Clinical trial NCT05591755
Conditions: Seasonal Allergic Conjunctivitis
Sponsor: Bausch & Lomb Incorporated
Start date: 2022-11-18; Completion date: 2023-08-09
Enrollment: 229 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the efficacy of Combo compared to its individual components and compared to vehicle in a population of subjects with seasonal allergic conjunctivitis.

Detailed description:

Arms: arm 1: Brimonidine Tartrate 0.025%/ Ketotifen Fumarate 0.035% Ophthalmic Solution arm 2: Ketotifen fumarate ophthalmic solution 0.035% arm 3: Brimonidine tartrate ophthalmic solution 0.025% arm 4: Vehicle ophthalmic solution
Interventions: intervention 1: Brimonidine Tartrate 0.025%/ Ketotifen Fumarate 0.035% Ophthalmic Solution intervention 2: Ketotifen fumarate ophthalmic solution 0.035% intervention 3: Brimonidine tartrate ophthalmic solution 0.025% intervention 4: Experimental: Vehicle ophthalmic solution
Intervention descriptions: intervention 1: Brimonidine Tartrate 0.025%/ Ketotifen Fumarate 0.035% Ophthalmic Solution intervention 2: Ketotifen fumarate ophthalmic solution 0.035% intervention 3: Brimonidine tartrate ophthalmic solution 0.025% intervention 4: Experimental: Vehicle ophthalmic solution

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol: 910 
Protocol Title: 
A Multi-Center, Double-Masked, Randomized, 
Parallel-Group, Vehicle-Controlled Evaluation of 
the Onset and Duration of Action of the 
Combination Drug Product Brimonidine Tartrate 
0.025%/ Ketotifen Fumarate 0.035% Ophthalmic 
Solution Compared to its Components and Vehicle 
in an Allergen BioCube® (ABC®) Clinical Trial in 
Subjects with Seasonal Allergic Conjunctivitis 
Protocol Number: 
910 
Study Phase: 
3 
Investigational Product 
Name: 
Brimonidine Tartrate 0.025%/ Ketotifen Fumarate 
0.035% Ophthalmic Solution (Combo) 
IND Number: 
153035 
Indication: 
Seasonal Allergic Conjunctivitis 
Investigators: 
Multi-Center 
8 sites 
Sponsor: 
Bausch & Lomb, Incorporated 
400 Somerset Corporate Boulevard 
Bridgewater, NJ 08807 
Contract Research 
Organization: 
Ora, Inc. 
300 Brickstone Square, Third Floor 
Andover, MA 01810 
IRB/IEC: 
Alpha IRB 
1001 Avenida Pico, Suite C, #497 
San Clemente, CA 92673 
Confidentiality Statement 
This protocol contains confidential, proprietary information of Ora, Inc. and/or Bausch & 
Lomb Incorporated. Further dissemination, distribution or copying of this protocol or its 
contents is strictly prohibited. 
Date 
Original Protocol: 
30 June 2022 
Amendment 1: 
10 January 2023 
Amendment 2: 
31 Jul 2023 
NCT 05591755




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Clinical Trial Protocol: 910 
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SYNOPSIS 
Protocol Title: 
A Multi-Center, Double-Masked, Randomized, 
Parallel-Group, Vehicle-Controlled Evaluation 
of the Onset and Duration of Action of the 
Combination Drug Product Brimonidine 
Tartrate 0.025%/ Ketotifen Fumarate 0.035% 
Ophthalmic Solution Compared to its 
Components and Vehicle in an Allergen 
BioCube® (ABC®) Clinical Trial in Subjects 
with Seasonal Allergic Conjunctivitis 
Protocol Number: 
910 
Investigational Product: 
Brimonidine Tartrate 0.025%/ Ketotifen 
Fumarate 0.035% Ophthalmic Solution 
(Combo) 
Study Phase: 
3 
Primary Objective(s): 
To evaluate the efficacy of Combo compared 
to its individual components and compared to 
vehicle in a population of subjects with 
seasonal allergic conjunctivitis. 
Secondary Objective(s): 
Not Applicable. 
Overall Study Design: 
Structure: 
The study will consist of 2 visits: a screening 
visit to verify subjects are eligible to participate 
and a qualification/treatment visit to evaluate 
the onset of action and potential for an 8 hour 
duration of effectiveness for the brimonidine 
tartrate/ ketotifen fumarate combo drug product 
compared to its individual components and 
vehicle. 
Screening Period: At Visit 1, subjects will sign 
the informed consent form (ICF) and an allergic 
skin test will be performed, if required. At Visit 
2, subjects will undergo 90 minutes of exposure 
to pollen1 in the ABC®. Subjects who have a 
sufficient ocular allergy score (defined as a 
 
1 Exposure will be to an allergen that elicited a positive reaction via skin testing. 


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bilateral score of ≥2 in both ocular itching and 
ocular redness) at the 90 minute time point will 
be randomized 1:1:1:1 to receive one of the 
following bilaterally at Visit 2:  
 Brimonidine tartrate 0.025%/ Ketotifen 
Fumarate 0.035% combination 
ophthalmic solution (Combo)  
 Ketotifen fumarate ophthalmic 
solution, 0.035%  
 Brimonidine tartrate ophthalmic 
solution, 0.025%  
 Vehicle ophthalmic solution 
 
Treatment Period: Treatment will begin at 
Visit 2 following the 90 minute time point. 
Following instillation of investigational 
product, randomized subjects will remain 
exposed to pollen in the ABC® for an 
additional 8 hours. Assessments will be 
conducted at the designated time points. 
If subjects do not have a sufficient ocular 
allergy score at the 90 minute time point and 
also have a positive skin test reaction to both 
ragweed and timothy grass, they may be re-
screened for Visit 2 using the alternate pollen. 
In the event that subjects do not receive a full 
90 minutes of pollen exposure (e.g. early exit 
from BioCube, mechanical issue with pollen 
distribution, etc.), subjects may also be eligible 
for re-screening. Re-screening should take 
place at least one week following the initial 
Visit 2 and should be within the specified 
study visit windows.   
Duration: 
This trial consists of 2 office visits over a 
period of approximately 2 to 61 days. 
Controls: 
 Ketotifen fumarate ophthalmic 
solution, 0.035%  
 Brimonidine tartrate ophthalmic 
solution, 0.025%  


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 Vehicle ophthalmic solution
Dosage/ Instillation: 
At Visit 2, a trained study technician will 
instill 1 drop of the assigned investigational 
product into each eye. 
Summary of Visit 
Schedule: 
Visit 1 (Day -60 to Day -1): Screening / 
Informed Consent / Skin Test 
Visit 2 (Day 1): ABC® Qualification Exposure/ 
Randomization/ Treatment / ABC® 8hr 
Exposure/ Exit  
Measures Taken to Reduce 
Bias: 
Randomization will be used to avoid bias in 
the assignment of subjects to investigational 
product, to increase the likelihood that known 
and unknown subject attributes (e.g., 
demographics and baseline characteristics) are 
evenly balanced across treatment groups, and 
to enhance the validity of statistical 
comparisons across treatment groups. Finally, 
masked treatment will be used to reduce 
potential of bias during data collection and 
evaluation of clinical endpoints. 
Study Population Characteristics: 
Number of Subjects: 
Approximately 360 subjects will be screened 
in order to enroll approximately 224 subjects, 
56 subjects per treatment group 
Condition/Disease: 
Seasonal Allergic Conjunctivitis. 
Inclusion Criteria: 
Subjects must:  
 
1. be at least 18 years of age of either sex 
and any race; 
2. provide written informed consent and 
sign the Health Information Portability 
and Accountability Act (HIPAA) form; 
3. be willing and able to follow all 
instructions and attend all study visits; 
4. provide proof of COVID-19 
vaccination2; 
 
2 Visit 2 should occur at least two weeks after full vaccination.  


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5. be able and willing to discontinue 
wearing contact lenses for at least 72 
hours prior to Visit 2 and for the 
duration of the visit; 
6. have seasonal allergic conjunctivitis to 
ragweed or timothy grass documented 
by a self-reported history of ocular 
allergic symptoms for the last 2 
consecutive years during the ragweed 
or timothy grass seasons and a positive 
skin test reaction to ragweed or timothy 
grass pollen as confirmed by the 
allergic skin test given at or within 24 
months of the subject’s Visit 1; 
7. (If female and of childbearing 
potential) agree to have urine 
pregnancy testing performed at Visit 2 
(must be negative); must not be 
lactating; and must agree to use at least 
1 medically acceptable form of birth 
control throughout the study duration, 
for at least 14 days prior to and 1 
month after receiving investigational 
drug. 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 
receiving investigational drug (Visit 2). 
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);  
8. (If male and with female partner of 
childbearing potential) must use at least 


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1 medically acceptable form of birth 
control. Note: 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 
receiving investigational drug (Visit 2). 
Without a vasectomy, must use 
condoms with spermicidal 
foam/gel/film/cream/suppository 
throughout the study duration, for at 
least 14 days prior to and 1 month after 
investigational drug (Visit 2); 
9. have a calculated visual acuity (VA) of 
0.7 logMAR or better in each eye as 
measured using an Early Treatment 
Diabetic Retinopathy Study (ETDRS) 
chart at Visit 1;   
10. have a positive Allergen BioCube 
challenge response to pollen exposure 
at the 90 minute time point of ABC® 
exposure at Visit 2, defined as bilateral 
score of >2 in ocular itching and ocular 
redness.
Exclusion Criteria: 
Subjects may not: 
 
1. have known contraindications or 
sensitivities to the use of any of the 
investigational product medication or 
components;  
2. have a history of mild persistent, 
moderate or severe asthma within the 
preceding 5 years according to the 
National Heart, Blood, and Lung 
Institute classification (with the 
exception of exercise induced asthma).  
Note: Subjects with fall induced 
asthma that is either mild persistent 
(defined as >1 per week, but <1 per 
day), moderate persistent, or severe 
persistent will be excluded. 
3. have an upper respiratory tract or sinus 
infection within the previous 2 weeks 
of Visit 1; 


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4. have a history of anaphylaxis or poor 
tolerability of previously administered 
allergen; 
5. have a compromised lung function at 
Visit 1 (defined as a peak expiratory 
flow rate [PEFR] that is below 80% of 
the predicted average PEFR, as 
calculated by gender, age, and 
measured height from the Mini-Wright 
instruction’s table: Normal Adult 
Predicted Average Peak Expiratory 
Flow).  
6. have an abnormal blood pressure 
(defined as ≤ 90 or ≥ 160 (systolic) 
measured in mmHg or ≤ 60 or ≥ 100 
(diastolic) measured in mmHg) at Visit 
1; 
7. have any ocular condition that, in the 
opinion of the investigator, could affect 
the subject’s safety or trial parameters 
(including but not limited to narrow 
angle glaucoma, clinically significant 
blepharitis, follicular conjunctivitis, 
iritis, pterygium, or a diagnosis of dry 
eye); 
8. have had ocular surgical intervention 
within three months prior to Visit 1, or 
during the trial or a history of refractive 
surgery six months prior to Visit 1, or 
have systemic surgery planned during 
the clinical trial or within 30 days after; 
9. have a known history of retinal 
detachment, diabetic retinopathy, or 
active retinal disease; 
10. have an active ocular infection 
(bacterial, viral or fungal), active 
uveitis, or positive history of an ocular 
herpetic infection at any visit; 
11. use any of the following disallowed 
medications during the period indicated 
below prior to Visit 2:   
3 Days 
 systemic or ocular H1 
antihistamine, H1 
antihistamine/mast-cell stabilizer 


