Clinical trial NCT04971031
Conditions: Dry Eye
Sponsor: Aldeyra Therapeutics, Inc.
Start date: 2021-06-15; Completion date: 2021-09-08
Enrollment: 158 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Multi-Center Randomized, Double-Masked, Parallel Design, Vehicle-Controlled Phase 2 Clinical Trial to Assess the Efficacy and Safety of 0.25% Reproxalap Ophthalmic Solution Compared to Vehicle in Subjects with Dry Eye Disease

Detailed description:

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%) administered 7 times over two consecutive days. intervention 2: Vehicle Ophthalmic Solution administered 7 times over two consecutive days.

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol: ADX-102-DED-024  
 
 
 
 
 
 
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Clinical Trial Protocol: ADX-102-DED-024 
Protocol Title: 
A Multi-Center Randomized, Double-Masked, Parallel 
Design, Vehicle-Controlled Phase 2 Clinical Trial to 
Assess the Efficacy and Safety of 0.25% Reproxalap 
Ophthalmic Solution Compared to Vehicle in Subjects 
with Dry Eye Disease 
Protocol Number: 
ADX-102-DED-024  
Study Phase: 
2 
Investigational Product Name: 
0.25% Reproxalap Ophthalmic Solution  
 
 
Indication: 
Dry Eye Disease (DED) 
Investigator: 
Multi-Center 
Sponsor/Contract Research 
Organization: 
Aldeyra Therapeutics, Inc. 
131 Hartwell Ave. 
Lexington, MA 02421 USA 
 
 
 
 
 
 
 
Date 
Original Protocol: 
12May2021 
Amendment #1: 
12Oct2021 
Confidentiality Statement 
This protocol contains confidential, proprietary information of Ora, Inc. and Aldeyra 
Therapeutics, Inc. Further dissemination, distribution, or copying of this protocol or its contents 
is strictly prohibited. 






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• Visit 3 = Day 2 CAE® & Study Exit 
 
Subjects will be randomized 1:1 to receive either 
reproxalap or vehicle.  
Measures Taken to Reduce Bias: 
ADX-102-DED-024 is a randomized treatment 
assignment, double-masked trial. 
Study Population Characteristics: 
Number of Subjects: 
Approximately 150 subjects are expected to be 
enrolled in the trial.  
Condition/Disease: 
Dry Eye Disease (DED) 
Inclusion Criteria: 
Subjects must meet all of the following criteria: 
1. 18 years of age (either gender and any race); 
2. Ability to provide written informed consent and 
sign the Health Information Portability and 
Accountability Act (HIPAA) form; 
3. Reported history of dry eye for
 
 
4. Reported history of use or desire to use eye drops 
for dry eye symptoms 
 
5. Corneal fluorescein staining sum 
 
 
 
.  
6. Response to the CAE at Visit 1, as defined by: 
a. 
 
 
 
 
 
 
 
 
 
 
 
Exclusion Criteria: 
Subjects must not meet any of the following criteria: 
1. Clinically significant slit lamp findings 
 
 


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2. Diagnosis of an ongoing ocular infection 
 
 
3. Contact lens use 
 
 
4. Artificial tear eye drop use 
 
 
 
5. Previous laser-assisted in situ keratomileusis 
(LASIK) surgery 
; 
6. Cyclosporine 0.05% or 0.09% or lifitegrast 5.0% 
ophthalmic solution 
 
7. Systemic 
corticosteroid 
or 
other 
immunomodulator therapy 
 
 
 
  
8. Planned ocular and/or lid surgeries 
 
 
 
9. Temporary punctal plugs 
 
 
10. Use of and unwillingness to discontinue topical 
ophthalmic prescriptions 
 
 
 
 
 
 
 
 
 
11. Corrected visual acuity 
 
 
 


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12. Pregnancy, nursing, or planned pregnancy during 
the conduct of the trial; 
13. Unwillingness to submit a urine pregnancy test at 
Visit 1 and Visit 3 (or early termination visit) if of 
childbearing 
potential. 
(Non-childbearing 
potential is defined as a woman who is 
permanently 
sterilized 
[e.g., 
has 
had 
a 
hysterectomy or tubal ligation], or is post-
menopausal [without menses for 12 consecutive 
months]); 
14. If of childbearing potential (female or male), 
unwillingness to use an acceptable means of birth 
control. (Acceptable methods of contraception 
include: hormonal – oral, implantable, injectable, 
or transdermal contraceptives; mechanical – 
spermicide in conjunction with a barrier such as a 
diaphragm or condom; intrauterine device [IUD]; 
or surgical sterilization of partner.  For non-
sexually active males or females, abstinence may 
be regarded as an adequate method of birth 
control; however, if the subject becomes sexually 
active during the study, he/she must agree to use 
adequate birth control as defined above for the 
remainder of the trial.); 
15. Known allergy and/or sensitivity to the test article 
or its components; 
16. A condition that the investigator feels may put the 
subject at significant risk, may confound the study 
results, or may interfere significantly with the 
subject’s participation in the trial; 
17. Current enrollment in an investigational drug or 
device study or have used an investigational drug 
or device within 30 days of Visit 1; 
18. Use of reproxalap ophthalmic solution in the past 
year; 


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19. Current use of any medication 
 
 
 
20. Inability or unwillingness to follow instructions, 
including participation in all study assessments 
and visits. 
Study Formulations and 
Formulation Numbers: 
0.25% Reproxalap Ophthalmic Solution  
Evaluation Criteria: 
Primary Endpoint: 
 
• Conjunctival redness 
 
 in CAE 
 
• Visual analog scale eye dryness score 
 
 
 
• Schirmer’s Test change from baseline 
 
 
 
 
• Visual analog scale eye dryness score 
 
  
• Ora Calibra® Ocular Discomfort Scale
 
 
 
• Ocular Discomfort & 4-Symptom Questionnaire 
 
  
• Ora Calibra® Conjunctival Allergen Challenge 
Ocular Itching Scale 
 
 
• Conjunctival Redness 
 
 
Exploratory Endpoints 
• Change in tear RASP levels 
 
 
• Conjunctival redness, Ora Calibra® Ocular 
Discomfort Scale, and visual analog scale dryness 
 
 
Safety Endpoints: 
• Visual acuity 
• Slit-lamp evaluation 


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• Adverse event query 
• Intraocular Pressure (IOP) 
• Dilated fundoscopy 
General Statistical Methods and Types of Analyses: 
Statistical analyses will be detailed in the statistical analysis plan (SAP), which will dominate 
any statistical language herein. Any changes to protocol stated analyses will also be detailed in 
the SAP. 
Sample Size: 
 
 
 
 
 
 
 
 
 
 
Multiplicity Considerations: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0.001 


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Primary Efficacy Analyses: 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


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Safety Analyses: 
 
 
 
 
 
Summary of Known and Potential Risks and Benefits to Human Subjects: 
Refer to Investigator’s Brochure. 


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TABLE OF CONTENTS 
Clinical Trial Protocol: ADX-102-DED-024 ....................................................................1 
SYNOPSIS ..........................................................................................................................3 
TABLE OF CONTENTS ................................................................................................11 
List of Abbreviations .......................................................................................................14 
1 
INTRODUCTION...................................................................................................15 
2 
STUDY OBJECTIVES ...........................................................................................16 
3 
CLINICAL HYPOTHESES ..................................................................................16 
4 
OVERALL STUDY DESIGN ................................................................................17 
5 
STUDY POPULATION .........................................................................................18 
5.1 
Number of Subjects (approximate) .............................................................18 
5.2 
Study Population Characteristics ...............................................................18 
5.3 
Inclusion Criteria .........................................................................................18 
5.4 
Exclusion Criteria .........................................................................................19 
5.5 
Withdrawal Criteria (if applicable) ............................................................20 
6 
STUDY PARAMETERS ........................................................................................20 
6.1 
Primary Endpoint .........................................................................................20 
6.2 
Safety Endpoints ...........................................................................................21 
6.3 
Secondary Endpoints ...................................................................................21 
7 
STUDY MATERIALS ............................................................................................21 
7.1 
Study Treatment(s) .......................................................................................21 
7.1.1 
Formulations .....................................................................................21 
7.1.2 
Study Drug Packaging Configuration ...............................................21 
7.1.3 
Study Drug Storage and Accountability ...........................................22 
7.1.4 
Instructions for Dispensation, Use, and Administration ...................22 
7.2 
Other Study Supplies ...................................................................................22 
8 
STUDY METHODS AND PROCEDURES .........................................................22 
8.1 
Subject Entry Procedures ............................................................................22 
8.1.1 
Overview ...........................................................................................22 
8.1.2 
Informed Consent..............................................................................23 
8.1.3 
Washout Intervals .............................................................................23 
8.1.4 
Procedures for Final Study Entry ......................................................23 
8.1.5 
Methods for Assignment to Treatment Groups: ...............................23 
8.2 
Concurrent Therapies ..................................................................................23 
8.2.1 
Prohibited Medications/Treatments ..................................................24 
8.2.2 
Escape Medications ..........................................................................24 
8.2.3 
Special Diet or Activities ..................................................................24 
8.3 
Examination Procedures ..............................................................................24 
8.3.1 
Procedures to be Performed at the Study Visit with Regard to Study 
Objective(s) ....................................................................................................24 
8.4 
Schedule of Visits, Measurements and Dosing ..........................................27 
8.4.1 
Scheduled Visits................................................................................27 


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8.4.2 
Unscheduled Visits ...........................................................................27 
8.5 
Subject Disposition .......................................................................................28 
8.5.1 
Completed Subjects ..........................................................................28 
8.5.2 
Discontinued Subjects .......................................................................28 
8.6 
Study Termination .......................................................................................28 
8.7 
Study Duration .............................................................................................28 
8.8 
Monitoring and Quality Assurance ............................................................28 
9 
ADVERSE EVENTS ..............................................................................................29 
9.1 
Adverse Event ...............................................................................................29 
9.1.1 
Severity .............................................................................................29 
9.1.2 
Relationship to Study Procedures .....................................................29 
9.1.3 
Expectedness .....................................................................................30 
9.2 
Serious Adverse Events ................................................................................30 
9.3 
Procedures for Reporting Adverse Events .................................................31 
9.3.1 
Reporting a Suspected Unexpected Adverse Reaction .....................31 
9.3.2 
Reporting a Serious Adverse Event ..................................................32 
9.4 
Procedures for Unmasking Study Drug .....................................................32 
9.5 
Procedures for Reporting Adverse Events .................................................33 
10 
STATISTICAL HYPOTHESES AND METHODS OF ANALYSES ...............33 
10.1 Analysis Populations ....................................................................................33 
10.2 Statistical Hypotheses ...................................................................................33 
10.3 Sample Size ...................................................................................................34 
10.4 Statistical Analysis ........................................................................................34 
10.4.1 General Considerations .......................................................................34 
10.4.2 Unit of Analysis ................................................................................35 
10.4.3 Missing Data .....................................................................................35 
10.4.4 Multiplicity Considerations ..............................................................35 
10.4.5 Primary Efficacy Analysis ................................................................36 
10.4.7 Secondary Efficacy Analyses ...........................................................37 
10.4.8  Exploratory Efficacy Analyses .......................................................38 
10.4.9 Safety Variables ................................................................................38 
11 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES ................................38 
11.1 Protection of Human Subjects .....................................................................38 
11.1.1 Subject Informed Consent.................................................................38 
11.1.2 Institutional Review Board (IRB) Approval .....................................39 
11.2 Ethical Conduct of the Study ......................................................................39 
11.3 Subject Confidentiality ................................................................................39 
11.4 Documentation ..............................................................................................39 
11.4.1 Retention of Documentation .............................................................40 
11.5 Labeling, Packaging, Storage, Accountability, and Return or Disposal of Study 
Drug ...............................................................................................................40 
11.5.1 Labeling/Packaging ...........................................................................40 
11.5.2 Storage of Study Drug ......................................................................40 
11.5.3 Accountability of Study Drug ...........................................................40 


