/Excruciating (score 10)”. This type of severity scale has been validated as an assessment of 
pain intensity in multiple populations. Moreover, it has been recommended as the primary endpoint for 
use in clinical trials for chronic pain (Ferreira-Valente et al. 2011; Dworkin et al. 2005; Farrar et al. 2001; 
Caraceni et al. 2002; Satitpitakul et al. 2017).
The 10-point scale will be used as a co-primary endpoint in this study . The scale is illustrated below 
(Figure 1):
The subject will be asked to mark a single line on the scale that best corresponds to their answer for the 
following question about their pain over the past 24 hours. 
“On a scale from 0-10, what was the intensity of your Ocular Discomfort, at its worst, over the past 
24 hours?” 
Figure 1. Ocular Discomfort Scale
The above scale will be measured at Screening and each study visit: Baseline (prior to first dose), Day 28
± 7d, Day 56 ± 7d, and Day 84 ± 7d.
Baseline and screening assessments may be combined as long as the window between the Baseline and 
Screening visit is fewer than 7 days. When the visits are combined, only one (1) Baseline (before dosing) 
assessment is required.
Appendix 3 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 
2). 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.


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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 2. Validated Bulbar Redness Scale 
 
 
Source: Shulze, 2007 
This manner of testing with increments of 10 was 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 re-test. 
The above scale will be measured at Screening and at each study visit: Baseline (prior to first dose), Day 
28 ± 7d, Day 56 ± 7d, and Day 84 ± 7d. 
Baseline and screening assessments may be combined as long as the window between the Baseline and 
Screening visit is fewer than 7 days. When the visits are combined, only one (1) Baseline (before dosing) 
assessment is required. 


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Appendix 4 Symptom Assessment iN Dry Eye (SANDE)
Administer the questionnaire at Baseline on Day 1 (prior to dosing), and again at all subsequent clinic 
visits; Day 28 ± 7d, Day 56 ± 7d, and Day 84 ± 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 symptoms (Figure 3).
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 3. SANDE Questionnaire


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Appendix 5 Ocular Surface Disease Index (OSDI)
Figure 4. OSDI Questionnaire


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Encourage subjects to answer all questions. 
The OSDI score will be calculated = [ (SUM of scores) x 25]/Number of Questions answered 


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The above scale will be measured at Screening and at each study visit: Baseline (prior to first dose), Day 
28 ± 7d, Day 56 ± 7d, and Day 84 ± 7d. At Screening, the OSDI score (range, 0-100) is converted to a 
“severity score” (range, 0-3) to aid in the diagnosis of oGVHD (Appendix 1).
Baseline and screening assessments may be combined as long as the window between the Baseline and 
Screening visit is fewer than 7 days. When the visits are combined, only one (1) Baseline (before dosing) 
assessment is required.
Appendix 6. 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.


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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 5 and 6. The dots are ordered on a log scale.
Figure 5. 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 6). 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 6. Lissamine Green Conjunctival Staining Pattern and Grade (NEI Scale)


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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 8. 
Table 8. 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: Day 1 Baseline (prior to first dose), Day 28
± 7d, Day 56 ± 7d, and Day 84 ± 7d.
Appendix 7 Ocular Surface Staining: Fluorescein
Fluorescein dye (approximately 5 µL of 1% solution) will be applied over the surface of both eyes to 
assess corneal fluorescein staining. A Wratten #12 yellow filter may be used to enhance the ability to 
grade staining. 
Fluorescein solution
The examiner will instill 5 μL of 1% sodium fluorescein solution or Fluorescein Ophthalmic Strips may 
be used into the inferior conjunctival cul-de-sac of each eye. If the strips will be used:
1) Place a drop of saline onto the strip.
2) When the drop has saturated the impregnated tip, shake the excess into a waste bin with a sharp 
flick.
3) Pull down the right lower lid and tap the strip onto the lower tarsal conjunctiva.
To achieve maximum fluorescence, the examiner should wait approximately 2-3 minutes after instillation 
before performing the evaluation. The left eye is evaluated after the right eye.
Corneal Fluorescein Staining (CFS) with Severity Points
This assessment shall be conducted at Screening in each eye as part of the definitive diagnosis for 
oGVHD (see Appendix 1). A Wratten #12 yellow filter may be used to enhance the ability to grade 
staining at the slit lamp. Scoring is indicated in Table 9. 


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Table 9. Corneal Fluorescein Staining (CFS) with Severity Points
Severity 
Points/eye * 
Description and Grade
Slit Lamp Micrograph of CFS 
grading scale
0 
None ; Grade 0 
1 
Minimal staining; Grade 1 
2 
Mild/moderate staining; Grade 2 
3 
Severe staining; Grade 3 
Source: Ogawa, 2013
*Corneal fluorescein severity points are added to severity points of three other tests to get oGVHD aggregate score for each eye; 
the aggregate, in turn, is used to diagnose/classify oGVHD in each eye (Ogawa, 2013) (Refer to appendix 18.1)
Corneal Fluorescein Staining without Severity Points (NEI scale)
This assessment shall be used at each study visit: Baseline (prior to first dose), Day 28 ± 7d, Day 56 ± 7d, 
and Day 84 ± 7d. Each eye shall be graded separately. At baseline this assessment (see Table 10) should 
be performed before the Schirmer’s test with anesthetic and after the slit lamp examination. 