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drug combinations, H1 
antihistamine- vasoconstrictor drug 
combinations; 
7 Days 
 decongestants; 
 monoamine oxidase inhibitors; 
 all other topical ophthalmic 
preparations (including artificial 
tears); 
 lid scrubs; 
 prostaglandins or prostaglandin 
derivatives; 
 ocular, topical, or systemic 
nonsteroidal anti-inflammatory 
drugs (NSAIDs); 
*Baby aspirin (81 mg) is allowed as 
long as a stable dose has been 
maintained for at least 30 days prior to 
Visit 2 and will continue to be 
maintained for the duration of the trial. 
14 Days 
 inhaled, ocular, topical, or systemic 
corticosteroids or mast cell 
stabilizers;  
45 Days 
 depot-corticosteroids; 
60 Days 
 immunosuppressive or cancer 
chemotherapeutic agents; 
12. have any significant illness (including, 
but not limited to, poorly controlled 
hypertension, poorly controlled 
diabetes, a history of status 
asthmaticus, a history of organ 
transplantation, a history of persistent 
moderate or severe asthma, a history of 
moderate to severe allergic asthmatic 
reactions to any of the clinical trial 
allergens, any autoimmune disease 
requiring therapy, or severe 
cardiovascular disease or arrhythmia) 
that, at the investigators’ discretion, 
could be expected to interfere with the 
subject’s health or with the clinical trial 


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parameters or put the subject at any 
unnecessary risk; 
13. have a history of glaucoma, ocular 
hypertension or an intraocular pressure 
(IOP) that is less than 5 mmHg or 
greater than 22 mmHg in either eye at 
Visit 1;  
14. develop a compromised lung function 
(defined as a PEFR drop of 15% or 
more from Visit 1 baseline value) at 
Visit 23; 
15. have used an investigational drug or 
medical device within 30 days of Visit 
1 or be concurrently enrolled in another 
investigational trial; 
16. be a female who is currently pregnant, 
planning a pregnancy, or lactating; 
17. 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; 
18. have been randomized in the Bausch & 
Lomb 909 study.
Study Formulations and 
Formulation Numbers: 
Test Article:   Brimonidine tartrate 0.025%/ 
ketotifen fumarate 0.035% combination 
ophthalmic solution (Combo), 
 
 
  
 
    
Active Control #1:  Ketotifen fumarate 
0.035% ophthalmic solution, containing 
benzalkonium chloride, glycerin, mannitol, 
povidone, and water for injection. 
Hydrochloric acid and/or sodium hydroxide 
may be used to adjust pH. 
Active Control #2:   Brimonidine tartrate 
0.025% ophthalmic solution containing 
benzalkonium chloride, glycerin, mannitol, 
povidone, and water for injection.  
 
3 If occurs at more than one assessment, per the investigator’s discretion. 


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Hydrochloric acid and/or sodium hydroxide 
may be used to adjust pH.  
Vehicle Control:  Vehicle ophthalmic 
solution, containing benzalkonium chloride, 
glycerin, mannitol, povidone, and water for 
injection.  Hydrochloric acid and/or sodium 
hydroxide may be used to adjust pH.    
Evaluation Criteria: 
 
Efficacy Measures and 
Endpoints: 
Primary Effectiveness Parameters 
 Ocular itching score (average score of 
the subject’s two eyes) evaluated by the 
subject at 10(±1), 30(±1), 60(±5), 
360(±5), 420(±5), and 480(±5) minutes 
post-instillation of assigned IP at Visit 
2 
 
 
 Ocular redness (average score of the 
subject’s two eyes) evaluated by the 
Investigator using slit lamp at 10(±1), 
30(±1), 60(±5), 360(±5), 420(±5), and 
480(±5) minutes post-instillation of 
assigned IP at Visit 2 
 
 
 
Secondary Effectiveness Parameters 
 Tearing evaluated by the subject 
(average score of the subject’s two 
eyes) at 10(±1), 30(±1), 60(±5), 
360(±5), 420(±5), and 480(±5) minutes 
post-instillation of assigned IP at Visit 
2 
 
 
 Lid swelling (average score of the 
subject’s two eyes) evaluated by the 
subject at 10(±1), 30(±1), 60(±5), 
360(±5), 420(±5), and 480(±5) minutes 
post-instillation of assigned IP at Visit 
2 
 
 
 Chemosis (average score of the 
subject’s two eyes) evaluated by the 
Investigator using slit lamp at 10(±1),




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 Slit Lamp Biomicroscopy 
 Intraocular Pressure (IOP) 
 Dilated Fundoscopy 
 Vital signs 
 Peak Expiratory Flow Rate (PEFR)
General Statistical Methods and Types of Analyses 
Continuous variables will be summarized using the mean, standard deviation, median, 
minimum, and maximum. Categorical variables will be summarized using frequencies 
and percentages. 
 
Unit of Analysis 
 
The primary efficacy parameters are measured at the subject level and will be 
summarized as such.   
 
Analysis Populations 
 
Intent to Treat (ITT) Set: The ITT set will consist of all randomized subjects who are 
instilled with study drug.  The ITT population will be analyzed as randomized. 
 
Full Analysis Set (FAS): The FAS will consist of all randomized subjects who are 
instilled with study drug and have at least one post-instillation of IP assessment of 
both primary endpoints.  The FAS population will be analyzed as randomized. 
 
Per Protocol Set (PP Set): The PP Set will consist of FAS subjects with no protocol 
violations considered to affect the evaluability of efficacy, as determined through 
masked review of deviations prior to unmasking.  The PP population will be analyzed 
as treated. 
 
Safety Set: The Safety Set will include all subjects who receive any amount of study 
medication.  The safety population will be analyzed as treated. 
 
Safety Analysis 
 
The number and percentage of subjects with specific treatment-emergent adverse events 
(AEs) will be summarized for each treatment group. The number of subjects will be 
tabulated by MedDRA System Organ Class and preferred term within each system 
organ class. Visual acuity, biomicroscopy findings, IOP, and dilated fundoscopy, vital 
signs, and peak expiratory flow rate will be summarized descriptively.   
  
Primary Effectiveness Analyses 
 
Statistical success will be achieved if all of the following conditions are met at Visit 2. 
 
1. 
The Combo is superior in ocular itching to Vehicle. 
2.
The Combo is superior in ocular redness to Vehicle.


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3. 
The Combo is superior in ocular itching to brimonidine tartrate 
ophthalmic solution, 0.025%. 
4. 
The Combo is superior in ocular redness to ketotifen fumarate 
ophthalmic solution, 0.035%. 
 
Superiority will be demonstrated for comparisons above if the treatment effect is 
statistically significant in accordance with the below.  
Hypothesis testing will be split into two groups. Hypotheses associated with the first 
three time points will constitute the first group and hypotheses associated with the latter 
three time points  will constitute the second group.  
Testing of the first three time points will be performed first. If the treatment effect is 
not statistically significant (one-sided α = 0.0083=0.025/3 to account for the three 
timepoints) at any of the three time points, then the condition is not met.  
If the treatment effect is statistically significant for at least one of the first three 
timepoints, then the second group of hypotheses is tested.  
If the treatment effect was statistically significant for exactly one of the three 
comparisons in the first group, this leaves 0.0083 alpha unused and all three treatment 
effects in the second group of hypotheses must be statistically significant at the unused 
one-sided alpha=0.0083/3=0.0028 in order for this condition to be met.  
If the treatment effect was statistically significant for exactly two of the three 
comparisons in the first group, this leaves 0.0167 alpha unused and at least two 
treatment effects in the second group of hypotheses must be statistically significant at 
the unused one-sided alpha=0.01673=0.0056 in order for this condition to be met.  
If the treatment effect was statistically significant for all three comparisons in the first 
group, this leaves 0.025 alpha unused, and at least one treatment effect in the second 
group of hypotheses must be statistically significant at the unused one-sided 
alpha=0.025/3=0.0083 in order for this condition to be met.  
 
 
 
Hypotheses 
 
For each primary endpoint (ocular itching and ocular redness) at each of the six 
evaluation time points post-instillation of IP, superiority hypotheses will be tested 
comparing the Combo to a comparator ketotifen fumarate 0.035% (for ocular redness), 
brimonidine tartrate 0.025% (for ocular itching), or Vehicle (for ocular redness and 
ocular itching)]. The null hypothesis (𝐻଴) is that the mean score for the subjects in the 
Combo group (𝜇்) is greater than or equal to the mean score for the subjects in the 
comparator group (𝜇஼). The alternative hypothesis (𝐻ଵ) is that the mean score for the 
subjects in the test group is less than the mean score for the subjects in the control group. 
 
𝐻଴: 𝜇்≥𝜇஼ 
𝐻ଵ: 𝜇்< 𝜇஼ 
 
 
Methods


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Each primary endpoint will be summarized by post-instillation of IP time point at Visit 
2 by treatment group using continuous summary statistics and analyzed using an 
ANCOVA model with terms for baseline value and treatment for the ITT population. 
Missing data will be imputed using multiple imputation methods. Least square means 
for each treatment group and for the difference between treatment groups will be 
presented from the model together with two-sided p-values and 95% confidence 
intervals..  
 
Secondary summaries of the primary endpoints by post-instillation of IP time point at 
Visit 2 will be given for the difference in mean ocular itching between the Combo and 
ketotifen fumarate 0.035% and between ketotifen fumarate 0.035% and vehicle as well 
as for the difference in mean ocular redness between the Combo and brimonidine 
tartrate 0.025% and between brimonidine tartrate 0.025% and vehicle. Missing data will 
be imputed using multiple imputation techniques. Continuous summary statistics 
including two-sided 95% t-distribution confidence intervals around the difference in 
means will be provided. 
 
Sample Size Calculations:  
 
A sample size of 50 subjects in each treatment group yields 95% power to demonstrate 
each of the following: 
 
Combo is superior to vehicle in ocular itching (evaluated by the subject)  
 
Combo is superior to vehicle in ocular redness (evaluated by the Investigator) 
 
Combo is superior to brimonidine tartrate ophthalmic solution, 0.025% in 
ocular itching (evaluated by the subject)  
 
Combo is superior to ketotifen fumarate ophthalmic solution, 0.035% in ocular 
redness (evaluated by the Investigator) 
 
 assuming a one-sided α = 0.0028, a true mean difference of 0.65 units and a common 
standard deviation of 1.0 units at each time point for each measure.  
To allow for 10% dropouts, 56 subjects will be randomized in each of the treatment 
groups. 
Summary of Known and Potential Risks and Benefits to Human Subjects 
Refer to Investigator’s Brochure (IB). 


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TABLE OF CONTENTS  
TABLE OF CONTENTS…………………………………………………………..16 
LIST OF ABBREVIATIONS ............................................................................................19 
1 
INTRODUCTION ....................................................................................................21 
2 
STUDY OBJECTIVES .............................................................................................22 
3 
CLINICAL HYPOTHESES .....................................................................................22 
4 
OVERALL STUDY DESIGN ..................................................................................22 
5 
STUDY POPULATION ...........................................................................................23 
 
Number of Subjects (approximate)…...………………………………… 23 
 
Study Population Characteristics………………………………………...23 
 
Inclusion Criteria………………………………………………………...23 
 
Exclusion Criteria……....………………………………………………..24 
 
Withdrawal Criteria (if applicable)………………………………………26 
6 
STUDY PARAMETERS ..........................................................................................26 
 
Efficacy Measures and Endpoints………………………………………..26 
6.1.1 
   Primary Efficacy Measure(s) and Endpoints ..................................26 
6.1.2 
   Secondary Efficacy Measure(s) and Endpoints ..............................27 
 
Exploratory Measures……………………………………………………27 
 
Safety Measures………………………………………………………….27 
7 
STUDY MATERIALS .............................................................................................28 
 
Study Treatment(s)……………………………………………………….28 
7.1.1 
Study Treatment(s)/ Formulation(s) .................................................28 
7.1.2 
Instructions for Use and Administration ...........................................28 
 
Other Study Supplies…………………………………………………….28 
8 
STUDY METHODS AND PROCEDURES ............................................................28 
 
Subject Entry Procedures………………………………………………...28 
8.1.1 
Overview ...........................................................................................28 
8.1.2 
Informed Consent..............................................................................28 
8.1.3 
Washout Intervals .............................................................................29 
8.1.4 
Procedures for Final Study Entry ......................................................29 
8.1.5 
Methods for Assignment to Treatment Groups: ...............................29 
 
Concurrent Therapies………………………………………………...…..30 
8.2.1 
Prohibited Medications/Treatments ..................................................30 
8.2.2 
Escape Medications ..........................................................................30 
8.2.3 
Special Diet or Activities ..................................................................30 
 