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11.5.4 Return or Disposal of Study Drug ....................................................40 
11.6 Recording of Data on Source Documents and electronic Case Report Forms 
(eCRFs) ..........................................................................................................41 
11.7 Handling of Biological Specimens ...............................................................41 
11.8 Publications ...................................................................................................41 
12 
REFERENCES ........................................................................................................41 
Appendix 1:  Schedule of Visits and Measurements ...................................................43 
Appendix 2: Examination Procedures, Tests, Equipment, and Techniques .....44 
Appendix 3:  Amendment Summary of Changes Table .............................................53 
Appendix 4:  Sponsor and Ora Approvals ..................................................................61 
Appendix 5:  Investigator’s Signature .........................................................................62 
 
 


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List of Abbreviations 
AE 
adverse event 
CAE 
Controlled Adverse Environment® 
CFR 
Code of Federal Regulations 
DED 
dry eye disease 
DES 
dry eye syndrome 
DHHS 
Department of Health and Human Services 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Information Portability and Accountability Act 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
institutional/independent review board 
LogMAR 
logarithm of the minimum angle of resolution 
Ora 
Ophthalmic Research Associates, Inc. 
OTC 
over the counter 
RASP 
reactive aldehyde species 
SAE 
serious adverse event 
µL  
microliter  
VA 
visual acuity 
VAS 
Visual analog scale 
 
 


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1 INTRODUCTION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2 STUDY OBJECTIVES 
To evaluate the efficacy of reproxalap, as assessed by conjunctival redness, Schirmer’s Test, and 
ocular dryness 
 Controlled Adverse Environment® 
(CAE) in subjects with dry eye disease. 
 
3 CLINICAL HYPOTHESES 
The clinical hypothesis is that reproxalap is more effective than vehicle in reducing the signs and 
symptoms of DED.  
 
 




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• CAE exposure 
 with Ocular Dryness 
VAS, and Ora Calibra® Ocular Discomfort Scale, 
and Conjunctival Redness Assessments 
• Tear Collection 
 
• IOP and Dilated Fundoscopy 
• Study Exit 
 
5 STUDY POPULATION 
5.1 
Number of Subjects (approximate) 
Approximately 300 subjects will be screened to enroll approximately 150 subjects 
across approximately 5 sites. 
5.2 
Study Population Characteristics 
All subjects must be at least 18 years of age, be of either sex and of any race, have a 
subject-reported history of dry eye disease, and meet all of the inclusion criteria and 
none of the exclusion criteria. 
5.3 
Inclusion Criteria 
Each subject must meet each of the following criteria: 
1. 18 years of age (either gender and any race); 
2. Ability to provide written informed consent and sign the Health Information 
Portability and Accountability Act (HIPAA) form; 
3. Reported history of dry eye 
 
4. Reported history of use or desire to use eye drops for dry eye symptoms 
 
 
5.  Corneal fluorescein staining sum 
 
 Ora Calibra Scale at Visit 1. 
6. Response to the CAE at Visit 1, as defined by: 
a.  
 
 
  
 
 
 
 


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5.4 
Exclusion Criteria 
Each subject may not meet any of the following criteria: 
1. Clinically significant slit lamp findings at Visit 1 
 
 
 
 
 
2. Diagnosis of an ongoing ocular infection 
 
 
3. Contact lens use 
 
 
4. Artificial tear eye drop use 
 
 
5. Previous laser-assisted in situ keratomileusis (LASIK) surgery 
 
 
 
6. Cyclosporine 0.05% or 0.09% or lifitegrast 5.0% ophthalmic solution use 
 
 
7. Systemic corticosteroid therapy or other immunomodulator 
 
 
  
8. Planned ocular and/or lid surgeries 
 
 
9. Temporary punctal plugs 
 
 
10. Use of and unwillingness to discontinue topical ophthalmic prescriptions
 
 
 
 
11. Corrected visual acuity 
 
 
 
12. Pregnancy, nursing, or planned pregnancy during the conduct of the trial; 
13. Unwillingness to submit a urine pregnancy test at Visit 1 and Visit 3 (or early 
termination visit) if of childbearing potential.  (Nonchildbearing potential is 


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defined as a woman who is permanently sterilized [e.g., has had a hysterectomy or 
tubal ligation], or is post-menopausal [without menses for 12 consecutive months]); 
14. If of childbearing potential (female or male), unwillingness to use an acceptable 
means of birth control. (Acceptable methods of contraception include: hormonal – 
oral, implantable, injectable, or transdermal contraceptives; mechanical – 
spermicide in conjunction with a barrier such as a diaphragm or condom; 
intrauterine device [IUD]; or surgical sterilization of partner.  For non-sexually 
active males or females, abstinence may be regarded as an adequate method of birth 
control; however, if the subject becomes sexually active during the study, he/she 
must agree to use adequate birth control as defined above for the remainder of the 
trial.); 
15. Known allergy and/or sensitivity to the test article or its components; 
16. A condition that the investigator feels may put the subject at significant risk, may 
confound the study results, or may interfere significantly with the subject’s 
participation in the trial; 
17. Current enrollment in an investigational drug or device study or have used an 
investigational drug or device within 30 days of Visit 1; 
18. Use of reproxalap ophthalmic solution in the past year; 
19. Current use of any medication 
 
 
20. Inability or unwillingness to follow instructions, including participation in all study 
assessments and visits. 
5.5 
Withdrawal Criteria (if applicable) 
Subjects may voluntarily withdraw from the trial at any time. Additionally, subjects 
may be discontinued for safety reasons as determined by the investigator and/or 
Medical Monitor. 
6 STUDY PARAMETERS 
6.1 
Primary Endpoint  
• Conjunctival redness 
 
 
• Visual analog scale eye dryness score 
 
  
• Schirmer’s Test 
 
 


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6.2 
Safety Endpoints 
• Visual acuity 
• Slit-lamp evaluation 
• Adverse event query 
• Intraocular Pressure (IOP) 
• Dilated fundoscopy 
 
6.3 
Secondary Endpoints 
• Visual analog scale eye dryness score 
 
 
• Ora Calibra® Ocular Discomfort Scale 
 
 
• Ocular Discomfort & 4-Symptom Questionnaire 
 
 
• Ora Calibra® Conjunctival Allergen Challenge Ocular Itching Scale 
 
 
• Conjunctival redness 
 
6.4 
Exploratory Endpoints 
• Change in tear RASP levels 
 
 
• Conjunctival redness, Ora Calibra® Ocular Discomfort Scale, and visual analog 
scale dryness score 
 
7 STUDY MATERIALS 
7.1 
Study Treatment(s) 
7.1.1 Formulations 
Randomized Study Treatments 
• 0.25% Reproxalap Ophthalmic Solution  
• Vehicle 
7.1.2 Study Drug Packaging Configuration 
For Visit 1 only, vehicle vials are packaged in 5-count pouches, which will then be 
packaged into kits. These kits will be made of 2 of the 5-count pouches. 
Study drug and vehicle vials are packaged in 5-count pouches, which will then be 
packaged into kits that will supply for the study duration.  These kits will be made 
of 2 of the 5-count pouches. 


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7.1.3 Study Drug Storage and Accountability 
The study drug must be stored in a secure area accessible only to the investigator 
and his/her designees. The study drug will be administered only to subjects 
entered into the clinical study, in accordance with the conditions specified in this 
protocol. 
  
 
 
The study drug is to only be prescribed by the principal investigator or his/her 
named sub investigator(s), and is to only be used in accordance with this protocol. 
The study drug must only be distributed to subjects properly qualified under this 
protocol to receive study drug. The investigator must keep an accurate accounting 
of the study drug by maintaining a detailed inventory. This includes the amount of 
study drug received by the site, amount dispensed to subjects, amount returned to 
the site by the subjects, and the amount returned to the Sponsor upon the 
completion of the study.   
7.1.4 Instructions for Dispensation, Use, and Administration 
• At Visit 1, qualified subjects will be assigned a vehicle kit. Subjects will use 
two vials from the kit for Visit 1 in-office doses. After use, vials will be placed 
into a zip locked bag labeled with subject’s initials and screening number for 
accountability. 
• At Visit 2, qualified subjects will be randomized and will be assigned a single 
kit of 2 pouch supply of Reproxalap Ophthalmic Solution 0.25% or Vehicle. 
Subjects will be dosed in office four times (QID) by trained site staff.  
• At Visit 3, subjects will be dosed three times in-office from the same kit by 
trained site staff.  
• Subjects will be instructed to close their eyes for two minutes after instillation. 
7.2 
Other Study Supplies 
Tear collection supplies, Schirmer’s Test strips, Scale to weigh Schirmer’s strips, 2% 
preservative-free sodium Fluorescein Solution, Fluorescein Strips, ETDRS Series 
2000 Chart 1 & Chart 2, eye occluder, alcohol swabs. 
8 STUDY METHODS AND PROCEDURES 
8.1 
Subject Entry Procedures 
8.1.1 Overview 
Subjects as defined by the criteria in section 5.2, 5.3, and 5.4 will be considered 
for entry into the trial. 


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8.1.2 Informed Consent 
Prior to each subject’s participation in the clinical trial (i.e., changes in a 
subject’s medical treatment and/or study related procedures), the clinical trial 
will be discussed with the subjects, and subjects wishing to participate must 
give written informed consent using an informed consent form. The informed 
consent form must be the most recent version that has received 
approval/favorable review by a properly constituted Independent Review 
Board. 
8.1.3 Washout Intervals 
Prohibited medications, treatments, and activities are outlined in the exclusion 
criteria. 
8.1.4 Procedures for Final Study Entry 
Subjects must satisfy all of the inclusion criteria and none of the exclusion 
criteria in order to be entered into the study. 
8.1.5 Methods for Assignment to Treatment Groups: 
At Visit 1 each subject who signs the informed consent will be assigned a 
screening number. All screening numbers will be assigned in strict numerical 
sequence at each site and no numbers will be skipped or omitted.   
At Visit 2, a patient who meets all the eligibility criteria will be randomized to 
receive treatment reproxalap or vehicle in a 1:1 ratio. Patients will be assigned a 
randomization number and kit number via IWRS. 
The site staff will dispense to the patient the study kit labeled with the 
corresponding kit number. Both the randomization number and the dispensed 
study drug kit number will be recorded on the patient’s source document and 
eCRF.   
 
8.2 
Concurrent Therapies 
The use of any applicable concurrent medications, prescription or OTC medications is 
to be recorded on the subject’s source document along with the reason the medication 
was taken. 
Concurrent enrollment in an investigational drug or medical device study is not 
permitted. 


