Clinical trial NCT05062330
Conditions: Dry Eye
Sponsor: Aldeyra Therapeutics, Inc.
Start date: 2021-08-28; Completion date: 2022-03-04
Enrollment: 361 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The TRANQUILITY 2 Trial: Multi-Center Randomized, Double-Masked, Parallel Design, Vehicle-Controlled Phase 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 Ophthalmic Solution
Intervention descriptions: intervention 1: Reproxalap Ophthalmic Solution (0.25%) administered 7 times over two consecutive days intervention 2: Vehicle Ophthalmic Solution administered 7 times over two consecutive days

Protocol documents:
Prot_SAP_000.pdf: 
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Clinical Trial Protocol: ADX-102-DED-023 
Protocol Title: 
The TRANQUILITY 2 Trial: A Multi-Center 
Randomized, Double-Masked, Parallel Design, 
Vehicle-Controlled Phase 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-023  
Study Phase: 
3 
Investigational Product Name: 
0.25% Reproxalap Ophthalmic Solution  
 
 
Indication: 
Dry Eye Disease (DED) 
Investigator: 
Multi-Center 
Sponsor/Contract Research 
Organization: 
Aldeyra Therapeutics, Inc. 
131 Hartwell Ave. 
Lexington, MA 02421 USA 
IRB/IEC: 
 
 
 
 
 
 
Date 
 
 
 
 
Amendment #2: 
18May2022 
Confidentiality Statement: This protocol contains confidential, proprietary information of 
 
Inc. and Aldeyra Therapeutics, Inc. Further dissemination, distribution, or copying of this 
protocol or its contents is strictly prohibited. 


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STUDY PERSONNEL 
SPONSOR PERSONNEL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MEDICAL MONITOR 
 
 
 
 
 
 
 
 
 


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SYNOPSIS 
Protocol Title: 
The TRANQUILITY 2 Trial: A Multi-Center 
Randomized, 
Double-Masked, 
Parallel 
Design, 
Vehicle-Controlled Phase 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-023 
Investigational Product: 
0.25% Reproxalap Ophthalmic Solution (reproxalap) 
Study Phase: 
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 
(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  


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• Visit 2 = Day 1, Randomization/Baseline 
• Visit 3 = Day 2 CAE & Study Exit 
 
Subjects will be randomized 1:1 to receive either 
reproxalap or vehicle.  
Measures Taken to Reduce Bias: 
ADX-102-DED-023 is a randomized treatment 
assignment, double-masked trial. 
Study Population Characteristics: 
Number of Subjects: 
Approximately 350 subjects are expected to be 
enrolled in the trial.  
Condition/Disease: 
Dry Eye Disease (DED) 
Inclusion Criteria: 
Subjects must meet all of the following criteria: 
1. 18 years of age (either gender and any race); 
2. Ability to provide written informed consent and 
sign the Health Information Portability and 
Accountability Act (HIPAA) form; 
3. Reported history of dry eye for 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; 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Exclusion Criteria: 
Subjects must not meet any of the following criteria: 


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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 
(bacterial, viral, or fungal), 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 
or 
other 
immunomodulator therapy (not including inhaled 
corticosteroids) 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 prescriptions (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 


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(logMAR) + 0.7 as assessed by Early Treatment 
of Diabetic Retinopathy Study (ETDRS) scale 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; 
17. Current enrollment in an investigational drug or 
device study or have used an investigational drug 
or device within 30 days of Visit 1; 
18. Use of reproxalap ophthalmic solution in the past 
year; 


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19. Current use of any medication 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 Endpoints: 
 
 
• Schirmer’s Test overall mean change from 
baseline (CFB) before and after the fourth dose 
on Day 1  
 
• Schirmer’s Test greater than or equal to 10mm 
responder analysis of change from baseline 
before and after the fourth dose on Day 1 
Secondary Endpoints: 
• Overall mean CFB of Conjunctival Redness over 
90 minutes in the CAE at Day 2 
• Overall mean CFB of Eye Dryness (VAS; Visual 
Analog Scale) over 90 minutes in the CAE at 
Day 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


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• 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
• Overall mean CFB of Conjunctival Redness over 
Days 1 and 2 (excluding CAE) 
Exploratory Endpoints: 
• Change in tear RASP levels before and after Dose 1 
and 2 on Day 1 and Dose 3 on Day 2 
• Conjunctival redness, 
 
 
 and visual analog scale dryness 
score by time point during the CAE 
 
Safety Endpoints: 
• Visual acuity 
• Slit-lamp evaluation 
• Adverse event query 
• Intraocular Pressure (IOP) 
• Dilated fundoscopy 
General Statistical Methods and Types of Analyses: 