Examination Procedures…………………………………………………31 
8.3.1 
Procedures to be Performed at Each Study Visit with Regard to 
Study Objective(s) ............................................................................31 
8.3.1.1 
VISIT 1 (Day -45 to Day -1): Screening/ Informed Consent/ Skin Test
 
………………………………………………………………………………31 
8.3.1.1 
VISIT 2 (Day 1): ABC Qualification Exposure/ Randomization/ 
Treatment/ ABC® 8hr Exposure/ Exit ................................................................... 32 
 
Schedule of Visits, Measurements and Dosing…………………………..34 
8.4.1 
Scheduled Visits................................................................................34 


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8.4.2 
Unscheduled Visits ...........................................................................35 
 
Compliance with Protocol………………………………………………..35 
 
Subject Disposition………………………………………………………35 
8.6.1 
Completed Subjects ..........................................................................35 
8.6.2 
Discontinued Subjects .......................................................................35 
 
Study Termination ....……………………………………………………36 
 
Study Duration…………………………………………………………...36 
 
Monitoring and Quality Assurance………………………………………36 
9 
ADVERSE EVENTS ................................................................................................36 
 
Definition of Adverse Event (AE)……………………………………….36 
9.1.1 
Assessment of Severity of Adverse Events ......................................37 
9.1.2 
Assessment of Causality of Adverse Events .....................................38 
 
Serious Adverse Events…………………………………………………38 
9.2.1 
Expedited Serious Adverse Events ...................................................41 
9.2.2 
Pregnancy ..........................................................................................41 
 
General Guidelines for Reporting Adverse Events………………………42 
 
Procedures for Unmasking (if applicable)……………………………….44 
10 
STATISTICAL HYPOTHESES AND METHODS OF ANALYSES .....................44 
 
Assessment of Efficacy…………………………………………………..44 
10.1.1 Primary Efficacy ...............................................................................44 
10.1.2 Secondary Efficacy ...........................................................................46 
10.1.3 Exploratory Endpoints ......................................................................46 
10.1.4 Statistical Hypothesis Testing and Control of Multiplicity ..............47 
10.1.5 General Considerations .....................................................................47 
10.1.6 Missing Efficacy Data Imputations ..................................................48 
10.1.7 Sensitivity Efficacy Analyses ...........................................................48 
10.1.8 Subgroup Analyses ...........................................................................49 
 
Assessment of Safety…………………………………………………….49 
10.2.1 Adverse Events .................................................................................49 
10.2.2 Safety Laboratory Tests ....................................................................50 
10.2.3 Vital Sign Measurements ..................................................................50 
10.2.4 Concomitant Medications .................................................................50 
 
Subject Disposition………………………………………………………50 
 
Demographics and Baseline Characteristics……………………………..50 
 
Protocol Deviations………………………………………………………50 
 
Compliance………………………………………………………………51 
 
Interim Analyses…………………………………………………………51 
 
Additional Statistical Considerations…………………………………….51 
10.8.1 Analysis Populations .........................................................................51 
10.8.2 Sample Size Determination...............................................................51 
10.8.3 Multicenter Issues .............................................................................52 
10.8.4 Multiplicity Issues .............................................................................52 
10.8.5 Windowing Rules..............................................................................52 
11 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES ....................................52 


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Protection of Human Subjects…………………………………………...52 
11.1.1 Subject Informed Consent.................................................................52 
11.1.2 Institutional Review Board (IRB) Approval .....................................53 
 
Ethical Conduct of the Study…………………………………………….53 
 
Subject Confidentiality…………………………………………………..53 
 
Documentation…………………………………………………………...53 
11.4.1 Retention of Documentation .............................................................53 
 
Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Investigational Product…………………………………………………………………..54 
11.5.1 Labeling/Packaging...........................................................................54 
11.5.2 Storage of Investigational Product ....................................................54 
11.5.3 Accountability of Investigational Product ........................................54 
11.5.4 Return or Disposal of Investigational Product ..................................54 
 
Recording of Data on Source Documents and Electronic Case Reports 
Forms (eCRFs)……………………..…………………………………………………….54 
 
Handling of Biological Specimens………………………………………55 
 
Publications………………………………………………………………55 
12 
REFERENCES .........................................................................................................55 
13 
APPENDICES ..........................................................................................................58 
Appendix 1: Schedule of Visits and Measurements ..........................................................58 
Appendix 2: Examination Procedures, Tests, Equipment, and Techniques ......................59 
Appendix 3: Handling of Biological Specimens ...............................................................66 
Appendix 4: Protocol Amendment Summary ....................................................................67 
Appendix 5: Sponsor Approvals ........................................................................................68 
Appendix 6: Ora Approvals ...............................................................................................69 
Appendix 7: Investigator’s Signature ................................................................................70 
 
 
 
 
 


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LIST OF ABBREVIATIONS 
ABC® 
Allergen BioCube® 
AE 
adverse event 
BAK 
benzalkonium chloride 
BCVA 
best-corrected visual acuity 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CRA 
clinical research associate 
CRO 
contract research organization 
DHHS 
Department of Health and Human Services 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EEU 
environmental exposure unit 
EOS 
end of study  
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
investigational new drug application 
IOP 
intraocular pressure 
IP 
investigational product 
IRB 
institutional review board 
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 
NSAID  
nonsteroidal anti-inflammatory drug 
OD 
right eye 
OS 
left eye 
OTC 
over the counter 
PEFR 
peak expiratory flow rate 


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PNIF 
peak nasal inspiratory flow 
PP 
per protocol 
RTSM 
Randomization and Trial Supply Management 
SAC 
seasonal allergic conjunctivitis 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
TEAE 
treatment-emergent adverse event 
TNSS 
total nasal symptom score 
USP 
United States Pharmacopeia 
VA 
visual acuity 
 
 


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1 INTRODUCTION 
Allergic conjunctivitis is a common yet underdiagnosed inflammatory condition of the 
eye that affects the quality of life of patients worldwide (Rosario, 2011; Leonardi, 2015; 
Dupuis, 2020; Alexander, 2005). The prevalence of allergic conjunctivitis has been on 
the rise over the past several decades and it is estimated that up to 40% of the North 
American population is affected (Singh, 2010; Brozek, 2015).  
Acute allergic conjunctivitis represents the majority of all ocular allergy incidences and 
95% can be classified as intermittent/seasonal or persistent/perennial, depending on the 
frequency of symptoms throughout the year which is dictated by the type of 
environmental allergens (O’Brien, 2013; Butrus, 2005; Bielory, 2019). Intermittent or 
seasonal allergic conjunctivitis, also known as hay fever, is caused by outdoor allergens, 
such as tree or grass pollen, and is usually experienced during the warmer months. 
Persistent or perennial allergic conjunctivitis is caused by indoor allergens, like dust 
mites or animal dander, and is experienced year-round. Both types of acute allergic 
conjunctivitis present bilaterally and are characterized by the hallmark ocular symptom of 
pruritus (itching) and sign of redness (Ono, 2005; Palmares, 2010; Villegas, 2021; 
Bielory, 2012). Patients may also experience tearing, discharge, or swelling, and often 
suffer from other comorbidities such as allergic rhinitis and asthma (Rosario, 2011; 
Miyazaki, 2020).  
Acute allergic conjunctivitis occurs in previously sensitized individuals when 
environmental allergens contact the ocular mucosa and trigger a type 1 allergic response 
(Dupuis, 2020). This type 1 response is defined by IgE-mediated mast cell degranulation 
and can be divided into an early phase and a late phase. The early phase occurs within 
seconds and lasts up to 30 minutes during which mast cells release preformed mediators 
(e.g., histamine, tryptase) followed by the synthesis and release of additional mediators 
and cytokines (e.g., leukotrienes, prostaglandins, IL-4). The late phase occurs after 
several hours and is characterized by the recruitment and infiltration of active 
inflammatory cells that continue to cause inflammation which can lead to tissue damage 
(Ono, 2005; Chigbu, 2018).  
The Allergen BioCube® (ABC®) is an environmental exposure unit (EEU) that allows for 
precise control over the type and concentration of allergen to which a patient is exposed. 
Additionally, confounding factors such as temperature and air quality can be regulated to 
reduce variability within and between studies. The ABC® has been technically and 
clinically validated for both timothy grass and ragweed pollen in allergic conjunctivitis 
and allergic rhinitis. In these studies, the ABC® uniformly distributed these allergens at 
prespecified concentrations which reproduced clinically relevant signs and symptoms 
upon patient exposure (Gomes, 2016; Angjeli, 2017). The ABC® has also been used to 
assess the efficacy of both known (fluticasone furoate nasal spray) and unknown 
(iodixanol) drugs in the treatment of allergic rhinitis (Lane, 2011; Gomes, 2019).  
Current therapies for allergic conjunctivitis include antihistamines, mast cell stabilizers, 
and dual-action therapies. While many of these therapies are effective in providing 


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temporary relief, there still remains an unmet need specifically for patients affected by 
more chronic forms of ocular allergy. 
The purpose of this study is to evaluate the efficacy of Brimonidine Tartrate 0.025%/ 
Ketotifen Fumarate 0.035% Ophthalmic Solution (Combo) compared to its individual 
components in a population of subjects with seasonal allergic conjunctivitis. Alaway® 
(ketotifen fumarate, 0.035%) is a second generation histamine H1 antagonist and is 
currently approved for the temporary relief of itchy eyes due to ragweed, pollen, grass, 
animal hair and dander (Abelson, 2003; Alaway® Ketotifen Fumarate Ophthalmic 
Solution, 0.035% (OTC) Label, approved accessed 2021). Lumify®(brimonidine tartrate, 
0.025%) is a selective alpha2-AR agonist that acts as a topical vasoconstrictor for relief 
of ocular redness. When used as directed, Lumify® did not demonstrate tachyphylaxis and 
virtually no rebound redness was observed (Ackerman, 2019; Lumify® Brimonidine 
Tartrate Ophthalmic Solution, 0.025% Label, approved 2020 accessed). By combining 
the antihistamine ketotifen fumarate with the vasoconstrictor brimonidine tartrate, the 
Combo is intended to utilize the unique attributes of each active agent to reduce ocular 
itching and redness for up 8 hours.  
2 STUDY OBJECTIVES 
The primary objective is to evaluate the efficacy of Combo compared to its individual 
components and compared to vehicle in a population of subjects with seasonal allergic 
conjunctivitis. 
3 CLINICAL HYPOTHESES 
It is hypothesized that Combo will be more efficacious than its individual components 
and vehicle in subjects with seasonal allergic conjunctivitis.  
4 OVERALL STUDY DESIGN 
This is a multi-center, double-masked, randomized parallel-group, vehicle-controlled 
study. 
The study will consist of 2 visits: a screening visit to verify subjects are eligible to 
participate and a qualification/treatment visit to evaluate the onset of action and potential 
for an 8 hour duration of effectiveness for the brimonidine tartrate/ ketotifen fumarate 
combo drug product compared to its individual components and vehicle. 
At Visit 1, subjects will sign the informed consent form (ICF) and an allergic skin test 
will be performed, if required. At Visit 2, subjects will undergo 90 minutes of exposure to 
pollen4 in the ABC®. Subjects who have a sufficient ocular allergy score (defined as a 
 
4 Exposure will be to an allergen that elicited a positive reaction via skin testing. 


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bilateral score of ≥2 in both ocular itching and ocular redness) at the 90 minute time point 
will be randomized 1:1:1:1 to receive one of the following bilaterally at Visit 2:  
 Brimonidine tartrate 0.025%/ Ketotifen fumarate 0.035% combination ophthalmic 
solution (Combo)  
 Ketotifen fumarate ophthalmic solution, 0.035% 
 Brimonidine tartrate ophthalmic solution, 0.025%  
 Vehicle ophthalmic solution 
 
Treatment will begin at Visit 2 following the 90 minute time point. Following instillation 
of investigational product, randomized subjects will remain exposed to pollen in the 
ABC® for an additional 8 hours. Assessments will be conducted at the designated time 
points.   
If subjects do not have a sufficient ocular allergy score at the 90 minute time point and 
also have a positive skin test reaction to both ragweed and timothy grass, they may be re-
screened for Visit 2 using the alternate pollen. In the event that subjects do not receive a 
full 90 minutes of pollen exposure (e.g. early exit from BioCube, mechanical issue with 
pollen distribution, etc.), subjects may also be eligible for re-screening. Re-screening 
should take place at least one week following the initial Visit 2 and should be within the 
specified study visit windows.  
5 STUDY POPULATION 
 
Number of Subjects (approximate) 
Approximately 360 subjects will be screened in order to enroll approximately 224 
subjects, 56 subjects per treatment group. 
 
