Clinical trial NCT04207736
Conditions: Allergic Conjunctivitis
Keywords: reproxalap INVIGORATE ADX-102
Sponsor: Aldeyra Therapeutics, Inc.
Start date: 2019-12-05; Completion date: 2021-02-16
Enrollment: 95 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The INVIGORATE Trial: A Randomized, Double-masked, Crossover Design, Phase 3 Clinical Trial to Assess the Efficacy and Safety of Subjects With Seasonal Allergic Conjunctivitis.

Detailed description:
The INVIGORATE Trial: A Randomized, Double-masked, Crossover Design, Vehicle-controlled Phase 3 Clinical Trial to Assess the Efficacy and Safety of Reproxalap Ophthalmic Solution (0.25%) Compared to Vehicle in Subjects With Seasonal Allergic Conjunctivitis Using the Environmental Exposure Chamber (EEC).

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Reproxalap Ophthalmic Solution (0.25%) intervention 2: Vehicle Ophthalmic Solution
Intervention descriptions: intervention 1: Reproxalap Ophthalmic Solution (0.25%) dosed in the Environmental Exposure Chamber. intervention 2: Vehicle Ophthalmic Solution dosed in the Environmental Exposure Chamber.

Protocol documents:
Prot_000.pdf: 
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PROTOCOL ADX-102-AC-017 
The INVIGORATE Trial: A SINGLE-CENTER, RANDOMIZED, DOUBLE-
MASKED, CROSSOVER DESIGN, VEHICLE-CONTROLLED, PHASE 3 
CLINICAL TRIAL TO ASSESS THE EFFICACY AND SAFETY  OF 
REPROXALAP OPHTHALMIC SOLUTION (0.25%) COMPARED TO 
VEHICLE IN SUBJECTS WITH SEASONAL ALLERGIC CONJUNCTIVITIS 
USING THE ENVIRONMENTAL EXPOSURE CHAMBER (EEC) 
PROTOCOL VERSION AND DATE: VERSION 6.0, 24 MAR 2021 
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-017 
Protocol Title: The INVIGORATE Trial: A single-center, randomized, double-masked, crossover 
design, vehicle-controlled, Phase 3 clinical trial to assess the efficacy and safety of reproxalap 
ophthalmic solution (0.25%) compared to vehicle 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-017, and will 
conduct the trial in accordance with the International Council for Harmonisation (ICH) guidelines 
on Good Clinical Practice (GCP) and applicable regulatory requirements.  
 
 


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PROTOCOL REVISION HISTORY 
 
 
  
 
 
 
  
  
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


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Table 1 Schedule of Events and Assessments 
 
 


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SYNOPSIS 
Name of Sponsor Company:  
Aldeyra Therapeutics, Inc. 
Drug Under Study:  
Reproxalap  
Title of Protocol:   The INVIGORATE Trial: A single-center, randomized, double-masked, crossover 
design, vehicle-controlled, Phase 3 clinical trial to assess the efficacy and safety of reproxalap ophthalmic 
solution (0.25%) compared to vehicle in subjects with seasonal allergic conjunctivitis using the 
environmental exposure chamber (EEC).  
Protocol Number: 
Sponsor Study Code: ADX-102-AC-017 
Study Code: 19-MO-003-B 
Phase:  
3 
Indication:  
Allergic Conjunctivitis 
Subject Population: Subjects 18 years of age and older with allergic conjunctivitis  
Number of Subjects:  
Approximately 670 subjects with seasonal allergic conjunctivitis to ragweed will be screened in order to 
randomize approximately 126 subjects, with approximately 100 subjects completing the trial.  
Number of Center(s):  
One 
Test Products / Doses / Mode of Administration: 
Eligible subjects will be randomized 1:1 to one of two treatment sequences of AB or BA where:  
• 
Treatment A:  Reproxalap Ophthalmic Solution (0.25%) 
• 
Treatment B:   Vehicle Ophthalmic Solution 
 
Approximately 126 subjects (approximately 63 per treatment sequence) will be enrolled. 
Criteria for Evaluation: 
Primary Endpoint: 
 
Change from baseline in Ocular Itching score on a 9-point scale (0-4) from 110-210 minutes 
Key Secondary Endpoint: 
 
Change from baseline in Conjunctival Redness on a 9-point scale (0-4) over the duration of the 
chamber (approximately 12 to 212 minutes) 
Secondary Endpoints: 
 
Change from baseline in Tearing on a 4-point scale (0-3) over the duration of the chamber 
(approximately 10 to 210 minutes) 
 
Change from baseline in total ocular symptom score (TOSS, sum of itching, redness, and tearing 
scores) on an 11-point composite score  over the duration of the chamber (approximately 10 to 212 
minutes) 
Safety Measures: 
 
Adverse Events (reported, elicited, and observed) 
 
Snellen Visual Acuity (VA) 
 
Slit Lamp Examination (SLE) 
 
Non-contact Intraocular Pressure Tonometry (NCT), as detailed in Table 1.  


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 
Dilated and undilated fundus examination 
Study Design:  
The double-masked, vehicle-controlled, randomized, two-way crossover clinical trial allows for the testing 
of Reproxalap Ophthalmic Solution (0.25%) versus Vehicle Ophthalmic Solution in subjects with ragweed-
induced allergic conjunctivitis in the EEC.  
The clinical trial consists of four visits to the clinic (one Medical Screening visit, one Screening EEC visit, 
and two 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). While subjects are in the EEC,  the average sessional 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 


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(un-dilated), 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 
 
.  In the event of an 
 failure, paper diary cards will be used 
as a back-up to collect symptom scores.  Itching will be rated by the subject on the 
 using a 9-
point, discrete, scale (i.e, 0-4 with 0.5 increments). 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 scale (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. 
 
 
 
Visit 2 Pre-EEC entry (Baseline):  
1) Subject assessment for ocular itching and tearing 
  
, and  
2) Staff-assessed conjunctival redness will be recorded 
 
.  
Visit 2 Post-EEC entry:  
1) Subject assessment for ocular itching and tearing 
 
. 
2) Staff-assessed conjunctival redness will be recorded at 
 
. 
 
 
 
 
 
 
  
At the 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) or Vehicle Ophthalmic Solution (Treatment B). Qualified site staff will instill one drop of the 
randomized treatment into each eye at approximately time zero 
 prior to entry to the EEC after 
all the pre-EEC assessments are done.  
Visit 3 Pre-EEC entry (Baseline):  
1) Subject assessment for ocular itching and tearing will be recorded 
  
 and  
2) Staff-assessed conjunctival redness will be recorded 
 
.  


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Visit 3 Post-EEC entry:  
1) Subject assessment for ocular itching and tearing will occur 
 
. 
2) Staff-assessed conjunctival redness will be recorded 
 
. 
 
At approximately 90-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 
 
 
. 
 
Visit 3 Post-EEC exit (at approximately t = 215 minutes):  
1) Subject assessment for ocular itching and tearing will occur 
 
. 
2) Staff-assessed conjunctival redness will be recorded 
 
. 
At the 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) or Vehicle Ophthalmic Solution 
(Treatment B)]. Before EEC entry, 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 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 worn contact lens within two weeks prior to the Baseline EEC Screening Visit (Visit 2) and are 
unwilling to discontinue use for the duration of the study 
 
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; 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Have received an investigational product in the last 30 days prior to the baseline EEC visit (Visit 2); 
 
Have a clinically relevant sensitization to other allergens if clinical symptoms are expected to 
interfere during the study, at the discretion of the investigator;  
 
 


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Statistical Analysis:  
Approximately 670 subjects with ragweed-induced, moderate-to-severe allergic conjunctivitis will be 
screened in order to randomize approximately 126 subjects, and for approximately 100 subjects to complete 
the study. Approximately sixty-three (63) subjects will be assigned to each of two (2) treatment sequences, 
AB and BA.  
 
