Conditions: Ocular Redness
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 380
Healthy volunteers: no

Brief summary:
This is a multi-center, double-masked, randomized, active-controlled, parallel-group, efficacy and safety study that will enroll 386 participants at up to six clinical sites. Participants with ocular redness will be randomized to receive either brimonidine tartrate ophthalmic solution 0.025%, preservative-free formulation, or Lumify® (brimonidine tartrate ophthalmic solution 0.025%). Participants will be treated with study drug for approximately 4 weeks.

Detailed description:

Arms:
arm 1: Brimonidine tartrate ophthalmic solution 0.025% preservative-free formulation arm 2: Lumify® (brimonidine tartrate ophthalmic solution 0.025%)

Interventions: intervention 1: Brimonidine tartrate ophthalmic solution 0.025% preservative-free formulation intervention 2: Lumify® (brimonidine tartrate ophthalmic solution 0.025%)
Intervention descriptions: intervention 1: Brimonidine tartrate ophthalmic solution 0.025% preservative-free formulation. Participants will instill 1 drop of the assigned investigational drug in each eye 4 times a day approximately 4 hours apart for up to 4 consecutive weeks. intervention 2: Lumify® (brimonidine tartrate ophthalmic solution 0.025%). Participants will instill 1 drop of the assigned investigational drug in each eye 4 times a day approximately 4 hours apart for up to 4 consecutive weeks.

Protocol document:
Prot_000.pdf: 
Protocol Number 908   
 
Version 2.0, 27 OCT 2021  
 
 
 
 
 
Page 1 of 66 
1.0 
TITLE PAGE 
 
Clinical Study Protocol 
 
  
 
 
A Multi-Center, Double-Masked, Randomized, Active-Controlled, Parallel-Group 
Study Comparing the Efficacy and Safety of Brimonidine Tartrate Ophthalmic 
Solution 0.025% Preservative-Free Formulation with Lumify® 0.025% in Adult 
Subjects with Ocular Redness 
Protocol # 908 
 
Developmental phase of study: 3 
 
Version: 2.0 
 
 
 
Date: 27 OCT 2021 
 
 
 
Sponsor  
Bausch & Lomb, Incorporated  
400 Somerset Corporate Boulevard 
Bridgewater, NJ 08807 
 
This clinical investigation is being conducted in accordance with the Declaration of Helsinki on Ethical 
Principles for Medical Research Involving Human Subjects and with Good Clinical Practice (GCP), as 
required by the US Code of Federal Regulations applicable to clinical studies (21CFR Parts 11, 50, 54, 56 
and [312]; 42 USC 282(j); International Conference on Harmonisation (ICH) Harmonised Tripartite 
Guideline E6(R2): GCP and E2A: Safety Data Management and applicable local regulations, including the 
archiving of essential documents. 
 
Lumify® is a registered trademark of Bausch & Lomb, Incorporated and its affiliates. 
 
Revision Chronology:  
[Final, Original v1.0]  
- 
[23 NOV 2020] 
[Amendment 1, v2.0] 
- 
[27 OCT  2021] 
 
CONFIDENTIALITY STATEMENT 
This protocol contains confidential information about a product provided by Bausch & Lomb, 
Incorporated.  This information is provided for the exclusive use of the investigators 
participating in this study.  Nothing herein may be disclosed to any person or party without 
prior written approval of Bausch & Lomb, Incorporated. 
  




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Protocol Number 908   
 
Version 2.0, 27 OCT 2021  
 
 
 
 
 
Page 3 of 66 
INVESTIGATOR STATEMENT OF AGREEMENT 
 
A MULTI-CENTER, DOUBLE-MASKED, RANDOMIZED, ACTIVE-
CONTROLLED, PARALLEL-GROUP STUDY COMPARING THE EFFICACY 
AND SAFETY OF BRIMONIDINE TARTRATE OPHTHALMIC SOLUTION 
0.025% PRESERVATIVE-FREE FORMULATION WITH LUMIFY® 0.025% IN 
ADULT SUBJECTS WITH OCULAR REDNESS 
PROTOCOL 
STUDY # 908 
I have read the attached protocol and I agree that it contains all information necessary to 
conduct this study as described and agree to abide by all provisions set forth therein.  
I agree to conduct this study properly, ethically, and safely in accordance with 
internationally recognized code of good clinical practices (ICH GCP), as required by 
applicable local laws and regulations. I will not initiate the study until I have obtained 
written approval by the appropriate Institutional Review Board (IRB)/Ethics Committee 
(EC) and have complied with all financial and administrative requirements of the 
governing body of the clinical institution and the Sponsor. I will obtain written informed 
consent (and, if applicable, assent for children) from each study subject prior to performing 
any study specific procedures which are not my routine standard of care.  
I understand that my signature/e-signature on a case report form (CRF)/electronic case 
report form (eCRF) indicates that the data therein has been reviewed and accepted by me. 
I understand that this document and related information is subject to confidentiality terms 
found in my signed Confidentiality or Clinical Services Agreement. I agree to protect the 
confidentiality of my patients, as required by all local privacy regulations, when allowing 
the Sponsor of this clinical investigation, and/or relevant regulatory authorities and 
IRB/ECs, direct access to my medical records for study subjects. 
I will provide all study personnel under my supervision copies of the protocol and access 
to all information provided by the Sponsor that is necessary for the proper conduct of this 
study. I will discuss this material with them to ensure that they are fully informed about 
the test article and all study related procedures and required documentation. 
__________________________________________________ 
_______________________ 
Principal Investigator, Printed Name 
Date 
__________________________________________________ 
_______________________ 
Signature 
Site Number 
Upon signing, provide a copy of this page to the Sponsor and retain a copy for your files.  




Protocol Number 908   
 
Version 2.0, 27Oct2021 
 
Page 5 of 66 
 
 
  
2.0 
SYNOPSIS  
 
Bausch & Lomb, Incorporated Study # 908  
Title: 
A Multi-Center, Double-Masked, Randomized, Active-Controlled, 
Parallel-Group Study Comparing the Efficacy and Safety of 
Brimonidine Tartrate Ophthalmic Solution 0.025% Preservative-
Free Formulation with Lumify® 0.025% in Adult Subjects with 
Ocular Redness 
Phase of study:  
Phase 3 
Number of study centers 
and subjects: 
Approximately  386 subjects will be enrolled in this study at 6 sites.   
Location: 
United States 
Planned study period: 
Approximately 21 weeks  
Objective(s): 
Primary Objective:  To demonstrate that the efficacy of brimonidine 
tartrate ophthalmic solution preservative-free formulation (BTOS-PF) 
0.025% is non-inferior to Lumify® 0.025% for treating ocular redness in a 
population of adult subjects. 
Secondary Objective(s):  To compare the safety of BTOS-PF 0.025% 
with Lumify® 0.025%. 
Study design: 
Multi-center, double-masked, randomized, active-controlled, parallel-
group, efficacy and safety study  
 
Study duration: 
Approximately 5 weeks   
Subject population: 
Healthy adult (≥ 18 years of age) subjects with ocular redness 
Inclusion criteria: 
Subjects MUST:  
1. Be at least 18 years of age at the time of Informed Consent 
signing of either gender and any race or ethnicity;  
2. Provide written informed consent and sign the HIPAA form;  
3. Be willing and able to follow all instructions and attend all study 
visits; 
4. Have a history of vasoconstrictor (redness relief drops) use within 
the last 6 months, or a desire to use OTC vasoconstrictors for 
redness relief;  
5. Be able to self-administer eye drops satisfactorily or have a 
subject’s care provider at home1 routinely available for this 
purpose;  
6. (If female and of childbearing potential) agree to have urine 
pregnancy testing performed at Visit 1 (must be negative) and at 
exit visit; must not be lactating; and must agree to use at least 1 
 
1 If a care provider or surrogate will be used to administer eye drops, then he/she must be present at Visit 1 
to administer eye drops in-office. 


Protocol Number 908   
 
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Page 6 of 66 
 
 
  
Bausch & Lomb, Incorporated Study # 908  
medically acceptable form of birth control2  throughout the study 
duration and for at least 14 days prior to the first dose of study 
drug (Visit 1) and for 1 month after the last dose of investigational 
drug. Note: Women considered capable of becoming pregnant 
include all females who have experienced menarche and have not 
experienced menopause (as defined by amenorrhea for greater 
than 12 consecutive months) and have not undergone successful 
surgical sterilization (hysterectomy, bilateral tubal ligation, or 
bilateral oophorectomy); 
7. (If male and with female partner of childbearing potential) must 
use at least 1 medically acceptable form of birth control3;   
8. A calculated best-corrected (if necessary) visual acuity of 0.3 
logMAR or better in each eye, as measured using an ETDRS 
chart;    
9. At Visit 1 (Baseline), show a baseline redness score >1 unit (ie, 
greater than 1 unit) in both eyes on a 0 to 4 unit scale as scored 
by the Investigator using the Investigator Ocular Redness Scale;    
10. Have stable ocular health (defined as no ocular conditions 
requiring therapy or surgical intervention during the study). 
Exclusion criteria: 
Subjects MUST NOT:  
1. Have known contraindications or sensitivity to the use of any of 
the investigational drug(s) or their components, or any other 
medications required by the protocol;  
2. Have had ocular surgical intervention within 3 months prior to 
screening or during the study and/or a history of refractive surgery 
within the past 6 months;  
3. Have the presence of an active ocular infection (bacterial, viral, 
or fungal) or positive history of an ocular herpetic infection at any 
visit;  
4. Use any of the following disallowed medications during the 
period indicated prior to screening and for the duration of the study:  
- 
All topical ophthalmic agents including artificial tear products, 
eye whiteners (e.g., vasoconstrictors), ocular decongestants, ocular 
antihistamines, ocular corticosteroids, dilating drops, (excluding 
dilated ophthalmoscopy  exam at Visit 1) and contact lenses: 5 days   
- 
Systemic antihistamines or decongestants: 7 days  
 
2 Acceptable forms of birth control are true abstinence (when this is in line with the preferred and usual 
lifestyle of the subject), spermicide with barrier, oral contraceptive, injectable or implantable method of 
contraception, transdermal contraceptive, intrauterine device, or surgical sterilization of male partner at least 
3 months prior to the first dose of investigational drug (Visit 1). 
3 Acceptable forms of birth control are true abstinence (when this is in line with the preferred and usual 
lifestyle of the subject) or vasectomy at least 3 months prior to the first dose of study drug (Visit 1). Without 
a vasectomy, must use condoms with spermicidal foam/gel/film/cream/suppository at least 14 days prior to 
the first dose of investigational drug (Visit 1) and for 1 month after the last dose of the investigational drug 
(Visit 3). 


Protocol Number 908   
 
Version 2.0, 27Oct2021 
 
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Bausch & Lomb, Incorporated Study # 908  
- 
Systemic corticosteroids or cancer chemotherapy, and/or any 
other systemic medications which the investigator feels may confound 
study data, or interfere with subject’s study participation: 14 days  
5. Have prior (within 7 days of beginning investigational drug) or 
currently active significant illness that could compromise 
participation, in the opinion of the investigator;   
6. Have prior (within 30 days of beginning investigational drug) or 
anticipated concurrent use of an investigational drug or device during 
the study period;  
7. Have an ocular or systemic condition or a situation which, in the 
investigator’s opinion, may put the subject at increased risk, confound 
study data, or interfere significantly with the subject’s study 
participation;   
8. Have planned surgery (ocular or systemic) during the trial period 
or within 30 days after the study period;  
9. Be currently breast feeding or planning to breast feed during the 
study period or is a female who is currently pregnant, is planning a 
pregnancy, or has a positive urine pregnancy test at Visit 1; 
10. Have a diagnosis of ocular hypertension or glaucoma at screening; 
11. Have symptoms that, in the opinion of the investigator, may be 
associated with COVID-19 or in the last 14 days came into contact 
with someone diagnosed with COVID-19. 
Investigational product, 
dose & mode of 
administration: 
Investigational Product:  Brimonidine tartrate ophthalmic solution 0.025% 
preservative-free formulation 
Brimonidine tartrate ophthalmic solution preservative-free formulation 
(BTOS-PF) contains 0.025% of the active brimonidine tartrate, purified 
water, boric acid, sodium borate decahydrate, potassium chloride, calcium 
chloride dihydrate, glycerin, sodium chloride, and pH adjusted with 
hydrochloric acid and sodium hydroxide. 
Dosage/Dose Regimen:  Subjects will be randomly assigned at Visit 1 to 
receive 1 of the following treatments four times a day (QID) bilaterally:   
Brimonidine tartrate ophthalmic solution 0.025%, preservative-free 
formulation (N= 193)  
• 
Lumify® (brimonidine tartrate ophthalmic solution 0.025%) (N= 
193)  
• 
Randomization 
is 
at 
a 
ratio 
of 
1:1 
(investigational 
product:comparator).    
Subjects will instill 1 drop of the assigned investigational drug in each eye 
QID approximately 4 hours apart for up to 4 consecutive weeks.  
Duration of treatment: 
4 weeks  
Comparator treatment : 
Comparator Product:  Lumify® (brimonidine tartrate ophthalmic solution 
0.025%) 
Lumify® contains 0.025% of the active brimonidine tartrate, purified 
water, benzalkonium chloride, boric acid, sodium borate decahydrate, 


Protocol Number 908   
 
Version 2.0, 27Oct2021 
 
Page 8 of 66 
 
 
  
Bausch & Lomb, Incorporated Study # 908  
potassium chloride, calcium chloride dihydrate, glycerin, sodium chloride, 
and pH adjusted with hydrochloric acid and sodium hydroxide. 
Study procedures: 
Summary of Visit Schedule:  
Screening Visit (Day -28 to Day 1) 
• 
Informed Consent/HIPAA 
• 
Demographic Data and Medical/Medication/Ocular History 
 
Visit 1 (Baseline; Day 1):  
• 
Enrollment 
• 
Urine Pregnancy Test (for females of childbearing potential) 
• 
Pre-instillation ocular redness assessment  
• 
In-office investigational drug instillation 
• 
Drop comfort/descriptor assessment 
• 
Ocular redness assessment at 1 (+0.5), 5(+1), 15(+1), 30(+1), 
60(+10), 90(+10), 120(+15), 180(+15), 240(+15), 360(+15), and 
480(+15) minutes post-instillation 
• 
Safety assessments (AEs, vital signs, physical examination, 
visual acuity, slit lamp biomicroscopy, intraocular pressure 
[IOP], and ophthalmoscopy) 
 
Visit 2 (Day 15 ± 2 days):  
• 
Pre-instillation ocular redness assessment 
• 
In-office investigational drug instillation 
• 
Ocular redness assessment at approximately 1 and 5 minutes 
post-instillation 
• 
Safety assessment (AEs, vital signs, visual acuity, and slit lamp 
biomicroscopy) 
 
Visit 3 (Day 29 + 2 days):  
• 
Pre-instillation ocular redness assessment 
• 
In-office investigational drug instillation 
• 
Ocular redness assessment at approximately 1 and 5 minutes 
post-instillation 
• 
Safety assessment (AEs, vital signs, physical examination, visual 
acuity, slit lamp biomicroscopy, IOP, and ophthalmoscopy) 
 
Visit 4 (Day 36 + 1 day):  
• 
In-office ocular redness rebound assessment 
• 
Urine Pregnancy Test (for females of childbearing potential) 
• 
Safety assessment (AEs, visual acuity, and slit lamp 
biomicroscopy) 
• 
Study Exit 
Criteria for Evaluation: 
Primary Efficacy Endpoint:  


Protocol Number 908   
 
Version 2.0, 27Oct2021 
 
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Bausch & Lomb, Incorporated Study # 908  
Ocular redness score evaluated by the investigator prior to investigational 
drug instillation and at 5(+1), 15(+1), 30(+1), 60(+10), 90(+10), 120(+15), 
180(+15), and 240(+15) minutes after investigational drug instillation (0-
4 unit scale, allowing half unit increments) at Visit 1 
Secondary Efficacy Endpoints:  
Secondary efficacy endpoints will be evaluated hierarchically, as follows:  
1. Change from pre-instillation ocular redness score evaluated by 
the investigator at 1 (+0.5) minute after investigational drug 
instillation (0-4 unit scale, allowing half unit increments) at Visit 
1;   
2. Change from pre-instillation ocular redness score evaluated by 
the investigator (0-4 unit scale, allowing half unit increments) at:  
i. 
1 minute after investigational drug instillation at Visit 2 
ii. 
5 minutes after investigational drug instillation at Visit 
2 
iii. 
1 minute after investigational drug instillation at Visit 3 
iv. 
5 minutes after investigational drug instillation at Visit 
3 
3. Change from pre-instillation ocular redness score evaluated by 
the investigator at 360 (+15) minutes after investigational drug 
instillation (0-4 unit scale, allowing half unit increments) at Visit 
1; and  
4. Change from pre-instillation ocular redness score evaluated by 
the investigator at 480 (+15) minutes after investigational drug 
instillation (0-4 unit scale, allowing half unit increments) at Visit 
1.  
5. Ocular redness score evaluated by the subject as captured in 
subjects’ dosing diary throughout the treatment period (0-4 unit 
scale, NOT allowing half unit increments). 
Tolerability Measures: 
• 
Drop comfort assessment (0-10 unit scale) assessed upon 
instillation, at 30 seconds, and at 1 minute post-instillation at 
Visit 1 
• 
Drop comfort descriptor questionnaire assessed at 3 minutes post-
instillation at Visit 1 
Safety Measures: 
• 
Ocular and non-ocular adverse events, vital signs, and ophthalmic 
examination at each visit 
• 
Ocular Rebound defined as: 
o 
Increase of at least 1 unit in mean ocular redness score 
evaluated by the Investigator at Visit 4 (0-4 unit scale, 
allowing half unit increments) compared to pre-
instillation score at Visit 1, or   
o 
Increase of at least 1 unit in mean ocular redness score 
evaluated by the subject as captured in subject dosing 
diaries in the follow-up period, after dosing has ceased 
(0-4 unit scale, NOT allowing half unit increments) 
compared to diary day 1 (pre-dose morning assessment). 
Sample Size 
386 Subjects 


Protocol Number 908   
 
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Bausch & Lomb, Incorporated Study # 908  
Statistical methods: 
Quantitative variables, including demographics at baseline, will be 
summarized descriptively using number of subjects (n), mean, median, 
standard deviation, minimum, and maximum. Qualitative variables will be 
summarized using counts and percentages.   
BTOS-PF 0.025% will be compared to Lumify® 0.025% for the primary 
efficacy parameter of ocular redness as evaluated by the investigator (post-
instillation assessments) for each of eight times at Visit 1 using two-sided 
95% confidence intervals around the difference between means (Test 
minus Standard) constructed as for 2-sample t-tests. If the upper 
confidence limit does not exceed 0.22 points at any time point, then the 
null hypothesis will be rejected in favor of the alternative hypothesis and 
the Test formulation will be statistically successful in this endpoint. 
The primary analyses will be performed on the Intent-to-Treat (ITT) 
population without imputation if all eight Visit 1 post-instillation time 
points have missing data for the primary endpoint for less than 5% of 
subjects, and sensitivity analysis will be performed on the Primary Per-
Protocol (PPP) population without imputation. If there is at least one Visit 
1 time point for which at least 5% of subjects have missing data for the 
primary endpoint, then the primary analysis will be performed on the ITT 
population with an imputation strategy accounting for the reason for 
missing (e.g. intercurrent events), and sensitivity analyses will be 
performed on the PPP utilizing the same imputation strategy, as well as on 
the ITT and PPP populations without imputation. Secondary efficacy 
analyses will be based on the ITT population with an imputation strategy 
accounting for the reason for missing (e.g. intercurrent events) if at least 
5% of subjects have missing data for that endpoint. A non-inferiority 
margin of 0.22 units will be used to evaluate the secondary efficacy 
endpoints of investigator-rated redness and a non-inferiority margin of 1.0 
units will be used to evaluate the secondary efficacy endpoint of subject-
rated redness. The secondary efficacy parameter of ocular redness as 
recorded in the subject diaries will be analyzed using a generalized linear 
model accounting for repeated measures. Daily averages will be used for 
each subject.  The change from pre-instillation at each visit and/or time 
point will also be compared using 2-sample t-tests. Additionally, a 
responder analysis will compare the percentage of subjects with total 
clearing (redness scores of 0) in the 2 treatment groups for each post-
instillation time point at each visit.  
BTOS-PF 0.025% will also be compared to Lumify® 0.025% for the 
tolerability parameter of drop comfort using 2-sample t-tests for each 
assessment time point. The tolerability parameter will be analyzed using 
the safety population. The results for the drop comfort descriptor 
questionnaire will be summarized descriptively by treatment group. 
All safety parameters will be analyzed using the safety population.  Safety 
of BTOS-PF 0.025% compared to Lumify® 0.025% will be assessed by 
the review of all of the safety parameters. 
The number of subjects reporting an adverse event (AE) during the study 
as well as the number of AEs will be presented. The number of subjects 
and events for treatment-emergent adverse events (TEAEs) will be 
tabulated by MedDRA System Organ Class and by preferred term within 
each System Organ Class for each treatment and overall using the most 
recently available version of MedDRA. The number of subjects reporting 


Protocol Number 908   
 
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Bausch & Lomb, Incorporated Study # 908  
TEAEs will also be summarized by relationship to investigational drug as 
well as severity. Serious adverse events (SAEs) additionally will be 
summarized.   
The results of the slit lamp biomicroscopy, IOP, visual acuity, and vital 
signs will be summarized using descriptive statistics by treatment group 
and visit. Change from baseline will also be presented in the same manner. 
The ocular rebound evaluated by the investigator (at Visit 4) and by the 
subject (between Visit 3 – Visit 4) will be summarized separately using 
descriptive statistics by treatment. 


