Clinical trial NCT03709121
Conditions: Conjunctivitis, Allergic
Keywords: reproxalap ADX-102 allergic conjunctivitis
Sponsor: Aldeyra Therapeutics, Inc.
Start date: 2018-10-02; Completion date: 2019-03-20
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
An Exploratory Clinical Trial Evaluating Reproxalap Ophthalmic Solutions (0.25% and 0.5%) in Subjects with Seasonal Allergic Conjunctivitis Using the Environmental Exposure Chamber (EEC)

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: Reproxalap Ophthalmic Solution (0.25%) intervention 2: Reproxalap Ophthalmic Solution (0.5%) intervention 3: Vehicle Ophthalmic Solution
Intervention descriptions: intervention 1: Reproxalap Ophthalmic Solution (0.25%) dosed twice. intervention 2: Reproxalap Ophthalmic Solution (0.5%) dosed twice. intervention 3: Vehicle Ophthalmic Solution dosed twice.

Protocol documents:
Prot_000.pdf: 
Proprietary and Confidential 
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PROTOCOL ADX-102-AC-011 
AN EXPLORATORY CLINICAL TRIAL EVALUATING REPROXALAP 
OPHTHALMIC SOLUTIONS (0.25% AND 0.5%) IN SUBJECTS WITH 
SEASONAL ALLERGIC CONJUNCTIVITIS USING THE ENVIRONMENTAL 
EXPOSURE CHAMBER (EEC) 
PROTOCOL VERSION AND DATE: FINAL VERSION 4.0 22 NOV 2018 
ALDEYRA THERAPEUTICS, INC. 
131 HARTWELL AVENUE, SUITE 320 
 
LEXINGTON, MA 02421, U.S.A.  
 
 
Sponsor Signature:  
 
 
 
 
 
                                                        
 
 
 
 
 
  
 
 
Conduct: In accordance with the ethical principles that originate from the Declaration of Helsinki 
and that are consistent with International Council for Harmonisation (ICH) guidelines on Good 
Clinical Practice (GCP) and regulatory requirements as applicable. 
 
CONFIDENTIALITY STATEMENT 
This document contains information that is confidential and proprietary to Aldeyra Therapeutics, 
Inc.  This information is being provided to you solely for the purpose of evaluating or conducting 
a clinical study for Aldeyra Therapeutics. You may disclose the contents of this document only 
to study personnel under your supervision who need to know the contents for this purpose and 
to your Institutional Review Board (IRB)/Research Ethics Board (REB)/Independent Ethics 
Committee (IEC); otherwise the contents of this document may not be disclosed without the 
prior authorization from Aldeyra Therapeutics. The foregoing shall not apply to disclosure 
required by governmental regulations or laws. Any supplemental information that may be added 
to this document also is confidential and proprietary to Aldeyra Therapeutics and must be kept 
in confidence in the same manner as the contents of this document. 


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INVESTIGATOR STATEMENT 
 
Protocol Number: ADX-102-AC-011 
Protocol Title: An Exploratory Clinical Trial Evaluating Reproxalap Ophthalmic Solutions (0.25% 
and 0.5%) in Subjects with Seasonal Allergic Conjunctivitis Using the Environmental Exposure 
Chamber (EEC) 
I understand that all information concerning reproxalap in connection with this clinical trial and not 
previously published is confidential. This confidential information includes the Investigator’s 
Brochure, Clinical Trial Protocol, Case Report Form, clinical methodology, and basic scientific 
data. 
I will not initiate this study without approval from the Institutional Review Board (IRB)/Research 
Ethics Board (REB)/Independent Ethics Committee (IEC) and I understand that any changes in 
the protocol must be approved in writing by Aldeyra Therapeutics, Inc., and the Institutional 
Review Board/Ethics Committee before they can be implemented, except when necessary to 
eliminate immediate hazards to the subjects. 
I will use only the informed consent form approved by Aldeyra Therapeutics, Inc. and by my 
IRB/REB/IEC and will fulfill all responsibilities for submitting pertinent information to the 
IRB/REB/IEC responsible for this study.  
By my signature below, I attest that I have read, understand, and agree to abide by all the 
conditions, instructions, and restrictions contained in Protocol Number ADX-102-AC-011, and will 
conduct the trial in accordance with the International Council for Harmonisation (ICH) guidelines 
on Good Clinical Practice (GCP) and applicable regulatory requirements.  
 
Site Name 
 
 
 
 
Site Address  
 
 
 
 
Investigator’s Printed Name 
 
 
Investigator’s Signature  
 
Date 
 
 


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PROTOCOL REVISION HISTORY 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Aldeyra Therapeutics, Inc.                                                                              Protocol ADX-102-AC-011 
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Aldeyra Therapeutics, Inc.                                                                              Protocol ADX-102-AC-011 
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Aldeyra Therapeutics, Inc.                                                                              Protocol ADX-102-AC-011 
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SYNOPSIS 
Name of Sponsor Company:  
Aldeyra Therapeutics, Inc. 
Drug Under Study:  
Reproxalap  
Title of Protocol: An Exploratory Clinical Trial Evaluating Reproxalap Ophthalmic Solutions (0.25% and 
0.5%) in Subjects with Seasonal Allergic Conjunctivitis Using the Environmental Exposure Chamber (EEC) 
Protocol Number: 
Sponsor Study Code: ADX-102-AC-011 
Study Code: 18-MO-001 
Phase:  
1b 
Indication:  
Allergic Conjunctivitis 
Subject Population: Subjects 18 years of age and older with allergic conjunctivitis  
Number of Subjects:  
Approximately 260 subjects with seasonal allergic conjunctivitis to ragweed will be screened in the EEC in 
order to randomize approximately 75 subjects, and with 60 subjects completing the trial.  
Number of Center(s):  
One 
Test Products / Doses / Mode of Administration: 
Eligible subjects will be randomized 1:1:1 to one of three treatment sequences of ABC, BCA and CAB 
where:  
• 
Treatment A:  Reproxalap Ophthalmic Solution (0.25%) 
• 
Treatment B:  Reproxalap Ophthalmic Solution (0.5%) 
• 
Treatment C:  Vehicle Ophthalmic Solution 
Approximately 75 subjects (approximately 25 per treatment sequence) will be enrolled. 
Exploratory Objective:   
To evaluate the feasibility of using the EEC clinical trial design to assess the activity of Reproxalap 
Ophthalmic Solutions (0.25% and 0.5%) in an allergic conjunctivitis population. 
To assess safety, tolerability, and pharmacodynamic activity of Reproxalap Ophthalmic Solutions (0.25% 
and 0.5%) compared to Vehicle Ophthalmic Solution in the treatment of seasonal allergic conjunctivitis in 
subjects allergic to ragweed using the EEC with exposure to airborne ragweed pollen. 
Clinical Trial Assessments and Endpoints: 
The clinical trial is exploratory in nature and the safety, tolerability, and pharmacodynamic activity of 
Reproxalap Ophthalmic Solutions (0.25% and 0.5%) will be compared to Vehicle Ophthalmic Solution in 
subjects with allergic conjunctivitis in an EEC model. Pharmacodynamic endpoints for assessments of 
ocular itching, redness, and tearing will be evaluated. As an exploratory study, there are no primary 
endpoints and no formal statistical hypotheses. 
Safety Endpoints: 
Safety assessments will include Snellen visual acuity (VA), slit lamp examination (SLE) and non-contact 
intraocular pressure tonometry (NCT) as detailed in Table 1. Dilated fundus examination at screening Visit 
1 and at Visit 5 and undilated fundus examination will be performed at Visits 2, 3 and 4. Adverse event 
(AEs; reported, elicited and observed) assessments will be performed at Visit 2 through Visit 5. 
 


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Study Design:  
The double-masked, vehicle-controlled, randomized, three-way crossover clinical trial allows for the testing 
of two concentrations of Reproxalap Ophthalmic Solution (0.25% and 0.5%) versus Vehicle Ophthalmic 
Solution in subjects with ragweed-induced allergic conjunctivitis in the EEC.  
The clinical trial consists of five visits to the clinic (one Medical Screening visit, one Screening EEC visit, 
and three EEC treatment visits). The EEC sessions will be separated by an approximate two-week washout 
period to ensure adequate elimination of responses caused by allergen exposure in the EEC and allow the 
recuperation of mast cells. 
The EEC clinical research facility is a room designed with the capacity and control mechanisms to expose 
participants to airborne ragweed pollen grains and maintains target temperature and relative humidity 
throughout.  
The EEC has 100% fresh HEPA-filtered clean air to which commercially obtained air dried, non-defatted 
short ragweed (Ambrosia artemesiifolia) pollen (Greer Laboratories, Lenoir, NC) will be introduced and 
circulated throughout the room with tight humidity and temperature controls as described previously 
(Ronborg et al 1996). Airborne ragweed pollen counts will be maintained at 3500 ± 500 grains per cubic 
meter by continuous monitoring and feedback regulation of the pollen emission measured. The controlled 
pollen challenge, over time, allows evaluation of subject responses at any time-point throughout the 
challenge process. 
 
 
At the Medical Screening Visit (Visit 1) occurring between 2 days to 8 weeks prior to Visit 2, subjects will 
undergo the informed consent process, and information about demographics, baseline characteristics, 
medical history, social history, physical examination will be performed and concomitant medication will be 
collected. Vital signs and samples for standard clinical safety laboratory tests will be obtained. A urine 
pregnancy test will be administered to women of childbearing potential (WOCBP). Subjects will undergo 
ophthalmic examinations (Snellen VA, SLE, NCT, and a dilated fundus examination) to ensure initial 
eligibility criteria are met. A skin prick test for a panel of test allergens will be conducted; results must be 
positive (i.e., a wheal that is 3 mm greater than the negative control) for at least one test allergen and must 
include ragweed in order to proceed to Visit 2. 
At the EEC Screening Visit (Visit 2), qualified site staff will update concomitant medications, collect AEs, as 
applicable and collect vital signs. A urine pregnancy test will be administered to WOCBP. Fundus exam, 
Snellen VA, SLE, subject rating of symptoms, and staff grading of conjunctival redness will be performed to 
ensure the anterior segment of the eye is healthy. 
 
 
At all EEC sessions, assessments of ophthalmic evaluations will be collected
 
). For subject-reported symptoms of ocular itching, a standard 9-point 


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(i.e., 0-4 with 0.5 unit increments) and a standard VAS scale (0-100 mm) will be employed. For subject rated 
ocular tearing, a 4-point scale (0-3) will be employed. For staff-assessed grading of conjunctival redness, a 
standard 9-point (i.e., 0-4 with 0.5 unit increments) will be employed. Additionally, Total Ocular Symptom 
Score (TOSS) is a composite score of ocular itching (0 – 4), ocular tearing (0 – 3) and ocular redness (0 – 
4) with a maximum score of 11 units will be analyzed. 
 
 
 
Pre-EEC entry (Baseline):  
1) Subject assessment for ocular itching and tearing will be recorded 
  
, and  
2) Staff-assessed conjunctival redness will be recorded 
 
.  
Post-EEC entry:  
1) Subject assessment for ocular itching and tearing will occur
 
;  
2) Staff-assessed conjunctival redness will be recorded 
 
.  
 
 
 
 
 
At Randomization/Treatment EEC Session One (Visit 3), qualified site staff will update concomitant 
medications, collect AEs, as applicable and collect vital signs. A urine pregnancy test will be administered 
to WOCBP. Ophthalmic evaluations will be conducted (Fundus exam, Snellen VA, NCT, SLE, subject rating 
of symptoms, and staff grading of conjunctival redness). 
 
 
 
  
Subjects will be randomized to receive a first dose of either Reproxalap Ophthalmic Solution (0.25%) 
(Treatment A), Reproxalap Ophthalmic Solution (0.5%) (Treatment B), or Vehicle Ophthalmic Solution 
(Treatment C). Qualified site staff will instill one drop of the randomized treatment into each eye at 
approximately five minutes prior to entry to the EEC after all the pre-EEC assessments are done.  
Pre-EEC entry (Baseline):  
1) Subject assessment for ocular itching and tearing will be recorded 
  
, and  
2) Staff-assessed conjunctival redness will be recorded
 
.  
Post-EEC entry:  
1) Subject assessment for ocular itching and tearing will occur 
 
;  
2) Staff-assessed conjunctival redness will be recorded 
 
.  


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At approximately 95-minutes post-EEC entry (and after subject assessed itching and tearing and staff 
assessed conjunctival redness for all time-points post first dose have been completed), a second dose (one 
drop in each eye) of the same randomized treatment will be administered in each eye by the qualified site 
staff. Subject will continue to assess symptoms of ocular itching and tearing after the second dose
 
 
, and staff-assessed conjunctival redness will be recorded at approximately post 
second dose
 
. 
Post-EEC exit (approximately t = 215 minutes):  
1) Subject assessed ocular itching and tearing will continue 
 
;  
2) Staff assessed conjunctival redness will continue to be recorded post-EEC exit 
 
. Subjects will be asked to return in 
2 weeks (± 3 days) for Visit 4. 
At Treatment EEC  Session Two (Visit 4), all procedures performed at Visit 3 will be repeated except that 
each subject will be given a different treatment depending on the treatment sequence the subject was 
randomized to [Reproxalap Ophthalmic Solution (0.25%) (Treatment A), Reproxalap Ophthalmic Solution 
(0.5%) (Treatment B), or Vehicle Ophthalmic Solution (Treatment C)].  
At the end of the EEC session, subjects will be asked to return in approximately two weeks (± 3 days) for 
Visit 5. 
At Treatment EEC Session Three (Visit 5), all procedures performed at Visit 4 will be repeated except that 
each subject will be given a different treatment depending on the treatment sequence the subject was 
randomized to [Reproxalap Ophthalmic Solution (0.25%) (Treatment A), Reproxalap Ophthalmic Solution 
(0.5%) (Treatment B), or Vehicle Ophthalmic Solution (Treatment C)]. At the end of the visit, a urine 
pregnancy test will be administered to WOCBP.  
Subjects will undergo ophthalmic examinations (Snellen VA, SLE, NCT, and a dilated fundus examination), 
clinical safety labs and vital signs will be collected to ensure safety prior to exit of the clinical trial. 
Criteria for Inclusion: 
Each subject must:  
• 
Be at least 18 years of age at the time of screening of either sex or any race;  
• 
Provide written informed consent;  
• 
Be willing and able to follow instructions, and can attend all required clinical trial visits;  
• 
Have at least a two-year history of moderate-to-severe ragweed-induced allergic conjunctivitis 
based on principal investigator’s judgement;  
• 
Have a positive skin prick test to ragweed pollen within the past year of the Medical Screening Visit 
(Visit 1); 
 
 
 
 
 
  


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• 
Confirmed absence of pregnancy according to a negative urine pregnancy test at the Medical 
Screening Visit (Visit 1); 
• 
WOCBP must agree to use a reliable and highly effective method of birth control with a low failure 
rate (i.e., less than 1% per year) when used consistently and correctly (e.g., implants, injectables, 
combined oral contraceptives, some intrauterine devices [IUDs], sexual abstinence, or 
vasectomized partners) during the clinical trial, as judged by the investigator.   
Criteria for Exclusion: 
Each subject must not: 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Have a history of blepharitis, dry eye syndrome, herpes simplex keratitis, or herpes zoster keratitis; 
• 
Have a history of uveitis in the past three years; 
• 
Have a presence of any ocular infection (bacterial, viral, or fungal) or active ocular inflammation 
(e.g., follicular conjunctivitis, allergic conjunctivitis) within 14 days prior to the Medical Screening 
Visit (Visit 1); 
• 
Have a presence of any chronic ocular degenerative condition or ocular inflammation that, in the 
opinion of the investigator, is likely to worsen over the course of the clinical trial; 
 
 
 
 
 
 
 
  


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• 
Use any prescription or over-the-counter topical ocular medications during the clinical trial;  
• 
Use of any medication not previously specified that impairs either allergy skin testing or EEC 
evaluation at the discretion of the Investigator; 
• 
Have history of moderate-to-severe asthma (a score of greater than Global Initiative of Asthma 
(GINA) Score of 1) or allergy-induced asthma to ragweed; 
• 
Have systemic signs of infection (e.g., fever, current treatment with antibiotics); 
• 
Have a systemic disease or uncontrolled medical condition, which, in the opinion of the investigator, 
could interfere with clinical trial measurements or subject compliance. Such diseases or conditions 
would include, but are not limited to, cancer, alcoholism, drug dependency or abuse, or psychiatric 
disease; 
 
 
• 
WOCBP who are pregnant, nursing, or not using an effective means of contraception; 
 
 
 
 
• 
Chronic systemic medications in place for less than one month, or a change in the dosage of such 
medications within the month prior to the Medical Screening Visit (Visit 1). Subjects receiving anti-
allergy injections may be enrolled if the dose has been stable for three months prior to the Medical 
Screening Visit (Visit 1) and no changes are planned during the clinical trial period; 
• 
Have a diagnosis of moderate-to-severe pinguecula or pterygium (particularly if it results in chronic 
erythema), Stevens-Johnson Syndrome, ocular cicatricial pemphigoid, mucous membrane 


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pemphigoid, significant conjunctival scarring, chemical burn, herpetic or neurotrophic keratitis, 
Cryopyrin Associated Periodic Syndrome (CAPS), or keratoconus; 
 
  
 
 
Statistical Analysis:  
Approximately 150 subjects with ragweed-induced, moderate-to-severe allergic conjunctivitis will be 
screened in the EEC in order to randomize approximately 75 subjects, and for 60 subjects to complete the 
study. Approximately twenty-five (25) subjects will be assigned to each of three (3) treatment sequences, 
ABC, BCA, and CAB. While not based on formal power considerations, 60 subjects completed is sufficient 
to produce reasonably reliable statistical conclusions based on the following; 
 
 
Prior to database lock, the Sponsor will finalize a statistical analysis plan (SAP) that will detail all planned 
analyses. Any analyses conducted in addition to those specified in the SAP will be clearly documented as 
post hoc. 
In brief, the efficacy analyses of all efficacy endpoints will be carried out in the Intent-to-Treat (ITT) 
population. Supportive analyses may also be provided for Itching endpoint(s) using the Per-Protocol (PP) 
population. 
Descriptive statistics of all activity endpoints as well individual data listings will be presented by treatment 
group and efficacy measures. For each efficacy endpoints, treatment comparisons will be made between 
Reproxalap Ophthalmic Solutions (0.25% and 0.5%) and vehicle. The treatment comparison will be 
performed using a mixed-effects Analysis of Covariance Model (ANCOVA) for a crossover study for 3 
periods. 
 