 
 
  
Prior to database lock, the Sponsor will finalize a statistical analysis plan (SAP) that will detail all planned 
analyses and will dominate any statistical analysis described herein. Any analyses conducted in addition to 
those specified in the SAP will be clearly documented as post hoc. 
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. 
For the primary efficacy endpoint, Reproxalap Ophthalmic Solution (0.25%) will be compared to vehicle. 
Treatment comparisons at pre-specified time points (every 10 minutes from 110 to 210 minutes following 
chamber entry) will be performed by using a Mixed Model Repeated Measures (MMRM) approach for a 
crossover study with 2 periods.   
Secondary efficacy endpoints will be analyzed by using a similar approach as the primary efficacy variable, 
except over the duration of the chamber (approximately 10 to 212 minutes), as assessed by a single p value 
for the treatment term. Further details of the analysis plan will be described in statistical analysis plan 
document (SAP). 
 


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Table 1. Schedule of Events and Assessments  


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


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Table 4. Schedule of Subject Assessed Itching and Tearing Post-EEC Exit (starting at approximately t = 215) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 5. Schedule of Staff-Assessed Conjunctival Redness Recording Post-EEC Exit (starting at approximately t = 215) 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
INVESTIGATOR STATEMENT ................................................................................................... 2 
PROTOCOL REVISION HISTORY ............................................................................................. 3 
SYNOPSIS  ............................................................................................................................... 13 
TABLE OF CONTENTS ............................................................................................................ 23 
LIST OF TABLES ...................................................................................................................... 26 
LIST OF FIGURES ................................................................................................................... 27 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...................................................... 28 
1 
INTRODUCTION .................................................................................................... 29 
 
Allergic Conjunctivitis .............................................................................................. 29 
 
Therapeutic Rationale for Reproxalap in Allergic Conjunctivitis .............................. 29 
 
Clinical Trials of Reproxalap ................................................................................... 33 
1.3.1 
Ocular Indications ............................................................................................. 33 
 
Rationale for Use of the Allergy Environmental Exposure Chamber (EEC) ............. 35 
 
Minimization of Risk ................................................................................................ 35 
 
Potential Benefit ..................................................................................................... 36 
 
Rationale for Dose Selection .................................................................................. 36 
2 
CLINICAL TRIAL OBJECTIVE AND ENDPOINTS .................................................. 36 
 
Primary Objective ................................................................................................... 36 
 
Clinical Trial Assessments and Endpoints .............................................................. 37 
 
Efficacy Endpoints: ................................................................................................. 38 
 
Safety Endpoints .................................................................................................... 38 
3 
INVESTIGATIONAL PLAN ..................................................................................... 38 
 
Overall Clinical Trial Design and Plan ..................................................................... 38 
 
Assigning Subjects to Treatment Groups ................................................................ 41 
3.2.1 
Subject Numbering ........................................................................................... 41 
3.2.2 
Randomization .................................................................................................. 42 
 
Masking and Unmasking ........................................................................................ 42 
3.3.1 
Masking ............................................................................................................ 42 
3.3.2 
Emergency Unmasking ..................................................................................... 42 
 
Safety Oversight ..................................................................................................... 43 
 
Clinical Trial Duration for Individual Subjects .......................................................... 43 
4 
CLINICAL TRIAL POPULATION SELECTION ....................................................... 43 


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Inclusion Criteria ..................................................................................................... 43 
 
Exclusion Criteria .................................................................................................... 43 
5 
SUBJECT DISPOSITION ....................................................................................... 45 
 
Completed Subjects ............................................................................................... 45 
 
Discontinued Subjects ............................................................................................ 45 
 
Subject Withdrawal and Replacement .................................................................... 46 
6 
INVESTIGATIONAL TREATMENT ......................................................................... 46 
 
Description of Investigational Product ..................................................................... 46 
 
Packaging and Labeling ......................................................................................... 46 
 
Investigational Product Storage .............................................................................. 46 
 
Investigational Product Accountability ..................................................................... 46 
 
Investigational Product Retention ........................................................................... 47 
 
Investigational Product Administration .................................................................... 47 
 
Concomitant Therapy and Procedures ................................................................... 47 
6.7.1 
Prohibited Concurrent Therapies and Procedures ............................................ 47 
7 
CLINICAL TRIAL PROCEDURES .......................................................................... 47 
 
Informed Consent ................................................................................................... 47 
 
Eligibility Review ..................................................................................................... 47 
 
Demographics, Medical History, and Social History ................................................ 48 
 
Physical Examination: ............................................................................................ 48 
 
Concomitant Medications ....................................................................................... 48 
 
Adverse Events ...................................................................................................... 48 
 
Vital Signs .............................................................................................................. 48 
 
Clinical Laboratory Tests ........................................................................................ 48 
7.8.1 
Hematology ...................................................................................................... 48 
7.8.2 
Chemistry ......................................................................................................... 49 
7.8.3 
Pregnancy Test................................................................................................. 49 
7.8.4 
COVID-19 Test (SARS-CoV-2 PCR) ................................................................. 49 
 
Skin Prick Test ....................................................................................................... 49 
 
Ophthalmic Examinations ....................................................................................... 49 
7.10.1 
Visual Acuity ............................................................................................... 49 
7.10.2 
Slit Lamp Exam ........................................................................................... 49 
7.10.3 
Non-Contact Intraocular Pressure Tonometry (NCT) .................................. 49 
7.10.4 
Fundoscopy ................................................................................................ 50 
 
Symptom Collection ................................................................................................ 50 


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7.11.1 
Staff-Assessed Symptom Collection ........................................................... 50 
7.11.2 
Subject-Reported Symptoms ...................................................................... 50 
 
Environmental Exposure Chamber ......................................................................... 50 
 
Randomization ....................................................................................................... 50 
 
Investigational Product Treatment .......................................................................... 50 
8 
CLINICAL TRIAL ACTIVITIES ................................................................................ 51 
 
COVID-19 Screening .............................................................................................. 51 
 
Medical Screening Visit (Visit 1) ............................................................................. 51 
 
Screening EEC Visit (Visit 2) .................................................................................. 51 
 
Treatment EEC Session One (Visit 3) ..................................................................... 52 
 
Treatment EEC Session Two / Clinical Trial Exit (Visit 4) ........................................ 52 
9 
ADVERSE EVENT REPORTING ........................................................................... 52 
9.1.1 
Adverse Events................................................................................................. 52 
9.1.2 
Treatment-Emergent Adverse Events ............................................................... 54 
9.1.3 
Serious Adverse Events .................................................................................... 54 
9.1.4 
Unexpected Adverse Events ............................................................................. 55 
9.1.5 
Reporting Serious Adverse Events ................................................................... 55 
9.1.6 
Follow-up of Adverse Events ............................................................................ 56 
9.1.7 
Reporting Serious Adverse Events to Regulatory Health Authorities/ 
Institutional Review Boards/Research Ethics Boards/Independent 
Ethics Committees ...................................................................................... 56 
9.1.8 
Reporting Pregnancies ..................................................................................... 57 
10 
STATISTICS ........................................................................................................... 57 
 
Analysis Populations .............................................................................................. 57 
 
Statistical Hypotheses ............................................................................................ 58 
 
Sample Size ........................................................................................................... 58 
 
Demographic and Baseline Medical History ............................................................ 58 
 
Accountability and Background Characteristics ...................................................... 58 
10.5.1 
Enrollment and Disposition.......................................................................... 58 
10.5.2 
Subject Characteristics ............................................................................... 58 
10.5.3 
Treatment Compliance ................................................................................ 59 
 
Primary Efficacy Analysis ....................................................................................... 59 
 
Secondary Efficacy Analysis ................................................................................... 59 
 
Safety Analysis ....................................................................................................... 59 
 
Missing Data ........................................................................................................... 59 


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Adjustment for Multiplicity ....................................................................................... 60 
11 
QUALITY CONTROL AND QUALITY ASSURANCE .............................................. 60 
 