Protocol Number 908   
 
Version 2.0, 27Oct2021 
 
Page 12 of 66 
 
 
  
3.0 
TABLE OF CONTENTS 
PAGE 
1.0 TITLE PAGE ....................................................................................................................................... 1 
INVESTIGATOR STATEMENT OF AGREEMENT.............................................................................. 3 
PERSONNEL AND FACILITIES .............................................................................................................. 4 
2.0 SYNOPSIS ............................................................................................................................................ 5 
3.0 TABLE OF CONTENTS ...................................................................................................................12 
4.0 LIST OF ABBREVIATIONS ............................................................................................................15 
5.0 INTRODUCTION ..............................................................................................................................17 
6.0 STUDY OBJECTIVES AND PURPOSE..........................................................................................18 
7.0 INVESTIGATOR AND STUDY ADMINISTRATIVE PROCEDURES ......................................18 
8.0 INVESTIGATIONAL PLAN.............................................................................................................18 
 OVERALL STUDY DESIGN AND PLAN DESCRIPTION ..........................................................................18 
9.0 SELECTION OF STUDY POPULATION AND WITHDRAWAL OF SUBJECTS ...................19 
 SUBJECT INCLUSION CRITERIA .........................................................................................................19 
 SUBJECT EXCLUSION CRITERIA ........................................................................................................20 
 SUBJECT DISCONTINUATION / WITHDRAWAL CRITERIA ...................................................................21 
 LOST TO FOLLOW-UP ........................................................................................................................22 
10.0 TREATMENT PLAN .........................................................................................................................22 
 STUDY DURATION ............................................................................................................................22 
 METHODS OF ASSIGNING SUBJECTS TO TREATMENT GROUPS ..........................................................22 
 DESCRIPTION OF TEST ARTICLE(S)/TREATMENT(S) ..........................................................................22 
 DESCRIPTION OF COMPARATOR / PRODUCT(S)/TREATMENT(S) ........................................................22 
 INSTRUCTIONS FOR USE AND ADMINISTRATION ...............................................................................23 
 OTHER MATERIALS ...........................................................................................................................23 
 MASKING/UNMASKING OR BLINDING/UNBLINDING .........................................................................23 
 RANDOMIZATION METHOD ...............................................................................................................24 
 PRIOR AND PROHIBITED CONCOMITANT MEDICATIONS OR THERAPY...............................................24 
 
TREATMENT COMPLIANCE ..........................................................................................................24 
 
PROTOCOL DEVIATIONS AND VIOLATIONS ..................................................................................24 
11.0 STUDY DRUG MATERIALS AND MANAGEMENT...................................................................25 
 NAME OF INVESTIGATIONAL PRODUCTS ...........................................................................................25 
11.1.1 
Packaging and Labeling ....................................................................................................25 
11.1.2 
Storage Requirements / Handling and Disposal of Study Drug ........................................25 
11.1.3 
Treatment Replacement ....................................................................................................26 
11.1.4 
Study Drug Accountability ...............................................................................................26 
 EFFICACY AND SAFETY VARIABLES .................................................................................................26 
11.2.1 
Primary Efficacy Variables ...............................................................................................26 
11.2.2 
Secondary Efficacy Variables ...........................................................................................26 
11.2.3 
Safety Variables ................................................................................................................27 
11.2.4 
Tolerability Variables .......................................................................................................27 
12.0 STUDY METHODS, PROCEDURES AND EVALUATIONS.......................................................27 
 STUDY VISITS ...................................................................................................................................27 
12.1.1 
Screening Visit (Day -28 to Day 1) ..................................................................................27 
12.1.2 
Visit 1 (Baseline; Day 1) ...................................................................................................28 
12.1.3 
Visit 2 (Day 15 + 2 days) ..................................................................................................29 


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12.1.4 
Visit 3 (Day 29 + 2 days) ..................................................................................................30 
12.1.5 
Visit 4 (Day 36 + 1 day) ...................................................................................................31 
12.1.6 
Unscheduled Visits ...........................................................................................................32 
12.1.7 
Missed Visits.....................................................................................................................32 
 POST-STUDY FOLLOW-UP .................................................................................................................32 
 STUDY COMPLETION .........................................................................................................................32 
12.3.1 
Early Study Termination ...................................................................................................32 
 ADVERSE EVENTS .............................................................................................................................32 
12.4.1 
Definition of Adverse Event .............................................................................................32 
12.4.2 
General Guidelines for Reporting Adverse Events ...........................................................33 
12.4.3 
Serious Adverse Events ....................................................................................................34 
12.4.4 
Assessment of Severity of Adverse Events .......................................................................37 
12.4.5 
Assessment of Causality of Adverse Events .....................................................................37 
12.4.6 
Expedited Serious Adverse Events ...................................................................................37 
12.4.7 
Pregnancy .........................................................................................................................38 
13.0 STATISTICS .......................................................................................................................................40 
 ASSESSMENT OF EFFICACY ...............................................................................................................40 
13.1.1 
Primary Efficacy ...............................................................................................................40 
13.1.1 
Primary Efficacy Endpoints ..............................................................................................40 
13.1.2 
Secondary Efficacy ...........................................................................................................40 
13.1.3 
Supportive Efficacy ..........................................................................................................41 
13.1.4 
Statistical Hypothesis Testing and Control of Multiplicity ...............................................42 
13.1.5 
General Considerations .....................................................................................................42 
13.1.6 
Missing Efficacy Data Imputations ...................................................................................43 
13.1.7 
Sensitivity Efficacy Analyses ...........................................................................................43 
13.1.8 
Subgroup Analyses ...........................................................................................................43 
 ASSESSMENT OF TOLERABILITY .......................................................................................................44 
 ASSESSMENT OF SAFETY ..................................................................................................................44 
13.3.1 
Adverse Events .................................................................................................................44 
13.3.2 
Safety Laboratory Tests ....................................................................................................45 
13.3.3 
Vital Sign Measurements ..................................................................................................45 
13.3.4 
Concomitant Medications .................................................................................................45 
 SUBJECT DISPOSITION .......................................................................................................................45 
 DEMOGRAPHICS AND BASELINE CHARACTERISTICS .........................................................................45 
 PROTOCOL DEVIATIONS ....................................................................................................................45 
 COMPLIANCE ....................................................................................................................................46 
 INTERIM ANALYSES ..........................................................................................................................46 
 ADDITIONAL STATISTICAL CONSIDERATIONS ...................................................................................46 
13.9.1 
Analysis Populations .........................................................................................................46 
13.9.2 
Sample Size Determination ...............................................................................................46 
13.9.3 
Multiplicity Issues .............................................................................................................47 
13.9.4 
Windowing Rules .............................................................................................................47 
14.0 QUALITY CONTROL AND QUALITY ASSURANCE ................................................................47 
 STUDY MONITORING ........................................................................................................................47 
 SOURCE DOCUMENTATION ...............................................................................................................48 
 CASE REPORT FORMS .......................................................................................................................48 
 AUDITS AND INSPECTIONS ................................................................................................................48 
 DATA QUALITY ASSURANCE ............................................................................................................48 
15.0 ETHICS AND ADMINISTRATIVE ISSUES ..................................................................................49 
 ETHICAL CONDUCT OF THE STUDY ...................................................................................................49 
 ETHICS REVIEW ................................................................................................................................49 
 WRITTEN INFORMED CONSENT .........................................................................................................49 
 SUBJECT DATA PROTECTION ............................................................................................................50 
 FINANCIAL DISCLOSURE ...................................................................................................................50 


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 INVESTIGATOR OBLIGATIONS ...........................................................................................................50 
 CHANGES TO THE PROTOCOL ............................................................................................................50 
 CONFIDENTIALITY/PUBLICATION OF THE STUDY AND STUDY RESULTS ...........................................50 
16.0 DATA HANDLING AND RECORD KEEPING .............................................................................51 
 INSPECTION OF RECORDS ..................................................................................................................51 
 RETENTION OF RECORDS ..................................................................................................................52 
17.0 REFERENCES ....................................................................................................................................53 
18.0 APPENDIX A ......................................................................................................................................54 
 VISUAL ACUITY PROCEDURES ..........................................................................................................54 
 SLIT LAMP BIOMICROSCOPY/EXTERNAL EYE EXAM PROCEDURES ..................................................55 
 INTRAOCULAR PRESSURE .................................................................................................................59 
 DILATED OPHTHALMOSCOPY............................................................................................................59 
 VITAL SIGNS .....................................................................................................................................59 
 PHYSICAL EXAMINATION ..................................................................................................................60 
 DROP COMFORT ASSESSMENTS ........................................................................................................61 
 INVESTIGATOR EVALUATED SIGNS ...................................................................................................63 
 SUBJECT DOSING AND REDNESS GRADING DIARIES .........................................................................64 
 
SCHEDULE OF VISITS AND PARAMETERS .....................................................................................66 
 
 
List of tables 
List of Figures 
List of Appendices 
 


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4.0 
LIST OF ABBREVIATIONS 
Abbreviation 
/Acronym  
Term  
AE  Adverse Event 
AR adrenergic receptor 
BCVA Best-Corrected Visual Acuity 
B&L Bausch & Lomb 
BTOS brimonidine tartrate ophthalmic solution 
BPM Beats per Minute 
CFR Code of Federal Regulations 
cGCPs Good Clinical Practices 
CRA Clinical Research Associate 
CRO Clinical Research Organization 
DHHS Department of Health and Human Services 
ERC Ethics Review Committee 
eCRF electronic Case Report Form 
EDC Electronic Data Capture 
EOS End of Study 
EOT End of Treatment 
ETDRS Early Treatment of Diabetic Retinopathy Study 
ET Early Termination 
FDA United States Food and Drug Administration 
GCPs Good Clinical Practice 
HEENT Heart, eye, ears, nose, throat 
HIPAA Health Insurance Portability and Accountability Act 
ICF Informed Consent Form  
ICH International Conference on Harmonisation 
IEC Independent Ethics Committee 
IND Investigational new drug application 
IOP Intraocular Pressure 
IRB Institutional Review Board 
ISO International Organization for Standardization 
ITT Intent to Treat 
IWRS Interactive Web Response System  
LBs Pounds 
LogMAR Logarithm of Minimum Angle of Resolution 
LOCF Last Observation Carried Forward 
MedDRA Medical Dictionary for Regulatory Activities 
mmHg Millimeters of Mercury 
OTC Over-the-counter 


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PF Preservative Free 
PP Per Protocol 
QID Four Times Daily 
SAE Serious Adverse Event 
SOP Standard Operating Procedure 
VA Visual Acuity 
WHO World Health Organization 
 


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5.0 
INTRODUCTION 
Ocular redness is one of the most common ophthalmic conditions and can be caused by 
inflammation of almost any part of the eye, the lacrimal glands, the eyelids, or by a 
defective tear film. The most common cause of ocular redness is an inflammation in the 
conjunctiva, which can be caused by allergies, exposure to environmental irritants, or as a 
reaction to infectious agents (e.g., bacteria or virus). Vasoconstriction of arteriolar capillary 
beds, and/or venular networks, provides beneficial relief of vascular-induced tissue 
congestion. Topical vasoconstrictors used to treat congestion in the eye (ocular redness) or 
nose are highly efficacious, but tachyphylaxis (tolerance or loss of effectiveness) and 
rebound congestion are common and restrict long term use. The rebound congestion is 
thought to be related to generalized ischemia and secondary release of an inflammatory 
cascade brought about by vasoconstriction. 
Current over-the-counter vasoconstrictors are either α1-adrenergic receptor (AR) specific 
or have a mixed affinity for both α1-ARs and α2-ARs. There is mounting evidence that 
vasoconstrictor side effects, including tachyphylaxis and rebound redness observed with 
the current non-selective, mixed α1- and α2-AR agonists used to treat ocular redness, are 
due to action at the α1-ARs. 
Brimonidine is a third generation α2-AR agonist introduced in 1996. Brimonidine has a 
very high selectivity for α2-ARs, and is used, under prescription, for the treatment of 
increased intraocular pressure (IOP) in glaucoma patients. The mechanism of action is two-
fold: a reduction of aqueous humor flow and increased uveoscleral outflow (Toris, 1995). 
Brimonidine tartrate developed for treatment of IOP was first approved under the brand 
name Alphagan® at concentrations of 0.2% and 0.5%. Both concentrations have since been 
discontinued. These were not discontinued for safety or efficacy reasons. Brimonidine 
tartrate for treatment of IOP is currently sold as Alphagan P® at concentrations of 0.15% 
and 0.1%. 
Recently, Bausch & Lomb (B&L) developed a low dose (0.025%) brimonidine tartrate 
ophthalmic solution which was approved by FDA in December of 2017 under the brand 
name Lumify®. Lumify® is sold over-the-counter for relief of ocular redness due to minor 
irritations.  Lumify® has been demonstrated as an effective treatment of eye redness while 
minimizing the side effects of tachyphylaxis (tolerance or loss of effectiveness) or rebound 
congestion commonly associated with other products currently on the market for redness 
relief. 
For some patients, frequent exposure of the ocular surface to the preservative 
benzalkonium chloride (BAK) can induce or exacerbate existing ocular irritation, 
burning/stinging, itching, dryness, and redness (Gomes, 2017; Walsh, 2019). A 
preservative-free formulation of Lumify® would potentially offer a less-irritating ocular 
decongestant option to patients with ocular redness with no apparent underlying cause.  
B&L has developed a preservative-free formulation of brimonidine tartrate ophthalmic 
solution 0.025%, which contains all of the same components as Lumify® with the exception 
of BAK, with the goal to improve the irritation occasionally reported with frequent use of 
BAK-preserved eye drops while maintaining the redness-relieving effect of the active 
brimonidine tartrate. 


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6.0 
STUDY OBJECTIVES AND PURPOSE 
The Primary Objective is to demonstrate that the efficacy of brimonidine tartrate 
ophthalmic solution preservative-free formulation (BTOS-PF) 0.025% is non-inferior to 
Lumify® 0.025% for treating ocular redness in a population of adult subjects. 
The Secondary Objective is to compare the safety of BTOS-PF 0.025% with Lumify® 
0.025%. 
7.0 
INVESTIGATOR AND STUDY ADMINISTRATIVE PROCEDURES 
• 
The study will be conducted at up to six investigative sites located in the United States.  
• 
The study will be conducted by Principal Investigators who are determined by the 
Sponsor to be suitably qualified by training and experience to conduct this study in 
compliance with all applicable GCPs and Federal or Local Laws and Regulations. Sub-
Investigators will be identified on the Statement of Investigator Agreement Form/ Form 
FDA 1572. 
• 
Approximately 386 subjects will be enrolled at up to six investigative sites. Each 
investigative site is expected to enroll approximately 65 subjects. In the event that the 
selected site does not meet full enrollment, the Sponsor may decide to add additional 
site(s) to satisfy the enrollment requirements of the study. 
8.0 
INVESTIGATIONAL PLAN 
 
Overall Study Design and Plan Description 
This is a multi-center, double-masked, randomized, active-controlled, parallel-group, 
efficacy and safety study that will enroll 386 subjects at up to six clinical sites. Subjects 
with ocular redness will be randomized to receive either brimonidine tartrate ophthalmic 
solution 0.025%, preservative-free formulation, or Lumify® (brimonidine tartrate 
ophthalmic solution 0.025%). Subjects will be treated with study drug for approximately 4 
weeks. 
Five visits will take place during this study: Screening Visit (Day -28 to 1), Visit 1 
(Baseline; Day 1), Visit 2 (Day 15 ± 2 days), Visit 3 (Day 29 + 2 days), and Visit 4 (Study 
Exit; Day 36 + 1 day).  Efficacy assessments will be performed at Visits 1, 2, and 3.  
Tolerability assessments will be performed at Visit 1. Safety assessments will be performed 
at all visits. 
Efficacy assessments include ocular redness evaluated by the investigator in-office and 
ocular redness evaluated by the subject as captured in subjects’ dosing diary. Tolerability 
assessments include drop comfort assessment and drop comfort descriptor questionnaire, 
both evaluated by the subject. Safety assessments include adverse events, vital signs, 
BCVA, IOP, dilated ophthalmoscopy, biomicroscopy, and ocular rebound. 
 


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9.0 
SELECTION OF STUDY POPULATION AND WITHDRAWAL OF 
SUBJECTS 
A total of up to 386 subjects at up to six clinical sites in the United States with ocular 
redness will be enrolled in this clinical investigation.  
 
Subject Inclusion Criteria 
A subject will be eligible for inclusion in this study if he/she meets all of the following 
criteria:   
Subjects MUST:  
1. Be at least 18 years of age at the time of Informed Consent signing of either gender and 
any race or ethnicity;  
2. Provide written informed consent and sign the HIPAA form;  
3. Be willing and able to follow all instructions and attend all study visits; 
4. Have a history of vasoconstrictor (redness relief drops) use within the last 6 months, or 
a desire to use OTC vasoconstrictors for redness relief;  
5. Be able to self-administer eye drops satisfactorily or have a subject’s care provider at 
home1 routinely available for this purpose;  
6. (If female and of childbearing potential) agree to have urine pregnancy testing 
performed at Visit-1(must be negative) and at exit visit; must not be lactating; and must 
agree to use at least 1 medically acceptable form of birth control2  throughout the study 
duration and for at least 14 days prior to the first dose of study drug (Visit 1) and for 1 
month after the last dose of investigational drug. Note: Women considered capable of 
becoming pregnant include all females who have experienced menarche and have not 
experienced menopause (as defined by amenorrhea for greater than 12 consecutive 
months) or have not undergone successful surgical sterilization (hysterectomy, bilateral 
tubal ligation, or bilateral oophorectomy);  
7. (If male and with female partner of childbearing potential) must use at least 1 medically 
acceptable form of birth control3   
8. A calculated best-corrected (if necessary) visual acuity of 0.3 logMAR or better in each 
eye, as measured using an ETDRS chart;    
9. At Visit 1 (Baseline), show a baseline redness score >1 unit (ie, greater than 1 unit) in 
both eyes on a 0 to 4 unit scale as scored by the Investigator using the Investigator 
Ocular Redness Scale;    
10. Have stable ocular health (defined as no ocular conditions requiring therapy or surgical 
intervention during the study).  
1 If a care provider or surrogate will be used to administer eye drops, then he/she must be present at Visit 1 
to administer eye drops in-office. 
2 Acceptable forms of birth control are true abstinence (when this is in line with the preferred and usual 
lifestyle of the subject), spermicide with barrier, oral contraceptive, injectable or implantable method of 
contraception, transdermal contraceptive, intrauterine device, or surgical sterilization of male partner at least 
3 months prior to the first dose of investigational drug (Visit 1). 


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3 Acceptable forms of birth control are true abstinence (when this is in line with the preferred and usual 
lifestyle of the subject) or vasectomy at least 3 months prior to the first dose of study drug (Visit 1).Without 
a vasectomy, must use condoms with spermicidal foam/gel/film/cream/suppository at least 14 days prior to 
the first dose of investigational drug (Visit 1) and for 1 month after the last dose of the investigational drug 
(Visit 3). 
 
 
Subject Exclusion Criteria 
A subject will be ineligible for inclusion in this study if he/she meets any of the following 
criteria:   
Subjects MAY NOT:  
1. Have known contraindications or sensitivity to the use of any of the investigational 
drug(s) or their components, or any other medications required by the protocol;  
2. Have had ocular surgical intervention within 3 months prior to screening or during 
the study and/or a history of refractive surgery within the past 6 months;  
3. Have the presence of an active ocular infection (bacterial, viral, or fungal) or 
positive history of an ocular herpetic infection at any visit;  
4. Use any of the following disallowed medications during the period indicated prior 
to screening and for the duration of the study:  
− All topical ophthalmic agents including artificial tear products, eye whiteners 
(e.g., vasoconstrictors), ocular decongestants, ocular antihistamines, ocular 
corticosteroids, dilating drops (excluding dilated ophthalmoscopy exam at Visit 
1), and contact lenses: 5 days   
− Systemic antihistamines or decongestants: 7 days  
− Systemic corticosteroids or cancer chemotherapy, and/or any other systemic 
medications which the investigator feels may confound study data, or interfere 
with subject’s study participation: 14 days  
5. Have prior (within 7 days of beginning investigational drug) or currently active 
significant illness that could compromise participation, in the opinion of the 
investigator;   
6. Have prior (within 30 days of beginning investigational drug) or anticipated 
concurrent use of an investigational drug or device during the study period;  
7. Have an ocular or systemic condition or a situation which, in the investigator’s 
opinion, may put the subject at increased risk, confound study data, or interfere 
significantly with the subject’s study participation;   
8. Have planned surgery (ocular or systemic) during the trial period or within 30 days 
after the study period;  
9. Be currently breast feeding or planning to breast feed during the study period or is 
a female who is currently pregnant, is planning a pregnancy, or has a positive urine 
pregnancy test at Visit 1;  


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10. Have a diagnosis of ocular hypertension or glaucoma at screening; 
11. Have symptoms that, in the opinion of the investigator, may be associated with 
COVID-19 or in the last 14 days came into contact with someone diagnosed with 
COVID-19. 
 
Subject Discontinuation / Withdrawal Criteria 
A subject MUST be discontinued prior to the final study visit for any of the following 
reasons: 
• 
Voluntary withdrawal:  All subjects are free to withdraw from participating in this 
study at any time and for whatever reason, specified or unspecified, and without 
prejudice. No constraints will be placed on ordinary subject management, and 
subjects, when appropriate, will be placed on other conventional therapy upon request 
or whenever clinically necessary as determined by their physician. 
• 
Death: Complete SAE form 
• 
Subject becomes pregnant: Subject will discontinue study drug immediately, but will 
be followed to term. Complete pregnancy and SAE forms if applicable and report to 
the same contacts using the same reporting procedure for an SAE under Section 
11.4.6.  
• 
If any adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best 
interest of the subject as determined by the Investigator. Complete AE form. 
• 
Lost to Follow-Up: See Section 9.4 below.  
• 
Lack of Efficacy: Subject requires alternate treatment for ocular redness and the risk 
of continuing the subject in the study outweighs the benefit as determined by the 
investigator. 
• 
Study Terminated by Sponsor: An indication that a clinical study was stopped by its 
Sponsor. 
A subject MAY be discontinued (at the discretion of the Investigator, Sponsor, and/or the 
IRB/IEC) prior to the final study visit for several reasons, including, but not limited to:  
• Serious adverse event (SAE) occurring during the course of the study that 
precludes continued treatment or follow-up  
• Significant non-compliance with study requirements (Protocol Violation): 
Contact the Sponsor or designee before making decision. 
• When concomitant therapy likely to interfere with the results of the study is 
reported, or required by the subject (the investigator will report all such 
information on the source documents/electronic case report forms (eCRFs) 
and decide, in accordance with the sponsor, whether the subject is to be 
withdrawn) 
Prior to discontinuing a subject, every effort should be made to contact the subject, 
schedule a final study visit, obtain as much follow-up data as possible, and to retrieve all 
study materials. Adverse events will be followed as described in section 12.4. Subject 
withdrawals will be documented clearly on the source document and applicable eCRF.  
The assessments scheduled for Visit 3 should be performed at this early termination visit. 


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Notification of subject withdrawals will be made to the Sponsor. 
 
Lost to Follow-up 
Subjects who do not return for their scheduled visits as defined by the visit window and 
cannot be contacted, may be considered lost to follow-up. Attempts to contact the subjects 
should include at least 2 phone calls, emails and/or text messages and a certified letter.  All 
follow-up attempts will be documented and kept with the subject’s source documentation, 
and the applicable eCRFs will be completed. For subjects that are lost to follow-up, the 
date of early termination will be the date of the last attended clinic visit and the date of last 
dose will be the date of the last in-office instillation. 
10.0 TREATMENT PLAN 
 
Study Duration 
The estimated time of study duration, from the start of enrollment to completion of the end 
of study (EOS) assessments for the final subject is approximately 21 weeks.  For each 
subject, the estimated time on study medication, from baseline to end of treatment (EOT) 
visit is 4 weeks. 
 
Methods of Assigning Subjects to Treatment Groups 
At Visit 1, approximately 386 subjects will be randomly assigned at a ratio of 1:1 to the 
following treatments: 
• Brimonidine tartrate ophthalmic solution 0.025%, preservative-free formulation 
(BTOS-PF) (N = 193) 
• Lumify® (brimonidine tartrate ophthalmic solution 0.025%) (N= 193) 
 
Description of Test Article(s)/Treatment(s) 
The test article, BTOS-PF, contains 0.025% of the active brimonidine tartrate, purified 
water, boric acid, sodium borate decahydrate, potassium chloride, calcium chloride 
dihydrate, glycerin, sodium chloride, and pH adjusted with hydrochloric acid and sodium 
hydroxide.   
The dosing regimen for BTOS-PF 0.025% is 4 times per day (QID) approximately 4 hours 
apart for a duration of 4 weeks. 
 
Description of Comparator / Product(s)/Treatment(s) 
The comparator product, Lumify®, contains 0.025% of the active brimonidine tartrate, 
purified water, benzalkonium chloride, boric acid, sodium borate decahydrate, potassium 
chloride, calcium chloride dihydrate, glycerin, sodium chloride, and pH adjusted with 
hydrochloric acid and sodium hydroxide. 
The dosing regimen for Lumify® is QID approximately 4 hours apart for a duration of 4 
weeks. 


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Instructions For Use and Administration 
Study drug will be provided as a study kit (carton). Each study kit will contain pouches 
that each hold 5 single-use vials. One single-use vial will be used to dose both eyes 1 time. 
Subjects will instill 1 drop of the assigned investigational drug in each eye QID 
approximately 4 hours apart.  Subjects should dispose of the single-use vial in the provided 
zip-lock bag after instillation of 1 drop in both eyes.  Subjects should not use any remaining 
solution in the vial for a subsequent dose.  
 
Other Materials 
• Clarity HCG will be used for pregnancy tests.   
• Fluress® ocular anesthetic agent (fluorescein sodium and benoxinate 
hydrochloride ophthalmic solution USP) will be used for the intraocular 
pressure (Section 18.3) 
• Dilating drops will be used for dilated ophthalmoscopy (Section 18.4) 
 
Masking/Unmasking or Blinding/Unblinding  
Subjects will be assigned to treatments based on a randomization schedule.  The 
Investigator, site staff, subject, CRO, and Sponsor personnel involved in the monitoring or 
conduct of the study will be masked to the treatment assignments. The randomization list 
will be produced prior to study enrollment by a statistician not otherwise involved in the 
trial.  
Due to differences in test article and comparator, there will be an Unmasked Designee who 
will be responsible for the handling of study kits and activities surrounding the use of study 
kits.  
Each site must have a unmasked Designee that will be responsible for: 
• 
all study kit dispensation and accountability,  
• 
daily diary dosing education/review,  
• 
all discussions with study subjects related to study kit 
This unmasked designee shall not participate in any other trial procedures and not report 
this information to other staff. Subjects will be instructed to administer the study drug out 
of the sight of the Investigator or site staff other than the unmasked designee. Subjects will 
be instructed not to show or discuss the properties of the assigned study drug to the 
Investigator or site staff other than the unmasked designee, unless instructed to do so. 
When the management of a subject’s condition requires knowledge of the treatment 
assignment, the investigator, or designee, will obtain the trial treatment assignment from 
the Interactive-Web Response System (IWRS). If possible, the medical emergency should 
be discussed with the medical monitor prior to obtaining the treatment assignment, or as 
soon after as. 
The Investigator must record the date, time, and reason for unmasking the study drug 
treatment in the source documentation. 


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Randomization Method 
Each subject who signs an informed consent form will be assigned a unique Subject 
number in the IWRS.  Once a subject meets all qualification criteria at Visit 1, he/she will 
be randomized to brimonidine tartrate ophthalmic solution 0.025%, preservative free 
formulation or Lumify® (brimonidine tartrate ophthalmic solution 0.025% in a 1:1 ratio. 
Subject numbers will be assigned in a sequential order starting at the lowest number 
available. No numbers will be skipped or omitted. Subject numbers will be created (in the 
following format, 3-digit site number plus 3-digit subject number) in the IWRS. 
Randomization will be used to avoid bias in the assignment of subjects to treatment, to 
increase the likelihood that known and unknown subject attributes (e.g., demographics and 
baseline characteristics) are evenly balanced across the IWRS treatment groups, and to 
enhance the validity of statistical comparisons across treatment groups. Masked treatment 
will be used to reduce potential of bias during data collection and evaluation of clinical 
endpoints.  
A trained unmasked Designee will be instructed to dispense the appropriate kit that 
corresponds to the assigned subject number according to the randomization list.  
 