 
 
 
 
 The endpoints that will be analyzed are the following; 
AUC 0-212 mins for Itching on VAS scale  
AUC 0-212 mins for Itching on 9 points scale 
AUC 0-210 mins for Conjunctival Redness on 9 points scale 
AUC 0-212 mins for Tearing on 4 points scale 
AUC 0-212 mins for TOSS  
AUC 0-92 mins for Itching on VAS scale  
AUC 92-212 mins for Itching on VAS scale  
AUC 0-32 mins for Itching assessed by VAS Scale 
AUC 32-72 mins for Itching assessed by VAS Scale 
All 0 time-point measurements will be pre-EEC entry/ baseline values. All the time-points are approximate 
values 
 
Additional Exploratory Analyses 
In addition, descriptive statistics including Change from Baseline (CFB) for each treatment and each post-
EEC time-point may be derived and used as exploratory efficacy endpoints to evaluate the efficacy of 
Reproxalap Ophthalmic Solutions (0.25% and 0.5%). Other exploratory analyses may be added post-hoc. 


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Table 2. 
Schedule of Staff-Assessed Conjunctival Redness Recording 
 
 
Table 3. 
Schedule of Subject Assessed Itching and Tearing  


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Table 4. 
Schedule of Staff-Assessed Conjunctival Redness Recording Post-EEC Exit 
 
 
 
 
 
 
 
Table 5. 
Schedule of Subject Assessed Itching and Tearing Post-EEC Exit 
 
 


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TABLE OF CONTENTS 
INVESTIGATOR STATEMENT ................................................................................................... 2 
PROTOCOL REVISION HISTORY ............................................................................................. 3 
SYNOPSIS 11 
TABLE OF CONTENTS ............................................................................................................ 21 
LIST OF TABLES ...................................................................................................................... 24 
LIST OF FIGURES ................................................................................................................... 24 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...................................................... 26 
1 
INTRODUCTION .................................................................................................... 27 
 
Allergic Conjunctivitis .............................................................................................. 27 
 
Therapeutic Rationale for Reproxalap in Allergic Conjunctivitis .............................. 27 
 
Clinical Trials of Reproxalap ................................................................................... 29 
1.3.1 
Ocular Indications ............................................................................................. 29 
 
Rationale for Use of the Allergy Environmental Exposure Chamber (EEC) ............. 31 
 
Minimization of Risk ................................................................................................ 31 
 
Potential Benefit ..................................................................................................... 32 
 
Rationale for Dose Selection .................................................................................. 32 
2 
CLINICAL TRIAL OBJECTIVE AND ENDPOINTS .................................................. 32 
 
Exploratory Objectives ............................................................................................ 32 
 
Clinical Trial Assessments and Endpoints .............................................................. 33 
 
Safety Endpoints .................................................................................................... 34 
 
Exploratory Efficacy Endpoints ............................................................................... 34 
 
Additional Exploratory Analyses ............................................................................. 34 
3 
INVESTIGATIONAL PLAN ..................................................................................... 35 
 
Overall Clinical Trial Design and Plan ..................................................................... 35 
 
Assigning Subjects to Treatment Groups ................................................................ 38 
3.2.1 
Subject Numbering ........................................................................................... 38 
3.2.2 
Randomization .................................................................................................. 38 
 
Masking and Unmasking ........................................................................................ 38 
3.3.1 
Masking ............................................................................................................ 38 
3.3.2 
Emergency Unmasking ..................................................................................... 38 
 
Safety Oversight ..................................................................................................... 39 
 
Clinical Trial Duration for Individual Subjects .......................................................... 39 


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4 
CLINICAL TRIAL POPULATION SELECTION ....................................................... 39 
 
Inclusion Criteria ..................................................................................................... 39 
 
Exclusion Criteria .................................................................................................... 40 
5 
SUBJECT DISPOSITION ....................................................................................... 41 
 
Completed Subjects ............................................................................................... 41 
 
Discontinued Subjects ............................................................................................ 41 
 
Subject Withdrawal and Replacement .................................................................... 42 
6 
INVESTIGATIONAL TREATMENT ......................................................................... 42 
 
Description of Investigational Product ..................................................................... 42 
 
Packaging and Labeling ......................................................................................... 42 
 
Investigational Product Storage .............................................................................. 43 
 
Investigational Product Accountability ..................................................................... 43 
 
Investigational Product Retention ........................................................................... 43 
 
Investigational Product Administration .................................................................... 43 
 
Concomitant Therapy and Procedures ................................................................... 43 
6.7.1 
Prohibited Concurrent Therapies and Procedures ............................................ 43 
7 
CLINICAL TRIAL PROCEDURES .......................................................................... 44 
 
Informed Consent ................................................................................................... 44 
 
Eligibility Review ..................................................................................................... 44 
 
Demographics, Medical History, and Social History ................................................ 44 
 
Physical Examination: ............................................................................................ 44 
 
Concomitant Medications ....................................................................................... 44 
 
Adverse Events ...................................................................................................... 44 
 
Vital Signs .............................................................................................................. 44 
 
Clinical Laboratory Tests ........................................................................................ 45 
7.8.1 
Hematology ...................................................................................................... 45 
7.8.2 
Chemistry ......................................................................................................... 45 
7.8.3 
Pregnancy Test................................................................................................. 45 
 
Skin Prick Test ....................................................................................................... 45 
 
Ophthalmic Examinations ....................................................................................... 45 
7.10.1 
Visual Acuity ............................................................................................... 45 
7.10.2 
Slit Lamp Exam ........................................................................................... 45 
7.10.3 
Non-Contact Intraocular Pressure Tonometry (NCT) .................................. 46 
7.10.4 
Fundoscopy ................................................................................................ 46 


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Symptom Collection ................................................................................................ 46 
7.11.1 
Staff-Assessed Symptom Collection ........................................................... 46 
7.11.2 
Subject-Reported Symptoms ...................................................................... 46 
 
Environmental Exposure Chamber ......................................................................... 46 
 
Randomization ....................................................................................................... 47 
 
Investigational Product Treatment .......................................................................... 47 
8 
CLINICAL TRIAL ACTIVITIES ................................................................................ 47 
 
Medical Screening Visit (Visit 1) ............................................................................. 47 
 
Screening EEC Visit (Visit 2) .................................................................................. 47 
 
Treatment EEC Sessions One and Two (Visits 3 and 4) ......................................... 48 
 
Treatment EEC Session Three / Clinical Trial Exit (Visit 5) ..................................... 48 
9 
ADVERSE EVENT REPORTING ........................................................................... 48 
9.1.1 
Adverse Event .................................................................................................. 48 
9.1.2 
Treatment-Emergent Adverse Events ............................................................... 50 
9.1.3 
Serious Adverse Events .................................................................................... 50 
9.1.4 
Unexpected Adverse Event............................................................................... 51 
9.1.5 
Reporting Serious Adverse Events ................................................................... 51 
9.1.6 
Follow-up of Adverse Events ............................................................................ 52 
9.1.7 
Reporting Serious Adverse Events to Regulatory Health Authorities/ 
Institutional Review Boards/Research Ethics Boards/Independent 
Ethics Committees ...................................................................................... 52 
9.1.8 
Reporting Pregnancies ..................................................................................... 53 
10 
STATISTICS ........................................................................................................... 53 
 
Sample Size ........................................................................................................... 53 
 
Analysis Populations .............................................................................................. 53 
 
Demographic and Baseline Medical History ............................................................ 54 
 
Exploratory Efficacy Analyses ................................................................................. 54 
 
Safety Analysis ....................................................................................................... 54 
 
Statistical Hypotheses ............................................................................................ 54 
 
Adjustment for Multiplicity ....................................................................................... 55 
 
Exploratory Efficacy Analysis .................................................................................. 55 
 
Accountability and Background Characteristics ...................................................... 55 
10.9.1 
Enrollment and Disposition.......................................................................... 55 
10.9.2 
Subject Characteristics ............................................................................... 55 
10.9.3 
Treatment Compliance ................................................................................ 56 


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11 
QUALITY CONTROL AND QUALITY ASSURANCE .............................................. 56 
12 
CLINICAL TRIAL ADMINISTRATION ..................................................................... 56 
 
Institutional Review Board / Research Ethics Board / Independent Ethics 
Committee ........................................................................................................ 56 
 
Ethical Conduct of the Clinical Trial ........................................................................ 56 
 
Subject Informed Consent ...................................................................................... 57 
 
Confidentiality ......................................................................................................... 57 
 
Protection of Subject Data ...................................................................................... 57 
 
Clinical Trial Monitoring .......................................................................................... 58 
 
Case Report Forms and Source Documents .......................................................... 58 
 
Access to Source Documents and Audits ............................................................... 59 
 
Protocol Deviations and Violations ......................................................................... 59 
 
Amendments to the Protocol .................................................................................. 59 
 
Discontinuation of the Clinical Trial ......................................................................... 59 
 
Investigator Responsibilities ................................................................................... 59 
 
Financial Disclosure ............................................................................................... 60 
 
Registration of Clinical Studies and Disclosure of Results ...................................... 60 
 
Publication and Disclosure Policy ........................................................................... 60 
13 
RETENTION OF RECORDS .................................................................................. 60 
14 
REFERENCES ....................................................................................................... 62 
 
List of Tables 
Table 1. 
Schedule of Events and Assessments ............................................................... 18 
Table 2. 
Schedule of Staff-Assessed Conjunctival Redness Recording ................................ 19 
Table 3. 
Schedule of Subject Assessed Itching and Tearing ................................................ 19 
Table 4. 
Schedule of Staff-Assessed Conjunctival Redness Recording Post-EEC Exit ........ 20 
Table 5. 
Schedule of Subject Assessed Itching and Tearing Post-EEC Exit ......................... 20 
Table 6. 
Clinical Exposure to Topical Ocular Reproxalap ..................................................... 30 
Table 7. 
Topical Ocular Reproxalap Clinical Trial Outcomes ................................................ 30 
 
List of Figures 
Figure 1. 
Percent Ocular Itch Score Reduction from Vehicle for 0.2% Olopatadine and 
0.5% Reproxalap (ADX-102) .................................................................................. 28 


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Figure 2. 
Mean AUC 10-60 Statistically Lower in Drug Groups vs. Vehicle Group 
(ADX-102-AC-004, Test Article Administration 10 Minutes Pre-Challenge, 
Seasonal Allergens) ............................................................................................... 29 
Figure 3. 
Photographic Ocular Redness ................................................................................ 33 
Figure 4. 
Clinical Trial Design ................................................................................................ 35 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AC 
Allergic conjunctivitis  
AE 
Adverse event 
ANCOVA 
Analysis of Covariance 
AUC 
Area under the curve 
BP 
Blood Pressure 
CFB 
Change from baseline 
CRF 
Case report form 
CTA 
Clinical Trial Application 
EEC 
Environmental Exposure Chamber 
EDC 
Electronic data capture 
 
 
GCP 
Good Clinical Practice 
GINA 
Global Initiative of Asthma 
ICH 
International Council for Harmonisation 
IgE 
Immunoglobulin E 
IND 
Investigational New Drug  
IOP 
Intraocular pressure 
IP 
Investigational product 
IUD 
Intrauterine device 
NCT 
Non-contact IOP tonometry 
QID 
Four times daily 
 
 
RR 
Respiratory Rate 
SAE 
Serious adverse event 
SOP 
Standard Operating Procedure 
SBECD 
Sulfobutylether-beta-cyclodextrin 
SD 
Standard deviation 
SLE 
Slit lamp examination 
TOSS 
Total ocular symptom score 
VA 
Visual acuity 
VAS 
Visual analog scale 
WOCBP 
Women of childbearing potential 
 


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1 
INTRODUCTION 
 Allergic Conjunctivitis 
Acute allergic conjunctivitis (AC), experienced by approximately 40% of the general population 
(Singh et al., 2010), is associated with Type I (immediate) hypersensitivity reactions. Type I 
reactions involve immunoglobulin E (IgE)-mediated release of histamine and other mediators from 
mast cells and basophils. Mast cell degranulation leads to release of inflammatory mediators and 
activation of enzymatic cascades generating pro-inflammatory mediators (Mishra et al, 2011). In 
the eye, release of a variety of mediators leads to inflammation of the conjunctival mucosa that 
also affects the cornea and eyelids, resulting in symptoms that include itching and burning, 
tearing, chemosis (conjunctival edema), conjunctival injection, hyperemia, eyelid edema, and 
mucus discharge. Although allergic conjunctivitis patients may also experience photophobia, 
allergic shiners (dark circles), and concurrent signs and symptoms of asthma or rhinitis, the 
absence of itching precludes a diagnosis of AC (Albrecht 2011). 
Aldehydes are pro-inflammatory mediators of both allergic (TH2) and autoimmune (TH1) 
diseases, and elevated levels of toxic aldehydes are associated with allergic conjunctivitis and 
other ocular and systemic diseases (Bacsi et al 2005). Thus, aldehyde sequestering agents 
represent a novel and potentially broadly applicable therapeutic approach for the treatment of 
inflammation.  
The symptoms of allergic conjunctivitis that occur within minutes of allergen exposure are likely 
due primarily to the release of histamine (Leonardi 2013), which peaks in tears around five 
minutes and significantly diminishes over 20 to 30 minutes (Ackerman et al. 2016). Immediately 
following, and to some degree concurrently with, the rapid rise and fall of histamine levels, the 
symptoms of allergic conjunctivitis are perpetuated by non-histaminic inflammatory mediators, 
including cellular infiltrate, cytokines, leukotrienes, proteases, and other factors (Leonardi 2013) 
likely to be diminished by aldehyde sequestering agents such as reproxalap, but not 
antihistamines. 
 Therapeutic Rationale for Reproxalap in Allergic Conjunctivitis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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 Rationale for Use of the Allergy Environmental Exposure Chamber 
(EEC) 
The allergy Environmental Exposure Chamber (EEC) has been used over the last 20 years to 
assess anti-allergy medications such as ocular drops, nasal sprays and oral formulations of 
allergy treatments including antihistamines and corticosteroids (Bielory 2012, Day et al., 2000, 
Bilkhu at al., 2014, Goldstein at al., 2015). The EEC has yet to be used for registration studies in 
AC.  
The main advantage of the EEC is the ability to control environmental factors such as humidity 
and temperature (unlike field studies) while delivering a steady and consistent level of airborne 
allergen similar to natural environmental exposure on peak pollen days (Ronborg et al., Day et 
al.,2006, Goldstein et al.,2015). Use of the EEC allows for better assessment of the dose 
response, onset of action, and potentially the optimal magnitude of treatment effects. Because of 
the controlled environment of the EEC, there is very low variability in outcomes and reduced 
confounding factors (Ronborg et al., 1996, Day et al., 2006). Furthermore, a strong correlation 
between symptoms experienced during controlled exposure and in-field allergen exposure has 
been demonstrated (Day et al., 2006). One potential limitation of this model for the development 
of treatment for moderate to severe AC is that subjects are exposed to the allergen through 
multiple mucous membranes; the eyes, nose and respiratory tract (Goldstein at al., 2015). 
However, multiple studies have demonstrated the ability to distinguish system organ specific 
clinical signs and symptoms (Baroody et al., 2009; Crampton., 2002; Abelson et al., 2005 and 
Salapatek et al., 2011). In this study, the ocular system clinical signs and symptoms will be 
evaluated by validated, standardized scales.  
EEC studies have evaluated allergic conjunctivitis and the associated ocular hyperemia, pruritus, 
and tearing symptoms with total symptom scores with individual ocular symptom score (rated 0-
3) and a composite scale of total ocular symptom scores (TOSS) (Salapatek et al., 2008). In this 
study, the focus will be to utilize the EEC model to evaluate the ocular signs and symptoms of 
allergy. The EEC model mimics the natural airborne allergen exposure that patients would 
encounter in their everyday lives, whilst providing the control and consistency that reduces the 
variability seen with outdoor environmental exposure (Devillier et al., 2011, Ronborg et al., 1996).  
 Minimization of Risk  
In clinical trials with Reproxalap Ophthalmic Solution in various strengths in different ocular 
indications, no safety signal or treatment related SAEs have been observed (Section 1.3.1). 
 