Pandemic COVID-19 Response Plan ..................................................................... 60 
12 
CLINICAL TRIAL ADMINISTRATION ..................................................................... 61 
 
Institutional Review Board / Research Ethics Board / Independent Ethics 
Committee ........................................................................................................ 61 
 
Ethical Conduct of the Clinical Trial ........................................................................ 62 
 
Subject Informed Consent ...................................................................................... 62 
 
Confidentiality ......................................................................................................... 62 
 
Protection of Subject Data ...................................................................................... 63 
 
Clinical Trial Monitoring .......................................................................................... 63 
 
Case Report Forms and Source Documents .......................................................... 63 
 
Access to Source Documents and Audits ............................................................... 64 
 
Protocol Deviations and Violations ......................................................................... 64 
 
Amendments to the Protocol .................................................................................. 64 
 
Discontinuation of the Clinical Trial ......................................................................... 65 
 
Investigator Responsibilities ................................................................................... 65 
 
Financial Disclosure ............................................................................................... 65 
 
Registration of Clinical Studies and Disclosure of Results ...................................... 65 
 
Publication and Disclosure Policy ........................................................................... 65 
13 
RETENTION OF RECORDS .................................................................................. 65 
14 
REFERENCES ....................................................................................................... 67 
 
List of Tables 
Table 1. 
Schedule of Events and Assessments .................................................................... 20 
Table 2. 
Schedule of Subject Assessed Itching and Tearing ................................................ 21 
Table 3. 
Schedule of Staff-Assessed Conjunctival Redness Recording ................................ 21 
Table 4. 
Schedule of Subject Assessed Itching and Tearing Post-EEC Exit (starting 
at approximately t = 215) ........................................................................................ 22 
Table 5. 
Schedule of Staff-Assessed Conjunctival Redness Recording Post-EEC Exit 
(starting at approximately t = 215) .......................................................................... 22 
Table 6. 
Clinical Exposure to Topical Ocular Reproxalap ..................................................... 33 
Table 7. 
Topical Ocular Reproxalap Clinical Trial Outcomes ................................................ 34 
 


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List of Figures 
Figure 1. 
Ocular Itch Score Area Under the Curve in the Phase 3 ALLEVIATE Trial ............. 30 
Figure 2. 
Two-Point Ocular Itch Score Improvement Responder Proportions 0.25% 
Reproxalap vs. Vehicle in the Phase 3 ALLEVIATE Trial ........................................ 31 
Figure 3. 
Ocular Itch in Phase 1/2 Allergen Chamber Trial (0.25% Reproxalap) .................... 32 
Figure 4. 
Ocular Redness in Allergen Chamber Trial (0.25% Reproxalap) ............................ 32 
Figure 5. 
Photographic Ocular Redness ................................................................................ 37 
Figure 6. 
Clinical Trial Design ................................................................................................ 39 
 
 
 


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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 
COVID-19 
Corona Virus Disease 2019 
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 
MMRM 
Mixed Model Repeated Measures 
NCT 
Non-contact IOP tonometry 
QID 
Four times daily 
 
 
PCR 
Polymerise Chain Reaction 
RASP 
Reactive Aldehyde Species 
RR 
Respiratory Rate 
SAE 
Serious adverse event 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SOP 
Standard Operating Procedure 
 
 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 Therapeutic Rationale for Reproxalap in Allergic Conjunctivitis 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


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 Clinical Trials of Reproxalap 
 
 
 
 
  
 
 
 


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 Rationale for Use of the Allergy Environmental Exposure 
Chamber (EEC) 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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2 
CLINICAL TRIAL OBJECTIVE AND ENDPOINTS 
 Primary Objective 
The primary  objective of the clinical trial is: 
 
To evaluate the efficacy and safety of Reproxalap Ophthalmic Solution (0.25%) compared 
to Vehicle Ophthalmic Solution for the treatment of allergic conjunctivitis using the EEC 
clinical trial design 


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 Clinical Trial Assessments and Endpoints 
The double-masked, vehicle-controlled, randomized, two-way crossover, Phase 3 clinical trial will 
evaluate the efficacy of Reproxalap Ophthalmic Solution (0.25%) versus Vehicle Ophthalmic 
Solution in subjects with ragweed-induced allergic conjunctivitis in the EEC.  
Ocular itching will be rated by the subject 
 using a 9-point, discrete, 0-4 scale 
with 0.5 increments as shown below.  
*0.5 increments between each score are permitted in this scale. 
Tearing will be rated by the subject 
 using a 4-point discrete 0-3 scale as shown 
below. 
 
 
  
Figure 5. 
Photographic Ocular Redness  
 


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*0.5 increments between each score are permitted in this scale. 
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. 
 Efficacy Endpoints: 
The change from baseline will be derived for each treatment visit between approximately 10-212 
minutes and will be used to assess the activity of Reproxalap Ophthalmic Solution.  
Primary Endpoint: 
 
Change from baseline in Ocular Itching score on a 9-point scale (0-4) from 110-210 
minutes 
Key Secondary Endpoint: 
 
Change from baseline in Conjunctival Redness on a 9-point scale (0-4) over the duration 
of the chamber (approximately 12 to 212 minutes)  
Secondary Endpoints: 
 
Change from baseline in Tearing on a 4-point scale (0-3) over the duration of the chamber 
(approximately 10 to 210 minutes) 
 
Change from baseline in TOSS on an 11-point composite score (sum of itching, tearing, 
and redness) over the duration of the chamber (approximately 10 to 212 minutes) 
 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 4 and undilated fundus examination will be performed at Visits 2 
and 3. Adverse event (AEs; reported, elicited and observed) assessments will be performed at 
Visit 2 through Visit 4. 
3 
INVESTIGATIONAL PLAN 
 Overall Clinical Trial Design and Plan  
The double-masked, vehicle-controlled, randomized, two-way crossover clinical trial allows for the 
testing of Reproxalap Ophthalmic Solution (0.25%) versus Vehicle Ophthalmic Solution in 
subjects with ragweed-induced allergic conjunctivitis in the EEC. 
The clinical trial consists of four visits to the clinic (one Medical Screening visit, one Screening 
EEC visit, and two EEC treatment visits).The three EEC sessions (one EEC screening and two 
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 6. 


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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 6. 
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. 
At all EEC sessions, assessments of ophthalmic evaluations will be collected 
 
 Wilson et al., 2014). In the event of an 
 
failure, paper diary cards will be used as a back-up to collect symptom scores.  For subject-
reported symptoms of ocular itching, a standard 9 point (i.e., 0-4 with 0.5 unit increments) 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 


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grading of conjunctival redness will be performed to ensure the anterior segment of the eye is 
healthy. 
 
Visit 2 Pre-EEC entry (Baseline):  
1) Subject assessment for ocular itching and tearing will be recorded 
 
, and  
2) Staff-assessed conjunctival redness will be recorded 
 
.  
Visit 2 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 the 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) or Vehicle Ophthalmic Solution (Treatment B). Qualified site staff will instill 
one drop of the randomized treatment into each eye at approximately time zero 
 prior 
to entry to the EEC after all the pre-EEC assessments are done.  


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Visit 3 Pre-EEC entry (Baseline):  
1) Subject assessment for ocular itching and tearing will be recorded 
 
, and  
2) Staff-assessed conjunctival redness will be recorded 
 
.  
Visit 3 Post-EEC entry:  
1) Subject assessment for ocular itching and tearing will occur 
 
. 
2) Staff-assessed conjunctival redness will be recorded 
 
. 
At approximately 90-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 
 
 
. 
Visit 3 Post-EEC exit (starting at 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 at least two weeks for Visit 4. 
At the 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) or Vehicle 
Ophthalmic Solution (Treatment B)].  
Before EEC entry, 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. 
 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. 