Prior and Prohibited Concomitant Medications or Therapy 
All therapies and medications administered 30 days prior to screening and through study 
exit must be recorded in the source documentation and in the appropriate section of the 
eCRF.  
 Treatment Compliance 
Any subject who does not follow instructions to a degree that, in the Sponsor or 
Investigator’s opinion, jeopardizes the subject’s well-being or the validity of the study, 
may be discontinued.  
 Protocol Deviations and Violations 
A deviation from the protocol is an unintended and/or unanticipated departure from the 
procedures and/or processes approved by the sponsor and the IRB/IEC and agreed to by 
the investigator.  Deviations usually have an impact on individual subjects or a small group 
of subjects and do not involve inclusion/exclusion or primary endpoint criteria. 
A protocol violation occurs when there is non-adherence to the protocol that results in a 
significant, additional risk to the subject; when the subject or investigator has failed to 
adhere to significant protocol requirements (inclusion/exclusion criteria), and the subject 
was enrolled without prior sponsor approval; or when there is non-adherence to FDA 
regulations and/or ICH GCP guideline. 
The investigator may implement a deviation from the protocol to eliminate an immediate 
hazard to study subjects without prior IRB/IEC approval.  As soon as possible after such 
an occurrence, the implemented deviation, as well as the reasons for it, and any proposed 
protocol amendment(s) should be submitted to the IRB/IEC for review and approval.  It 
should also be submitted to the sponsor for agreement, and to the regulatory authorities, if 
required. 


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The date of and reason for deviations will be documented in all cases. Significant  protocol 
deviations impacting the safety of the subject or the integrity of the study must be reported 
by the Investigator to the IRB/EC immediately. Reporting of all other protocol deviations 
must adhere to the requirements of the governing IRB/EC.  
Protocol assessments will continue until the end of the study, unless the protocol deviations 
put the subject at risk or the subject’s condition requires that he/she be discontinued from 
the study. 
11.0 STUDY DRUG MATERIALS AND MANAGEMENT 
 
Name of Investigational Products 
• 
Brimonidine tartrate ophthalmic solution 0.025%, preservative-free formulation  
• 
Lumify® (brimonidine tartrate ophthalmic solution 0.025%) 
 
11.1.1 
Packaging and Labeling 
The investigational materials will be packaged and labeled in a manner consistent 
with the study design. They will be labelled according to the regulatory requirements 
and in compliance with the Code of Federal Regulations 21 part 312, section 312.6. 
The labels for the investigational materials will contain but not limited to the 
following: 
• 
Protocol number 
• 
Kit number 
• 
Contents 
• 
Investigational new drug statement 
• 
Storage conditions 
• 
Name and address of the sponsor 
11.1.2 
Storage Requirements / Handling and Disposal of Study Drug 
Study drug will be supplied to the investigator by the Sponsor and must be stored in a 
controlled-access, environmentally controlled area as per the label. The investigational 
product must be kept in an appropriate, secure area (e.g., locked cabinet, or other contained 
space). 
There are no special procedures required for preparing the study drug for this trial. Study 
material are stored at the recommended storage conditions 15° - 25° C (59-77° F).  
All used, unused and returned product must be returned to the Sponsor at the address below. 
It will be at the Sponsor's permission to allow disposal of product at the site as per site 
destruction procedures.  Site is to contact sponsor for permission on material disposal on 
site.  Instructions will be provided by the Sponsor regarding final disposition of all study 
drug in compliance with applicable regulations. 
 


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Bausch + Lomb 
1400 N Goodman St. 
Clinical Trial Materials / A56 
Rochester, NY 14609 
11.1.3 
Treatment Replacement 
Any additional or replacement (in the case of loss or damage) of study kits must be ordered 
through the randomization system. 
11.1.4 
Study Drug Accountability 
The Investigator will be responsible for keeping current and accurate records of the amount 
of study received and dispensed, and its disposition. The drug must be stored under the 
appropriate conditions in a secure area and is to be dispensed only to subjects enrolled in 
the study, in accordance with the conditions specified in this protocol. During the course 
of the study, the Investigator must maintain an inventory of all drug dispensed to or 
returned by the subject, including subject numbers and visit numbers. 
At time points throughout the study and/or upon completion of the study, the 
Sponsor/Sponsor's representative will review and verify the Investigator's accountability 
records. Following verification, and as directed by the Sponsor, all used, unused and 
returned product must be returned to the Sponsor at the address noted above in Section 
11.1.2 (handling and disposal of study drug), or with the Sponsor's permission, disposed of 
at the site in an appropriate manner.  Instructions will be provided by the Sponsor regarding 
final disposition of all study drug in compliance with applicable regulations. 
 
Efficacy and Safety Variables 
11.2.1 
Primary Efficacy Variables 
• Ocular redness score evaluated by the investigator prior to investigational drug 
instillation and at 5(+1), 15(+1), 30(+1), 60(+10), 90(+10), 120(+15), 180(+15), and 
240(+15) minutes after investigational drug instillation (0-4 unit scale, allowing half 
unit increments) at Visit 1 
11.2.2 
Secondary Efficacy Variables 
Secondary efficacy endpoints will be evaluated hierarchically, as follows:  
1. Change from pre-instillation ocular redness score evaluated by the investigator at 1 
(+0.5) minute after investigational drug instillation (0-4 unit scale, allowing half 
unit increments) at Visit 1;   
2. Change from pre-instillation ocular redness score evaluated by the investigator (0-
4 unit scale, allowing half unit increments)at:   
i. 
1 minute after investigational drug instillation at Visit 2 
ii. 
5 minutes after investigational drug instillation at Visit 2 
iii. 
1 minute after investigational drug instillation at Visit 3 
iv. 
5 minutes after investigational drug instillation at Visit 3 


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3. Change from pre-instillation ocular redness score evaluated by the investigator at 
360 (+15) minutes after investigational drug instillation (0-4 unit scale, allowing 
half unit increments) at Visit 1; and  
4. Change from pre-instillation ocular redness score evaluated by the investigator at 
480 (+15) minutes after investigational drug instillation (0-4 unit scale, allowing 
half unit increments) at Visit 1.  
5. Ocular redness score evaluated by the subject as captured in subjects’ dosing diary 
throughout the treatment period (0-4 unit scale, NOT allowing half unit 
increments). 
11.2.3 
Safety Variables 
• Ocular and non-ocular adverse events, vital signs, and ophthalmic examination at each 
visit 
• Ocular Rebound defined as:  
o Increase of at least 1 unit in mean ocular redness score evaluated by the Investigator 
at Visit 4 (0-4 unit scale, allowing half unit increments) compared to pre-instillation 
score at Visit 1, or   
o Increase of at least 1 unit in mean ocular redness score evaluated by the subject as 
captured in subject dosing diaries in the follow-up period, after dosing has ceased 
(0-4 unit scale, NOT allowing half unit increments) compared to diary day 1 (pre-
dose morning assessment). 
11.2.4 
Tolerability Variables 
• Drop comfort assessment (0-10 unit scale) assessed upon instillation, at 30 seconds, 
and at 1 minute post-instillation at Visit 1 
• Drop comfort descriptor questionnaire assessed at 3 minutes post-instillation at Visit 1 
12.0 STUDY METHODS, PROCEDURES AND EVALUATIONS 
 
Study Visits 
Refer to Appendix A for a schedule of visits and parameters and Appendix B for methods 
of clinical evaluation.  
12.1.1 
Screening Visit (Day -28 to Day 1) 
Following identification of a potential subject, the Investigator (or designee) will explain 
the purpose of the study, procedures, risks/benefits, and subject responsibilities to the 
potential subject. The subject’s willingness and ability to meet the follow-up requirements 
of the study will be determined. If the subject chooses to participate in the investigation, 
written informed consent will be obtained. The subject and the person obtaining written 
consent, will sign and date the IRB/EC-approved ICF, at which point the subject is 
considered part of the study population. The original signed document will be retained in 
the subject records, and a copy will be provided to the subject. In addition, the applicable 
privacy regulation requirements must be met. 


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• Informed Consent/HIPAA: Prior to any changes in a subject’s medical 
treatment and/or study visit procedures, the study will be discussed with each 
subject, and subjects wishing to participate must give written informed 
consent and sign a HIPAA form. The informed consent process will be 
captured in the subject’s source documentation. 
Prior to randomization at Visit 1, if it is determined the subject did not in fact 
meet certain criteria, the subject will be a screen failure.  The subject may be 
brought back at a later date to re-attempt the screening process. Subject will be 
considered a new subject when re-attempting the screening process. The subject 
will sign the informed consent again and a new subject number will be assigned.  
• Demographic Data and Medical/Medication/Ocular History: Collect and 
record all demographic data, medical history, any medications and any 
underlying condition(s). Current underlying conditions, including those that 
began within the last 30 days, which resolved before screening must be 
recorded. Record any medications the subject is taking, as well as those the 
subject may have taken but discontinued within the 30 days prior to screening. 
Medical/medication history and inclusion/exclusion review may be performed 
at the time of Screening Visit and confirmed at Visit 1.  
If there is no washout period, the Screening Visit and Visit 1 can occur on the same day. 
12.1.2 
Visit 1 (Baseline; Day 1) 
• Update Medication History: Collect and record any changes or new 
medications that may have started or that require follow-up from the last visit. 
If a subject uses a disallowed medication, that subject will be exited from the 
study.   
• Urine Pregnancy Test1(for females of childbearing potential): Women of 
childbearing potential must have a negative urine pregnancy test to continue 
in the study and must agree to use an adequate method of contraception and 
associated footnotes in order to be enrolled. 
• Best Corrected Visual Acuity at Distance Utilizing an ETDRS Chart: 
Subjects must have a score of 0.3 logMAR or better in each eye in order to 
qualify (see Appendix A). 
• Slit Lamp Biomicroscopy: A slit lamp exam will be performed to exclude 
subjects with disallowed ocular conditions (see Appendix A).  
• Ocular Redness Assessment: Redness will be assessed by the investigator 
using the 0-4 Investigator Ocular Redness Scale (see Appendix A). 
• Intraocular Pressure: Intraocular pressure will be measured (see Appendix 
A). It is recommended that subjects should wait a minimum of 10 minutes 
after instillation of Fluress® before instilling investigational drug. 
 
1 See section for reporting pregnancies and follow-up (enrolled subjects only). 


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• Physical Exam including vital signs (see Appendix A).  
• Dilated Ophthalmoscopy: A dilated ophthalmoscopy will be performed by the 
investigator to evaluate the presence or absence of clinically significant 
fundus abnormalities and vitreous pathology (see Appendix A). 
• Review of Applicable Inclusion/Exclusion Criteria: The investigator will 
verify the trained study technician’s review of inclusion/exclusion criteria. 
• Enrollment/Randomization:  Qualifying subjects will be assigned a unique 
subject number and randomized through IWRS to receive either brimonidine 
tartrate ophthalmic solution 0.025% preservative free or Lumify®. An 
unmasked designee will distribute the appropriate study kit.  
• Investigational Drug Dispensation and Instillation:  Drug dispensation of one 
kit for self-administered dosing until Visit 2. An unmasked designee will 
observe the subject (or subject’s care provider; if applicable) instill 
investigational drug according to the directions for use. The investigational 
drug kit number and the time of instillation will be recorded. 
• Drop Comfort Assessment: Drop comfort will be assessed immediately upon 
instillation, at 30 seconds, and at 1 minute post-instillation (0 – 10 scale). 
• Drop Comfort Descriptor Questionnaire: The subject will select 3 descriptor 
terms for drop comfort at 3 minutes post-instillation. 
• Post-Instillation Ocular Redness Assessment: Redness will be assessed by the 
investigator at 1(+0.5), 5(+1), 15(+1), 30(+1), 60(+10), 90(+10), 120(+15), 
180(+15), 240(+15), 360 (+15), and 480(+15) minutes after investigational 
drug instillation using the 0-4 Investigator Ocular Redness Scale. 
• Slit Lamp Biomicroscopy (Post-Instillation) 
• Investigational Drug and Dosing/Redness Diary Dispensation: Enrolled 
subjects (or subject’s care provider, if applicable) will be instructed to instill 1 
drop of investigational drug in each eye, 4 times daily for approximately 4 
weeks beginning the next morning. Subjects will be instructed on how to 
complete their daily diary and ocular redness assessments using the 
photographic scale provided. 
Subjects will be instructed to record the time of dosing in the diary. 
Subjects will be instructed NOT to dose within 3.5 hours of arrival on the day 
of their next scheduled study visit (Visit 2). They will also be instructed to bring 
both used/unused investigational drug and their daily diary to the next visit 
(Visit 2) for a compliance check. 
• Adverse Event Query 
• Schedule Visit 2 
12.1.3 
 Visit 2 (Day 15 + 2 days) 
• Investigational Drug and Dosing/Redness Diary Review and Collection:  


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Unmasked designee will collect study kit (used and unused investigational 
material) dispensed at Visit 1. The dosing diary will be collected and reviewed 
for compliance and to address any queries.   
• Update Medication History: Collect and record any changes or new 
medications that may have started or that require follow-up from the last visit. 
If a subject uses a disallowed medication, that subject will be exited from the 
study.   
• Adverse Event Query 
• Best Corrected Visual Acuity at Distance Utilizing an ETDRS Chart:  
A clinically significant visual acuity decrease (defined as an increase of 0.22 
or greater in logMAR score) from Visit 1 will be considered an adverse event. 
• Vital Signs (without body weight) 
• Slit Lamp Biomicroscopy  
• Ocular Redness Assessment: Redness will be assessed   at Visit 2 by the 
investigator using the 0-4 Investigator Ocular Redness Scale. 
• Post-Instillation Ocular Redness Assessment: Redness will be assessed by the 
investigator approximately 1 and 5 minutes after investigational drug 
instillation using the 0-4 Investigator Ocular Redness Scale. 
• Slit Lamp Biomicroscopy (Post instillation) 
• Investigational Drug and Dosing/Redness Diary Dispensation: Enrolled 
subjects (or subject’s care provider, if applicable) will be instructed to 
continue their at-home dosing QID, approximately every 4 hours. Subjects 
will be instructed to continue to complete their daily diary and ocular redness 
assessments using the provided photographic scale as instructed. 
Subjects will continue to record the time of dosing in the diary. 
Subjects will be instructed NOT to dose within 3.5 hours of arrival on the day 
of their next scheduled study visit (Visit 3). They will also be instructed to bring 
both used/unused investigational drug and their daily diary to the next visit 
(Visit 3) for a compliance check. 
• Schedule for Visit 3 
12.1.4 
Visit 3 (Day 29 + 2 days) 
• Collection of Study Drug kit & Diary 
Unmasked designee will collect study kit (used and unused investigational 
material) dispensed at Visit 2. Dosing diary will be collected and reviewed for 
compliance and to address any queries.  
• Update Medication History 
• Adverse Event Query 


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• Best Corrected Distance Visual Acuity Utilizing an ETDRS Chart:  
A clinically significant visual acuity decrease (defined as an increase of 0.22 
or greater in logMAR score) from Visit 1 will be considered an adverse event. 
• Slit Lamp Biomicroscopy  
• Ocular Redness Assessment: Redness will be assessed as at Visit 3 by the 
investigator using the 0-4 Investigator Ocular Redness Scale. 
• Investigational Drug Instillation:  An unmasked designee will instill 
investigational drug according to the directions for use. The investigational 
drug kit number and the time of instillation will be recorded.   
• Post-Instillation Ocular Redness Assessment: Redness will be assessed by the 
investigator approximately 1 and 5 minutes post investigational drug 
instillation using the 0-4 Investigator Ocular Redness Scale. 
• Slit Lamp Biomicroscopy (Post-Instillation) 
• Intraocular Pressure 
• Physical Exam including Vital Signs 
• Dilated Ophthalmoscopy: A dilated ophthalmoscopy will be performed by the 
investigator to evaluate the presence or absence of clinically significant 
fundus abnormalities and vitreous pathology (see Appendix A). 
• Redness Diary Dispensation: Subjects will be instructed to complete ocular 
redness assessments QID with intervals of approximately 4 hours up until the 
night before their next visit (Visit 4) using the photographic scale provided. 
They will also be instructed to bring their diary to their next visit (Visit 4).  
• Schedule for Visit 4 
12.1.5 
 Visit 4 (Day 36 + 1 day) 
• Update Medication History 
• Adverse Event Query 
• Diary Collection: The redness diary will be collected and reviewed to address 
any queries.  
• Urine Pregnancy Test (for females of childbearing potential) 
• Best Corrected Visual Acuity at Distance Utilizing an ETDRS Chart:  
A clinically significant visual acuity decrease (defined as an increase of 0.22 
or greater in logMAR score) from Visit 1 will be considered an adverse event. 
• Slit Lamp Biomicroscopy  
• Ocular Redness Assessment: Redness will be assessed as at Visit 4 by the 
investigator using the 0-4 Investigator Ocular Redness Scale. 
• Exit: Subjects will be exited from the study. 


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12.1.6 
Unscheduled Visits 
Additional visits may be scheduled, as necessary, to ensure the safety and well-being of 
subjects. All additional exams should be fully documented in the source documents and on 
Unscheduled Visit eCRFs, as appropriate. Visits intended to fulfill scheduled visit 
requirements that fall outside the designated scheduled visit range, are not considered 
Unscheduled Visits. In these cases, the visit data will be collected and transcribed to the 
appropriate scheduled visit eCRF. 
If a subject is seen for multiple visits during a given visit timeframe, the data from the visit 
that is intended to meet the protocol requirements for the scheduled visit should be captured 
on the visit eCRF. Where such a determination cannot be made, the first visit within the 
scheduled visit interval will be used for completion of the protocol required scheduled visit 
eCRF. Data from any additional visits within a scheduled visit interval will be captured on 
an Unscheduled Visit eCRF. 
12.1.7 
Missed Visits 
If a subject misses any scheduled follow-up visit and cannot be seen prior to the start of 
the visit range for the next scheduled follow-up visit, the visit is considered missed.  
 
Post-Study Follow-up 
If a subject requires further follow-up of ongoing AEs upon discontinuation or completion 
of the study, the Investigator should schedule post-study follow-up visits, as necessary.  
 
Study Completion 
The Sponsor will notify the CRO when to contact the IRB/EC to inform them that the study 
is complete. 
12.3.1 
Early Study Termination 
If during the study it becomes evident to the Sponsor that the study should be stopped 
prematurely, the study will be terminated and appropriate notification will be given to the 
Investigator(s), IRB/EC, and FDA, as applicable. The Sponsor will instruct the 
Investigators to stop dispensing study materials/treatment and the Sponsor will arrange for 
study closeout visits for  each site. 
 
Adverse Events 
12.4.1 
Definition of Adverse Event 
Definition of Adverse Event/ (AE): 
An adverse event is any untoward medical occurrence in a subject participating in a clinical 
study, which does not necessarily have a causal relationship with the study 
product/procedure.  Therefore, an adverse event includes:   
• Any unfavorable and/or unintended sign (including an abnormal laboratory finding), 
symptom, or disease onset, that occurs at any time between the signing of the ICF and 


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study exit, without any judgement about causality (i.e., whether or not it is considered 
to be related to the study product) 
• Exacerbation, worsening, or progression of a pre-existing illness, including an increase 
in severity, frequency, and/or duration of a pre-existing episodic event or condition 
• Events occurring from drug overdose (accidental or intentional), drug abuse or misuse, 
drug hypersensitivity, drug extravasation, drug interactions, drug dependency, events 
occurring from drug withdrawal and medication errors 
• A condition detected or diagnosed after study product administration even though it 
may have been present prior to the start of the study 
A treatment-emergent adverse event (TEAE) is defined as an AE with a start date on or 
after the first dose of study drug, or that worsened following administration of study drug.   
An AE does not include the following: 
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
transfusion) as event terms; the condition that led to the procedure is the AE if it 
meets the definition of an AE. 
• Situations where an untoward medical occurrence has not occurred (e.g., 
hospitalization for cosmetic elective surgery; and social and/or convenience 
admissions). 
Symptoms associated with disease, which are consistent with the subject’s usual clinical 
course; unless the subject experiences worsening of their symptom(s) or the symptom(s) 
meet the criteria for an SAE. 
12.4.2 
General Guidelines for Reporting Adverse Events 
It is the responsibility of the investigator to document all AEs that occur during the course 
of the study. Throughout the study, efforts will be made by the investigator to remain alert 
to possible AEs.  The period of observation for collection of AEs extends from the time 
the subject gives informed consent until the last study visit or discontinuation from the 
study.  The first concern will always be the safety of the subject, and appropriate medical 
intervention will be made.   
The AEs should be documented as a single medical diagnosis. When this is not possible, 
the AE should be documented in terms of signs and/or symptoms observed by the 
investigator or reported by the subject at each study visit. Each AE which appears to be 
independent of any prior event will be reported separately.  
All AEs occurring after the subject signs the informed consent through the last study visit 
must be reported, regardless of whether or not the AEs are considered drug-related. All 
AEs, whether in response to a query, observed by the study site personnel, or reported 
spontaneously by the subject, will be recorded. Any AEs deemed related to treatment 
reported or observed at the final study/treatment visit will be followed until stabilization or 
resolution (or up to 30 days after final study visit).  
At each visit during the study, the subject will be assessed for the occurrence of new and 
ongoing AEs. Tolerability signs and symptoms that result in the subject’s requiring a 


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concomitant therapy, interruption of treatment, or discontinuation from the study will be 
reported as an AE. The following data will be collected on all AEs and recorded on the 
appropriate eCRF: 
• 
Event name (diagnosis preferred, if unknown, record the signs/symptoms) 
• 
Onset date and end date 
• 
Maximum intensity (severity) 
• 
Seriousness 
• 
Action taken regarding study drug 
• 
Corrective treatment/therapy, if given 
• 
Outcome 
• 
Resolution 
The investigator will also provide an assessment of the causal relationship to the study drug 
(for pre-treatment AEs, causality is “not related”).   
All AEs must be reported regardless of whether the AEs are considered drug-related.   
In order to ensure the safety of the subjects, the investigator should take appropriate 
measures to follow all subjects with adverse events until clinical recovery is complete, 
progression has been stabilized, the subject is lost to follow-up, or until death.  This may 
result in the need for observations to continue beyond the last planned protocol specified 
visit, and additional investigations may be requested by the monitoring team.  Refer to 
Section 12.2 for follow-up of AEs following study exit. 
Laboratory results, vital signs, or ECG abnormalities are to be recorded as AEs only if: 
• the result is clinically significant 
• the subject is symptomatic 
• the subject requires either corrective treatment or consultation 
• the lab result, vital sign, or ECG abnormality leads to study drug discontinuation or 
dose modification  
• the event fulfills a criterion for an SAE 
In addition, the investigator’s assessment of causality will be recorded.  
Vital sign abnormalities are to be recorded as AEs only if they are clinically significant 
(for example: are symptomatic, requiring corrective treatment, leading to discontinuation 
or fulfilling a seriousness criterion). 
12.4.3 
Serious Adverse Events 
An AE is considered “serious” if it meets at least one of the following criteria.  The event:   
• Results in death 
• Is life threatening (places the subject at immediate risk of death) 
NOTE:   The term “life-threatening” in the definition of “serious” refers to an event in 
which the subject was at risk of death at the time of the event.  It does not 


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refer to an event which hypothetically might have caused death if it were more 
severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
NOTE:  The term “hospitalization” refers to admission to a hospital as an in-patient 
for more than 24 hours.  Therefore, an adverse event would meet the SAE 
criterion of “requires hospitalization” only if the event necessitated admission 
to a health care facility for longer than 24 hours.  Elective hospitalization for 
an intervention that was already planned before inclusion of the subject in the 
study, hospitalization solely for the purpose of diagnostic tests (even if related 
to an AE), hospital admission for social circumstances, and admission to a 
day-care facility may not constitute sufficient grounds to be considered an 
SAE.   
Cases in which subjects are retained in the emergency room for more than 24 
hours but not admitted for medical care should be evaluated individually, 
because the criterion “otherwise medically significant” may apply (see 
below).  
• Results in persistent or significant disability/incapacity 
NOTE: The term “disability” means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include 
experiences of relatively minor medical significance (e.g., uncomplicated 
headache, influenza, or sprained ankle) that may transiently interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
• Is a congenital anomaly/birth defect 
• Is considered otherwise medically significant, as determined by the PI or medically 
qualified sub-investigator 
NOTE: The term “medically significant” refers to important medical events that may 
not immediately be life threatening or result in death or hospitalization, but, 
based upon appropriate medical judgment, they jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes 
listed in the definition of an SAE. 
Examples of such medically significant events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood 
dyscrasias, convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.   
Spontaneous abortion, elective abortion and ectopic pregnancy will be considered SAEs 
and must be reported to the sponsor within 24 hours of awareness of the event. 
Subjects will be withdrawn from the study if an SAE is identified and thought to be related 
to the study drug. 
The investigator is responsible for the reporting of all SAEs.   
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clinical trial (i.e., subject number) are clearly visible on every page/copy of source 
document that is provided to the monitoring team.  For laboratory results, include the 
laboratory normal ranges.   
After the EOS visit, the investigator does not need to actively monitor subjects for new 
SAEs. However, if the investigator becomes aware of a new or previously unreported 
serious adverse event within 30 days after the last investigational drug instillation, the event 
should be reported to the sponsor/designee within 24 hours of learning of the event.  If the 
investigator becomes aware of a new or previously unreported SAE after 30 days from the 
last investigational drug instillation, only SAEs considered related to the study drug should 
be reported to the sponsor within 24 hours of the investigator’s knowledge of the event. 
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial SAE Report Form cases for the purposes 
of expedited reporting. 
12.4.4 
Assessment of Severity of Adverse Events 
The severity of an AE will be graded as follows: 
Mild 
 