Study Population Characteristics 
Subjects of at least 18 years of age of either sex and any race, with a diagnosis of 
seasonal allergic conjunctivitis, who meet all of the inclusion criteria and none of the 
exclusion criteria. 
 
Inclusion Criteria 
Subjects must:  
 
1. be at least 18 years of age of either sex and any race; 
2. provide written informed consent and sign the Health Information Portability and 
Accountability Act (HIPAA) form; 
3. be willing and able to follow all instructions and attend all study visits; 


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4. provide proof of COVID-19 vaccination5;  
5. be able and willing to discontinue wearing contact lenses for at least 72 hours 
prior to Visit 2 and for the duration of the visit; 
6. have seasonal allergic conjunctivitis to ragweed or timothy grass documented by a 
self-reported history of ocular allergic symptoms for the last 2 consecutive years 
during the ragweed or timothy grass seasons and a positive skin test reaction to 
ragweed or timothy grass pollen as confirmed by the allergic skin test given at or 
within 24 months of the subject’s Visit 1; 
7. (If female and of childbearing potential) agree to have urine pregnancy testing 
performed at Visit 2 (must be negative); must not be lactating; and must agree to 
use at least 1 medically acceptable form of birth control throughout the study 
duration, for at least 14 days prior to and 1 month after receiving investigational 
drug. 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 receiving investigational drug (Visit 2). 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);  
8. (If male and with female partner of childbearing potential) must use at least 1 
medically acceptable form of birth control. Note: 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 receiving 
investigational drug (Visit 2). Without a vasectomy, must use condoms with 
spermicidal foam/gel/film/cream/suppository throughout the study duration, for at 
least 14 days prior to and 1 month after investigational drug (Visit 2); 
9. have a calculated visual acuity (VA) of 0.7 logMAR or better in each eye as 
measured using an Early Treatment Diabetic Retinopathy Study (ETDRS) chart at 
Visit 1;   
10. have a positive Allergen BioCube challenge response to pollen exposure at the 90 
minute time point of ABC® exposure at Visit 2, defined as bilateral score of >2 in 
ocular itching and ocular redness. 
 
Exclusion Criteria 
Exclusion Criteria:  
Subjects may not: 
 
1. have known contraindications or sensitivities to the use of any of the 
investigational product medication or components;  
 
5 Visit 2 should occur at least two weeks after full vaccination.  


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2. have a history of mild persistent, moderate or severe asthma within the preceding 
5 years according to the National Heart, Blood, and Lung Institute classification 
(with the exception of exercise induced asthma).  
Note: Subjects with fall induced asthma that is either mild persistent (defined as 
>1 per week, but <1 per day), moderate persistent, or severe persistent will be 
excluded. 
3. have an upper respiratory tract or sinus infection within the previous 2 weeks of 
Visit 1;  
4. have a history of anaphylaxis or poor tolerability of previously administered 
allergen; 
5. have a compromised lung function at Visit 1 (defined as a peak expiratory flow 
rate [PEFR] that is below 80% of the predicted average PEFR, as calculated by 
gender, age, and measured height from the Mini-Wright instruction’s table: 
Normal Adult Predicted Average Peak Expiratory Flow).  
6. have an abnormal blood pressure (defined as ≤ 90 or ≥ 160 (systolic) measured in 
mmHg or ≤ 60 or ≥ 100 (diastolic) measured in mmHg) at Visit 1; 
7. have any ocular condition that, in the opinion of the investigator, could affect the 
subject’s safety or trial parameters (including but not limited to narrow angle 
glaucoma, clinically significant blepharitis, follicular conjunctivitis, iritis, 
pterygium, or a diagnosis of dry eye); 
8. have had ocular surgical intervention within three months prior to Visit 1, or 
during the trial or a history of refractive surgery six months prior to Visit 1, or 
have systemic surgery planned during the clinical trial or within 30 days after; 
9. have a known history of retinal detachment, diabetic retinopathy, or active retinal 
disease; 
10. have an active ocular infection (bacterial, viral or fungal), active uveitis, or 
positive history of an ocular herpetic infection at any visit; 
11. use any of the following disallowed medications during the period indicated 
below prior to Visit 2:   
3 Days 
 systemic or ocular H1 antihistamine, H1 antihistamine/mast-cell stabilizer 
drug combinations, H1 antihistamine- vasoconstrictor drug combinations; 
7 Days 
 decongestants; 
 monoamine oxidase inhibitors; 
 all other topical ophthalmic preparations (including artificial tears); 
 lid scrubs; 
 prostaglandins or prostaglandin derivatives; 
 ocular, topical, or systemic nonsteroidal anti-inflammatory drugs (NSAIDs); 
*Baby aspirin (81 mg) is allowed as long as a stable dose has been maintained 
for at least 30 days prior to Visit 2 and will continue to be maintained for the 
duration of the trial. 
14 Days 
 inhaled, ocular, topical, or systemic corticosteroids or mast cell stabilizers;  
45 Days 


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 depot-corticosteroids; 
60 Days 
 immunosuppressive or cancer chemotherapeutic agents; 
12. have any significant illness (including, but not limited to, poorly controlled 
hypertension, poorly controlled diabetes, a history of status asthmaticus, a history 
of organ transplantation, a history of persistent moderate or severe asthma, a 
history of moderate to severe allergic asthmatic reactions to any of the clinical 
trial allergens, any autoimmune disease requiring therapy, or severe 
cardiovascular disease or arrhythmia) that, at the investigators’ discretion, could 
be expected to interfere with the subject’s health or with the clinical trial 
parameters or put the subject at any unnecessary risk; 
13. have a history of glaucoma, ocular hypertension or an intraocular pressure (IOP) 
that is less than 5 mmHg or greater than 22 mmHg in either eye at Visit 1;  
14. develop a compromised lung function (defined as a PEFR drop of 15% or more 
from Visit 1 baseline value) at Visit 26; 
15. have used an investigational drug or medical device within 30 days of Visit 1 or 
be concurrently enrolled in another investigational trial; 
16. be a female who is currently pregnant, planning a pregnancy, or lactating; 
17. 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; 
18. have been randomized in the Bausch & Lomb 909 study. 
 
Withdrawal Criteria (if applicable) 
Subjects may voluntarily withdraw from the study at any time.  
Additionally, subjects may be discontinued for safety reasons as determined by the 
investigator (see Section 8.6.2).   
6 STUDY PARAMETERS 
 
Efficacy Measures and Endpoints 
6.1.1 Primary Efficacy Measure(s) and Endpoints 
 Ocular itching score (average score of the subject’s two eyes) evaluated by the 
subject at 10(±1), 30(±1), 60(±5), 360(±5), 420(±5), and 480(±5) minutes post-
instillation of assigned IP at Visit 2 
 
 Ocular redness (average score of the subject’s two eyes) evaluated by the 
Investigator using slit lamp at 10(±1), 30(±1), 60(±5), 360(±5), 420(±5), and 
480(±5) minutes post-instillation of assigned IP at Visit 2 
 
 
 
6 If occurs at more than one assessment, per the investigator’s discretion. 


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6.1.2 Secondary Efficacy Measure(s) and Endpoints 
 Tearing evaluated by the subject (average score of the subject’s two eyes) at 
10(±1), 30(±1), 60(±5), 360(±5), 420(±5), and 480(±5) minutes post-instillation 
of assigned IP at Visit 2 
 
 Lid swelling (average score of the subject’s two eyes) evaluated by the subject at 
10(±1), 30(±1), 60(±5), 360(±5), 420(±5), and 480(±5) minutes post-instillation 
of assigned IP at Visit 2 (
 
 Chemosis (average score of the subject’s two eyes) evaluated by the Investigator 
using slit lamp at 10(±1), 30(±1), 60(±5), 360(±5), 420(±5), and 480(±5) minutes 
post-instillation of assigned IP at Visit 2 
 
 
Exploratory Measures 
 Nasal itching evaluated by the subject at 10(±1), 30(±1), 60(±5), 360(±5), 
420(±5), and 480(±5) minutes post-instillation of assigned IP at Visit 2 
 
 
 Rhinorrhea evaluated by the subject at 10(±1), 30(±1), 60(±5), 360(±5), 420(±5), 
and 480(±5) minutes post-instillation of assigned IP at Visit 2 
 
 
 Nasal congestion evaluated by the subject at 10(±1), 30(±1), 60(±5), 360(±5), 
420(±5), and 480(±5) minutes post-instillation of assigned IP at Visit 2 
 
 
 Sneezing evaluated by the subject at 10(±1), 30(±1), 60(±5), 360(±5), 420(±5), 
and 480(±5) minutes post-instillation of assigned IP at Visit 2 
 
 
 Total nasal symptom scores (TNSS) evaluated by the subject at 10(±1), 30(±1), 
60(±5), 360(±5), 420(±5), and 480(±5) minutes post-instillation of assigned IP at 
Visit 2 (composite score of Nasal Itching, Nasal Congestion, Rhinorrhea and 
Sneezing) 
 Peak Nasal Inspiratory Flow (PNIF) measured pre-ABC® exposure to 8 hours 
post-instillation of assigned IP at Visit 2 (measured by means of a peak flow 
meter in L/min) 
 
Safety Measures 
 Adverse Events (AEs; reported, elicited and observed) 
 Best Corrected VA at Distance Utilizing an ETDRS chart  
 Slit Lamp Biomicroscopy 
 Intraocular Pressure (IOP) 
 Dilated Fundoscopy 
 Vital signs 
 Peak Expiratory Flow Rate (PEFR) 


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7 STUDY MATERIALS 
 
Study Treatment(s) 
7.1.1 Study Treatment(s)/ Formulation(s) 
 Brimonidine tartrate 0.025%/ Ketotifen fumarate 0.035% combination ophthalmic 
solution (Combo) (n = 56) 
 Ketotifen fumarate ophthalmic solution 0.035% (n = 56) 
 Brimonidine tartrate ophthalmic solution 0.025% (n = 56) 
 Vehicle ophthalmic solution (n = 56) 
 
7.1.2 Instructions for Use and Administration 
 At Visit 2, a trained study technician will instill 1 drop of the assigned 
investigational product into each eye while subjects are in the ABC®.  
 