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3.2.2 Randomization  
Eligible subjects will be randomized 1:1 to one of two treatment sequences of AB or BA, where:  
 
Treatment A:  Reproxalap Ophthalmic Solution (0.25%) 
 
Treatment B:  Vehicle Ophthalmic Solution 
Approximately 126 subjects (approximately 63 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.  
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.  


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 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 four clinic visits over a period of approximately 12 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 Investigator’s  judgement;  
5. Have a positive skin prick test to ragweed pollen within the past year of the Medical 
Screening Visit (Visit 1); 
 
 
 
 
 
 
 
  
 
 
 
 
  
9. Confirmed absence of pregnancy according to a negative urine pregnancy test at the 
Medical Screening Visit (Visit 1); 
10. 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:  
 
 
 
 
  


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3. Have worn contact lens within two weeks prior to the Baseline EEC Screening Visit (Visit 
2) and are unwilling to discontinue use for the duration of the study; 
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; 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
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 


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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; 
 
 
 
 
 
 
 
 
 
 
 
 
 
20. Have received an investigational product in the last 30 days prior to the baseline EEC 
visit (Visit 2);  
21. Have a clinically relevant sensitization to other allergens if clinical symptoms are expected 
to interfere during the study, at the discretion of investigator; 
 
 
 
 
 
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: 
 
Subject request/withdrawal; 
 
AEs; 
 
Positive COVID-19 test result; 
 
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.  


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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. 
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 4) 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 
 
 
  
 
 
 
  
 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 


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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 
4). 
 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). 
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. 


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 Demographics, Medical History, and Social History 
Demographic information to be captured include 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 Investigator’s 
discretion.  
 Concomitant Medications 
Concomitant medications used 30 days prior to consent to treat any medical conditions will be 
recorded in the electronic CRF. Any changes in dosage or new medications added must be 
recorded in the subject electronic 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 electronic 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 4 prior to study exit.  
 Clinical Laboratory Tests 
Blood and/or urine samples for standard clinical safety laboratory will be collected at the Medical 
Screening Visit (Visit 1) and the second Treatment EEC Session (Visit 4) 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. 


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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 
prior to all EEC Sessions (Visits 2 through 4). 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.  
7.8.4 COVID-19 Test (SARS-CoV-2 PCR) 
Within 5 days of study visits 2, 3, and 4 a nasopharyngeal or oropharyngeal swab will be collected 
at the clinical site for SARS-CoV-2 PCR testing. Subjects with a positive test result will be 
excluded/withdrawn from the study. 
 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 4). 
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 
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 4). 
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 4). 


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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 4) . Specifically, dilated fundoscopy will be performed 
at Visit 1 and Visit 4 and undilated fundoscopy will be performed at Visits 2 through 3. 
 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  
 
). In the event of an 
 failure, paper diary cards will be used as a 
back-up to collect symptom scores.  Refer to Table 3 and Table 5 for the Schedules of Staff 
Assessed conjunctival redness and Table 2 and Table 4 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). Tearing assessment will be done on a standard 4-point (i.e. 0-3 scale).  
 Environmental Exposure Chamber 
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 controlled 
pollen challenge, over time, allows evaluation of subject responses at any time-point throughout 
the challenge process. 
 
At the Treatment EEC Sessions (Visits 3 through 4), IP treatment will 
be administered just prior to EEC entry and approximately 90 minutes post-EEC entry.  
 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 4), the subject will receive IP according to the 
treatment sequence the subject was randomized to. The subject will receive one dose of IP just 


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prior to EEC entry and then another dose will be administered approximately 90 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) 
 
 COVID-19 Screening 
The following procedures will be performed as part of COVID-19 screening: 
 
Subjects will be pre-screened based upon a COVID-19 questionnaire at each visit; 
 
Body temperature will be measured at each visit.  This measurement may be in addition 
to other vitals taken at the visit; 
 
A nasopharyngeal/oropharyngeal swab will be collected for COVID-19 testing within 5 
days prior to each EEC session (Visits 2, 3, and 4).  
 
Most recent COVID-19 test result 
 will be reviewed prior to 
entering the EEC at Visits 2, 3, and 4.  Subjects will be allowed to enter the EEC only if 
COVID-19 test result is negative. 
Subject’s further participation in the study will be based on the results of the COVID-19 test results 
and procedures. 
 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) 


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 
Obtain symptom collection (staff-assess and subject-reported) pre- and post-EEC entry 
(Section 7.11)  
 
 drop administration just prior to EEC entry 
 
EEC session (Section 7.12) 
 Treatment EEC Session One (Visit 3) 
 
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 Two / Clinical Trial Exit (Visit 4) 
 
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 Events 
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.  


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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 
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 electronic 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. 


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The following are guidelines to be used by the investigator to judge the event severity of 
an AE: 
 
 
 
 
 
 
 
 
 
 
 
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; 


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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 
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 Events  
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: 
 
 
 (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).  


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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.  
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.  


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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 
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 
 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. 
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. 
  
 
 
 
 


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 Statistical Hypotheses 
The following hypotheses will be tested comparing reproxalap to vehicle in this cross-over 
design. The null hypotheses must be rejected for the dosing regimen to claim efficacy.  
H0: There is no difference between reproxalap and vehicle in the change from baseline in Ocular 
Itching score on a 9-point scale (0-4) from 110-210 minutes.  
H1: The change from baseline in Ocular Itching score on a 9-point scale (0-4) is smaller with 
reproxalap than with vehicle in the ITT population from 110- 210  minutes.  
 Sample Size 
Approximately 670 subjects with ragweed-induced, moderate-to-severe allergic conjunctivitis will 
be screened in the EEC in order to randomize approximately 126 subjects, and for 100 subjects 
to complete the study. Approximately sixty-three (63) subjects will be assigned to each of two (2) 
treatment sequences, AB and BA.  
 
 
 
 
  
Prior to database lock, the Sponsor will finalize a statistical analysis plan (SAP) that will detail all 
planned analyses and will dominate any statistical analysis herein. Any analyses conducted in 
addition to those specified in the SAP will be clearly documented as post hoc. 
 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. 
 Accountability and Background Characteristics 
10.5.1 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. 
10.5.2 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 
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. 


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10.5.3 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). 
 
 Primary Efficacy Analysis 
The efficacy analyses of all efficacy endpoints will be carried out in the ITT population. Supportive 
analyses may also be provided for Itching endpoint(s) using the PP population. 
Descriptive statistics of all activity endpoints as well as individual data listings will be presented 
by treatment group and efficacy measures. 
For the primary efficacy endpoint, treatment comparisons will be made between Reproxalap 
Ophthalmic Solution (0.25%) and vehicle. The treatment comparisons will be performed at pre-
specified time points (every 10 minutes from 110 minutes to 210 minutes following chamber entry) 
by using a Mixed Model Repeated Measures(MMRM) approach for a crossover study with two 
periods.  
 
 
 
 Secondary Efficacy Analysis 
Secondary efficacy endpoints will be analyzed by using a similar approach as the primary efficacy 
variable, except over the duration of the chamber (approximately 10 to 210 minutes, as assessed 
by a single p value for the treatment term. Further details of the analysis plan will be described in 
statistical analysis plan document (SAP). 
 Safety Analysis 
Adverse events will be coded using the MedDRA dictionary.  
Frequencies and percentages will be provided per treatment group of subjects with treatment-
emergent adverse events (TEAEs), serious TEAEs, and TEAEs causing premature 
discontinuation. An adverse event is treatment-emergent if it occurs or worsens after the first dose 
of randomized study treatment. Furthermore, frequencies will be given of subjects with TEAEs by 
system organ class, by system organ class and preferred term, by system organ class, preferred 
term and maximal severity, by system organ class, preferred term and strongest relationship, and 
by system organ class, preferred term, maximal severity, and strongest relationship. Separate 
analyses will be performed for ocular specific and all adverse events (including systemic).  
Other safety endpoints including visual acuity, slit lamp biomicroscopy, intraocular pressure (IOP), 
tear osmolarity and dilated fundoscopy will be summarized by treatment group and visit using 
descriptive statistics. Changes or shifts from baseline will also be summarized where appropriate. 
For assessments performed by eye, worst eye (study eye) and fellow eye will be summarized 
separately. 
 Missing Data  
 
 


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 Adjustment for Multiplicity 
 
 
11 QUALITY CONTROL AND QUALITY ASSURANCE 
 will implement and maintain quality control procedures to insure that the study 
is conducted, and that the data are generated, documented, and reported in compliance with the 
protocol, GCP and applicable regulatory documents. 
 