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Only the cornea will be evaluated. Corneal staining will be graded in 5 zones (Central (3mm), Superior, 
Inferior, Nasal, Temporal). Each zone will be graded from 0 to 3 based on the density of punctate 
staining (maximum score/eye =15).
Each eye (OS and OD) will be graded according to the NEI Scale.
Table 10. Corneal Fluorescein Scoring (NEI Scale)
Grade
Staining Pattern
Description (Investigators impression)
0 
No staining normal, negative slit lamp 
findings
1 
Minimal staining; mild superficial 
stippling
2 
Mild/moderate staining; punctate staining 
including superficial abrasion of the 
cornea
3 
Severe-very severe staining; abrasion or 
corneal erosion
Source: Lemp MA. 1995
Appendix 8. Conjunctival Injection with Severity Points
To determining subject eligibility, conjunctival injection grading of each eye, OS and OD, will be 
assessed at the Screening visit. The assessment will be used as part of the definitive diagnosis for oGVHD 
(see Appendix 1). Scoring is demonstrated below in Table 11. 


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Table 11. Conjunctival Injection Scoring 
 
Conjunctival 
Injection 
Severity 
points/eye* 
Slit Lamp Micrograph of CFS 
grading scale 
None 
0 
 
Mild/moderate 
injection 
1 
Severe 
injection 
2 
Source: Ogawa, 2013 
*Conjunctival injection severity points are added to severity points of three other tests to get oGVHD aggregate score for each 
eye; the aggregate, in turn, is used to diagnose/classify oGVHD in each eye (Ogawa, 2013) 


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Appendix 9. Visual Acuity
Visual Acuity Testing
18.9.1.1 Best-Corrected Visual Acuity (BCVA)
In this study, visual acuity is a safety (not efficacy) endpoint. For BCVA, please use your local ETDRS 
standard of care for testing. The Snellen equivalent should be recorded in the CRF for each eye.


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Appendix 10. Intraocular Pressure (IOP)
Intraocular Pressure (IOP) will be measured in both eyes. IOP will be measured at Screening and at each 
study visit: Baseline (prior to first dose), Day 28 ± 7d, Day 56 ± 7d, and Day 84 ± 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.


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Appendix 11. 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 13: 
Table 12. 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


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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 
Abnormal 
seconds or 1 minute 
(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) 
Global 
Per 1x1 mm slit 
evaluation 
0 
None; Optically 
Normal 
empty, compared 
bilaterally 
1+ 
Faint haze (any 
Abnormal 
appreciable light in 
slit beam) or not equal 
CS/NCS 
bilaterally 
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. 

SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN 
Document Title: 
OCU-300-301 Statistical Analysis Plan 
Study Title: 
A Phase 3 Randomized, Placebo-Controlled, Double-Masked, Multicenter, 
Safety and Efficacy Study of Brimonidine Tartrate Nanoemulsion Eye 
Drops in Patients with ocular Graft-vs-Host Disease (oGVHD) 
Protocol Number: 
OCU-300-301 (25May2018) and Amendment 1(15 Sep2018) 
Study Phase 
Phase III 
Product Name: 
OCU300 (Brimonidine Tartrate Ophthalmic Nanoemulsion 0.18%) 
Sponsor: 
Ocugen, Inc. 
5 Great Valley Parkway, Suite 160 Malvern, PA 19355 USA 
Prepared by 
Brightech International LLC 
285 Davidson Avenue, Suite 504 
Somerset, NJ 08873, USA 
NCT #NCT03591874


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REVISION HISTORY 
 
Version 1.0 
August 23, 2018 
Version 2.0 
January, 2020 
Version 2.1 
May, 2020, updated the list of TFLs for interim 
analysis in Appendix . 


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Signature 
 
 
I have carefully read this statistical analysis plan and agree to the described methods and proceedings. 
 
 
Authorized Signatory: 
 
 
, Ocugen, Inc. 
 
 
   
 
  
 
Name 
 Signature 
 
 Date 
 
 
 
 
 
Designated CRO Authorized Representative, Brightech International LLC, Project Biostatistician 
 
 
 
 
Name 
Signature 
Date 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................................ 4 
LIST OF TABLES ...................................................................................................................................... 6 
LIST OF ABREVIATIONS ......................................................................................................................... 6 
1. 
INTRODUCTION ....................................................................................................................... 9 
2. 
STUDY DESIGN .......................................................................................................................... 9 
2.1. Overall Study Design.................................................................................................................... 9 
2.2. Study Objectives ........................................................................................................................... 9 
2.3. Study Endpoints ........................................................................................................................... 9 
2.3.1 
Co-primary Endpoints ...................................................................................................... 10 
2.3.2 
Secondary Endpoints ........................................................................................................ 10 
2.3.3 
Exploratory Endpoints ...................................................................................................... 10 
3 
STUDY SCHEDULE ................................................................................................................ 10 
4 
STATISTICAL ANALYSIS PLAN ......................................................................................... 12 
4.1 
General Statistical Methods and Types of Analysis............................................................ 12 
4.2 
Power and Sample Size ......................................................................................................... 12 
4.3 
Analysis Populations ............................................................................................................. 13 
Safety Analysis Population ............................................................................................................... 13 
Intent-to-treat (ITT) Population ...................................................................................................... 13 
Per-protocol (PP) Population ............................................................................................................ 13 
4.4 
Unit of Analysis ...................................................................................................................... 13 
4.5 
Definition of Baseline Value.................................................................................................. 13 
4.6 
Patient Disposition ................................................................................................................. 13 
4.7 
Patient Characteristics ........................................................................................................... 13 
4.8 
Concomitant Therapy ........................................................................................................... 14 
4.9 
Efficacy Analysis.................................................................................................................... 14 
4.5.1 
Primary Efficacy Analyses ................................................................................................ 14 
4.5.2 
Secondary Efficacy Analysis ............................................................................................. 15 
4.5.3 
Exploratory Efficacy Analysis .......................................................................................... 15 
4.5.4 
Missing Data ...................................................................................................................... 16 
4.5.5 
Sensitivity Analysis ............................................................................................................ 16 
4.5.6 
Categorical Variable Analysis .......................................................................................... 16 