Awareness of a sign or symptom but is easily tolerated, 
requires no treatment, and does not interfere with 
subject’s daily activities 
Moderate 
 
Low level of concern to the subject and may interfere with 
daily activities but can be relieved by simple therapeutic 
care. 
Severe 
Interrupts the subject’s daily activity and requires 
systemic therapy or other treatment 
12.4.5 
Assessment of Causality of Adverse Events 
The relationship of an AE to the study product will be assessed using the following 
guidelines, based upon available information: 
Related 
 
There is at least a reasonable possibility that the AE/SAE 
is related to the study drug. Reasonable possibility means 
that there is evidence to suggest a causal relationship 
between the drug and the AE. 
Not Related 
 
There is little or no reasonable possibility that the 
AE/SAE is related to the study drug. This assessment 
implies that the AE/SAE has little or no temporal 
relationship to the study drug and/or a more likely or 
certain alternative etiology exists. 
12.4.6 
Expedited Serious Adverse Events 
Any suspected unexpected serious adverse event considered related to the study drug may 
warrant expedited reporting. In addition, any unexpected SAE related to a subject’s 
participation in the study (or related to the conduct of the study), regardless of whether or 


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not the study drug was administered, will be evaluated by Global  Pharmacovigilance and 
Risk Management to determine if expedited reporting is required. For example, an 
unexpected, severe SAE that could be associated with the study procedures and could 
modify the study conduct requires expedited reporting. 
Each expedited safety report will routinely include a brief cover memorandum, the 
completed MedWatch Form FDA 3500A, a clinical analysis of the event with any similar 
events that have occurred with the product, and any additional pertinent information 
recommended by the study medical monitor. Once the report is compiled, the study center’s 
investigator must submit the expedited safety report to the local IRB/IEC within the 
required reporting timeframe. Follow-up reports should be submitted when requested or 
when pertinent information becomes available. The principal investigator must retain a 
complete copy of each expedited safety report as it was submitted to the IRB/IEC. It is 
important that the principal investigator review these expedited reports, as they contain 
safety information that may be relevant to each of the participating subjects. 
12.4.7 
Pregnancy 
All female subjects of childbearing potential and male subjects with female partners of 
childbearing potential must use an effective method of birth control during the course of 
the study, in a manner such that risk of contraceptive failure is minimized.  Abstinence is 
allowed as a birth control method.  Before enrolling a female subject of childbearing 
potential or a male subject with a female partner of childbearing potential, the investigator 
must review the following information about study participation: 
• Informed consent requirement 
• Contraceptives in current use 
By signing the informed consent form, the investigator or designee asserts that he/she has 
discussed this information with the subject and provided appropriate counseling.  
Following the review of this information, the subject must sign the informed consent form 
to enroll in the study.  During the study, all subjects should be instructed to contact the 
investigator immediately if they suspect that they or their partners might be pregnant (e.g., 
missed or late menstrual period). 
If a subject or investigator suspects that the subject may be pregnant prior to randomization, 
the study drug must be withheld until the results of laboratory pregnancy testing are 
available.  If pregnancy is confirmed, the subject is considered to be a screen failure, must 
not continue in the study, and must not receive study drug.  If pregnancy is suspected while 
the subject is receiving study treatment, the study drug must immediately be withheld until 
the result of pregnancy testing is known.  If pregnancy is confirmed, the study drug will be 
permanently discontinued, and the subject and neonate will be followed until 30 days after 
the pregnancy comes to term.  A Pregnancy Report form will be submitted to the sponsor, 
both when pregnancy is confirmed, and 30 days after the delivery date.  Information 
provided on the Pregnancy Report Form must include the outcome of the pregnancy and 
any complications occurring during the pregnancy or the delivery.   
If a subject is withdrawn from the study and is found to be pregnant within 30 days of 
withdrawal, the subject and neonate will be followed until 30 days after the pregnancy 
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13.0 STATISTICS 
 
Assessment of Efficacy 
13.1.1 
Primary Efficacy 
13.1.1 
Primary Efficacy Endpoints 
The primary efficacy endpoint is 
• Ocular redness score evaluated by the investigator prior to investigational drug 
instillation and at 5(+1), 15(+1), 30(+1), 60(+10), 90(+10), 120(+15), 180(+15), 
and 240(+15) minutes after investigational drug instillation (0-4 unit scale, 
allowing half unit increments) at Visit 1 
BTOS-PF 0.025% will be compared to Lumify® 0.025% for the primary efficacy parameter 
of ocular redness as evaluated by the investigator (post-instillation assessments) for each 
of the eight time points at Visit 1 using two-sided 95% confidence intervals around the 
difference between means (BTOS-PF 0.025% minus Lumify® 0.025%) constructed as for 
two-sample t-tests with a non-inferiority limit of 0.22 units. The primary analyses will be 
performed on the Intent-to-Treat (ITT) population without imputation if all eight Visit 1 
post-instillation time points have missing data for the primary endpoint for less than 5% of 
subjects and sensitivity analysis will be performed on the Primary Per-Protocol (PPP) 
population without imputation. If there is at least one Visit 1 time point for which at least 
5% of subjects have missing data for the primary endpoint, then the primary analysis will 
be performed on the ITT population with an imputation strategy accounting for the reason 
for missing (e.g. intercurrent events), and sensitivity analyses will be performed on the PPP 
utilizing the same imputation strategy, as well as on the ITT and PPP populations without 
imputation. Secondary efficacy analyses will be based on the ITT population with an 
imputation strategy accounting for the reason for missing (e.g. intercurrent events) if at 
least 5% of subjects have missing data for that endpoint.    
13.1.2 
Secondary Efficacy 
Secondary efficacy endpoints will be evaluated hierarchically, as follows: 
1. Change from pre-instillation ocular redness score evaluated by the investigator at 1 
(+0.5) minute after investigational drug instillation (0-4 unit scale, allowing half 
unit increments) at Visit 1;   
2. Change from pre-instillation ocular redness score evaluated by the investigator (0-
4 unit scale, allowing half unit increments) at: 
i. 
1 minute after investigational drug instillation at Visit 2 
ii. 
5 minutes after investigational drug instillation at Visit 2 
iii. 
1 minute after investigational drug instillation at Visit 3 
iv. 
5 minutes after investigational drug instillation at Visit 3 


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3. Change from pre-instillation ocular redness score evaluated by the investigator at 
360 (+15) minutes after investigational drug instillation (0-4 unit scale, allowing 
half unit increments) at Visit 1; and  
4. Change from pre-instillation ocular redness score evaluated by the investigator at 
480 (+15) minutes after investigational drug instillation (0-4 unit scale, allowing 
half unit increments) at Visit 1.  
5. Ocular redness score evaluated by the subject as captured in subjects’ dosing diary 
throughout the treatment period (0-4 unit scale, NOT allowing half unit 
increments). 
Secondary efficacy endpoint analyses will be based on the ITT population with imputation 
of missing data as detailed in Section 13.1.6 for a secondary efficacy endpoint if at least 
5% of subjects have missing data for that endpoint. Sensitivity analyses for secondary 
efficacy analyses will be performed in the same manner as the sensitivity analyses for the 
primary efficacy analyses with the PPP replaced with the Secondary Per-Protocol (SPP) 
population.  
The change from pre-instillation in investigator-rated redness will be compared between 
treatment groups utilizing the same methods as in the primary efficacy analyses [i.e. two-
sided 95% confidence intervals around the difference between group means (BTOS-PF  
0.025% minus Lumify® 0.025%) constructed as for two-sample t-tests for each post-
instillation time point at each visit]. Two-sample t-tests will also be performed. BTOS-PF  
0.025% will be considered statistically non-inferior to Lumify® 0.025% for the change from 
pre-instillation in investigator-rated redness at a given time and visit if the upper confidence 
limit does not exceed 0.22 units. 
Ocular redness as recorded in the subject diaries at Visit 2 and Visit 3 will be analyzed 
using a generalized linear model accounting for repeated measures. Daily averages for each 
date recorded in subject diaries will be used for each subject. If the upper limit of the 95% 
confidence around the LS mean difference (BTOS-PF 0.025% minus Lumify® 0.025%) is 
less than 1 unit, BTOS-PF 0.025% will be declared statistically non-inferior to Lumify® 
0.025% for the subject-rated ocular redness assessment.  
Statistical inference for the secondary efficacy endpoints will only be performed if the 
primary efficacy analyses are considered successful (Section 13.1.4). Inference for the 
secondary efficacy endpoints will proceed hierarchically in the order listed above. 
13.1.3 
Supportive Efficacy 
The supportive efficacy endpoint is: 
• Total clearance of ocular redness assessed by the Investigator at each post-
instillation time point at each visit. 
Subjects with total clearance of ocular redness (redness score of 0 based on investigator 
assessment) will be summarized using counts and percentages by treatment group for each 
post-instillation time point at each visit.  Treatment comparisons will be made separately 
for each time point using Pearson’s chi-squared test or Fisher’s exact test if any of the cell 
counts are less than five. 


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13.1.4 
Statistical Hypothesis Testing and Control of Multiplicity 
At each of eight post-instillation times at Visit 1, the null hypothesis (𝐻𝐻0) is that the 
difference between the mean redness scores for the Test (𝜇𝜇𝑇𝑇) and Standard (𝜇𝜇𝑆𝑆) 
formulations is 0.22 points or greater. The alternative hypothesis (𝐻𝐻1) is that the difference 
is less than 0.22 points. 
𝐻𝐻0: 𝜇𝜇𝑇𝑇−𝜇𝜇𝑆𝑆≥0.22 
𝐻𝐻1: 𝜇𝜇𝑇𝑇−𝜇𝜇𝑆𝑆< 0.22 
The non-inferiority margin is the absolute value of one half of the smallest (in absolute 
value) upper confidence limit around the difference in redness scores (test minus control) 
observed over eight post-instillation times (5 to 240 minutes) during each of two placebo-
controlled randomized clinical trials (B&L studies 11-100-0015 and 861). 
The hypotheses above will be tested for each of the eight post-instillation times at Visit 1 
utilizing two-sided 95% confidence intervals around the difference between means (BTOS-
PF 0.025% minus Lumify® 0.025%) constructed as for two-sample t-tests. If the upper 
confidence limit does not exceed 0.22 units at any of the eight time points, then the study 
will be considered a success and BTOS-PF 0.025% will be considered statistically non-
inferior to Lumify® 0.025% for investigator-rated ocular redness. 
By requiring that the null hypotheses must be rejected at all eight post-instillation times to 
demonstrate success for the primary efficacy endpoint, the familywise type I error rate for 
the primary efficacy hypothesis tests is bounded above by the significance level of each 
hypothesis test (two-sided α = 0.05).  
Statistical inference will be performed for the secondary efficacy endpoints only if the 
primary efficacy endpoints demonstrate non-inferiority and statistical inference for the 
secondary efficacy endpoints will be performed in a hierarchical manner in the order from 
the list of endpoints in Section 13.1.2.  
13.1.5 
 General Considerations 
Quantitative variables, including demographics at baseline, will be summarized 
descriptively using number of subjects (n), mean, median, standard deviation, minimum, 
and maximum. Qualitative variables will be summarized using counts and percentages.  
Differences between treatment groups will be calculated as BTOS-PF 0.025% minus 
Lumify® 0.025%. 
Baseline values will be defined as the last non-missing measure prior to initiation of 
study treatment. Change from baseline will be calculated as follow-up measure minus 
baseline measure. 
All efficacy analyses will use a 2-sided alpha = 0.05 test unless otherwise stated and 
corresponding 2-sided 95% confidence intervals (CIs) will be presented as applicable. 
For efficacy, tolerability, and non-ocular safety analyses, the unit of analysis will be the 
subject. In the cases where assessments are recorded for each eye, the average of the eyes 
will be used.  Adverse events will also be summarized at the subject level; if an AE occurs 
in either or both eyes, the subject will be counted as having the AE.  For other ocular safety 
analyses, the unit of analysis will be each eye (with summaries showing results for the right 


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eye (OD) and the left eye (OS) separately), with the exception of ocular rebound which 
will use the averages from both eyes such that the unit of analysis will be the subject.  
Statistical methods will be more fully described in a separate Statistical Analysis Plan. 
13.1.6 
Missing Efficacy Data Imputations 
The primary efficacy analysis will be conducted with intercurrent events handled in the 
following manners: 
1. Withdrawal due to lack of efficacy or adverse events [assumed to be missing not at 
random (MNAR)]: missing data will be imputed employing single imputation using 
worst observation carried forward [hypothetical strategy] 
2. Missing data without withdrawal or withdrawal due to reasons other than lack of 
efficacy or adverse events [assumed to be missing at random (MAR)]: missing data 
will be imputed employing multiple imputation using randomized treatment-based 
Markov Chain Monte Carlo (MCMC) methodology to impute non-monotone 
missing and using randomized treatment-based regression methodology to impute 
monotone missing [hypothetical strategy]. 
Intercurrent events for secondary efficacy analyses will be handled utilizing the same 
strategy for the primary efficacy analysis, with the following addition: 
3. Discontinuation of study drug and non-optimal compliance will be ignored (that is, 
measured values will be used regardless of compliance or discontinuation of study 
drug) [treatment policy strategy]. 
Additional sensitivity analyses will be performed assuming all missing values due to 
withdrawal of any kind imputed employing:  
• Single imputation using worst observation carried forward. 
• Multiple imputation using randomized treatment-based regression methodology 
Additional sensitivity analyses will also be performed using observed data only.  
13.1.7 
Sensitivity Efficacy Analyses 
If imputation is not performed for the primary efficacy analysis, the analysis will be 
repeated on the PPP population without imputation. If imputation is required for the 
primary efficacy analysis, the analysis will be repeated on the PPP population with 
imputation and on the PPP and ITT populations without imputation as sensitivity analyses. 
Sensitivity analyses for secondary efficacy analyses will be performed in the same manner 
as the sensitivity analyses for the primary efficacy analyses with the PPP replaced with the 
Secondary Per-Protocol (SPP) population. 
13.1.8 
Subgroup Analyses 
Any planned subgroup analyses will be formally described in the study Statistical Analysis 
Plan. 


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Assessment of Tolerability 
The tolerability endpoints are: 
• Drop comfort assessment (0-10 unit scale) assessed by subjects immediately upon 
instillation, at 30 seconds, and at 1 minute post-instillation at Visit 1 
• Drop comfort descriptor questionnaire assessed at 3 minutes post-instillation at 
Visit 1 
BTOS-PF 0.025% will be compared to Lumify® 0.025% for the tolerability parameter of 
drop comfort using two-sample t-tests for each assessment time point. The tolerability 
parameter will be analyzed using the safety population. The results for the drop comfort 
descriptor questionnaire will be summarized descriptively by treatment group. 
 
Assessment of Safety 
The following safety variables will be recorded: 
• Vital Signs (resting blood pressure and pulse) 
• Adverse Events (reported, elicited, and observed) 
• Best Corrected Visual Acuity (BCVA) at Distance 
• Slit Lamp Biomicroscopy 
• Intraocular Pressure (IOP) 
• Ocular Rebound defined as: 
o Increase of at least 1 unit in mean ocular redness score evaluated by the 
Investigator at Visit 4 (0-4 unit scale, allowing half unit increments) 
compared to pre-instillation score at Visit 1, or   
o Increase of at least 1 unit in mean ocular redness score evaluated by the 
subject as captured in subject dosing diaries in the follow-up period, after 
dosing has ceased (0-4 unit scale, NOT allowing half unit increments) 
compared to diary day 1 (pre-dose morning assessment). 
All safety parameters will be analyzed using the safety population. The safety of BTOS-
PF 0.025% compared to Lumify® 0.025% will be assessed by the review of all of the safety 
parameters. 
The results of the slit lamp biomicroscopy, IOP, visual acuity, and vital signs will be 
presented by treatment and visit with numerical summaries. Change from baseline will also 
be presented in the same manner. The ocular rebound evaluated by the investigator (at Visit 
4) and by the subject (between Visit 3 – Visit 4) will be summarized separately using 
descriptive statistics by treatment. For assessments performed by eye, left eye and right eye 
will be summarized separately. 
13.3.1 
Adverse Events 
Adverse events (AEs) will be coded using the MedDRA dictionary. Frequencies and 
percentages of treatment-emergent adverse events (TEAEs) will be summarized at the 
subject level by system organ class and preferred term for all TEAEs, treatment related 
TEAEs, serious TEAEs, and TEAEs causing premature treatment discontinuation by 


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treatment group. An AE is treatment emergent if it occurs or worsens after the first dose 
of study medication. Similar summaries will be presented for all TEAEs by maximal 
severity. Separate summaries will be performed for ocular and non-ocular AEs.  
13.3.2 
Safety Laboratory Tests 
No safety laboratory tests will be conducted for this study. 
13.3.3 
Vital Sign Measurements 
Vital signs as well as changes from baseline in vital sign measurements will be summarized 
with descriptive statistics for each treatment group at all applicable study visits. 
13.3.4 
Concomitant Medications 
All previous concomitant medications will be classified based on terminology from the 
WHO Drug Dictionary. Previous therapies and concomitant medications data will be 
presented in data listings. 
 
Subject Disposition 
Subject disposition will be presented in terms of the numbers and percentages of subjects 
who completed the study and discontinued from the study. Disposition will be summarized 
by treatment group and for all subjects. 
The number of randomized subjects in each of the analysis populations (ITT, PP, and 
Safety) will be displayed by treatment. 
The number and percentage of subjects who prematurely discontinue from the study and 
the reasons for study discontinuation will be summarized by treatment group for all 
subjects. 
 
Demographics and Baseline Characteristics 
Subject demographics including age, sex, ethnicity, race and iris color and baseline 
characteristics including results of physical exams and ophthalmoscopy will be 
summarized using the appropriate descriptive statistics. 
 
Protocol Deviations 
All protocol deviations will be reported to the sponsor and recorded throughout the study. 
A tabulation of protocol deviations (including categorizations of major and minor) will be 
presented. 
Important protocol deviations leading to exclusion from the Primary Per-Protocol 
Population will include the following. 
• Ineligibility 
• Missing primary endpoint data at any time point of Visit 1 
• Out of window primary endpoint data at any time point of Visit 1 
• Use of any prohibited medication potentially affecting the primary endpoint at Visit 
1 


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Additional important deviations leading to exclusion from the Primary and Secondary Per-
Protocol Populations may be identified prior to unmasking of the treatment assignments. 
 
Compliance 
Subjects will be provided with a dosing/redness diary to document QID dosing. 
Compliance rates will be summarized using continuous summary statistics and presented 
by treatment group on the Safety population. In addition, a discrete summary of the 
compliance rate categories (non-compliant, compliant, and over compliant) will be 
provided by treatment group. 
 
Interim Analyses 
There are no interim analyses planned for this study. 
 
Additional Statistical Considerations 
13.9.1 
Analysis Populations 
• Intent-to-Treat Population: The intent-to-treat (ITT) population includes all 
randomized subjects who receive at least one dose of study medication, and 
complete at least one post instillation ocular redness evaluation at Visit 1. Subjects 
will be analyzed according to the treatment to which they were randomized. 
• Primary Per-Protocol Population: The primary per-protocol (PPP) population will 
include subjects in the ITT who do not have significant protocol deviations likely 
to affect the primary endpoint analysis. Protocol deviations will be assessed prior 
to database lock and unmasking. Subjects in the PPP population will be analyzed 
as treated. 
• Secondary Per-Protocol Population: The secondary per-protocol (SPP) population 
will include subjects in the ITT who do not have significant protocol deviations 
likely to affect the secondary endpoints and analyses. Protocol deviations will be 
assessed prior to database lock and unmasking. Subjects in the SPP population will 
be analyzed as treated. 
• Safety Population: The safety population includes all randomized subjects who 
received at least 1 dose of study drug. All subjects in the safety population will be 
analyzed according to the treatment they received. All safety analyses will be based 
on the safety population. 
13.9.2 
Sample Size Determination 
A sample size of 183 subjects per treatment group will have approximately 90% power to 
demonstrate non-inferiority of BTOS-PF 0.025% to Lumify® 0.025% at all eight post-
instillation times at Visit 1 using a two-sample t-test and assuming a non-inferiority limit 
of 0.22 units, mean difference of 0 units, and a common standard deviation of 0.50 units. 
Assuming a 5% dropout rate, 193 subjects will be randomized to each treatment group (386 
total subjects). 
 


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13.9.3 Multicenter Issues 
The study will be conducted at six investigational centers in North America with the 
intention of pooling the results for analysis. Site specific data summaries for the primary 
endpoint, however, will be presented. 
13.9.4 
Multiplicity Issues 
The Type I error rate for the primary efficacy analysis will be controlled by requiring the 
primary efficacy hypotheses test results to be statistically significant for all eight times at 
Visit 1 to declare success for the primary endpoint. The overall Type I error rate including 
the primary and secondary efficacy analyses will be controlled by a hierarchical testing 
structure. Specifically, statistical inference for the secondary efficacy analyses will only be 
performed if the primary analyses are successful, after which inference for the secondary 
efficacy endpoints will be performed in a hierarchical manner in the order of the secondary 
endpoints from Section 13.1.2. 
13.9.5 
Windowing Rules 
The timing of all study visits is relative to Baseline (Day 1). 
14.0 QUALITY CONTROL AND QUALITY ASSURANCE 
Study Monitoring 
Sponsor representatives must be allowed to visit all study site locations to assess the data, 
quality, and study integrity in a manner consistent with applicable health authority 
regulations and the procedures adopted by the Sponsor.  
Prior to the start of the study, member(s) of the Sponsor will review the protocol, CRF, 
regulatory obligations, and other material or equipment relevant to the conduct of the study 
with the Investigator/Sub-Investigator(s) and relevant study site personnel.  
Monitoring visits and telephone consultations will occur as per the monitoring plan, or as 
necessary, during the course of the investigation to verify the following: 
•
the rights and well-being of subjects are protected
•
the conduct of the investigation is in compliance with the currently approved
protocol/amendment, ICH GCPs and IRB/EC requirements
•
the integrity of the data, including adequate study documentation
•
the facilities remain acceptable
•
the Investigator and site personnel remains qualified and able to conduct the study
•
test article accountability
During the course of the study, if the Sponsor determines that an Investigator is 
non-compliant with the study plan and/or applicable regulatory requirements, the Sponsor 
will take action to secure compliance. In addition, the Sponsor may terminate the 
Investigator’s participation in the study if appropriate, or if the Investigator remains 
non-compliant despite the Sponsor’s actions.  


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Source Documentation 
All medical information obtained at each study visit must be recorded in the subject’s 
record (source documentation) in real time as it is collected. Source documentation consists 
of original subject documents, as well as data and records with information relevant to the 
subject and his/her participation in the study.  
 
Case Report Forms 
Subject data required by this protocol are to be recorded on eCRFs. The Investigator and 
his/her study site personnel will be responsible for completing the eCRFs. The Investigator 
is required to verify that all of the requested information is accurately recorded on the 
eCRFs. All information requested on the eCRFs needs to be supplied, including subject 
identification and, date(s), assessment values, etc., and any omission or discrepancy will 
require explanation. All information on eCRFs must be traceable to source documents.  
The study monitor will be responsible for reviewing and verifying the data recorded on the 
eCRFs, utilizing the original source documentation and will query discrepant findings. The 
Investigator and study site personnel will be responsible for answering all queries.  
A copy of the eCRFs will be retained by the Investigator, who must ensure that it is stored 
in a secure place. 
 
Audits and Inspections 
The study will be conducted under the sponsorship of  B&L in conformation with all 
appropriate local and federal regulations, as well as ICH guidelines. Interim and end of 
study audits of raw data, study files, and final report may be conducted by B&L Quality 
Assurance Department or designee.  
The sponsor is responsible for implementing and maintaining quality assurance and quality 
control systems to ensure that studies are conducted and data are generated, documented, 
and reported in compliance with the protocol, GCP, and applicable regulatory 
requirements. In addition, the sponsor will be responsible for securing agreement from all 
involved parties to ensure direct access to all study related investigational centers, source 
data/documents, eCRFs, and reports for the purpose of monitoring and auditing by the 
sponsor, and inspection by domestic and foreign regulatory authorities. 
 
Data Quality Assurance 
During the course of the trial a clinical research associate (CRA) will make routine site 
visits to review protocol compliance, assess IMP accountability, and ensure the trial is 
being conducted according to the pertinent regulatory requirements. The review of the 
subjects’ medical records will be performed in a manner that adequately maintains subject 
confidentiality. Further details of the trial monitoring (including medical monitoring) will 
be outlined in a monitoring plan. 
Domestic and foreign regulatory authorities, and quality assurance, sponsor and or its 
designees may carry out on-site inspections and/or audits which may include source data 
checks. Therefore, direct access to the original source data will be required for inspections 
and/or audits. All inspections and audits will be carried out with consideration to data 


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protection as well as subject confidentiality to the extent that local, state, and federal laws 
apply. 
15.0 ETHICS AND ADMINISTRATIVE ISSUES 
 
Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles originating from the 
Declaration of Helsinki, ICH guidelines, GCP, and in compliance with local regulatory 
requirements. The investigator agrees, when signing the protocol, to adhere to the 
instructions and procedures described in it and thereby to adhere to the principles of GCP. 
 