 
All participant data relating to the clinical trial will be recorded on electronic CRF unless 
transmitted to the sponsor or designee electronically (e.g., laboratory data). The investigator 
is responsible for verifying that data entries are accurate and correct by electronically signing 
the CRF. 
 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
 
The investigator must permit study-related monitoring, audits, IRB//IEC review, and regulatory 
agency inspections and provide direct/remote access to source data documents. 
 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study 
is being conducted in accordance with the currently approved protocol, written SOPs, study 
specific plans and any other study agreements, ICH GCP, and all applicable regulatory 
requirements. 
 
Separate risk management plan will be developed prior to start of the study in accordance 
with ICH E6 (R2). 
The Sponsor may conduct audit visits at clinical study site or remotely to verify adherence to the 
study protocol, the protection of the rights and well-being of the subjects and the accuracy and 
completeness of reported study data recorded on the source documentation. 
 
 Pandemic COVID-19 Response Plan 
Regulatory authorities have recognized that the Corona Virus Disease 2019 (COVID-19) 
pandemic may impact the conduct of clinical study. COVID-19 pandemic has created a lot of 
uncertainty in the current situation and has put subject’s safety, protocol compliance and data 
validity at high risk. 
Due to COVID-19 pandemic, challenges may arise for clinical study conduct, for example, 
quarantines of site personnel/study participants, travel limitations, interruptions to the supply chain 
for the IP(s), or other considerations if site personnel or study participants become infected with 


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COVID-19. These challenges may lead to difficulties in meeting protocol specified procedures, 
including administration or use of investigational product, housing duration or adhering to protocol 
specified visits and laboratory/diagnostic testing.  
To accommodate these challenges and mitigate safety risks associated with COVID-19, changes 
may be required from approved protocol which include (but not limited to) conducting the study in 
multiple groups, change in study procedures timing, change in subject’s housing duration, 
additional test or parameter may be performed to standard inclusion or exclusion criteria at the 
discretion of Investigator/designee, etc. The changes made to the procedure will prioritize subject’s 
safety and data validity and integrity. For any significant change, as per regulatory guidelines, a 
planned protocol deviation will be filled and notified to IRB and/or local regulatory (as applicable). 
All participants will be pre-screened prior to enrolment into the study and evaluated for risk factors 
and symptoms of COVID-19 according to the most recent regional Public Health guidelines20 
available at the time of pre-screening. The screening is conducted through telephone at the time 
of appointment confirmation and again when the subject arrives at the clinic for any visit. 
Additional health checks including body temperature or other vital sign monitoring, etc. may be 
performed during the study at the discretion of Investigator/designee, even if not specified in the 
protocol. Subject who is tested positive to COVID-19 during the study will be withdrawn from the 
study. This subject and other subjects in close contact will be handled as per applicable local 
Public Health Guidelines. 
As the science and regulations are continuously being adapted to the evolving information around 
the pandemic, additional measures apart from the ones mentioned here may be undertaken to 
ensure subject safety and appropriate study conduct. The IRB and the sponsor would be informed 
for their review and approval as applicable.  
Risk Mitigation plan/Risk Evaluation and Mitigation strategy will be made to minimize the risk for 
COVID-19 exposure and to handle possible situations during COVID-19 pandemic. 
 
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. 


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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, 
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 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. 


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 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 
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 electronic 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. 


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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 
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/remote 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. 


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 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 
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 


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 
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.  
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: 
Aldeyra Therapeutics, Inc. 
Statistical Analysis Plan 
Protocol No: ADX-102-AC-017  
Final: V1.0, 26Mar2021 
P a g e  1 | 24 
 
 
Statistical Analysis Plan 
 
The INVIGORATE Trial: A Single-Center, Randomized, Double-Masked, 
Crossover Design, Vehicle-Controlled, Phase 3 Clinical Trial to Assess the 
Efficacy and Safety of Reproxalap Ophthalmic Solution (0.25%) 
Compared to Vehicle in Subjects with Seasonal Allergic Conjunctivitis 
Using the Environmental Exposure Chamber (EEC) 
 
 
Protocol Number: 
ADX-102-AC-017 
Protocol Version and Date: 
Version 6.0, 24Mar2021  
 
 
 
 
 
Sponsor: 
Aldeyra Therapeutics, Inc 
Indication:  
Allergic Conjunctivitis 
Analysis Plan Date: 
26Mar2021 
Analysis Plan Version: 
Version 1.0 
 
 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior 
written consent of Aldeyra Therapeutics, Inc. is strictly prohibited except to the extent required under 
applicable laws or regulations.  Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 
 


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Protocol No: ADX-102-AC-017  
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SPONSOR SIGNATURE PAGE 
Protocol Title: 
The INVIGORATE Trial: a single-center, randomized, double-
masked, crossover design, vehicle-controlled, phase 3 clinical trial to 
assess the efficacy and safety of reproxalap ophthalmic solution 
(0.25%) compared to vehicle in subjects with seasonal allergic 
conjunctivitis using the environmental exposure chamber (EEC) 
Protocol Number: 
ADX-102-AC-017 
Sponsor:  
Aldeyra Therapeutics, Inc. 
131 Hartwell Avenue, Suite 320 
Lexington, MA 02421 
By signing this document, I acknowledge that I have read the document and approve of the 
planned statistical analyses described herein. I agree that the planned statistical analyses are 
appropriate for this study, are in accordance with the study objectives, and are consistent with 
the statistical methodology described in the protocol and all applicable regulatory guidance 
and guidelines. 
Author: 
 
 
 
 
 
  
 
 
Approver:  
 
 
 
 
  
 
 
 
 
 
 


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Table of Contents 
SPONSOR SIGNATURE PAGE.................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................ 5 
ABBREVIATIONS ...................................................................................................................................... 6 
1. INTRODUCTION .................................................................................................................................. 7 
2. STUDY DESIGN ................................................................................................................................... 7 
2.1 
OVERVIEW OF STUDY DESIGN ............................................................................................ 7 
2.2 
Sample Size ................................................................................................................................ 11 
2.3 
Randomization and Masking ..................................................................................................... 12 
2.3.1 
Randomization ........................................................................................................... 12 
2.3.2 
Masking ...................................................................................................................... 12 
3. STUDY OBJECTIVES AND ENDPOINTS ....................................................................................... 12 
3.1 
Primary Objective ...................................................................................................................... 12 
3.2 
Endpoints Assessment ............................................................................................................... 12 
3.2.1 
Clinical Trial Assessments and Endpoints ................................................................. 12 
3.2.2 
Efficacy Endpoints ..................................................................................................... 13 
4. DEFINITIONS AND CONVENTIONS FOR DATA HANDLING ................................................... 13 
4.1 
Definition of Baseline ................................................................................................................ 13 
4.2 
Handling of Missing Data .......................................................................................................... 14 
4.3 
Unscheduled Visits for Safety Analysis ..................................................................................... 14 
4.4 
Handling of Partial Dates for Medications................................................................................. 14 
4.5 
Handling Partial Dates for Adverse Events ............................................................................... 14 
5. ANALYSIS POPULATIONS .............................................................................................................. 14 
5.1 
Enrolled Population ................................................................................................................... 14 
5.2 
Safety Population ....................................................................................................................... 15 
5.3 
Intent-to-Treat (ITT) Population ................................................................................................ 15 
5.4 
Completer Population ................................................................................................................ 15 
5.5 
Per-Protocol (PP) Population ..................................................................................................... 15 
5.6 
Application of Analysis Population ........................................................................................... 15 
6. STATISTICAL CONSIDERATIONS ................................................................................................. 15 
6.1 
General Statistical Procedures ................................................................................................... 16 
6.2 
Subject Disposition .................................................................................................................... 16 
6.3 
Extent of Study Drug Exposure ................................................................................................. 17 
6.4 
Protocol Deviations .................................................................................................................... 17 
6.5 
Demographic and Baseline Characteristics ................................................................................ 17 
6.6 
Medical and Social History ........................................................................................................ 18 
6.7 
Prior and Concomitant Medications .......................................................................................... 18 
7. Safety Analysis ..................................................................................................................................... 18 
7.1 
Ophthalmic Examination Findings ............................................................................................ 18 
7.2 
Adverse Events .......................................................................................................................... 19 
7.3 
Clinical Laboratory Tests ........................................................................................................... 20 