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4.6 
Interim Analysis and Sample Size Re-Estimation .............................................................. 16 
4.7 
Safety Analysis ....................................................................................................................... 17 
4.7.1 
Adverse Events .................................................................................................................. 17 
4.7.2 
Ophthalmic Exam Findings .............................................................................................. 18 
4.7.3 
Vital Signs .......................................................................................................................... 18 
4.8 
Study drug administration .................................................................................................... 18 
4.9 
Pharmacokinetic Analyses .................................................................................................... 18 
4.10 
Visit Windows ........................................................................................................................ 18 
5. Appendix ........................................................................................................................................ 19 
REFERENCES .................................................................................................................................. 22 


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LIST OF TABLES 
Table 1. List of Abbreviations ....................................................................................................................... 6 
Table 2. Study of Schedule of Events ......................................................................................................... 10 
Table 3. Critical Values for Interim Analysis .............................................................................................. 17 
 
 
LIST OF ABREVIATIONS 
Table 1. List of Abbreviations 
 
Abbreviation or specialist term 
Explanation 
ADL 
Activities of daily living 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AEI 
Adverse events of interest 
ATC 
Anatomic-Therapeutic-Chemical 
BCVA 
Best corrected visual acuity 
BID 
Twice daily 
CD34+ 
Transmembrane phosphoglycoprotein; protein encoded by the 
CD34 gene 
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 
ECM 
Extracellular matrix 
eCRF 
Electronic case report form 
EDTRS 
Early Treatment Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
FGF2 
Fibroblast growth factor 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GVHD 
Graft-vs-Host Disease 
HR 
Heart rate 


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Abbreviation or specialist term 
Explanation 
ICD 
Informed consent document 
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 
logMAR 
Logarithm of the Minimum Angle of Resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
mm 
Millimeter 
MMRM 
Mixed model of repeated measurements 
NCI-CTCAE 
National Cancer Institute’s Common Terminology Criteria for 
Adverse Events 
NEI 
National Eye Institute 
NIH 
National Institute of Health 
OBS 
Ophthalmic Buffered Saline 
OD 
Right eye 
ODD 
Orphan Drug Designation 
ODS 
Ocular Discomfort Score 
oGVHD 
Ocular Graft-vs-Host Disease 
OR 
Ocular surface redness 
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 


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Abbreviation or specialist term 
Explanation 
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 
TGF-β 
Transformed growth factor-beta 
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 


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1. INTRODUCTION 
 
This SAP is a detailed technical extension of the clinical Study Protocol and follows the principles of the 
International Conference on Harmonization (ICH) guidelines E3, E6 and E9 and the relevant Working 
Instructions (WIs) and Standard Operating Procedures (SOPs). 
The purpose of the SAP is to ensure the appropriate analysis of the study data by using pre-specified 
statistical approaches to the analysis prior to the database lock. 
Any further changes to the protocol or CRF may necessitate updates to the SAP. This SAP was written as 
a separate document, completed after finalizing the protocol, and prior to locking and unblinding the 
clinical datasets. This SAP includes a more technical and detailed elaboration of the statistical analyses 
stated in the protocol. 
The statistical analyses will be conducted using the SAS® software version 9.4 or later 
2. STUDY DESIGN 
 
2.1. 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 diagnosis of definite oGVHD will be randomly assigned in a 2:1 (test: control) fashion to receive either 
Brimonidine Nanoemulsion Eye Drops 0.18% investigational product (test) or ophthalmic buffered saline 
(placebo). 
Up to 5 study visits are planned: including a screening period (Day -7 to 0), and four on-therapy visits at 
Day 1, Day 28 ± 7 days (Week 4), Day 56 ± 7 days (Week 8), and Day 84 ± 7 days (Week 12) (See Table 
2). 
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 84 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. 
2.2. Study Objectives 
 
The primary objective of this study is to evaluate the safety, tolerability, and efficacy of Brimonidine 
Nanoemulsion Eye Drops for the treatment of ocular redness and ocular discomfort in patients with ocular 
oGVHD. 
 