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8.2.1 Prohibited Medications/Treatments 
Prohibited medications, treatments, and activities are outlined in the exclusion 
criteria. 
8.2.2 Escape Medications 
Not applicable. 
8.2.3 Special Diet or Activities 
Not applicable. 
8.3 
Examination Procedures 
8.3.1 Procedures to be Performed at the Study Visit with Regard to Study 
Objective(s) 
Visit 1 (Day -14 -16/+2, Screening) 
• Informed Consent and HIPAA 
• Demographics 
 
• Medical/Medication & Ocular History 
• Urine Pregnancy Test (as needed) 
• Symptom Questionnaires: 
o Ocular Discomfort & 4-Symptom Questionnaire 
o Ora Calibra® Ocular Discomfort Scale 
o Ocular Dryness Visual Analog Scale 
o Ora Calibra® Conjunctival Allergen Challenge Ocular Itching 
Scale 
• Visual Acuity (ETDRS) 
• Slit Lamp Biomicroscopy with Conjunctival Redness assessment 
• Fluorescein Staining using the Ora Calibra® Corneal and Conjunctival 
Staining Scale 
• Inclusion/Exclusion Criteria Review 
• In-Office Vehicle Instillation by trained site staff 
 
 
• CAE Exposure 
 
 
 
 
  
 
 
 
 
 
 
 
 
• Slit Lamp Biomicroscopy with Conjunctival Redness assessment 


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• Schirmer’s Test  
• Intraocular Pressure 
• Dilated Exam 
• Schedule for Visit 2 
Visit 2 (Day 1, Baseline and In-Office Dosing) 
• Medical/Medication Update 
• Adverse Event Query 
• Visual Acuity (ETDRS) 
• Slit Lamp Biomicroscopy 
• Symptom Questionnaires 
o Ocular Discomfort & 4-Symptom Questionnaire 
o Ora Calibra® Ocular Discomfort Scale 
o Ocular Dryness Visual Analog Scale  
o Ora Calibra® Conjunctival Allergen Challenge Ocular Itching 
Scale 
• Conjunctival Redness Photography 
• Inclusion/Exclusion Criteria Review 
• Randomization/Enrollment 
• Pre-dose #1 Schirmer’s Test 
 
 
 
 
• In-Office Dose #1 
• Post-dose #1 Schirmer’s Test 
 
 
 
 
 
 
 Pre-dose #2 Tear Collection 
 
• In-Office Dose # 2 
• Post-dose #2 Tear Collection 
  
 
 
 
• Pre-dose #3 Tear Collection 
 
• In-Office Dose #3 
• Post-dose #3 Tear Collection 
 
 
• In-Office Dose #4 
• Conjunctival Redness Photography 
 


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• Symptom Questionnaires 
 
o Ocular Discomfort & 4-Symptom Questionnaire  
o Ocular Discomfort  
o Ocular Dryness Visual Analog Scale  
o Ora Calibra® Conjunctival Allergen Challenge Ocular Itching 
Scale  
Visit 3 (Day 2, CAE®) 
• Medical/Medication Update 
• Adverse Event Query 
• Urine Pregnancy Test (as needed) 
• Visual Acuity (ETDRS) 
• Slit Lamp Biomicroscopy 
• Conjunctival Redness Photography 
• Symptom Questionnaires: 
o Ocular Discomfort & 4-Symptom Questionnaire 
o Ora Calibra® Ocular Discomfort Scale 
o Ocular Dryness Visual Analog Scale 
o Ora Calibra® Conjunctival Allergen Challenge Ocular Itching 
Scale 
• Pre-dose #1 Tear Collection 
 
• In-Office Dose #1 
 
• CAE Exposure 
 with: 
o Ocular Dryness Visual Analog Scale
 
  
o Ora Calibra® Ocular Discomfort Scale 
 
 
o Conjunctival Redness 
 
 
  
• In-Office Dose #2 
 
  
• Post-CAE exit Tear Collection
 
• In-Office Dose #3
 
• Symptom Questionnaires started
 
 
o Ocular Discomfort & 4-Symptom Questionnaire  
o Ocular Discomfort  
o Ocular Dryness Visual Analog Scale  
o Ora Calibra® Conjunctival Allergen Challenge Ocular Itching 
Scale  
• Post-Dose #3 Tear Collection 
 
• Slit Lamp Biomicroscopy 


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• Intraocular Pressure 
• Dilated Exam 
• Study Exit 
 
Early Termination/Discontinuation  
If a subject is discontinued from the study prior to Visit 3, then all safety evaluations 
that are to be performed at Visit 3 should be performed on the day of 
discontinuation (early termination) or at the discretion of the investigator.  
Adverse Events (both elicited and observed) and serious adverse events (SAEs) will 
be monitored throughout the trial.  The investigator will promptly review all 
adverse events (both elicited and observed) for accuracy and completeness.  All 
adverse events will be documented on the appropriate source document and case 
report form. 
If a female reports a pregnancy or has a positive pregnancy test during the study 
the investigator will notify Ora immediately.  The investigator shall request from 
the subject and/or the subject’s physician copies of all related medical reports 
during the pregnancy and shall document the outcome of the pregnancy.  The 
investigator will retain these reports together with the subject’s source documents 
and will provide a copy of all documentation to Ora. The pregnant subjects will be 
discontinued from the trial as per the exclusion criteria. 
8.4 
Schedule of Visits, Measurements and Dosing 
8.4.1 Scheduled Visits 
Refer to Appendix 1 for a schedule of visits and measurements. 
8.4.2 Unscheduled Visits 
These visits may be performed in order to ensure subject safety. All procedures 
performed at an unscheduled visit will be recorded in the source documents and 
on the Unscheduled Visit eCRF pages. Any procedure indicated in the eCRF 
that is not performed should be indicated as “Not done.” 
Evaluations that may be conducted at an Unscheduled Visit include: 
• Slit-lamp Biomicroscopy; 
• Visual Acuity; 
• Intraocular Pressure; 
• Urine Pregnancy Test; 
• Dilated Fundoscopy; 


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• Assessment of Adverse Events; 
• Assessment of concurrent medications and/or treatments; and 
• Any other assessments needed in the judgment of the investigator. 
8.5 
Subject Disposition 
8.5.1 Completed Subjects 
A completed subject is one who has not been discontinued from the study and 
has completed all applicable assessments. 
8.5.2 Discontinued Subjects 
Subjects may be discontinued prior to their completion of the study due to: 
• adverse events 
• protocol violations 
• administrative reasons (e.g., inability to continue) 
• subject choice 
• Sponsor termination of study 
• other 
Note: In addition, any subject may be discontinued for any sound medical 
reason. 
Notification of a subject discontinuation and the reason for discontinuation will 
be made to Ora and will be clearly documented on the source document. 
Discontinuations due to COVID-19 will be indicated as COVID-19 related. 
8.6 
Study Termination 
The clinical trial may be stopped at any time by the investigator, or Ora with appropriate 
notification. 
8.7 
Study Duration 
An individual subject’s participation is estimated to be approximately 2 – 4 weeks.  
8.8 
Monitoring and Quality Assurance 
During the course of the study a monitor, or designee, will make routine site visits to 
review protocol compliance, assess study drug accountability and storage conditions, 
subject safety, and ensure the study is being conducted according to the pertinent 
regulatory requirements.  The review of the subjects’ medical records will be 
performed in a manner that adequately maintains subject confidentiality.  Further 
details of the study monitoring will be outlined in a monitoring plan. 


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Regulatory authorities of domestic and foreign agencies, Ora quality assurance and or 
its designees may carry out on-site inspections and audits which may include source 
data checks. Therefore, direct access to the original source data will be required for 
inspections and audits.  All inspections and audits will be carried out giving 
consideration to data protection as well as subject confidentiality to the extent that 
local, state, and federal laws apply. 
9 ADVERSE EVENTS 
9.1 
Adverse Event 
For the purposes of this trial, an adverse event is defined as any untoward medical event 
occurring after the subject’s signing of the informed consent until they are exited from 
the trial. An adverse event can therefore be any unfavorable and unintended sign, 
symptom, or disease occurring after the subject started the clinical trial, without any 
judgment about causality. Any pre-existing medical condition that worsens during the 
trial will also be considered a new adverse event. Documentation regarding the adverse 
event should be made as to the nature, date of onset, end date, severity, relationship to 
study procedure, expectedness, action(s) taken, seriousness, and outcome of any sign 
or symptom observed by the investigator or reported by the patient upon indirect 
questioning.  
9.1.1 Severity 
Severity of an adverse event is defined as a qualitative assessment of the degree 
of intensity of an adverse event as determined by the investigator or reported to 
him/her by the patient/subject. The assessment of severity is made irrespective 
of relationship to study procedures or seriousness of the event and should be 
evaluated according to the following scale: 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.1.2 Relationship to Study Procedures 
The relationship of each AE to the study procedures should be determined by 
the investigator using these explanations. Decisive factors for the assessment of 
causal relationship of an AE to the study procedures include, but may not be 


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limited to, temporal relationship between the AE and the procedure, known side 
effects of the procedure medical history, and/or concomitant medication: 
• Definite: When there are good reason and sufficient documentation to 
demonstrate a direct causal relationship between study procedure and 
AE; 
• Probable: When there are good reasons and sufficient documentation to 
assume a causal relationship in the sense of plausible, conceivable, 
likely but not necessarily highly probable. 
• Possible: When there is sufficient information to accept the possibility 
of a causal relationship in the sense of not impossible and not unlikely, 
although the connection is uncertain or doubtful, for example; due to 
missing data or insufficient evidence. 
• None: When there is sufficient information to accept a lack of a causal 
relationship, in the sense of impossible and improbable. 
• Unclassified: When the causal relationship is not assessable for 
whatever reason due to insufficient evidence, conflicting data or poor 
documentation. 
9.1.3 Expectedness 
The expectedness of an adverse event should be determined based upon existing 
safety information about the study procedures. Therefore, the following 
definition will be used: 
• Unexpected: An adverse event that is not listed in the safety information 
available for the study procedure at the specificity or severity that has 
been observed. 
• Expected: An adverse event that is listed in the safety information 
available for the study procedure at the specificity and severity that has 
been observed. 
• Not Applicable: Any adverse event that is unrelated to the study 
procedure. 
9.2 
Serious Adverse Events 
An adverse event is considered serious if, in the view of either the investigator or 
Sponsor, it results in any of the following outcomes: 
• Death; 
• A life-threatening adverse event; 


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o Note: An adverse event is considered “life-threatening” if, in the view 
of either the investigator or sponsor, its occurrence places the patient or 
subject at immediate risk of death. It does not include an adverse event 
that, had it occurred in a more severe form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization; 
o 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; observation/short stay units; rehabilitation facilities; 
hospice facilities; nursing homes; or clinical research/phase 1 units. 
o 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; 
o Note: A serious adverse event 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. 
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
9.3 
Procedures for Reporting Adverse Events 
All adverse events and their outcomes must be reported to Ora and the IRB as required 
by the IRB, federal, state, or local regulations and governing health authorities and 
recorded on the appropriate source document. 
9.3.1 Reporting a Suspected Unexpected Adverse Reaction 
All adverse events that are related (definite, probable, possible) and 
‘unexpected’ are to be reported to Ora and the IRB as required by the IRB, 
federal, state, or local regulations and governing health authorities. 


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9.3.2 Reporting a Serious Adverse Event 
To ensure subject safety, all serious adverse events, regardless of relationship 
to the investigational product, must be immediately reported. All information 
relevant to the serious adverse event must be recorded on the appropriate source 
documents. The investigator is obligated to pursue and obtain information 
requested by Ora in addition to that information reported on the source 
document. All subjects experiencing a serious adverse event must be followed 
up and the outcome reported. 
In the event of a serious adverse event, the investigator must notify Ora 
immediately; obtain and maintain in his/her files all pertinent medical records, 
information, and medical judgments from colleagues who assisted in the 
treatment and follow-up of the subject; provide Ora with a complete case 
history and inform the IRB of the adverse event within their guidelines for 
reporting serious adverse events. 
Contact information for reporting serious adverse events (SAEs): 
 
 
 
 
 
 
 
 
 
 
9.4 
Procedures for Unmasking Study Drug 
All subjects, investigators, and study personnel involved with the conduct of the study 
will be masked with regard to treatment assignments. When medically necessary, the 
investigator may need to determine what treatment arm has been assigned to a subject.  
When possible (i.e., in non-emergent situations), Ora and/or the study sponsor should be 
notified, when possible, before unmasking study drug as described in the following 
paragraph. 
If an investigator identifies a medical need for unmasking the treatment assignment of a 
subject, he/she should contact Ora and/or the medical monitor prior to unmasking the identity 
of the IP, if possible. Ora will ask the site to complete and send them the Unmasking Request 
Form. Ora will notify Aldeyra and jointly will determine if the unmasking request should be 
granted. They may consult the medical monitor as needed. The result of the request will be 
documented on the Unmasking Request Form. If approval is granted to unmask a subject, 
written permission via the Unmasking Request Form will be provided to the investigator. The 
investigator will unmask the subject via IWRS. The investigator will complete the 
Unmasking Memo form and include it in the subject’s study file and provide a copy for the 


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Trial Master File (TMF). For each unmasked request, the reason, date, signature, and name 
of the person who unmasked the subject, must be noted in the subject’s study file. 
 