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7.4 
Vital Signs .................................................................................................................................. 21 
8. Efficacy Analysis ................................................................................................................................. 21 
8.1 
Primary Efficacy Analysis ......................................................................................................... 21 
8.2 
Key and Secondary Efficacy Analysis ....................................................................................... 22 
9. Appendix .............................................................................................................................................. 24 
 
 
 


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LIST OF TABLES 
Table 1: Schedule of Events and Assessments ............................................................................................. 8 
Table 2. Application of Populations on Tables ........................................................................................... 15 
 
 


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ABBREVIATIONS  
Abbreviation 
Explanation 
AE 
Adverse Event 
AR1 
First-order Autoregressive  
ATC 
Anatomical Therapeutic Chemical 
CI 
Confidence Interval 
CRF 
Case Report Form 
CS 
Compound Symmetric  
EEC 
Environmental Exposure Chamber 
 
 
IOP 
Intraocular Pressure 
ITT 
Intent-to-Treat  
MedDRA 
Medical Dictionary for Regulatory Activities  
MMRM 
Mixed Model Repeated Measures 
NCT 
Non-Contact IOP Tonometry 
PP 
Per-Protocol  
PT 
Preferred Term  
SD 
Standard Deviation 
SLE 
Slit Lamp Examination 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TOSS 
Total Ocular Symptom Score 
VA 
Visual Acuity 
WHO 
World Health Organization 
WOCBP 
Women of Childbearing Potential 
  
 


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Protocol No: ADX-102-AC-017  
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1.  INTRODUCTION 
This statistical analysis plan is designed to outline the statistical methods for protocol ADX-102-
AC-017: 
“The INVIGORATE Trial: A single-center, randomized, double-masked, crossover design, 
vehicle-controlled, Phase 3 clinical trial to assess the efficacy and safety of reproxalap ophthalmic 
solution (0.25%) compared to vehicle in subjects with seasonal allergic conjunctivitis using the 
environmental exposure chamber (EEC)”  
This document has been prepared based on protocol amendment version 6.0 dated 24 March 2021 
.  
2. STUDY DESIGN 
2.1 
OVERVIEW OF STUDY DESIGN 
The double-masked, vehicle-controlled, randomized, two-way crossover clinical trial allows for 
the testing of Reproxalap Ophthalmic Solution (0.25%) versus Vehicle Ophthalmic Solution in 
subjects with ragweed-induced allergic conjunctivitis in the Environmental Exposure Chamber 
(EEC). 
The clinical trial consists of four visits to the clinic (one Medical Screening visit, one Screening 
EEC visit, and two 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 controlled pollen challenge, over time, allows evaluation of subject responses at any time-
point throughout the challenge process. 


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Figure 1: Study Design 
 
Eligible subjects will be randomized 1:1 to one of two treatment sequences of AB or BA where: 
• Treatment A: Reproxalap Ophthalmic Solution (0.25%) 
• Treatment B: Vehicle Ophthalmic Solution 
 
Approximately 126 subjects (approximately 63 per treatment sequence) will be enrolled and will 
follow the schedule for assessments (Table 1) . 
Table 1: Schedule of Events and Assessments 


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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. 
At all EEC sessions, assessments of ophthalmic evaluations will be collected 
 
. In the event of an 
 failure, paper diary cards will be 
used as a back-up to collect symptom scores. For subject-reported symptoms of ocular itching, a 
standard 9 point (i.e., 0-4 with 0.5 unit increments) 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. 
 
 


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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. 
 
Visit 2 Pre-EEC entry (Baseline): 
1) Subject assessment for ocular itching and tearing will be recorded 
 
, and 
2) Staff-assessed conjunctival redness will be recorded 
 
. 
Visit 2 Post-EEC entry: 
1) Subject assessment for ocular itching and tearing will occur
 
. 
2) Staff-assessed conjunctival redness will be recorded
 
. 
 
 
 
 
 
 
 
At the 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) or Vehicle Ophthalmic Solution (Treatment B). Qualified site staff will 
instill one drop of the randomized treatment into each eye at approximately time zero 
 
prior to entry to the EEC after all the pre-EEC assessments are done. 
Visit 3 Pre-EEC entry (Baseline): 


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1) Subject assessment for ocular itching and tearing will be recorded 
 
 and 
2) Staff-assessed conjunctival redness will be recorded 
 
. 
Visit 3 Post-EEC entry: 
1) Subject assessment for ocular itching and tearing will occur 
 
. 
2) Staff-assessed conjunctival redness will be recorded 
 
. 
At approximately 90-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. 
 
 
 
 
 
Visit 3 Post-EEC exit (starting at 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 at least two weeks for Visit 4. 
At the 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) or 
Vehicle Ophthalmic Solution (Treatment B)]. 
Before EEC entry, 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. 
2.2 
Sample Size 
Approximately 670 subjects with ragweed-induced, moderate-to-severe allergic conjunctivitis will 
be screened in the EEC in order to randomize approximately 126 subjects, and for 100 subjects to 


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Protocol No: ADX-102-AC-017  
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complete the study. Approximately sixty-three (63) subjects will be assigned to each of two (2) 
treatment sequences, AB and BA. 
 
 
 
 
2.3 
Randomization and Masking 
2.3.1 Randomization 
Eligible subjects will be randomized 1:1 to one of two treatment sequences of AB or BA where: 
• Treatment A: Reproxalap Ophthalmic Solution (0.25%) 
• Treatment B: Vehicle Ophthalmic Solution 
 
Approximately 126 subjects (approximately 63 per treatment sequence) will be enrolled. 
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.  
2.3.2 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. STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Primary Objective 
• To evaluate the efficacy and safety of Reproxalp Ophthalmic Solution (0.25%) compared 
to Vehicle Ophthalmic Solution for the treatment of allergic conjunctivitis using the EEC 
clinical trial design 
3.2 
Endpoints Assessment 
3.2.1 Clinical Trial Assessments and Endpoints 
• Ocular itching rated by the subject 
 using a 9-point, discrete, 0-4 scale 
with 0.5 increments 
• Tearing rated by the subject 
 using a 4-point discrete 0-3 scale 
• Ocular redness in the nasal and temporal conjunctiva separately in both eyes, based on a 
descriptive and photographic scale from 0-4 
with 0.5 steps 


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• Total Ocular Symptom Score (TOSS): composite score of ocular itching (0 – 4), ocular 
tearing (0 – 3) and ocular redness (0 – 4) with a maximum score of 11 units 
3.2.2 Efficacy Endpoints 
3.2.2.1 Primary Efficacy Endpoint 
• Change from baseline in ocular itching score on a 9-point scale (0-4) from 110-210 minutes 
3.2.2.2 Key Secondary Endpoint 
• Change from baseline in conjunctival redness on a 9-point scale (0-4) during the chamber 
(approximately 12 to 212 minutes) 
3.2.2.3 Secondary Endpoints 
• Change from baseline in tearing on a 4-point scale (0-3) during the chamber (approximately 
10 to 210 minutes) 
• Change from baseline in TOSS on an 11-point composite score (sum of maximum score 
of itching, tearing and redness) during the chamber (approximately 10 to 212 minutes) 
• Safety Endpoints 
• Ophthalmic examinations 
− Snellen visual acuity (VA) 
− Slit lamp examination (SLE) 
− Non-contact intraocular pressure tonometry (NCT)  
− Dilated fundus examination at screening Visit 1 and at Visit 4 
− Undilated fundus examination at Visits 2 and 3 
• Adverse events 
• Vital signs 
• Clinical laboratory tests   
4. DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
4.1 
Definition of Baseline 
For Safety evaluations, baseline is defined as the last non-missing value measured prior to 
initiation of study drug.  
 