 
2.3. Study Endpoints 


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2.3.1 
Co-primary Endpoints 
 
Two primary efficacy endpoints will be tested: 
• 
Ocular Redness based on a 100-point Validated Bulbar Redness (VBR) scale measuring change 
in appearance from baseline (pre-dose) to Day 84 
• 
Ocular discomfort based on a 10-point Visual Analog Scale (VAS) measuring change in intensity 
from baseline (pre-dose) to Day 84 
2.3.2 
Secondary Endpoints 
Change in Symptom Assessment iN Dry Eye (SANDE) questionnaire scores from baseline to 
Day 84 
2.3.3 
Exploratory Endpoints 
• 
Change from baseline in Validated Bulbar Redness (VBR) score at Days 28 and 56 
• 
Change from baseline in Ocular Discomfort Score at Days 28 and 56 
• 
Change from baseline in OSDI at 12 weeks (Day 84) 
• 
Change from baseline in corneal fluorescein staining at 12 weeks (Day 84) 
• 
Change from baseline in corneal lissamine green (LG) staining at 12 weeks (Day 84) 
• 
Change from baseline in conjunctival lissamine green (LG) staining at 12 weeks (Day 84) 
• 
Change from baseline in tear secretion as measured by Schirmer’s test 
• 
Clinical global impression of change in signs and symptoms from baseline (physician’s rating) 
• 
Subject global assessment of overall change from baseline (subject’s rating) 
 
3 
STUDY SCHEDULE 
 
The study schedule can be found on Table 2 
Table 2. Study of Schedule of Events 
 
 
 
Screening and Baseline 
Visit* 
Dosing and Evaluation 
Visit number 
Day (Time) 
Day –7 to 
Day –0 
Day 1 
(Baseline) 
Day 28 ± 7d 
(Week 4) 
Day 56 ± 7d 
(Week 8) 
Day 84 ± 7d 
(Week 12) 
Informed consent 
X 
Eligibility criteria 
X 
X 
Demographic Information 
X 
Medical/surgical/ocular history1 
X 
Body weight and height2 
X 
Vital signs (body temperature, 
heart rate, blood pressure, 
respiratory rate)3 
X 
X 
X 
X 
Review of prior and concomitant 
medications4 
X 
X 
X 
X 
X 
Urine collection and Pregnancy 
test (females of childbearing 
capacity only; hCG dipstick)5 
X 
X 
X 
X 
X 


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Ocular Discomfort 
10-point VAS6 
X 
X 
X 
X 
X 
OSDI; ocular 
surface disease 
index (points)7 
X 
X 
X 
X 
X 
Visual acuity8 
X 
X 
X 
X 
Symptom 
Assessment in Dry 
eye (SANDE)9 
X 
X 
X 
X 
Ocular redness 100 
-point VBR scale 
via slit lamp10 
X 
X 
X 
X 
X 
Conjunctival 
Injection (points)11 
X 
Slit lamp 
ophthalmic exam 
X 
X 
X 
X 
X 
Corneal fluorescein 
stain (CFS; 
points)12 
X 
Corneal fluorescein 
stain (NEI scale)13 
X 
X 
X 
X 
Corneal Lissamine 
green14 
X 
X 
X 
X 
Conjunctival 
Lissamine green 
stain15 
X 
X 
X 
X 
Schirmer’s test 
with anesthesia 
(mm, points)16 
X 
X 
X 
X 
X 
Intraocular 
pressure17 
X 
X 
X 
X 
X 
Clinical Global 
Impression (CGI) 
X 
X 
X 
Subject Global 
Assessment (SGA) 
X 
X 
X 
Randomization 
X 
Dispense/Instill Investigative 
Product 
X18 
X 
X 
Adverse event surveillance 
X 
X 
X 
X 
X 
Diary recording and review19 
X 
X 
X 
X 
*Maximum 7-day screening period prior to randomization. Duplication of assessments during this period is not 
required; however, results of some assessments (e.g. corneal fluorescein staining) will be used for both screening and 
baseline purposes. 
 
1. 
The ocular history will include any previously diagnosed ophthalmic abnormalities and ocular surgeries (including 
laser procedures). 
2. 
BMI to be auto-calculated from weight and height using the BMI formula; BMI= (Weight in pounds/ (Height in inches 
X Height in inches)) x 703 
3. 
Baseline Vital signs on Day 1 to be completed at least 30 ± 10 mins before dose on Day 1. All other vitals to be 
completed before ocular assessments on Days 28, 56, and 84 
4. 
Review of prior and concomitant medications and regimens will occur at all study visits. Corticosteroid-containing eye 
drops are not allowed within 14 days prior to Screening or during the study. Subjects will be permitted to continue all 
their current ocular treatments, including the use of artificial tears, eyelid massage, punctal plugs, or warmcompresses, 
if they commit to using the same brand/regimen throughout the study. None of the ocular treatments, whether OTC or 
prescription (e.g. Restasis® ,Xiidra® or Cequa®) 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. If a punctal 
plug is lost during the study, it may be replaced. 
5. 
hCG = human chorionic gonadotrophin. A urine pregnancy test is required at screening. A urine pregnancy test may be 
performed at any time during study participation if pregnancy is suspected. 
6. 
To evaluate intensity of Ocular Discomfort, patients will be asked to rate their worst ocular pain/discomfort in the 
preceding 24 hours using a 10-point scale ranging from “None” (score 0 to “Unbearable/Excruciating” (score 10). 