Other Study Supplies 
 Pregnancy tests (Clarity HCG RAC Medical Boca Raton, FL) 
 Fluress® ocular anesthetic agent (fluorescein sodium and benoxinate 
hydrochloride ophthalmic solution USP) for intraocular pressure 
 Dilating drops for dilated fundoscopy 
 Allergens used for skin testing and in the ABC® (Ragweed and Timothy grass) 
8 STUDY METHODS AND PROCEDURES 
 
Subject Entry Procedures 
8.1.1 Overview 
Subjects as defined by the criteria in sections 5.2, 5.3, and 5.4 will be considered for 
entry into this study. 
8.1.2 Informed Consent 
Prior to a subject’s participation in the trial (i.e., changes in a subject’s medical treatment 
and/or study related procedures), the study will be discussed with each subject, and 
subjects wishing to participate must give written informed consent using an informed 
consent form.  The informed consent form must be the most recent version that has 
received approval/favorable review by a properly constituted Institutional Review 
Board/Independent Ethics Committee (IRB/IEC). Failure to obtain a signed ICF renders 
the subject ineligible for the study.  
In the event that a subject has a medical condition, medication/contact lens washout, or 
needs to speak with the Investigator prior to Visit 1, the subject will be given an informed 


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consent form. Medical/medication history, demographics, skin test, and 
inclusion/exclusion review may be performed at the time of informed consent signing 
prior to Visit 1, but must be confirmed at Visit 1 (with the exception of demographics and 
skin test). 
8.1.3 Washout Intervals 
Subjects will adhere to the following medication washout intervals during the period 
indicated prior to Visit 2 and will refrain from using these medications during the study:  
3 Days 
 contact lenses (72 hour washout) 
 systemic or ocular H1 antihistamine, H1 antihistamine/mast-cell stabilizer 
drug combinations, H1 antihistamine- vasoconstrictor drug combinations; 
7 Days 
 decongestants; 
 monoamine oxidase inhibitors; 
 all other topical ophthalmic preparations (including artificial tears); 
 lid scrubs; 
 prostaglandins or prostaglandin derivatives; 
 ocular, topical, or systemic nonsteroidal anti-inflammatory drugs (NSAIDs); 
*Baby aspirin (81 mg) is allowed as long as a stable dose has been maintained 
for at least 30 days prior to Visit 2 and will continue to be maintained for the 
duration of the trial. 
14 Days 
 inhaled, ocular, topical, or systemic corticosteroids or mast cell stabilizers;  
45 Days 
 depot-corticosteroids; 
60 Days 
 immunosuppressive or cancer chemotherapeutic agents; 
 
8.1.4 Procedures for Final Study Entry 
Subjects must meet all of the inclusion criteria and none of the exclusion criteria in order 
to be enrolled in the study.  
8.1.5 Methods for Assignment to Treatment Groups: 
All subjects screened for the study who sign an ICF will be assigned a screening number 
that will be entered in the Screening and Enrollment Log. The screening number will 
consist of three (3) digits, starting with 001.   
Once a subject meets all qualification criteria at Visit 2, he/she will be randomized to 
brimonidine tartrate 0.025%/ ketotifen fumarate 0.035% combination ophthalmic solution 
(Combo), ketotifen fumarate ophthalmic solution 0.035%, brimonidine tartrate ophthalmic 
solution 0.025%, or Vehicle in a 1:1:1:1 ratio. Each subject who is randomized will be 
assigned a unique Randomization number in the Randomization and Trial Supply 


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Management (RTSM). Randomization numbers will be assigned in a sequential order 
starting at the lowest number available. No numbers will be skipped or omitted. 
Randomization numbers will be 5 digits and will be created in the RTSM. 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 RTSM 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. 
 
Concurrent Therapies 
The use of any concurrent medication, prescription or over-the-counter, is to be recorded 
on the subject’s source document and corresponding electronic case report form (eCRF) 
along with the reason the medication was taken. 
Concurrent enrollment in another investigational drug or medical device study is not 
permitted. 
8.2.1 Prohibited Medications/Treatments 
Refer to Section 8.1.3 for a complete list of washout periods for the following prohibited 
medications and treatments: 
 contact lenses 
 systemic or ocular H1 antihistamine, H1 antihistamine/mast-cell stabilizer drug 
combinations, H1 antihistamine- vasoconstrictor drug combinations 
 decongestants 
 monoamine oxidase inhibitors 
 all other topical ophthalmic preparations (including artificial tears) 
 lid scrubs 
 prostaglandins or prostaglandin derivatives 
 ocular, topical, or systemic nonsteroidal anti-inflammatory drugs (NSAIDs)  
*Baby aspirin (81 mg) is allowed as long as a stable dose has been maintained for at 
least 30 days prior to Visit 2 and will continue to be maintained for the duration of the 
trial. 
 inhaled, ocular, topical, or systemic corticosteroids or mast cell stabilizers  
 depot-corticosteroids 
 immunosuppressive or cancer chemotherapeutic agents  
8.2.2 Escape Medications 
Subjects may receive either anti-itch cream or Calamine lotion (depending on the 
washout) after the skin test has been completed at Visit 1.  
8.2.3 Special Diet or Activities 
Not Applicable. 


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Examination Procedures 
8.3.1 Procedures to be Performed at Each Study Visit with Regard to Study 
Objective(s) 
8.3.1.1 VISIT 1 (Day -60 to Day -1): Screening/ Informed Consent/ Skin Test 
Informed Consent/HIPAA: Prior to any changes in a subject’s medical treatment and/or 
any 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. 
 
In the event that a subject has a medical condition, medication/contact lens washout, or 
needs to speak with the Investigator prior to Visit 1, the subject will be given an 
informed consent form. Medical/medication history, demographics, skin test, and 
inclusion/exclusion review may be performed at the time of informed consent signing 
prior to Visit 1, but must be confirmed at Visit 1 (with the exception of demographics 
and skin test). 
 
 Demographic Data and Medical/Medication/Ocular and Non-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 
thirty days (30), which may have been 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 sixty days (60) prior to Visit 1. 
 
 Allergic Skin Test, if applicable: A diagnostic test for allergic disease (skin test) will 
be performed if there is no documented skin test within the past 24 months. Subjects 
may receive either anti-itch cream or Calamine lotion (depending on the washout) after 
the skin test has been completed. 
 
 Best Corrected Visual Acuity Utilizing an ETDRS Chart: Subjects must have a score 
of 0.7 logMAR or better in each eye in order to qualify. This initial visual acuity will 
be deemed the Baseline visual acuity. The use of correction will be documented. If a 
subject uses correction at this visual acuity then they should use the same correction 
throughout all subsequent visual acuity assessments.   
 
 Slit Lamp Biomicroscopy:  A slit lamp exam will be performed in both eyes to exclude 
subjects with disallowed ocular conditions. Findings of abnormality which are not 
exclusionary should be recorded as Medical History, as applicable.  
 
 Peak Expiratory Flow Rate (PEFR) Measurement:  Baseline PEFR measurement will 
be done (as outlined in Appendix 2) to exclude subjects with a compromised lung 
function (defined as a PEFR that is below 80% the predicted average). 
 


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 Vital Signs: Resting blood pressure and pulse will be measured. Subjects with an 
abnormal blood pressure (defined as ≤ 90 or ≥ 160 (systolic) measured in mmHg or ≤ 60 or ≥ 
100 (diastolic) measured in mmHg) will be excluded. 
 
 Intraocular Pressure: Intraocular pressure (IOP) will be measured in each eye by 
contact tonometry. Subjects with an IOP of less than 5 mmHg or greater than 22 mmHg 
in either eye will be excluded.  
 
 Dilated Fundoscopy: A dilated fundus examination will be performed by the 
Investigator to evaluate the presence or absence of clinically significant fundus 
abnormalities and vitreous pathology. Findings should be recorded as Medical History, 
as applicable.  
 Review of Inclusion/Exclusion Criteria: A review of protocol inclusion and exclusion 
criteria will be confirmed for each subject. 
 
 Adverse Event Query 
 
 Schedule Visit 2: Qualifying subjects will be scheduled for Visit 2. 
 
8.3.1.1 VISIT 2 (Day 1): ABC Qualification Exposure/ Randomization/ Treatment/ 
ABC® 8hr Exposure/ Exit 
 Update of Medical/Medication History:  Collect and record any changes or new 
medications/conditions that may have started or that require follow-up from the last 
visit. 
 
 Adverse Event Query 
 
 Urine Pregnancy Test (for females of childbearing potential): Females of childbearing 
potential must have a negative urine pregnancy test to continue in the study and must 
agree to use an acceptable method of contraception throughout participation in the 
study. 
 
 Pre-ABC® 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. 
 
 Pre-ABC® Slit Lamp Biomicroscopy 
 
 Pre-ABC® Ocular and Nasal Allergic Signs and Symptoms Assessment 
 
 Peak Expiratory Flow Rate (PEFR) Measurement: Subjects who develop a 
compromised lung function (defined as a PEFR drop of 15% or more from Visit 1 


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baseline value) may be excluded if occurs at more than one assessment, per the 
investigator’s discretion. 
 
 Peak Nasal Inspiratory Flow 
 
 Vital signs 
 
 Review of Inclusion/Exclusion Criteria 
 
 90 Minute Qualification Exposure in ABC®: The study subjects will be exposed to 
ragweed or timothy grass pollen in the ABC® for 90 minutes prior to enrollment 
qualification review. Assessment of ocular and nasal allergic signs and symptoms will 
be evaluated by the subjects and Investigator at 90(±5) minutes during ABC® exposure. 
PEFR will be collected at 60(±15) minutes during exposure in the ABC®. PEFR 
measurement will be done to exclude subjects with a compromised lung function 
(defined as a PEFR drop of 15% or more from Visit 1 baseline value)7. Measurement 
of PNIF will be collected at 90(±15) minutes during exposure in the ABC®.  
 
 Review of Applicable Inclusion/Exclusion Criteria: Subjects must have a bilateral score 
of ≥2 in ocular itching and ocular redness at the 90-minute timepoint. 
If subjects do not have a sufficient ocular allergy score at the 90 minute time point 
and also have a positive skin test reaction to both ragweed and timothy grass, they 
may be re-screened for Visit 2 using the alternate pollen. In the event that subjects do 
not receive a full 90 minutes of pollen exposure (e.g. early exit from BioCube, 
mechanical issue with pollen distribution, etc.), subjects may also be eligible for re-
screening. Re-screening should take place at least one week following the initial Visit 
2 and should be within the specified study visit windows.  
 Enrollment/Randomization: Treatment will be randomly assigned in a 1:1:1:1 ratio 
according to the randomization schedule. Subjects who meet all of the inclusion 
criteria and none of the exclusion criteria and qualify to continue in the study will be 
assigned a sequential Randomization number (5 digits) in the RTSM and randomly 
assigned to receive either Combo, brimonidine tartrate 0.025%, ketotifen fumarate 
0.035%, or Vehicle. Randomization numbers will be assigned in a sequential order 
starting at the lowest number available. No numbers will be skipped or omitted.  
 
 Instillation of Investigational Product: The assigned investigational product will be 
administered by a trained study technician. The technician will instill one drop of the 
assigned investigational product into each eye and the time of instillation will be 
recorded.  
 
 
7 If occurs at more than one assessment, per the investigator’s discretion. 


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 8 Hour Post-Treatment Exposure in ABC®: Following instillation of investigational 
product, randomized subjects will be exposed to pollen in the ABC® for up to an 
additional 8 hours.  Assessment of ocular and nasal allergic signs and symptoms will 
be evaluated by the subjects and Investigator at 10(±1), 30(±1), 60(±5), 360(±5), 
420(±5), and 480(±5) minutes post-instillation of investigational product. 
Measurements of PNIF will be collected 60(±15) and 480(±15) minutes post-treatment. 
PEFR will be collected 120(±15), 240(±15), 360(±15), and 480(±15) minutes post-
treatment.    
Subjects can exit the ABC® up to three times, for no longer than 15 minutes on each 
occasion, before it will be considered a protocol violation. Time of exit and re-entry 
will be recorded. 
 
 Post-ABC® Visual Acuity Utilizing an ETDRS Chart 
 
 Post-ABC® Slit Lamp Biomicroscopy 
 
 Intraocular Pressure 
 
 Dilated Fundoscopy 
 
 Adverse Event Query 
 
 Study Exit 
 
Adverse Events (AEs) (both elicited and observed) will be monitored throughout the 
study. All AEs (both elicited and observed) will be promptly reviewed by the investigator 
for accuracy and completeness. All AEs will be documented on the appropriate eCRF. 
If a female has a positive pregnancy test during the study, then the investigator will notify 
Ora immediately. The investigator shall request from the subject and/or the subject’s 
physician copies of all related medical reports during the pregnancy and shall document 
the outcome of the pregnancy. The investigator will retain these reports together with the 
subject’s source documents and will provide a copy of all documentation to Ora. 
 
Schedule of Visits, Measurements and Dosing 
8.4.1 Scheduled Visits 
Refer to Appendix 1 for a schedule of visits and measurements. 
If a subject is discontinued at a scheduled study visit, the remaining assessments should 
be captured on the Unscheduled Visit/Early Exit Visit pages of the Source Document and 
corresponding eCRF. 