 
 
 
 
 


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While subjects are in the EEC, they will be exposed to ragweed pollen for approximately 3.5 hours 
and are expected to experience allergy symptoms (itchy eyes, watery eyes and eye redness 
and/or itchy nose, nasal congestion, runny nose, sneezing) typically experienced during the 
ragweed pollen season. They will be receiving either active or vehicle treatment that may or may 
not relieve their allergy symptoms to a certain degree. Subjects will be monitored with regular 
medical health checks during the EEC Sessions in this study and will be treated according to the 
investigator’s evaluation. Subjects with known anaphylactic reactions and moderate to severe 
asthma are excluded from this trial, please defer to detailed inclusion and exclusion criteria. The 
revised crietria allowing screened failed subjects to be reconsidered for the trial, is not anticipated 
to introduce any additional known risks, Subjects will have washed out from prior ragweed 
exposure 
Some known risks are also associated with skin prick testing like soreness, minor bruising, 
redness and/or irritation (itching, burning and/or stinging) at the site where the skin test is done. 
A very rare severe allergic reaction, anaphylaxis can occur. It may be life threatening with clinical 
signs and symptoms such as breathing difficulties, hives, swelling of the skin or tongue, itchy skin, 
or a decrease in blood pressure. The clinical staff on site is trained per site medical SOPs. 
Emergency care is available on-site to treat, if an allergic reaction or anaphylaxis develop. 
 Potential Benefit 
The ADX-102-AC-011 clinical trial will evaluate reproxalap in an EEC setting in allergic 
conjunctivitis patients. No direct benefits are expected from participating in the clinical trial. 
Safety of the clinical dosing regimen in this trial is supported by a large number of pre-clinical and 
clinical, ocular and systemic, and toxicology and pharmacokinetic studies in which no serious 
safety concerns were noted.  
 Rationale for Dose Selection 
Ophthalmic dosing is the optimal route of administration for ocular allergy treatments. The dosage 
and dosage regimen were selected based on nonclinical and clinical studies described in  
Section 1.3. 
2 
CLINICAL TRIAL OBJECTIVE AND ENDPOINTS 
 Exploratory Objectives 
The exploratory objectives of the clinical trial are: 
• 
To evaluate the feasibility of using the EEC clinical trial design to assess the activity of 
Reproxalap Ophthalmic Solutions (0.25% and 0.5%) in an allergic conjunctivitis 
population. 
• 
To assess safety, tolerability, and pharmacodynamic activity of Reproxalap Ophthalmic 
Solutions (0.25% and 0.5%) compared to Vehicle Ophthalmic Solution in the treatment of 


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seasonal allergic conjunctivitis in subjects allergic to ragweed using the EEC with 
exposure to airborne ragweed pollen. 
  Clinical Trial Assessments and Endpoints 
The clinical trial is exploratory in nature to the safety, tolerability, and pharmacodynamic activity 
of Reproxalap Ophthalmic Solutions (0.25% and 0.5%) compared to Vehicle Ophthalmic Solution 
in subjects with allergic conjunctivitis in an EEC model. There are no primary endpoints and no 
formal statistical hypotheses. 
The assessments used in this trial include ocular itching self-assessed by each subject using two 
scales, a Visual Analog Scale (VAS) and a 9-point scale. 
VAS is measured on a 0-100 mm continuous scale where 0 is considered no itching and 100 is 
considered maximum itch. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Figure 3. 
Photographic Ocular Redness  


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 Safety Endpoints 
Safety assessments will include Snellen visual acuity (VA), slit lamp examination (SLE) and non-
contact intraocular pressure tonometry (NCT) as detailed in Table 1. Dilated fundus examination 
at screening Visit 1 and at Visit 5 and undilated fundus examination will be performed at Visits 2, 
3 and 4. Adverse event (AEs; reported, elicited and observed) assessments will be performed at 
Visit 2 through Visit 5. 
 Exploratory Efficacy Endpoints 
The following endpoints will be derived for each treatment visit and will be used to assess the 
activity of Reproxalap Ophthalmic Solutions. 
• 
AUC 0-212 mins for Itching on VAS scale 
• 
AUC 0-212 mins for Itching on 9 points scale 
• 
AUC 0-210 mins for Conjunctival Redness on 9 points scale 
• 
AUC 0-212 mins for Tearing on 4 points scale 
• 
AUC 0-212 mins for TOSS  
• 
AUC 0-92 mins for Itching on VAS scale  
• 
AUC 92-212 mins for Itching on VAS scale  
• 
AUC 0-32 mins for Itching assessed by VAS Scale 
• 
AUC 32-72 mins for Itching assessed by VAS Scale 
All 0 time-point measurements will be pre-EEC entry/ baseline values. All the time-points are approximate 
values. 
 Additional Exploratory Analyses 
In addition, change from baseline (CFB) for each treatment and each post-EEC time-points may 
be derived and used as exploratory efficacy endpoint and used to evaluate the efficacy of 
Reproxalap Ophthalmic Solutions (0.25% and 0.5%). Other exploratory analyses may be added 
post-hoc. 


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3 
INVESTIGATIONAL PLAN 
 Overall Clinical Trial Design and Plan  
The double-masked, vehicle-controlled, randomized, three-way crossover clinical trial allows for 
the testing of two concentrations of Reproxalap Ophthalmic Solution (0.25% and 0.5%) versus 
Vehicle Ophthalmic Solution in subjects with ragweed-induced allergic conjunctivitis in the EEC. 
The clinical trial consists of five visits to the clinic (one Medical Screening visit, one Screening 
EEC visit, and three EEC treatment visits).The four EEC sessions (one EEC screening and three 
EEC treatment sessions) will be separated by an approximate two-week washout period to ensure 
adequate elimination of responses caused by allergen exposure in the EEC and allow the 
recuperation of mast cells, please refer to Figure 4 
The EEC clinical research facility is a room designed with the capacity and control mechanisms 
to expose participants to airborne ragweed pollen grains and maintains target temperature and 
relative humidity throughout. 
The use of the controlled EEC allergen exposure has been validated to provide spatial and 
temporal airborne allergen uniformity and to mimic the natural exposure on a peak allergen day. 
 
Figure 4. Clinical Trial Design 
 
 
At the Medical Screening Visit (Visit 1), subjects will undergo the informed consent process, and 
information about demographics, baseline characteristics, medical history, social history, physical 
examination will be performed and concomitant medication will be collected. Vital signs and 
samples for standard clinical safety laboratory tests will be obtained. A urine pregnancy test will 
be administered to women of childbearing potential (WOCBP).  
Subjects will undergo ophthalmic examinations (Snellen VA, SLE, NCT, and a dilated fundus 
examination) to ensure initial eligibility criteria are met. A skin prick test for a panel of test allergens 
will be conducted; results must be positive (i.e., a wheal that is 3 mm greater than the negative 
control) for at least one test allergen and must include ragweed in order to proceed to Visit 2. 


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At all EEC sessions, assessments of ophthalmic evaluations will be collected 
 
. For subject-reported symptoms 
of ocular itching, a standard 9 point (i.e., 0-4 with 0.5 unit increments) and a standard VAS scale 
(0-100 mm) will be employed and subject reported tearing assessed by a 4-point (0-3) scale will 
be employed. For staff-assessed grading of conjunctival redness, a standard 9-point (i.e., 0-4 with 
0.5 unit increments) will be employed.
 
 
 
 
At the EEC Screening Visit (Visit 2), qualified site staff will update concomitant medications and 
collect AEs, as applicable and perform tests for vital signs. A urine pregnancy test will be 
administered to WOCBP. Fundus exam, Snellen VA, SLE, subject rating of symptoms, and staff 
grading of conjunctival redness will be performed to ensure the anterior segment of the eye is 
healthy. 
 
Pre-EEC entry (Baseline):  
1) Subject assessment for ocular itching and tearing will be recorded 
 
, and  
2) Staff-assessed conjunctival redness will be recorded 
 
.  
Post-EEC entry:  
1) Subject assessment for ocular itching and tearing will occur 
 
 2) Staff-assessed 
conjunctival redness will be recorded 
 
  
Please refer to Table 2, Table 3, Table 4 and Table 5 for schedule of staff and subject assessment 
time-points. 
 
 
 
 
 
 
 
At Randomization/Treatment EEC Session One (Visit 3), qualified site staff will update 
concomitant medications, collect AEs, as applicable and collect vital signs. A urine pregnancy test 
will be administered to WOCBP. Ophthalmic evaluations will be conducted (Fundus exam, 
Snellen VA, NCT SLE, subject rating of symptoms, and staff grading of conjunctival redness). 
 
 
 
Subjects will be randomized to receive a first dose of either Reproxalap Ophthalmic Solution 
(0.25%) (Treatment A), Reproxalap Ophthalmic Solution (0.5%) (Treatment B), or Vehicle 
Ophthalmic Solution (Treatment C). Qualified site staff will instill one drop of the randomized 


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treatment into each eye at approximately five minutes prior to entry to the EEC after all the pre-
EEC assessments are done.  
Pre-EEC entry (Baseline):  
1) Subject assessment for ocular itching and tearing will be recorded 
 
 and  
2) staff-assessed conjunctival redness will be recorded 
 
.  
Post-EEC entry:  
1) Subject assessment for ocular itching and tearing will occur 
 
  
2) Staff-assessed conjunctival redness will be recorded a
 
.  
At approximately 95-minutes post-EEC entry (and after subject assessed itching and tearing 
and staff assessed conjunctival redness for all time-points post first dose have been completed), 
a second dose (one drop in each eye) of the same randomized treatment will be administered in 
each eye by the qualified site staff. Subject will continue to assess symptoms of ocular itching 
and tearing after the second dose
 
, and staff-assessed 
conjunctival redness will be recorded at approximately post second dose
 
. 
Post-EEC exit (approximately t=215 minutes):  
1) Subject assessed ocular itching and tearing will continue a
 
  
2) Staff assessed conjunctival redness will continue to be recorded post-EEC exit 
 
  
Subjects will be asked to return in at least two weeks for Visit 4. 
At Treatment EEC Session Two (Visit 4), all procedures performed at Visit 3 will be repeated 
except that each subject will be given a different treatment dependent on the treatment sequence 
the subject was randomized to [Reproxalap Ophthalmic Solution (0.25%) (Treatment A), 
Reproxalap Ophthalmic Solution (0.5%) (Treatment B), or Vehicle Ophthalmic Solution 
(Treatment C)].  
At the end of the EEC session, subjects will be asked to return in at least two weeks (± 3 days) 
for Visit 5. 
At Treatment EEC Session Three (Visit 5), all procedures performed at Visit 4 will be repeated 
except that each subject will be given a different treatment dependent on the treatment sequence 
the subject was randomized to [Reproxalap Ophthalmic Solution (0.25%) (Treatment A), 
Reproxalap Ophthalmic Solution (0.5%) (Treatment B), or Vehicle Ophthalmic Solution 
(Treatment C)]. At the end of the visit, a urine pregnancy test will be administered to WOCBP. 
Subjects will undergo ophthalmic examinations (Snellen VA, SLE, NCT, and a dilated fundus 
examination), clinical safety lab tests and vital signs will be collected to ensure safety prior to exit 
of the clinical trial. 


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 Assigning Subjects to Treatment Groups 
3.2.1 Subject Numbering 
Each subject screened for the clinical trial will be assigned a unique subject number that will be 
used to identify the subject throughout subject participation in the clinical trial. If a subject fails to 
be randomized, the reason should be documented in the source documents and case report form 
(CRF). The subject will be considered a screen failure. 
3.2.2 Randomization  
Eligible subjects will be randomized 1:1:1 to one of three treatment sequences of ABC, BCA, 
CAB, where:  
• 
Treatment A:  Reproxalap Ophthalmic Solution (0.25%) 
• 
Treatment B:  Reproxalap Ophthalmic Solution (0.5%) 
• 
Treatment C:  Vehicle Ophthalmic Solution 
Approximately 75 subjects (approximately 25 per treatment sequence) will be enrolled. 
 Masking and Unmasking 
3.3.1 Masking 
Investigators, qualified site personnel, and subjects will be masked to the investigational product 
(IP) administered. The Sponsor will also be masked to the IP administered until database lock. 
3.3.2 Emergency Unmasking 
Emergency unmasking should only be performed when necessary to treat the subject. Most often, 
knowledge of the possible treatment assignments is sufficient to treat a clinical trial subject who 
presents with an emergency condition. 
The investigator should make every effort to contact the Medical Monitor to discuss the subject’s 
emergency and the need to unmask, prior to unmasking any subject. 
In situations in which the investigator has tried but is unable to reach the Medical Monitor, best 
judgement on the part of the investigator should be used, based on the nature and urgency of the 
clinical situation, and may proceed with unmasking without having successfully reached and 
discussed the situation with the Medical Monitor. Once a subject's treatment assignment has been 
unmasked, the Medical Monitor should be notified within 24 hours of unmasking of the treatment, 
without revealing the treatment.  
If the investigator determines that emergency unmasking is necessary, the investigator should 
identify the given subject’s IP kit, which contains a scratch-off laminate under which the treatment 
is identified, along with the associated lot number. In order to unmask, the investigator should 
scratch off the laminate, using a flat object and applying pressure, to reveal the treatment 
assigned for that subject.  
The emergency unmasking should be performed by the designated site personnel. The 
investigator must also indicate in source documents and in the CRF that the mask was broken 
and provide the date, time, and reason for breaking the mask.  