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7. 
OSDI will be completed at all visits and is assessed on a scale of 0 to 100, with higher scores representing greater 
disability. In determining subject eligibility, 0-3 points will be assessed based on the score. (Ogawa, 2013) 
8. 
Subjects should use the most recent correction to attain their best-corrected visual acuity (BCVA). 
9. 
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 on Day 1 prior to first dose 
(Baseline), Day 28, Day 56, and Day 84. 
10. 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. 
11. In determining subject eligibility, conjunctival injection grading of each eye, OS and OD, will be assessed, with Grade 
0 = none [0 points]; Grade 1 = mild/moderate injection [1 point]; and Grade 2 = severe injection [2 points]. (Ogawa, 
2013) 
12. In determining subject eligibility, corneal fluorescein stain (CFS) grading of each eye, OS and OD, will be assessed, 
with Grade 0 = no staining [0 points], Grade 1 = minimal staining [1 point], Grade 2 = mild/moderate staining [2 
points], Grade 3 = severe staining [3 points] (Ogawa, 2013) 
13. Each eye (OS and OD) CFS=corneal fluorescein stain grading. Corneal staining will be graded in 5 zones in each eye 
using the NEI scale. Each zone will be graded from 0 to 3 based on the density of punctate staining (maximum 
score/eye =15) 
14. Corneal lissamine green staining using a solution made from Lissamine Green Ophthalmic Strips. Corneal staining will 
be graded in 5 zones in each eye using the NEI scale. Each zone will be graded from 0 to 3 based on the density of 
punctate staining (maximum score/eye =15) 
15. 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 using the NEI scale (maximum score/eye = 6). 
16. Anesthetize each eye (OS and OD) with a drop of proparacaine. Insert Schirmer strips into lower lid for 5 min. If 
tearing exceeds 15 mm [0 points]; 11-15 min [1 point]; 6-10 mm [2 points]; <5 mm [3 points] (Ogawa, 2013). 
17. Measure intraocular pressure using Goldman applanation tonometry. 
18. 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 each 
study visit (except the Day 84 visit) for self-administration during the study. 
19. Subject diaries must be reviewed by the study staff at each visit prior to the subject leaving the clinic. 
 
 
4 
STATISTICAL ANALYSIS PLAN 
 
4.1 General Statistical Methods and Types of Analysis 
 
In general, continuous variables will be presented as the number of non-missing values, mean, standard 
deviation, median, minimum, maximum, and quartiles. For categorical variables, descriptive statistics will 
include counts and percentages per category. Confidence intervals (CI) will be computed when 
appropriate, usually as 95% intervals. 
In general, data will not be imputed with the exception of the primary and key secondary efficacy 
endpoints. 
4.2 Power and Sample Size 
The sample size is calculated based on limited data (
, May 24, 2017) on OSDI/SGA (as 
proxy endpoints to ocular discomfort), and ocular redness score (as a proxy endpoint for VBR). With a 
two-sided alpha of 0.05, a sample size of 60 patients in a 2:1 randomization (40 in OCU300, 20 in 
control) would provide more than 90% power to detect a difference of 0.47 (SD 0.39) in the mean 
difference in change from baseline in the validated bulbar redness score (VBR). This sample size provides 
about 85% of power to detect a clinically meaningful difference in ocular discomfort as measured by the 
ocular discomfort score (ODS). 


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4.3 Analysis Populations 
Safety Analysis 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. 
Intent-to-treat (ITT) Population 
 
The ITT set will be the primary analysis set for the efficacy endpoints and will include all randomized 
subjects. 
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 violations. 
4.4 Unit of Analysis 
 
For eye-specific assessments (e.g., ocular redness), the unit of analysis for the efficacy measures will be 
the average of study-eligible eyes in each subject. Efficacy measures will be summarized using the 
average value between the two eyes within a subject and within a visit. For subject-level assessments (e.g. 
ocular discomfort), the unit of analysis for the efficacy measures will be the subject. Safety analyses will 
be performed on each eye separately (OD and OS) with the exception of adverse events, which will be 
presented at the subject level, where ocular adverse events will be considered as occurring if either eye 
had the adverse event. Safety measures captured at the subject level will be summarized at the subject 
level. 
 
 
4.5 Definition of Baseline Value 
The last non-missing value prior to the first dose, or the last non-missing value prior to the randomization 
date if the subject was randomized but not treated, is considered the baseline value. 
 
 
4.6 Patient Disposition 
The number of subjects screened (who signed informed consent form), number of screen failures and 
number of subjects who were randomized, who were treated, will be summarized. 
The number of subjects who completed study, who early discontinued from study after randomization 
will be summarized by treatment. The percentages will be calculated with the number of randomized 
subjects as denominator. The reasons for early discontinuation from the study will also be summarized. 
4.7 Patient Characteristics 
Demographic and baseline disease characteristics will be summarized by treatment and listed for the 
Intent-to-Treat, Safety, and Per-Protocol populations separately. 


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4.8 Concomitant Therapy 
The concomitant medications will be summarized by treatment for the ITT Population. The concomitant 
therapies will be mapped using the World Health Organization (WHO) DRUG dictionary will be further 
classified using Anatomic-Therapeutic-Chemical (ATC) codes for reporting purposes. 
 
 
4.9 Efficacy Analysis 
 
4.5.1 
Primary Efficacy Analyses 
 
The primary evaluation of efficacy will be a co-primary endpoint of and bulbar redness as measured by 
VBR and ocular discomfort as measured by the ODS after 14 weeks dosing (Day 84). The primary 
efficacy analysis will be performed on the Intent-to-Treat population. 
The following two sets of hypotheses will be tested as the primary hypotheses of the study. 
Hypothesis 
The statistical hypotheses for the primary endpoint of the mean change from baseline bulbar redness score 
(VBR) at 14 weeks (Day 84) are as follows: 
 
H01:  The difference (OCU 300 minus placebo), between study eyes treated with the OCU 300 
and study eyes treated with placebo (OBS) in the mean change from baseline VBR score 
at 14 weeks (Day 84) = 0. 
 