 
  


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4.2 
Handling of Missing Data 
Generally, imputation of missing data will not be performed. 
4.3 
Unscheduled Visits for Safety Analysis 
All unscheduled visit values will be excluded from summary tables but will be included on data 
listing.  
4.4 
Handling of Partial Dates for Medications  
When determining prior or concomitant medications, partial start dates of prior and concomitant 
medications will be assumed to be the earliest possible date consistent with the partial date.  
For the purposes of analysis, incomplete medication start dates and stop dates will be imputed.  
• If a medication start date is incomplete, January will be imputed for missing month and/or 
the first day of the month will be imputed for missing day.  
• If a medication stop date is incomplete, December will be imputed for missing month and 
the last day of the month will be imputed for missing day.  
• If the imputed medication stop date is after the date of study completion, the date of study 
completion will be used instead. 
4.5 
Handling Partial Dates for Adverse Events 
When determining the treatment emergent AE, partial dates will be handled as follows.  
• If the day of the month is missing, the onset day will be set to the first day of the month 
unless it is the same month and year as first dose date. In this case, the onset date will be 
assumed to be the first date of treatment. 
• If the onset day and month are both missing, the day and month will be assumed to be 
January 1, unless the event occurred in the same year as the study treatment. In this case, 
the event onset will be coded to the day of treatment to conservatively report the event as 
treatment-emergent.  
• A missing onset date will be coded as the day of treatment. If the resulting onset date is 
after a reported date of resolution, the onset date will be set equal to the date of resolution.   
• Imputation of partial dates is used only to determine whether an event is treatment-
emergent; data listings will present the partial date as recorded in the eCRF. 
5. ANALYSIS POPULATIONS 
5.1 
Enrolled Population 
Enrolled Population includes all subjects with a signed informed consent form.  


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5.2 
Safety Population 
Safety Population includes all randomized subjects who use at least one dose of investigational 
drug (Reproxalap Ophthalmic Solution or Vehicle Ophthalmic Solution), regardless of whether 
clinical trial assessments were performed.  
5.3 
Intent-to-Treat (ITT) Population  
ITT Population includes all randomized subjects who use at least one dose of investigational drug 
and have any post-dose assessments. Subjects are evaluated according to the investigational drug 
treatment of the visit as per the randomized treatment sequence. 
5.4 
Completer Population 
Completer population will include all randomized subjects who received investigational drug 
dosing at all two EEC treatment visits. 
5.5 
Per-Protocol (PP) Population 
Per-Protocol Population includes all subjects in Completer Population without a major deviation 
from the protocol.  
5.6 
Application of Analysis Population  
Unless otherwise noted, the analysis populations that will be used for creating the summary tables 
of each type is provided in Table 2.   
Table 2. Application of Populations on Tables 
6. STATISTICAL CONSIDERATIONS 
All analyses described in this plan are considered a priori analyses in that they have been defined 
prior to locking the database.  All other analyses, if any, designed subsequently to locking the 
database, will be considered post hoc analyses and will be described as exploratory analyses in the 
Clinical Study Report.  


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All summaries and statistical analysis will be performed 
.  
6.1 
General Statistical Procedures 
Frequency distributions for categorical variables will be provided as number of patients in the 
category and the percentages of the total number of patients in the given population as noted. 
Percentages will be reported to one decimal place.  
The descriptive statistics for continuous variables will be number of subjects (n), mean, standard 
deviation (SD), median, minimum and maximum.   Mean and median will be reported to 1 more 
decimal place than the raw data, while the SD will be reported to 2 more decimal places than the 
raw data. Minimum and maximum will be reported the same as the original data.  
All statistical tests will be two-sided with a significance level of 0.05 (α = 0.05) unless otherwise 
specified. Confidence interval (CI) for differences between treatment will be two-sided at 95% 
confidence interval.   
P-value will be rounded to at most 3 decimal places and will be reported as < 0.001 if it is smaller 
than 0.001. 
Unless otherwise specified, subjects’ characteristics at baseline will be summarized by treatment 
sequences (Reproxalap 0.25%/Vehicle, Vehicle/Reproxalap 0.25%). Safety and efficacy will be 
summarized by treatment (Reproxalap 0.25%, Vehicle) where appropriate. 
In general, all listings will be ordered by subject number and visit for available data unless 
otherwise specified in the text.   
6.2 
Subject Disposition  
Frequency and percentage of subject disposition will be summarized by treatment sequence and 
all subjects for Enrolled Population including: 
• Number of subjects with screen failure 
• Number of subjects randomized 
• Number of subjects in each analysis population 
• Number of subjects who completed each treatment 
− Reproxalap Ophthalmic Solution 0.25% 
− Vehicle Ophthalmic Solution 
• Number of subjects only completed first treatment session 
Percentage will be based on number of subjects randomized.   
Study discontinuation will be summarized by treatment for Safety Population including:  
• Number of subjects discontinued from study 
• Reasons for study discontinuation 


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− Subject request/withdrawal 
− Adverse event 
− Pregnancy 
− Protocol violations 
− Administrative reasons 
− Sponsor termination 
− Any sound medical reason 
− Other 
Percentage is based on number of subjects in Safety Population. 
Subjects’ disposition will be listed for Enrolled Population. In addition, subjects excluded from 
study will be listed for Enrolled Population.  
6.3 
Extent of Study Drug Exposure  
Exposure of study drug will be listed for Safety Population.  
6.4 
Protocol Deviations 
Protocol deviations will be reviewed, assessed and documented by sponsor personnel before 
database lock. 
Number and percentage of subjects with protocol deviation will be tabulated by treatment for 
Safety Population. 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 
All protocol deviations will be listed for Enrolled Population.  
6.5 
Demographic and Baseline Characteristics 
Subjects’ demographic and baseline characteristics will be summarized by treatment sequence and 
for all subjects including: 


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• Age at screening (years). If not reported, calculated as integer of (date of informed consent 
signed – date of birth)/365.25 and rounded to integer. 
• Sex 
• Race 
• Ethnicity 
• Height (cm)  
• Weight (kg) 
• BMI (body mass index, kg/m2), calculated as weight (kg) / height (m)2 
Demographics and baseline characteristics will be listed for ITT Population.  
6.6 
Medical and Social History 
Medical and social history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) 
   
The frequency count and percentage of patients experiencing any medical conditions will be 
tabulated by system organ classifications (SOC) and preferred term (PT) for each treatment.  If a 
preferred term or system organ class was reported more than once for a subject, the subject would 
only be counted once in the incidence for that preferred term or system organ class. 
Medical history data will be listed for ITT Population. 
6.7 
Prior and Concomitant Medications 
All 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 medications are medications used 30 days prior to consent to treat any medical conditions 
and will be documented at medical screening visit.   
Concomitant medications are medications being taken on or after first dose the study drug.   
Medications taken 30 days prior to informed consent date and were ongoing on the date of the first 
dose will be considered concomitant medications. Medications with missing end date are assumed 
to be concomitant medications.  
Prior and concomitant medications will be listed ONLY for ITT Population.  
7. Safety Analysis 
7.1 
Ophthalmic Examination Findings 
Ophthalmic examination results will be summarized by anatomical location (eye) and side (left, 
right and both) at pre and post-EEC entry treatment sessions for Safety Population for following 
tests:  