Ethics Review 
This protocol, proposed informed consent form and other information to subjects, and all 
appropriate amendments will be properly reviewed and approved by an Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC). A signed and dated 
notification of the IRB/IEC approval will be provided to the sponsor and investigator prior 
to study initiation. The name and occupation of the chairman and members of the IRB/IEC 
will be supplied to the Sponsor. The investigator will provide required progress reports and 
report all SAEs to the IRB/IEC as required by the IRB/IEC. 
The Investigator should ensure that his/her participation in the study, in addition to the 
protocol, subject recruitment materials (written information or materials including web 
pages, radio advertisements, television spots or written text developed to encourage subject 
enrollment) and the ICF to be used in this study are approved by their institution IRB/EC, 
or if not using their institution's IRB/EC, approved by the reviewing central IRB/EC prior 
to entering any subjects in the study. Documentation of IRB/EC approval of the study 
protocol and informed consent must be provided to the Sponsor prior to initiation of the 
study. In addition, the Investigator must ensure that the reviewing IRB/EC has provided 
approval for any protocol amendments prior to implementation. If the amendment 
necessitates a revision to the ICF, the Investigator should ensure the revised form is also 
submitted to and approved by the Sponsor and the IRB/EC prior to implementation.  
 
Written Informed Consent 
Written informed consent/assent, in accordance with local clinical investigation 
regulations, must be obtained prior to participation in the study. The investigator or 
designee will discuss the purpose of the study with each subject, and provide a description 
of the study drug (including any potential and possible side effects) and the study 
procedures. Information must be given both in oral and written form. Subject information 
will be provided in a language understandable to the subject and may not include any 
language that appears to waive any of the subject‘s legal rights or appears to release the 
investigator, the sponsor or the institution from liability or negligence.  
The investigator will provide the prospective subject sufficient time to consider whether or 
not to participate, minimizing the possibility of coercion or undue influence and will 
discuss any questions the subject may have. The investigator will explain to the subject 
that participation in the study is voluntary and that withdrawal from the study is possible 
at any time without detriment to care. The consent must include acknowledgment that 


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medical records and medical data derived from the study may be forwarded to the Sponsor 
or to responsible local or federal authorities.  
No subject can enter the study or have any study related procedures performed before 
his/her written informed consent has been obtained. The original signed and dated informed 
consent form will be retained with the study records, and a copy of the signed form will be 
given to the subject.  
An informed consent template will be supplied by the sponsor or designee. Any changes 
to the informed consent form must be agreed to by the Sponsor or designee prior to 
submission to the IRB/IEC, and a copy of the approved version must be provided to the 
sponsor or designee after IRB/IEC approval. 
 
Subject Data Protection 
Subject data will be protected by ensuring that no captured data contain subject names, 
addresses, telephone numbers, email addresses, or other direct personally identifying 
information. It is acknowledged that subject demographics (including age at the time of 
consent), medical histories, and prior concomitant medication uses, along with the name 
and address of the enrolling investigator may allow for personal identification of study 
participants. Other than where necessary to meet regulatory requirements, all data collected 
in this study will be presented in tabulated (i.e., aggregate) form and listings containing 
information that could be used to identify an individual subject will not be included in any 
public disclosures of the study data or the study results. 
 
Financial Disclosure 
Financial disclosures will be obtained from all investigators in order to document any 
potential conflicts of interest. 
 
Investigator Obligations 
The investigator agrees, when signing the protocol, to adhere to the instructions and 
procedures described in it and thereby to adhere to the principles of Good Clinical Practice 
(GCP). 
 
Changes to the Protocol 
The investigators must read the protocol thoroughly and must follow the instructions 
exactly. Whenever possible, any planned deviations should be agreed to by prior discussion 
between the sponsor and the investigator, with appropriate documentation of Sponsor 
approval prior to effecting the changes agreed upon. Any amendment to the protocol 
containing major modifications (particularly if it may involve an increased risk to the 
subjects) will be approved by the IRB/IEC before it may be implemented. No change in 
the conduct of the study can be instituted without written approval from the Sponsor. 
 
Confidentiality/Publication of the Study and Study Results 
All the data furnished to the investigator and his/her staff and all data obtained through this 
protocol will be regarded as confidential and proprietary in nature and will not be disclosed 


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to any third party, except for the FDA or other regulatory body, without written consent 
from the Sponsor. 
All study data generated as a result of this study will be regarded as confidential, until 
appropriate analysis and review by the Sponsor or its designee and the Investigator(s) are 
completed. The results of the study may be published or presented by the Investigator(s) 
after the review by, and in consultation and agreement with the Sponsor, and such that 
confidential or proprietary information is not disclosed. 
Prior to publication or presentation, a copy of the final text should be forwarded by the 
Investigator(s) to the Sponsor or its designee, for comment. Such comments shall aim to 
ensure the scientific integrity of the proposed publications and/or presentations and ensure 
that the data and material referring to Sponsor products and activities receive fair, accurate, 
and reasonable presentation. 
16.0 DATA HANDLING AND RECORD KEEPING 
 
Inspection of Records 
Investigators must maintain detailed records on all study subjects who are enrolled in the 
study or undergo screening. Data will be recorded in the subject’s source documents and 
in applicable study logs provided by the Sponsor. Source documents include subject 
medical records, hospital charts, clinic charts, investigator subject study files, as well as 
the results of diagnostic tests (e.g., laboratory tests). All required data should be recorded 
in the study documentation completely for prompt data review. Upon study completion or 
at any other time specified by the Sponsor or designee, the appropriate study documents 
must be submitted. 
The investigator must keep accurate separate records (source documentation) of all subject 
visits, being sure to include all pertinent study related information. At a minimum, this 
includes the following information: 
• 
A statement indicating that the subject has been enrolled in the study and the subject 
number 
• 
Date that informed consent was obtained 
• 
Evidence that the subject meets study eligibility requirements (e.g., medical history, 
screening evaluations) 
• 
Dates of all study related visits and results of any evaluations/procedures 
performed, including who performed each assessment at each visit 
• 
Use of any concurrent medications / therapies during the study 
• 
Documentation of study drug accountability 
• 
Any and all side effects and AEs must be thoroughly documented to conclusion 
• 
Results of any diagnostic tests conducted during the study 
• 
The date the subject exited the study and a statement indicating that the subject 
completed the study or was discontinued early, including the reason for 
discontinuation 


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Notes describing telephone conversations and all electronic mail with the subject or the 
sponsor (sponsor’s designee) concerning the study must be recorded or kept on file. All 
source documents must be made available to the sponsor and the sponsor’s designated 
monitor upon request. 
 
Retention of Records 
The investigator should properly store and maintain all study records in accordance with 
sponsor directives. All records relating to the conduct of this study are to be retained by 
the investigator until notified by the Sponsor in writing that the records may be destroyed.  
The investigator will allow representatives of the Sponsor’s monitoring team and quality 
control department, the governing IRB/IEC, the FDA, and other applicable regulatory 
agencies to inspect all study records, eCRFs, and corresponding portions of the subject’s 
clinic and/or hospital medical records at regular intervals throughout the study. These 
inspections are for the purpose of verifying adherence to the protocol, completeness and 
accuracy of the data being entered onto the eCRF, and compliance with FDA or other 
regulatory agency regulations. 
 
 


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17.0 REFERENCES 
Gomes, JAP, et al. TFOS DEWS II iatrogenic report. The Ocular Surface. 2017; 15: 511-
538. 
Toris, C. B., et al. Effects of brimonidine on aqueous humor dynamics in human eyes. Arch 
Ophthalmol 1995; 113(12): 1514-1517. 
Walsh K, Jones L. The use of preservatives in dry eye drops. Clinical Ophthalmology. 
2019; 13: 1409-1425 
 
 
 


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18.0 APPENDIX A 
 
Visual Acuity Procedures 
LogMAR Visual Acuity must be assessed using an ETDRS chart. The procedure used will 
be consistent with the recommendations provided for using the ETDRS eye chart. Visual 
Acuity should be evaluated at the beginning of each visit in the study (i.e. prior to slit-lamp 
examination). Visual acuity testing should be done with best (most recent) correction.   
Equipment 
The visual acuity chart to be used is the ETDRS chart. If smaller reproduction (18" by 18", 
e.g., from Prevent Blindness) wall charts are used, the subject viewing distance should be 
exactly 10 feet (or as specified by the manufacturer). In ALL cases, for purposes of 
standardizing the testing conditions during the study, all sites must use only the 'R' charts, 
and the right eye should be tested first. For reflectance (wall) charts, the chart should be 
placed frontally and well-illuminated. 
Measurement Technique 
The chart should be at a comfortable viewing angle. The right eye should be tested first. 
The subject should attempt to read each letter, line-by-line, left to right, beginning with 
line 1 at the top of the chart. The subject should be told that the chart has letters only, no 
numbers. If the subject reads a number, he or she should be reminded that the chart contains 
no numbers, and the examiner should then request a letter in lieu of the number. The subject 
should be asked to read slowly, so as to achieve the best identification of each letter. He/she 
is not to proceed to the next letter until he/she has given a definite response. 
If the subject changes a response (e.g., 'that was a "C" not an "O"') before he has read aloud 
the next letter, then the change must be accepted. If the subject changes a response having 
read the next letter, then the change is not accepted. The examiner should never point to 
the chart or to specific letters on the chart during the test. 
A maximum effort should be made to identify each letter on the chart. When the subject 
says he or she cannot read a letter, he or she should be encouraged to guess. If the subject 
identifies a letter as one of two letters, he or she should be asked to choose one letter and, 
if necessary, to guess. When it becomes evident that no further meaningful readings can be 
made, despite encouragement to read or guess, the examiner should stop the test for that 
eye. However, all letters on the last line should be attempted as letter difficulties vary and 
the last may be the only one read correctly. The number of letters missed or read incorrectly 
should be noted. 
LogMAR Visual Acuity Calculations 
The last line in which a letter is read correctly will be taken as the base logMAR reading. 
To this value will be added the number "N x 0.02" where 'N' represents the total number 
of letters missed up to and included in the last line read. This total sum represents the 
logMAR visual acuity for that eye. 
For example: Subject correctly reads 4 of 5 letters on the 0.2 line, and 2 of 5 letters on the 
0.1 line. 
Base logMAR = 0.1 


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N (total number of letters incorrect on line 0.2 as well as 0.1) = 4 
N x T (T=0.02) = 0.08 
Base logMAR + (N x T) = 0.1 + 0.08 
logMAR VA = 0.18 
Repeat the procedure for the left eye. 
In order to provide standardized and well-controlled assessments of visual acuity during 
the study, all visual acuity assessments at a single site must be consistently done using the 
same lighting conditions and same correction if possible during the entire study. If the same 
correction cannot be used (ie, a subject forgets his glasses), the subject’s prescription as 
documented at Visit 1 should be placed in a trial frame or phoroptor for visual acuity 
assessment. 
 
Slit Lamp Biomicroscopy/External Eye Exam Procedures 
Slit lamp biomicroscopy will be performed during the study. Observations for the slit lamp 
biomicroscopy examination will be graded as described below. For ‘Lid and Lid Margin’ 
Erythema and ‘Conjunctiva’ Erythema/Hyperemia parameters, half grade answers (e.g. 
0.5, 1.5, 2.5, and 3.5) will be accepted. If necessary, sodium fluorescein will be used to 
assess corneal epithelial damage. 
 
Lid and Lid Margin 
 
 
Erythema 
None 
 
   0= 
Normal 
Mild            
   1= 
Redness localized to a small region of the lid(s) margin OR skin 
Moderate 
 
   2= 
Redness of most or all the lid(s) margin OR skin 
Severe 
 
   3= 
Redness of most or all the lid(s) margin AND skin 
Very Severe 
   4= 
Marked diffuse redness of both lid(s) margin AND skin 
0.5 unit increments ARE allowed 
 
Swelling 
None 
 
   0= 
Normal 
Mild            
   1= 
Localized to a small region of the lid(s) 
Moderate 
 
   2= 
Diffuse, most or all the lid(s) but not prominent/protruding 
Severe 
 
   3= 
Diffuse, most or all of the lid(s) AND prominent/protruding 
Very Severe 
   4= 
Diffuse AND prominent/protruding AND eversion of the lid(s) 
0.5 unit increments ARE NOT allowed 


Protocol Number 908   
 
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Conjunctiva (Palpebral and Bulbar) 
 
Erythema/Hyperemia 
None 
 
   0= 
Normal 
Mild            
   1= 
Slight localized injection 
Moderate 
 
   2= 
Pink color, confined to palpebral OR bulbar conjunctiva 
Severe 
 
   3= 
Red color of the palpebral AND/OR bulbar conjunctiva 
Very Severe 
   4= 
Marked dark redness of the palpebral AND/OR bulbar 
conjunctiva 
0.5 unit increments ARE allowed 
 
Chemosis 
 
None 
 
   0= 
Normal 
Mild            
   1= 
Slight localized swelling 
Moderate 
 
   2= 
Moderate/medium localized swelling or mild diffuse swelling 
Severe 
 
   3= 
Severe diffuse swelling 
Very Severe 
   4= 
Very prominent/protruding diffuse swelling 
 
0.5 unit increments ARE NOT allowed 
 
Ora proprietary scales – Not for distribution without permission


Protocol Number 908   
 
Version 2.0, 27Oct2021 
 
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Cornea  
 
Edema 
None 
 
   0= 
Transparent and clear 
Mild            
0.5= 
Trace, localized epithelial haze 
Moderate 
 
   1= 
Dull glass appearance that may include fine individual droplets 
Severe 
 
   2= 
Dull glass appearance of epithelium with large number of 
vacuoles 
Very Severe 
   3= 
Epithelial bullae and/or stromal edema, localized or diffuse, with  
or without stromal striae 
Erosion- Evaluated with fluorescein staining, if epithelial damage is noted 
 
None 
              0= 
No epithelial damage 
Mild 
              1= 
Slight epithelial damage confined to a small focus 
Moderate                  2= 
Regionally dense epithelial damage (1mm or greater in diameter) 
with underlying structure moderately visible 
Severe 
              3= 
Marked epithelial damage over a large area of the cornea 
 
0.5 unit increments ARE NOT allowed 
 
Endothelial Condition 
 
None 
 
   0= 
Normal 
Mild            
   1= 
Mild endothelial irregularities 
Moderate 
 
   2= 
Moderate striae and/or stromal edema 
Severe 
 
   3= 
Severe striae with stromal edema 
Very Severe 
   4= 
Severe striae, stromal thickening, and bullous keratopathy 
 
0.5 unit increments ARE NOT allowed 
 
 
 
 


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Lens Pathology 
 
None 
 
   0= 
No cataract 
Mild            
   1= 
Minimal lens opacity 
Moderate 
 
   2= 
Early lens opacity 
Severe 
 
   3= 
Intermediate lens opacity 
Very Severe 
   4= 
Advanced lens opacity 
 
0.5 unit increments ARE NOT allowed 
Ora proprietary scales – Not for distribution without permission 
 
Anterior Chamber (slit beam=0.3mm wide, 1.0 mm long) 
 
Cells 
None 
 
   0= 
No cells seen 
Mild            
   1= 
1-5 cells seen 
Moderate 
 
   2= 
6-15 cells seen 
Severe 
 
   3= 
16-30 cells seen 
Very Severe 
   4= 
>30 cells seen 
 
0.5 unit increments ARE NOT allowed 
 
Flare 
None 
 
   0= 
No Tyndall effect 
Mild            
   1= 
Tyndall effect barely discernible 
Moderate 
 
   2= 
Tyndall beam in the anterior chamber is moderately intense 
Severe 
 
   3= 
Tyndall beam in the anterior chamber is severely intense 
Very Severe 
   4= 
Tyndall beam is very severely intense. The aqueous has a white 
and milky appearance. 
 
0.5 unit increments ARE NOT allowed 
 
Ora proprietary scales – Not for distribution without permission 
 


Protocol Number 908   
 
Version 2.0, 27Oct2021 
 
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Intraocular Pressure 
Applanation tonometry, Goldmann tonometer required.  Do NOT use non-contact 
tonometry.  It is recommended that Fluress® (fluorescein sodium and benoxinate 
hydrochloride ophthalmic solution USP) be used as the anesthetic.  It is recommended that 
subjects should wait a minimum of 10 minutes after instillation of Fluress® before instilling 
investigational drug.   
 
IOP should always be measured/recorded before pupil dilation.  
 
 
Dilated Ophthalmoscopy 
At Visit 1 (Day 1) and Visit 4 (Day 36+1), a dilated ophthalmoscopy examination will be 
performed to evaluate the presence or absence of clinically significant fundus abnormalities 
and vitreous pathology.   
Observations will be graded as Normal or Abnormal.  Abnormal findings that are clinically 
significant (as determined by the investigator that may interfere with study parameters or 
otherwise confound the data) and those that are not clinically significant will be described. 
An indirect ophthalmoscopy examination should be performed if retinal disease is detected.  
 
• Vitreous:  Examination should emphasize the visual axis.  
• Retina, Macula, Choroid:  Include an observation of the retina and its blood vessels. Eyes 
should be excluded from the study if active inflammation is present at Visit 1.  
• Optic Nerve:  Significant damage or cupping to the optic nerve should be noted. 
 
It is recommended that tropicamide 1% ophthalmic solution be used for pupil dilation. The 
use of cyclopentolate 1% ophthalmic solution is recommended (in adults) as a secondary 
dilating medication, should the need arise.  The use of phenylephrine dilating drops is 
disallowed in this study. 
 
 
Vital Signs 
Each subject will have vital signs assessments i.e., body weight (lbs), heart rate (bpm), and 
blood pressure (mmHg), conducted at Visits 1 and 3 (if enrolled). At Visit 2, vital signs 
will be collected without body weight. Vital signs are to be conducted by qualified staff 
member who may be any of the following: a Board-certified Investigator or sub-
Investigator, Nurse Practitioner, Registered Nurse, Physician’s Assistant, or trained 
Research Coordinator.   
• Heart Rate (bpm) 
Heart rate will be measured with the subjects who have been in a resting state 
(seated) for at least 5 minutes.  Pulse will be counted for 30 seconds and multiplied 
by 2, and recorded in beats per minute. 


Protocol Number 908   
 
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• Systolic/ Diastolic Blood Pressure (mmHg) 
Systolic and diastolic blood pressure should be measured in the same arm each time 
using a calibrated sphygmomanometer with the subjects who have been in a resting 
state (seated upright) at least 5 minutes.  Blood pressure will be recorded in mm 
Hg. 
 
Physical Examination 
Each subject will have a physical examination conducted at Visit 1 and at Visit 3 (if 
enrolled).  A physical examination may be conducted by a Board-certified Investigator or 
sub-Investigator, Nurse Practitioner or Physician’s Assistant. The physical examination 
will also include an assessment of the following: 
 
• General health 
• Head, Eyes, Ears, Nose, Throat (HEENT) 
• Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Drop Comfort Assessments 
Drop Comfort Assessment Scale 
 
Ora Calibra® Drop Comfort Scale (Subject-Reported): 
Will be assessed upon instillation, at 30 seconds, and 1 minute post-instillation of the 
investigational drug, using the following scale for a subject’s eyes: 
 
Right Eye: 
 
0             1           2            3             4             5            6            7             8              9       10  
 
 
very comfortable                                                                                 very uncomfortable  
 
 
Left Eye: 
 
0             1           2            3             4             5            6            7             8              9       10  
 
 
very comfortable                                                                                 very uncomfortable  
 
 
 
Ora proprietary scales – Not for distribution without permission 
 
 


Protocol Number 908   
 
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Ora Calibra® Drop Descriptor Query (Subject-Reported): 
 
 
The subjects will be asked to choose three words that best describe how each eye drop 
feels in both of his/her eyes approximately 3 minutes post-instillation:  
 
Burning  
 
 
 
 
 
 
 
Refreshing  
Comfortable   
 
 
 
 
 
 
Smooth  
Cool   
 
 
 
 
 
 
 
Soothing  
Filmy   
 
 
 
 
 
 
 
Sticky  
Gentle  
 
 
 
 
 
 
 
Gritty   
Stinging 
 
 
 
 
 
 
 
Irritating  
 
 
 
 
 
 
 
Please write any additional descriptions if not on list 
 
OTHER:________________________________________________________  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol Number 908   
 
Version 2.0, 27Oct2021 
 
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Investigator Evaluated Signs 
 
INVESTIGATOR EVALUATED SIGNS: 
Ora Calibra® Ocular Hyperemia Scale 
 
Ocular Redness: 
 
   0 =None 
 
1.0 =Mild-Slightly dilated blood vessels; color of vessels is typically pink; can be 
quadrantal. 
2.0 =Moderate-More apparent dilation of blood vessels; vessel color is more intense 
(redder); involves the majority of the vessel bed 
 
3.0 =Severe-Numerous and obvious dilated blood vessels; in the absence of chemosis the 
color is deep red, may be less red or pink in presence of chemosis, is not quadrantic. 
4.0 =Extremely Severe-Large, numerous, dilated blood vessels characterized by unusually 
severe deep red color, regardless of grade of chemosis, which involves the entire 
vessel bed. 
 
0.5 unit increments are allowed  
 
Ora proprietary scales – Not for distribution without permission 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol Number 908   
 
Version 2.0, 27Oct2021 
 
Page 64 of 66 
 
 
  
 
Subject Dosing and Redness Grading Diaries 
 
Sample Dosing and Redness Grading Diary Instructions: 
Visit X Dosing/Redness Diary Instructions 
 
DOSING INSTRUCTIONS 
• Please dose ONE (1) drop in each eye with the study drops FOUR (4) times a 
day starting the morning after your Visit 1 appointment. Below is an example 
of a dosing schedule:  
o Dose 1 (8:00AM) 
o Dose 2 approximately 4 hours after Dose 1 (12:00PM) 
o Dose 3 approximately 4 hours after Dose 2 (4:00PM) 
o Dose 4 approximately 4 hours after Dose 3 (8:00PM) 
 
**DO NOT dose any earlier than 3.5 hours after your previous dose** 
 
• Check YES if dose was taken or check NO if dose was not taken 
• Be sure to record what time you took your dose in your diary 
DIARY INSTRUCTIONS 
• You will need to assess your ocular redness at the following times:  
o Once BEFORE Dose 1, and then approximately 2 MINUTES AFTER Dose 1 
o Once BEFORE Dose 2, and then approximately 2 MINUTES AFTER Dose 2 
o Once BEFORE Dose 3, and then approximately 2 MINUTES AFTER Dose 3 
o Once BEFORE Dose 4, and then approximately 2 MINUTES AFTER Dose 4 
• Be sure to record what time you assessed your ocular redness after each dose. 
• Please DO NOT dose within 3.5 hours of your next appointment (Visit X) 
 
Visit X Appointment 
Date: ____________________ 
Time: ____________________ 
 
 
 


Protocol Number 908   
 
Version 2.0, 27Oct2021 
 
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GENERAL INSTRUCTIONS 
• Use a black pen to fill out your diary.  DO NOT use white-out or pencil. 
• At the top of each page, please fill out your ‘Site Number’, ‘Subject Number’, 
and ‘Initials’ with the information given to you by the study staff. 
• Enter the date for each day, in the following format: DD/MMM/YYYY.   
For example, January 10th, 2012 would be written as 10/JAN/2012. 
• If you make an error, draw a SINGLE LINE through the error, and then 
DATE and INITIAL below the line.  Then enter the correct value or score. 
 
• You should keep your investigational drug at room temperature (15-25° [59-
77°F]).  Keep the pouches of single-use vials out of sunlight, and do not 
freeze or refrigerate the investigational drug.  Keep away from children. 
• Wash your hands thoroughly before using the study drops. 
• To prevent contamination, do not touch the tip of the single-use vial to your eye, 
eyelids, surrounding areas or other surfaces.  
• Look up and gently pull down the lower eye lid with one hand.  With your other 
hand, hold the single-use vial upside down over each target eye, and slowly squeeze 1 
drop onto the lower surface of each eye.  Gently close your eye and allow the drop to 
be absorbed.  DO NOT squeeze your eyelids shut.   
• Keep un-used vials in the labeled pouch prior to use.  
• Used vials should be placed in the supplied ‘Used Vials’ bag. DO NOT re-use the 
vial even if there is solution left inside. 
• You MUST bring back your completed dosing diary and used & unused 
investigational drug with you to your next visit (Visit X).   
 