HA1:  The difference (OCU 300 minus placebo), between study eyes treated with the OCU 300 
and study eyes treated with placebo in the mean change from baseline VBR score at 14 
weeks (Day 84) ≠ 0. 
 
The statistical hypotheses for the primary endpoint of the mean change from baseline ocular discomfort 
score (ODS) at 14 weeks (Day 84) are as follows: 
 
H02:  The difference (OCU 300 minus placebo), between subjects treated with the OCU 300 and 
subjects treated with placebo (OBS) in the mean change from baseline ODS at 14 weeks 
(Day 84) = 0. 
 
HA2:  The difference (OCU 300 minus placebo), between subjects treated with the OCU 300 and 
subjects treated with placebo (OBS) in the mean change from baseline ODS at 84 weeks 
(Day 84) ≠ 0. 
 
 
To control family-wise type I error, the primary endpoints will be tested with the Hochberg procedure: 
• 
If the p-values for both VBR and ODS are less or equal to 0.05, then both null hypotheses will be 
rejected, and alternative hypotheses claimed; 
• 
If the p-value for either parameter VBR or ODS is greater than 0.05, then a p-value of 0.025 will 
be required to reject the null hypothesis for the test on the other parameter; 


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The primary efficacy analyses will be conducted on the ITT population and the comparison will be made 
based on the randomized treatment. The same set of efficacy analyses will also be performed on the per- 
protocol population. For efficacy endpoints where measurements from both eyes are available, a single 
mean will be calculated for the analyses. For continuous endpoints, the change from baseline will be 
summarized with descriptive statistics for the values at baseline, values at each time point (Days 28, 56 
and 84), 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. The percent change from baseline may also be 
summarized in a similar manner. 
Primary and key secondary continuous endpoints will be analyzed using a mixed model of repeated 
measurements (MMRM) under a missing at random (MAR) assumption. The model will use an 
unstructured covariance matrix and include treatment, visit, and visit-by-treatment interaction as fixed 
terms. From this model, the by-visit results will be presented. 
The SAS code for the analysis will be: 
proc mixed; 
class subject treatment visit; 
model Y = baseline treatment visit 
treatment*visit; 
repeated time / sub = subject type = un; 
lsmeans treatment*visit /slice=visit cl ; 
estimate 'treatment difference at visit' treatment -1 1 
treatment * visit 0 0 0 0  -1 1 
0 0 -1 1 
0  0 
-1 1 0 0 
0 0/cl; 
run; 
 
 
4.5.2 
Secondary Efficacy Analysis 
 
Change in Symptom Assessment iN Dry Eye (SANDE) questionnaire scores from baseline to Day 84. 
This variable will be analyzed using a mixed model of repeated measurements (MMRM) under a missing 
at random (MAR) assumption, similar to the analysis for the primary endpoints. 
4.5.3 
Exploratory Efficacy Analysis 
 
The following exploratory efficacy variables will be analyzed to compare OCU 300 versus control. 
Continuous variables will be analyzed using a mixed model of repeated measurements (MMRM) under a 
missing at random (MAR) assumption, similar to the analysis for the primary endpoints. CMH tests will 
be performed on categorical variables: 
• 
Change from baseline in Validated Bulbar Redness (VBR) score at Days 28 , 56 and 84 
• 
Change from baseline in Ocular Discomfort Score at Days 28 , 56 and 84 
• 
Change from baseline in OSDI at Days 28, 56 and at 12 weeks (Day 84) 
• 
Change from baseline in corneal fluorescein staining at Days 28, 56 and at 12 weeks (Day 84) 


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• 
Change from baseline in corneal lissamine green (LG) staining at Days 28, 56 and at 12 weeks 
(Day 84) 
• 
Change from baseline in conjunctival lissamine green (LG) staining at Days 28, 56 and at 12 
weeks (Day 84) 
• 
Change from baseline in tear secretion as measured by Schirmer’s test at Days 28 , 56 and 84 
• 
Clinical global impression of change in signs and symptoms from baseline (physician’s rating) at 
Days 28 , 56 and 84 
• 
Subject global assessment of overall change from baseline (subject’s rating) at Days 28 , 56 and 
84 
 
4.5.4 
Missing Data 
 
Primary and key secondary continuous endpoints will be analyzed using a mixed model of repeated 
measurements (MMRM) under a missing at random (MAR) assumption. A sensitivity analysis using 
pattern-mixture model with control- based pattern imputation will be performed to compare with the 
results of the primary analysis. 
Exploratory analyses will be based on observed data. Missing data will not be imputed. 
 
 
4.5.5 
Sensitivity Analysis 
 
A sensitivity analysis using pattern-mixture model with control- based pattern imputation (as described by 
B. Ratitch, M. O’Kelly, 2011) will be performed to compare with the results of the primary analysis. 
Multiple (100) imputations will be performed (using proc mi, in SAS) and the analyzed using proc 
mixed). The results will be combined (using proc mianalyze in SAS) using Rubin’s method (Rubin, 
1987). 
4.5.6 
Categorical Variable Analysis 
 
For categoric endpoints, such as the severity scores, the analysis will be performed by using the Cochran– 
Mantel–Haenszel test (CMH) method controlling for baseline scores. The null hypothesis for categorical 
endpoints is that there is no association between the treatment assignment and the outcomes for each 
category, the alternative hypothesis is that there is association 
The typical SAS code will be 
 
proc freq data=indata; 
tables Treatment*Response / cmh; 
run; 
 