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Any AE or SAE associated with breaking the mask must be recorded and reported as specified 
in the protocol. The investigator has the responsibility to contact the Sponsor or designee within 
24 hours of unmasking. In the event of a drug-related, serious, unexpected AE, the Sponsor’s 
Pharmacovigilance Department or designee will be provided with the treatment assignment for 
the subject for regulatory reporting. 
If treatment assignment is unmasked, the treatment will be discontinued immediately, and the 
subject will be discontinued from the clinical trial.  
The mask may be broken in the case of a pregnancy should the subject desire this information.  
 Safety Oversight  
During the clinical trial, subject safety will be monitored on a continuous basis by the Medical 
Monitor until the last subject completes the last scheduled clinical trial assessment. 
 Clinical Trial Duration for Individual Subjects 
The clinical trial consists of five clinic visits over a period of approximately 14 weeks. 
4 
CLINICAL TRIAL POPULATION SELECTION 
 Inclusion Criteria 
In order to be considered eligible for the clinical trial, subjects must: 
1. Be at least 18 years of age at the time of screening of either sex or any race;  
2. Provide written informed consent;  
3. Be willing and able to follow instructions, and can attend all required clinical trial visits;  
4. Have at least a two-year history of moderate-to-severe ragweed-induced allergic 
conjunctivitis based on Principal Investigator’s  judgement;  
5. Have a positive skin prick test to ragweed pollen within the past year of the Medical 
Screening Visit (Visit 1); 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
10. Confirmed absence of pregnancy according to a negative urine pregnancy test at the 
Medical Screening Visit (Visit 1); 


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11. WOCBP must agree to use a reliable and highly effective method of birth control with a 
low failure rate (i.e., less than 1% per year) when used consistently and correctly (e.g., 
implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], 
sexual abstinence, or vasectomized partners) during the clinical trial, as judged by the 
investigator. 
 Exclusion Criteria 
Subjects must not:  
 
 
 
  
 
 
 
 
4. Have a history of blepharitis, dry eye syndrome, herpes simplex keratitis, or herpes zoster 
keratitis; 
5. Have a history of uveitis in the past three years; 
6. Have a presence of any ocular infection (bacterial, viral, or fungal) or active ocular 
inflammation (e.g., follicular conjunctivitis, allergic conjunctivitis) within 14 days prior to the 
Medical Screening Visit (Visit 1); 
7. Have a presence of any chronic ocular degenerative condition or ocular inflammation that, 
in the opinion of the investigator, is likely to worsen over the course of the clinical trial; 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 


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9. Use any prescription or over-the-counter topical ocular medications during the clinical trial;  
10. Use of any medication not previously specified that impairs either allergy skin testing or 
EEC evaluation at the discretion of the investigator; 
11. Have history of moderate-to-severe asthma (a score of greater than Global Initiative of 
Asthma (GINA) Score of 1) or allergy-induced asthma to ragweed; 
12. Have systemic signs of infection (e.g., fever, current treatment with antibiotics); 
13. Have a systemic disease or uncontrolled medical condition, which, in the opinion of the 
investigator, could interfere with clinical trial measurements or subject compliance. Such 
diseases or conditions would include, but are not limited to, cancer, alcoholism, drug 
dependency or abuse, or psychiatric disease; 
 
15. WOCBP who are pregnant, nursing, or not using an effective means of contraception; 
 
 
18. Chronic systemic medications in place for less than one month, or a change in the dosage 
of such medications within the month prior to the Medical Screening Visit (Visit 1). Subjects 
receiving anti-allergy injections may be enrolled if the dose has been stable for three 
months prior to the Medical Screening Visit (Visit 1) and no changes are planned during 
the clinical trial period; 
19. Have a diagnosis of moderate-to-severe pinguecula or pterygium (particularly if it results 
in chronic erythema), Stevens-Johnson Syndrome, ocular cicatricial pemphigoid, mucous 
membrane pemphigoid, significant conjunctival scarring, chemical burn, herpetic or 
neurotrophic keratitis, Cryopyrin Associated Periodic Syndrome (CAPS), or keratoconus; 
 
 
 
5 
SUBJECT DISPOSITION 
 Completed Subjects 
A completed subject is one who has not been discontinued from the clinical trial. 
 Discontinued Subjects 
Subjects may be discontinued prior to their completion of the clinical trial due to: 


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• 
Subject request/withdrawal; 
• 
AEs; 
• 
Positive pregnancy results 
• 
Protocol violations; 
• 
administrative reasons (e.g., inability to continue, lost to follow-up); 
• 
Sponsor termination of the clinical trial 
• 
Any sound medical reason, as determined by the investigator; or 
• 
Other.  
Notification of a subject discontinuation and the reason for discontinuation will be made to the 
Sponsor or designee and will be clearly documented on the eCRF. Subjects who are discontinued 
from the clinical trial will not be replaced. 
 Subject Withdrawal and Replacement 
Subjects may voluntarily withdraw from the clinical trial at any time.  
Any female subject will be removed from the clinical trial should pregnancy occur during the 
course of the clinical trial. The subject will undergo a pregnancy test at the clinical trial exit visit 
(Visit 5) for confirmation. The pregnancy test must be confirmed by two additional tests and 
confirmed by the investigator. If the test result is positive a second and third time, the principal 
investigator (or sub-investigator if the principal investigator is not present) will inform the subject. 
The investigator will document the outcome of the pregnancy and provide a copy of the 
documentation to the Sponsor. 
Additionally, subjects may be discontinued for safety or sound medical reasons, as determined 
by the investigator or Sponsor (see Section 5.2). 
Reason for withdrawal will be included in the electronic CRF, and all efforts should be made to 
schedule the subject for a clinical trial exit visit (Visit 5) to complete exit procedures. Any subject 
withdrawn for the trial because of an AE will be followed until the AE is resolved, or as clinically 
required. The investigator will prepare a written summary of the event and document the available 
follow-up information on the electronic CRF.  
6 
INVESTIGATIONAL TREATMENT 
 Description of Investigational Product 
 
  
 
 
  
  
 
 Packaging and Labeling 
 
 
 


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Labels will be in the local language and comply with the legal requirements of each country. 
Clinical supplies are to be administered only in accordance with the protocol. IP labels will not 
bear any statement that is false or misleading in any manner or represent that the IP is safe or 
effective for the purposes for which it is being investigated.  
 Investigational Product Storage  
 
 
 
  
 Investigational Product Accountability 
The investigator or designated qualified site staff is responsible for monitoring the inventory of IP 
and for the accountability of all used and unused IP. Inventories must be carefully and accurately 
documented according to applicable state, federal, and local regulations, current Good Clinical 
Practices (GCPs), including the International Council for Harmonisation (ICH) guidelines, and 
clinical trial procedures. IP accountability will be verified by the clinical trial monitor during site 
visits and at the completion of the trial.  
The investigator or designated qualified site staff will maintain accurate records of receipt and 
condition of IP, including dates of receipt. In addition, accurate records will be kept of the date of 
IP dispensed and the subject to whom IP was dispensed. Any reasons for departure from the 
protocol-specified dispensing regimen must also be recorded. 
 Investigational Product Retention  
IP must be retained until completion or termination of the clinical trial, and written authorization 
from the Sponsor has been received. All unused and used IP drug should be destroyed at the site 
or returned to the distributor, as specified by Sponsor. It is the investigator’s responsibility to 
ensure that the Sponsor has provided written authorization prior to return or destruction, and that 
appropriate records of the disposal are documented and maintained. No used or unused IP may 
be disposed until fully accounted for by the clinical trial monitor. 
 Investigational Product Administration 
IP will be administered by qualified site staff at the designated clinical trial visits (Visits 3 through 
5). 
 Concomitant Therapy and Procedures 
The use of any concomitant medication, prescription or over-the-counter, taken within 30 days 
prior to Visit 1, is to be recorded on the source document and corresponding electronic CRF along 
with the reason the medication was taken. 
Concurrent enrollment in another investigational drug or medical device clinical trial is not 
permitted. 
6.7.1 Prohibited Concurrent Therapies and Procedures 
Prohibited medications, treatments, and procedures during the clinical trial are outlined in the 
Exclusion Criteria (Section 4.2). 


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7 
CLINICAL TRIAL PROCEDURES 
Clinical trial assessments and evaluations should be performed by the investigator and/or 
qualified site staff according to Schedule of Events and Assessments (Table 1).Refer to the 
Clinical Trial Activities Schedule (Section 8). 
 Informed Consent  
Informed consent forms must be approved for use by the reviewing Institutional Review Board 
(IRB)/Research Ethics Board (REB)/Independent Ethics Committee (IEC). Informed consent must 
be obtained for all subjects participating in the clinical trial prior to performing any procedures. 
The informed consent process must be adequately documented in the source records. 
 Eligibility Review 
The investigator or qualified site staff will confirm that all inclusion and exclusion criteria have 
been met. 
 Demographics, Medical History, and Social History 
Demographic information to be captured include subject initials (where locally permitted), date of 
birth (alternatively year of birth, if full date of birth is not allowed to be collected for legal reasons), 
age, sex, race, and ethnicity will be obtained from the subject and recorded in the CRF. 
Medical and social history will be recorded in the CRF. Current underlying conditions, including 
conditions diagnosed within the last 30 days of consent, which may have resolved before 
screening, must be recorded. 
 Physical Examination:  
A physical examination will be performed including but may not be limited to an evaluation of the 
cardiovascular, gastrointestinal, respiratory and central nervous systems at Screening. An oral 
examination will also be conducted. Additional examinations may be obtained on Principal 
Investigator’s discretion.  
 Concomitant Medications 
Concomitant medications used 30 days prior to consent to treat any medical conditions will be 
recorded in the CRF. Any changes in dosage or new medications added must be recorded in the 
subject CRF. The Sponsor and investigator or qualified site staff will review and evaluate 
concomitant medication usage on an ongoing basis. 
 Adverse Events 
AEs will be collected from the time the subject signs the informed consent form through 30 days 
after the last dose of IP. AEs must be recorded in the CRF. The Sponsor and investigator or 
qualified site staff will review and evaluate AEs on an ongoing basis. See Section 9 for further 
detail on AE reporting. 
 Vital Signs 
Vital sign assessments will be taken with the subject in the sitting or supine position after 
5 minutes at rest and will include body temperature, pulse rate, blood pressure (BP), and 
respiratory rate (RR) prior to EEC entry and at end of Visit 5 prior to study exit.  


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 Clinical Laboratory Tests 
Blood and urine samples for standard clinical safety laboratory will be collected at the Medical 
Screening Visit (Visit 1) and the third Treatment EEC Session (Visit 5) as part of study exit 
procedures. Samples will be collected at the site by the investigator or qualified site staff.  
The investigator must categorize all abnormal laboratory values as either clinically significant or 
not clinically significant. Clinical significance is defined as any variation in laboratory parameters, 
which has medical consequences resulting in an alteration in the subject’s medical care. In case 
of clinically significant laboratory results, the investigator will continue to monitor the subject with 
additional laboratory assessments until values have reached normal range and/or baseline levels. 
Clinically significant laboratory results should be reported as an adverse event in accordance with 
Section 9. 
7.8.1 Hematology 
Hematology profile includes hemoglobin, hematocrit, red blood cell (RBC) count, white blood cell 
(WBC) count, and absolute platelet count. 
7.8.2 Chemistry 
Serum chemistry profile includes albumin, alkaline phosphatase (ALP), ALT (SGPT), AST 
(SGOT), BUN, calcium, carbon dioxide (CO2), chloride, total cholesterol, creatinine, creatinine 
phosphokinase (CPK), glucose, phosphate, potassium, sodium, total protein, and uric acid. 
7.8.3 Pregnancy Test 
For WOCBP, a urine pregnancy test will be collected at the Medical Screening Visit (Visit 1), and 
all EEC Sessions (Visits 2 through 5). Results must be available and confirmed to be negative 
before the subject may be enrolled in the clinical trial. IP must be discontinued for any subject 
with a positive pregnancy test result.  
 Skin Prick Test 
A skin prick test for a standard panel of test allergens will be conducted including cat, dust, 
ragweed, grass or tree pollen. Results must be positive (i.e., a wheal 3 mm greater than the 
negative control) for at least one test allergen and must include ragweed in order to proceed to 
the Screening EEC Visit (Visit 2). 
 Ophthalmic Examinations 
7.10.1 Visual Acuity 
VA will be measured using a Snellen eye chart. VA will be measured at the Medical Screening 
Visit (Visit 1), and pre- and post-entry to the EEC at the Screening and Treatment EEC Sessions 
(Visits 2 through 5). 
7.10.2 Slit Lamp Exam 
SLE observations will be graded as “normal” or “abnormal.” Abnormal findings will be categorized 
as clinically significant (findings that may interfere with trial parameters or otherwise confound the 


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data as determined by the investigator) or not clinically significant. The cornea, conjunctiva, 
anterior chamber, lens, and eyelid will be examined. 
SLE will be conducted at the Medical Screening Visit (Visit 1), and pre- and post-entry to the EEC 
at the Screening and Treatment EEC Sessions (Visits 2 through 5). 
7.10.3 Non-Contact Intraocular Pressure Tonometry (NCT) 
Intraocular pressure will be measured using non-contact tonometry. NCT will be measured at the 
Medical Screening Visit (Visit 1), prior to and post-EEC at the Treatment EEC Sessions (Visits 3 
through 5). 
7.10.4 Fundoscopy 
Dilated or undilated fundoscopy will be performed by the investigator or qualified staff to evaluate 
for clinically significant fundus abnormalities and vitreous pathology. Fundoscopy will be 
performed at the Medical Screening Visit (Visit 1), pre-EEC at Visit 2, and post-EEC at the 
Treatment EEC Sessions (Visits 3 through 5) . Specifically dilated fundoscopy will be performed 
at Visit 1 and Visit 5 and undilated fundoscopy will be performed at Visits 2 through 4. 
 Symptom Collection 
At all EEC sessions (pre- and post-entry), assessments of ophthalmic signs and symptoms will 
be collected by qualified site staff and subjects  
 
 Refer to Table 2 and Table 4 for the Schedules of Staff Assessed 
conjunctival redness and Table 3 and Table 5 for the Schedule of Subject Assessed Itching and 
Tearing for details on collection time-points. 
7.11.1 Staff-Assessed Symptom Collection 
At designated time-points, qualified site staff will assess conjunctival redness in each subject 
using a standard 9-point scale (i.e., 0-4 scale with 0.5 unit increments). 
7.11.2 Subject-Reported Symptoms 
At designated time-points, subjects will be asked to report and rate symptoms associated with 
allergic conjunctivitis, including ocular itching, using a standard 9-point scale (i.e., 0-4 scale with 
0.5 unit increments). Ocular itching will also be rated using a standard VAS scale (0-100 mm). 
Tearing assessment will be done on a standard 4-point (i.e. 0-3 scale).  
 Environmental Exposure Chamber 
 
 
  
 
 
 
 
 


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 Randomization  
After eligibility is confirmed, subjects will be randomized as described in Section 3.2.2. 
 Investigational Product Treatment 
At Treatment EEC Sessions (Visits 3 through 5), the subject will receive IP according to the 
treatment sequence the subject was randomized to. The subject will receive one dose of IP just 
prior to EEC entry and then another dose will be administered approximately 95 minutes post-
EEC entry. IP will be administered by designated site staff only. 
Refer to Section 6 for details on IP treatment. 
8 CLINICAL TRIAL ACTIVITIES  
Clinical trial activities are summarized in the Schedule of Events and Assessments (Table 1) 
 Medical Screening Visit (Visit 1) 
• 
Obtain written informed consent (Section 7.1) 
• 
Review eligibility criteria (Section 7.2) 
• 
Collect demographic information and document medical and social history (Section 7.3)  
• 
Perform physical examination (Section 7.4) 
• 
Collect concomitant medications (Section 7.5) 
• 
Perform VA, SLE, NCT, and dilated fundoscopy (Section 7.10) 
• 
Collect vital signs and samples for laboratory testing (Sections 7.7 and 7.8) 
• 
Collect urine sample for pregnancy test, if applicable (Section 7.8.3) 
• 
Perform skin prick test (Section 7.9) 
 Screening EEC Visit (Visit 2) 
• 
Review eligibility criteria (Section 7.2) 
• 
Collect concomitant medications and adverse events (Sections 7.5 and 9) 
• 
Collect vital signs and perform urine pregnancy test (Sections 7.7 and 7.8.3) 
• 
Perform VA and SLE and fundus examination (Section 7.10) 
• 
Obtain symptom collection (staff-assess and subject-reported) pre- and post-EEC entry 
(Section 7.11)  
• 
 
• 
EEC session (Section 7.12) 