 
 
 


Protocol Number 908   
 
Version 2.0, 27Oct2021 
 
Page 66 of 66 
 
 
  
 Schedule of Visits and Parameters 
All study tasks should be performed by qualified study site personnel as indicated on the 
delegation of authority log under the supervision of the Principal Investigator. Furthermore, 
the in-office baseline (prior to first drug instillation) assessments at Visit 1 of ocular 
redness, slit-lamp examination, IOP, and ophthalmoscopy must be performed by an 
ophthalmologist. 
PROCEDURE/ASSESSMENTS 
Screening 1 
Visit 1 
(Baseline) 
Visit 2 
Visit 3 
Visit 4 
Day -28 to 
Day 1 
Day 1 
Day 15 
± 2 
Day 29 
+ 2 
Day 36 
+ 1 
Informed consent/HIPAA 2 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Concomitant Medications  
X 
X 
X 
X 
X 
Urine Pregnancy Test (for females of childbearing 
potential) 3 
 
X 
 
X12 
X 
Physical Examination 4 
 
X 
 
X 
 
Vital Signs 5 
 
X 
X 
X 
 
BCVA at Distance 
 
X 
X 
X 
X 
Slit lamp biomicroscopy 6 
 
X 
X 
X 
X 
Intraocular Pressure (IOP) 
 
X 
 
X 
 
Dilated Ophthalmoscopy 
 
X 
 
X 
 
Randomization 
 
X 
 
 
 
In-Office Redness Assessment 
 
X 7 
X 8 
X8 
X 
In-Office Investigational Drug Instillation 
 
X 9 
X 10 
X10 
 
Drop Comfort/Descriptor Assessment 11 
 
X 
 
 
 
Dispense Investigational Drug and Dosing Diary10 
 
X 
X 
 
 
Collect Investigational Drug and Dosing Diary10 
 
 
X 
X 
 
Dispense Redness Grading Diary 
 
 
 
X 
 
Collect Redness Grading Diary 
 
 
 
 
X 
Assessment of adverse events 
X 
X 
X 
X 
X 
Exit 
 
 
 
 
X 
 
 
1 If there is no washout period, the Screening Visit and Visit 1 can occur on the same day. 
2 Informed consent must be signed before any study-related procedure can be performed. If washout of a medication is necessary, 
informed consent must be obtained prior to Visit 1. 
3 Women considered capable of becoming pregnant include all females who have experienced menarche and have not experienced 
menopause (as defined by amenorrhea for greater than 12 consecutive months) or have not undergone surgical sterilization 
(hysterectomy, bilateral tubal ligation, or bilateral oophorectomy). 
4 Physical examination includes general health, head, eyes, ears, nose, throat (HEENT), and any other comments. 
5 Vital signs (resting blood pressure and pulse) with body weight will be collected at Visits 1 and 3 and without body weight at Visit 2. 
6 Evaluated prior to and post investigational drug instillation at Visits 1, 2, and 3. 
7 Investigator will evaluate ocular redness prior to investigational drug instillation and at 1 (+0.5), 5(+1), 15(+1), 30(+1), 60(+10), 
90(+10), 120(+15), 180(+15), 240(+15), 360(+15), and 480(+15) minutes post investigational drug instillation. 
8 Investigator will evaluate ocular redness prior to investigational drug instillation and approximately 1 and 5 minutes post-instillation.   
9 Performed by the subject or subject’s caregiver while under the observation of the unmasked designee. 
10 Performed by the unmasked designee. 
11 Subjects will assess comfort upon instillation, at 30 seconds, and at 1 minute post-instillation using 0-10 unit scale for each eye at 
Visit 1. Subjects also will select comfort descriptor terms from a predetermined list at 3 minutes post-instillation at Visit 1. 
12 Complete urine pregnancy test if visit-3 is early termination visit 

SAP_001.pdf: 
 
FORM.152.05 Updated 22JUL2019 
 STATISTICAL ANALYSIS PLAN  
A Multi-Center, Double-Masked, Randomized, Active-Controlled, 
Parallel-Group Study Comparing the Efficacy and Safety of 
Brimonidine Tartrate Ophthalmic Solution 0.025% Preservative-Free 
Formulation with Lumify® 0.025% in Adult Subjects with Ocular 
Redness 
 
 
Sponsor:  
 
Bausch + Lomb, Incorporated 
 
 
 
400 Somerset Corporate Boulevard 
 
 
 
Bridgewater, NJ 08807 
 
Protocol Number: 
# 908 
 
 
Author:   
 
Raghu Vishnubhotla 
 
 
 
Principal Biostatistician 
Statistics & Data Corporation 
 
Date:   
 
16JAN2023 
Version:  
 
1.0 
 


Page 2 of 38
A Multi-Center, Double-Masked, Randomized, Active-Controlled, Parallel-Group Study Comparing 
the Efficacy and Safety of Brimonidine Tartrate Ophthalmic Solution 0.025% Preservative-Free 
Formulation with Lumify® 0.025% in Adult Subjects with Ocular Redness
Protocol Number:
# 908
SAP Version: 
1.0
SAP Date: 
16JAN2023
Statistical Analysis Plan Approval
Prepared by:
Raghu Vishnubhotla
Date
Principal Biostatistician
Statistics & Data Corporation
Reviewed by:
_____________
Kalyani Kothapalli
Date
VP, Biostatistics
Statistics & Data Corporation
Approved by:
Gary Mosehauer
Date
Director, Biostatistics
Bausch & Lomb Incorporated
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Protocol # 908 SAP, Version 1.0 
16JAN2023 
Confidential & Proprietary 
Page 3 of 38 
 
Table of Contents 
List of Abbreviations ...................................................................................................................................... 6 
1. 
Introduction........................................................................................................................................ 7 
2. 
Study Objectives ............................................................................................................................... 7 
2.1 Primary Endpoint ............................................................................................................................... 7 
2.2 Secondary Endpoints ........................................................................................................................ 7 
2.3 Exploratory Endpoint ......................................................................................................................... 8 
2.4 Safety Variables ................................................................................................................................ 8 
2.5 Tolerability Variables ......................................................................................................................... 8 
2.6 Statistical Hypotheses ....................................................................................................................... 9 
2.7 Estimands .......................................................................................................................................... 9 
3. 
Study Design and Procedures ........................................................................................................ 10 
3.1 General Study Design ..................................................................................................................... 10 
3.2 Schedule of Visits and Assessments .............................................................................................. 10 
4. 
Study Treatments ............................................................................................................................ 13 
4.1 Method of Assigning Subjects to Treatment Groups ...................................................................... 13 
4.2 Masking and Unmasking ................................................................................................................. 13 
5. 
Sample Size and Power Considerations ......................................................................................... 13 
5.1 Justification of Non-Inferiority Margin .............................................................................................. 14 
6. 
Data Preparation ............................................................................................................................. 14 
6.1 Input Data ........................................................................................................................................ 14 
6.2 Output Data ..................................................................................................................................... 14 
7. 
Analysis Populations ....................................................................................................................... 15 
7.1 Intent-to-Treat.................................................................................................................................. 15 
7.2 Primary Per Protocol ....................................................................................................................... 15 
7.3 Secondary Per-Protocol .................................................................................................................. 15 
7.4 Safety .............................................................................................................................................. 15 
8. 
General Statistical Considerations .................................................................................................. 15 


Protocol # 908 SAP, Version 1.0 
16JAN2023 
Confidential & Proprietary 
Page 4 of 38 
8.1 Units of Analysis .............................................................................................................................. 15 
8.2 Missing or Inconclusive Data Handling ........................................................................................... 15 
8.3 Definition of Baseline ...................................................................................................................... 16 
8.4 Data Analysis Conventions ............................................................................................................. 16 
8.5 Adjustments for Multiplicity .............................................................................................................. 17 
9. 
Disposition of Subjects .................................................................................................................... 17 
10. 
Demographic and Pretreatment Variables ...................................................................................... 18 
10.1 Demographic Variables ................................................................................................................... 18 
11. 
Medical History and Concomitant Medications ............................................................................... 18 
11.1 Medical History ................................................................................................................................ 18 
11.2 Concomitant Medications and Procedures ..................................................................................... 19 
12. 
Dosing Compliance and Treatment Exposure ................................................................................ 19 
12.1 Dosing Compliance ......................................................................................................................... 19 
12.2 Treatment Exposure ........................................................................................................................ 20 
13. 
Efficacy Analyses ............................................................................................................................ 20 
13.1 Primary Analysis ............................................................................................................................. 20 
13.1.1 
Sensitivity Analysis .............................................................................................................. 22 
13.2 Secondary Analyses ....................................................................................................................... 23 
13.2.1 
Sensitivity Analysis for Secondary Endpoints ..................................................................... 24 
13.2.2 
Redness Diary Data Analysis .............................................................................................. 24 
13.3 Exploratory Efficacy Analysis .......................................................................................................... 25 
13.4 Subgroup Analysis .......................................................................................................................... 26 
14. 
Safety Analyses .............................................................................................................................. 26 
14.1 Adverse Events ............................................................................................................................... 26 
14.2 Best Corrected Visual Acuity  at Distance ...................................................................................... 28 
14.3 Slit-Lamp Biomicroscopy Examination ............................................................................................ 28 
14.4 Intraocular Pressure ........................................................................................................................ 29 
14.5 Ocular Rebound .............................................................................................................................. 29 


Protocol # 908 SAP, Version 1.0 
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Confidential & Proprietary 
Page 5 of 38 
14.6 Physical Examination ...................................................................................................................... 30 
14.7 Vital Signs ....................................................................................................................................... 30 
14.8 Dilated Ophthalmoscopy ................................................................................................................. 30 
15. 
Tolerability Analysis ........................................................................................................................ 30 
15.1 Drop Comfort Assessment .............................................................................................................. 30 
15.2 Drop Comfort Questionnaire ........................................................................................................... 31 
16. 
Changes from Protocol-Stated Analyses ........................................................................................ 31 
17. 
References ...................................................................................................................................... 31 
18. 
Revision History .............................................................................................................................. 31 
19. 
Tables .............................................................................................................................................. 31 
20. 
Listings ............................................................................................................................................ 35 
 
 
 


Protocol # 908 SAP, Version 1.0 
16JAN2023 
Confidential & Proprietary 
Page 6 of 38 
List of Abbreviations 
Abbreviation 
Definition 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
BCVA 
Best Corrected Visual Acuity 
BTOS-PF 
Birmonidine Tartate Ophthalmic Solution, Preservative-free Formulation 
CI 
Confidence Interval 
CRO 
Clinical Research Organization 
CS 
Clinically Significant 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
ICH 
International Conference on Harmonisation 
IOP 
Intraocular Pressure 
ITT 
Intent-to-Treat 
IWRS 
Interactive Web Response System 
LOCF 
Last Observation Carried Forward 
logMAR 
Logarithm of the Minimum Angle of Resolution 
MAR 
Missing at Random 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MNAR 
Missing Not at Random 
NCS 
Not Clinically Significant 
OD 
Oculus dexter (Right Eye) 
OS 
Oculus sinister (Left Eye) 
OU 
Oculus uterque (Both Eyes) 
PDF 
Portable Document Format 
PPP 
Primary Per-Protocol 
PT 
Preferred Term 
RTF 
Rich Text Format 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDC 
Statistics & Data Corporation 
SDTM 
Study Data Tabulation Model 
SOC 
System Organ Class 
SPP 
Secondary Per-Protocol 
TEAE 
Treatment-Emergent Adverse Event 
TE-SAE 
Treatment-Emergent Serious Adverse Event 
WHO Drug 
World Health Organization Drug Dictionary 
WOCF 
Worst Observation Carried Forward 
 
 


Protocol # 908 SAP, Version 1.0 
16JAN2023 
Confidential & Proprietary 
Page 7 of 38 
1. Introduction 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and reporting for 
protocol 908, Version 2.0 dated 27OCT2021. 
This SAP is being written with due consideration of the recommendations outlined in the most recent 
International Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials, the most recent ICH E9 (R1) Guideline entitled Addendum on Estimands and 
Sensitivity Analysis in Clinical Trials to the Guideline on Statistical Principals for Clinical Trials, and the most 
recent ICH E3 Guideline entitled Guidance for Industry: Structure and Content of Clinical Study Reports. 
This SAP describes the data that will be analyzed and the subject characteristics, efficacy, and safety 
assessments that will be evaluated. This SAP provides details of the specific statistical methods that will 
be used. The statistical analysis methods presented in this document will supersede the statistical analysis 
methods described in the clinical protocol. If additional analyses are required to supplement the planned 
analyses described in this SAP, they may be completed and will be identified in the clinical study report. 
2. Study Objectives 
The primary objective is to demonstrate that the efficacy of brimonidine tartrate ophthalmic solution 
preservative-free formulation (BTOS-PF) 0.025% is non-inferior to Lumify® 0.025% for treating ocular 
redness in a population of adult subjects. 
The secondary objective is to compare the safety of BTOS-PF 0.025% with Lumify® 0.025%. 
2.1 
Primary Endpoint 
The primary efficacy endpoint is 
x 
Ocular redness score evaluated by the investigator prior to investigational drug instillation and at 
5(+1), 15(+1), 30(+1), 60(+10), 90(+10), 120(+15), 180(+15), and 240(+15) minutes after 
investigational drug instillation (0-4 unit scale, allowing half unit increments) at Visit 1. 
2.2 
Secondary Endpoints 
Secondary efficacy endpoints will be evaluated hierarchically, as follows:  
1. Change from pre-instillation ocular redness score evaluated by the investigator at 1 (+0.5) minute 
after investigational drug instillation (0-4 unit scale, allowing half unit increments) at Visit 1 
2. Change from pre-instillation ocular redness score evaluated by the investigator (0-4 unit scale, 
allowing half unit increments) at: 
i. 
1 minute after investigational drug instillation at Visit 2  
ii. 
5 minutes after investigational drug instillation at Visit 2  
iii. 
1 minute after investigational drug instillation at Visit 3  
iv. 
5 minutes after investigational drug instillation at Visit 3  


Protocol # 908 SAP, Version 1.0 
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Confidential & Proprietary 
Page 8 of 38 
3. Change from pre-instillation ocular redness score evaluated by the investigator at 360 (+15) 
minutes after investigational drug instillation (0-4 unit scale, allowing half unit increments) at Visit 
1 
4. Change from pre-instillation ocular redness score evaluated by the investigator at 480 (+15) 
minutes after investigational drug instillation (0-4 unit scale, allowing half unit increments) at Visit 
1.  
5. Ocular redness score evaluated by the subject as captured in subjects’ redness grading diary 
throughout the treatment period (0-4 unit scale, NOT allowing half unit increments).  
2.3 
Exploratory Endpoint 
The supportive efficacy endpoint is: 
x 
Total clearance of ocular redness assessed by the investigator at each post-instillation time point 
at each visit. 
2.4 
Safety Variables 
The following safety variables will be recorded: 
x 
Adverse Events (AEs; reported, elicited, and observed) 
x 
Best Corrected Visual Acuity (BCVA) at Distance 
x 
Slit Lamp Biomicroscopy 
x 
Intraocular Pressure (IOP) 
x 
Ocular Rebound defined as: 
o 
Increase of at least 1 unit in mean ocular redness score evaluated by the investigator at 
Visit 4 (0-4 unit scale, allowing half unit increments) compared to pre-instillation score at 
Visit 1, or 
o 
Increase of at least 1 unit in mean ocular redness score evaluated by the subject as 
captured in subject’s redness diary in the follow-up period after dosing has ceased (0-4 
unit scale, NOT allowing half unit increments) compared to diary day 1 (pre-dose morning 
assessment) 
x 
Vital Signs (resting blood pressure and pulse) 
x 
Physical Examination 
x 
Dilated ophthalmoscopy 
 
2.5 
Tolerability Variables  
x 
Drop comfort assessment (0-10 unit scale) assessed upon instillation, at 30 seconds, and at 1 
minute post instillation at Visit 1 
x 
Drop comfort descriptor questionnaire assessed at 3 minutes post-instillation at Visit 1 


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2.6 
Statistical Hypotheses 
At each of eight post-instillation times at Visit 1, the null hypothesis (ܪ଴) is that the difference between the 
mean redness scores for the Test (ߤ்) and Control (ߤ௖) formulations is 0.22 points or greater. The alternative 
hypothesis (ܪଵ) is that the difference is less than 0.22 points. 
ܪ଴: ߤ்−ߤ௖≥0.22 
ܪଵ: ߤ்− ߤ௖< 0.22 
The non-inferiority margin is the absolute value of one half of the smallest (in absolute value) upper 
confidence limit around the difference in redness scores (test minus control) observed over eight post-
instillation times (5 to 240 minutes) during each of two placebo controlled randomized clinical trials (B&L 
studies 11-100-0015 and 861). 
The hypotheses above will be tested for each of the eight post-instillation times at Visit 1 utilizing two-sided 
95% confidence intervals (CIs) around the difference between means (BTOS-PF 0.025% minus Lumify® 
0.025%) constructed as for two-sample t-tests. If the upper confidence limit does not exceed 0.22 units at 
any of the eight time points, then the study will be considered a success, and BTOS-PF 0.025% will be 
considered statistically non-inferior to Lumify® 0.025% for investigator-rated ocular redness. 
By requiring that the null hypotheses must be rejected at all eight post-instillation times to demonstrate 
success for the primary efficacy endpoint, the familywise type I error rate for the primary efficacy hypothesis 
tests is bounded above by the significance level of each hypothesis test (two-sided α = 0.05). 
Statistical inference will be performed for the secondary efficacy endpoints only if the primary efficacy 
endpoints demonstrate non-inferiority and statistical inference for the secondary efficacy endpoints will be 
performed in a hierarchical manner in the order from the list of endpoints in Section 2.2. 
2.7 
Estimands 
The primary comparisons in this trial will be between brimonidine tartrate ophthalmic solution preservative-
free formulation (BTOS-PF) 0.025% versus Lumify® 0.025% at 5(+1), 15(+1), 30(+1), 60(+10), 90(+10), 
120(+15), 180(+15), and 240(+15) minutes after investigational drug instillation (0-4 unit scale, allowing half 
unit increments) at Visit 1 for the Intent-to-Treat (ITT) population using the following estimands. 
x 
Population: subjects with ocular redness defined through enrollment criteria 
x 
Endpoint:  
o 
Ocular redness score evaluated by the investigator prior to investigational drug instillation 
and at 5(+1), 15(+1), 30(+1), 60(+10), 90(+10), 120(+15), 180(+15), and 240(+15) minutes 
after investigational drug instillation at Visit 1. 
x 
Intercurrent event:  
o 
Non-optimal compliance is ignored. [treatment policy strategy] 
o 
Missing data due to withdrawal due to lack of efficacy or AEs (assumed to be missing not at 
random [MNAR]) will be imputed employing single imputation using worst observation carried 
forward (WOCF) [hypothetical strategy].  


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o 
Ocular redness scores on or after the use of prohibited medication will be set to missing 
(assumed to be MNAR) for the remainder of the study and will be imputed using single 
imputation of last observation carried forward (LOCF) [hypothetical strategy].   
o 
Missing data without withdrawal or withdrawal due to reasons other than lack of efficacy or AEs 
(assumed to be missing at random [MAR]): will be imputed employing randomized treatment-
based Fully Conditional Specification (FCS) regression methodology [hypothetical strategy]. 
o 
 
x 
Population-level summary:  
o 
Difference in the mean ocular redness at 5(+1), 15(+1), 30(+1), 60(+10), 90(+10), 120(+15), 
180(+15), and 240(+15) minutes after investigational drug instillation at Visit 1 between BTOS-
PF 0.025%  and Lumify® 0.025%. 
 
3. Study Design and Procedures 
3.1 
General Study Design 
This is a multi-center, double-masked, randomized, active-controlled, parallel-group, efficacy and safety 
study that will enroll approximately 386 subjects at up to six clinical sites. Subjects with ocular redness will 
be randomized to receive either brimonidine tartrate ophthalmic solution 0.025%, preservative-free 
formulation, or Lumify® (brimonidine tartrate ophthalmic solution 0.025%). Subjects will be treated with 
study drug for approximately 4 weeks. 
Five visits will take place during this study: Screening Visit (Day -28 to 1), Visit 1 (Baseline; Day 1), Visit 2 
(Day 15 ± 2 days), Visit 3 (Day 29 + 2 days), and Visit 4 (Study Exit; Day 36 + 1 day). Efficacy assessments 
will be performed at Visits 1, 2, and 3. Tolerability assessments will be performed at Visit 1. Safety 
assessments will be performed at selected visits. 
Efficacy assessments include ocular redness evaluated by the investigator in-office and ocular redness 
evaluated by the subject as captured in subject’s redness diary. Tolerability assessments include drop 
comfort assessment and drop comfort descriptor questionnaire, both evaluated by the subject. Safety 
assessments include AEs, vital signs, BCVA, IOP, dilated ophthalmoscopy, slit lamp biomicroscopy, and 
ocular rebound. 
Study visits will be referred to in all tables and listings by the scheduled visit name. Error! Reference 
source not found. shows the scheduled study visits, their planned study day and the acceptable visit 
window for each study visit: 
3.2 
Schedule of Visits and Assessments 
The schedule of visits and assessments is provided in Table 1. 


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Table 1 Schedule of Assessments: 
PROCEDURE/ASSESSMENTS 
Screening1 
Visit 1 
(Baseline) 
Visit 2 
Visit 3 
Visit 4 
Day -28 to 
Day 1 
Day 1 
Day 15 ± 2 
Day 29 + 2 
Day 36 + 1 
Informed consent/HIPAA2 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical History  
X 
 
 
 
 
Concomitant Medications  
X 
X 
X 
X 
X 
Urine Pregnancy Test (for females of childbearing potential)3 
 
X 
 
X 
X 
Physical Examination4 
 
X 
 
X 
 
Vital Signs5 
 
X 
X 
X 
 
BCVA at Distance 
 
X 
X 
X 
X 
Slit lamp biomicroscopy6 
 
X 
X 
X 
X 
Intraocular Pressure (IOP) 
 
X 
 
X 
 
Dilated Ophthalmoscopy 
 
X 
 
X 
 
Randomization 
 
X 
 
 
 
In-Office Redness Assessment 
 
X7 
X8 
X8 
X 
In-Office Investigational Drug Instillation 
 
X9 
X10 
X10 
 
Drop Comfort/Descriptor Assessment11 
 
X 
 
 
 
Dispense Investigational Drug and Dosing Diary10 
 
X 
X 
 
 
Collect Investigational Drug and Dosing Diary10 
 
 
X 
X 
 
Dispense Redness Grading Diary 
 
 
 
X 
 
Collect Redness Grading Diary 
 
 
 
 
X 
Assessment of adverse events 
X 
X 
X 
X 
X 
Exit 
 
 
 
 
X 
1 If there is no washout period, the Screening Visit and Visit 1 can occur on the same day. 
2 Informed consent must be signed before any study-related procedure can be performed. If washout of a medication is necessary, informed consent must be 
obtained prior to Visit 1. 


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3 Women considered capable of becoming pregnant include all females who have experienced menarche and have not experienced menopause (as defined by 
amenorrhea for greater than 12 consecutive months) or have not undergone surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy). 
4 Physical examination includes general health, head, eyes, ears, nose, throat (HEENT), and any other comments. 
5 Vital signs (resting blood pressure and pulse) with body weight will be collected at Visits 1 and 3 and without body weight at Visit 2. 
6 Evaluated prior to and post investigational drug instillation at Visits 1, 2, and 3. 
7 Investigator will evaluate ocular redness prior to investigational drug instillation and at 1 (+0.5), 5(+1), 15(+1), 30(+1), 60(+10), 90(+10), 120(+15), 180(+15), 
240(+15), 360(+15), and 480(+15) minutes post investigational drug instillation. 
8 Investigator will evaluate ocular redness prior to investigational drug instillation and approximately 1 and 5 minutes post-instillation. 
9 Performed by the subject or subject’s caregiver while under the observation of the unmasked designee. 
10 Performed by the unmasked designee. 
11 Subjects will assess comfort upon instillation, at 30 seconds, and at 1 minute post-instillation using 0-10 unit scale for each eye at Visit 1. Subjects also will 
select comfort descriptor terms from a predetermined list at 3 minutes post-instillation at Visit 1. 
12 Complete urine pregnancy test if Visit-3 is early termination visit 
 


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4. Study Treatments 
x 
Investigational Product: Brimonidine tartrate ophthalmic solution 0.025% preservative-free 
formulation  
x 
Comparator Product: Lumify® (brimonidine tartrate ophthalmic solution 0.025%) 
4.1 
Method of Assigning Subjects to Treatment Groups 
At Visit 1, approximately 386 subjects will be randomly assigned at a ratio of 1:1 to the following treatments: 
x 
Brimonidine tartrate ophthalmic solution 0.025%, preservative-free formulation (BTOS-PF) (N = 
193) 
x 
Lumify® (brimonidine tartrate ophthalmic solution 0.025%) (N= 193) 
Each subject who signs an informed consent form will be assigned a unique subject number in the 
Interactive Web Response System (IWRS). Once a subject meets all qualification criteria at Visit 1, they 
will be randomized to brimonidine tartrate ophthalmic solution 0.025%, preservative free formulation or 
Lumify® (brimonidine tartrate ophthalmic solution) 0.025% in a 1:1 ratio. Subject numbers will be assigned 
in a sequential order starting at the lowest number available. No numbers will be skipped or omitted. Subject 
numbers will be created (in the following format, 3-digit site number plus 3-digit subject number) in the 
IWRS. Randomization will be used to avoid bias in the assignment of subjects to treatment, to increase the 
likelihood that known and unknown subject attributes (e.g., demographics and baseline characteristics) are 
evenly balanced across the treatment groups, and to enhance the validity of statistical comparisons across 
treatment groups. Masked treatment will be used to reduce potential of bias during data collection and 
evaluation of clinical endpoints. 
4.2 
Masking and Unmasking 
Subjects will be assigned to treatments based on a randomization schedule. The investigator, site staff, 
subject, clinical research organization (CRO), and Sponsor personnel involved in the monitoring or conduct 
of the study will be masked to the treatment assignments. The randomization list will be produced prior to 
study enrollment by a statistician not otherwise involved in the trial. 
5. Sample Size and Power Considerations 
A sample size of 183 subjects per treatment group will have approximately 90% power to demonstrate non-
inferiority of BTOS-PF 0.025% to Lumify® 0.025% at all eight post-instillation times at Visit 1 using a two-
sample t-test and assuming a non-inferiority limit of 0.22 units, mean difference of 0 units, and a common 
standard deviation of 0.50 units with one-sided alpha of 0.025. Assuming a 5% dropout rate, 193 subjects 
will be randomized to each treatment group (386 total subjects). 