 
4.6 Interim Analysis and Sample Size Re-Estimation 


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Since the sample size is calculated using indirect information, a sample size re-estimation is planned at an 
interim analysis when data from 50% of patients are available. If the conditional power is less than 90%, 
the sample size will be increased to provide sufficient power. To control type I error, a two-sided alpha of 
0.0002 (0.0001 one-sided) will be spent at the interim analysis, and the two-sided alpha for the final 
analysis will be 0.0498 (one-sided 0.0249). If sample size is modified, the final critical value of 0.0498 
will be adjusted to control type I error. 
Table 3. Critical Values for Interim Analysis 
 
Time 
Critical value 
Nominal alpha 
Cumulative alpha 
0.5 
3.7190 
0.0001 
0.0001 
1 
1.9617 
0.0249 
0.025 
 
If the sample size is modified, the final critical value will be adjusted according to Gao, Ware, Mehta 
(2008) to control type I error. The final analysis will be based on Gao, Liu, Mehta (2013). 
The planed analyses for interim analysis are listed in the Appendix. 
4.7 Safety Analysis 
All subjects who enter the study will be assessed for safety. 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. 
Clinically significant negative changes from baseline will be analyzed as adverse events. 
4.7.1 
Adverse Events 
 
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. 
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 (SOC), by system organ class and preferred term (PT) , 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. 
The following AE summaries will be presented in tables: 
• 
An overall summary of the AEs, including the number and percentage of patients reporting AE, the 
number and percentage of patients with AE possibly related or related to study treatment, number and 
percentage of patients reporting serious AE, the number and percentage of patients with serious AE 
possibly related or related to study treatment, the number and percentage of patients discontinuing 


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treatment due to AE, the number and percentage of patients’ death due to AE, presented by treatment 
group. 
• 
A breakdown of the number and percentage of patients reporting TEAEs, categorized by system 
organ class (SOC) and preferred term (PT), presented by treatment group. 
• 
A breakdown of the number and percentage of patients reporting TEAEs, categorized by SOC and 
PT, presented by treatment group and severity. 
• 
Number and percentage of patients reporting TEAEs, leading to treatment discontinuation, 
categorized by SOC and PT, presented by treatment group. Patients’ TEAEs leading to treatment 
discontinuation will also be listed. 
• 
Patients with TEAEs possibly related or related to study treatment, categorized by SOC and PT, 
presented by treatment group. 
• 
Patients with TEAEs possibly related or related to study treatment, categorized by SOC and PT, 
presented by treatment group and severity. 
• 
Number and percentage of patients reporting Serious AEs (SAEs), categorized by SOC and PT, 
presented by treatment group. 
• 
Number and percentage of patients reporting Serious AEs (SAEs), categorized by SOC and PT, 
presented by treatment group and severity. 
4.7.2 
Ophthalmic Exam Findings 
Number and percentage of subjects with normal, abnormal, clinically significant abnormal and non- 
clinically significant ophthalmic exam findings will be summarized by visit by treatment group. 
 
4.7.3 
Vital Signs 
 
Descriptive statistics of patients’ vital signs by treatment group and scheduled study visit will be 
summarized including number of patients, mean, standard deviation, median and range. 
Individual values of vital signs will be listed. 
4.8 Study drug administration 
 
Study drug dosing record, missed doses of study drug together with the reason for the missed dosage will 
be listed. 
4.9 Pharmacokinetic Analyses 
 
None in this study 
4.10 Visit Windows 
 
Visit windows will be as described in the protocol: screening period (Day -7 to 0), Day 1, Day 28 ± 7 
days (Week 4), Day 56 ± 7 days (Week 8), and Day 84 ± 7 days (Week 12). 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. 


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5. Appendix 
The planned tables, figures and listings for interim analysis are listed below: 
 
No. 
Category 
Title 
Population 
1 
Table 
Subject disposition and analysis population 
All subjects 
screened 
2 
Table 
Subject disposition and analysis population 
Randomized 
Subjects of Study 
Disposition 
3 
Table 
Subject disposition status by study site 
All subjects 
screened 
4 
Table 
Baseline demographics 
SAF 
5 
Table 
Baseline demographics 
ITT Subjects of 
Study Disposition 
6 
Table 
Baseline disease characteristics 
SAF 
7 
Table 
Baseline disease characteristics 
ITT Subjects of 
Study Disposition 
8 
Table 
Previous medications 
ITT 
9 
Table 
Concomitant medications 
ITT 
10 
Table 
Study-eligible Eye Validated Bulbar Redness Score- 
Summary Statistics, and MMRM Analyses of Change from 
Baseline 
ITT Subjects of 
Study Disposition 
11 
Table 
Ocular discomfort - Summary Statistics, and MMRM 
Analyses of Change from Baseline 
ITT Subjects of 
Study Disposition 
12 
Table 
Symptom Assessment iN Dry Eye (SANDE) - Summary 
Statistics, and MMRM Analyses of Change from Baseline 
ITT Subjects of 
Study Disposition 
13 
Table 
Overall Summary of Adverse Events 
SAF 
14 
Table 
Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term - Ocular AE 
SAF 
15 
Table 
Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term - Non-ocular AE 
SAF 
16 
Table 
Treatment-Emergent Adverse Events by System Organ 
Class, Preferred Term and Maximum Severity -Ocular AE 
SAF 
17 
Table 
Treatment-Emergent Adverse Events by System Organ 
Class, Preferred Term and Maximum Severity - Non-ocular 
AE 
SAF 
18 
Table 
Treatment-Emergent Adverse Events Leading to Treatment 
Discontinuation by System Organ Class and Preferred Term 
-Ocular AE 
SAF 
19 
Table 
Treatment-Emergent Adverse Events Leading to Treatment 
Discontinuation by System Organ Class and Preferred Term 
-Non-ocular AE 
SAF 
20 
Table 
Treatment-Emergent Adverse Events Related or Probably 
Related to Study Treatment by System Organ Class and 
Preferred Term -Ocular AE 
SAF 
21 
Table 
Treatment-Emergent Adverse Events Related or Probably 
Related to Study Treatment by System Organ Class and 
Preferred Term -Non-ocular AE 
SAF 


