Conditions: Dry Eye Dry Eye Syndromes
Keywords: reproxalap ADX-102 Tranquility
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 329
Healthy volunteers: no

Brief summary:
The TRANQUILITY Trial: Multi-Center Randomized, Double-Masked, Parallel Design, Vehicle-Controlled Phase 2/3 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 Opthalmic Solution
Intervention descriptions: intervention 1: Reproxalap Ophthalmic Solution (0.25%) administered over two consecutive days (Day one pre-dry eye chamber and Day two dry eye chamber assessment). intervention 2: Vehicle Ophthalmic Solution administered over two consecutive days (Day one pre-dry eye chamber and Day two dry eye chamber assessment).

Protocol document:
Prot_000.pdf: 
Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 1 of 58 
Clinical Trial Protocol: ADX-102-DED-019 
Protocol Title: 
The TRANQUILITY Trial: A Multi-Center 
Randomized, Double-Masked, Parallel Design, 
Vehicle-Controlled Phase 2/3 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-019  
Study Phase: 
2/3 
Investigational Product Name: 
0.25% Reproxalap Ophthalmic Solution  
IND/IDE/PMA Number: 
 
Indication: 
Dry Eye Disease (DED) 
Investigator: 
Multi-Center 
Sponsor/Contract Research 
Organization: 
Aldeyra Therapeutics, Inc. 
131 Hartwell Ave. 
Lexington, MA 02421 USA 
IRB/IEC: 
 
 
 
 
 
 
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. 
 
Date 
Original Protocol: 
30Oct2020 
Amendment #1: 
23Feb2021 
Amendment #2: 
26Apr2021 
Amendment #3: 
5Nov2021 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 2 of 58 
STUDY PERSONNEL 
SPONSOR PERSONNEL 
Chief Development Officer: 
 
 
 
 
ORA PERSONNEL 
Department Vice President: 
 
 
 
 
Department Senior Director: 
 
 
 
 
Clinical Project Manager: 
 
 
 
 
 
MEDICAL MONITOR 
Medical Monitor: 
 
 
 
 
 
 
 
 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 3 of 58 
SYNOPSIS 
Protocol Title: 
The 
TRANQUILITY 
Trial: 
A 
Multi-Center 
Randomized, 
Double-Masked, 
Parallel 
Design, 
Vehicle-Controlled Phase 2/3 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-019 
Investigational Product: 
0.25% Reproxalap Ophthalmic Solution (reproxalap) 
Study Phase: 
2/3 
Primary Objective(s): 
 
To evaluate the efficacy of reproxalap, as assessed by 
conjunctival redness, Schirmer’s Test, and symptoms 
after dosing prior to and during exposure to the 
Controlled Adverse Environment® (CAE) in subjects 
with dry eye disease 
 
Overall Study Design: 
Structure: 
Multi-center, double-masked, randomized parallel 
design trial 
Duration: 
An individual subject’s participation is estimated to be 
approximately 16-32 days.  
Controls: 
Vehicle Ophthalmic Solution (vehicle) 
Dosage/Dose Regimen: 
Test article (reproxalap or vehicle) will be dosed 
topically in both eyes. 
 
Test article will be administered QID on Day 1 (Visit 
2).  On Day 2 (Visit 3), test article will be 
administered once within 10 minutes prior to the CAE 
entry, once 45 minutes after initiation of the CAE, and 
once at CAE® exit.  
Summary of Visit Schedule: 
Three visits over the course of approximately 2 
weeks: 
 
• Visit 1 = Day -14 -16/+2, Screening  


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 4 of 58 
• Visit 2 = Day 1, Randomization/Baseline 
• Visit 3 = Day 2 CAE® & Study Exit 
 
Twenty subjects who meet the enrollment criteria will 
participate in an Initial Cohort. The Initial Cohort 
phase will be limited to Visit 1 (Screening), Visit 2 
(Day 1), and Visit 3 (Day 2). Subjects will be 
randomized 1:1 to receive either reproxalap or 
vehicle. Results from the Initial Cohort phase will be 
analyzed to confirm endpoints, and statistical power 
for the remainder of the trial.   
Measures Taken to Reduce Bias: 
ADX-102-DED-019 is a randomized treatment 
assignment, double-masked trial. 
Study Population Characteristics: 
Number of Subjects: 
Twenty subjects are expected to be enrolled in the 
Initial Cohort of the trial. 
Approximately 300 subjects are expected to be 
enrolled in the Main Cohort of 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 at least 6 months 
prior to Visit 1; 
4. Reported history of use or desire to use eye drops 
for dry eye symptoms within 6 months of Visit 1; 
5. Corneal fluorescein staining sum 
 
 
 in at least one eye on 
the Ora Calibra Scale at Visit 1.  
6. Response to the CAE at Visit 1, as defined by: 
a. 
 
 
 
 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 5 of 58 
 
 
 
 
 
 
Exclusion Criteria: 
Subjects must not meet any of the following criteria: 
1. Clinically significant slit lamp findings at Visit 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2. Diagnosis of an ongoing ocular infection 
 or active ocular 
inflammation at Visit 1; 
3. Contact lens use within 7 days of Visit 1 or 
anticipate using contact lenses during the trial; 
4. Artificial tear eye drop use
 
 
 
 
5. Previous laser-assisted in situ keratomileusis 
(LASIK) surgery within the last 12 months; 
6. 
 
 
7. Systemic 
corticosteroid 
or 
other 
immunomodulator therapy 
 
 within 14 days of Visit 1 or any 
planned immunomodulatory therapy throughout 
the study period;  
8. Planned ocular and/or lid surgeries over the study 
period or any ocular surgery within 6 months of 
Visit 1; 
9. Temporary punctal plugs during the study that 
have not been stable within 30 days of Visit 1; 
10. Use of and unwillingness to discontinue topical 
ophthalmic prescription (including medications 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 6 of 58 
for 
glaucoma) 
or 
over-the-counter 
(OTC) 
solutions (not including artificial tears), gels, or 
scrubs for the duration of the trial (excluding 
medications allowed for the conduct of the trial); 
11. Corrected visual acuity 
 
 
 
 in 
both eyes at Visit 1; 
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; 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 7 of 58 
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. 
 
 
19. Current use of any medication known to cause 
ocular drying that is not used on a stable dosing 
regimen for at least 30 days prior to Visit 1; 
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 assessed via digital 
photography over 90 minutes in CAE 
 
Secondary Endpoints: 
• Visual analog scale eye dryness score 
 
 in CAE  
• Ora Calibra® Ocular Discomfort Scale 
 
n CAE 
• Schirmer’s Test 
 
 on Day 1 
 
Exploratory Endpoints: 
• Visual analog scale 
 assessed over 
Days 1 and 2 
 
• Ora Calibra® Ocular Discomfort Scale assessed 
over Days 1 and 2 (excluding CAE) 
• Ocular Discomfort & 4-Symptom Questionnaire 
assessed over Days 1 and 2, and before and after 
CAE 
• Ora Calibra® Conjunctival Allergen Challenge 
Ocular Itching Scale 
 
 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 8 of 58 
• Change in tear RASP levels 
 
 
• Conjunctival Redness 
 
 
• Conjunctival redness, Ora Calibra® Ocular 
Discomfort Scale, and visual analog scale dryness 
score 
 
 
Safety Endpoints: 
• Visual acuity 
• Slit-lamp evaluation 
• 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: 
Assuming 
 overall mean change from baseline in conjunctival 
redness (Ora Calibra® Scale) during the CAE at Day 2 between the two groups and a common 
standard deviation 
 
 
 
 
 
Multiplicity Considerations: 
 
 
 
  
 
Primary Efficacy Analyses: 
Overall mean change from baseline of conjunctival redness during the 
 will be 
assessed via mixed effect model for repeated measures 
of change from baseline 
 with baseline score 
 
  
The primary endpoint will be assessed using the ITT population 
 
 
Sensitivity analyses for the primary analyses will include the following: 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 9 of 58 
• 
 
 
 
 
 
 
 
 
Secondary Efficacy Analyses: 
For secondary efficacy endpoints during the 
 CAE, 
 
will be assessed via 
 
 with baseline score as a covariate, nominal time, and treatment group, as fixed effects 
with correlated errors due to eye and nominal time point for eye level assessments. For 
subject level assessments 
, the model will have correlated errors due to 
nominal time point. 
 
Overall mean change from baseline of Schirmer’s Test 
 will 
be assessed 
with baseline score as a covariate 
 
time point 
 and treatment group as fixed effects with correlated errors 
due to eye and time point. 
 
Exploratory Efficacy Analyses: 
 
 
 
 
 
 
 
 
 
 
 
Primary analyses of exploratory efficacy endpoints will utilize the ITT population with 
observed data only. 
All efficacy analyses conducted on the ITT population will be conducted using the Initial 
Cohort population only with observed data. 
 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 10 of 58 
Safety Analyses: 
 
 
 
 
 
Summary of Known and Potential Risks and Benefits to Human Subjects: 
Refer to Investigator’s Brochure. 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 11 of 58 
TABLE OF CONTENTS 
Clinical Trial Protocol: ADX-102-DED-019 ....................................................................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 ...........................................................................................20 
6.3 
Secondary Endpoints ...................................................................................21 
6.4 
Exploratory 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 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 12 of 58 
8.4.1 
Scheduled Visits................................................................................27 
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 ..................................................31 
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 ...................................................................................................33 
10.4 Statistical Analysis ........................................................................................34 
10.4.1 General Considerations .......................................................................34 
10.4.2 Unit of Analysis ................................................................................34 
10.4.3 Missing Data .....................................................................................34 
10.4.4 Multiplicity Considerations ..............................................................34 
10.4.5 Primary Efficacy Analysis ................................................................35 
10.4.6 Secondary Efficacy Analyses ...........................................................36 
10.4.7  Exploratory Efficacy Analyses .......................................................36 
10.4.8 Safety Variables ................................................................................36 
11 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES ................................37 
11.1 Protection of Human Subjects .....................................................................37 
11.1.1 Subject Informed Consent.................................................................37 
11.1.2 Institutional Review Board (IRB) Approval .....................................37 
11.2 Ethical Conduct of the Study ......................................................................38 
11.3 Subject Confidentiality ................................................................................38 
11.4 Documentation ..............................................................................................38 
11.4.1 Retention of Documentation .............................................................38 
11.5 Labeling, Packaging, Storage, Accountability, and Return or Disposal of Study 
Drug ...............................................................................................................38 
11.5.1 Labeling/Packaging ...........................................................................38 
11.5.2 Storage of Study Drug ......................................................................39 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 13 of 58 
11.5.3 Accountability of Study Drug ...........................................................39 
11.5.4 Return or Disposal of Study Drug ....................................................39 
11.6 Recording of Data on Source Documents and electronic Case Report Forms 
(eCRFs) ..........................................................................................................39 
11.7 Handling of Biological Specimens ...............................................................39 
11.8 Publications ...................................................................................................40 
12 
REFERENCES ........................................................................................................40 
Appendix 1:  Schedule of Visits and Measurements ...................................................41 
Appendix 2: Examination Procedures, Tests, Equipment, and Techniques .....42 
Appendix 3:  Amendment Summary of Changes Table .............................................51 
Appendix 4:  Sponsor and Ora Approvals ..................................................................57 
Appendix 5:  Investigator’s Signature .........................................................................58 
 
 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 14 of 58 
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 
MAR 
Missing at random 
MNAR 
Missing not at random 
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 
 
 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 15 of 58 
1 INTRODUCTION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 16 of 58 
2 STUDY OBJECTIVES 
To evaluate the efficacy of reproxalap, as assessed by conjunctival redness, 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 CLINICAL HYPOTHESES 
The clinical hypothesis is that reproxalap is more effective than vehicle in reducing the signs and 
symptoms of DED.  
 
 




Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 18 of 58 
• CAE exposure 
 with Ocular Dryness 
VAS, and Ora Calibra® Ocular Discomfort Scale, 
and Conjunctival Redness Assessments 
• Tear Collection at specified time points 
• IOP and Dilated Fundoscopy 
• Study Exit 
 
5 STUDY POPULATION 
5.1 
Number of Subjects (approximate) 
Approximately 40 subjects will be screened in the Initial Cohort to enroll 20 subjects 
at one site. An additional 600 subjects will be screened in the Main Cohort to enroll 
approximately 300 subjects across approximately 8 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 for at least 6 months prior to Visit 1; 
4. Reported history of use or desire to use eye drops for dry eye symptoms within 6 
months of Visit 1; 
5.  Corneal fluorescein staining sum 
 in at 
least one eye on the Ora Calibra Scale at Visit 1. 
6. Response to the CAE at Visit 1, as defined by: 
a.  A 
 in the visual analog scale eye dryness score 
in at 
least one eye during at least two consecutive time points in CAE and; 
b. A 
 in conjunctival redness score measured via digital 
photography in at least one eye during at least two consecutive time points in CAE.1  
1Eye does not need to be the same eye as inclusion 5 or 6a. 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 19 of 58 
5.4 
Exclusion Criteria 
Each subject may not meet any of the following criteria: 
1. Clinically significant slit lamp findings at Visit 1 that may include active 
blepharitis, meibomian gland dysfunction (MGD), lid margin inflammation, or 
active ocular allergies that require therapeutic treatment, and/or in the opinion of 
the investigator may interfere with study parameters; 
2. Diagnosis of an ongoing ocular infection 
 or active 
ocular inflammation at Visit 1; 
3. Contact lens use within 7 days of Visit 1 or anticipate using contact lenses during 
the trial; 
4. Artificial tear eye drop use within 2 hours of Visit 1 or within 24 hours of Visit 2 
(drops cannot be used on the day of Visit 2 or Visit 3); 
5. Previous laser-assisted in situ keratomileusis (LASIK) surgery within the last 12 
months; 
6. Cyclosporine 0.05% or 0.09% or lifitegrast 5.0% ophthalmic solution use within 90 
days of Visit 1; 
7. Systemic corticosteroid therapy or other immunomodulator (not including inhaled 
corticosteroids) within 14 days of Visit 1 or anticipate such therapy throughout the 
study period;  
8. Planned ocular and/or lid surgeries over the study period or any ocular surgery 
within 6 months of Visit 1; 
9. Temporary punctal plugs during the study that have not been stable within 30 days 
of Visit 1; 
10. Use of and unwillingness to discontinue topical ophthalmic prescription (including 
medications for glaucoma) or over-the-counter (OTC) solutions (not including 
artificial tears), gels or scrubs for the duration of the trial (excluding medications 
allowed for the conduct of the trial); 
11. Corrected visual acuity greater than or equal to logarithm of the minimum angle of 
resolution 
 
 at Visit 1; 
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 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 20 of 58 
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 
 solution in the past year; 
19. Current use of any medication known to cause ocular drying that is not used on a 
stable dosing regimen for at least 30 days prior to Visit 1; 
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 assessed via digital photography 
 in 
CAE 
6.2 
Safety Endpoints 
• Visual acuity 
• Slit-lamp evaluation 
• Adverse event query 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 21 of 58 
• Intraocular Pressure (IOP) 
• Dilated fundoscopy 
6.3 
Secondary Endpoints 
• Visual analog scale eye dryness score 
 
in CAE  
• Ora Calibra® Ocular Discomfort Scale 
 
in CAE 
• Schirmer’s Test 
 on Day 1  
 
6.4 
Exploratory Endpoints 
• Visual analog scale eye dryness score 
excluding 
CAE) 
• Ora Calibra® Ocular Discomfort Scale 
excluding 
CAE) 
• Ocular Discomfort & 4-Symptom Questionnaire 
 
and before and after CAE 
• Ora Calibra® Conjunctival Allergen Challenge Ocular Itching Scale assessed 
 
• Change in tear RASP levels 
 
 
• Conjunctival Redness 
 
• 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 
 
 
 
  
 
 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 22 of 58 
7.1.3 Study Drug Storage and Accountability 
 
 
 
  
 
 
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 14 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.  
 
 
 
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 
 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. 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 23 of 58 
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 or vehicle in a 1:1 ratio. Patients will be assigned a 
randomization number and kit number via paper randomization list for the Initial 
Cohort and by IWRS for the Main Cohort. 
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. 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 24 of 58 
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 
 
with: 
o Ocular Dryness Visual Analog Scale 
  
o Ora Calibra® Ocular Discomfort Scale 
 
o Conjunctival Redness Photography 
 
 
 
• Slit Lamp Biomicroscopy with Conjunctival Redness assessment 
• Schirmer’s Test  
• Intraocular Pressure 




Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 26 of 58 
o Weigh Schirmer’s Test strip before and after use 
• Schedule for Visit 3 
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 
 
• In-Office Dose #1 
 
• CAE Exposure 
 with: 
o Ocular Dryness Visual Analog Scale 
  
o Conjunctival Redness 
 
 
  
o Ora Calibra® Ocular Discomfort Scale 
 
• In-Office 
 
  
• Post-CAE exit 
 
• In-Office Dose #3 
 
• 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  
• Post-dose #3 
 
• Slit Lamp Biomicroscopy 
• Intraocular Pressure 
• Dilated Exam 
• Study Exit 
 
 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 27 of 58 
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; 
• Assessment of Adverse Events; 
• Assessment of concurrent medications and/or treatments; and 
• Any other assessments needed in the judgment of the investigator. 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 28 of 58 
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) 
• 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. 
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. 
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. 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 29 of 58 
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 
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; 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 30 of 58 
• 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; 
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; 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 31 of 58 
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. 
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 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 32 of 58 
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 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. 
 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 33 of 58 
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: 
• 
 
 
 
 
 
 
 
 
 
 
 
 
  
All analyses will be performed for the ITT population and, in addition, on the PP population as 
sensitivity analyses, as needed. Descriptive statistics of safety data will be calculated for the 
safety population.   
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.  
  
 
   
  
 
 
 
 
10.3 Sample Size 
Assuming a difference of 
 
 
 
, 149 evaluable subjects per arm will have 
 to detect a 
statistically significant difference at a two-sided alpha level 
. These estimates are based on 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 34 of 58 
the
 
from the ADX-102-DED-024 study. 
10.4 Statistical Analysis 
10.4.1 General Considerations 
Quantitative variables will be summarized descriptively using number of subjects (n), mean, 
standard deviation, median, minimum, and maximum.  Qualitative variables will be 
summarized using counts and percentages. 
All summaries will be presented by treatment group.  Summaries will be provided for 
demographics, baseline medical history, concurrent therapies, and subject disposition. 
For the purpose of summarization, medical history, concurrent therapies, and adverse events will 
be coded to MedDRA and WHODrug dictionaries, as appropriate.  
 
Baseline measures are defined 
 
  
 
  
 
 
 
All analyses will be 
 will be 
provided where appropriate. 
The statistical analysis plan (SAP) will detail the statistical procedures, and will dominate any 
text herein. 
10.4.2 Unit of Analysis 
Safety endpoints will be analyzed for both eyes.  
 
 
 
 
 Assessment scales are detailed 
in the Appendices. 
10.4.3 Missing Data 
As sensitivity measures, efficacy analyses will be conducted with multiple imputation utilizing 
methods such as treatment-based 
 
 Per-
protocol population analysis will also be conducted to assess sensitivity. Further details and 
changes will be described in the SAP. 
10.4.4 Multiplicity Considerations 
 
 
 
.  




Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 36 of 58 
10.4.6 Secondary Efficacy Analyses 
For secondary efficacy endpoints during the 
 CAE, 
 
 
 
 
 
The primary efficacy analysis 
 
 will be analyzed 
 
 
 
Primary analyses of secondary efficacy endpoints will utilize the ITT population with observed 
data only. 
10.4.7  Exploratory Efficacy Analyses 
For efficacy endpoints recorded 
 
 
 
 will be utilized. 
 
 
 
  
 
 
 
 
 
All efficacy analyses conducted on the ITT population will be conducted using the Initial Cohort 
population only with observed data. 
Additional exploratory efficacy analyses may be conducted. Further details of the exploratory 
analysis plan will be described in SAP. 
10.4.8 Safety Variables 
Adverse events will be coded using the MedDRA dictionary. 
Frequencies and percentages will be provided per treatment group of subjects with treatment-
emergent adverse events (TEAEs), serious TEAEs, and TEAEs causing premature 
discontinuation. An adverse event is treatment-emergent if it occurs or worsens after the first dose 
of randomized study treatment. Furthermore, frequencies will be given of subjects with TEAEs by 
system organ class, by system organ class and preferred term, by system organ class, preferred 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 37 of 58 
term and maximal severity, by system organ class, preferred term and strongest relationship, and 
by system organ class, preferred term, maximal severity, and strongest relationship. Separate 
analyses will be performed for ocular specific and all adverse events (including systemic). 
 
 
  
 
  
 
11 COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES 
The ADX-102-DED-019 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. 
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-019 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. 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 38 of 58 
11.2 Ethical Conduct of the Study 
The ADX-102-DED-019 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. 
 
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. 
 
 
  


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 39 of 58 
Each pouch will contain five ampules to provide a sufficient supply of 
randomized study drug. 
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. 
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 
See Appendix 2 “Examination Procedures, Tests, Equipment, and Techniques” for 
tear collection procedures.  Processing, shipping, and handling procedures will be 
done by following the Laboratory Manual. 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 40 of 58 
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 
Augustin AJ, Spitznas M, Kaviani N, Meller D, Koch FH, Grus F, Göbbels MJ. Oxidative 
reactions in the tear fluid of patients suffering from dry eyes. Graefes Arch Clin Exp 
Ophthalmol. 1995 Nov;233(11):694-8. PubMed PMID: 8566825. 
Boyer NP, Higbee D, Currin MB, Blakeley LR, Chen C, Ablonczy Z, Crouch RK, Koutalos Y. 
Lipofuscin and N-retinylidene-N-retinylethanolamine (A2E) accumulate in retinal pigment 
epithelium in absence of light exposure: their origin is 11-cis-retinal. J Biol Chem. 2012 
Jun 22;287(26):22276-86. doi: 10.1074/jbc.M111.329235. 
Choi W, Lian C, Ying L, Kim GE, You IC, Park SH, Yoon KC. Expression of Lipid Peroxidation 
Markers in the Tear Film and Ocular Surface of Patients with Non-Sjogren Syndrome: 
Potential Biomarkers for Dry Eye Disease. Curr Eye Res. 2016 Sep;41(9):1143-9. doi: 
10.3109/02713683.2015.1098707. 
Esterbauer H, Schaur RJ, Zollner H. Chemistry and biochemistry of 4-hydroxynonenal, 
malonaldehyde and related aldehydes. Free Radic Biol Med. 1991;11(1):81-128. Review. 
PubMed PMID: 1937131. 
Gomes PJ, Brady TC, Hollander D, Clark D. A Randomized, Multi-Center, Double-Masked, 
Vehicle-Controlled, Parallel-Group Phase 2b Allergic Conjunctivitis Clinical Trial of 
Topical Ocular ADX-102, a Novel Aldehyde Sequestering Agent.Investigative 
Ophthalmology & Visual Science July 2018, Vol.59, 5571 
O'Brien PJ, Siraki AG, Shangari N. Aldehyde sources, metabolism, molecular toxicity 
mechanisms, and possible effects on human health. Crit Rev Toxicol. 2005 Aug;35(7):609-
62. Review. PubMed PMID: 16417045. 
 
Mandell KJ, Clark D, Chu DS, Foster CS, Sheppard J, Brady TC. Randomized Phase 2 Trial of 
Reproxalap, a Novel Reactive Aldehyde Species Inhibitor, in Patients with Noninfectious 
Anterior Uveitis: Model for Corticosteroid Replacement. J Ocul Pharmacol Ther. 2020 Sep 
22. doi: 10.1089/jop.2020.0056. 
 
Schaumberg, D.A.; Dana, R.; Buring, J.E.; Sullivan, D.A. 2009. 'Prevalence of dry eye disease 
among US men: estimates from the Physicians' Health Studies', Arch Ophthalmol, 127: 
763-8. 
 
Sheppard J, Brady TC; Ousler G, Hollander D, Clark, d. A Multi-Center, Randomized, Double-
Masked, Parallel-Group, Vehicle-Controlled Phase 2b Dry Eye Disease Clinical Trial to 
Evaluate the Safety and Efficacy of Topical Ocular Reproxalap, a Novel RASP Inhibitor. 
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 5206 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 41 of 58 
Appendix 1:  Schedule of Visits and Measurements 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 42 of 58 
Appendix 2: Examination Procedures, Tests, Equipment, and Techniques 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
Confidential 
 
Page 43 of 58 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
Confidential 
 
Page 44 of 58 
 
 
 
 
 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 45 of 58 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
Confidential 
 
Page 46 of 58 
 
 
 
 
 
 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 47 of 58 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
Confidential 
 
Page 48 of 58 
 
 
 
 
 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 49 of 58 
 
 
 
 
 




Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 51 of 58 
Appendix 3:  Amendment Summary of Changes Table  


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
Confidential 
 
Page 52 of 58 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
Confidential 
 
Page 53 of 58 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 54 of 58 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
Confidential 
 
Page 55 of 58 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
Confidential 
 
Page 56 of 58 


Clinical Trial Protocol: ADX-102-DED-019 
Ora, Inc. 
Amendment 3.0 5Nov2021 
Confidential 
Page 57 of 58 
Appendix 4:  Sponsor and Ora Approvals 
Protocol Title: 
The TRANQUILITY Trial: A Multi-Center Randomized, Double-
Masked, Parallel Design, Vehicle-Controlled Phase 2/3 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-019 
Protocol Date: 
5 November 2021 
This clinical trial protocol was subject to critical review and has been approved by the Sponsor. 
The following personnel contributed to writing and/or approving this protocol. 


Clinical Trial Protocol: ADX-102-DED-019  
 
 
 
 
 
 
Ora, Inc. 
 
 Amendment 3.0 5Nov2021 
 
 
Confidential 
 
Page 58 of 58 
Appendix 5:  Investigator’s Signature 
 
Protocol Title: 
The TRANQUILITY Trial: A Multi-Center Randomized, Double-
Masked, Parallel Design, Vehicle-Controlled Phase 2/3 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-019 
Protocol Date: 
5 November 2021 
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. 


Document History
SignNow E-Signature Audit Log
All dates expressed in MM/DD/YYYY (US)
Document name:
Signature Page
Document created:
11/05/2021 16:27:06
Document pages:
1
Document ID:
6b9c6d672c14474e8623b17fb5d4d355c0b6be7b
Document Sent:
11/05/2021 16:28:14 UTC
Document Status:
Signed
11/05/2021 16:28:39UTC

SAP_001.pdf: 
 
STATISTICAL ANALYSIS PLAN  
The TRANQUILITY Trial: A Multi-Center Randomized, Double-Masked, 
Parallel Design, Vehicle-Controlled Phase 2/3 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-019 
 
 
Author:   
 
 
 
 
 
Date:    
 
17-NOV-2021 
Version:  
 
2.0 
 
SIGN


 
 
 
Page 2 of 41 
 
The TRANQUILITY Trial: A Multi-Center Randomized, Double-Masked, Parallel Design, Vehicle-
Controlled Phase 2/3 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-019 
 
SAP Version:   
2.0 
SAP Date:   
 
17-NOV-2021 
 
Statistical Analysis Plan Approval 
 
 
 
 
 
 
Prepared by: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reviewed by:  
 
 
 
 
          
_____________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
17-Nov-2021 | 15:22 MST
17-Nov-2021 | 19:24 EST




Protocol ADX-102-DED-019 SAP, Version 2.0 
 
Confidential & Proprietary 
Page 3 of 41 
 
 
 
 
 
 
Approved by: 
 
 
 
 
 
 
 
 
 
 
 
Approved by: 
 
 
 
 


Document History
SignNow E-Signature Audit Log
All dates expressed in MM/DD/YYYY (US)
Document name:
Aldeyra ADX-102-DED-019 Statistical Analysis Plan V2.0 17-NOV-2021
Document created:
11/17/2021 22:20:14
Document pages:
41
Document ID:
32f5fbfe725245dca5b1a6008fa3f33e31893ae2
Document Sent:
11/17/2021 22:20:48 UTC
Document Status:
Signed
11/17/2021 23:39:40UTC


Protocol ADX-102-DED-019 SAP, Version 2.0 
 
Confidential & Proprietary 
Page 3 of 41 
 
 
 
 
 
 
Approved by
 
 
 
 
 
 
 
 
 
 
 
Approved by:
 
 
 
 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 4 of 41 
 
Table of Contents 
1. 
Introduction .............................................................................................................................. 9 
2. 
Study Objectives ...................................................................................................................... 9 
3. 
Study Endpoints ....................................................................................................................... 9 
3.1 Primary Endpoints .................................................................................................................... 9 
3.2 Secondary Variables ................................................................................................................ 9 
3.3 Exploratory Variables ............................................................................................................... 9 
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 ..................................................................................... 12 
5. 
Study Treatments ................................................................................................................... 13 
5.1 Method of Assigning Subjects to Treatment Groups ............................................................. 13 
5.2 Masking and Unmasking ........................................................................................................ 13 
6. 
Sample Size and Power Considerations ................................................................................ 13 
7. 
Data Preparation .................................................................................................................... 14 
7.1 Input Data ............................................................................................................................... 14 
7.2 Output Data ............................................................................................................................ 14 
8. 
Analysis Populations .............................................................................................................. 15 
8.1 Intent-to-Treat......................................................................................................................... 15 
8.2 Initial Cohort ........................................................................................................................... 15 
8.3 Per Protocol ............................................................................................................................ 15 
8.4 Safety ..................................................................................................................................... 15 
9. 
General Statistical Considerations ......................................................................................... 15 
9.1 Unit of Analysis ...................................................................................................................... 15 
9.2 Missing or Inconclusive Data Handling .................................................................................. 15 
9.3 Definition of Baseline ............................................................................................................. 16 
9.4 Data Analysis Conventions .................................................................................................... 16 
9.5 Adjustments for Multiplicity ..................................................................................................... 17 
10. 
Disposition of Subjects ........................................................................................................... 17 
11. 
Demographic, Previous Participation in Reproxalap Trials, and Pretreatment Variables ..... 18 
11.1 Demographic Variables .......................................................................................................... 18 
11.2 Previous Participation in Reproxalap Trials ........................................................................... 18 
11.3 Pretreatment Variables .......................................................................................................... 19 
12. 
Medical History and Concomitant Medications ...................................................................... 19 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 5 of 41 
12.1 Medical History ....................................................................................................................... 19 
12.2 Concomitant Medications and Procedures ............................................................................ 19 
13. 
Dosing Compliance and Treatment Exposure ....................................................................... 20 
13.1 Dosing Compliance ................................................................................................................ 20 
13.2 Treatment Exposure ............................................................................................................... 20 
14. 
Efficacy Analyses ................................................................................................................... 20 
14.1 Primary Analysis .................................................................................................................... 21 
14.1.1 
Primary Analyses Methods ........................................................................................ 21 
14.1.1.1 
Mixed Model Repeated Measures 
...................... 22 
14.1.1.2 
Mixed Model Repeated Measures 
 ........ 22 
14.1.1.3 
Additional Sensitivity Analyses ........................................................................... 23 
14.2 Secondary Analyses .............................................................................................................. 23 
14.2.1 
Overall Mean Change from Baseline of Eye Dryness Score (VAS) 
 
 
.................................................................................... 23 
14.2.2 
Overall Mean Change From Baseline of Ocular Discomfort Scale (Ora Calibra® Scale)  
 
 
..................................................... 24 
14.2.3 
Unanesthetized Schirmer’s Test at Visit 2 (Day 1) 
 24 
14.3 Exploratory Analyses ............................................................................................................. 25 
14.3.1 
Eye Dryness Score from the Visual Analog Scale
 
 
 
14.3.2 
Ocular Discomfort Scale (Ora Calibra® Scale)  
 
 
 
14.3.3 
Ocular Discomfort & 4-Symptom Questionnaire (Ora Calibra® Scale) ...................... 26 
14.3.3.1 
Ocular Discomfort & 4-Symptom Questionnaire (Ora Calibra® Scale) 
 
14.3.3.2 
Ocular Discomfort & 4-Symptom Questionnaire (Ora Calibra® Scale) 
 
 
 
14.3.4 
Conjunctival Allergen Challenge Ocular Itching Scale (Ora Calibra® Scale) ............. 26 
14.3.4.1 
Conjunctival Allergen Challenge Ocular Itching Scale (Ora Calibra® Scale) 
  
14.3.4.2 
Conjunctival Allergen Challenge Ocular Itching Scale (Ora Calibra® Scale)  
 
 
 
 
14.3.5 
Conjunctival Redness 
 
27 
14.3.6 
Tear Reactive Aldehyde Species 
 27 
14.3.7 
Conjunctival Redness (Ora Calibra® Scale) 
 
14.3.8 
Eye Dryness (VAS) 
 28 
14.3.9 
Ocular Discomfort Scale (Ora Calibra® Scale) 
 
28 
15. 
Efficacy Analyses of the Initial Cohort .................................................................................... 28 
16. 
Summary of Efficacy Analyses .............................................................................................. 29 
17. 
Safety Analyses ..................................................................................................................... 29 
17.1 Adverse Events ...................................................................................................................... 29 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 6 of 41 
17.1.1 
Severity ...................................................................................................................... 30 
17.1.2 
Relationship to Study Procedures .............................................................................. 31 
17.1.3 
Expectedness ............................................................................................................. 31 
17.1.4 
Serious Adverse Events ............................................................................................. 32 
17.2 Visual Acuity (Early Treatment Diabetic Retinopathy Study) ................................................. 32 
17.3 Slit-Lamp Biomicroscopy ........................................................................................................ 33 
17.4 Dilated Fundoscopy Examination........................................................................................... 33 
17.5 Intraocular Pressure (IOP) ..................................................................................................... 33 
18. 
Changes from Protocol-Stated Analyses ............................................................................... 33 
19. 
References ............................................................................................................................. 33 
20. 
Revision History ..................................................................................................................... 33 
21. 
Tables ..................................................................................................................................... 34 
22. 
Listings ................................................................................................................................... 39 
 
 
 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 7 of 41 
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 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 8 of 41 
WHODrug 
World Health Organization Drug Dictionary 
 
 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 9 of 41 
1. Introduction 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and reporting for 
protocol ADX-102-DED-019, Amendment 3.0, dated 5-NOV-2021. 
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 reactive aldehyde species 
(RASP) levels, Schirmer’s Test, and symptoms after dosing 
 to the Controlled 
Adverse Environment® (CAE®) in subjects with dry eye disease (DED). 
3. Study Endpoints 
3.1 
Primary Endpoints 
The primary efficacy variable is the following: 
• 
Conjunctival redness 
 
3.2 
Secondary Variables 
The secondary efficacy variables are the following: 
• 
Visual analog scale (VAS) eye dryness score 
 
  
• 
Ora Calibra® Ocular Discomfort Scale 
 
 
• 
Schirmer’s Test 
 
 
3.3 
Exploratory Variables 
The exploratory efficacy variables are the following: 
• 
VAS eye dryness score 
 
• 
Ora Calibra® Ocular Discomfort Scale 
 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 10 of 41 
• 
Ocular Discomfort & 4-Symptom Questionnaire 
 
 
• 
Ora Calibra® Conjunctival Allergen Challenge Ocular Itching Scale 
 
 
• 
Change in tear RASP levels 
 
• 
Conjunctival redness 
 
• 
Conjunctival redness, Ora Calibra® Ocular Discomfort Scale, and VAS dryness score 
 
 
3.4 
Safety Variables 
The safety variables include the following:  
• 
Visual acuity 
• 
Slit-lamp evaluation 
• 
Adverse event (AE) query 
• 
Intraocular Pressure (IOP) 
• 
Dilated fundoscopy 
3.5 
Statistical Hypotheses 
The following hypothesis will be tested comparing reproxalap to vehicle. The null hypothesis 
must be rejected for the dosing regimen to claim efficacy. 
 
 
 
 
 
 
3.6 
Estimands 
The primary comparisons in this trial will be between reproxalap versus vehicle 
 
 
 
Estimand 1  
• 
 
 
  
 
 
 
 
  


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 11 of 41 
o 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
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 
 
 
 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 12 of 41 
4.2 
Schedule of Visits and Assessments 
Table 2. Schedule of Visits and Assessments 
 
 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 13 of 41 
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. 
Planned unmasking was executed for subjects in the initial cohort for sample size and power calculations.  
6. Sample Size and Power Considerations 
 
 
 
 
 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 14 of 41 
 
 
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 
 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 obtainded 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 following the 
 
 
 
SDTM will follow the 
l and will be implemented using the 
 
 at the time of study start. 
 
 
 
 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 15 of 41 
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. Subjects in the initial cohort will not be included in the ITT Population for 
efficacy analyses. 
 
 
 
 
 
 
 
8.2 
Initial Cohort 
The Initial Cohort Population includes all randomized subjects in the Initial Cohort. Subjects in the Initial 
Cohort will be analyzed as randomized. 
8.3 
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. 
8.4 
Safety 
The Safety Population includes all randomized subjects who receive at least one dose of investigational 
product. Subjects in the Safety Population will be analyzed as treated. The Safety Population includes 
subjects in the initial cohort who receive at least one dose of investigational product. 
9. General Statistical Considerations 
9.1 
Unit of Analysis 
Safety endpoints will be analyzed 
 
 
 
 
 
 
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: 
  


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 16 of 41 
• 
 
 
  
 
 
 
 
 
 
 
 
Partial/missing end date:  
• 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
The PP population analysis will also be conducted to 
assess sensitivity. 
9.3 
Definition of Baseline 
Baseline is defined  
 
 
 
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 
 
 
 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 17 of 41 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
9.5 
Adjustments for Multiplicity 
The primary endpoint of the overall mean change from baseline of conjunctival redness 
 
 
 
 
 
10. Disposition of Subjects 
Subject disposition will be presented in terms of the numbers and percentages of subjects who were 
randomized 
 
 
 
 
  
 
 
 
 
 
. A subject listing will be provided that includes the date 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 18 of 41 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 In addition, a listing of all subjects affected by 
COVID-19 will be produced. 
11. Demographic, Previous Participation in Reproxalap Trials, and Pretreatment Variables 
11.1 
Demographic Variables 
The demographic variables collected in this study 
 
 
 
. 
Age (years) will be summarized, overall and by treatment, using continuous descriptive statistics.  
 
 
 
 
 
 
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.  
 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 19 of 41 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
 
 
 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 
. 
 
 
 
 
 
. 
Listings of medical history will be generated separately for ocular and non-ocular data. 
12.2 
Concomitant Medications and Procedures 
Concomitant medications and procedures will be coded using World Health Organization Drug Dictionary 
 
 
 
 
 
 
 
 
 
 
 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 20 of 41 
 
 
 
 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 (% compliance) will be assessed 
 
 
 
 
 
 
 
 
  
A subject listing of dosing compliance will also be produced. 
13.2 
Treatment Exposure 
Extent of treatment exposure for subjects 
 
 
 
 
 
. A subject listing of treatment 
exposure will also be produced. 
14. Efficacy Analyses 
All efficacy analyses described in this section will have SAS code specified in the SAP 
 
 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 21 of 41 
14.1 
Primary Analysis 
The primary endpoint will be deemed to have been met 
 
 
 
 
 
14.1.1 PRIMARY ANALYSES METHODS 
The endpoint of overall mean change from baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 22 of 41 
14.1.1.1 
MIXED MODEL REPEATED MEASURES 
 
 
 
Overall mean change from baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14.1.1.2 
MIXED MODEL REPEATED MEASURES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 23 of 41 
14.1.1.3 
ADDITIONAL SENSITIVITY ANALYSES 
Additional sensitivity analyses will be performed 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
14.2 
Secondary Analyses 
14.2.1 OVERALL MEAN CHANGE FROM BASELINE OF EYE DRYNESS SCORE (
 
 
 
 
 
 
 
 
Subjects will be 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
  
 
 
 
. A subject listing of the eye dryness during 
the CAE will be generated. 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 24 of 41 
14.2.2 OVERALL MEAN CHANGE FROM BASELINE OF OCULAR DISCOMFORT SCALE (ORA CALIBRA® SCALE)  
 
 
 
 
 
Ocular Discomfort will be assessed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
A subject listing of the Ocular Discomfort 
Scale during the CAE® will be generated. 
14.2.3 UNANESTHETIZED SCHIRMER’S TEST 
 
 
 
 
Unanesthetized Schirmer’s test will be assessed for each eye. 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 A subject listing of the 
unanesthetized Schirmer’s test will be generated. 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 25 of 41 
14.3 
Exploratory Analyses 
14.3.1 EYE DRYNESS SCORE FROM THE VISUAL ANALOG SCALE 
 
 
 
 
 
 
 
Subjects will be asked to rate eye dryness 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 A subject listing of the eye dryness outside 
of the CAE® will be generated. 
14.3.2 OCULAR DISCOMFORT SCALE (ORA CALIBRA® SCALE)  
 
 
 
 
 
 
 
Ocular Discomfort Scale will be assessed 
 
 
 
 
 
 
 
 
 
 
  
 
 
   


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 26 of 41 
 A subject listing of the Ocular Discomfort 
Scale outside of the CAE® will be generated. 
14.3.3 OCULAR DISCOMFORT & 4-SYMPTOM QUESTIONNAIRE (ORA CALIBRA® SCALE) 
Ocular Discomfort and dry eye symptoms will be assessed 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
    
 A subject listing of the Ocular Discomfort & 
4-Symptom Questionnaire will be generated. 
14.3.3.2 
OCULAR DISCOMFORT & 4-SYMPTOM QUESTIONNAIRE (ORA CALIBRA® SCALE) 
 
 
 
Overall mean CFB of each Ocular Discomfort & 4-Symptom Questionnaire 
 
 
 
 
 
 
  
 A subject listing of the Ocular Discomfort & 
4-Symptom Questionnaire will be generated. 
14.3.4 CONJUNCTIVAL ALLERGEN CHALLENGE OCULAR ITCHING SCALE (ORA CALIBRA® SCALE) 
Subjects will rate the severity of their ocular itching symptom
 
 
 
.  
14.3.4.1 
CONJUNCTIVAL ALLERGEN CHALLENGE OCULAR ITCHING SCALE (ORA CALIBRA® SCALE)  
  
 
 
 
 
Overall mean CFB of ocular itching 
 
 
 
 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 27 of 41 
 
 
   
A subject listing of the Conjunctival Allergen 
Challenge Ocular Itching Scale will be generated. 
14.3.4.2 
CONJUNCTIVAL ALLERGEN CHALLENGE OCULAR ITCHING SCALE (ORA CALIBRA® SCALE)  
 
 
 
Overall mean CFB of ocular itching 
 
 
 
 
 
 
 
  
14.3.5 CONJUNCTIVAL REDNESS (ORA CALIBRA SCALE 
 
 
 
 
 
Each subject eye at each visit/time point will be assessed 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 A subject listing of the conjunctival redness 
outside of the CAE® will be generated. 
14.3.6 TEAR REACTIVE ALDEHYDE SPECIES 
 
 
 
 
Tears will be collected 
 
 
 
 
 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 28 of 41 
 
  
 
 
   
A subject listing of the tear RASP will be 
generated. 
14.3.7 CONJUNCTIVAL REDNESS (ORA CALIBRA® SCALE) 
 
 
 
 
 
 
For conjunctival redness during the CAE® 
 
 
 
 
 
 
 
14.3.8 EYE DRYNESS (VAS) 
 
 
 
 
 
 
For eye dryness (VAS) 
 
 
 
 
 
 
 
 
 
14.3.9 OCULAR DISCOMFORT SCALE (ORA CALIBRA® SCALE) 
 
 
 
 
 
 
For ocular discomfort 
 
 
 
 
 
 
 
15. Efficacy Analyses of the Initial Cohort 
All efficacy analyses stated in section 14 using the ITT population will be repeated using the Initial Cohort 
only with the following exceptions: 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 29 of 41 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
16. Summary of Efficacy Analyses 
A summary of all efficacy analyses will be presented. 
 
 
 
 
 
17. Safety Analyses 
All safety analyses will be conducted using the Safety Population using observed data only. 
17.1 
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 
  
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. 
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 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 30 of 41 
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 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. 
17.1.1 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 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: 
• 
 
 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 31 of 41 
• 
 
 
 
 
 
 
Subjects experiencing more than one AE within a given SOC or PT are counted once within that SOC or 
PT for the maximal severity. 
17.1.2 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. 
17.1.3 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. 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 32 of 41 
17.1.4 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. 
17.2 
Visual Acuity (Early Treatment Diabetic Retinopathy Study) 
The logarithm of the minimum angle of resolution (
 
  
 
A subject listing of visual acuity will also be produced. 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 33 of 41 
17.3 
Slit-Lamp Biomicroscopy 
A slit-lamp biomicroscopy 
 
 
 
 
 
 
 
 A subject listing of the slit-lamp biomicroscopy parameters will also be 
produced. 
17.4 
Dilated Fundoscopy Examination 
An dilated fundoscopy examination 
 
 
  
 
 
 
A subject listing of the dilated fundoscopy parameters will also be produced. 
17.5 
Intraocular Pressure (IOP) 
Subjects’ IOP 
 
 
 
. A subject listing of IOP will also be produced. 
18. Changes from Protocol-Stated Analyses 
There are no changes from protocol-stated analyses.  
19. References 
No references cited. 
20. Revision History 
Documentation of revision to the SAP will commence after approval of the final version 1.0. 
20.1 
Revision 01 
This revision was issued following 
 
 
 
 
 
 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 34 of 41 
21. Tables 
Tables (10 tables) in boldface font will be delivered in topline package. 
Table Number 
Title 
Population 
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 
Participation in Previous 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 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 35 of 41 
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 14.1.5.3 
Ocular Concomitant Procedures  
ITT Population 
Table 14.1.5.4  
Non-Ocular Concomitant Procedures  
ITT Population 
Table 14.2.1.1  
Overall 
Mean 
Change 
from 
Baseline 
of 
Conjunctival Redness (Ora Calibra Scale) during 
 
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 
Conjunctival Redness (Ora Calibra Scale) 
 
   
ITT Population with 
Observed Data Only 
Table 14.2.1.4  
Overall Mean Change from Baseline of Conjunctival 
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 
Table 14.2.2.2 
Overall Mean Change from Baseline of Eye 
Dryness (Visual Analog Scale) 
 
   
ITT Population with 
Observed Data Only 
Table 14.2.2.3   
Overall Mean Change from Baseline of Ocular 
Discomfort Scale (Ora Calibra Scale) 
 
   
ITT Population with 
Observed Data Only 
Table 14.2.2.4   
Overall Mean Change from Baseline of Ocular 
Discomfort Scale (Ora Calibra Scale) 
 
   
ITT Population with 
Observed Data Only 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 36 of 41 
Table 14.2.2.5 
Unanethetized Schirmer’s Test 
 
 
ITT Population with 
Observed Data Only 
Table 14.2.3.1   
Eye Dryness (Visual Analog Scale) 
 
   
ITT Population with 
Observed Data Only 
Table 14.2.3.2 
Ocular Discomfort Scale (Ora Calibra Scale) 
 
 
ITT Population with 
Observed Data Only 
Table 14.2.3.3   
Ocular Discomfort & Four-Symptom Questionnaire 
(Ora Calibra Scale) 
 
 
ITT Population with 
Observed Data Only 
Table 14.2.3.4   
Ocular Discomfort & Four-Symptom Questionnaire 
(Ora Calibra Scale) 
 
 
ITT Population with 
Observed Data Only 
Table 14.2.3.5  
Conjunctival Allergen Challenge Ocular Itching Scale 
(Ora Calibra Scale) 
 
  
ITT Population with 
Observed Data Only 
Table 14.2.3.6 
Conjunctival Allergen Challenge Ocular Itching Scale 
(Ora Calibra Scale) 
 
 
ITT Population with 
Observed Data Only 
Table 14.2.3.7  
Tear Reactive Aldehyde Species 
 
ITT Population with 
Observed Data Only 
Table 14.2.3.8  
Conjunctival Redness (Ora Calibra Scale) 
 
 
ITT Population with 
Observed Data Only 
Table 14.2.3.9 
Conjunctival Redness (Ora Calibra Scale) 
 
 
ITT Population with 
Observed Data Only 
Table 14.2.3.10 
Eye Dryness (Visual Analog Scale) 
 
 
ITT Population with 
Observed Data Only 
Table 14.2.3.11 
Ocular Discomfort Scale (Ora Calibra Scale) 
 
 
ITT Population with 
Observed Data Only 
Table 14.2.4.1  
Overall Mean Change from Baseline of Conjunctival 
Redness (Ora Calibra Scale) 
 
Initial 
Cohort 
Population 
with 
Observed Data Only 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 37 of 41 
Table 14.2.4.2 
Overall Mean Change from Baseline of Eye Dryness 
(Visual Analog Scale) 
 
   
Initial 
Cohort 
Population 
with 
Observed Data Only 
Table 14.2.4.3 
Overall Mean Change from Baseline of Eye Dryness 
(Visual Analog Scale) 
 
   
Initial 
Cohort 
Population 
with 
Observed Data Only 
Table 14.2.4.4 
Overall Mean Change from Baseline of Ocular 
Discomfort Scale (Ora Calibra Scale) 
 
 
Initial 
Cohort 
Population 
with 
Observed Data Only 
Table 14.2.4.5 
Overall Mean Change from Baseline of Ocular 
Discomfort Scale (Ora Calibra Scale) 
 
 
Initial 
Cohort 
Population 
with 
Observed Data Only 
Table 14.2.4.6 
Unanesthetized Schirmer’s Test 
 
 
Initial 
Cohort 
Population 
with 
Observed Data Only 
Table 14.2.4.7 
Eye Dryness (Visual Analog Scale) 
 
   
Initial 
Cohort 
Population 
with 
Observed Data Only 
Table 14.2.4.8 
Ocular Discomfort Scale (Ora Calibra Scale) 
 
 
Initial 
Cohort 
Population 
with 
Observed Data Only 
Table 14.2.4.9 
Ocular Discomfort & Four-Symptom Questionnaire 
(Ora Calibra Scale) 
 
  
Initial 
Cohort 
Population 
with 
Observed Data Only 
Table 14.2.4.10 
Tear Reactive Aldehyde Species 
 
Initial 
Cohort 
Population 
with 
Observed Data Only 
Table 14.2.4.11 
Conjunctival Redness (Ora Calibra Scale)
 
 
Initial 
Cohort 
Population 
with 
Observed Data Only 
Table 14.2.4.12 
Eye Dryness (Visual Analog Scale) 
 
 
Initial 
Cohort 
Population 
with 
Observed Data Only 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 38 of 41 
Table 14.2.4.13 
Ocular Discomfort Scale (Ora Calibra Scale) 
 
 
Initial 
Cohort 
Population 
with 
Observed Data Only 
Table 14.2.5 
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 
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 
Safety Population 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 39 of 41 
Severity, and Strongest Relationship to Study 
Procedure  
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 (ETDRS) 
  
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 
22. Listings 
 
Listing Number 
Title 
Population 
Listing 16.1.7  
Randomization Schedule  
All 
Randomized 
Subjects 
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 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 40 of 41 
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  
Eye Dryness (Visual Analog Scale) 
 
  
All 
Randomized 
Subjects 
Listing 16.2.6.4  
Eye Dryness (Visual Analog Scale) 
 
  
All 
Randomized 
Subjects 
Listing 16.2.6.5  
Ocular Discomfort Scale (Ora Calibra 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 & 4-Symptom Questionnaire (Ora 
Calibra Scale)  
All 
Randomized 
Subjects 
Listing 16.2.6.8  
Conjunctival Allergen Challenge Ocular Itching Scale 
(Ora Calibra Scale)  
All 
Randomized 
Subjects 
Listing 16.2.6.9  
Tear Reactive Aldehyde Species  
All 
Randomized 
Subjects 
Listing 16.2.6.10 
Unanesthetized Schirmer’s Test 
All 
Randomized 
Subjects 
Listing 16.2.6.11  
Fluorescein Corneal and Conjunctival Staining (Ora 
Calibra Scale)  
All 
Randomized 
Subjects 


Protocol ADX-102-DED-019 SAP, Version 2.0 
17-NOV-2021 
Confidential & Proprietary 
Page 41 of 41 
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