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8.4.2 Unscheduled Visits 
For Unscheduled Visits, the reason for the visit should be clearly documented on the 
appropriate eCRF, including findings from all evaluations that are completed.  
These visits may be performed to ensure subject safety. All information gathered at 
unscheduled visits should be recorded on the Unscheduled Visit/ Early Exit Visit pages 
of the Source Document and corresponding eCRF.  
Evaluations that may be conducted at an Unscheduled Visit (as appropriate, depending on 
the reason for the visit), include:  
 Update of Medical/Medication History 
 Assessment of Adverse Events 
 Best Corrected VA at Distance Utilizing an ETDRS chart 
 Slit Lamp Biomicroscopy 
 Intraocular Pressure (IOP) 
 Dilated Fundoscopy 
 Peak Expiratory Flow Rate (PEFR) 
 
Compliance with Protocol 
At Visit 2, subjects are expected to remain exposed in the ABC® with the exception of 
any assessments that may need to be performed outside of the room. When necessary, 
subjects are allowed to exit the ABC® up to three times, for no longer than 15 minutes on 
each occasion, before it will be considered a protocol violation. Time of exit and re-entry 
will be recorded.  
Subjects who are inappropriately enrolled may be discontinued from the study. The 
reason for such discontinuation will be recorded as “protocol violation” in the source 
document and on the appropriate page in the eCRF.  
Site staff will review concomitant medication use at each visit. Any new medication (or) 
changes in existing concomitant medication use will be recorded in the source document 
and on the Concomitant medication eCRF.  
 
Subject Disposition 
8.6.1 Completed Subjects 
A completed subject is one who has not been discontinued from the study. 
8.6.2 Discontinued Subjects 
Subjects may be discontinued prior to their completion of the study due to: 


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 
subject request/withdrawal 
 
AEs 
 
protocol violations 
 
administrative reasons (e.g., inability to continue, lost to follow up) 
 
sponsor termination of study 
 
other 
Note: In addition, any subject may be discontinued for any sound medical reason. 
Notification of a subject discontinuation and the reason for discontinuation will be made 
to Ora and/or sponsor and will be clearly documented on the eCRF. 
 
Study Termination 
The study may be stopped at any time by the investigator, the sponsor, and/or Ora with 
appropriate notification. 
 
Study Duration 
This trial consists of 2 office visits over a period of approximately 2 to 61 days. 
 
Monitoring and Quality Assurance 
During the course of the study an Ora monitor, or designee, will make routine site visits 
to review protocol compliance, assess IP accountability, and ensure the study 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 study monitoring will be outlined in a monitoring 
plan. 
Regulatory authorities of domestic and foreign agencies, Ora quality assurance 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 giving 
consideration to data protection as well as subject confidentiality to the extent that local, 
state, and federal laws apply. 
9 ADVERSE EVENTS 
 
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:    


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 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 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. 
 
9.1.1 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 
 


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9.1.2 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. 
 
 
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 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, 


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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.    
Within 24 hours following the investigator’s knowledge of an SAE, the investigator must: 
 Report the SAE to the sponsor/designee. 
All SAEs occurring between screening and 30 days after the last administered dose 
of study drug (inclusive) must be reported to the sponsor/designee, independent of 
the circumstance or suspected cause, and regardless of the relationship to the study 
drug or protocol, within 24 hours from the time the event was reported to the 
investigator.  For events occurring beyond the 30-day period after the last 
application of study drug, or for any timeframe greater than 30 days deemed 
medically significant, only SAEs considered related to the study drug should be 
reported promptly to the sponsor. 
If the subject dies during participation in the study or during recognized follow-up 
period, and if cause of death is not available within the 24-hour reporting period, 
“death” must be reported as an SAE term to meet the timelines. Cause of death 
must be actively queried and submitted as a follow-up report. 
 Fax or email a completed Serious Adverse Event Report to the following Ora 
designee: 
CRO Contact: 
 
  
 


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Once the SAE Report has been reviewed by the Medical Monitor, the form will be 
faxed or emailed to the following Sponsor designee: 
Sponsor Contact: 
  
  
  
 
Include copies of all confirmatory examinations carried out and the dates on 
which these examinations were performed.  Care should be taken to ensure that 
the subject's identity is protected (personal identifiers are redacted), and the date 
and subject identifier in the clinical trial (i.e., subject number) are clearly visible 
on every page/copy of source document provided to the sponsor.  For laboratory 
results, include the laboratory normal ranges.    
 Investigators should not wait to receive additional information before notifying 
the sponsor of an SAE.  If only limited information is initially available, follow-
up reports are required. 
Within 48 hours following the investigator’s knowledge of an SAE, the investigator 
must: 
 Enter the information related to the SAE in the appropriate sections of the eCRF. 
 Send notification of the SAE to the monitoring team after investigator approval of 
the eCRF 
All further data updates should be recorded in the eCRF within one working day of 
knowledge of this additional information.  Send notification of the updated SAE 
information to the monitoring team after investigator approval of the eCRF.  
Additional documentation (e.g., laboratory data, concomitant medication, subject 
status, etc.), should be sent by fax or e-mail to the monitoring team within one 
working day of knowledge of this information.  Care should be taken to ensure that 
the subject's identity is protected (personal identifiers are redacted) and the date and 
subject identifier in the 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 


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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. 
9.2.1 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 
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, 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. 
9.2.2 Pregnancy 
All female subjects of childbearing potential and male subjects with female partners of 
childbearing potential must use at least 1 medically acceptable form of birth control 
throughout the study duration, for at least 14 days prior to and 1 month after receiving the 
investigational drug (Visit 2), 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 


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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 
comes to term.   
All confirmed pregnancies must be immediately reported to the sponsor/designee and 
medical monitor on a Pregnancy Report form within 24 hours of the investigator’s 
awareness of the pregnancy.  If a pregnancy is associated with an SAE, an SAE report 
form should also be submitted to the sponsor/designee and medical monitor within 24 
hours of the investigator’s awareness.  Abnormal pregnancy outcomes (e.g., spontaneous 
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered 
SAEs.  
Completed SAE Report Forms and completed Pregnancy Report Forms should be 
transmitted to the sponsor/designee and the medical monitor using the contact 
information provided in Section 9.2 above: 
If/when the investigator becomes aware of any new information regarding a pregnancy, 
the sponsor/designee and medical monitor should be notified of these updates as soon as 
the new information becomes available.  Updates should be documented on a Pregnancy 
Report Form and sent by fax or email using the contact information provided above.  The 
report should be marked as a follow-up report” and should include the updated status of 
the pregnancy.  The original Pregnancy Report Form is not to be altered.   
 
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.   


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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 
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”). Rationale MUST be provided for 
any “not related” assessment and is recommended for “related” assessments.     
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.   
If a subject requires further follow-up of ongoing AEs/SAEs upon discontinuation or 
completion of the study, the Investigator should schedule post-study follow-up visits, as 
necessary. Final outcomes should be reported to Ora and Sponsor for post-study follow-
up. If the subject is lost to follow-up, the investigator should make 3 reasonable attempts 
to contact the subject via telephone, post, or certified mail. All follow-up will be 
documented in the subject’s source document. Non-serious AEs identified on the last 
scheduled contact must be recorded on the AE eCRF with the status noted.  
If the Investigator becomes aware of any new information regarding an SAE (i.e., 
resolution, change in condition, or new treatment), a new SAE/Unanticipated Report 
Form must be completed and faxed to Ora Inc. within 24 hours. The original SAE form is 


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not to be altered. The report should describe whether the event has resolved or continues 
and how the event was treated 
Laboratory results, vital signs, or ECG abnormalities are to be recorded as AEs (or SAEs, 
if applicable) only if at least one of the following apply: 
 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 (or SAEs, if applicable) only if they 
are clinically significant (for example: are symptomatic, requiring corrective treatment, 
leading to discontinuation or fulfilling a seriousness criterion). 
Site staff will provide subjects with the main office number plus a 24-hour number to 
report any adverse events or safety concerns. This information will be listed on the 
Informed Consent Form and a copy will be provided to the subject at their Visit 1. 
 
Procedures for Unmasking (if applicable) 
When medically necessary, the investigator may need to determine what treatment has 
been assigned to a subject. When possible (i.e., in non-emergent situations), Ora and/or 
the sponsor should be notified before unmasking IP. 
 
10 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
 Assessment of Efficacy 
10.1.1 Primary Efficacy 
The primary efficacy endpoints are 
 Ocular itching score (average score of the subject’s two eyes) evaluated by the 
subject at 10(±1), 30(±1), 60(±5), 360(±5), 420(±5), and 480(±5) minutes post-
instillation of assigned IP at Visit 2 
 
 
 Ocular redness (average score of the subject’s two eyes) evaluated by the 
Investigator using slit lamp at 10(±1), 30(±1), 60(±5), 360(±5), 420(±5), and 
480(±5) minutes post-instillation of assigned IP at Visit 2 
 
 
 


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Statistical success will be achieved if all of the following conditions are met at Visit 2. 
1. 
The Combo is superior in ocular itching to Vehicle. 
2. 
The Combo is superior in ocular redness to Vehicle. 
3. 
The Combo is superior in ocular itching to brimonidine tartrate 0.025%. 
4. 
The Combo is superior in ocular redness to ketotifen fumarate 0.035%. 
 
Each primary endpoint will be summarized by post-instillation of IP time point at Visit 2 
by treatment group using continuous summary statistics for the FAS population, and 
sensitivity analyses will be performed on the PP population. Missing data will be imputed 
using multiple imputation techniques. Treatment effects will be estimated, and the 
statistical hypotheses will be tested using two-sample t-tests assuming equal variances.   
Superiority will be demonstrated for comparisons above if the treatment effect is 
statistically significant in accordance with the below.  
Hypothesis testing will be split into two groups. Hypotheses associated with the first three 
time points will constitute the first group and hypotheses associated with the latter three 
time points  will constitute the second group.  
Testing of the first three time points will be performed first. If the treatment effect is not 
statistically significant (one-sided α = 0.0083=0.025/3 to account for the three timepoints) 
at any of the three time points, then the condition is not met.  
If the treatment effect is statistically significant for at least one of the first three timepoints, 
then the second group of hypotheses is tested.  
If the treatment effect was statistically significant for exactly one of the three comparisons 
in the first group, this leaves 0.0083 alpha unused and all three treatment effects in the 
second group of hypotheses must be statistically significant at the unused one-sided 
alpha=0.0083/3=0.0028 in order for this condition to be met. 
If the treatment effect was statistically significant for exactly two of the three comparisons 
in the first group, this leaves 0.0167 alpha unused and at least two treatment effects in the 
second group of hypotheses must be statistically significant at the adjusted unused one-
sided alpha=0.0167/3=0.0056 in order for this condition to be met. 
If the treatment effect was statistically significant for all three comparisons in the first 
group, this leaves 0.025 alpha unused, and at least one treatment effect in the second group 
of hypotheses must be statistically significant at the adjusted unused one-sided 
alpha=0.025/3=0.0083 in order for this condition to be met. 
Summaries of the primary endpoints by  post-instillation of IOP time point at Visit 2 will 
be given for the difference in mean ocular itching between the Combo and ketotifen 
fumarate 0.035% and between ketotifen fumarate 0.035% and vehicle as well as for the 
difference in mean ocular redness between the Combo and brimonidine tartrate 0.025% 
and between brimonidine tartrate 0.025% and vehicle. Missing data will be imputed using 
multiple imputation techniques. Continuous summary statistics including two-sided 95% 
t-distribution confidence intervals around the difference in means will be provided 


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10.1.2 Secondary Efficacy 
The secondary endpoints are: 
 Tearing (average score of the subject’s two eyes) evaluated by the subject at 
10(±1), 30(±1), 60(±5), 360(±5), 420(±5), and 480(±5) minutes post-instillation 
of assigned IP at Visit 2 
 
 Lid swelling (average score of the subject’s two eyes) evaluated by the subject at 
10(±1), 30(±1), 60(±5), 360(±5), 420(±5), and 480(±5) minutes post-instillation 
of assigned IP at Visit 2 
 
 Chemosis (average score of the subject’s two eyes) evaluated by the Investigator 
using slit lamp at 10(±1), 30(±1), 60(±5), 360(±5), 420(±5), and 480(±5) minutes 
post-instillation of assigned IP at Visit 2 
 