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No. 
Category 
Title 
Population 
22 
Table 
Treatment-Emergent Adverse Events Related or Probably 
Related to Study Treatment by System Organ Class, 
Preferred Term and Sevirity -Ocular AE 
SAF 
23 
Table 
Treatment-Emergent Adverse Events Related or Probably 
Related to Study Treatment by System Organ Class, 
Preferred Term and Sevirity -ocular AE 
SAF 
24 
Table 
Treatment-Emergent Serious Adverse Events by System 
Organ Class and Preferred Term-Ocular AE 
SAF 
25 
Table 
Treatment-Emergent Serious Adverse Events by System 
Organ Class and Preferred Term-Non-ocular AE 
SAF 
26 
Table 
Treatment-Emergent Serious Adverse Events by System 
Organ Class, Preferred Term and Severity-Ocular AE 
SAF 
27 
Table 
Treatment-Emergent Serious Adverse Events by System 
Organ Class, Preferred Term and Severity-Non-ocular AE 
SAF 
28 
Table 
Treatment-Emergent Serious Adverse Events Related or 
Probably Related to Study Treatment by System Organ 
Class and Preferred Term-Ocular AE 
SAF 
29 
Table 
Treatment-Emergent Serious Adverse Events Related or 
Probably Related to Study Treatment by System Organ 
Class and Preferred Term-Non-ocular AE 
SAF 
30 
Table 
Treatment-Emergent Adverse Events with Fatal Outcome- 
Ocular AE 
SAF 
31 
Table 
Treatment-Emergent Adverse Events with Fatal Outcome- 
Non-ocular AE 
SAF 
32 
Table 
Treatment-Emergent Adverse Events Related or Probably 
Related to Study Treatment with Fatal Outcome-Ocular AE 
SAF 
33 
Table 
Treatment-Emergent Adverse Events Related or Probably 
Related to Study Treatment with Fatal Outcome-Non-ocular 
AE 
SAF 
34 
Figure 
Study-eligible Eye Validated Bulbar Redness Score – LS 
Mean of Change from Baseline 
ITT Subjects of 
Study Disposition 
35 
Figure 
Ocular discomfort – LS Mean of Change from Baseline 
ITT Subjects of 
Study Disposition 
36 
Figure 
Symptom Assessment iN Dry Eye (SANDE) – LS Mean of 
Change from Baseline 
ITT Subjects of 
Study Disposition 
37 
Listing 
Subject disposition 
Randomized 
patients 
38 
Listing 
Screen failures and withdrawals prior to randomization 
Non-randomized 
subjects 
39 
Listing 
Analysis populations and reasons for exclusion 
Randomized 
patients 
40 
Listing 
Demographics 
ITT 
41 
Listing 
Diagnosis of Definite oGVHD 
ITT 
42 
Listing 
Previous and concomitant medications 
ITT 
43 
Listing 
Validated Bulbar Redness 
ITT 
44 
Listing 
Ocular Discomfort 
ITT 
45 
Listing 
Symptom Assessment iN Dry Eye (SANDE) 
ITT 
46 
Listing 
Listing of non-treatment-emergent ocular adverse events 
SAF 


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No. 
Category 
Title 
Population 
47 
Listing 
Listing of non-treatment-emergent non-ocular adverse 
events 
SAF 
48 
Listing 
Listing of treatment-emergent ocular adverse events 
SAF 
49 
Listing 
Listing of treatment-emergent non-ocular adverse events 
SAF 
50 
Listing 
Listing of treatment-emergent serious ocular adverse events 
SAF 
51 
Listing 
Listing of treatment-emergent serious non-ocular adverse 
events 
SAF 
 
Note: SAF = Safety Population; ITT = Intent-to-treat Population. 
Study disposition: a subject has either “Yes” or “No” for the header question “Did the subject complete 
the study?” on the “Study Completion” CRF page. 


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REFERENCES 
 
• 
Ratitch, B., O’Kelly M.: Implementation of Pattern-Mixture Models Using Standard SAS/STAT 
Procedures , 2011. PharmaSUG2011 - Paper SP04. 2011. 
https://pharmasug.org/proceedings/2011/SP/PharmaSUG-2011-SP04.pdf 
• 
Rubin, D.B. (1987), Multiple Imputation for Nonresponse in Surveys, New York: John Wiley & 
Sons, Inc. 
• 
Gao, P. , Ware, J.H. , Mehta, C., (2008), Sample size re-estimation for adaptive sequential 
designs. Journal of Biopharmaceutical Statistics, 18: 1184–1196, 2008 
• 
Gao,P., Liu, L.Y., and Mehta C. (2013). Exact inference for adaptive group sequential designs . 
Statistics in Medicine . 32 3991–4005, 2013