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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. 
Multiplicity Considerations: 
To control for multiplicity among primary and secondary endpoints, endpoints will be tested in 
a fixed sequence at a study-wide two-sided alpha level of 0.05. The primary and secondary 
endpoints will be tested in the fixed testing sequence as follows: 
Primary Endpoint: 
1. Schirmer’s Test overall mean change from baseline (CFB) before and after the fourth 
dose on Day 1  
2. Schirmer’s Test greater than or equal to 10mm responder analysis of change from 
baseline before and after the fourth dose on Day 1 
Secondary Endpoints: 
3. Overall mean CFB of Conjunctival Redness over 90 minutes in the CAE at Day 2 
4. Overall mean CFB of Eye Dryness (VAS; Visual Analog Scale) over 90 minutes in the 
CAE at Day 2 
5. Overall mean CFB of Eye Dryness (VAS) assessed over Days 1 and 2 (excluding 
CAE) 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
 


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Formal statistical testing of primary and secondary endpoints in the fixed sequence will halt 
upon a P-value greater than or equal to 0.05. All remaining endpoints in the sequence will be 
considered exploratory. 
No type I error control will be utilized for exploratory endpoints; thus, exploratory 
comparisons are considered hypothesis generating. 
 
Sample Size: 
 
 
 
  
 
 
 
Primary Efficacy Analyses: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Safety Analyses: 
Safety endpoints will be summarized using descriptive statistics. For qualitative safety 
assessments, counts and percentages will be reported at the eye level and subject level, where 
appropriate. For quantitative safety assessments, endpoints will be summarized at the eye level 
using continuous summary statistics. 
 
Summary of Known and Potential Risks and Benefits to Human Subjects: 
Refer to Investigator’s Brochure. 


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TABLE OF CONTENTS 
Clinical Trial Protocol: ADX-102-DED-023 ....................................................................1 
SYNOPSIS ..........................................................................................................................3 
TABLE OF CONTENTS ................................................................................................12 
List of Abbreviations .......................................................................................................15 
1 
INTRODUCTION...................................................................................................16 
2 
STUDY OBJECTIVES ...........................................................................................17 
3 
CLINICAL HYPOTHESES ..................................................................................17 
4 
OVERALL STUDY DESIGN ................................................................................18 
5 
STUDY POPULATION .........................................................................................19 
5.1 
Number of Subjects (approximate) .............................................................19 
5.2 
Study Population Characteristics ...............................................................19 
5.3 
Inclusion Criteria .........................................................................................19 
5.4 
Exclusion Criteria .........................................................................................20 
5.5 
Withdrawal Criteria (if applicable) ............................................................21 
6 
STUDY PARAMETERS ........................................................................................21 
6.1 
Primary Endpoint .........................................................................................21 
6.2 
Safety Endpoints ...........................................................................................21 
6.3 
Secondary Endpoints ...................................................................................22 
6.4 
Exploratory Endpoints .................................................................................23 
7 
STUDY MATERIALS ............................................................................................23 
7.1 
Study Treatment(s) .......................................................................................23 
7.1.1 
Formulations .....................................................................................23 
7.1.2 
Study Drug Packaging Configuration ...............................................23 
7.1.3 
Study Drug Storage and Accountability ...........................................23 
7.1.4 
Instructions for Dispensation, Use, and Administration ...................23 
7.2 
Other Study Supplies ...................................................................................24 
8 
STUDY METHODS AND PROCEDURES .........................................................24 
8.1 
Subject Entry Procedures ............................................................................24 
8.1.1 
Overview ...........................................................................................24 
8.1.2 
Informed Consent..............................................................................24 
8.1.3 
Washout Intervals .............................................................................24 
8.1.4 
Procedures for Final Study Entry ......................................................24 
8.1.5 
Methods for Assignment to Treatment Groups: ...............................25 
8.2 
Concurrent Therapies ..................................................................................25 
8.2.1 
Prohibited Medications/Treatments ..................................................25 
8.2.2 
Escape Medications ..........................................................................25 
8.2.3 
Special Diet or Activities ..................................................................25 
8.3 
Examination Procedures ..............................................................................25 
8.3.1 
Procedures to be Performed at the Study Visit with Regard to Study 
Objective(s) ....................................................................................................25 
8.4 
Schedule of Visits, Measurements and Dosing ..........................................28 