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• Visual acuity measured using a Snellen eye chart  
• Slit lamp examination (SLE)  
• Non-contact intraocular pressure tonometry (NCT), measured using non-contact tonometry  
• Fundoscopy including: 
− Dilated fundus examination at Visit 4 
− Undilated fundus examination at Visits 3 
7.2 
Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding 
dictionary 
 preferred term (PT) and system organ classification (SOC).    
An AE will be considered treatment emergent (TEAE) if it begins or worsens in severity after the 
first dose of the study drug through 30 days after the last dose of study drug, or the date of initiation 
of another investigational agent or surgical intervention.  
Drug-related TEAEs are defined as definitely related, possibly related, or probably related to study 
drug. Any AEs with missing relationship to study drug will be considered as related to study drug. 
All TEAEs with start dates prior to first dose date in Visit 4 EEC Treatment Session will be 
classified as AEs occurred in Visit 3 EEC Treatment Session.    
An overall summary for number of subjects with events in each treatment will be provided 
including: 
• Number of subjects with at least one TEAE 
• Number of subjects with at least one Ocular TEAE 
• Number of subjects with at least one drug-related TEAE 
• Number of subjects with at least one drug-related Ocular TEAE 
• Number of subjects with at least one serious TEAE 
• Number of subjects with at least one serious Ocular TEAE 
• Number of subjects with at least one TEAE leading to study discontinuation  
• Number of subjects with at least one Ocular TEAE leading to study discontinuation  
An AE is classified as an ocular AE if system organ class is coded as eye disorders. 
The following types of summary for each treatment will be provided. Summaries will be sorted by 
decreasing frequency of PT within SOC which will be sorted alphabetically. 
• TEAEs by SOC and PT 
• Ocular TEAEs by SOC and PT 
• Non-Ocular TEAEs by SOC and PT 
• TEAEs by Casualty, SOC and PT 


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• Ocular TEAEs by Casualty, SOC and PT 
• Non-Ocular TEAEs by Casualty, SOC and PT 
• Serious TEAE by SOC and PT 
• Ocular Serious TEAE by SOC and PT 
• Non-Ocular Serious TEAE by SOC and PT 
• TEAE by SOC, PT and maximum Severity 
• Ocular TEAE by SOC, PT and maximum Severity 
• Non-Ocular TEAE by SOC, PT and maximum Severity 
• TEAEs leading to study discontinuation by SOC and PT 
• Ocular TEAEs leading to study discontinuation by SOC and PT 
• Non-Ocular TEAEs leading to study discontinuation by SOC and PT 
If a preferred term or system organ class was reported more than once for a subject, the subject 
would only be counted once in the incidence for that preferred term or system organ class.  
• In the tabulation of TEAE by severity, only the most severe PT or SOC for each subject 
will be included.  Missing severity will be counted as Severe. 
• In the summary of drug-related TEAEs, the strongest relationship will in included.  
Listing will be provided including for Safety Population: 
• All AEs 
• Serious TEAEs 
• TEAEs leading to study discontinuation 
7.3 
Clinical Laboratory Tests  
Standard clinical safety laboratory (chemistry and hematology) collected at the Medical Screening 
Visit (Visit 1) and the second Treatment EEC Session (Visit 4) as part of study exit procedures 
include following parameters: 
• Hematology profile: hemoglobin, hematocrit, red blood cell (RBC) count, white blood cell 
(WBC) count, and absolute platelet count 
• Serum chemistry profile: 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. 
All laboratory tests including pregnancy testing will be provided. Separate listing will also be 
provided for clinically significant abnormal laboratory values.    


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7.4 
 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 4 prior to study exit. 
Observed and changes from baseline for vital signs will be summarized by visit.  Baseline is 
defined as the last non-missing measurement taken prior to the first dose. 
Listing will be provided for ITT Population.  
8. Efficacy Analysis 
The efficacy evaluation will be performed to assess the activity of Reproxalap Ophthalmic 
Solution based on the subjects reported ocular itching using a standard 9-point scale (0-4 scale 
with 0.5-unit increments) and tearing on a standard 4-point (0-3 scale) and trained staff assessed 
conjunctival redness using a standard 9-point scale (0-4 scale with 0.5 unit increments).  
For all staff assessed and subject reported symptoms where values from both eyes are obtained at 
the same timepoint, the average score from both eyes will be used for analysis.  
The following analysis will be performed for all efficacy endpoints using ITT Population:  
• Observed and changes from baseline by visit and treatment  
• Analysis using Mixed Model Repeated Measures (MMRM) using all available data 
collected during the EEC 
• Plots for mean score over time, and mean changes of score from baseline over time 
 
 
The onset of action time point and the duration of action will be reported for each efficacy endpoint 
whenever applicable. Duration of action will be the longest (in minutes) series of time points over 
which majority is statistically significant in favor of test drug, including the first and last time 
points in the series. Onset of action will be the first time point in the duration series. If two or more 
duration series are equivalent in length (in minutes), then the onset will be the first time point in 
the series that occurs earliest. 
Subjects’ assessment at Screening EEC and Post-EEC exit time points will be listed ONLY. All 
efficacy data will be listed for ITT Population.  
8.1 
Primary Efficacy Analysis 
The primary efficacy endpoint is the change from baseline (pre-dose) in ocular itching scores on a 
9-point scale (0-4 scale with 0.5-unit increments) from 110-212 minutes between Reproxalap 
Ophthalmic Solution (0.25%) and vehicle.  


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Observed and changes from baseline duration treatment period will be summarized by visit and 
treatment for ITT, PP, and Completer populations.  
Primary efficacy analyses will be carried out in the ITT population. Supportive analyses for 
primary efficacy endpoint will also be provided using the PP population and the Completer 
population if more than 10% of ITT population is excluded from PP population. 
The treatment comparison will be performed by using a Mixed Model Repeated Measures 
(MMRM) approach for a crossover study with 2 treatment periods (Visit 3 treatment EEC Session 
One and Visit 4 treatment EEC Session Two).
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
  
Reproxalap Ophthalmic Solution will be claimed to be better than Vehicle if the estimated change 
of ocular itch score from baseline based on MMRM model in the Reproxalap group is statistically 
lower than that of the Vehicle group
 
   
If the MMRM model does not converge with any correlation structure, then a within-subject t-test 
(baseline-adjusted, if useful) will be used to compare the score difference across treatment groups 
at each time point.  
 
   
8.2 
Key and Secondary Efficacy Analysis  
The key secondary efficacy endpoint is  
• Change from baseline in conjunctival redness on a 9-point scale (0-4) during the chamber 
(approximately 10 to 210 minutes) 
The secondary efficacy endpoints are 


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• Change from baseline in tearing on a 4-point scale (0-3) during the chamber (approximately 
10 to 210 minutes) 
• Change from baseline in TOSS on an 11-point composite score (sum of itching, tearing, 
and redness) during the chamber (approximately 10 to 210 minutes) 
TOSS will be derived as the sum of ocular itching, conjunctival redness and tearing symptoms at 
each time point.  
Observed and changes from baseline duration treatment EEC session will be summarized by visit 
and treatment for ITT population.  
All secondary efficacy endpoints will be analyzed using a similar approach as the primary efficacy 
variable for the ITT Population.  Reproxalap Ophthalmic Solution will be claimed to be better than 
Vehicle on secondary efficacy endpoints if the estimated overall corresponding changes from 
baseline score from MMRM model in the Reproxalap group is statistically lower than that of the 
Vehicle group during the chamber (approximately 10 to 210 minutes). 
 
 


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