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 Treatment EEC Sessions One and Two (Visits 3 and 4) 
• 
Review eligibility criteria (Section 7.2) 
• 
Collect concomitant medications and adverse events (Sections 7.5 and 9) 
• 
Collect vital signs (Section 7.7) 
• 
Collect urine sample for pregnancy test (Section 7.8.3) 
• 
Perform VA, SLE, NCT, and undilated fundus exams (Section 7.10) 
• 
Randomization to IP treatment sequence (Section 7.13) 
• 
Obtain symptom collection (staff-assessed and subject-reported) pre- and post-EEC entry 
per Table 2 and Table 4 and Table 3 and Table 5 (Section 7.11) 
• 
IP treatment (Section 7.14) 
• 
EEC session (Section 7.12) 
 Treatment EEC Session Three / Clinical Trial Exit (Visit 5) 
• 
Review eligibility criteria (Section 7.2) 
• 
Collect concomitant medications and adverse events (Sections 7.5 and 9) 
• 
Collect vital signs and samples for laboratory testing (Sections 7.7 and 7.8) 
• 
Collect urine sample for pregnancy test (Section 7.8.3) 
• 
Perform VA, SLE, NCT, and dilated fundus exams (Section 7.10) 
• 
Obtain symptom collection (staff-assessed and subject-reported) pre- and post-EEC entry 
per Table 2 and Table 4 and Table 3 and Table 5 (Section 7.11) 
• 
IP treatment (Section 7.14) 
• 
EEC session (Section 7.12) 
• 
Clinical trial exit 
9 
ADVERSE EVENT REPORTING 
AEs will be collected from the time the subject signs the informed consent form through 30 days 
after the last IP administration. 
9.1.1 Adverse Event 
An AE is any untoward medical occurrence in a patient administered an IP, which does not 
necessarily have a causal relationship with the IP treatment. Therefore, an AE can be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of the IP, whether or not it is considered related to the IP.  
Abnormal laboratory and other abnormal investigational findings (i.e., physical exam) should not 
be reported as AEs unless they are associated with clinical signs and symptoms, lead to treatment 
discontinuation, or are otherwise considered clinically relevant by the investigator. In cases of 
surgical or diagnostic procedures, the condition/illness leading to such a procedure is considered 


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as the AE rather than the procedure itself. In case of a fatality, the cause of death is considered 
as the AE, and the death is considered as its outcome. 
9.1.1.1 Events Not to Be Considered as Adverse Events 
Pre-existing medical conditions/signs/symptoms present before the EEC Screening Visit (Visit 2) 
that do not worsen in severity or frequency during the clinical trial are defined as baseline medical 
conditions, and are not to be considered AEs. 
Pregnancies are not considered AEs but must be reported, see Section 9.1.8. 
9.1.1.2 Recording Adverse Events 
All AEs must be recorded in the site’s clinical trial records and the AE CRF. Investigators should 
use correct medical terminology when recording events and avoid abbreviations.  
The investigator should attempt to establish a diagnosis of the AE based on signs, symptoms, 
and/or other clinical information. The diagnosis, and not the individual signs/symptoms, or 
laboratory abnormalities, should be documented in the subject’s source documents and the CRF 
unless the etiology of the event is unknown. If signs/symptoms cannot be medically characterized 
as a single diagnosis or syndrome at the time of reporting, each individual event should be 
recorded as an AE. If a diagnosis is subsequently established, it should be reported as follow-up 
information. 
An assessment should be made at each visit (or more frequently if necessary) of any changes in 
severity, the suspected relationship to IP, the interventions required to treat it, and the outcome. 
9.1.1.3 Assessment of Causality and Severity 
For each AE recorded, the investigator will make an assessment of causality and severity as 
follows: 
1. Relationship to IP: The investigator must assess whether they consider an AE to be drug-
related. In assessing this relationship, the investigator must use information about the drug 
as outlined in the Investigator’s Brochure, the subject’s pre-existent medical 
conditions/concurrent medication, and chronology of the event relative to drug 
administration. The following definitions will be used: 
• 
Definitely Related 
• 
Probably Related 
• 
Possibly Related 
• 
Unlikely to be related 
• 
Not Related 
2. Event Severity: The investigator will be asked to use their medical judgment to assess the 
severity of the AE. 
The following are guidelines to be used by the investigator to judge the event severity of 
an AE: 
• 
Mild - awareness of sign or symptom, but easily tolerated 
• 
Moderate - discomfort enough to cause interference with usual activity 


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• 
Severe - incapacitating with inability to work or perform usual activity 
3. Expectedness: The expectedness of an AE should be determined based on upon existing 
safety information about the IP using the following explanations: 
• 
Unexpected: an AE that is not listed in the IB or is not listed at the specificity or 
severity that has been observed. 
• 
Expected: an AE that is listed in the IB at the specificity and severity that has been 
observed. 
• 
Not applicable: an AE unrelated to the IP. 
AE events that are mentioned in the IB as occurring with a class of products or as 
anticipated from the pharmacological/mechanical (or other) properties of the product, but 
are not specifically mentioned as occurring with the particular product under investigation, 
are to be considered unexpected. 
The investigator should initially classify the expectedness of an AE, but the final 
classification is subject to the determination of the Sponsor’s Medical Monitor. 
4. Duration: Start and end dates and times, or if continuing. 
5. Frequency: whether the event is a single episode, recurrent or continuous. 
6. Action taken. 
7. Whether it constitutes a SAE, per definition below. 
8. Outcome: resolved, resolved with sequelae, continuing, death, or unknown (only for 
subjects that are lost to follow-up). 
9.1.2 Treatment-Emergent Adverse Events 
A TEAE is defined as an AE that occurred during the clinical trial after the first dose of IP or was 
present prior to dosing, and exacerbates after the first dose of IP.  
9.1.3 Serious Adverse Events 
An SAE is any AE that results in any of the following outcomes: 
• 
death; 
• 
a life-threatening AE; 
Note:  An AE is considered “life-threatening” if, in the view of either the investigator or 
Sponsor/designee, the subject is at immediate risk of death as a result of the AE. "Life 
threatening" does not include an AE that, had it occurred in a more severe form, might 
have caused death. 
• 
inpatient hospitalization or prolongation of existing hospitalization; 
Note:  The term “inpatient hospitalization” refers to any inpatient admission (even if less 
than 24 hours). For chronic or long-term inpatients, inpatient admission includes transfer 
within the hospital to an acute/intensive care inpatient unit. Inpatient hospitalization does 


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not include: emergency room visits; outpatient/same-day/ambulatory procedures; or 
admission to observation/short stay units, rehabilitation facilities, hospice facilities, nursing 
homes, or clinical research/Phase 1 units. 
Note:  The term “prolongation of existing hospitalization” refers to any extension of an 
inpatient hospitalization beyond the stay anticipated or required for the reason for the initial 
admission, as determined by the investigator or treating physician. 
• 
a persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions;  
Note:  A serious adverse event (SAE) specifically related to visual threat would be 
interpreted as any potential impairment or damage to the subject’s eyes (e.g., 
hemorrhage, retinal detachment, central corneal ulcer, or damage to the optic nerve). 
• 
a congenital anomaly/birth defect; and, 
• 
other serious (Important Medical Events) events that do not fit other outcomes, where the 
event may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in the SAE definition, based upon appropriate medical judgement. 
9.1.4 Unexpected Adverse Event  
An unexpected adverse event is defined as an AE, the nature or severity of which is not consistent 
with the information in the Investigator’s Brochure. 
9.1.5 Reporting Serious Adverse Events 
The investigator is responsible for reporting all SAEs, regardless of causality, to the Sponsor 
designee within 24 hours of learning of the occurrence. SAEs should be sent to: Inflamax 
Research Limited. 
 (Local toll-free numbers will be provided on the SAE report form cover sheet.) 
The reporting timeframe starts when the subject signs the informed consent or assent form 
through 30 days after the last IP administration. At a minimum, a description of the event and the 
Investigator’s judgment of causality must be provided at the time of the initial report. These 
preliminary reports will be followed by detailed descriptions that will include copies of hospital 
case reports, autopsy reports, and other documents when requested and applicable. 
A follow-up SAE Report must be submitted within 24 hours of the investigator receiving the 
follow-up information (such as information regarding complications, progression or resolution).  
An SAE that is considered completely unrelated to a previously reported event should be reported 
separately as a new SAE. 
The procedures for reporting SAEs are as follows: 
• 
Complete the “Serious Adverse Event Report Form.” The investigator may contact 
Pharmacovigilance via the telephone hotline for assistance with SAE reporting. 
• 
Fax or email the SAE Form to the attention of Pharmacovigilance within 24 hours of 
the investigator’s knowledge of the event.  


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The original copy of the SAE Report Form and the fax confirmation sheet (or email) must be kept 
with the source documentation at the clinical trial site. 
Follow-up information should be communicated the same way, using a new SAE Report Form 
stating that it is a follow-up to the previously reported SAE and giving the date of the original 
report. The follow-up information should describe whether the event has resolved or continues, if 
and how it was treated, and whether the subject continued or withdrew from clinical trial 
participation.  
The investigator and qualified site staff should institute any supplemental investigations of SAEs 
based on their clinical judgment of likely causative factors. This may include clinical laboratory 
tests not specified in the protocol, histopathologic examinations, or consultations with specialists. 
The Sponsor or their designee may also request the investigator to conduct supplemental 
assessments.  
If the SAE was not previously documented in the Investigator’s Brochure and is thought to be 
related to IP, the Sponsor or their designee may urgently require further information from the 
investigator for regulatory authority reporting. The Sponsor may need to issue an investigator 
Notification to inform all investigators involved in any clinical trial with the same drug that this SAE 
has been reported. 
The investigator should notify Pharmacovigilance of any death or SAE occurring after a subject 
has withdrawn from the clinical trial when such a death occurs within 30 days of the last dose of 
IP and may reasonably be related to the IP. 
9.1.6 Follow-up of Adverse Events 
All AEs will be followed until stabilization/resolution or until clinical database lock.  
All SAEs will undergo active follow-up until resolved or the event becomes chronic or stable. 
Follow-up data for SAEs obtained after clinical database lock will be incorporated into the safety 
database.  
9.1.7 Reporting Serious Adverse Events to Regulatory Health Authorities/ 
Institutional 
Review 
Boards/Research 
Ethics 
Boards/Independent 
Ethics 
Committees 
The investigator is responsible for following all local regulations for the reporting of safety 
information, including the reporting of SAEs to their local IRB/REB/IEC. 
The investigator must promptly report to his or her local IRB/REB/IEC all unanticipated problems 
involving risks to subjects. This includes death from any cause and all serious adverse events 
reasonably or possibly associated with the use of IP.  
The Sponsor or their designee is responsible for appropriate reporting of relevant AEs, suspected 
unexpected serious adverse reactions (SUSARs) involving IP, to all regulatory authorities.  
In addition, the Sponsor or designee will be responsible for the submission of safety letters 
(e.g., SUSARs) to the central IRB/REB/IEC and to participating investigators of all SUSARs 
involving IP according to applicable regulations.  
After termination of the clinical trial (determined as last subject, last visit), any unexpected safety 
issue that changes the risk-benefit analysis and is likely to have an impact on the subjects who 


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have participated in it, will be reported by the Sponsor as soon as possible to the competent 
authority (ies) concerned together with proposed actions. 
9.1.8 Reporting Pregnancies 
Pregnancies will be reported from the time the subject signs the informed consent form through 
final clinical trial visit or 30 days after the last IP administration, whichever is later. 
To ensure subject safety, each pregnancy in a subject on IP must be reported to 
Pharmacovigilance within 24 hours of learning of its occurrence. Subjects who become pregnant 
will be withdrawn from the clinical trial. The pregnancy should be followed up to determine 
outcome, including spontaneous or voluntary termination, details of the birth, and the presence 
or absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications.  
Pregnancy should be recorded on a subject’s source documents and a Pregnancy Notification 
and Outcome Form and reported by the investigator to Pharmacovigilance using the same 
procedure for reporting SAEs detailed in Section 9.1.5. A pregnancy, by itself, is not an SAE. 
Pregnancy follow-up should also be recorded and should include an assessment of the possible 
relationship to the IP of any pregnancy outcome. Any pregnancy-related SAE (e.g., spontaneous 
abortion, birth defect) or any other SAE experienced during pregnancy must be recorded on a 
separate SAE Report Form and reported per SAE reporting procedures in Section 9.1.5. 
10 STATISTICS 
 Sample Size 
 
 
 
  
 
 
 
Prior to database lock, the Sponsor will finalize a statistical analysis plan (SAP) that will detail all 
planned analyses. Any analyses conducted in addition to those specified in the SAP will be clearly 
documented as post hoc. 
Since the clinical trial is exploratory in nature to assess the safety, tolerability, and 
pharmacodynamic activity of reproxalap ophthalmic solution utilizing a novel dosing regimen, 
there are no primary endpoints and no formal statistical hypotheses. There will be no multiplicity 
adjustments for the exploratory efficacy measures or for the exploratory pharmacodynamics 
measures. 
 Analysis Populations 
The statistical analysis will be based on the analysis populations as defined below: 
Safety Population 
All randomized subjects who use at least one dose of IP, 
regardless of whether clinical trial assessments were 
performed. 


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Intent-to-Treat (ITT) Population 
All randomized subjects who use at least one dose of IP and 
have any post-dose assessments. Subjects are evaluated 
according to the IP treatment of the visit as per the 
randomized treatment sequence. 
Per-Protocol (PP) Population 
All ITT subjects will be considered PP if IP dosing occurs 
and do not have a major deviation from the protocol. 
  
 
 
 
 
 Demographic and Baseline Medical History 
The demographic and baseline medical history data will be summarized descriptively. For 
quantitative variables, the summaries will include the number of observations, mean, standard 
deviation, median, minimum, and maximum. Qualitative variables will be summarized using 
counts and percentages. 
 Exploratory Efficacy Analyses 
 
 
 
 
 
 
 
 
Prior to database lock, the Sponsor will finalize a statistical analysis plan (SAP) that will detail all 
planned analyses. Any analyses conducted in addition to those specified in the SAP will be clearly 
documented as post hoc. 
 Safety Analysis 
The primary safety variable is the incidence of subjects with any adverse event during the entire 
trial. The percentage of subjects with specific treatment-emergent adverse events will be 
summarized for each treatment group. A treatment-emergent adverse event is defined as any 
event not present prior to the initiation of the treatments or any event already present that worsens 
in either intensity or frequency following exposure to the treatments. Incidence will be tabulated 
by Medical Dictionary for Regulatory Activities system organ class and preferred term within each 
system organ class. 
The secondary safety variables of Snellen visual acuity [VA], slit lamp examination [SLE], non-
contact IOP tonometry [NCT] and un-dilated fundus examination will be summarized descriptively. 
All evaluations of safety will be described in the SAP. 
 Statistical Hypotheses 
This is a Phase 1b exploratory clinical trial to assess the safety, tolerability, and pharmacodynamic 
activity of Reproxalap Ophthalmic Solution utilizing a novel dosing regimen in subjects with 


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allergic conjunctivitis in an environmental design. There are no primary endpoints and no formal 
statistical hypotheses. 
 Adjustment for Multiplicity 
As this is a Phase 1b clinical trial with no primary or secondary endpoints, there will be no 
multiplicity adjustments for the exploratory efficacy measures or for the exploratory 
pharmacodynamics measures. 
 Exploratory Efficacy Analysis 
A detailed SAP, including dictionaries used for coding and software used, will be finalised prior 
to the unmasking of the randomization code. The SAP will provide full details of the analyses, 
the data displays, and the algorithms to be used for data derivations. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exploratory Analysis 
Additional exploratory efficacy analyses such as individual time-point analyses and time to event 
analyses may be performed and will be reported as described above.  
 Accountability and Background Characteristics 
10.9.1 Enrollment and Disposition 
The number of subjects enrolled, by study population and investigative site, will be presented by 
treatment group. The primary reasons for discontinuation will be summarized by treatment and 
based on the safety population. The number and percentage of subjects with protocol deviations 
or subjects requiring rescue therapy leading to exclusion from the PP population will be presented 
by reason for exclusion, stratified by treatment. All deviations and rescued subjects will be listed. 
10.9.2 Subject Characteristics 
Subject characteristics will be obtained at the Screening prior to randomization and will be 
summarized by treatment group and overall. Summaries will include descriptive statistics for 