 
Statistical inference for the secondary endpoints will only be performed if the primary 
efficacy analyses are considered successful. Secondary endpoints will be evaluated 
hierarchically in the order presented above.  Success for each secondary endpoint will 
follow the same criteria as the primary endpoint. Sensitivity analyses for the secondary 
endpoints will be performed in the same manner as the sensitivity analyses for the 
primary endpoints.  
10.1.3 Exploratory Endpoints 
Exploratory endpoints include: 
 Nasal itching evaluated by the subject at 10(±1), 30(±1), 60(±5), 360(±5), 
420(±5), and 480(±5) minutes post-instillation of assigned IP at Visit 2 (0-4 scale) 
 Rhinorrhea evaluated by the subject at 10(±1), 30(±1), 60(±5), 360(±5), 420(±5), 
and 480(±5) minutes post-instillation of assigned IP at Visit 2
 
 Nasal congestion evaluated by the subject at 10(±1), 30(±1), 60(±5), 360(±5), 
420(±5), and 480(±5) minutes post-instillation of assigned IP at Visit 2 
 
 Sneezing evaluated by the subject at 10(±1), 30(±1), 60(±5), 360(±5), 420(±5), 
and 480(±5) minutes post-instillation of assigned IP at Visit 2 
 
 Total nasal symptom scores (TNSS) evaluated by the subject at 10(±1), 30(±1), 
60(±5), 360(±5), 420(±5), and 480(±5) minutes post-instillation of assigned IP at 
Visit 2 (composite score of Nasal Itching, Nasal Congestion, Rhinorrhea and 
Sneezing) 
 Peak Nasal Inspiratory Flow (PNIF) measured pre-ABC® exposure to 8 hours 
post-instillation of assigned IP at Visit 2 (measured by means of a peak flow 
meter in L/min) 
 
The first five exploratory endpoints will be analyzed in the same manner as the primary 
efficacy endpoints. For PNIF, treatment effects will be estimated at 8 hours post-
installation of IP at Visit 2, and the statistical hypotheses will be tested using two-sample 
t-tests assuming equal variances. P-values for all exploratory results will be considered 
descriptive. 


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10.1.4 Statistical Hypothesis Testing and Control of Multiplicity 
At each of six post-instillation times at Visit 2, the null hypothesis (𝐻଴) is that the 
difference between the mean redness (or itching) scores for the Test (𝜇்) and Standard 
(𝜇ௌ) formulations is 0 points or greater. The alternative hypothesis (𝐻ଵ) is that the 
difference is less than 0 points. 
𝐻଴: 𝜇்−𝜇ௌ≥0 
𝐻ଵ: 𝜇்−𝜇ௌ< 0 
 
The hypotheses above will be tested for each of the six post-instillation times at Visit 2.  
Each primary endpoint will be summarized by post-instillation of IP time point at Visit 2 
by treatment group using continuous summary statistics and analyzed using an ANCOVA 
model with terms for baseline value and treatment for the ITT population. Missing data 
will be imputed using multiple imputation methods. Least square means for each 
treatment group and for the difference between treatment groups will be presented from 
the model together with two-sided p-values and 95% confidence intervals.. Success will 
be determined as per the criteria in Section 10.1.1. 
Statistical inference will be performed for the secondary efficacy endpoints only if the 
primary efficacy endpoints demonstrate success 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 10.1.2.  
10.1.5 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 Combo minus Vehicle, 
Combo minus brimonidine tartrate 0.025%, or Combo minus ketotifen fumarate 0.035%. 
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. 
For efficacy 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 eye 
(OD) and the left eye (OS) separately). 
Statistical methods will be more fully described in a separate Statistical Analysis Plan. 


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10.1.6 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.  
10.1.7 Sensitivity Efficacy Analyses 
Supportive analyses on the primary efficacy endpoint will include an evaluation of the 
treatment effect using an analysis of covariance model with the primary efficacy variable 
as the dependent variable, treatment as a factor, and baseline score as a covariate. 
The analysis on the primary efficacy endpoint will be repeated on the PP population with 
imputation and on the PP and FAS 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. 
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 


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 Control-based multiple imputation for subjects who drop out due to adverse events 
and/or lack of efficacy 
 
10.1.8 Subgroup Analyses 
Subgroup analyses will be performed on the primary and secondary efficacy endpoints by 
age group, sex, and race. 
 
Any other planned subgroup analyses will be formally described in the study Statistical 
Analysis Plan. 
 Assessment of Safety 
The following safety variables will be recorded: 
 Adverse Events (AEs; reported, elicited and observed) 
 Best Corrected VA at Distance Utilizing an ETDRS chart  
 Slit Lamp Biomicroscopy 
 Intraocular Pressure (IOP) 
 Dilated Fundoscopy 
 Vital signs 
 Peak Expiratory Flow Rate (PEFR) 
All safety parameters will be analyzed using the safety population. The safety of Combo 
compared to brimonidine tartrate 0.025%, ketotifen fumarate 0.035%, and vehicle 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 at Baseline at Visit 2 with numerical summaries. Change from 
baseline to Visit 2 will also be presented in the same manner. Shift tables will be 
presented to assess the results of the dilated fundoscopy. For assessments performed by 
eye, left eye and right eye will be summarized separately. 
10.2.1 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 
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.  


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10.2.2 Safety Laboratory Tests 
No safety laboratory tests will be conducted for this study. 
10.2.3 Vital Sign Measurements 
Vital signs as well as changes from baseline to Visit 2 in vital sign measurements will be 
summarized with descriptive statistics for each treatment group. 
10.2.4 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 (FAS, 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 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 Per-Protocol Population will 
include the following. 
 Ineligibility 
 Missing primary endpoint data at any time point of Visit 2 
 Out of window primary endpoint data at any time point of Visit 2 
 Use of any prohibited medication potentially affecting the primary endpoint at Visit 
2 


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Additional important deviations leading to exclusion from the Per-Protocol Populations 
may be identified prior to unmasking of the treatment assignments. 
 Compliance 
Compliance will not be evaluated in this study. 
 Interim Analyses 
There are no interim analyses planned for this study. 
 Additional Statistical Considerations 
10.8.1 Analysis Populations 
 Intent to Treat Set (ITT): The ITT population will consist of all randomized 
subjects who are instilled with study drug.  The ITT population will be 
analyzed as randomized. 
 Full Analysis Set (FAS): The FAS will consist of all randomized subjects who 
are instilled with study drug and have at least one post-instillation of IP 
assessment of both primary endpoints.  The FAS population will be analyzed 
as randomized. 
 
 Per Protocol Set (PP Set): The PP Set will consist of FAS subjects with no 
protocol violations considered to affect the evaluability of efficacy, as 
determined through masked review of deviations prior to unmasking.  The PP 
population will be analyzed as treated. 
 
 Safety Set: The Safety Set will include all subjects who receive any amount of 
study medication.  The safety population will be analyzed as treated. 
 
10.8.2 Sample Size Determination 
A sample size of 50 subjects in each treatment group yields 95% power to demonstrate 
each of the following: 
 Combo is superior to vehicle in ocular itching (evaluated by the subject)  
 Combo is superior to vehicle in ocular redness (evaluated by the Investigator)  
 Combo is superior to brimonidine tartrate 0.025% in ocular itching (evaluated by 
the subject)  
 Combo is superior to ketotifen fumarate 0.035% in ocular redness (evaluated by 
the Investigator) 
 
assuming a one-sided α = 0.0028, a true mean difference of 0.65 units and a common 
standard deviation of 1.0 units at each time point for each measure.   
 


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To allow for 10% dropouts, 56 subjects will be randomized in each of the treatment  
groups. 
 
10.8.3 Multicenter Issues 
The study will be conducted at up to 8 investigational centers in the United States with 
the intention of pooling the results for analysis. Site specific data summaries for the 
primary endpoint, however, will be presented. 
 
10.8.4 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 four 
conditions in Section 10.1.1 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 10.1.2. 
10.8.5 Windowing Rules 
The timing of all study visits is relative to Baseline (Day 1). 
11 COMPLIANCE WITH GOOD CLINICAL PRACTICES, 
ETHICAL CONSIDERATIONS, AND ADMINISTRATIVE 
ISSUES 
This study will be conducted in compliance with the protocol, current Good Clinical 
Practices (GCPs), including the International Conference on Harmonisation (ICH) 
Guidelines, and in general, consistent with the Declaration of Helsinki. In addition, all 
applicable local, state, and federal requirements relevant to the use of IP in the countries 
involved will be adhered to. 
 Protection of Human Subjects 
11.1.1 Subject Informed Consent 
Informed consent must take place before any study specific procedures are initiated. 
Signed and dated written informed consent must be obtained from each subject prior to 
enrollment into the study. 
All informed consent/assent forms must be approved for use by the sponsor and receive 
approval/favorable opinion from an IRB/IEC prior to their use. If the consent form 
requires revision (e.g., due to a protocol amendment or significant new safety 
information), it is the investigator’s responsibility to ensure that the amended informed 
consent is reviewed and approved by Ora prior to submission to the governing IRB/IEC 


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and that it is read, signed and dated by all subjects subsequently enrolled in the study as 
well as those currently enrolled in the study. 
11.1.2 Institutional Review Board (IRB) Approval 
This study is to be conducted in accordance with IRB regulations (U.S. 21 CFR Part 
56.103). The investigator must obtain appropriate IRB approval before initiating the 
study and re-approval at least annually. 
Only an IRB/IEC approved version of the informed consent form will be used. 
 Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles that originated 
with the Declaration of Helsinki. 
 Subject Confidentiality 
All personal study subject data collected and processed for the purposes of this study 
should be maintained by the investigator and his/her staff with adequate precautions as to 
ensure that the confidentiality of the data is in accordance with local, state, and federal 
laws and regulations. 
Monitors, auditors and other authorized representatives of Ora, the sponsor, the IRB/IEC 
approving this study, the FDA, the DHHS, other domestic government agencies, and 
other foreign regulatory agencies will be granted direct access to the subject’s original 
medical and study records for verification of the data and/or clinical trial procedures. 
Access to this information will be permitted to the aforementioned individuals to the 
extent permitted by law. 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the IP may ultimately be marketed, but the subject’s 
identity will not be disclosed in these documents. 
 Documentation 
Source documents may include a subject’s medical records, hospital charts, clinic charts, 
the investigator’s study subject files, as well as the results of diagnostic tests such as X-
rays, laboratory tests, and EKGs. The investigator’s copy of the eCRFs serves as the 
investigator’s record of a subject’s study-related data. 
11.4.1 Retention of Documentation 
All study related correspondence, subject records, consent forms, record of the 
distribution and use of all IP, and copies of eCRFs should be maintained on file for at 
least two years after the last approval of a marketing application in an ICH region and 
until there are no pending or contemplated marketing applications in an ICH region; or 
until at least two years have elapsed since the formal discontinuation of clinical 
development of the IP. These documents will be retained for a longer period if required 


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by the applicable regulatory requirements or by an agreement with the sponsor. It is the 
responsibility of the sponsor to inform the investigator/institution as to when these 
documents no longer need to be retained. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address 
of the new custodian. 
 Labeling, Packaging, Storage, Accountability, and Return or Disposal 
of Investigational Product 
11.5.1 Labeling/Packaging 
The investigational materials will be packaged and labeled in a manner consistent with 
the study design. They will be labelled according to the local regulatory requirements.  
11.5.2 Storage of Investigational Product 
The IP must be stored in a secure area accessible only to the investigator and his/her 
designees. The IP will be administered only to subjects entered into the clinical study, in 
accordance with the conditions specified in this protocol. 
11.5.3 Accountability of Investigational Product 
The IP is to only be prescribed by the principal investigator or his/her named sub-
investigator(s) and is to only be used in accordance with this protocol. The IP must only 
be distributed to subjects properly qualified under this protocol to receive IP. 
The investigator must keep an accurate accounting of the IP received from the sponsor on 
the Product Accountability Log.  
11.5.4 Return or Disposal of Investigational Product 
All IP will be returned to the sponsor at the end of the study. 
 Recording of Data on Source Documents and Electronic Case Reports 
Forms (eCRFs) 
The investigator is responsible for ensuring that study data is completely and accurately 
recorded on each subject’s eCRF, source document, and all study-related material. All 
study data should also be attributable, legible, contemporaneous, and original. Recorded 
datum should only be corrected in a manner that does not obliterate, destroy, or render 
illegible the previous entry (e.g., by drawing a single line through the incorrect entry and 
writing the revision next to the corrected data). An individual who has corrected a data 
entry should make clear who made the correction and when, by adding to the correction 
his/her initials as well as the date of the correction. 