9.5 
Procedures for Reporting Adverse Events 
Adverse events that are ongoing at the end of the study visit will be followed.  Phone calls 
will be placed with any subject who experiences an adverse event until the issue is resolved 
or the condition is considered ongoing and stable. 
10 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
10.1 Analysis Populations 
 The following analysis populations will be considered: 
• 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
10.2 Statistical Hypotheses 
The following hypothesis will be tested comparing reproxalap to vehicle.  The null hypotheses 
must be rejected for the dosing regimen to claim efficacy.  
  
 
   
  
 
 
  
 
 
  
 
 
 




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10.4.2 Unit of Analysis 
  
 
 
 
 
 
10.4.3 Missing Data 
 
 
 
 
 Multiplicity Considerations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


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10.4.5 Primary Efficacy Analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  


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• 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
. Further details will 
be specified in the SAP. 
10.4.7 Secondary Efficacy Analyses 
 
 
 
 
 
 
 
 
 
 
 
  


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10.4.8  Exploratory Efficacy Analyses 
 
 
  
 
 
 
Further details of the exploratory 
analysis plan will be described in SAP. 
10.4.9 Safety Variables 
Adverse events will be coded using the MedDRA dictionary. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
11 COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES 
The ADX-102-DED-024 clinical trial will be conducted in compliance with the protocol, 
current Good Clinical Practices (GCPs), including the International Council for 
Harmonization (ICH) Guidelines, and in general, consistent with the Declaration of Helsinki.  
In addition, all applicable local, state, and federal requirements in the countries involved will 
be adhered to. 
11.1 Protection of Human Subjects 
11.1.1 Subject Informed Consent 
Informed consent/assent must take place before any study specific procedures 
are initiated. Signed and dated written informed consent must be obtained from 
each subject and/or from the legal guardian prior to enrollment into the study. 


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All informed consent/assent forms must be approved for use by Ora and receive 
approval/favorable opinion from an IRB prior to their use. If the consent form 
requires revision (e.g., due to a protocol amendment or significant new safety 
information), it is the investigator’s responsibility to ensure that the amended 
informed consent is reviewed and approved by sponsor prior to submission to 
the governing IRB and that it is read, signed and dated by all subjects 
subsequently enrolled in the study as well as those currently enrolled in the 
study. If informed consent is taken under special circumstances (oral informed 
consent), then the procedures to be followed must be determined by Ora and 
provided in writing by Ora prior to the consent process. 
11.1.2 Institutional Review Board (IRB) Approval 
The ADX-102-DED-024 clinical trial is to be conducted in accordance with 
Institutional Review Board regulations (U.S. 21 CFR Part 56.103). The investigator 
must obtain appropriate IRB approval before initiating the trial and re-approval at least 
annually. 
Only an IRB approved version of the informed consent form will be used. 
11.2 Ethical Conduct of the Study 
The ADX-102-DED-024 clinical trial will be conducted in accordance with the ethical 
principles that originated with the Declaration of Helsinki. 
11.3 Subject Confidentiality 
All personal study subject data collected and processed for the purposes of this trial 
should be maintained by the investigator and his/her staff with adequate precautions as 
to ensure that the confidentiality of the data in accordance with local, state, and federal 
laws and regulations. 
Monitors, auditors and other authorized representatives of Ora, the IRB approving this 
trial, the FDA, the DHHS, other domestic government agencies, and other foreign 
regulatory agencies will be granted direct access to the study subject’s original medical 
and study records for verification of the data and clinical trial procedures. Access to 
this information will be permitted to the aforementioned individuals to the extent 
permitted by law. 
11.4 Documentation 
Source documents may include a subject’s medical records, hospital charts, clinic 
charts, the investigator’s study subject files, as well as the results of diagnostic tests 
such as X-rays, laboratory tests, and EKGs. The investigator’s copy of the source 
documents serves as the investigator’s record of a subject’s study-related data. 
 


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11.4.1 Retention of Documentation 
All trial related correspondence, patient records, consent forms, and copies of source 
documents should be maintained on file for at least two years. These documents will 
be retained for a longer period if required by the applicable regulatory requirements or 
by an agreement with the Sponsor. It is the responsibility of the Sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained. 
If the responsible investigator retires, relocates, or for other reasons withdraws from 
the responsibility of keeping study records, custody must be transferred to a person 
who will accept the responsibility. Ora must be notified in writing of the name and 
address of the new custodian. 
11.5 Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Study Drug 
11.5.1 Labeling/Packaging 
Investigational drug will be packaged and labeled into clinical kits. 
 
 
 
 
11.5.2 Storage of Study Drug 
The study drug must be stored in a secure area accessible only to the investigator 
and his/her designees. The study drug will be administered only to subjects 
entered into the clinical study, in accordance with the conditions specified in this 
protocol. 
  
 
 
11.5.3 Accountability of Study Drug 
The study drug is to only be prescribed by the principal investigator or his/her 
named sub investigator(s), and is to only be used in accordance with this 
protocol.  The study drug must only be distributed to subjects properly qualified 
under this protocol to receive study drug. The investigator must keep an accurate 
accounting of the study drug by maintaining a detailed inventory.  This includes 
the amount of study drug received by the site, amount dispensed to subjects, 
amount returned to the site by the subjects, and the amount returned to the 
Sponsor upon the completion of the study.  
11.5.4 Return or Disposal of Study Drug 
All study drug will be returned to the sponsor or their designee or destroyed on 
behalf of the Sponsor following local regulations. 


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11.6 Recording of Data on Source Documents and electronic Case Report Forms 
(eCRFs) 
The investigator is responsible for ensuring that study data is completely and accurately 
recorded on each subject’s eCRF and all study-related material.  All study data should 
also be attributable, legible, contemporaneous, and original. Recorded datum should 
only be corrected in a manner that does not obliterate, destroy, or render illegible the 
previous entry (e.g., by drawing a single line through the incorrect entry and writing 
the revision next to the corrected data). An individual who has corrected a data entry 
should make clear who made the correction and when, by adding to the correction 
his/her initials as well as the date of the correction. 
11.7 Handling of Biological Specimens 
The ADX-102-DED-024 clinical trial entails the collection of certain biospecimens 
from you, you should be aware that even if your personal identifiers are removed from 
the identifiable private information surrounding your biospecimens or removed from 
the biospecimens themselves, the information or biospecimens will not be used for 
future research in other studies or distributed to another investigator for future research 
studies without receiving additional informed consent from you for such activities. 
11.8 Publications 
Authorship and manuscript composition will reflect cooperation among all parties 
involved in the study. Authorship will be established before writing the manuscript. 
Ora will have the final decision regarding the manuscript and publication. 
12 REFERENCES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 1:  Schedule of Visits and Measurements 


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Appendix 2: Examination Procedures, Tests, Equipment, and Techniques 


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Appendix 3:  Amendment Summary of Changes Table  


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Appendix 5:  Investigator’s Signature 
 
Protocol Title: 
A Multi-Center Randomized, Double-Masked, Parallel Design, 
Vehicle-Controlled Phase 2 Clinical Trial to Assess the Efficacy and 
Safety of 0.25% Reproxalap Ophthalmic Solution Compared to 
Vehicle in Subjects with Dry Eye Disease 
Protocol Number: 
ADX-102-DED-024 
Protocol Date: 
12Oct2021 
I agree to implement and conduct the study diligently and in strict compliance with the protocol, 
good clinical practices, and all applicable laws and regulations. I agree to maintain all information 
supplied by Ora in confidence and, when this information is submitted to an Institutional Review 
Board (IRB) or another group, it will be submitted with a designation that the material is 
confidential. 
I have read this protocol in its entirety, including the above statement, and I agree to all aspects. 



SAP_001.pdf: 
 
STATISTICAL ANALYSIS PLAN  
A Multi-Center Randomized, Double-Masked, Parallel Design, Vehicle-
Controlled Phase 2 Clinical Trial to Assess the Efficacy and Safety of 
0.25% Reproxalap Ophthalmic Solution Compared to Vehicle in 
Subjects with Dry Eye Disease 
 
 
 
Sponsor:   
 
Aldeyra Therapeutics, Inc. 
 
 
 
 
 
 
Protocol Number: 
ADX-102-DED-024 
 
 
Author:   
 
 
 
 
Date:    
 
18OCT2021 
Version:  
 
1.0 
 
SIGN


 
 
 
Page 2 of 40 
 
A Multi-Center Randomized, Double-Masked, Parallel Design, Vehicle-Controlled Phase 2 Clinical 
Trial to Assess the Efficacy and Safety of 0.25% -Reproxalap Ophthalmic Solution Compared to 
Vehicle in Subjects with Dry Eye Disease 
Protocol Number: 
ADX-102-DED-024 
 
SAP Version:   
1.0 
SAP Date:   
 
18OCT2021 
 
Statistical Analysis Plan Approval 
 
 
 
 
 
 
Prepared by: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reviewed by:  
 
 
 
 
          
_____________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
19-Oct-2021 | 20:22 MST
20-Oct-2021 | 10:14 MST




Protocol ADX-102-DED-024 SAP, Version 1.0 
18OCT2021 
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Page 3 of 40 
 
 
 
 
 
 
Approved by
 
 
 
 
 
 
 
 
 
 
 
Approved by
 
 
 
 


Protocol ADX-102-DED-024 SAP, Version 1.0 
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Table of Contents 
1. 
Introduction .............................................................................................................................. 9 
2. 
Study Objectives ...................................................................................................................... 9 
3. 
Study Endpoints ....................................................................................................................... 9 
3.1 Primary Endpoint ...................................................................................................................... 9 
3.2 Secondary Endpoints ............................................................................................................... 9 
3.3 Exploratory Endpoints ............................................................................................................ 10 
3.4 Safety Variables ..................................................................................................................... 10 
3.5 Statistical Hypotheses ............................................................................................................ 10 
3.6 Estimands ............................................................................................................................... 10 
4. 
Study Design and Procedures ............................................................................................... 11 
4.1 General Study Design ............................................................................................................ 11 
4.2 Schedule of Visits and Assessments ..................................................................................... 13 
5. 
Study Treatments ................................................................................................................... 14 
5.1 Method of Assigning Subjects to Treatment Groups ............................................................. 14 
5.2 Masking and Unmasking ........................................................................................................ 14 
6. 
Sample Size and Power Considerations ................................................................................ 14 
7. 
Data Preparation .................................................................................................................... 15 
7.1 Input Data ............................................................................................................................... 15 
7.2 Output Data ............................................................................................................................ 15 
8. 
Analysis Populations .............................................................................................................. 16 
8.1 Intent-to-Treat......................................................................................................................... 16 
8.2 Per Protocol ............................................................................................................................ 16 
8.3 Safety ..................................................................................................................................... 16 
9. 
General Statistical Considerations ......................................................................................... 16 
9.1 Unit of Analysis ...................................................................................................................... 16 
9.2 Missing or Inconclusive Data Handling .................................................................................. 16 
9.3 Definition of Baseline ............................................................................................................. 17 
9.4 Data Analysis Conventions .................................................................................................... 17 
9.5 Adjustments for Multiplicity ..................................................................................................... 18 
10. 
Disposition of Subjects ........................................................................................................... 19 
11. 
Demographic, Previous Participation in Reproxalap Trials, and Pretreatment Variables ..... 20 
11.1 Demographic Variables .......................................................................................................... 20 
11.2 Previous Participation in Reproxalap Trials ........................................................................... 20 
11.3 Pretreatment Variables .......................................................................................................... 20 
12. 
Medical History and Concomitant Medications ...................................................................... 21 
12.1 Medical History ....................................................................................................................... 21 


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12.2 Concomitant Medications and Procedures ............................................................................ 21 
13. 
Dosing Compliance and Treatment Exposure ....................................................................... 21 
13.1 Dosing Compliance ................................................................................................................ 21 
13.2 Treatment Exposure ............................................................................................................... 22 
14. 
Efficacy Analyses ................................................................................................................... 22 
14.1 Primary Analysis .................................................................................................................... 22 
14.1.1 
Overall Mean Change from Baseline of Conjunctival Redness 
 
 22 
14.1.1.1 
Mixed Model Repeated Measures using Scores from Each Eye ....................... 23 
14.1.1.2 
Mixed Model Repeated Measures using Average Scores from Each Eye ........ 24 
14.1.1.3 
Additional Sensitivity Analyses ........................................................................... 24 
14.1.2 
Overall Mean Change from Baseline of Eye Dryness Score 
 
14.1.2.1 
Additional Sensitivity Analyses ........................................................................... 25 
14.1.3 
Mean Change from Baseline of Unanesthetized Schirmer’s Test 
 
#1 25 
14.1.3.1 
Mixed Model Repeated Measures Using Scores From Each Eye ..................... 25 
14.1.3.2 
Additional Sensitivity Analyses ........................................................................... 26 
14.2 Secondary Analyses .............................................................................................................. 26 
14.2.1 
Conjunctival Redness (Ora Calibra® Scale) 
 
 
 
14.2.2 
Eye Dryness Score 
 
 
 
14.2.3 
Ocular Discomfort Scale (Ora Calibra® Scale) ........................................................... 27 
14.2.3.1 
Ocular Discomfort Scale (Ora Calibra® Scale)  
 
 
 
14.2.3.2 
Overall Mean Change From Baseline of Ocular Discomfort Scale (Ora Calibra® Scale)  
 
 27 
14.2.4 
Ocular Discomfort & 4-Symptom Questionnaire (Ora Calibra® Scale) ...................... 28 
14.2.4.1 
Ocular Discomfort & 4-Symptom Questionnaire (Ora Calibra® Scale) 
 
14.2.4.2 
Ocular Discomfort & 4-Symptom Questionnaire (Ora Calibra® Scale) 
 
 
 
14.2.5 
Conjunctival Allergen Challenge Ocular Itching Scale (Ora Calibra® Scale) ............. 28 
14.2.5.1 
Conjunctival Allergen Challenge Ocular Itching Scale (Ora Calibra® Scale) 
  
14.2.5.2 
Conjunctival Allergen Challenge Ocular Itching Scale (Ora Calibra® Scale)  
 
 
 
 
14.3 Exploratory Analyses ............................................................................................................. 29 
 
 
 
 
 
 
 
 
 
 
30 
15. 
Summary of Efficacy Analyses .............................................................................................. 30 
16. 
Safety Analyses ..................................................................................................................... 30 


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16.1 Adverse Events ...................................................................................................................... 30 
16.1.1 
Severity ...................................................................................................................... 31 
16.1.2 
Relationship to Study Procedures .............................................................................. 32 
16.1.3 
Expectedness ............................................................................................................. 32 
16.1.4 
Serious Adverse Events ............................................................................................. 33 
16.2 Visual Acuity (Early Treatment Diabetic Retinopathy Study) ................................................. 33 
16.3 Slit-Lamp Biomicroscopy ........................................................................................................ 34 
16.4 Dilated Fundoscopy Examination........................................................................................... 34 
16.5 Intraocular Pressure (IOP) ..................................................................................................... 34 
17. 
Changes from Protocol-Stated Analyses ............................................................................... 34 
18. 
References ............................................................................................................................. 34 
19. 
Revision History ..................................................................................................................... 34 
20. 
Tables ..................................................................................................................................... 34 
21. 
Listings ................................................................................................................................... 38 
 
 
 


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List of Abbreviations 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical 
CAC 
Conjunctival Allergen Challenge 
CAE® 
Controlled Adverse Environment® 
CI 
Confidence Interval 
CS 
Clinically Significant 
DED 
Dry Eye Disease 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
ICH 
International Conference on Harmonisation 
IOP 
Intraocular Pressure 
ITT 
Intent-to-Treat 
IWRS 
Interactive Web Response System 
logMAR 
Logarithm of the Minimum Angle of Resolution 
LS 
Least Squares 
MAR 
Missing at Random 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model Repeated Measures 
MNAR 
Missing Not at Random 
NCS 
Not Clinically Significant 
OD 
Oculus dexter (Right Eye) 
OS 
Oculus sinister (Left Eye) 
PDF 
Portable Document Format 
PMM 
Pattern Mixture Model 
PP 
Per Protocol 
PT 
Preferred Term 
RASP 
Reactive Aldehyde Species 
RDC 
Remote Data Capture 
RTF 
Rich Text Format 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDC 
Statistics & Data Corporation 
SDTM 
Study Data Tabulation Model 
SE 
Standard Error 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TMF 
Trial Master File 
VAS 
Visual Analog Scale 


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WHODrug 
World Health Organization Drug Dictionary 
 
 


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1. Introduction 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and reporting for 
protocol ADX-102-DED-024, version 2.0, dated 12OCT2021. 
This SAP is being written with due consideration of the recommendations outlined in the most recent 
International Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials, E9(R1) Statistical Principles for Clinical Trials: Addendum: Estimands and 
Sensitivity Analysis in Clinical Trials and the most recent ICH E3 Guideline entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports.  
This SAP describes the data that will be analyzed and the subject characteristics, efficacy, and safety 
assessments that will be evaluated. This SAP provides details of the specific statistical methods that will 
be used. The statistical analysis methods presented in this document will supersede the statistical analysis 
methods described in the clinical protocol. If additional analyses are required to supplement the planned 
analyses described in this SAP, they may be completed and will be identified in the clinical study report. 
2. Study Objectives 
To evaluate the efficacy of reproxalap, as assessed by conjunctival redness, tear RASP levels, Schirmer’s 
Test, and symptoms after dosing prior to and during exposure to the Controlled Adverse Environment® 
(CAE) in subjects with dry eye disease. 
3. Study Endpoints 
3.1 
Primary Endpoint 
The primary efficacy endpoint is comprised of the following: 
• 
Conjunctival redness 
 
• 
Visual analog scale (VAS) 
 
• 
Schirmer’s test 
 
3.2 
Secondary Endpoints 
The secondary efficacy endpoints are the following: 
• Visual analog scale (VAS) eye dryness score 
  
• Ora Calibra® Ocular Discomfort Scale 
 
 
• Ocular Discomfort & 4-Symptom Questionnaire 
  
• Ora Calibra® Conjunctival Allergen Challenge Ocular Itching Scale 
  
 redness 
 


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at Visit 3 in the ITT 
population using observed data only. The following estimand will be used for the primary analysis of the 


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primary endpoint of overall mean change from baseline 
 
 
Estimand 1  
• 
Population: subjects with DED, defined through enrollment criteria 
• 
Endpoint:  
o 
Overall mean change from baseline in conjunctival redness in each eye 
 
 
o 
Overall mean change from baseline in eye dryness 
 
o 
Mean change from baseline in Schirmer’s test 
 
• 
Intercurrent events:  
o 
 
 
 
 
 
 
 
 
• 
Population-level summary:  
o 
Difference in the overall mean change from baseline in conjunctival redness in
 
 
o 
Difference in the overall mean change from baseline in eye dryness 
 
 
o 
Difference in the mean change from baseline in Schirmer’s test 
 
 
4. Study Design and Procedures 
4.1 
General Study Design 
Study visits will be referred to in all tables and listings as the expected study day corresponding to the visit 
to enable reviewers to understand the assessment timing without referring to the protocol visit schedule. 
Table 1 shows the scheduled study visits, their planned study day (note that there is no Day 0 and that Day 
1 corresponds to the day of randomization), and the acceptable visit window for each study visit: 
Table 1. Study Visit Windows 
Scheduled Visit 
Planned Study Day 
Visit Window 
Visit 1 
Day -14 
-16/+2 days 
Visit 2 
Day 1 
N/A 
Visit 3 
Day 2 
N/A 


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4.2 
Schedule of Visits and Assessments 
Table 2. Schedule of Visits and Assessments 
 
 


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5. Study Treatments 
5.1 
Method of Assigning Subjects to Treatment Groups 
At Visit 1 (Day -14), each subject who signs the informed consent will be assigned a screening number. All 
screening numbers will be assigned in strict numerical sequence at each site and no numbers will be 
skipped or omitted.   
At Visit 2 (Day 1), a subject who meets all the eligibility criteria will be randomized in a 1:1 ratio to receive 
treatment with either 0.25% Reproxalap Ophthalmic Solution or placebo. Subjects will be assigned a 
randomization number and kit number via paper randomization list for the Initial Cohort and by interactive 
web response system (IWRS) for the Main Cohort. 
The site staff will dispense to the subject the study kit labeled with the corresponding kit number. Both the 
randomization number and the dispensed study drug kit number will be recorded on the subject’s source 
document and electronic case report form (eCRF).    
5.2 
Masking and Unmasking 
All subjects, investigators, and study personnel involved with the conduct of the study will be masked with 
regard to treatment assignments. When medically necessary, the investigator may need to determine what 
treatment arm has been assigned to a subject.  When possible (i.e., in non-emergent situations), Ora and/or 
the study Sponsor should be notified, when possible, before unmasking study drug as described in the 
following paragraph. 
If an investigator identifies a medical need for unmasking the treatment assignment of a subject, he/she 
should contact Ora and/or the medical monitor prior to unmasking the identity of the IP, if possible. Ora will 
ask the site to complete and send them the Unmasking Request Form. Ora will notify Aldeyra and jointly 
will determine if the unmasking request should be granted. They may consult the medical monitor as 
needed. The result of the request will be documented on the Unmasking Request Form. If approval is 
granted to unmask a subject, written permission via the Unmasking Request Form will be provided to the 
investigator. The investigator will unmask the subject via scratch-off labels on the kits for the Initial Cohort 
Only. The investigator will unmask the subject using IWRS for the Main Cohort. The investigator will 
complete the Unmasking Memo form and include it in the subject’s study file and provide a copy for the 
Trial Master File (TMF). For each unmasked request, the reason, date, signature, and name of the person 
who unmasked the subject must be noted in the subject’s study file. 
6. Sample Size and Power Considerations 
 
 
 
 
 


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7. Data Preparation 
7.1 
Input Data 
Study data will primarily be recorded on the eCRFs supplied by Statistics & Data Corporation (SDC) using 
). 
 is delivered as a single-instance, multi-
tenant Software-as-a-Service (SaaS) EDC system and is developed, maintained, and hosted by 
 
. These data sources are described in detail in data transfer agreements developed between data 
management and the respective external laboratory or reading center: 
• 
Tear RASP data 
• 
Conjunctival redness photography scores 
When all prerequisites for database lock have been met, including availability of all masked external data, 
the database will be locked. Following database lock, approval will be obtained from the Sponsor to unmask 
the study. Once the study has been unmasked, unmasked laboratory data will be sent to SDC. Any changes 
to the database after data have been locked can only be made with the approval of the Sponsor in 
consultation with SDC.  
Final analysis will be carried out after the following have occurred: 
• 
Database lock has occurred, including receipt of all final versions of external vendor data, with 
written authorization provided by appropriate SDC and Sponsor personnel. 
• 
Protocol deviations have been identified and status defined (major/minor deviations). 
• 
Analysis populations have been determined. 
• 
Randomized treatment codes have been unmasked. 
7.2 
Output Data 
Data from EDC and external data will be transferred to SDC Biostatistics and incorporated into standard 
formats 
). Data will then be mapped to analysis datasets 
using the 
  Both 
 will be used to create the 
subject listings, while all tables and figures will be based on the 
 
SDTM will follow the 
 and will be implemented using the 
 
 most current at the time of study start. 
data will follow the 
 and will be implemented using the 
 
 
Any discrepancies in the validation will be noted in reviewer’s guides accompanying the final data transfers. 
 


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8. Analysis Populations 
8.1 
Intent-to-Treat 
The Intent-to-Treat (ITT) Population includes all randomized subjects. Subjects in the ITT Population will 
be analyzed as randomized. 
8.2 
Per Protocol 
The Per-Protocol (PP) Population includes subjects in the ITT Population who do not have significant 
protocol deviations and who complete the study. Protocol deviations will be assessed prior to database lock 
and unmasking. Subjects in the PP Population will be analyzed as treated. 
8.3 
Safety 
The Safety Population includes all randomized subjects who receive at least one dose of investigational 
product. 
 
. 
9. General Statistical Considerations 
9.1 
Unit of Analysis 
Safety endpoints will be analyzed for both eyes 
 
will be made on 
samples pooled 
 resulting in a single measurement for each subject 
and time point. Conjunctival redness, Schirmer’s Test, and ocular discomfort scores from the Ora Calibra 
Ocular Discomfort Scale will be collected and analyzed for each eye. Eye dryness from the Visual Analog 
Scale (VAS) and Ocular Discomfort & 4-Symptom Questionnaire scores will be collected at the subject level 
Ocular itching from the Ora Calibra® Conjunctival Allergen Challenge will 
be collected in both eyes and analyzed 
. Assessment scales are detailed in the 
appendices of the study protocol. 
9.2 
Missing or Inconclusive Data Handling 
Partial/missing start and end dates for AEs and concomitant medications required to flag data as treatment-
emergent or concomitant with treatment will be imputed as follows: 
Partial/missing start date:  
• 
Dates with missing day only will be imputed as the 1st of the month unless the month and year are 
same as the month and year of first dose of study medication, in which case missing day will be 
imputed as the first dose day of study medication.  
• 
Dates with both day and month missing will be imputed as 1 Jan unless the year is same as the 
year of first dose of study medication, in which case missing day and month will be imputed as the 
first dose day and month of study medication. 
• 
Completely missing dates will be imputed as the first dose date of study medication unless the end 
date is on or before the first dose date of study medication, in which case missing date will be 
imputed as 1 Jan of the same year as the end date. 


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Partial/missing end date:  
• 
Dates with missing day only will be imputed as the last day of the month unless the month and year 
are the same as the month and year of the last dose of study medication, in which case missing 
day will be imputed as the last dose day of study medication.  
• 
Dates with both day and month missing will be imputed as 31 Dec unless the year is same as the 
year of the last dose of study medication, in which case missing day and month will be imputed as 
the last dose day and month of study medication.  
• 
If the ongoing flag is missing or “Yes” then the date will not be imputed unless death date is 
available, in which case the missing date will be imputed as the death date. If ongoing is “No” then 
the missing end date will be imputed as the last dose date. 
• 
If the imputed date is after the date of death, then the end date will be set equal to the date of 
death.  
The original dates will be displayed in data listings and the imputed dates will be used in derivations only 
(study day, treatment-emergence status, etc). 
 
 
9.3 
Definition of Baseline 
Baseline is defined as the last measurement prior to the first dose of study treatment, 
 
Change from baseline will be calculated as post-baseline measurement – baseline 
measurement. 
9.4 
Data Analysis Conventions 
All data analysis will be performed by SDC after the study is completed and the database has been locked 
and released for unmasking. Statistical programming and analyses will be performed 
 
 
. Output will be provided 
 for tables and 
 
 All study data will be listed by subject, 
treatment, and visit (as applicable) based on 
. 
Summaries for continuous and ordinal variables will include 
 
 
 
 
 
 
 
  


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All statistical tests will be 
 
 
 
 
Unless otherwise specified, summaries will be presented by treatment group and, where appropriate, visit. 
Listings will be sorted by subject number, visit/time point, and parameter as applicable. 
 
9.5 
Adjustments for Multiplicity 
 
 
 
 
 
 
 
 
Step 
Endpoint 
Allocated Two-
sided Alpha 
Level 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


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 Disposition of Subjects 
Subject disposition will be presented in terms of the numbers and percentages of subjects who were 
randomized who were included in the following analysis populations: ITT, PP, and Safety; and who 
completed the study and discontinued from the study. Subjects who are not discontinued from the study 
will be considered study completers. Disposition will be summarized by treatment group and for all subjects. 
Percentages will be calculated using randomized subjects as the denominator unless otherwise specified.  
The reasons for premature study discontinuation will be summarized by treatment group for all discontinued 
subjects. Percentages will be calculated using discontinued subjects as the denominator. The reasons for 
study discontinuation that will be summarized include AE(s), protocol violation(s), administrative reasons, 
Sponsor termination of study, subject choice, and other. COVID-19 related discontinuations will be 
summarized similarly by treatment group as well. A subject listing will be provided that includes the date of 
discontinuation, reason for study discontinuation, and an indication of COVID-19 relatedness with a 
description. 
The number and percentage of subjects with any deviation, major deviation, and minor deviation will be 
summarized by treatment group for all randomized subjects. The protocol deviations that will be 
summarized include the following categories: 
 
 
 
 
 
 A subject listing will be provided that includes the visit, date of the deviation, 


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the deviation category, the deviation description, and the classification of whether the deviation was judged 
to be major or minor in a masked review. 
 
  
Subject listings will be provided that include randomization information such as randomization number, 
treatment group, and date. Listings will also be provided to include subject data for inclusion and exclusion 
criteria violations and exclusions from the study populations. 
 
 
11. Demographic, Previous Participation in Reproxalap Trials, and Pretreatment Variables 
11.1 
Demographic Variables 
The demographic variables collected in this study include 
 
 Subjects who record 
 
 
 
Age (years) will be summarized, overall and by treatment, using continuous descriptive statistics.  Age will 
also be categorized 
  Age will be reported in years and calculated 
using the following formula: 
Age = (Informed Consent Date – Date of Birth) / 365.25, truncated as an integer 
The number and percentage of subjects will be presented, 
 
 
A subject listing that includes all demographic variables, including informed consent, will be provided. 
11.2 
Previous Participation in Reproxalap Trials 
The number of subjects and percentages of subjects that dosed with randomized study drug in previous 
Reproxalap trials will be summarized by treatment group and for all subjects in the ITT population.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subjects who did not dose under previous Reproxalap studies will be summarized as well. 
11.3 
Pretreatment Variables 
All baseline efficacy and safety variables will be summarized by eye (or subject level) by treatment group 
and all randomized subjects. 
 


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 Quantitative variables will be summarized by using descriptive statistics with qualitative variables 
summarized by counts and percentages. Summaries will be provided of the ITT and Safety Populations. 
12. Medical History and Concomitant Medications 
12.1 
Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) Version 23.1. 
 
 
 
 
 
 
Listings of medical history will be generated separately for 
 
12.2 
Concomitant Medications and Procedures 
Concomitant medications and procedures will be coded using World Health Organization Drug Dictionary 
(WHODrug) 
 and summarized to the therapeutic drug class 
 
 and preferred name. If the 
 is not provided, 
then the next lowest classification that is provided in the coding dictionary will be used. The preferred name 
will be defined as the active ingredient; if the active ingredient is not provided or includes more than two 
ingredients (e.g., multivitamins), then the drug name will be summarized as the preferred name. Any 
uncoded terms will be summarized under the 
 
Concomitant medications are defined as those medications listed as having been taken (1) prior to initiation 
of study drug administration and continuing for any period of time following the first administration of study 
drug or (2) at any time following the first administration of study drug. Prior medications are defined as 
those medications as having been taken prior to initiation of study drug administration but not continuing 
any time following the first administration of study drug. 
Concomitant medications will be summarized 
. Medications will be tabulated for 
each treatment group using frequencies and percentages. 
 
 At each level of subject summarization, a subject will be counted once if he/she reports one 
or more medications. Percentages will be based on the number of subjects in each treatment group. Listings 
of concomitant medications will be generated separately for ocular and non-ocular data. 
13. Dosing Compliance and Treatment Exposure 
13.1 
Dosing Compliance 
Dosing compliance
 will be assessed by calculating the number of actual doses received 
and comparing that to the number of expected doses as follows: 


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The number of actual doses received will be calculated from in-office instillation eCRF page. 
 
 
 
 
Dosing compliance (%) will be summarized 
 
 The compliance category defined above will be summarized with discrete 
summary statistics.  
A subject listing of dosing compliance will also be produced. 
13.2 
Treatment Exposure 
Extent of treatment exposure for subjects who complete the study or those that discontinue the study 
 
 
 
 
Extent of treatment exposure for each subject exposed to study drug will be summarized with continuous 
descriptive statistics for each treatment group
 A subject listing of treatment 
exposure will also be produced. 
14. Efficacy Analyses 
All efficacy analyses described in this section will have 
 
 
14.1 
Primary Analysis 
The primary endpoint will be deemed to have been met if any of the 3 assessments that comprise the 
primary endpoint are achieved, as is described 
 
14.1.1 OVERALL MEAN CHANGE FROM BASELINE OF CONJUNCTIVAL REDNESS DURING THE CAE AT VISIT 3 
(DAY 2) 
The endpoint of overall mean change from baseline 
 
 
 
 
 
 
 
 


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These average scores for each separate eye will be used for analysis of the overall mean change from 
baseline of conjunctival redness. 
 
 
 
 
 
 
14.1.1.1 
MIXED MODEL REPEATED MEASURES USING SCORES FROM EACH EYE 
Overall mean change from baseline 
 
will be compared between reproxalap and vehicle. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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met, then the trial will have been deemed to have been successful in demonstrating sign activity of 
reproxalap. 
14.1.1.2 
MIXED MODEL REPEATED MEASURES USING AVERAGE SCORES FROM EACH EYE 
 
 
 
 
 
 
 
14.1.1.3 
ADDITIONAL SENSITIVITY ANALYSES 
 
 
  
 
 
• 
 
 
 
To examine the robustness of the redness analysis, the following additional sensitivity analyses will be 
executed: 
• 
 
 
 
 
 
14.1.2 OVERALL MEAN CHANGE FROM BASELINE OF EYE DRYNESS SCORE
 
 
 
 
Subjects will be asked to rate eye dryness 
 
 
 
 
  
 
 
 
 
 
  


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 A subject listing of the eye dryness during the CAE will be generated. 
14.1.2.1 
ADDITIONAL SENSITIVITY ANALYSES 
 
 
 
 
 
 
 
 
 
 
 
14.1.3 MEAN CHANGE FROM BASELINE OF UNANESTHETIZED SCHIRMER’S TEST
 
 
Unanesthetized Schirmer’s test will be assessed for each eye. 
 
 
 
 
. 
14.1.3.1 
MIXED MODEL REPEATED MEASURES USING SCORES FROM EACH EYE 
Mean CFB of unanesthetized Schirmer’s test 
 
 
 
 
 
 
 
 
 
 
 
 
A subject listing of the unanesthetized Schirmer’s test will be generated. 


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14.1.3.2 
ADDITIONAL SENSITIVITY ANALYSES 
Additional sensitivity analyses of the endpoint of mean change from baseline of unanesthetized Schirmer’s 
test 
 
 
 
 
 
 
 
 
 
14.2 
Secondary Analyses 
14.2.1 CONJUNCTIVAL REDNESS (ORA CALIBRA® SCALE) 
 
 
 
 
 
 
 
The overall mean CFB of the conjunctival redness 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
  
Analyses will use the ITT Population with observed data only. A subject listing of the conjunctival redness 
outside of the CAE® will be generated. 
14.2.2 EYE DRYNESS SCORE FROM THE VISUAL ANALOG SCALE 
 
 
 
 
 
 
 
 
 
 
 


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Analyses will use the ITT Population with observed data only. A subject listing of the eye dryness outside 
of the CAE® will be generated. 
14.2.3 OCULAR DISCOMFORT SCALE (ORA CALIBRA® SCALE) 
Ocular Discomfort will be assessed 
 
 
 
 
 
 
 
 
 
 
14.2.3.1 
OCULAR DISCOMFORT SCALE (ORA CALIBRA® SCALE)  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 A subject listing of the Ocular Discomfort 
Scale outside of the CAE® will be generated. 
14.2.3.2 
OVERALL MEAN CHANGE FROM BASELINE OF OCULAR DISCOMFORT SCALE (ORA CALIBRA® 
SCALE)  
 
 
 
 
 
 
 
 
 
 
  
A subject listing of the Ocular Discomfort 
Scale during the CAE® will be generated. 


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14.2.4 OCULAR DISCOMFORT & 4-SYMPTOM QUESTIONNAIRE (ORA CALIBRA® SCALE) 
 
 
 
 
 
14.2.4.1 
OCULAR DISCOMFORT & 4-SYMPTOM QUESTIONNAIRE (ORA CALIBRA® SCALE)  
  
 
 
 
 
 
 
 
 
 
 
    
 A subject listing of the Ocular Discomfort & 
4-Symptom Questionnaire will be generated. 
14.2.4.2 
OCULAR DISCOMFORT & 4-SYMPTOM QUESTIONNAIRE (ORA CALIBRA® SCALE) 
 
 
 
 
 
 
 
 
 
 
 
  
 A subject listing of the Ocular Discomfort & 
4-Symptom Questionnaire will be generated. 
14.2.5 CONJUNCTIVAL ALLERGEN CHALLENGE OCULAR ITCHING SCALE (ORA CALIBRA® SCALE) 
 
 
 
  
14.2.5.1 
CONJUNCTIVAL ALLERGEN CHALLENGE OCULAR ITCHING SCALE (ORA CALIBRA® SCALE)  
  
 
 
 
 
 
 
 
 
 
 
   


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A subject listing of the Conjunctival Allergen 
Challenge Ocular Itching Scale will be generated. 
14.2.5.2 
CONJUNCTIVAL ALLERGEN CHALLENGE OCULAR ITCHING SCALE (ORA CALIBRA® SCALE)  
 
 
 
 
 
 
 
 
 
 
 
 
  
14.3 
Exploratory Analyses 
14.3.1 TEAR REACTIVE ALDEHYDE SPECIES 
 
 
 
 
Tears will be collected from both eyes. 
 
 
 
 
 
  
 
 
   
A subject listing of the tear RASP will be 
generated. 
14.3.2 CONJUNCTIVAL REDNESS (ORA CALIBRA® SCALE) 
 
 
 
 
 
 
For conjunctival redness 
 
 
 
 
 
 
14.3.3 EYE DRYNESS (VAS) 
 
 
 
 
 
 
 
 
 


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14.3.4 OCULAR DISCOMFORT SCALE (ORA CALIBRA® SCALE) 
 
 
 
 
 
 
 
 
 
 
 
 
 
15. Summary of Efficacy Analyses 
A summary of all efficacy analyses will be presented. 
 
 
 
 
 
16. Safety Analyses 
All safety analyses will be conducted using the Safety Population 
. 
16.1 
Adverse Events 
For the purposes of this trial, an AE is defined as any untoward medical event occurring after the subject’s 
signing of the informed consent until they are exited from the trial. An AE can therefore be any unfavorable 
and unintended sign, symptom, or disease occurring after the subject started the clinical trial, without any 
judgment about causality. Any pre-existing medical condition that worsens during the trial will also be 
considered a new AE. Documentation regarding the AE should be made as to the nature, date of onset, 
end date, severity, relationship to study procedure, expectedness, action(s) taken, seriousness, and 
outcome of any sign or symptom observed by the investigator or reported by the patient upon indirect 
questioning.  
All AEs will be coded using the MedDRA Version 23.1.  
Treatment-emergent adverse events (TEAEs) are defined as any event that occurs or worsens on or after 
the day that randomized study treatment is initiated. Adverse events recorded in the eCRF which began 
prior to treatment will not be included in the summary tables but will be included in the AE data listings. 


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An overall summary will be presented that includes the number and percentage of subjects who 
experienced at least one AEs, ocular AEs, non-ocular AEs, SAEs, AEs by maximal severity, AEs by 
relationship to study procedure, AEs leading to treatment discontinuation, and AEs resulting in death by 
treatment arm for the Safety Population. In addition, overall TEAEs and the number and percentage of 
subjects who experienced at least one TEAE, ocular TEAEs, non-ocular TEAEs, TE-SAEs, TEAEs by 
maximal severity, TEAEs by relationship to study procedure, TEAEs leading to treatment discontinuation, 
and TEAEs resulting in death by treatment arm for the Safety Population.  
Separate summaries will be provided for the following categories of AEs:  
• 
Ocular AEs by SOC and PT 
• 
Non-ocular AEs by SOC and PT 
• 
Ocular TEAEs by SOC and PT 
• 
Non-ocular TEAEs by SOC and PT 
• 
Instillation Site Ocular TEAEs by Duration of Time  
• 
Ocular TEAEs by SOC, PT, and maximal severity  
• 
Non-ocular TEAEs by SOC, PT, and maximal severity  
• 
Ocular TEAEs by SOC, PT, and strongest relationship to study procedure 
• 
Non-ocular TEAEs by SOC, PT, and strongest relationship to study procedure 
• 
Ocular TEAEs by SOC, PT, maximal severity, and strongest relationship to study procedure 
• 
Non-ocular TEAEs by SOC, PT, maximal severity, and strongest relationship to study procedure 
• 
TEAEs That Led to Premature Treatment Discontinuation 
• 
SAEs 
Adverse Events and TEAEs will be summarized using discrete summary statistics and presented by 
treatment arm and all subjects for the Safety Population. If a subject reports the same PT multiple times 
within the same SOC, that PT will only be reported once within that SOC. As with the PT, if a subject reports 
multiple conditions within the same SOC, that SOC will only be reported once. In the summaries, SOCs will 
be listed in ascending alphabetical order. PTs will be listed in order of descending frequency within each 
SOC for all subjects. 
All AEs, ocular AEs, non-ocular AEs, and SAEs will be presented in subject listings. 
16.1.1 SEVERITY 
Severity of an AE is defined as a qualitative assessment of the degree of intensity of an AE as determined 
by the investigator or reported to them by the patient/subject. The assessment of severity is made 
irrespective of relationship to study procedures or seriousness of the event and should be evaluated 
according to the following scale: 
• 
 
 


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• 
 
 
 
 
 
 
Subjects experiencing more than one AE within a given SOC or PT are counted once within that SOC or 
PT for the maximal severity. 
16.1.2 RELATIONSHIP TO STUDY PROCEDURES 
The relationship of each AE to the study procedures should be determined by the investigator using these 
explanations. Decisive factors for the assessment of causal relationship of an AE to the study procedures 
include, but may not be limited to, temporal relationship between the AE and the procedure, known side 
effects of the procedure medical history, and/or concomitant medication: 
• 
Definite: When there are good reason and sufficient documentation to demonstrate a direct causal 
relationship between study procedure and AE; 
• 
Probable: When there are good reasons and sufficient documentation to assume a causal 
relationship in the sense of plausible, conceivable, likely but not necessarily highly probable. 
• 
Possible: When there is sufficient information to accept the possibility of a causal relationship in 
the sense of not impossible and not unlikely, although the connection is uncertain or doubtful, for 
example; due to missing data or insufficient evidence. 
• 
None: When there is sufficient information to accept a lack of a causal relationship, in the sense of 
impossible and improbable. 
• 
Unclassified: When the causal relationship is not assessable for whatever reason due to insufficient 
evidence, conflicting data or poor documentation. 
Subjects experiencing more than one AE within a given SOC or PT are counted once within that SOC or 
PT for the maximum relationship. 
16.1.3 EXPECTEDNESS 
The expectedness of an AE should be determined based upon existing safety information about the study 
procedures. Therefore, the following definition will be used: 
• 
Unexpected: An AE that is not listed in the safety information available for the study procedure at 
the specificity or severity that has been observed. 
• 
Expected: An AE that is listed in the safety information available for the study procedure at the 
specificity and severity that has been observed. 
• 
Not Applicable: Any AE that is unrelated to the study procedure. 


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16.1.4 SERIOUS ADVERSE EVENTS 
An AE is considered serious if, in the view of either the investigator or Sponsor, it results in any of the 
following outcomes: 
• 
Death; 
• 
A life-threatening adverse event; 
o 
Note: An adverse event is considered “life-threatening” if, in the view of either the 
investigator or Sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event that, had it occurred in a more severe form, 
might have caused death. 
• 
Inpatient hospitalization or prolongation of existing hospitalization; 
o 
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; 
observation/short stay units; rehabilitation facilities; hospice facilities; nursing homes; or 
clinical research/phase 1 units. 
o 
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; 
o 
Note: A serious adverse event 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. 
Important medical events that may not result in death, are not life-threatening, or do not require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
16.2 
Visual Acuity (Early Treatment Diabetic Retinopathy Study) 
The logarithm of the minimum angle of resolution (logMAR) visual acuity is assessed at each visit 
 
  
 
A subject listing of visual acuity will also be produced. 


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16.3 
Slit-Lamp Biomicroscopy 
A slit-lamp biomicroscopy
 will be performed 
 
 
 
 
 
 
 
A subject listing of the slit-lamp biomicroscopy parameters will also be 
produced. 
16.4 
Dilated Fundoscopy Examination 
A dilated fundoscopy examination 
 will be performed 
 
  
 
 
 
 A subject listing of the dilated fundoscopy parameters will also be produced. 
16.5 
Intraocular Pressure (IOP) 
Subjects’ IOP will be assessed 
 
 
 
. A subject listing of IOP will also be produced. 
17. Changes from Protocol-Stated Analyses 
No changes to protocol-stated analyses will be executed. 
18. References 
No references cited. 
19. Revision History 
Documentation of revision to the SAP will commence after approval of the final version 1.0. 
20. Tables 
Tables (10 tables) in boldface font will be delivered in topline package. 
 
Table Number 
Title 
Population 


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Table 14.1.1  
Subject Disposition  
All 
Screened 
Subjects 
Table 14.1.2.1  
Demographics   
ITT Population 
Table 14.1.2.2   
Demographics 
Safety Population 
Table 14.1.2.3 
Previous Participation in Reproxalap Trials 
ITT Population 
Table 14.1.3.1  
Baseline Disease Characteristics 
ITT Population 
Table 14.1.3.2  
Baseline Disease Characteristics 
Safety Population 
Table 14.1.4.1  
Ocular Medical History  
ITT Population 
Table 14.1.4.2  
Non-Ocular Medical History  
ITT Population 
Table 14.1.5.1  
Ocular Concomitant Medications  
ITT Population 
Table 14.1.5.2  
Non-Ocular Concomitant Medications  
ITT Population 
Table 14.2.1.1  
Overall 
Mean 
Change 
from 
Baseline 
of 
Conjunctival Redness (Ora Calibra® Scale) 
 
ITT Population with 
Observed 
Data 
Only 
Table 14.2.1.2   
Overall Mean Change from Baseline of Conjunctival 
Redness (Ora Calibra® Scale)
 
 
PP Population with 
Observed Data Only  
Table 14.2.1.3   
Overall Mean Change from Baseline of Conjunctival 
Redness (Ora Calibra® Scale) 
 
   
ITT Population with 
Observed Data Only 
Table 14.2.1.4  
Overall Mean Change from Baseline of Conjunctival 
Redness (Ora Calibra® Scale) 
 
   
ITT Population with 
Observed Data Only 
Table 14.2.1.5  
Overall Mean Change from Baseline of Conjunctival 
Redness (Ora Calibra® Scale) 
 
 
 ITT Population with 
PMM 
Table 14.2.1.6   
Overall Mean Change from Baseline of Conjunctival 
Redness (Ora Calibra® Scale) 
 
   
ITT Population with 
MCMC 
Table 14.2.2.1 
Overall Mean Change from Baseline of Eye 
Dryness (Visual Analog Scale) 
 
   
ITT Population with 
Observed 
Data 
Only 


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Table 14.2.2.2 
Overall Mean Change from Baseline of Eye Dryness 
(Visual Analog Scale) 
   
PP Population with 
Observed Data Only 
Table 14.2.2.3 
Overall Mean Change from Baseline of Eye Dryness 
(Visual Analog Scale) 
   
ITT Population with 
PMM 
Table 14.2.2.4 
Overall Mean Change from Baseline of Eye Dryness 
(Visual Analog Scale) 
   
ITT Population with 
MCMC 
Table 14.2.3.1 
Mean Change from Baseline of Unanesthetized 
Schirmer’s Test 
 
ITT Population with 
Observed 
Data 
Only 
Table 14.2.3.2 
Mean Change from Baseline of Unanesthetized 
Schirmer’s Test 
 
PP Population with 
Observed Data Only 
Table 14.2.3.3 
Mean Change from Baseline of Unanesthetized 
Schirmer’s Test 
 
ITT Population with 
PMM 
 
Table 14.2.3.4 
Mean Change from Baseline of Unanesthetized 
Schirmer’s Test 
 
ITT Population with 
MCMC 
Table 14.2.4.1  
Conjunctival Redness (Ora Calibra® Scale) 
 
ITT Population with 
Observed 
Data 
Only 
Table 14.2.4.2   
Eye Dryness (Visual Analog Scale) 
 
   
ITT Population with 
Observed 
Data 
Only 
Table 14.2.4.3 
Ocular Discomfort Scale (Ora Calibra® Scale) 
 
ITT Population with 
Observed 
Data 
Only 
Table 14.2.4.4   
Overall Mean Change from Baseline of Ocular 
Discomfort Scale (Ora Calibra® Scale) 
 
   
ITT Population with 
Observed 
Data 
Only 
Table 14.2.4.5   
Ocular Discomfort & Four-Symptom Questionnaire 
(Ora Calibra® Scale) 
 
 
ITT Population with 
Observed Data Only 
Table 14.2.4.6   
Ocular Discomfort & Four-Symptom Questionnaire 
(Ora Calibra® Scale) 
 
 
ITT Population with 
Observed Data Only 


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Table 14.2.4.7   
Conjunctival Allergen Challenge Ocular Itching 
Scale (Ora Calibra® Scale) 
 
  
ITT Population with 
Observed Data Only 
Table 14.2.4.8   
Conjunctival Allergen Challenge Ocular Itching 
Scale (Ora Calibra® Scale) 
 
 
ITT Population with 
Observed Data Only 
Table 14.2.5.1 
Tear Reactive Aldehyde Species – 
 
 
ITT Population with 
Observed Data Only 
Table 14.2.5.2 
Conjunctival Redness (Ora Calibra® Scale) 
 
 
ITT Population with 
Observed Data Only 
Table 14.2.5.3 
Eye Dryness (Visual Analog Scale) 
 
 
ITT Population with 
Observed Data Only 
Table 14.2.5.4 
Ocular Discomfort Scale (Ora Calibra® Scale) 
 
 
ITT Population with 
Observed Data Only 
Table 14.2.6  
Summary of Efficacy Analyses 
Multiple Populations 
Table 14.3.1.1  
Overall 
Summary 
of 
Adverse 
Events 
by 
Treatment Arm  
Safety Population 
Table 14.3.2.1  
Ocular Adverse Events by System Organ Class and 
Preferred Term  
Safety Population 
Table 14.3.2.2  
Non-Ocular Adverse Events by System Organ Class 
and Preferred Term  
Safety Population 
Table 14.3.3.1  
Ocular Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term  
Safety Population 
Table 14.3.3.2  
Non-Ocular Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term  
Safety Population 
Table 14.3.4   
Instillation Site Ocular TEAEs by SOC, PT, and 
Duration of Time   
Safety Population 
Table 14.3.5.1  
Ocular Treatment-Emergent Adverse Events by 
System Organ Class, Preferred Term, and Maximal 
Severity  
Safety Population 
Table 14.3.5.2  
Non-Ocular Treatment-Emergent Adverse Events by 
System Organ Class, Preferred Term, and Maximal 
Severity  
Safety Population 


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Table 14.3.6.1  
Ocular Treatment-Emergent Adverse Events by 
System Organ Class, Preferred Term, and Strongest 
Relationship to Study Procedure  
Safety Population 
Table 14.3.6.2  
Non-Ocular Treatment-Emergent Adverse Events by 
System Organ Class, Preferred Term, and Strongest 
Relationship to Study Procedure  
Safety Population 
Table 14.3.7.1  
Ocular Treatment-Emergent Adverse Events by 
System Organ Class, Preferred Term, Maximal 
Severity, and Strongest Relationship to Study 
Procedure  
Safety Population 
Table 14.3.7.2  
Non-Ocular Treatment-Emergent Adverse Events by 
System Organ Class, Preferred Term, Maximal 
Severity, and Strongest Relationship to Study 
Procedure  
Safety Population 
Table 14.3.8  
Treatment-Emergent Adverse Events That Led to 
Premature Discontinuation  
Safety Population 
Table 14.3.9  
Treatment-Emergent Serious Adverse Events  
Safety Population 
Table 14.3.10  
Visual Acuity 
  
Safety Population 
Table 14.3.11.1  
Slit Lamp Biomicroscopy  
Safety Population 
Table 14.3.11.2  
Shift in Slit Lamp Biomicroscopy  
Safety Population 
Table 14.3.12  
Intraocular Pressure 
  
Safety Population 
Table 14.3.13.1  
Dilated Fundoscopy  
Safety Population 
Table 14.3.13.2  
Shift in Dilated Fundoscopy  
Safety Population 
Table 14.3.14  
Compliance to Study Drug  
Safety Population 
Table 14.3.15  
Exposure to Study Drug  
Safety Population 
21. Listings 
 
 
Listing Number 
Title 
Population 
Listing 16.1.7  
Randomization Schedule  
All 
Randomized 
Subjects 


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Listing 16.2.1.1  
Subject Disposition  
All 
Randomized 
Subjects 
Listing 16.2.1.2  
Inclusion/Exclusion and Screen Failure  
All Screened Subjects 
Listing 16.2.2  
Protocol Deviations  
All Screened Subjects 
Listing 16.2.3.1  
Study Population Inclusion  
All 
Randomized 
Subjects 
Listing 16.2.3.2   
Subjects Affected by COVID-19  
All Screened Subjects 
Listing 16.2.4.1  
Demographics  
All Screened Subjects 
Listing 16.2.4.2  
Ocular Medical History  
All 
Randomized 
Subjects 
Listing 16.2.4.3  
Non-Ocular Medical History  
All 
Randomized 
Subjects 
Listing 16.2.4.4  
Ocular Concomitant Medications  
All 
Randomized 
Subjects 
Listing 16.2.4.5  
Non-Ocular Concomitant Medications  
All 
Randomized 
Subjects 
Listing 16.2.5.1  
Run-In Instillation  
All Screened Subjects 
Listing 16.2.5.2  
Study Drug Assignment, Instillation, and Replacement  
All 
Randomized 
Subjects 
Listing 16.2.5.3  
Study Drug Exposure and Dosing Compliance  
All 
Randomized 
Subjects 
Listing 16.2.5.4  
Study Drug Accountability  
All 
Randomized 
Subjects 
Listing 16.2.6.1  
Conjunctival Redness (Ora Calibra Scale) 
 
  
All 
Randomized 
Subjects 
Listing 16.2.6.2  
Conjunctival Redness (Ora Calibra Scale) 
 
  
All 
Randomized 
Subjects 
Listing 16.2.6.3 
Unanesthetized Schirmer’s Test 
All 
Randomized 
Subjects 
Listing 16.2.6.4  
Eye Dryness (Visual Analog Scale) 
 
  
All 
Randomized 
Subjects 


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Listing 16.2.6.5  
Eye Dryness (Visual Analog Scale) 
 
  
All 
Randomized 
Subjects 
Listing 16.2.6.6  
Ocular Discomfort Scale (Ora Calibra Scale) 
 
  
All 
Randomized 
Subjects 
Listing 16.2.6.7  
Ocular Discomfort Scale (Ora Calibra Scale) 
 
  
All 
Randomized 
Subjects 
Listing 16.2.6.8  
Ocular Discomfort & 4-Symptom Questionnaire (Ora 
Calibra Scale)  
All 
Randomized 
Subjects 
Listing 16.2.6.9  
Conjunctival Allergen Challenge Ocular Itching Scale 
(Ora Calibra Scale)  
All 
Randomized 
Subjects 
Listing 16.2.6.10  
Tear Reactive Aldehyde Species  
All 
Randomized 
Subjects 
Listing 16.2.6.11 
Fluorescein Corneal and Conjunctival Staining (Ora 
Calibra Scale)  
All 
Randomized 
Subjects 
Listing 16.2.7.1  
All Adverse Events  
All Screened Subjects 
Listing 16.2.7.2  
Ocular Adverse Events  
All Screened Subjects 
Listing 16.2.7.3  
Non-Ocular Adverse Events  
All Screened Subjects 
Listing 16.2.7.4  
Serious Adverse Events  
All Screened Subjects 
Listing 16.2.8.1  
Visual Acuity 
  
All 
Randomized 
Subjects 
Listing 16.2.8.2  
Slit-Lamp Biomicroscopy  
All 
Randomized 
Subjects 
Listing 16.2.8.3  
Intraocular Pressure (IOP)  
All 
Randomized 
Subjects 
Listing 16.2.8.4  
Dilated Fundoscopy  
All 
Randomized 
Subjects 
Listing 16.2.8.5  
Pregnancy Test  
All Female Screened 
Subjects 
Listing 16.2.8.6   
Tear Collection   
All 
Randomized 
Subjects