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continuous measures (sample size, mean, standard deviation [SD], median, minimum, maximum) 
and for categorical measures (sample size, frequency and percentages).  
Subject characteristics will be summarized on all study populations. 
10.9.3 Treatment Compliance  
Treatment compliance will be assessed in terms of the actual dose. Treatment compliance will be 
used to characterize the subjects and determine clinical evaluability for some analyses. Treatment 
compliance will be summarized within each treatment group by means of descriptive statistics 
(sample size, mean, SD, median, minimum and maximum). 
11 QUALITY CONTROL AND QUALITY ASSURANCE 
The Sponsor and the Contract Research Organization (CRO) conducting trial management will 
implement a system of quality assurance that includes all elements described in this protocol. 
Within this system, standard operating procedures (SOPs) from the Sponsor and CRO will be 
implemented to ensure that the clinical trial is conducted in compliance with regulatory 
requirements and GCP. Quality control will be applied to each stage of data handling to ensure 
that data are accurate, reliable and processed correctly.  
12 CLINICAL TRIAL ADMINISTRATION 
 Institutional Review Board / Research Ethics Board / Independent 
Ethics Committee  
The protocol and all protocol amendments must be signed and dated by the investigator and 
approved in writing by the applicable IRB/REB/IEC in accordance with GCP prior to 
implementation. In addition, the IRB/REB/IEC must approve the written informed consent and 
assent forms, any consent or assent form updates, subject recruitment procedures 
(e.g., advertisements), and any written information to be provided to subjects prior to 
implementation.  
The investigator must provide an annual report to the IRB/REB/IEC on the progress of the clinical 
trial including number of subjects enrolled, discontinued, and SAEs, unless otherwise specified 
by the IRB/REB/IEC. It is required that a yearly review of the protocol by the IRB/REB/IEC be 
documented in a letter from the IRB/REB/IEC. The investigator must provide notification to the 
IRB/REB/IEC of the completion, termination, or discontinuation of the clinical trial. 
The investigator must supply the Sponsor with copies of all written correspondence with the 
IRB/REB/IEC. 
The investigator will make all attempts to ensure that the IRB is constituted and operates in 
accordance with regulatory requirements, ICH GCP and any local requirements. 
 Ethical Conduct of the Clinical Trial 
The clinical trial will be carried out in keeping with national and local legal requirements, including 
in accordance with regulatory requirements outlined in Food and Drug Administration (FDA) Code 
of Federal Regulations (CFR) Title 21 [Part 50, Part 54, Part 56, Part 312 and Part 11] as well as 
the ICH GCP E6 Guidelines. This clinical trial was designed and shall be implemented and 
reported in accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, 


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with applicable local regulations [including European Directive 2001/20/EC, US CFR Title 21], 
and with the ethical principles laid down in the Declaration of Helsinki.  
 Subject Informed Consent 
The Sponsor will provide sample Informed Consent Forms for use in the clinical trial. Any changes 
to the proposed consent and assent forms suggested by the investigator must be agreed to by 
the Sponsor before submission to the IRB/REB/EC. The investigator or designee will provide the 
Sponsor with a copy of the IRB/REB/IEC-approved informed consent and assent forms prior to 
the start of the clinical trial.  
Before each subject is enrolled in the clinical trial, written informed consent will be obtained 
according to the regulatory and legal requirements of the participating site.  
The subjects should sign the current final IRB/REC/EC approved consent form. The process of 
obtaining informed consent and assent should be documented in the subject source documents. 
Each investigator must retain the original signed and dated informed consent and assent forms. 
A copy of the signed and dated informed consent and assent forms will be given to the subject. 
No subject can enter the clinical trial, or have clinical trial-specific assessments performed before 
his/her informed consent has been obtained. 
The Informed Consent Forms should be revised whenever there are substantial changes to 
procedures or when new information becomes available that may affect the willingness of the 
patient to participate. Revisions to the consent forms required during the clinical trial must be 
approved by the Sponsor, and a copy of the revised consent forms provided to the Sponsor. For 
any updated or revised forms, the subjects must be re-consented for continued participation in 
the clinical trial. 
 Confidentiality 
All clinical trial findings and documents will be regarded as confidential. The investigator and 
qualified site staff must not disclose such information without prior written approval from the 
Sponsor. The investigator agrees not to use or disclose protected health information other than 
as permitted or required by the subject authorization or as required by law. 
Subject confidentiality will be strictly maintained to the extent possible under the law. Subject 
names must not be disclosed.  Subjects will be identified on the CRFs and other documents 
submitted to the Sponsor by their initials (if locally permissible) and/or assigned subject number; 
not by name. Documents that identify the subject (e.g., the signed informed consent form) must 
be maintained in confidence by the investigator. All clinical trial documents are provided by the 
Sponsor in confidence to the investigator and qualified site staff. None of this material may be 
disclosed to any party not directly involved in the clinical trial without Sponsor’s written permission. 
The investigator must assure that subjects’ anonymity will be maintained. The investigator will 
maintain this for the longest period of time allowed by his/her own institution and, in any case, 
until further communication from the Sponsor. 
 Protection of Subject Data 
The collection and processing of personal data from subjects enrolled in the clinical trial will be 
limited to those data that are necessary to investigate the safety, quality, and utility of the IP) used 
in the clinical trial and to support the development and interpretation of the trials clinical outcomes 
assessments. 
The data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 


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technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of subjects confidential. 
The informed consent obtained from the subject includes explicit consent for the collection and 
processing of personal data and for the investigator to allow direct access to his or her original 
medical records for clinical trial-related monitoring, audit(s), IRB/REB/EC review, and regulatory 
inspection. The consent also addresses the transfer of the data to other entities and to other 
countries. 
 Clinical Trial Monitoring 
Prior to initiation of the clinical trial at a site, the Clinical Trial Monitor, who is an authorized 
individual designated by the Sponsor, will visit the site to verify the qualifications of the investigator 
and designated site staff, inspect the adequacy of the facilities, and inform the clinical trial team 
of responsibilities and the procedures to ensure proper conduct of the clinical trial. During the 
conduct of the clinical trial, the Clinical Trial Monitor will visit the sites to verify adherence to the 
protocol, assess drug accountability, data integrity, and subject safety. The monitors will conduct 
100% source document verification of subject data by comparing the CRFs with the source 
documents to ensure accuracy and consistency.  
All aspects of the clinical trial will be carefully monitored with respect to GCP and SOPs for 
compliance with applicable government regulations. The Clinical Trial Monitor will have access to 
all records necessary to ensure integrity of the data and safety of the subject, and will periodically 
review the progress of the clinical trial with the investigator. 
Frequent communication between the clinical site and the Sponsor is essential to ensure that the 
safety of the clinical trial is monitored adequately.  
 Case Report Forms and Source Documents 
An electronic data capture (EDC) system will serve as the data management system for the 
clinical trial.  
The investigator will be responsible for the accuracy of the data entered in the EDC system and 
ensure that the data collected are accurate and complete. Data will be monitored within the EDC 
system by the clinical trial monitor who has only reading rights. Any changes required following 
monitoring will be made by the investigator or qualified site staff and will be documented with a 
full audit trail within the EDC system. The responsible clinical trial monitor will check data at the 
monitoring visits to the clinical site.  
The investigator or qualified site staff will prepare and maintain adequate and accurate clinical 
trial documents (e.g., medical records, AE and concomitant medication reporting, source data 
collection forms, etc.) designed to record all observations and other pertinent data for each 
subject. It is recommended that the author of an entry in the source documents be identifiable. 
Source data may be directly captured from devices, transferred from third parties (e.g., laboratory 
data), or entered manually into the EDC system in use at the clinical center. In such case, many 
of the source data will only be available electronically. The remainder of the data, captured initially 
on paper, may be entered retrospectively into the EDC system. 
For each subject, CRF and corresponding source records will be maintained at each clinical site. 
CRFs should be completed in a timely manner, and every effort should be made to have forms 
completed and current in anticipation of a visit by the Sponsor or designee. Upon clinical trial 


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completion, the monitor will arrange for a final review of the clinical trial files, after which the file 
should be secured by storage for the appropriate period as specified in Section 13.  
The investigator will allow the Sponsor or designee(s), contract designees, authorized regulatory 
authority inspectors, and the IRB/REB/IEC to have direct access to all documents pertaining to 
the clinical trial.  
 Access to Source Documents and Audits 
Regulatory agencies may request access to all clinical trial records, including source documents, 
for inspection and copying, in keeping with country regulations. The investigator should 
immediately notify the Sponsor of any announced or unannounced regulatory agency inspections. 
An auditing inspection may also be conducted by the Sponsor representative or designee. Any 
aspect of the trial may be subject to audit by the Sponsor and/or inspection by regulatory 
authorities or the IRB/REB/IEC. Such audits/inspections may take place at the Sponsor’s site(s), 
the CRO, or at the clinical sites, including laboratories, pharmacies and any other facilities used 
for the clinical trial. The investigator will permit the designated Sponsor representatives and 
regulatory bodies to have direct access to the source documents to verify data represented in the 
EDC system.  
 Protocol Deviations and Violations 
Exceptions to the eligibility criteria will not be granted. It is expected that subjects will meet all 
eligibility criteria. Departures from the protocol should be avoided, unless required for the safety 
of the subject. Should other unexpected circumstances arise that will require deviation from 
protocol-specific procedures, the investigator should contact the Sponsor to discuss the 
appropriate course of action.  
The investigator should document all protocol deviations/violations in the subject’s CRF and 
source documents or the investigator Site File, if appropriate. Protocol deviations will be 
documented by the clinical trial monitor and will be included in the final clinical trial report. Protocol 
deviations should be submitted to IRB/REB/IEC, in accordance with the site’s IRB/REB/IEC 
requirements. 
 Amendments to the Protocol 
To alter the protocol, amendments must be written by the Sponsor and approvals must be 
received from all parties that approved the original protocol (IRB/REB/IEC, and if applicable, the 
local regulatory authorities) before implementation. Notwithstanding the need for approval of 
formal protocol amendments, the investigator is expected to take any immediate action required 
for the safety of any subject included in the clinical trial, even if this action represents a deviation 
from the protocol.  
The Sponsor may make administrative changes (i.e., changes that do not significantly affect 
subject safety, the clinical trial’s scope or scientific quality) without a formal protocol amendment. 
 Discontinuation of the Clinical Trial 
The Sponsor reserves the right to discontinue the clinical trial under the conditions specified in 
the clinical trial agreement. 
 Investigator Responsibilities 
The investigator(s) should be qualified by education, training, and experience to assume 
responsibility for the proper conduct of the clinical trial, should meet all the qualifications specified 
by the applicable regulatory requirement(s), and should provide evidence of such qualifications 


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through up-to-date curriculum vitae and/or other relevant documentation requested by the 
Sponsor, the IEC/REB/IRB, and/or the regulatory authority(ies). 
The investigator is responsible for ensuring that the clinical trial is performed in accordance with 
the protocol, current ICH guidelines on GCP, and applicable regulatory and local requirements. 
GCP is an international ethical and scientific quality standard for designing, conducting, recording, 
and reporting studies that involve the participation of human subjects. Compliance with this 
standard provides public assurance that the rights, safety, and well-being of subjects are 
protected, consistent with the principles that originated in the Declaration of Helsinki, and that the 
clinical trial data are credible. 
 Financial Disclosure 
The investigator is required to disclose any financial arrangement during the clinical trial and for 
one year after, whereby the outcome of the clinical trial could be influenced by the value of the 
compensation for conducting the clinical trial, or other payments the investigator received from 
the Sponsor. The following information is collected: any significant payments from the Sponsor or 
subsidiaries such as a grant to fund ongoing research, compensation in the form of equipment, 
retainer for ongoing consultation or honoraria; any proprietary interest in investigational product; 
any significant equity interest in the Sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998). 
 Registration of Clinical Studies and Disclosure of Results 
The Sponsor or designee will register and/or disclose the existence of and the results of clinical 
trials as required by law. 
 Publication and Disclosure Policy 
As is customary for multicenter trials, publication by individual clinical sites or 
investigator/institution will not be allowed without the explicit written permission of the Sponsor. 
The Sponsor will determine authorship of the principal clinical trial manuscript(s) in conjunction 
with the investigators, in abiding with current guidelines and requirements of medical journals. For 
such manuscript(s), masthead roles for investigators will be determined based on subject 
enrollment and scientific contributions to the clinical trial.  
13 RETENTION OF RECORDS 
The investigator agrees to adhere to the document retention procedures by signing the protocol. 
Essential documents, as listed below, must be retained by the investigator for as long as required 
by national and international regulations. The Sponsor will notify the investigator(s)/institution(s) 
when the clinical trial-related records are no longer required.  
Essential documents include but are not limited to: 
• 
IRB/REB/IEC approvals for the clinical trial protocol and all amendments 
• 
All source documents and laboratory records 
• 
CRF copies  
• 
Subjects' informed consent / assent forms (with clinical trial number and title of trial) 
• 
FDA form 1572 
• 
Any other pertinent clinical trial documents 
All source documents (e.g., informed consent forms, laboratory reports, progress notes, medical 
histories, physical and diagnostic findings, IP dispensing/disposition records) that support data in 
the CRFs of each subject must be retained in the files of the responsible investigator.  


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According to ICH guidelines for GCP, essential documents should be retained for a minimum of 
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 at least 2 years have 
elapsed since the formal discontinuation of clinical development of the investigational product. 
However, these documents should be retained for a longer period (25 years) if required by 
relevant regulatory or legal authorities. 
If the responsible investigator retires, relocates or for any other reason withdraws from the 
responsibility of keeping the clinical trial records, custody must be transferred to a person who 
will accept the responsibility. The Sponsor representative must be notified in writing of the name 
and address of the new custodian, prior to the transfer. 
No records should be disposed of without written approval of the Sponsor.  
 
 


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14 REFERENCES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 


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SAP_001.pdf: 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
AN 
EXPLORATORY 
CLINICAL 
TRIAL 
EVALUATING 
REPROXALAP 
OPHTHALMIC SOLUTIONS (0.25% AND 0.5%) IN SUBJECTS WITH SEASONAL 
ALLERGIC CONJUNCTIVITIS USING THE ENVIRONMENTAL EXPOSURE 
CHAMBER (EEC) 
 
 
Sponsor Protocol Number:  ADX-102-AC-011 
Final Version 4.0 Dated 22 NOV 2018 
 
     
     
 
 
Sponsor: 
Aldeyra Therapeutics, Inc. 
     131 Hartwell Avenue, Suite 320 
     Lexington, MA 02421 
USA 
 
 
    03 March 2019 
Final Version 1.0 
 




                                                                                           
 
 
 
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Abbreviations 
AE 
Adverse event 
ADR 
Adverse drug reaction 
ANCOVA 
Analysis of Covariance 
AUC 
Area under the curve 
DBP 
Diastolic Blood Pressure 
EEC 
Environmental Exposure Chamber 
 
 
GINA 
Global Initiative of Asthma 
ICH 
International Council for Harmonisation 
IgE 
Immunoglobulin E 
IND 
Investigational New Drug  
IOP 
Intraocular pressure 
IP 
Investigational product 
IUD 
Intrauterine device 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCT 
Non-contact IOP tonometr  
 
 
RR 
Respiratory Rate 
SBECD 
Sulfobutylether-beta-cyclodextrin 
SBP 
Systolic Blood Pressure 
SD 
Standard deviation 
SLE 
Slit lamp examination 
TOSS 
Total ocular symptom score 
VA 
Visual acuity 
WHO 
World Health Organization 


                                                                                           
 
 
 
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Table of Contents 
 
I. 
INTRODUCTION ........................................................................................................................... 7 
Responsibilities ................................................................................................................................................. 7 
II.  STUDY DESIGN ............................................................................................................................. 7 
Overview of Study Design and Dosing Regimen ............................................................................................... 7 
III.  INVESTIGATIONAL TREATMENT ..................................................................................... 17 
IV.  STUDY OBJECTIVES ................................................................................................................ 17 
V.  DETERMINATION OF SAMPLE SIZE ................................................................................ 17 
VI.  RANDOMIZATION AND MASKING .................................................................................... 17 
Emergency Unblinding .................................................................................................................................... 18 
Subject Numbering .......................................................................................................................................... 18 
VII. EFFICACY ASSESSMENTS ..................................................................................................... 18 
Staff-Assessed Symptom Collection ................................................................................................................. 18 
Subject Assessed Symptoms ............................................................................................................................. 19 
VIII. 
SAFETY ASSESSMENTS .................................................................................................. 20 
IX.  ANALYSIS POPULATIONS ..................................................................................................... 21 
Safety Population ............................................................................................................................................. 21 
Intent-to-Treat (ITT) Population ..................................................................................................................... 21 
COMPLETER POPULATION ....................................................................................................................... 21 
Per-Protocol (PP) Population ........................................................................................................................... 21 
X.  ENDPOINTS .................................................................................................................................. 21 
XI.  STATISTICAL METHODOLOGY ......................................................................................... 22 


                                                                                           
 
 
 
 
 
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XII. STATISTICAL ANALYSES ...................................................................................................... 24 
Missing Data .................................................................................................................................................... 24 
Adjustments for Multiplicity ........................................................................................................................... 24 
Interim Analysis .............................................................................................................................................. 25 
General Considerations ................................................................................................................................... 25 
Subject Populations and Disposition ................................................................................................................ 25 
Discontinuations .............................................................................................................................................. 26 
Protocol Deviations/Violations ......................................................................................................................... 26 
Data Sets Analyzed .......................................................................................................................................... 26 
Demographic and Other Baseline Characteristics ........................................................................................... 26 
Pre-eec MEASUREMENT for Visit 3, 4 and 5 ................................................................................................ 27 
Medical History And Concomitant Diseases. ................................................................................................... 27 
Concomitant Medication ................................................................................................................................. 27 
Study Drug Administration ............................................................................................................................. 28 
Efficacy Analyses ............................................................................................................................................. 28 
Safety Analyses ................................................................................................................................................ 30 
Change to the Planned Analyses ...................................................................................................................... 33 
Appendix 1: Calculations ................................................................................................................................... 34 
Tables, Listings and Figures (TLFs) ................................................................................................................ 34 


 
 
 
 
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Sponsor Protocol No. ALDNS2-203-D1 
 
 
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I. 
INTRODUCTION 
The purpose of the statistical analysis plan (SAP) is to describe the planned analyses and reporting 
for protocol 18-MO-001: 
 
“An Exploratory Clinical Trial Evaluating Reproxalap Ophthalmic Solutions (0.25% And 0.5%) 
In Subjects With Seasonal Allergic Conjunctivitis Using The Environmental Exposure Chamber 
(EEC)” 
 
This SAP is being written with due consideration of the recommendations outlined in the most 
recent International Council on Harmonization (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 (CSR).  
This SAP is a summative and definitive plan, based on the final protocol dated November 22, 2018 
(Version FINAL 4.0). 
 