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 Handling of Biological Specimens 
Not Applicable. 
 Publications 
Authorship and manuscript composition will reflect cooperation among all parties 
involved in the study. Authorship will be established before writing the manuscript. Ora 
and the sponsor will have the final decision regarding the manuscript and publication. 
 
 
 
 
 
 
 
 
 
12 REFERENCES 
1. 
Abelson MB, Chapin MJ, Kapik BM, Shams NB. Efficacy of ketotifen fumarate 
0.025% ophthalmic solution compared with placebo in the conjunctival allergen 
challenge model. Arch Ophthalmol. 2003;121(5):626-630. 
2. 
Ackerman SL, Torkildsen GL, McLaurin E, Vittitow JL. Low-dose brimonidine 
for relief of ocular redness: integrated analysis of four clinical trials. Clin Exp 
Optom. 2019;102(2):131-139. 
3. 
Alexander M, Berger W, Buchholz P, et al. The reliability, validity, and 
preliminary responsiveness of the Eye Allergy Patient Impact Questionnaire 
(EAPIQ). Health Qual Life Outcomes. 2005;3:67. 
4. 
Angjeli E, Gomes P, Lane KJ, Stein L, Abelson MB. Technical and clinical 
validation of the Allergen BioCube((R)) for timothy grass. Immun Inflamm Dis. 
2017;5(1):78-84. 
5. 
Bielory BP, O'Brien TP, Bielory L. Management of seasonal allergic 
conjunctivitis: guide to therapy. Acta Ophthalmol. 2012;90(5):399-407. 
6. 
Bielory L, Schoenberg D. Emerging Therapeutics for Ocular Surface Disease. 
Curr Allergy Asthma Rep. 2019;19(3):16. 


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7. 
Brozek G, Lawson J, Szumilas D, Zejda J. Increasing prevalence of asthma, 
respiratory symptoms, and allergic diseases: Four repeated surveys from 1993-
2014. Respir Med. 2015;109(8): 00832-990. 
8. 
Butrus S, Portela R. Ocular allergy: diagnosis and treatment. Ophthalmol Clin 
North Am. 2005;18(4):485-492, v. 
9. 
Chigbu DI, Minhas BK. Immunopathology of Allergic Conjunctivitis. Eur Med J. 
2018;3(1):76-83. 
10. 
Dupuis P, Prokopich CL, Hynes A, Kim H. A contemporary look at allergic 
conjunctivitis. Allergy Asthma Clin Immunol. 2020;16:5. 
11. 
Gomes PJ, Abelson MB, Stein L, Viirre E, Villafranca JE, Lasser EC. Iodixanol 
nasal solution reduces allergic rhinoconjunctivitis signs and symptoms in 
Allergen BioCube((R)): a randomized clinical trial. J Asthma Allergy. 
2019;12:71-81. 
12. 
Gomes PJ, Lane KJ, Angjeli E, Stein L, Abelson MB. Technical and clinical 
validation of an environmental exposure unit for ragweed. Journal of Asthma and 
Allergy. 2016;Volume 9:215-221. 
13. 
Lane K, Angjeli E, Gomes P, Abelson M, Shazley T, Contractor M. Validation 
and verification of the Allergen BioCube model with an intranasal corticosteroid. 
ARVO poster presentation; 2011. 
14. 
Leonardi A, Castegnaro A, Valerio AL, Lazzarini D. Epidemiology of allergic 
conjunctivitis: clinical appearance and treatment patterns in a population-based 
study. Curr Opin Allergy Clin Immunol. 2015;15(5):482-488. 
15. 
Miyazaki D, Fukagawa K, Okamoto S, et al. Epidemiological aspects of allergic 
conjunctivitis. Allergol Int. 2020;69(4):487-495. 
16. 
O'Brien TP. Allergic conjunctivitis: an update on diagnosis and management. 
Curr Opin Allergy Clin Immunol. 2013;13(5):543-549. 
17. 
Ono SJ, Abelson MB. Allergic conjunctivitis: update on pathophysiology and 
prospects for future treatment. J Allergy Clin Immunol. 2005;115(1):118-122. 
18. 
Palmares J, Delgado L, Cidade M, Quadrado MJ, Filipe HP, Season Study G. 
Allergic conjunctivitis: a national cross-sectional study of clinical characteristics 
and quality of life. Eur J Ophthalmol. 2010;20(2):257-264. 
19.  
Rosario N, Bielory L. Epidemiology of allergic conjunctivitis. Curr Opin  Allergy 
Clin Immunol. 2011;11(5):471-476.  
20. 
Singh K, Axelrod S, Bielory L. The epidemiology of ocular and nasal allergy in 
the United States, 1988-1994. J Allergy Clin Immunol. 2010;126(4):778-783 
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Villegas BV, Benitez-Del-Castillo JM. Current Knowledge in Allergic 
Conjunctivitis. Turk J Ophthalmol. 2021;51(1):45-54. 


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22. 
Alaway® Ketotifen Fumarate Ophthalmic Solution, 0.035% (OTC). Label.  
Bausch & Lomb; approved April 2021.2006.2006. 
23. 
Lumify® Brimonidine Tartrate Ophthalmic SSSolution, 0.025%. Label. Bausch 
& Lomb; approved September 2020. 
 
 




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APPENDIX 2: EXAMINATION PROCEDURES, TESTS, 
EQUIPMENT, AND TECHNIQUES 
Visual Acuity Procedures (ETDRS Chart) 
LogMAR visual acuity (VA) must be assessed using an Early Treatment Diabetic 
Retinopathy Study (ETDRS) chart. The procedure used will be consistent with the 
recommendations provided for using the ETDRS eye chart. VA should be evaluated at 
the beginning of each visit in the study (i.e., prior to slit-lamp examination). VA testing 
should be done with most recent correction. 
Equipment 
The VA 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 either Series 2000 
Chart 1 or Chart 2 or Chart R, and the right eye should be tested first.  The chart should 
remain the same for all visits at the site. 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 to be 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 1 of 2 letters, he or she should be asked to choose 1 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. 




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External magnification and biomicroscopy will be performed using a slit-lamp. 
Magnification will be consistent with standard clinical practice. The subject will be 
seated. 
Dilated Fundoscopy 
Dilated fundus exams will be performed using indirect ophthalmoscopy. The investigator 
will make observations of the vitreous, retina, macula, choroid and optic nerve.   
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 Fundoscopy 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.  
 Optic Nerve: Significant damage or cupping to the optic nerve should be noted. 
 
It is recommended that tropicamide 1% ophthalmic solution be used to dilate subjects. 
The use of cyclopentolate 1% ophthalmic solution is recommended as secondary dilating 
medication, should the need arise.   
Vital Signs 
Each subject will have vital signs assessments (resting blood pressure and pulse) 
conducted at Visit 1 and Visit 2. Vital signs are to be conducted by a qualified staff 
member who may be any of the following: a board-certified investigator or sub-
investigator, nurse practitioner, registered nurse, or physician’s assistant, or trained 
research coordinator.  
Systolic/Diastolic Blood Pressure (mmHg) 
Systolic and diastolic blood pressure should be measured in the same arm, when possible, 
each time using a manual or digital sphygmomanometer with the subjects who have been 
in a resting state (seated upright) at least 5 minutes. Blood pressure will be recorded in 
mmHg. 
Pulse (bpm) 
Pulse will be measured with the subjects who have been in a resting state (seated) for at 
least 5 minutes. Pulse may be measured manually by counting for 30 seconds and 
multiplying by 2 and recording in beats per minute (bpm) or it can be measured digitally 
and recorded. 


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Intraocular Pressure 
Intraocular pressure (IOP) will be measured in each eye by contact tonometry by the 
examiner and the results will be recorded in mmHg.  A single measurement is made to 
obtain a determination of IOP.  The same tonometer employing the investigator’s 
standard technique will be used throughout the study.  In addition, all reasonable efforts 
will be made to have the same examiner obtain all IOP measurements for a given subject. 
Peak Nasal Inspiratory Flow 
Peak nasal inspiratory flow (PNIF) readings will be made using an ‘in check’ inspiratory 
flow meter with nasal adaptor (Clement Clarke International, England). Measurements 
will be made in a standing position. Subjects will be instructed to exhale residual volume, 
place face mask over the mouth and nose to create a good seal around the face mask, and 
then inhale forcefully to total lung capacity, through the nose, with mouth closed. This 
maneuver should be a short, sharp inspiratory action of about 1 second in duration. Three 
measurements will be made. Subjects will be trained to perform the test at Visit 2. 
Detailed PNIF instructions are provided: 
1. Reset the instrument by holding vertically with the mouthpiece up with one hand 
and tapping lightly onto the other hand such that the small magnetic cylinder 
dislodges and pushes the red wheel all the way down. When this occurs, invert the 
instrument and make sure the magnet returns to its resting position.  
2. Attach the subject specific filter and mouth piece to the PNIF device. Ensure by 
asking the subject for their initials.  
3. Ask the subject to exhale fully.  
4. Ask the subject to press the mask tight against their face forming and air tight 
seal.  
5. Ask the subject, while standing, to hold the device horizontally.  
6. Ask the subject to inhale forcibly though their nose as fast and hard as they can. 
7. Ensure that the subject is NOT inhaling though their mouth.  
8.  Repeat the measurement 3 times and record all 3.  
9.  Place the mask back in the appropriate labeled bag.  
Peak Expiratory Flow Rate  
Peak expiratory flow rate (PEFR) will be measured with a hand held peak flow meter (at 
least 20-30 minutes after subjects have been exposed to room temperature). This test will 
be conducted for subject safety during all visits according to manufacturer instructions. 
Three measurements will be made on each occasion. Subjects will be trained to perform 
the test at Visit 1.  


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SUBJECT ALLERGEN SCALES 
Subject-Evaluated Symptoms (Ocular and Nasal) 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Nasal Allergic Symptoms 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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INVESTIGATOR SCALES 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ora proprietary scales – Not for distribution without permission 
 
 
 
 
 
 
 
 


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APPENDIX 3: HANDLING OF BIOLOGICAL SPECIMENS 
Not Applicable. 


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APPENDIX 4: PROTOCOL AMENDMENT SUMMARY 
Please refer to Summary of Changes Document. 






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APPENDIX 7: INVESTIGATOR’S SIGNATURE 
 
Protocol Title: 
A Multi-Center, Double-Masked, Randomized, Parallel-Group, 
Vehicle-Controlled Evaluation of the Onset and Duration of 
Action of the Combination Drug Product Brimonidine Tartrate 
0.025%/ Ketotifen Fumarate 0.035% Ophthalmic Solution 
Compared to its Components and Vehicle in an Allergen 
BioCube® (ABC®) Clinical Trial in Subjects with Seasonal 
Allergic Conjunctivitis 
Protocol Number: 
910 
Final Date: 
31 July 2023 
I agree to implement and conduct the study diligently and in strict compliance with the 
protocol, good clinical practices and all applicable laws and regulations. I agree to 
maintain all information supplied by Ora and the sponsor in confidence and, when this 
information is submitted to an Institutional Review Board (IRB), Ethical Review 
Committee (ERC) or another group, it will be submitted with a designation that the 
material is confidential. 
I have read this protocol in its entirety, including the above statement, and I agree to all 
aspects. 
Signed: 
 
 
Date:  
 
<enter name and credentials> 
<enter title> 
<enter affiliation> 
<enter address> Specify address and phone number for each study location. 
<enter phone number> 

SAP_001.pdf: