Clinical trial NCT05579730
Conditions: Allergic Conjunctivitis
Sponsor: Bausch & Lomb Incorporated
Start date: 2022-10-12; Completion date: 2023-07-22
Enrollment: 188 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the efficacy of Combo (Drug Product Brimonidine Tartrate 0.025%/Ketotifen Fumarate 0.035% Ophthalmic Solution) compared to its individual components and vehicle in a population of subjects with allergic conjunctivitis:

Detailed description:

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

Protocol documents:
Prot_002.pdf: 









































































































































SAP_003.pdf: 
 
STATISTICAL ANALYSIS PLAN  
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 for the Treatment of Allergic 
Conjunctivitis in the Conjunctival Allergen Challenge Model 
 
Sponsor:  
Bausch & Lomb, Incorporated 
400 Somerset Corporate Boulevard  
Bridgewater, NJ 08807 
 
 
 
 
Protocol Number: 
909 
 
 
 
Date:   
 
05JUL2023 
Version:  
 
Final 1.0 
 


 
 
 
Page 2 of 21 
 
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 for the Treatment of Allergic 
Conjunctivitis in the Conjunctival Allergen Challenge Model 
 
Protocol Number: 
909 
SAP Version:   
Final 1.0 
SAP Date:  
 
05JUL2023 
 
Statistical Analysis Plan Approval 
 
 
 
Prepared by: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reviewed by:  
 
 
 
 
 
_____________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Approved by:  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


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Table of Contents 
Table of Contents .......................................................................................................................................... 3 
List of Abbreviations ...................................................................................................................................... 5 
1. 
Introduction........................................................................................................................................ 6 
2. 
Study Objective and Study Parameters ............................................................................................ 6 
2.1 Study Objective ................................................................................................................................. 6 
2.2 Study Parameters ............................................................................................................................. 6 
2.2.1 
Efficacy Measures and Endpoints ............................................................................................. 6 
2.2.1.1 
Primary Efficacy Measures and Endpoints ....................................................................... 6 
2.2.1.2 
Secondary Efficacy Measures and Endpoints .................................................................. 6 
2.2.1.3 
Exploratory Efficacy Measures and Endpoints ................................................................. 7 
2.2.2 
Safety Measures ....................................................................................................................... 7 
2.2.3 
Tolerability Measures ................................................................................................................ 7 
2.3 Statistical Hypotheses and Adjustments for Multiplicity .................................................................... 7 
2.3.1 
Hypotheses ............................................................................................................................... 8 
3. 
Study Design and Procedures .......................................................................................................... 9 
3.1 General Study Design ....................................................................................................................... 9 
4. 
Treatment Plan ................................................................................................................................ 11 
4.1 Methods of Assigning Subjects to Treatment Groups .................................................................... 11 
5. 
Sample Size and Power Considerations ......................................................................................... 11 
6. 
General Statistical Considerations .................................................................................................. 11 
7. 
Analysis Populations ....................................................................................................................... 12 
7.1 Intent to Treat Set ........................................................................................................................... 12 
7.2 Full Analysis Set .............................................................................................................................. 12 
7.3 Per Protocol Set .............................................................................................................................. 12 
7.4 Safety Set ........................................................................................................................................ 12 
8. 
General Statistical Considerations .................................................................................................. 12 
8.1 Unit of Analysis................................................................................................................................ 12 
8.2 Missing Efficacy Data Imputations .................................................................................................. 12 
8.3 Other Missing or Inconclusive Data Handling ................................................................................. 13 
8.4 Scheduled/Unscheduled Visits........................................................................................................ 14 
8.5 Definition of Baseline ...................................................................................................................... 14 
9. 
Disposition of Subjects .................................................................................................................... 14 
10. 
Protocol Deviations ......................................................................................................................... 14 
11. 
Demographics and Baseline Characteristics .................................................................................. 15 
12. 
Medical History ................................................................................................................................ 15 
13. 
Prior or Concomitant Medications ................................................................................................... 15 


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14. 
Statistical Analyses ......................................................................................................................... 15 
14.1 Analyses of Primary Efficacy Endpoints ......................................................................................... 15 
14.1.1 Primary Analysis...................................................................................................................... 16 
14.1.2 Sensitivity Analyses................................................................................................................. 16 
14.1.3 Subgroup Analyses ................................................................................................................. 17 
14.2 Analyses of Secondary Efficacy Endpoints ..................................................................................... 17 
14.3 Analyses of Exploratory Efficacy Endpoints .................................................................................... 18 
14.4 Analyses of Safety Measures .......................................................................................................... 18 
14.4.1 Adverse Events ....................................................................................................................... 18 
14.4.2 BCVA Utilizing an ETDRS Chart ............................................................................................. 19 
14.4.3 Slit-Lamp Biomicroscopy ......................................................................................................... 19 
14.4.4 IOP .......................................................................................................................................... 19 
14.4.5 Dilated Fundoscopy ................................................................................................................ 19 
14.5 Analyses of Tolerability Measures .................................................................................................. 19 
14.5.1 Ora Calibra® Drop Comfort Assessment and Questionnaire .................................................. 19 
15. 
Interim Analyses .............................................................................................................................. 19 
16. 
Changes to the Analyses Planned in the Protocol .......................................................................... 20 
17. 
SAS® Codes for Multiple Imputations.............................................................................................. 20 
17.1 Randomized, Treatment-Based MCMC Methodology to Impute Non-monotone Missing Data ..... 20 
17.2 Randomized, Treatment-Based Regression Methodology for Monotone Missing Data ................. 20 
18. 
References ...................................................................................................................................... 21 
 
 
 




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1. 
Introduction 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and reporting for 
protocol 909, Amendment 3.0 (Version 4.0) dated 03Apr2023. 
This SAP is being written with due consideration of the recommendations outlined in the most recent 
International Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials and the most recent ICH E3 Guideline entitled Guidance for Industry: Structure 
and Content of Clinical Study Reports. 
This SAP describes the data that will be analyzed and the subject characteristics, efficacy, and safety 
assessments that will be evaluated. This SAP provides details of the specific statistical methods that will 
be used. The statistical analysis methods presented in this document will supersede the statistical analysis 
methods described in the clinical protocol. If additional analyses are required to supplement the planned 
analyses described in this SAP, they may be completed and will be identified in the clinical study report. 
2. 
Study Objective and Study Parameters  
2.1 
Study Objective 
The primary objective is to evaluate the efficacy of Brimonidine Tartrate 0.025%/Ketotifen Fumarate 0.035% 
Ophthalmic Solution (Combo) compared to its individual components and vehicle in a population of subjects 
with allergic conjunctivitis.  
2.2 
Study Parameters 
2.2.1 
Efficacy Measures and Endpoints 
2.2.1.1 
Primary Efficacy Measures and Endpoints 
• 
Ocular itching score (average score of the subject’s two eyes) evaluated by the subject at 3(±1), 
5(±1), and 7(±1) minutes post-conjunctival allergen challenge (CAC; 0-4 scale, allowing half unit 
increments) at Visits 4b and 5 
• 
Conjunctival redness score (average score of the subject’s two eyes) evaluated by the investigator 
at 7(±1), 15(±1), and 20(±1) minutes post-CAC (0-4 scale, allowing half unit increments) at Visits 
4b and 5 
2.2.1.2 
Secondary Efficacy Measures and Endpoints 
• 
Ciliary redness score (average score of the subject’s two eyes) evaluated by the investigator at 
7(±1), 15(±1), and 20(±1) minutes post-CAC (0-4 scale, allowing half unit increments) at Visits 4b 
and 5 


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• 
Episcleral redness score (average score of the subject’s two eyes) evaluated by the investigator at 
7(±1), 15(±1), and 20(±1) minutes post-CAC (0-4 scale, allowing half unit increments) at Visits 4b 
and 5 
2.2.1.3 
Exploratory Efficacy Measures and Endpoints 
• 
Eyelid swelling score (average score of the subject’s two eyes) evaluated by the subject at 7(±1), 
15(±1), and 20(±1) minutes post-CAC (0-3 scale, not allowing half unit increments) at Visits 4b and 
5 
• 
Tearing score (average score of the subject’s two eyes) evaluated by the subject at 7(±1), 15(±1), 
and 20(±1) minutes post-CAC (0-4 scale, not allowing half unit increments) at Visits 4b and 5 
• 
Chemosis score (average score of the subject’s two eyes) evaluated by the investigator at 7(±1), 
15(±1), and 20(±1) minutes post-CAC (0-4 scale, allowing half unit increments) at Visits 4b and 5 
• 
Rhinorrhea, nasal pruritus, ear or palate pruritus, and nasal congestion evaluated by the subject at 
7(±1), 15(±1), and 20(±1) minutes post-CAC (0-4 scale, not allowing half unit increments) at Visits 
4b and 5 
2.2.2 
Safety Measures 
• 
Adverse Events (AEs; reported, elicited and observed) 
• 
Best-corrected visual acuity (BCVA) at distance utilizing an Early Treatment Diabetic Retinopathy 
Study (ETDRS) chart 
• 
Slit-lamp Biomicroscopy  
• 
Intraocular Pressure (IOP) 
• 
Dilated Fundoscopy  
2.2.3 
Tolerability Measures 
• 
Ocular comfort grade (lowest score of the subject’s two eyes) assessed by the subject upon 
investigational product instillation and at 1 minute (± 0.5 minutes) after investigational product 
instillation at Visit 4a (0-10 unit scale) 
• 
Subject description of drop comfort questionnaire assessed at 3 minutes post-instillation at Visit 4a 
2.3 
Statistical Hypotheses and Adjustments for Multiplicity 
Statistical success will be achieved if all of the following conditions are met at Visits 4b for duration of action 
and Visit 5 for onset of action:  
• 
The Combo is superior in ocular itching and ocular redness to Vehicle. 
• 
The Combo is superior in ocular itching to brimonidine tartrate 0.025%. 
• 
The Combo is superior in ocular redness to ketotifen fumarate 0.035%. 


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Superiority will be demonstrated for the first bullet point above if all of the following are true. 
• 
For each endpoint, the estimated treatment effect (of the difference between ketotifen 
fumarate/brimonidine tartrate Combo ophthalmic solution and vehicle) is at least 0.5 units (one step) 
on a 5-point (nine step) scale at all three post-CAC time points at each of Visit 4b and 5. 
• 
For each endpoint, the estimated treatment effect is at least 1.0 unit (two steps) at two or three 
post-CAC time points at both Visits 4b and 5. 
• 
For each endpoint at each visit, hypothesis testing will start with the first two post-CAC time points. 
If the treatment effect is statistically significant (one-sided α = 0.0125=0.025/2 to account for the 
two time points) at both post-CAC time points, then this condition is met. If the treatment effect is 
statistically significant at only one of the time points, then the third time point is tested at the unused 
one-sided alpha of 0.0125. 
Superiority will be demonstrated for the second and third bullet points at the beginnng of Section 2.3 if all 
of the following are true. 
• 
The estimated treatment effect (of the difference between ketotifen fumarate/brimonidine tartrate 
Combo ophthalmic solution and the comparator) is at least 0.5 units (one step) on a 5-point (nine 
step) scale at all three post-CAC time points at each of Visit 4b and 5. 
• 
The estimated treatment effect is at least 1.0 unit (two steps) at two or three post-CAC time points 
at both Visits 4b and 5. 
• 
At each visit, hypothesis testing will start with the first two post-CAC time points. If the treatment 
effect is statistically significant (one-sided α = 0.0125=0.025/2 to account for the two time points) 
at both post-CAC time points, then this condition is met. If the treatment effect is statistically 
significant at only one of the time points, then the third time point is tested at the unused one-sided 
alpha of 0.0125. 
2.3.1 
Hypotheses 
Superiority Tests 
For each primary endpoint at each of the six evaluation times, two superiority hypotheses will be tested 
comparing the Combo to a comparator (Vehicle and either ketotifen fumarate 0.035% or brimonidine tartrate 
0.025%). The null hypothesis (𝐻𝐻0) is that the mean score for the subjects in the test (Combo) group (µ𝑇𝑇) is 
greater than or equal to the mean score for the subjects in the comparator group (µ𝐶𝐶). The alternative 
hypothesis (𝐻𝐻1) is that the mean score for the subjects in the test group is less than the mean score for the 
subjects in the comparator group. 
𝐻𝐻0: 𝜇𝜇𝑇𝑇  ≥ 𝜇𝜇𝐶𝐶 
𝐻𝐻1: 𝜇𝜇𝑇𝑇  < 𝜇𝜇𝐶𝐶 


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The hypotheses above will be tested for each of the six post-instillation times at Visits 4b and 5 (three post-
instillation times per visit) using an ANCOVA model with terms for baseline value and treatment. Success 
will be determined as per the criteria described in Section 2.3.  
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 2.2.1.2. 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. 
3. 
Study Design and Procedures 
3.1 
General Study Design 
This is a multi-center, double-masked, randomized, parallel-group, vehicle-controlled study. 
The study will consist of 6 study visits: a Screening Period of 3 study visits to verify subjects are eligible to 
participate and, following randomization, a Treatment Period of 3 study visits 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 an ocular allergen challenge titration using an allergen that elicited 
a positive reaction via skin testing. Subjects with a positive reaction post-CAC will undergo a confirmation 
CAC at Visit 3 with the same allergen qualified during Visit 2. 
Treatment will begin at Visit 4a after subjects are randomized 1:1:1:1 to receive either Combo bilaterally, 
ketotifen fumarate 0.035% ophthalmic solution bilaterally, brimonidine tartrate 0.025% ophthalmic solution 
bilaterally, or vehicle ophthalmic solution bilaterally. At this visit, subjects will receive an in-office dose of 
the treatment they were randomized to receive. Approximately 8 hours post-instillation of study medication, 
at Visit 4b, subjects will undergo a CAC. Subjects will receive a final dose of study medication at Visit 5 
approximately 15 minutes prior to CAC. Efficacy evaluations will be conducted at Visit 4b and Visit 5. 
 
 




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4. 
Treatment Plan 
4.1 
Methods of Assigning Subjects 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 4a, they will be randomized to 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 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. 
5. 
Sample Size and Power Considerations 
A sample size of 40 subjects in each treatment group will have at least 98% power to detect a difference in 
means of 1 unit at each time point assuming that the common standard deviation (SD) is 1 unit using a two-
group t-test with a 1.25% one-sided significance level. Given that both efficacy measures (itching and 
redness) must pass in order to declare success, the overall power is at least 96%. To allow for 10% 
dropouts, 45 subjects will be randomized in each of the treatment groups.  
6. 
General Statistical Considerations  
All data analysis will be performed by Statistics & Data Corporation (SDC) after the study is completed and 
the database has been locked. Analysis datasets will be created using data obtained from electronic data 
capture (EDC) and external data if applicable. Statistical programming and analyses will be performed using 
SAS® Version 9.4 or higher. Outputs will be provided in portable document format (PDF) for tables, listings, 
and figures using landscape format.  
All study data will be listed by subject, treatment, and visit (as applicable) based on all randomized subjects, 
unless otherwise specified. Listings will be sorted by subject number, visit date, time, and parameter as 
applicable. 
Summaries for continuous and ordinal variables will include the number of observations (n), arithmetic 
mean, SD, median, minimum, and maximum. Minima and maxima will be reported with the same precision 
as the raw values; means and medians will be presented to one additional decimal place than reported in 
the raw values. Standard deviations will be presented to two additional decimal places than reported in the 


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raw values. Summaries for discrete variables will include frequency counts and percentages. All 
percentages will be rounded to one decimal place (i.e., xx.x%). 
All statistical tests will be one-sided with a significance level of 0.05 (α = 0.05), unless otherwise specified. 
All p-values will be rounded to four decimal places; p-values less than 0.0001 will be presented as 
“<0.0001”; and p-values greater than 0.9999 will be presented as “>0.9999”. 
7. 
Analysis Populations 
7.1 
Intent to Treat Set 
The Intent to Treat (ITT) Set will include all subjects who are instilled with study drug. The ITT Set will be 
analyzed as randomized. 
7.2 
Full Analysis Set  
The Full Analysis Set (FAS) will consist of all randomized subjects who are instilled with study drug and 
have at least one post-instillation of study drug assessment of both primary endpoints. The FAS will be 
analyzed as randomized. 
7.3 
Per Protocol Set  
The Per Protocol (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 Set 
will be analyzed as treated. 
7.4 
Safety Set 
The Safety Set will include all subjects who receive any amount of study drug. The Safety Set will be 
analyzed as treated. 
8. General Statistical Considerations 
8.1 
Unit of Analysis 
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).  
8.2 
Missing Efficacy Data Imputations 
The primary efficacy analysis will be conducted with intercurrent events handled in the following manners: 


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1. Withdrawal due to lack of efficacy or AEs [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 AEs 
[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: 
• 
Discontinuation of study drug will be ignored (that is, measured values will be used regardless of 
compliance or discontinuation of study drug) [treatment policy strategy]. 
8.3 
Other Missing or Inconclusive Data Handling  
In general, there will be no imputation of missing data other than for partial or missing dates where complete 
dates are required to flag data as treatment-emergent or concomitant with treatment. Partial/missing start 
and end dates for AEs and concomitant medications will be imputed as follows: 
Partial/missing start date:  
• 
Dates with missing day only will be imputed as the 1st of the month unless the month and year are 
same as the month and year of the first dose date of study drug, in which case missing day will be 
imputed as the first dose day of study drug.  
• 
Dates with both day and month missing will be imputed as 1 Jan unless the year is same as the 
year of the first dose date of study drug, in which case missing day and month will be imputed as 
the day and month of the first dose of study drug. 
• 
Completely missing dates will be imputed as the first dose date of study drug unless the end date 
is on or before the first dose date, in which case missing date will be imputed as 1 Jan of the same 
year as the end date. 
Partial/missing end date:  
• 
Dates with missing day only will be imputed as the last day of the month.  
• 
Dates with both day and month missing will be imputed as 31 Dec.  
• 
If the ongoing flag is missing or “Yes” then the date will not be imputed. 
• 
If the imputed date is after the date of death, then the end date will be set equal to the date of 
death.  
The original dates will be displayed in data listings and the imputed dates will be used in derivations only 
(study day, treatment-emergence status, etc). 


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COVID-19-related missing data or visits will not be imputed for summaries and analyses but will be reported 
as protocol deviations and recorded in protocol deviation log.  
8.4 
Scheduled/Unscheduled Visits 
Only scheduled visits will be used for the visit-related summaries and analyses, unless specified otherwise. 
Unscheduled visits will be presented in data listings. 
8.5 
Definition of Baseline 
Baseline is defined as last non-missing assessment prior to the first dose of study drug. Change from 
baseline will be calculated as Post-baseline Visit – Baseline Visit. 
9. 
Disposition of Subjects 
A summary for subject disposition by treatment group and overall for all subjects will include: 
• 
Number of screen failures for all subjects only 
• 
Number of randomized subjects 
• 
Number and percentage of subjects for each of the study populations (ITT Set, FAS, PP Set, 
and Safety Set) 
• 
Number and percentage of subjects who completed the study. 
• 
Number and percentage of subjects discontinued from the study and the reasons for 
discontinuation.  
• 
Number and percentage of subjects who discontinued for reasons related to COVID-19 
Percentages for the subject disposition summary are based on number of randomized subjects.  
Subject listings will be provided that include disposition, informed consent date, inclusion and exclusion 
criteria, and exclusions from the analysis sets and reason for exclusion from population. Details of the study 
randomization, including randomization date and time, randomized and actual treatment, dispensed kit 
number, and reason for unmasking (if applicable) will also be included within a subject listing. 
10. 
Protocol Deviations 
The number and percentage of subjects with any deviation, important deviations, not-important deviations, 
deviations resulting excluding from PP Set, and COVID-19 related protocol deviations will be summarized 
by treatment group and overall for all subjects for the ITT Set.  
A subject listing will be provided for protocol deviations that includes the visit at which the deviation 
occurred, the deviation date, the deviation code, the deviation description, whether the deviation was 
related to COVID-19, and the classification of the deviation as important or not-important. 


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11. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will include sex, age in years at signing of ICF, age group (<65 
years, ≥65 years), race, ethnicity, and iris color for OD and OS). Subjects who record more than one race 
are grouped into the single category denoted as Multi-racial. Demographic data will be summarized by 
treatment group and overall for all subjects in the ITT Set.  
Allergic skin test results at Screening will be summarized by treatment group. A subject listing will be 
provided for Allergic skin test results as well as the CAC titration and confirmation results performed at 
Visits 2 and 3, respectively. 
Subject listings that includes all demographic data and allergic skin test data will be provided. 
12. 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 25.0. 
Ocular and non-ocular medical history will be summarized separately by system organ class (SOC), 
preferred term (PT), and treatment group for the ITT Set. If a subject has more than one SOC or PT within 
an SOC, they will only be summarized once for that SOC or PT 
Medical history data will be presented in a subject listing.  
13. 
Prior or Concomitant Medications 
Prior and concomitant medications will be coded using World Health Organization Drug Dictionary 
(WHODrug; Global B3, March 2022). Concomitant medications will be defined as medications used during 
on or after the first dose date of study drug. Prior medications will be defined as medications used prior to 
the first dose date of study drug. Ocular and non-ocular prior and concomitant medications used at the 
subject level will be summarized separately by the therapeutic drug class (Anatomical Therapeutic 
Chemical [ATC] 4 classification), preferred name, and treatment group for the Safety Set. If the ATC 4 
classification is not provided, the next lowest classification that is provided in the coding dictionary will be 
used. The preferred name will be defined as the active ingredient; if the active ingredient is not provided or 
includes more than two ingredients (e.g., multivitamins), then the drug name will be presented as the 
preferred name.  
Reported and coded terms (ATC class and preferred name) for ocular and non-ocular medications will be 
presented in separate subject listings.  
14. 
Statistical Analyses 
14.1 
Analyses of Primary Efficacy Endpoints  
The primary efficacy endpoints are: 


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• 
Ocular itching score (average score of the subject’s two eyes) evaluated by the subject at 3(±1), 
5(±1), and 7(±1) minutes post-CAC (0-4 scale, allowing half unit increments) at Visits 4b and 5 
• 
Conjunctival redness score (average score of the subject’s two eyes) evaluated by the investigator 
at 7(±1), 15(±1), and 20(±1) minutes post-CAC (0-4 scale, allowing half unit increments) at Visits 
4b and 5 
Statistical success will be achieved if all of the following conditions are met at Visits 4b for duration of action 
and Visit 5 for onset of action:  
• 
The Brimonidine Tartrate 0.025%/Ketotifen Fumarate 0.035% Ophthalmic Solution (Combo) is 
superior in ocular itching and ocular redness to Vehicle. 
• 
The Combo is superior in ocular itching to brimonidine tartrate 0.025%. 
• 
The Combo is superior in ocular redness to ketotifen fumarate 0.035%. 
Each primary endpoint will be summarized at baseline and for each post-instillation of study drug time point 
at Visits 4b and 5 by treatment group using continuous summary statistics for the ITT Set. 
14.1.1 Primary Analysis 
The primary efficacy analysis of primary efficacy endpoints will be conducted with intercurrent events 
handled in the following manners: 
1. Withdrawal due to lack of efficacy or AEs [assumed to be 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 AEs 
[assumed to be MAR]: missing data will be imputed employing multiple imputation using 
randomized, treatment-based MCMC methodology to impute non-monotone missing and using 
randomized, treatment-based regression methodology to impute monotone missing [hypothetical 
strategy].  
Treatment effects will be estimated and the statistical hypotheses will be tested using an analysis of 
covariance model (ANCOVA) with terms for baseline value and treatment. Estimated mean differences 
between treatment groups and associated 95% CI, and overall p-values will provided.  
14.1.2 Sensitivity Analyses  
The sensitivity analyses will include the imputation models, analysis methods, and analysis sets as stated 
on Table 2. 
 
 


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Table 2. Sensitivity Analyses Methods 
 
Missing Values Imputation 
Analysis Method(s) 
Analysis Set(s) 
1 
The same as the primary analysis 
ANCOVA 
PP Set 
2 
The same as the primary analysis 
two-sample t-tests assuming equal 
variances 
ITT Set 
3 
Multiple imputation using a 
randomized, treatment-based 
MCMC for non-monotone missing 
and a randomized, treatment-
based regression methodology for 
monotone missing 
ANCOVA, two-sample t-tests assuming 
equal variances 
ITT Set 
4 
Worst observation carried forward 
ANCOVA, two-sample t-tests assuming 
equal variances, Wicoxon rank sum 
test  
ITT Set 
5 
Observed values only 
ANCOVA, two-sample t-tests assuming 
equal variances Wilcoxon rank sum 
test,  
ITT Set, FAS, 
PP Set 
Note: ANCOVA model has the terms treatment and baseline value. 
Refer to Section 17 for SAS codes for multiple imputations. 
14.1.3 Subgroup Analyses  
Primary efficacy endpoints using observed values only based on the ITT Set will be analyzed in the same 
manner as the Sensitivity Analysis #5 (Table 2) for subgroups of age (<65 vs ≥65 years), sex (male vs 
female), and race (white vs others). 
14.2 
Analyses of Secondary Efficacy Endpoints 
The secondary efficacy endpoints include: 
• 
Ciliary redness score (average score of the subject‘s two eyes) evaluated by the investigator at 
7(±1), 15(±1), and 20(±1) minutes post-CAC (0-4 scale, allowing half unit increments) at Visits 4b 
and 5 
• 
Episcleral redness score (average score of the subject‘s two eyes) evaluated by the investigator at 
7(±1), 15(±1), and 20(±1) minutes post-CAC (0-4 scale, allowing half unit increments) at Visits 4b 
and 5 
Success for each secondary endpoint will follow the same criteria as the primary endpoint. Primary analysis 
for the secondary efficacy endpoints will be performed in the same manner as the primary analysis for 
primary efficacy endpoints. Sensitivity analyses for the secondary endpoints will be performed in the same 
manner as the sensitivity analyses for the primary endpoints (Table 2). 


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Secondary efficacy endpoints using observed values only based on the ITT Set will be analyzed in the 
same manner as the Sensitivity Analysis #5 (Table 2) for subgroup of age (<65 vs ≥65 years), sex (male 
vs female), and race (white vs others). 
14.3 
Analyses of Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints include: 
• 
Eyelid swelling score (average score of the subject’s two eyes) evaluated by the subject at 7(±1), 
15(±1), and 20(±1) minutes post-CAC (0-3 scale, not allowing half unit increments) at Visits 4b and 
5 
• 
Tearing score (average score of the subject’s two eyes) evaluated by the subject at 7(±1), 15(±1), 
and 20(±1) minutes post-CAC (0-4 scale, not allowing half unit increments) at Visits 4b and 5 
• 
Chemosis score (average score of the subject’s two eyes) evaluated by the investigator at 7(±1), 
15(±1), and 20(±1) minutes post-CAC (0-4 scale, allowing half unit increments) at Visits 4b and 5 
• 
Rhinorrhea, nasal pruritus, ear or palate pruritus, and nasal congestion evaluated by the subject at 
7(±1), 15(±1), and 20(±1) minutes post-CAC (0-4 scale, not allowing half unit increments) at Visits 
4b and 5 
Only observed values will be used for the analyses of the exploratory efficacy endpoints. The exploratory 
efficacy endpoints will be summarized descriptively at baseline and each post-baseline time points by 
treatment group. The exploratory efficacy endpoints will be analyzed using two-sample t-tests assuming 
equal variance and a ANCOVA model with the efficacy variable as the dependent variable, treatment as a 
factor, and baseline score as a covariate. P-values will provided. The analyses will be based on the ITT 
Set.  
14.4 
Analyses of Safety Measures 
14.4.1 Adverse Events 
AEs will be coded using the MedDRA Version 25.0.  
Treatment-emergent adverse events (TEAEs) are defined as AEs with onset dates on or after the first dose 
date of study drug. Incidences and percentages of TEAEs will be summarized at the subject level by SOC 
and PT for all TEAEs, treatment-related TEAEs, treatment-emergent serious adverse events (TE-SAEs), 
and TEAEs causing premature study drug withdrawal by treatment group. Similar summaries will be 
presented for all TEAEs by maximal severity. Separate summaries will be performed for ocular and non-
ocular AEs. The analyses will be based on the Safety Set.  
AEs, serious adverse events (SAEs), and AEs causing premature study drug withdrawal will be presented 
separately in subject listings. 


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14.4.2 BCVA Utilizing an ETDRS Chart 
Actual values for BCVA in logarithm of the minimum angle of resolution (logMAR) will be summarized for 
OD and OS separately by treatment group for Baseline, Visit 4b, and Visit 5. Change from baseline to Visit 
4b and Visit 5 will also be summarized. The analyses will be based on the Safety Set.  
14.4.3 Slit-Lamp Biomicroscopy 
Slit-lamp biomicroscopic results (normal, abnormal not clinically significant [NCS], abnormal clinically 
significant [CS]) for each region (cornea, conjunctiva, anterior chamber, iris, lens, and eyelid) will be 
summarized for OD and OS separately for baseline, Visit 4b, and Visit 5. Shift from baseline to Visit 4b and 
Visit 5 in the results will also be summarized. The analyses will be based on the Safety Set.  
14.4.4 IOP 
Actual values for IOP will be summarized for OD and OS separately by treatment group for Baseline and 
Visit 5. Change from baseline to Visit 5 will also be summarized. The analyses will be based on the Safety 
Set. 
14.4.5 Dilated Fundoscopy 
Dilated fundoscopic results (normal, abnormal NCS, abnormal CS) for each region (vitreous, retina, macula, 
optic nerve, and choroid) will be summarized for OD and OS separately for baseline and Visit 5. Shift from 
baseline to Visit 5 in the results will also be summarized. The analyses will be based on the Safety Set.  
14.5 
Analyses of Tolerability Measures 
14.5.1 Ora Calibra® Drop Comfort Assessment and Questionnaire  
Ora Calibra® Drop Comfort Assessment and Questionnaire will be performed at Visit 4a. Drop Comfort 
Assessment will be performed for 3 time points: immediately upon instillation, 1 minute post-instillation, 2 
minutes post-installation. Drop Comfort score is ranged from 0 to 10, not allowing half unit increments. For 
the Drop Comfort Questionnaire, assessed at 3 minutes post-instillation, subjects will select three words 
(from options of burning, comfortable, cool, filmy, gentle, gritty, irritating, refreshing, smooth, soothing, 
sticky, stinging, and other) that best describe how each eye drop feels in both eyes.  
Drop Comfort score will be summarized continuously by treatment group for each time point. For the Drop 
Comfort Questionnaire, number and percentages of subjects who selected any word will be summarized 
by treatment group and word for each time point. The analyses will be based on the Safety Set.  
15. 
Interim Analyses 
No interim analysis is planned. 


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16. 
Changes to the Analyses Planned in the Protocol 
No changes to the analyses that are planned in the protocol. 
17. 
SAS® Codes for Multiple Imputations 
17.1 
Randomized, Treatment-Based MCMC Methodology to Impute Non-monotone Missing Data 
The SAS® code for obtaining the imputed data will be dependent on the endpoint. 
PROC MI DATA = INDATA SEED = 7152 OUT = MDATA NIMPUTE = 20 
 
 
 
MINIMUM = 0 MAXIMUM = 4; 
 
 
 
BY TREATMENT; 
 
 
 
MCMC IMPUTE=MONOTONE; 
* For each primary endpoints at 3 minute post-CAC;  
VAR BASE_POST3MIN V4b_POST3MIN V5_POST3MIN; 
* For each primary endpoints at 5 minute post-CAC;  
VAR BASE_POST5MIN V4b_POST5MIN V5_POST5MIN; 
* For each primary endpoints at 7 minute post-CAC;  
VAR BASE_POST7MIN V4b_POST7MIN V5_POST7MIN; 
* For each secondary endpoints at 7 minute post-CAC;  
VAR BASE_POST7MIN V4b_POST7MIN V5_POST7MIN; 
* For each secondary endpoints at 15 minute post-CAC;  
VAR BASE_POST15MIN V4b_POST15MIN V5_POST15MIN; 
* For each secondary endpoints at 20 minute post-CAC;  
VAR BASE_POST20MIN V4b_POST20MIN V5_POST20MIN; 
RUN; 
 
17.2 
Randomized, Treatment-Based Regression Methodology for Monotone Missing Data 
PROC MI DATA = MDATA SEED = 543245 OUT = OUTDATA NIMPUTE = 1 
MINIMUM = 0 0 0  
MAXIMUM = 4 4 4  
BY TREATMENT _IMPUTATION_; 
* For each primary endpoints at 3 minute post-CAC;  
MONOTONE REG(V4b_POST3MIN = BASE_POST3MIN/ DETAILS); 
MONOTONE REG(V5_POST3MIN = BASE_POST3MIN V4b_POST3MIN/ DETAILS); 
VAR BASE_POST3MIN V4b_POST3MIN V5_POST3MIN; 
* For each primary endpoints at 5 minute post-CAC;  
MONOTONE REG(V4b_POST5MIN = BASE_POST5MIN/ DETAILS); 
MONOTONE REG(V5_POST5MIN = BASE_POST5MIN V4b_POST5MIN/ DETAILS); 
VAR BASE_POST5MIN V4b_POST5MIN V5_POST5MIN; 
* For each primary endpoints at 7 minute post-CAC;  
MONOTONE REG(V4b_POST7MIN = BASE_POST7MIN/ DETAILS); 
MONOTONE REG(V5_POST7MIN = BASE_POST7MIN V4b_POST7MIN/ DETAILS); 
VAR BASE_POST7MIN V4b_POST7MIN V5_POST7MIN; 
* For each secondary endpoints at 7 minute post-CAC;  
MONOTONE REG(V4b_POST7MIN = BASE_POST7MIN/ DETAILS); 
MONOTONE REG(V5_POST7MIN = BASE_POST7MIN V4b_POST7MIN/ DETAILS); 
VAR BASE_POST7MIN V4b_POST7MIN V5_POST7MIN; 


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* For each secondary endpoints at 15 minute post-CAC;  
MONOTONE REG(V4b_POST15MIN = BASE_POST15MIN/ DETAILS); 
MONOTONE REG(V5_POST15MIN = BASE_POST15MIN V4b_POST15MIN/ DETAILS); 
VAR BASE_POST15MIN V4b_POST15MIN V5_POST15MIN; 
* For each secondary endpoints at 20 minute post-CAC;  
MONOTONE REG(V4b_POST20MIN = BASE_POST20MIN/ DETAILS); 
MONOTONE REG(V5_POST20MIN = BASE_POST20MIN V4b_POST20MIN/ DETAILS); 
VAR BASE_POST20MIN V4b_POST20MIN V5_POST20MIN; 
RUN; 
18. 
References 
US Federal Register. (1998) International Conference on Harmonization; Guidance for Industry: Statistical 
Principles for Clinical Trials. Department of Health and Human Services: Food and Drug Administration.  
Federal Register, Vol. 63, No. 179, September 16, 1998, page 49583. (E9) 
US Federal Register. (2021) International Conference on Harmonization; Guidance for Industry: Statistical 
Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials E9(R1) 
US Federal Register. (1996) International Conference on Harmonization; Guidance for Industry: Structure 
and Content of Clinical Study Reports. Department of Health and Human Services: Food and Drug 
Administration.  Federal Register Vol. 61, July 17, 1996, page 37320. (E3)