The SAP includes details of data handling procedures and statistical methodology. The SAP also 
outlines the statistical programming specifications for the Tables, Listings and Graphs (TLGs). No 
interim analysis is planned for this study. 
 
The final statistical analysis will proceed exactly according to the SAP approved by the sponsor 
as well as by Inflamax Research.  
 
The statistical analysis methods presented in this document will supersede the statistical analysis 
methods in the clinical protocol. If additional analyses are required to supplement the planned 
analyses described in the SAP, they will be labeled as post-hoc and will be identified in the CSR. 
Responsibilities 
Inflamax Research will perform the statistical analyses described herein and is responsible for the 
production and quality control (QC) of tables, figures, and listings associated with the analyses 
other than the post hoc analyses.  
II. 
STUDY DESIGN 
OVERVIEW OF STUDY DESIGN AND DOSING REGIMEN  
ADX-102-AC-011/18-MO0001 is a single center study.  
The double-masked, vehicle-controlled, randomized, three-way crossover clinical trial allows for 


 
 
 
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Sponsor Protocol No. ALDNS2-203-D1 
 
 
03-Mar-2019 Final Version 1.0    
 
 
 
 
 
 
 
Page 8 of 34 
the testing of two concentrations of Reproxalap Ophthalmic Solution (0.25% and 0.5%) versus 
Vehicle Ophthalmic Solution in subjects with ragweed-induced allergic conjunctivitis in the 
EEC. 
The clinical trial consists of five visits to the clinic (one Medical Screening visit, one Screening 
EEC visit, and three EEC treatment visits).The four EEC sessions (one EEC screening and three 
EEC treatment sessions) will be separated by an approximate two-week washout period to ensure 
adequate elimination of responses caused by allergen exposure in the EEC and allow the 
recuperation of mast cells, please refer to  
 
 
 
 
 
Figure 1. 
Clinical Trial Design 
. 
Subjects 18 years or older with allergic conjunctivis are eligible for this study. For the detailed 
inclusion and exclusion criteria, please defer to the current version of protocol. 
Approximately 75 subjects (approximately 25 per treatment sequence) will be enrolled. 
The clinical trial is exploratory in nature and the safety, tolerability, and pharmacodynamic 
activity of Reproxalap Ophthalmic Solutions (0.25% and 0.5%) will be compared to Vehicle 
Ophthalmic Solution in subjects with allergic conjunctivitis in an EEC model. Pharmacodynamic 
endpoints for assessments of ocular itching, redness, and tearing will be evaluated. As an 
Eligible subjects will be randomized 1:1:1 to one of three treatment sequences of ABC, BCA and 
CAB where:  
• 
Treatment A:  Reproxalap Ophthalmic Solution (0.25%) 
• 
Treatment B:  Reproxalap Ophthalmic Solution (0.5%) 
• 
Treatment C:  Vehicle Ophthalmic Solution 


 
 
 
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Sponsor Protocol No. ALDNS2-203-D1 
 
 
03-Mar-2019 Final Version 1.0    
 
 
 
 
 
 
 
Page 9 of 34 
exploratory study, there are no primary endpoints and no formal statistical hypotheses. 
 
 
 
 
 
 
Figure 1. 
Clinical Trial Design 
 
At the Medical Screening Visit (Visit 1), subjects will undergo the informed consent process, and 
information about demographics, baseline characteristics, medical history, social history, 
physical examination will be performed and concomitant medication will be collected. Vital 
signs and samples for standard clinical safety laboratory tests will be obtained. A urine 
pregnancy test will be administered to women of childbearing potential (WOCBP).  
Subjects will undergo ophthalmic examinations (Snellen VA, SLE, NCT, and a dilated fundus 
examination) to ensure initial eligibility criteria are met. A skin prick test for a panel of test 
allergens will be conducted; results must be positive (i.e., a wheal that is 3 mm greater than the 
negative control) for at least one test allergen and must include ragweed in order to proceed to 


 
 
 
 
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Sponsor Protocol No. ALDNS2-203-D1 
 
 
03-Mar-2019 Final Version 1.0    
 
 
 
 
 
 
 
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Visit 2. 
At all EEC sessions, assessments of ophthalmic evaluations will be collected 
 
 For subject-reported 
symptoms of ocular itching, a standard 9 point (i.e., 0-4 with 0.5 unit increments) and a standard 
VAS scale (0-100 mm) will be employed and subject reported tearing assessed by a 4-point (0-3) 
scale will be employed. For staff-assessed grading of conjunctival redness, a standard 9-point 
(i.e., 0-4 with 0.5 unit increments) will be employed.
 
 
 
 
At the EEC Screening Visit (Visit 2), qualified site staff will update concomitant medications 
and collect AEs, as applicable and perform tests for vital signs. A urine pregnancy test will be 
administered to WOCBP. Fundus exam, Snellen VA, SLE, subject rating of symptoms, and staff 
grading of conjunctival redness will be performed to ensure the anterior segment of the eye is 
healthy. Designated site staff will administer saline solution in each eye just prior to EEC entry. 
 
Pre-EEC entry (Baseline):  
1) Subject assessment for ocular itching and tearing will be recorded 
 
and 
2) Staff-assessed conjunctival redness will be recorded
 
. 
 
Post-EEC entry:  
1) Subject assessment for ocular itching and tearing will occur
 
 2) Staff-assessed 
conjunctival redness will be recorded 
 
 
 
Please refer to Table2, Table3, Table 4 and Table 5 for schedule of staff and subject assessment 
time-points. 
  
 
 
 
 
 
 
 


 
 
 
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03-Mar-2019 Final Version 1.0    
 
 
 
 
 
 
 
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At Randomization/Treatment EEC Session One (Visit 3), qualified site staff will update 
concomitant medications, collect AEs, as applicable and collect vital signs. A urine pregnancy 
test will be administered to WOCBP. Ophthalmic evaluations will be conducted (Fundus exam, 
Snellen VA, NCT SLE, subject rating of symptoms, and staff grading of conjunctival redness). 
 
 
Subjects will be randomized to receive a first dose of either Reproxalap Ophthalmic Solution 
(0.25%) (Treatment A), Reproxalap Ophthalmic Solution (0.5%) (Treatment B), or Vehicle 
Ophthalmic Solution (Treatment C). Qualified site staff will instill one drop of the randomized 
treatment into each eye at approximately five minutes prior to entry to the EEC after all the pre-
EEC assessments are done.  
 
Pre-EEC entry (Baseline): 
 
1) Subject assessment for ocular itching and tearing will be recorded a
 
 and  
2) Staff-assessed conjunctival redness will be recorded 
 
. 
 
Post-EEC entry: 
 
1) Subject assessment for ocular itching and tearing will occur
 
  
2) Staff-assessed conjunctival redness will be recorded 
 
. 
 
At approximately 95-minutes post-EEC entry (and after subject assessed itching and tearing 
and staff assessed conjunctival redness for all time-points post first dose have been completed), a 
second dose (one drop in each eye) of the same randomized treatment will be administered in 
each eye by the qualified site staff. Subject will continue to assess symptoms of ocular itching 
and tearing after the second dose
 
 and staff-assessed 
conjunctival redness will be recorded 
 
 
 
Post-EEC exit (approximately t=215 minutes):  
1) Subject assessed ocular itching and tearing will continue 
 
;  


 
 
 
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Page 12 of 34 
2) Staff assessed conjunctival redness will continue to be recorded post-EEC exit
. 
 
Subjects will be asked to return in at least two weeks for Visit 4. 
 
At Treatment EEC Session Two (Visit 4), all procedures performed at Visit 3 will be repeated 
except that each subject will be given a different treatment dependent on the treatment sequence 
the subject was randomized to [Reproxalap Ophthalmic Solution (0.25%) (Treatment A), 
Reproxalap Ophthalmic Solution (0.5%) (Treatment B), or Vehicle Ophthalmic Solution 
(Treatment C)].  
 
At the end of the EEC session, subjects will be asked to return in at least two weeks (± 3 days) 
for Visit 5. 
 
At Treatment EEC Session Three (Visit 5), all procedures performed at Visit 4 will be repeated 
except that each subject will be given a different treatment dependent on the treatment sequence 
the subject was randomized to [Reproxalap Ophthalmic Solution (0.25%) (Treatment A), 
Reproxalap Ophthalmic Solution (0.5%) (Treatment B), or Vehicle Ophthalmic Solution 
(Treatment C)]. At the end of the visit, a urine pregnancy test will be administered to WOCBP. 
Subjects will undergo ophthalmic examinations (Snellen VA, SLE, NCT, and a dilated fundus 
examination), clinical safety lab tests and vital signs will be collected to ensure safety prior to 
exit of the clinical trial.  
 


 
 
 
 
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Table1. Schedule of Events and Assessments  


 
 
 
 
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Table 2. 
Schedule of Staff-Assessed Conjunctival Redness Recording 
Table 3. 
Schedule of Subject Assessed Itching and Tearing  


 
 
 
 
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Table 4. 
Schedule of Staff-Assessed Conjunctival Redness Recording Post-EEC Exit 
 
 
 
 
 
 
 
Table 5. 
Schedule of Subject Assessed Itching and Tearing Post-EEC Exit 
 
 
 
 
 
 
 


 
 
 
 
 
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III. 
INVESTIGATIONAL TREATMENT 
Reproxalap Ophthalmic Solutions (0.25% and 0.5%) and Vehicle Ophthalmic Solution are 
supplied as sealed Investigational Product (IP) kits, please refer to the current protocol for 
further. 
IV. 
STUDY OBJECTIVES 
 
To evaluate the feasibility of using the EEC clinical trial design to assess the activity of 
Reproxalap Ophthalmic Solutions (0.25% and 0.5%) in an allergic conjunctivitis population. 
 
 
To assess safety, tolerability, and pharmacodynamic activity of Reproxalap Ophthalmic Solutions 
(0.25% and 0.5%) compared to Vehicle Ophthalmic Solution in the treatment of seasonal allergic 
conjunctivitis in subjects allergic to ragweed using the EEC with exposure to airborne ragweed 
pollen.  
V. 
DETERMINATION OF SAMPLE SIZE  
 
 
 
 
VI. 
Randomization and Masking 
Eligible subjects will be randomized 1:1:1 to one of three treatment sequences of ABC, BCA, 
CAB, where:  
 
 
Treatment A: Reproxalap Ophthalmic Solution (0.25%)  
 
 
Treatment B: Reproxalap Ophthalmic Solution (0.5%)  
 
 
Treatment C: Vehicle Ophthalmic Solution  
 


 
 
 
 
 
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Approximately 75 subjects (approximately 25 per treatment sequence) will be enrolled with a 
target of 60 completers. As the actual discontinuation rate observed was lower than anticipated, 
the enrollment may be less than the planned 75 subjects.   
 
Investigators, qualified site personnel, and subjects will be masked to the treatment sequence and 
investigational product (IP) administered in each treatment visits. The Sponsor will also be 
masked to the IP administered information until database lock.  
EMERGENCY UNBLINDING 
Emergency unmasking should only be performed when necessary to treat the subject. Most 
often, knowledge of the possible treatment assignments is sufficient to treat a clinical trial 
subject who presents with an emergency condition. 
The investigator should make every effort to contact the Medical Monitor to discuss the subject’s 
emergency and the need to unmask, prior to unmasking any subject. Please defer to the protocol 
for further details. 
SUBJECT NUMBERING 
Each subject screened for the clinical trial will be assigned a unique subject number that will be 
used to identify the subject throughout their participation in the clinical trial. If a subject fails to 
be randomized, the reason should be documented in the source documents and case report form 
(CRF). The subject will be considered a screen failure. 
VII. 
EFFICACY ASSESSMENTS 
At all EEC sessions (pre- and post-entry), assessments of ophthalmic evaluations by subjects and 
qualified site staff will be collected using an electronic Patient Data Acquisition Tablet™ 
(ePDAT™). 
 
Refer to Table 2  (Schedule of Staff-Assessed Conjunctival Redness Recording) Table 3  
(Schedule of Subject Assessed Itching and Tearing Table 3for details on collection time points). 
STAFF-ASSESSED SYMPTOM COLLECTION 
At designated time points, qualified site staff will assess conjunctival redness in each subject using 
a standard 9-point (i.e., 0-4 scale with 0.5 unit increments). 
 
 
 
 


 
 
 
 
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SUBJECT ASSESSED SYMPTOMS 
At designated time points, subjects will be asked to report and rate symptoms associated with 
allergic conjunctivitis, including ocular itching and tearing. 
Ocular Itching 
 
1. A Visual Analog Scale (VAS) measured on a 0- 100 mm continuous scale where 0 is 
considered no itching and 100 is considered maximum itch. 
 
 
 


 
 
 
 
 
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Ocular Tearing 
 
 
  
 
  
  
  
  
  
  
  
  
  
 
 
  
  
  
 
 
  
 
 
 
 
 
 
VIII. 
SAFETY ASSESSMENTS  
Safety assessments will include the following: 
 Visual Acuity (VA) for Visit 1 through Visit 5. 
 Slit Lamp Examination (SLE) for Visit 1 through Visit 5. 
 Non-Contact intraocular pressure Tonometry (NCT) during Visit 1 and Visit 3 to Visit 5. 
 Dilated Fundus Examination as Screening Visit 1 and Visit 5 and undilated Fundas 
examination at Visit 2, 3 and 4. 
 Vital Signs (VS) for Visit 1 to Visit 5. 
 Safety Clinical Laboratory parameters at Screening Visit 1 and at Visit 5. 


 
 
 
 
 
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 Adverse Events (AEs:  reported, elicited and observed) from Visit 2 through Visit 5. 
IX. 
ANALYSIS POPULATIONS  
SAFETY POPULATION  
All randomized subjects who received at least one dose of IP, regardless of whether clinical trial 
assessments were performed. 
INTENT-TO-TREAT (ITT) POPULATION 
 
All randomized subjects who received at least one dose of IP and have any post-dose 
assessments. Subjects are evaluated according to the IP treatment of the visit as per the 
randomized treatment sequence. 
COMPLETER POPULATION 
 
COMPLETER population will include all randomized subjects who received IP dosing at all 
three EEC treatment visit.  
 