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5.1 
Justification of Non-Inferiority Margin 
The non-inferiority margin is the absolute value of one half of the smallest (in absolute value) upper 
confidence limit around the difference in redness scores (test minus control) observed over eight post-
instillation times (5 to 240 minutes) during each of two placebo-controlled randomized clinical trials (B&L 
studies 11-100-0015 and 861).
6. Data Preparation 
6.1 
Input Data 
Study data will primarily be recorded on the electronic Case Report Forms (eCRFs) supplied by Statistics 
& Data Corporation (SDC) using iMednet Electronic Data Capture (EDC) system.  
When all prerequisites for database lock have been met, including availability of all masked external data, 
the database will be locked. Following database lock, approval will be obtained from the Sponsor to unmask 
the study. Any changes to the database after data have been locked can only be made with the approval 
of the Sponsor in consultation with SDC.  
Final analysis will be carried out after the following have occurred: 
x 
Database lock has occurred, including receipt of all final versions of external vendor data, with 
written authorization provided by appropriate SDC and Sponsor personnel. 
x 
Protocol deviations have been identified and status defined (major/minor deviations). 
x 
Analysis populations have been determined. 
x 
Randomized treatment codes have been unmasked. 
6.2 
Output Data 
Data from EDC and external data will be transferred to Biostatistics and incorporated into standard formats 
following the Study Data Tabulation Model (SDTM). Data will then be mapped to analysis datasets using 
the Analysis Data Model (ADaM). Both SDTM- and ADaM-formatted data will be used to create the subject 
listings, while all tables and figures will be based on the ADaM-formatted data. 
SDTM will follow the SDTM Version 1.4 model and will be implemented using the SDTM Implementation 
Guide Version 3.3 and the SDTM Controlled Terminology Version 2022-09-30. ADaM data will follow the 
ADaM Version 2.1 model and will be implemented using the ADaM Implementation Guide Version 1.1. Both 
SDTM and ADaM will be validated using Pinnacle 21 Version 4.0.1. Any discrepancies in the validation will 
be noted in reviewer’s guides accompanying the final data transfers. 
Define.xml will be created for SDTM and ADaM using the Define-XML Version 2.0 model. 


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7. Analysis Populations 
7.1 
Intent-to-Treat 
The Intent-to-Treat (ITT) population includes all randomized subjects. Subjects will be analyzed according 
to the treatment to which they were randomized. 
7.2 
Primary Per Protocol 
The Primary Per-Protocol population (PPP) will include subjects in the ITT who do not have significant 
protocol deviations likely to affect the primary endpoint analysis. Protocol deviations will be assessed prior 
to database lock and unmasking. Subjects in the PPP population will be analyzed as treated. 
7.3 
Secondary Per-Protocol 
The Secondary Per-Protocol (SPP) population will include subjects in the ITT who do not have significant 
protocol deviations likely to affect the secondary endpoints and analyses. Protocol deviations will be 
assessed prior to database lock and unmasking. Subjects in the SPP population will be analyzed as treated. 
7.4 
Safety 
The Safety population includes all randomized subjects who received at least 1 dose of study drug. All 
subjects in the Safety population will be analyzed according to the treatment they received. All safety 
analyses will be based on the Safety population. 
8. General Statistical Considerations 
8.1 
Units of Analysis 
For efficacy, tolerability, and non-ocular safety analyses, the unit of analysis will be the subject. In the cases 
where assessments are recorded for each eye, the average of the eyes will be used. Adverse events will 
also be summarized at the subject level; if an AE occurs in either or both eyes, the subject will be counted 
as having the AE.  
8.2 
Missing or Inconclusive Data Handling 
In general, there will be no imputation of missing data other than as described in Section 2.7 and for partial 
or missing dates where complete dates are required to flag data as treatment-emergent or concomitant 
with treatment. Partial/missing start and end dates for AEs and concomitant medications will be imputed as 
follows: 
Partial/missing start date:  
x 
Dates with missing day only will be imputed as the 1st of the month unless the month and year are 
same as the month and year of first dose of study medication, in which case missing day will be 
imputed as the first dose day of study medication.  


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x 
Dates with both day and month missing will be imputed as 1 Jan unless the year is same as the 
year of first dose of study medication, in which case missing day and month will be imputed as the 
first dose day and month of study medication. 
x 
Completely missing dates will be imputed as the first dose date of study medication unless the end 
date is on or before the first dose date of study medication, in which case missing date will be 
imputed as 1 Jan of the same year as the end date. 
Partial/missing end date:  
x 
Dates with missing day only will be imputed as the last day of the month unless the month and year 
are the same as the month and year of the last dose of study medication, in which case missing 
day will be imputed as the last dose day of study medication.  
x 
Dates with both day and month missing will be imputed as 31 Dec unless the year is same as the 
year of the last dose of study medication, in which case missing day and month will be imputed as 
the last dose day and month of study medication.  
x 
If the ongoing flag is missing or “Yes” then the date will not be imputed unless death date is 
available, in which case the missing date will be imputed as the death date. If ongoing is “No” then 
the missing end date will be imputed as the last dose date. 
x 
If the imputed date is after the date of death, then the end date will be set equal to the date of 
death.  
The original dates will be displayed in data listings and the imputed dates will be used in derivations only 
(study day, treatment-emergence status, etc.). 
8.3 
Definition of Baseline 
For Ocular redness, baseline is defined as the last measurement prior to the first dose instillation at each 
visit.  
8.4 
Data Analysis Conventions 
All data analysis will be performed by SDC. Statistical programming and analyses will be performed using 
SAS® version 9.4 or higher. Output will be provided in rich text format (RTF) for tables and portable 
document format (PDF) for tables, listings, and figures using landscape orientation. All study data will be 
listed by subject, treatment, and visit (as applicable) based on all randomized subjects unless otherwise 
specified. 
Summaries for continuous and ordinal variables will include the number of observations (n), arithmetic 
mean, standard deviation (SD), median, minimum, and maximum. Minima and maxima will be reported with 
the same precision as the raw values; means and medians will be presented to one additional decimal 
place than reported in the raw values. Standard deviations will be presented to two additional decimal 
places than reported in the raw values. Summaries for discrete variables will include counts and 


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percentages. All percentages will be rounded to one decimal place (i.e., XX.X%). Differences between test 
treatment and control will be calculated as BTOS-PF 0.025% minus Lumify® 0.025 and change from 
baseline will be calculated as follow-up visit minus baseline.  
All statistical tests will be two-sided with a significance level of 0.05 (α = 0.05) unless otherwise specified. 
Confidence intervals for differences between treatment groups will be two-sided at 95% confidence. All 
p-values will be rounded to 4 decimal places; p-values less than 0.0001 will be presented as “<0.0001”; p-
values greater than 0.9999 will be presented as “>0.9999.” 
Unless otherwise specified, summaries will be presented by treatment group and, where appropriate, visit. 
Listings will be sorted by subject treatment, , visit/time point (as applicable), and parameter as applicable. 
8.5 
Adjustments for Multiplicity 
The Type I error rate for the primary efficacy analysis will be controlled by requiring the primary efficacy 
hypotheses test results to be statistically significant for all eight time points at Visit 1 (5(+1), 15(+1), 30(+1), 
60(+10), 90(+10), 120(+15), 180(+15), and 240(+15) minutes post-instillation) to declare success for the 
primary endpoint. The overall Type I error rate including the primary and secondary efficacy analyses will 
be controlled by a hierarchical testing structure. Specifically, statistical inference for the secondary efficacy 
analyses will only be performed if the primary analyses are successful, after which inference for the 
secondary efficacy endpoints will be performed in a hierarchical manner in the order of the secondary 
endpoints from Section 13.2. 
9. Disposition of Subjects 
Subject disposition will be presented in terms of the numbers and percentages of subjects who were 
randomized, completed the study by visit and overall, and discontinued from the study. Disposition will be 
summarized by treatment group and overall for all randomized subjects. 
The number of subjects in ITT, PPP, SPP, and Safety analysis populations will be displayed by treatment 
group and overall. Percentages of number of subjects will be calculated using randomized subjects as the 
denominator.  
The number and percentage of subjects prematurely discontinued from the study and the reasons for study 
discontinuation will be summarized by treatment group and overall for all randomized subjects. The reasons 
for study discontinuation that will be summarized include: AE, lost to follow-up, death, pregnant, lack of 
efficacy, study terminated by sponsor, voluntary withdrawal, and other. Treatment related discontinuations 
will also be displayed. A subject listing will be provided which includes the date and reason for premature 
study discontinuation in addition to the informed consent date and protocol version for which informed 
consent was signed. 
The number and percentage of subjects with any, major, and minor protocol deviations will be summarized 
by treatment group and overall for all randomized subjects. Protocol deviations will be classified as major 


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or minor prior to the closure of the database during a masked review of each protocol deviation. Major 
deviation or protocol violation is defined to have occurred when there is non-adherence to the protocol that 
results in a significant, additional risk to the subject; when the subject or investigator has failed to adhere 
to significant protocol requirements (inclusion/exclusion criteria), and the subject was enrolled without prior 
sponsor approval; or when there is non-adherence to FDA regulations and/or ICH GCP guideline.   
Important protocol deviations leading to exclusion from the Primary and Secondary Per-Protocol Population 
will include, but not limited to the following.  
1. Ineligibility 
2. Use of any prohibited medication potentially affecting the primary or secondary endpoints  
Exclusion from Primary or Secondary Per-Protocol Population will be reviewed prior to the closure of the 
database during a masked review of the data. 
The number of subjects with major protocol deviations along with deviation categories will be summarized 
by treatment group and overall, in a table. A subject listing will be provided which includes the date of the 
deviation, the deviation description, the action taken for the deviation, the classification of whether the 
deviation was judged to be major or minor, whether the deviation was COVID-19 related or not, and if the 
deviation excludes the subject from the Primary Per-Protocol and/or Secondary Per-Protocol analysis 
populations. 
10. Demographic and Pretreatment Variables 
10.1 
Demographic Variables 
The demographic variables collected in this study include date of birth, age, sex, childbearing potential, 
race, ethnicity, and iris color. Subjects who record more than one race will be grouped into a single category 
denoted as multi-racial. Iris color will be summarized at the subject level with a category for heterochromia 
if a subject records a different eye color for each eye. Demographic variables will be summarized for the 
ITT and Safety populations, separately. 
Age (years) will be summarized, overall and by treatment, using continuous descriptive statistics. Age will 
also be categorized as follows: < 65 years and ≥ 65 years.  
A subject listing that includes all demographic variables will be provided. 
11. Medical History and Concomitant Medications 
11.1 
Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) Version 25.0.  
Non-ocular medical history will be summarized using discrete summary statistics and presented by 
treatment group at the subject level by System Organ Class (SOC) and Preferred Term (PT) using the ITT 
Population. Ocular medical history will be similarly summarized at the subject level. If a subject reports the 


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same PT multiple times within the same SOC, that PT will only be reported once within that SOC. As with 
the PT, if a subject reports multiple conditions within the same SOC, that SOC will only be reported once. 
In the summaries, SOCs and PTs within an SOC will be ordered by descending frequency based on all 
subjects. 
Listings of medical history will be generated separately for ocular and non-ocular data. 
11.2 
Concomitant Medications and Procedures 
Concomitant medications will be coded using World Health Organization Drug Dictionary (WHO Drug) 
Global, B3, March 2022 and summarized to the therapeutic drug class (Anatomical Therapeutic Chemical 
[ATC] 4 classification) and preferred name. If the ATC 4 classification is not provided, then the next lowest 
classification that is provided in the coding dictionary will be used. The preferred name will be defined as 
the active ingredient; if the active ingredient is not provided or includes more than two ingredients (e.g., 
multivitamins), then the drug name will be summarized as the preferred name.  
Concomitant medications are defined as those medications listed as having been taken (1) prior to initiation 
of study drug administration and continuing for any period of time following the first administration of study 
drug or (2) at any time following the first administration of study drug. 
Concomitant medications will be summarized using the ITT population. Medications will be tabulated for 
each treatment group using frequencies and percentages. Subjects may have more than one medication 
per ATC class. At each level of subject summarization, a subject will be counted once if they report one or 
more medications. Percentages will be based on the number of subjects in each treatment group. In the 
summaries, ATC classes and preferred names within an ATC class will be ordered by descending frequency 
based on all subjects. 
Listings of concomitant medications and procedures will be generated. 
12. Dosing Compliance and Treatment Exposure 
12.1 
Dosing Compliance 
Subjects will be provided with a dosing diary to document QID dosing. Dosing compliance (% compliance) 
will be assessed by calculating the number of actual doses received and comparing that to the number of 
expected doses as follows: 
Compliance (%) = 
Number of Actual Doses Received x 100% 
 
Number of Expected Doses 
The number of actual doses received will be calculated by counting the number of dosed records in the 
subject diary and the in-office instillation CRF pages. From Visit 1 to Visit 3, subjects are expected to be 
dosed 4 times day, including in-office doses. However, on Visit 1, they get only 1 dose on-site and are 


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instructed to take no further doses at home. The at-home dosing starts on the day after Visit 1. The expected 
number of doses will be calculated as:  
For subjects who complete Visit 3 
 4 x [(Date of Visit 3– Date of First Dose)] +1 
 
For subjects who discontinue without completing Visit 3  
 
4 x [(Date of Study Last Dose from the Dosing Diary Page – Date of First Dose)]+1 
 
Subjects that discontinue without completing Visit 3 will be expected to take 4 doses on their last dose date. 
A categorical dosing compliance variable will also be derived as non-compliant (< 80%), compliant (≥ 80% 
and ≤ 125%), and over compliant (> 125%). 
Dosing compliance (%) will be summarized with continuous descriptive statistics for each treatment group 
using the ITT population. The compliance category defined above will be summarized with discrete 
summary statistics.  
A subject listing of dosing compliance will also be produced. 
12.2 
Treatment Exposure 
Extent of treatment exposure for completed or discontinued subjects will be calculated in days using the 
following: 
For subjects that complete Visit 3,  
Extent of Exposure (days) = (Date of Visit 3 – Date of First Dose) + 1 
For subjects don’t complete Visit 3 
Extent of Exposure (days) = (Date of Last Dose – Date of First Dose) + 1 
 
Extent of treatment exposure for each subject exposed to study drug will be summarized with continuous 
descriptive statistics for each treatment group using the safety population. A subject listing of study drug 
instillation will also be produced. 
13. Efficacy Analyses 
All assessment data for efficacy analyses will be provided in subject listings. 
13.1 
Primary Analysis 
The primary efficacy endpoint is 


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x 
Ocular redness score evaluated by the investigator prior to investigational drug instillation and at 5 
(+1), 15 (+1), 30 (+1), 60 (+10), 90 (+10), 120 (+15), 180 (+15), and 240 (+15) minutes after 
investigational drug instillation (0-4 unit scale, allowing half unit increments) at Visit 1. 
Summary statistics will be shown for the pre-dose ocular redness score and for each of the post-dose time 
points. BTOS-PF 0.025% will be compared to Lumify® 0.025% for the primary efficacy parameter of ocular 
redness as evaluated by the investigator (post-instillation assessments) for each of the eight time points at 
Visit 1 using two-sided 95% CIs around the difference between means (BTOS-PF30 0.025% minus Lumify® 
0.025%) constructed as for two-sample t-tests with a non-inferiority limit of 0.22 units. Missing data and 
intercurrent events for the primary endpoint will be treated as described in Section 2.7.  
 
Data will be transposed to horizontal structure before passing to PROC MI. 
PROC MI DATA=INDATA SEED=697471 NIMPUTE=30 OUT=OUT1 MINIMUM=0 MAXIMUM=4 
ROUND=0.5; 
Class trt01pn; 
VAR BASE POST_5min POST_15min POST_30min POST_60min POST_90min POST_120min 
POST_180min POST_240min; 
FCS REG (/details); 
RUN; 
where 
x 
INDATA is the name of the input dataset 
x 
Trt01pn is the planned treatment 
x 
OUT1 is the name of the output dataset 
x 
BASE is the baseline assessment 
x 
POST_5min is the assessment at 5 mins post dose 
x 
POST_15min is the assessment at 15 mins post dose 
x 
POST_30min is the assessment at 30 mins post dose 
x 
POST_60min is the assessment at 60 mins post dose 
x 
POST_90min is the assessment at 90 mins post dose 
x 
POST_120min is the assessment at 120 mins post dose 
x 
POST_180min is the assessment at 180 mins post dose 
x 
POST_240min is the assessment at 240 mins post dose 
The following SAS® code will then be used execute the t-test for each imputed dataset: 
PROC SORT DATA=OUT1; BY ATPTN _IMPUTATION_; RUN; 
where 
- OUT1 is the name of the input dataset 


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- ATPTN is the analysis time point 
- _IMPUTATION_ is the imputation number 
and 
ods output statistics=ttest (where=(method in ('', "Pooled"))); 
proc ttest data=out1 sides=2 alpha=0.05; 
 
by atptn _imputation_; 
 
class TRTPN;  
 
var aval; 
   run; 
where 
x 
OUT1 is the name of the input dataset 
x 
_IMPUTATION_ is the imputation number 
x 
TRTPN is the planned treatment 
x 
aval is the redness score 
The estimates and standard errors across imputations will be combined using the following code 
PROC MIANALYZE DATA=ttest; 
MODELEFFECTS mean; 
STDERR; 
ODS OUTPUT PARAMETERESTIMATES=PEST; 
RUN; 
13.1.1 SENSITIVITY ANALYSIS 
The following sensitivity analysis will be done on the primary endpoint 
x 
SP1: Repeat the primary efficacy analysis on the ITT population with observed data only. No single 
or multiple imputations will be performed. 
x 
SP2: Repeat the primary efficacy analysis on the ITT population where all the missing redness 
scores and redness scores on or after  prohibited medication use are imputed using the worst 
(highest) ocular redness score. No multiple imputations will be performed. 
x 
SP3: Repeat the primary efficacy analysis on the ITT population where all the missing redness 
scores and redness scores on or after  prohibited medication use in the BTOS-PF arm are imputed 
using the worst (highest) ocular redness score and the Lumify arm are imputed using the best 
(lowest) ocular redness scores. No multiple imputations will be performed. 
x 
SP4: Repeat the primary efficacy analysis on the PPP population with observed data only. No 
single or multiple imputations will be performed. 
x 
SP5: Repeat the primary efficacy analysis on the PPP using the same imputation strategy as 
primary efficacy endpoint.  


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x 
SP6: Repeat the primary efficacy analysis on the ITT population where all the missing values and 
redness scores on or after prohibited medication use are imputed using a regression based multiple 
imputation strategy. No single imputations will be performed. 
x 
SP7: Repeat the primary efficacy analysis on the ITT population where all the missing values and 
redness scores on or after prohibited medication use are imputed using multiple imputations with 
MNAR assumption by searching for the tipping point. The tipping point is the shift value causing 
the final test result to be reversed from non-inferior to inferior. The tipping point analysis will be 
done at each of the primary efficacy timepoints – (5, 15 30, 60, 90 120, 180 and 240 minutes post-
instillation). The shift value, mean difference with SE, and 95%CI will be presented. The shift range 
and size will be determined when executing the analysis. The following SAS code will be used.  
proc mi data=indata seed=987414 nimpute=30 out=out1; 
class trt01pn; 
fcs reg (/details); 
mnar adjust  (/shift=xx adjustobs=(trt=’BTOS-PF’)); /** shift value will be 
entered here. **/ 
var base post_5min post_15min post_30min post_60min post_90min post_120min 
post_180min post_240min; 
run; 
 
ods output statistics=ttest (where=(method in ('', "pooled"))); 
proc ttest data=out1 sides=2 alpha=0.05; 
by atptn _imputation_; 
class trtpn;  
var aval; 
run; 
 
proc mianalyze data=ttest; 
modeleffects mean; 
stderr; 
ods output parameterestimates=pest; 
run; 
13.2 
Secondary Analyses 
Secondary efficacy endpoints will be evaluated hierarchically, as follows:  
1. Change from pre-instillation ocular redness score evaluated by the investigator at 1 (+0.5) minute 
after investigational drug instillation (0-4 unit scale, allowing half unit increments) at Visit 1 
2. Change from pre-instillation ocular redness score evaluated by the investigator (0-4 unit scale, 
allowing half unit increments) at: 
i. 
1 minute after investigational drug instillation at Visit 2  


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ii. 
5 minutes after investigational drug instillation at Visit 2  
iii. 
1 minute after investigational drug instillation at Visit 3  
iv. 
5 minutes after investigational drug instillation at Visit 3  
3. Change from pre-instillation ocular redness score evaluated by the investigator at 360 (+15) 
minutes after investigational drug instillation (0-4 unit scale, allowing half unit increments) at Visit 1 
4. Change from pre-instillation ocular redness score evaluated by the investigator at 480 (+15) 
minutes after investigational drug instillation (0-4 unit scale, allowing half unit increments) at Visit 1 
5. Ocular redness score evaluated by the subject as captured in subjects’ redness grading diary 
throughout the treatment period (0-4 unit scale, NOT allowing half unit increments) 
Secondary efficacy endpoints 1 thorough 4 will be analyzed using the same estimand as the primary 
efficacy endpoint on the ITT population. Secondary endpoint 5, which is redness grading diary data will be 
analyzed as described in Section 13.2.2. 
The change from pre-instillation in investigator-rated redness will be compared between treatment groups 
utilizing the same methods as in the primary efficacy analyses [i.e. two sided 95% confidence intervals 
around the difference between group means (BTOS-PF 0.025% minus Lumify® 0.025%) constructed as 
for two-sample t-tests for each post-instillation time point at each visit]. BTOS-PF.025% will be considered 
statistically non-inferior to Lumify® 0.025% for the change from pre-instillation in investigator-rated redness 
at a given time and visit if the upper confidence limit does not exceed 0.22 units. 
13.2.1 SENSITIVITY ANALYSIS FOR SECONDARY ENDPOINTS  
The following sensitivity analyses will be performed for secondary endpoints 1 through 5. 
SS1: Repeat the secondary efficacy (endpoints 1 through 5) analyses on the SPP population using the 
same imputation strategy as the primary efficacy endpoint. 
SS2: Repeat the secondary efficacy (endpoints 1 through 5) analyses on the ITT population where the 
redness scores after intercurrent events (including missing redness scores and redness scores during 
prohibited medication use) are not imputed. 
SS3: Repeat the secondary efficacy (endpoints 1 through 5) analyses on the SPP population where the 
redness scores after intercurrent events (including missing redness scores and redness scores during 
prohibited medication use) are not imputed. 
 
13.2.2 REDNESS DIARY DATA ANALYSIS 
Ocular redness as recorded in the subject diaries from Visit 1 to Visit 2 and Visit 2 to Visit 3 post-instillation 
will be analyzed using a generalized linear model accounting for repeated measures. The model will contain 
treatment, day, and treatment by day interaction using a compound symmetry variance-covariance 
structure. If the model fails to converge, other variance-covariance structures will be used. Daily post-
instillation averages for each date recorded in subject diaries will be used for each subject. The daily 


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average will be computed and used if there is at least one score is provided per day. If there are no redness 
scores recorded on a day, the average will not be computed and daily average be left missing. Redness 
scores from start of prohibited medications until end of study  will not be used and set to missing. All the 
missing data will be imputed implicitly by the repeated measures mixed model.  
If the upper limit of the 95% confidence around the LS mean difference (BTOS-PF 0.025% minus Lumify® 
0.025%) is less than 0.19 unit, BTOS-PF 0.025% will be declared statistically non-inferior to Lumify® 
0.025% for the subject-rated ocular redness assessment. 
The repeated measures analysis will be done in SAS as below  
 
proc mixed data=afinal nobound; 
by avisit; 
class usubjid day trtpn; 
model aval =  day trtpn / alpha=0.05 solution ddfm=kenwardroger; 
repeated / subject = usubjid v vcorr type=un; 
lsmeans trtpn  / pdiff cl alpha=0.05 
run; 
where  
x 
aval is the daily average redness score 
x 
day is the scheduled study day 
x 
avisit is the visit range Visit 1- Visit 2, Visit 2 – Visit 3 
 
13.3 
Exploratory Efficacy Analysis 
The supportive efficacy endpoint is: 
x 
Total clearance of ocular redness assessed by the investigator at each post-instillation time point 
at each visit 
Subjects with total clearance of ocular redness (redness score of 0 based on investigator assessment) will 
be summarized using counts and percentages by treatment group for each post-instillation time point at 
each visit. Treatment comparisons will be made separately for each time point using Pearson’s chi-squared 
test or Fisher’s exact test if any of the expected cell counts are less than five. This analysis will be done on 
the ITT population. 
proc freq data=indata; 
by avisit atpt; 
table trtpn*critfl/chisq fisher; 
run; 
where  
x 
avisit is the visit 


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x 
atpt is the timepoint  
x 
critfl is criteria flag for subjects with total clearance at that 
visit. Y for subjects with total clearance and N otherwise.   
x 
trtpn is the planned treatment  
13.4 
Subgroup Analysis 
Ocular redness at Visit 1 using observed data only will be repeated for the following subgroups.   
x 
Age Category (<65, >=65) 
x 
Gender 
x 
Race  
x 
Ethnicity  
x 
Iris Pigmentation 
x 
Site 
Summary statistics, 95%CI for the mean, mean difference, associated 95% CI, and p-value from a two-
sample t-test between BTOS-PF and Lumify will be produced, Inferential statistics will be produced only if 
both the arms have at least 2 subjects in that subgroup.  
14. Safety Analyses 
All safety analyses will be conducted using the Safety population.. The safety of BTOSPF 0.025% 
compared to Lumify® 0.025% will be assessed by the review of all of the safety parameters. 
14.1 
Adverse Events 
An AE is any untoward medical occurrence in a subject participating in a clinical study, which does not 
necessarily have a causal relationship with the study product/procedure. The AE reporting period ends 
upon study exit. Study drug includes the investigational drug under evaluation and control given during any 
stage of the study. All AEs will be coded using the MedDRA Version 25.0.  
A treatment-emergent adverse event (TEAE) is defined as an AE with a start date on or after the first dose 
of study drug, or that worsened following administration of study drug. Adverse events recorded in the eCRF 
which are not treatment-emergent will not be included in the summary tables but will be included in the AE 
data listings. 
Severity of an AE is defined as a qualitative assessment of the degree of intensity of an AE as determined 
by the Investigator or reported to them by the subject. The assessment of severity is made irrespective of 
relationship to study drug or seriousness of the event and should be evaluated according to the following 
scale: 
x Mild: Awareness of a sign or symptom but is easily tolerated, requires no treatment, and does not 
interfere with subject’s daily activities. 
x Moderate: Low level of concern to the subject and may interfere with daily activities but can be 
relieved by simple therapeutic care. 


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x Severe: Interrupts the subject’s daily activities and requires systemic therapy or other treatment. 
The relationship of each AE to the study drug should be determined by the Investigator using these 
explanations: 
x 
Related: There is at least a reasonable possibility that the AE/Serious Adverse Event (SAE) is 
related to the study drug. Reasonable possibility means that there is evidence to suggest a 
causal relationship between the drug and the AE.. 
x 
Not Related: There is little or no reasonable possibility that the AE/SAE is related to the study 
drug. This assessment implies that the AE/SAE has little or no temporal relationship to the study 
drug and/or a more likely or certain alternative etiology exists.. 
Only related TEAEs are considered as treatment-related TEAEs. 
An overall summary will be presented that includes the number of events and the number and percentage 
of subjects who experienced at least TEAE, by treatment group and overall . This summary will also include 
breakdowns of TEAEs further categorized as ocular or non-ocular, treatment-related TEAEs, treatment-
emergent serious adverse events (TE-SAEs), TEAEs leading to early study treatment discontinuation, 
TEAEs by maximum severity for both ocular and non-ocular TEAEs, and TEAEs leading to death. 
Additional summaries of TEAEs will be provided showing the number and percentage of subjects who 
experienced at least one TEAE of each type, along with the number of such AEs observed, by treatment 
group. Non-ocular TEAEs will be summarized using discrete summary statistics and presented by treatment 
group at the subject level by SOC and PT. Ocular TEAEs will be similarly summarized at the subject level 
by treatment group. If a subject reports the same PT multiple times within the same SOC, that PT will only 
be reported once within that SOC. As with the PT, if a subject reports multiple conditions within the same 
SOC, that SOC will only be reported once. In the summary, SOCs will be listed in descending frequency of 
BTOS-PF; PTs will be listed in order of descending frequency for BTOS-PF within each SOC.  
Separate summaries will be provided for the following categories of TEAEs:  
x 
Ocular TEAEs  
x 
Non-ocular TEAEs  
x 
Treatment-related ocular TEAEs 
x 
Treatment-related non-ocular TEAEs 
x 
Ocular Treatment-emergent SAEs (TE-SAEs) 
x 
Non-ocular TE-SAEs 
x 
Non-serious TEAEs occurring in at least 1%, 2%, 3%, 4%, and 5% of subjects  in either treatment 
group. (five summaries) 
Summaries of TEAEs by maximum severity will be presented for ocular TEAEs and non-ocular TEAEs 
separately. The number of subjects with any TEAEs (along with percentages) will be tabulated by SOC and 


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PT within each SOC by treatment group. To count the number of subjects with any TEAEs, if a subject has 
multiple TEAEs coded to the same PT within the same SOC, the subject will be counted once under the 
maximum severity. 
The following tables will be repeated for the subgroups mentioned in Section 13.4 (Age category, Gender, 
Race, Ethnicity, Iris Pigmentation).  
1. Overall Summary of AEs  
2. Summary of Ocular AEs by SOC and PT 
3. Summary of Non-Ocular AEs by SOC and PT 
All AEs will be presented in a subject listing. The AEs leading to study treatment discontinuation will be 
listed separately. In addition, all SAEs will be presented in a separate listing. 
14.2 
Best Corrected Visual Acuity  at Distance 
The logarithm of the minimum angle of resolution (logMAR) visual acuity is assessed at Visits 1, 2, 3, and 
4 using an Early Treatment Diabetic Retinography Study (ETDRS) chart. Subjects should use their most 
recent correction to attain their BCVA. 
The observed and change from baseline BCVA will be summarized for each eye using continuous 
descriptive statistics by visit for each treatment group. A subject listing of visual acuity will also be produced. 
14.3 
Slit-Lamp Biomicroscopy Examination 
A slit-lamp biomicroscopy examination of the lid and lid margin: erythema, swelling; Conjunctiva: 
erythema/hyperemia, chemosis; cornea: edema, erosion, endothelial condition, lens pathology; and 
anterior chamber: cells, flare will be performed at each visit, and evaluated prior to and post investigational 
drug instillation at Visits 1, 2, and 3.  
Table 3 provides the slit-lamp biomicroscopy region and the corresponding grading scale for the results. 
 
 


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Table 3. Slit Lamp Biomicroscopy Regions and Grading Scales 
Region 
Grading Scale 
Cornea: Erosion 
0 (None)  
+1 (Mild)  
+2 (Moderate) 
+3 (Severe) 
Cornea: Edema 
0 (None) 
+0.5 (Mild) 
+1 (Moderate) 
+2 (Severe), 
+3 (Very Severe) 
Lid and Lid Margin: Swelling 
Conjunctiva: Chemosis 
Cornea: Endothelial Condition, Lens Pathology 
Anterior Chamber: Cells, Flare 
0 (None) 
+1 (Mild) 
+2 (Moderate) 
3 (Severe) 
+4 (Very Severe) 
Conjunctiva: Erythema/Hyperemia 
Lid and Lid Margin: Erythema 
0 (None) 
+0.5 
+1 (Mild) 
+1.5 
+2 (Moderate) 
+2.5 
+3 (Severe) 
+3.5 
+4 (Very Severe). 
The results will be summarized using counts and percentages for each treatment group at each visit for 
each eye. Percentages will be based on the number of subjects in each treatment group with responses. A 
subject listing of the slit-lamp biomicroscopy parameters will also be produced. 
Summary statistics including change from pre-instillation at Visit 1, 2 and 3 will also be produced.  
14.4 
Intraocular Pressure  
Subjects’ IOP will be assessed by non-contact tonometry in each eye at Visits 1 and 3. Results will be taken 
from a single measurement and will be recorded in mmHg. 
The IOP values and changes from baseline for each eye will be summarized using continuous descriptive 
statistics by visit and eye for each treatment group. A subject listing of IOP will also be produced. 
14.5 
Ocular Rebound 
  
Ocular Rebound defined as: 


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1. Increase of at least 1 unit in mean ocular redness score evaluated by the Investigator at Visit 4 (0-
4 unit scale, allowing half unit increments) compared to pre-instillation score at Visit 1.  
OR 
2. Increase of at least 1 unit in mean ocular redness score evaluated by the subject as captured in 
subject’s redness diary in the follow-up period, after dosing has ceased (0-4 unit scale, NOT 
allowing half unit increments) compared to diary day 1 (predose morning assessment). The mean 
ocular redness scores during the follow-up period is computed by taking the mean of the daily 
averages (as described in Section 13.2.2) from Visit 3 to Visit 4. This average score from Visit 3 to 
Visit 4 will be compared against the first available dairy score to calculate change.  
 The percentage of subjects meeting the investigator assessment  (criteria 1) and subject assessment 
(criteria 2) will be summarized separately for each treatment group. A subject listing of ocular rebound will 
also be produced. 
14.6 
Physical Examination 
The physical examination parameters for Head, Eye, Ear, Nose, and Throat; and General Health will be 
graded as normal, abnormal not clinically significant (NCS), and abnormal clinically significant (CS) and 
summarized by treatment group using counts and percentages at Visits 1 and 3 (including a summary of 
baseline values). A subject listing of the physical examination results will also be produced. 
14.7 
Vital Signs 
Vital signs, including systolic, diastolic BP, pulse,  and weightwill be summarized with continuous descriptive 
statistics at Visits 1, 2, and 3 by treatment group. Change from Visit 1 will also be summarized at Visits 2 
and 3. 
A subject listing of the vital signs results will also be produced. 
14.8 
Dilated Ophthalmoscopy 
Dilated Ophthalmoscopy parameters – Choroid, Eye, Vitreous Chamber, Macula, Optic Nerve and Retina 
, will be graded as normal, abnormal not clinically significant (NCS), and abnormal clinically significant (CS). 
These results will be summarized by treatment group at Visits 1 and 3 on the Safety Population. A subject 
listing of dilated ophthalmoscopy results will also be produced. 
15. Tolerability Analysis  
15.1 
Drop Comfort Assessment  
At Visit 1, drop comfort will be assessed, on a 0-10 scale where 0 is very comfortable and 10 is very 
uncomfortable, upon instillation, at 30 seconds post instillation, and 1 minute post instillation for both eyes. 
Drop comfort assessment scores will be summarized with continuous descriptive statistics at Visit 1 by 
treatment group. The scores will be averaged over both eyes and summarized.  
A subject listing of drop comfort assessment results will also be produced. 


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15.2 
Drop Comfort Questionnaire  
At Visit 1, 3 minutes post-instillation, the subject will be asked three questions assessing drop comfort using 
the response words Burning, Comfortable, Cool, Filmy, Gentle, Gritty, Irritating, Refreshing, Smooth, 
Soothing, Sticky, and Stinging. Subjects can also provide their own word response with an “Other” category. 
The counts and percentage of subjects in each of these response word categories will be summarized by 
treatment group. The results of those questions also will be presented in  the same listing as for drop 
comfort assessment.  
16. Changes from Protocol-Stated Analyses 
The following changes from the protocol are noted 
x 
Change in the definition of the ITT population. The definition in the protocol includes subjects who 
received at least one dose of study drug. This has been modified to include all randomized subjects.  
x 
The intercurrent event of use of prohibited medications is not mentioned in the protocol. The SAP 
includes analysis methods for handling this intercurrent event. 
x 
Additional sensitivity analyses not mentioned in the protocol have been added.  
x 
The protocol mentions that missing primary endpoint data at any time point of Visit 1 will be 
removed from the primary per-protocol population. however, the primary estimand imputations will 
handle these missing values.  
x 
The protocol states that Ocular TEAEs will be summarized by relationship to study drug. Instead, 
treatment-related ocular TEAEs will be summarized.  
x 
The non-inferiority limit for the secondary endpoint of redness diary has been updated to from 1 to 
0.19.   
17. References 
BL908 Study Protocol Version 2.0 Dated 27OCT2021 
18.  Revision History 
Documentation of revision to the SAP will commence after approval of the final version 1.0. 
19. Tables 
Tables that will be included in the topline delivery are shown in boldface font.  
Table Number 
Title  
Population 
Table 14.1.1.1 
Subject Disposition  
All Screened 
Subjects  
Table 14.1.2 
Major Protocol Deviations  
Intent-to-Treat 
Population 
Table 14.1.3.1 
Demographics  
Intent-to-Treat 
Population 
Table 14.1.3.2 
Demographics  
Safety Population 


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Table 14.1.4.1 
Ocular Medical History  
Intent-to-Treat 
Population 
Table 14.1.4.2 
Non-Ocular Medical History   
Intent-to-Treat 
Population 
Table 14.1.5.1 
Ocular Concomitant Medications  
Intent-to-Treat 
Population 
Table 14.1.5.2 
Non-Ocular Concomitant Medications  
Intent-to-Treat 
Population 
Table 14.1.5.3 
Treatment Compliance  
Safety Population 
Table 14.1.5.4 
Treatment Exposure to Study Drug  
Safety Population 
Table 14.2.1.1 
Ocular Redness at Visit 1 - Multiple Imputations with 
Primary Estimand  
Intent-to-Treat 
Population 
Table 14.2.1.2 
Ocular Redness at Visit 1 - Observed Data Only  
Intent-to-Treat 
Population 
Table 14.2.1.3 
Ocular Redness at Visit 1 - WOCF Imputation  
Intent-to-Treat 
Population 
Table 14.2.1.4 
Ocular Redness at Visit 1 - WBOCF Imputation  
Intent-to-Treat 
Population 
Table 14.2.1.5 
Ocular Redness at Visit 1 - Observed Data Only  
Primary Per-Protocol 
Population 
Table 14.2.1.6 
Ocular Redness at Visit 1 - Multiple Imputations with 
Primary Estimand  
Primary Per-Protocol 
Population 
Table 14.2.1.7 
Ocular Redness at Visit 1 - Multiple Imputations with MAR 
Assumption  
Intent-to-Treat 
Population 
Table 14.2.1.8 
Ocular Redness at Visit 1 – Tipping Point Analysis  
Intent-to-Treat 
Population 
Table 14.2.2.1.1 
Ocular Redness at Secondary Time Points  –  Multiple 
Imputations with Primary Estimand    
Intent-to-Treat 
Population 
Table 14.2.2.1.2 
Ocular Redness at Secondary Time Points –  Multiple 
Imputations with Primary Estimand    
Secondary Per-
Protocol Population 
Table 14.2.2.1.3 
Ocular Redness at Secondary Time Points – Observed 
Data Only 
Intent-to-Treat 
Population 
Table 14.2.2.1.4 
Ocular Redness at Secondary Time Points - Observed 
Data Only 
Secondary Per-
Protocol Population 
Table 14.2.2.2.1 
Ocular Redness Diary Grading - MMRM Analysis 
Intent-to-Treat 
Population 
Table 14.2.2.2.2 
Ocular Redness Diary Grading - MMRM Analysis 
Secondary Per-
Protocol Population 
Table 14.2.2.3.1 
Ocular Redness by Visit - Observed Data Only 
Intent-to-Treat 
Population 
Table 14.2.2.3.2 
Ocular Redness by Visit and Age - Observed Data Only  
Intent-to-Treat 
Population 
Table 14.2.2.3.3 
Ocular Redness by Visit and Sex - Observed Data Only 
Intent-to-Treat 
Population 
Table 14.2.2.3.4 
Ocular Redness by Visit and Race - Observed Data Only 
Intent-to-Treat 
Population 
Table 14.2.2.3.5 
Ocular Redness by Visit and Ethnicity - Observed Data 
Only 
Intent-to-Treat 
Population 


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Table 14.2.2.3.6 
Ocular Redness by Visit and Iris Color - Observed Data 
Only 
Intent-to-Treat 
Population 
Table 14.2.2.3.7 
Ocular Redness by Visit and Site - Observed Data Only 
Intent-to-Treat 
Population 
Table 14.2.2.4.1 
Ocular Redness Diary Grading – Observed Data Only  
Intent-to-Treat 
Population 
Table 14.2.2.4.2 
Ocular Redness Diary Grading by Age – Observed Data 
Only 
Intent-to-Treat 
Population 
Table 14.2.2.4.3 
Ocular Redness Diary Grading by Sex – Observed Data 
Only  
Intent-to-Treat 
Population 
Table 14.2.2.4.4 
Ocular Redness Diary Grading by Race – Observed Data 
Only  
Intent-to-Treat 
Population 
Table 14.2.2.4.5 
Ocular Redness Diary Grading by Ethnicity – Observed 
Data Only 
Intent-to-Treat 
Population 
Table 14.2.2.4.6 
Ocular Redness Diary Grading by Iris Color – Observed 
Data Only  
Intent-to-Treat 
Population 
Table 14.2.2.5.1 
Total Clearance of Ocular Redness by Time Point and 
Visit  
Intent-to-Treat 
Population 
Table 14.2.2.5.2 
Total Clearance of Ocular Redness by Time Point and 
Visit and Age  
Intent-to-Treat 
Population 
Table 14.2.2.5.3 
Total Clearance of Ocular Redness by Time Point and 
Visit and Sex 
Intent-to-Treat 
Population 
Table 14.2.2.5.4 
Total Clearance of Ocular Redness by Time Point and 
Visit and Race 
Intent-to-Treat 
Population 
Table 14.2.2.5.5 
Total Clearance of Ocular Redness by Time Point and 
Visit and Ethnicity 
Intent-to-Treat 
Population 
Table 14.2.2.5.6 
Total Clearance of Ocular Redness by Time Point and 
Visit and Iris Color 
Intent-to-Treat 
Population 
Table 14.3.1.1.1 
Overall Summary of Treatment-Emergent Adverse 
Events  
Safety Population 
Table 14.3.1.1.2 
Overall Summary of Treatment-Emergent Adverse Events 
by Age 
Safety Population 
Table 14.3.1.1.3 
Overall Summary of Treatment-Emergent Adverse Events 
by Sex 
Safety Population 
Table 14.3.1.1.4 
Overall Summary of Treatment-Emergent Adverse Events 
by Race 
Safety Population 
Table 14.3.1.1.5 
Overall Summary of Treatment-Emergent Adverse Events 
by Ethnicity 
Safety Population 
Table 14.3.1.1.6 
Overall Summary of Treatment-Emergent Adverse Events 
by Iris Pigmentation 
Safety Population 
Table 14.3.1.2.1 
Ocular Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term  
Safety Population 
Table 14.3.1.2.2 
Ocular Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term by Age 
Safety Population 
Table 14.3.1.2.3 
Ocular Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term by Sex 
Safety Population 


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Table 14.3.1.2.4 
Ocular Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term by Race 
Safety Population 
Table 14.3.1.2.5 
Ocular Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term by Ethinicity 
Safety Population 
Table 14.3.1.2.6 
Ocular Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term by Iris Pigmentation 
Safety Population 
Table 14.3.1.2.7 
Ocular Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term in at Least 1% of 
Subjects 
Safety Population 
Table 14.3.1.2.8 
Ocular Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term in at Least 2% of 
Subjects 
Safety Population 
Table 14.3.1.2.9 
Ocular Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term in at Least 3% of 
Subjects 
Safety Population 
Table 
14.3.1.2.10 
Ocular Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term in at Least 4% of 
Subjects 
Safety Population 
Table 
14.3.1.2.11 
Ocular Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term in at Least 5% of 
Subjects 
Safety Population 
Table 14.3.1.3 
Non-Ocular Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term  
Safety Population 
Table 14.3.1.4 
Treatment-Related Ocular Treatment-Emergent Adverse 
Events by System Organ Class and Preferred Term  
Safety Population 
Table 14.3.1.5 
Treatment-Related Non-Ocular Treatment-Emergent 
Adverse Events by System Organ Class and Preferred 
Term  
Safety Population 
Table 14.3.1.6 
Ocular Treatment-Emergent Serious Adverse Events by 
System Organ Class and Preferred Term  
Safety Population 
Table 14.3.1.7 
Non-Ocular Treatment-Emergent Serious Adverse Events 
by System Organ Class and Preferred Term  
Safety Population 
Table 14.3.1.8 
Ocular Treatment-Emergent Adverse Events by System 
Organ Class, Preferred Term, and Maximum Severity  
Safety Population 
Table 14.3.1.9 
Non-Ocular Treatment-Emergent Adverse Events by 
System Organ Class, Preferred Term, and Maximum 
Severity  
Safety Population 


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Table 14.3.2.1 
Best Corrected Visual Acuity (logMAR)  
Safety Population 
Table 14.3.2.2.1 
Slit Lamp Biomicroscopy - Qualitative Summary 
Safety Population 
Table 14.3.2.2.2 
Slit Lamp Biomicroscopy  - Quantitative Summary 
Safety Population 
Table 14.3.2.3 
Intraocular Pressure (mmHg)  
Safety Population 
Table 14.3.2.4 
Ocular Rebound   
Safety Population 
Table 14.3.2.6 
Physical Examination  
Safety Population 
Table 14.3.2.7 
Vital Signs  
Safety Population 
Table 14.3.3.1 
Drop Comfort Assessment  
Safety Population 
Table 14.3.3.2 
Drop Comfort Questionnaire  
Safety Population 
Table 14.3.4 
Dilated Ophthalmoscopy 
Safety Population 
20. Listings 
Listing Number 
Listing Name  
Population 
Listing 16.1.7  
Randomization Schedule 
All Randomized Subjects 
Listing 16.2.1  
Subject Disposition  
All Randomized Subjects 
Listing 16.2.2 
Protocol Deviations 
All Randomized Subjects 
Listing 16.2.3.1 
Analysis Populations  
All Randomized Subjects 
Listing 16.2.3.2 
Inclusion Exclusion Criteria 
All Randomized Subjects 
Listing 16.2.4.1 
Demographics  
All Randomized Subjects 
Listing 16.2.4.2 
Ocular Medical History  
All Randomized Subjects 
Listing 16.2.4.4 
Prior and Concomitant Medications  
All Randomized Subjects 
Listing 16.2.4.5 
Concomitant Procedures  
All Randomized Subjects 
Listing 16.2.5.1 
Study Drug Instillation - Diary  
All Randomized Subjects 
Listing 16.2.5.2 
In-Office Study Drug Instillation  
All Randomized Subjects 
Listing 16.2.5.3 
Study Drug Assignment 
All Randomized Subjects 
Listing 16.2.5.4 
Returned Study Kits 
All Randomized Subjects 


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Listing 16.2.6.1 
Ocular Redness In-Office Assessment  
All Randomized Subjects 
Listing 16.2.6.2.1 
Ocular Redness Diary Assessment  
All Randomized Subjects 
Listing 16.2.6.2.2 
Ocular Redness Diary Assessment - Daily 
Averages 
All Randomized Subjects 
Listing 16.2.7.1 
All Adverse Events  
All Randomized Subjects 
Listing 16.2.7.2 
Serious Adverse Events  
All Randomized Subjects 
Listing 16.2.7.3 
Adverse Events Leading to Study Drug 
Discontinuation  
All Randomized Subjects 
Listing 16.2.8.1 
Best Corrected Visual Acuity  
All Randomized Subjects 
Listing 16.2.8.2 
Slit Lamp Biomicroscopy  
All Randomized Subjects 
Listing 16.2.8.3 
Intraocular Pressure (mmHg)  
All Randomized Subjects 
Listing 16.2.8.4 
Dilated Ophthalmoscopy  
All Randomized Subjects 
Listing 16.2.8.5 
Physical Examination  
All Randomized Subjects 
Listing 16.2.8.6 
Vital Signs  
All Randomized Subjects 
Listing 16.2.8.7 
Urine Pregnancy Test Results - Female 
Subjects Only  
All Randomized Subjects 
Listing 16.2.9  
In-Office Study Drug Instillation Comfort 
Score and Questionnaire  
All Randomized Subjects 
 
 
Listing Number 
Title 
Population 
Listing 16.1.7  
Randomization Schedule 
All Randomized Subjects 
Listing 16.2.1  
Subject Disposition 
 


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Listing 16.2.3.1 
Analysis Populations 
All Randomized Subjects 
Listing 16.2.3.2 
Inclusion Exclusion Criteria 
All Randomized Subjects 
Listing 16.2.4.1 
Demographics  
All Randomized Subjects 
Listing 16.2.4.2 
Ocular Medical History  
All Randomized Subjects 
Listing 16.2.4.4 
Prior and Concomitant Medications  
All Randomized Subjects 
Listing 16.2.4.5 
Concomitant Procedures  
All Randomized Subjects 
Listing 16.2.5.1 
Study Drug Instillation - Diary  
All Randomized Subjects 
Listing 16.2.5.2 
In-Office Study Drug Instillation  
All Randomized Subjects 
Listing 16.2.6.1 
Ocular Redness In-Office Assessment  
All Randomized Subjects 
Listing 16.2.6.2 
Ocular Redness Diary Assessment  
All Randomized Subjects 
Listing 16.2.7.1 
All Adverse Events  
All Randomized Subjects 
Listing 16.2.7.2 
Serious Adverse Events  
All Randomized Subjects 
Listing 16.2.7.3 
Adverse Events Leading to Study Drug Discontinuation  
All Randomized Subjects 
Listing 16.2.8.1 
Best Corrected Visual Acuity  
All Randomized Subjects 
Listing 16.2.8.2 
Slit Lamp Biomicroscopy  
All Randomized Subjects 
Listing 16.2.8.3 
Intraocular Pressure (mmHg)  
All Randomized Subjects 
Listing 16.2.8.4 
Dilated Ophthalmoscopy  
All Randomized Subjects 
Listing 16.2.8.5 
Physical Examination  
All Randomized Subjects 
Listing 16.2.8.6 
Vital Signs  
All Randomized Subjects 
Listing 16.2.8.7 
Urine Pregnancy Test Results - Female Subjects Only  
All Randomized Subjects 


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Listing 16.2.9  
In-Office Study Drug Instillation Comfort Score and 
Questionnaire  
All Randomized Subjects