PER-PROTOCOL (PP) POPULATION  
All ITT subjects will be considered PP if IP dosing occurs and do not have a major deviation 
from the protocol. The following is a list of protocol violations which would exclude subjects 
from the PP population: 
 
 Subject did not receive IP as assigned. 
 Subject did not meet all inclusion/exclusion criteria. 
X. 
ENDPOINTS  
EFFICACY ENDPOINTS  
The following efficacy endpoints will be derived for each pharmacodynamic measures in each 
treatment visit and will be used to assess the activity of Reproxalap Ophthalmic Solutions. 
 AUC 0-212 mins for Itching on VAS scale 
 AUC 0-212 mins for Itching on 9 points scale 
 AUC 0-210 mins for Conjunctival Redness on 9 points scale 
 AUC 0-212 mins for Tearing on 4 points scale 
 AUC 0-212 mins for TOSS  
 AUC 0-92 mins for Itching on VAS scale  


 
 
 
 
 
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 AUC 92-212 mins for Itching on VAS scale  
 AUC 0-32 mins for Itching assessed by VAS Scale 
 AUC 32-92 mins for Itching assessed by VAS Scale 
 AUC 0-274 mins for Itching on VAS scale 
 AUC 0-274 mins for Itching on 9 points scale 
 AUC 0-270 mins for Conjunctival Redness on 9 points scale 
 AUC 0-274 mins for TOSS 
Since there are time windows available for symptom assessments, all time points above refers to 
the planned nominal time points and the actual elapsed time points may differ from the nominal 
time points. For detailed derivations of these parameters, please see SAP Appendix 1, Calculations. 
 
SAFETY ENDPOINTS 
 Adverse Events/Adverse Drug Reactions 
 Intraocular Pressure Readings (IOP) 
 Visual Acuity (VA) 
XI. 
STATISTICAL METHODOLOGY 
Summary Statistics 
Unless the list of summary statistics is specified for any summary table, the standard summary 
statistics that will be calculated for quantitative and qualitative variables are: 
Quantitative: 
sample size (number of subjects), mean, median, standard deviation, 
minimum and maximum of the raw data 
Qualitative: 
sample size (number of subjects), absolute and relative frequencies 
per class 
The summarization will be done by three treatment groups and at every scheduled time point (if 
applicable) for every endpoint. 
Reporting Precision 
Summary statistics will be presented to the following degree of precision: 


 
 
 
 
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Statistics 
Degree of precision 
Mean (of all kinds), Median, Quartiles, 
Confidence Intervals 
one more than the raw data 
Standard deviation, Standard error 
two more than the raw data 
Minimum, Maximum 
the same as the raw data 
P-value 
rounded to 3 decimal places and therefore 
presented as 0.xxx; P-values smaller than 
0.001 as ‘<.001’ 
Percentage, Coefficient of variation 
one decimal place 
 
Fractional numeric values will be presented with a zero to the left of the decimal point (for 
example, 0.12 - 0.30, not .12 - .30). 
Common Definitions and Labels 
Study Day is the number of days since administration of study drug during a Treatment Period, 
which is counted as Study Day 1. Study Day is derived separately for each of the 3 treatments. 
Nominal Time is the scheduled measurement time relative to the dose time. 
Study Time or Actual Elapsed Time is the time from the last administration of study drug.  So, 
for example, if study drug is administered at 08:00 on Day 1, 10:00 on Day 1 represents a study 
time (or actual elapsed time) of 2:00 hours. 
Data Collected Outside Study Schedule 
Data collected at visits that occurred outside the time windows specified in the protocol will be 
included in the data listings but will not be included in the analyses. 
Definition of Baseline  
In general, baseline is defined as the last observed measurement prior to the first dose of study 
medication during Pre-EEC entry at visit (visit 3, visit 4 and visit 5). If patient has more than one 
non-missing measurement at different time point prior to the first dose, average of these 
assessment score will be taken to derive the baseline value.  The baseline will be used in the 
change from baseline calculation for each treatment period.  
 


 
 
 
 
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Derived Variables 
 Age is calculated in years after rounding down as follows: 
Year of age = (Date [in days format] informed consent signed - Date [in days format] of birth) 
/ 365.25. 
 
 Efficacy assessments will be performed on both eyes. For conjunctival redness, assessments 
will be made in both temporal and nasal regions. For a symptom and at a specific EEC time 
point, from the multiple scores observed, the maximum score from both eyes and regions when 
applicable will represent the worst symptom score and thus will be used for the statistical 
analysis. This implies that all efficacy summary tables and treatments comparisons will use 
the maximum observed score at each ECC time points. The Listings of efficacy data however 
will provide all scores for the eyes and the regions as applicable. 
 
The efficacy endpoints AUC will also be derived using the maximum score at each time point. 
Similarly, TOSS will be derived using the maximum score at each time point for the ocular 
itching, conjunctival redness and tearing symptoms. 
 
 TOSS will be derived as the sum total of maximum score from ocular itching, conjunctival 
redness and tearing symptoms. However, the EEC time points for the ocular itching and tearing 
symptoms is different from the time points for the conjunctival redness. The scheduled time 
points for ocular itching will be used to represent the TOSS scheduled time points. 
XII. 
STATISTICAL ANALYSES 
MISSING DATA 
Any missing values for the efficacy endpoints for a subject during a visit and a specific time 
point will be imputed and replaced by the mean value calculated from all non-missing values of 
the same symptom for the same visit and the time point from all other subjects who has taken 
the same treatment in that visit. 
 
The imputed missing value for conjuctival redness and itchiness symptoms will be rounded to 
the nearest 0.5 value in order to match the observed scales. The imputed missing value for 
tearing symptom will be rounded to the nearest integer value in order to match the observed 
scale. 
ADJUSTMENTS FOR MULTIPLICITY 
No multiplicity adjustments will be conducted in this study. 
 


 
 
 
 
 
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INTERIM ANALYSIS 
No interim analysis is planned for this study. 
GENERAL CONSIDERATIONS 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
SUBJECT POPULATIONS AND DISPOSITION 
The listing of randomization scheme will be presented with subject identification, sex, age, race, 
and assignments to the treatment sequence. The following frequencies (number and percent) will 
be displayed by treatment group and for all subjects combined: 
 Subjects Randomized 
 Subjects who completed all treatment sessions 
 Subjects in the Safety Population 
 Subjects in the ITT Population 
 Subjects in the COMPLETER Population 
  Subjects in the PP Population 
 Subjects who withdrew early (total and by reason) 
 
The denominators for the percent calculations will be the number of subjects randomized, 
whether or not they are included in any of the analyses. 


 
 
 
 
 
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DISCONTINUATIONS 
In the event that any subject is withdrawn or withdraws from the study, a table presenting all 
subjects withdrawn will be provided. The listing will include subject identifier, visit at 
withdrawal, time point, treatment ID, and last treatment received prior to withdrawal and the 
specific reason(s) for withdraw. If a sufficient number of subject withdrawal happens, the 
frequencies (number and percent) of discontinuations by reason will be presented by last 
treatment administered and for all subjects combined. 
PROTOCOL DEVIATIONS/VIOLATIONS 
All deviations including but not limited to study inclusion or exclusion criteria, conduct of the 
trial, subject management or subject assessment will be listed. 
If numbers are sufficient, protocol deviations will be summarized (number and percent of 
subjects) by type of deviation. The protocol deviations will be grouped into different categories 
which may include, but are not limited to: 
 Missed visit 
 Inclusion/Exclusion criteria 
 Missed procedures/assessments 
 Informed consent 
 Documentation 
 Study drug administration 
 Safety 
 Lack of compliance 
DATA SETS ANALYZED 
A listing of subjects excluded from the Safety, ITT, COMPLETER and PP populations will be 
produced. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data and baseline characteristics will be listed by subject and summarized by 
Analysis Populations using standard summary statistics. 
 Gender, Ethnicity and Race 


 
 
 
 
 
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 Age (years), height (cm), weight (kg)  and BMI (kg/m2)  
 Systolic blood pressure (mm Hg) 
 Diastolic blood pressure (mm Hg) 
 Heart rate (beats/minute) 
 Pulse rate (beats/min) 
 Respiratory rate ( breaths/minute) 
 Medical History  
 Skin Prick Test 
 
Unless stated otherwise, percentages will be calculated out of the number of patients in the given 
Analysis Set. 
PRE-EEC MEASUREMENT FOR VISIT 3, 4 AND 5 
Summary statistics of following pre-EEC measurement at Visit 3 to Visit 5 will be tabulated by 
treatment, visit and eye. 
 Fundus exam 
 Snellen VA 
 NCT  
 SLE  
 Subject rating of ocular itching and tearing 
 Staff grading of conjunctival redness  
MEDICAL HISTORY AND CONCOMITANT DISEASES. 
Description of medical history and concomitant disease findings prior to screening will be coded 
using Medical Dictionary for Regulatory Activities (MedDRA) version 20.0 or higher. 
Medications will be coded according to the WHO drug dictionary which includes the WHO 
Drug Preferred Name and the ATC Classification Level 2 and 4. Prior and concomitant 
medication data will be listed by subject. 
 
A disease or illness reported at Screening reported as medical history without a start date will be 
included in medical history without a date assigned. Medical history will be sorted by 
descending overall frequency, by SOC and PT in the summary table. Medical history data 
listings will be sorted by treatment, patient number, start date, SOC and PT. 
CONCOMITANT MEDICATION 
Concomitant medication, prescription or over-the-counter will be defined as, taken within 30 
days prior to Visit 1 through to Visit 5, is to be recorded on the source document and 


 
 
 
 
 
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corresponding electronic CRF along with the reason the medication was taken. 
Medications will be coded according to the WHO drug dictionary which includes the WHO 
Drug Preferred Name and the ATC Classification Level 2 and 4. Prior and concomitant 
medication data will be listed by subject.  
STUDY DRUG ADMINISTRATION 
The dosing dates, times during Treatment Visits 3 to 5 will be listed by subject and visit. 
EFFICACY ANALYSES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
Treatment Comparisons 
 
 
 


 
 
 
 
 
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The following 3 contrasts will be evaluated for each primary endpoint:  
 
Reproxalap Ophthalmic Solution (0.50%) vs. Placebo 
 
Reproxalap Ophthalmic Solution (0.25%) vs. Placebo 
 
Reproxalap Ophthalmic Solution (0.50%) vs. Reproxalap Ophthalmic Solution (0.25%) 
 
 
 
 
  
 
POST HOC ANALYSIS 
1. Additional inferential analysis may be performed whereby additional covariates and other 
fixed factors may be used in models, depending on the significance of the term and the 
impact on contrast outcomes. 
2. Responder analyses may be performed whereby treatment response may be defined as 
one and two-point improvements from mean and within-subject baseline and peak scores. 
In addition to GEE, time to event analyses may also be performed. 
  
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
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SAFETY ANALYSES 
All safety data will be analyzed using Safety population.  
 
For safety analysis, summary descriptive statistics such as N, mean, SD, median, minimum and 
maximum will be provided by treatment group for continuous variables. Frequency distribution 
as number of subjects and percentage of subjects will be provided for categorical variables. No 
formal inferential tests will be performed on safety data. 
 
Adverse Events/Adverse Drug Reactions  
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding 
dictionary 
 preferred term (PT) and system organ classification (SOC).  
Subjects will multiple events within the same SOC and/or PT are only counted once within the 
respective frequencies. 
An AE will be considered treatment emergent (TEAE) if it begins or worsens in severity after the 
first dose of the double-blind Study Treatment through 28 days after the last dose of Study 
Treatment, or the date of initiation of another investigational agent or surgical intervention 
Each AE is to be evaluated for date/time of onset, duration, ocular versus non-ocular, severity, 
outcome and causal relationship with the study drug or other factors. 


 
 
 
 
 
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Derived and Imputed Data 
 
TEAEs will be assigned to a treatment based on the time of occurrence in relation to the last 
treatment administered prior to the onset of the TEAE. Time since last dose at time of onset will 
be calculated as the difference between the onset date and time and the date and time of the last 
dose of the treatment at onset. Time since last dose will be expressed in days, hours and minutes. 
Duration will be calculated for AEs that resolve as the difference between the resolution date and 
time and onset date and time.  Duration will be expressed in days, hours and minutes. 
 
Based on the MedDRA preferred term, subjects who experience the same AE on multiple 
occasions will be summarized at the maximum severity and most conservative relationship to the 
study medication. If 2 or more AEs are reported as a single event, the individual terms will be 
reported as separate AEs. 
 
Serious Adverse Events 
Serious adverse events (SAEs) are those events recorded as a “serious Adverse Event (Y)” on the 
adverse events page of the CRF. A summary of serious TEAEs and Serious treatment related 
TEAEs by SOC and PT will be prepared.  
Adverse Events Leading To Death 
Adverse events leading to death are those events with ‘Death’ recorded under Outcome in the 
adverse events page of the CRF. A summary of TEAEs and SAEs leading to death by SOC and 
PT will be prepared. A listing of AEs leading to death will be included with the TEAEs flagged. 
Data Summarization 
TEAEs will be classified and summarized according to the treatment at onset of the AE. The 
summary of TEAEs after the study drug administration on Visit 3 of Treatment Period 1 will be 
presented grouped by three treatments. 
 
The AEs will be summarized by MedDRA system organ class and preferred term for each 
treatment group. 
 
Treatment-emergent AEs (TEAEs) will be tabulated separately for safety population overall, and 
for ocular/non-ocular, by treatment group: 
 


 
 
 
 
 
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o Summary of TEAEs categorized by death, serious AEs, leading to withdrawal and 
related to study drug (safety/ocular/non-ocular) 
o Summary of TEAEs by system organ class and MedDRA preferred term (safety/ 
ocular/non-ocular) 
o Summary of TEAEs by severity (safety) 
o Summary of TEAEs by relation to study drug (safety) 
 
Adverse events will be listed as: 
 
o Adverse events by subject and AE number  
o Adverse events that caused the subject to discontinue 
o Serious AEs 
 
Severity.  
Severity is classified as mild, moderate or severe. Missing severity for TEAEs will be counted as 
severe. 
Adverse events with a missing relationship to study medication will be noted as “related” to 
study medication. If a patient reports the same AE more than once within the same SOC/PT, the 
AE with the strongest relationship to study medication will be used in the relationship 
summaries.  
Pregnancies 
Urine pregnancy tests will be performed from Screening Visit 1 through final treatment Visit 5. 
Pregnancy test results will be listed by subject and visit. 
 
Vital signs 
Blood pressure (systolic and diastolic, mm Hg), pulse rate (beats/min), respiratory rate 
(breaths/min) and body temperature (degree Celsius) will be assessed from Screening Visit 1 to 
final treatment Visit 5. The vital signs at EEC Visit 5 will be assessed at pre and post EEC time 
points, whereas the vital signs at EEC Visit 3 and Visit 4 will only be made at pre EEC time point. 
All vital signs data will be listed by subject, visit and time point as applicable. 
 
Fundus Assessment 
Fundus assessment will be performed at Screening Visit 1 to final treatment Visit 5, and will be 
listed by subject, visit and eye. 


 
 
 
 
 
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Intraocular Pressure Readings (IOP) 
Non-contact tonometry (NCT) assessment will be performed at Screening Visit 1 and at Visit 3 to 
Visit 5 to measure the Intraocular Pressure (IOP). The collected data (average of 3 readings for 
each eye) will be listed by subject, treatment, visit and time point as applicable. Summary statistics 
of the average of 3 IOP readings for treatment Visit 3 to Visit 5 for each eye will be tabulated by 
treatments and time points and presented for both Right and Left eyes. 
 
Visual Acuity (VA) 
VA assessment will be performed at each visit. Data will be listed by subject, visit, treatment, time 
point and eye as applicable. Summary statistics of Visual Acuity for treatment Visit 3 to Visit 5 
will be tabulated by treatment and eye. 
 
Slit lamp Assessment 
Slit lamp assessment will be performed at each visit. Data will be listed by subject, visit, treatment, 
time point and eye as applicable. Abnormalities and clinically significant findings will also be 
listed. 
CHANGE TO THE PLANNED ANALYSES 
The final version of the protocol specified additional efficacy assessments for Post-EEC exit time 
points. However, the list of efficacy endpoints in the protocol do not cover the data related to these 
Post-EEC exit time points. Therefore, the following additional efficacy endpoints were added in 
the SAP. 
 
 
AUC 0-274 mins for Itching on VAS scale 
 
AUC 0-274 mins for Itching on 9 points scale 
 
AUC 0-270 mins for Conjunctival Redness on 9 points scale 
 
AUC 0-274 mins for TOSS 


 
 
 
 
 
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

 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
TABLES, LISTINGS AND FIGURES (TLFS) 
The TLFs shells for this study is provided in a separate document SAP Mock TLFs. The shells may change due to unforeseen 
circumstances such as data formatting. These shells may not be reflective of every aspect of this study but are intended to show the 
general layout of the Tables, Listings and Figures that will be included in the final report. TLFs are numbered following the E3 
“Structure and Content of Clinical Study Report”.