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8.4.1 
Scheduled Visits................................................................................28 
8.4.2 
Unscheduled Visits ...........................................................................29 
8.5 
Subject Disposition .......................................................................................29 
8.5.1 
Completed Subjects ..........................................................................29 
8.5.2 
Discontinued Subjects .......................................................................29 
8.6 
Study Termination .......................................................................................30 
8.7 
Study Duration .............................................................................................30 
8.8 
Monitoring and Quality Assurance ............................................................30 
9 
ADVERSE EVENTS ..............................................................................................30 
9.1 
Adverse Event ...............................................................................................30 
9.1.1 
Severity .............................................................................................30 
9.1.2 
Relationship to Study Procedures .....................................................31 
9.1.3 
Expectedness .....................................................................................31 
9.2 
Serious Adverse Events ................................................................................32 
9.3 
Procedures for Reporting Adverse Events .................................................33 
9.3.1 
Reporting a Suspected Unexpected Adverse Reaction .....................33 
9.3.2 
Reporting a Serious Adverse Event ..................................................33 
9.4 
Procedures for Unmasking Study Drug .....................................................34 
9.5 
Procedures for Reporting Adverse Events .................................................34 
10 
STATISTICAL HYPOTHESES AND METHODS OF ANALYSES ...............34 
10.1 Analysis Populations ....................................................................................34 
10.2 Statistical Hypotheses ...................................................................................35 
10.3 Sample Size ...................................................................................................35 
10.4 Statistical Analysis ........................................................................................35 
10.4.1 General Considerations .......................................................................35 
10.4.2 Unit of Analysis ................................................................................36 
10.4.3 Missing Data .....................................................................................36 
10.4.4 Multiplicity Considerations ..............................................................36 
10.4.5 Primary Efficacy Analysis ................................................................37 
10.4.7 Secondary Efficacy Analyses ...........................................................39 
10.4.8 Exploratory Efficacy Analyses .........................................................39 
10.4.9 Safety Variables ................................................................................39 
11 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES ................................40 
11.1 Protection of Human Subjects .....................................................................40 
11.1.1 Subject Informed Consent.................................................................40 
11.1.2 Institutional Review Board (IRB) Approval .....................................40 
11.2 Ethical Conduct of the Study ......................................................................40 
11.3 Subject Confidentiality ................................................................................40 
11.4 Documentation ..............................................................................................41 
11.4.1 Retention of Documentation .............................................................41 
11.5 Labeling, Packaging, Storage, Accountability, and Return or Disposal of Study 
Drug ...............................................................................................................41 
11.5.1 Labeling/Packaging ...........................................................................41 
11.5.2 Storage of Study Drug ......................................................................41 


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11.5.3 Accountability of Study Drug ...........................................................42 
11.5.4 Return or Disposal of Study Drug ....................................................42 
11.6 Recording of Data on Source Documents and electronic Case Report Forms 
(eCRFs) ..........................................................................................................42 
11.7 Handling of Biological Specimens ...............................................................42 
11.8 Publications ...................................................................................................42 
12 
REFERENCES ........................................................................................................43 
Appendix 1:  Schedule of Visits and Measurements ...................................................44 
Appendix 2: Examination Procedures, Tests, Equipment, and Techniques .....45 
Appendix 3:  Amendment Summary of Changes Table .............................................54 
Appendix 4:  Sponsor and Ora Approvals ..................................................................59 
Appendix 5:  Investigator’s Signature .........................................................................60 
 
 


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List of Abbreviations 
AE 
adverse event 
 
 
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 
 
 
OTC 
over the counter 
RASP 
reactive aldehyde species 
SAE 
serious adverse event 
µL  
microliter  
VA 
visual acuity 
VAS 
Visual analog scale 
 
 


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1 INTRODUCTION 
Dry eye disease (DED) is the most prevalent form of ocular discomfort and irritation. The 
estimated population of individuals with mild to moderate DED ranges from 20 million Americans 
up to 1 out of every 5 Americans. DED can be related to external environmental factors such as 
low humidity in air-conditioned offices, winter heating, and dusty or windy outdoor environments. 
Behaviors including prolonged computer use and wearing contact lenses, and internal factors such 
as hormonal imbalance, autoimmune disease, systemic medications, anatomical changes, trauma, 
and aging are also contributors. Symptoms result in a mildly decreased quality of life at a minimum 
and, with increasing severity, loss of function and productivity, pain, light sensitivity, and 
emotional distress. The aging population in the United States and in other developing countries, 
and increasing computer use will continue to make DED more prevalent (Schaumberg et al, 2009). 
 
Given that there are few substantive treatments for DED, various over-the-counter (OTC) products 
are available to help provide temporary relief for DED and for all of the tear film abnormalities. 
OTC products aim to alleviate symptoms by replacing or retaining moisture on the ocular surface. 
Additionally, some artificial tear products contain demulcents to enhance lubrication. OTC 
products provide only short-lived action at best necessitating frequent dosing throughout the day. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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 
 
(CAE) in subjects with dry eye disease. 
 
3 CLINICAL HYPOTHESES 
The clinical hypothesis is that reproxalap is more effective than vehicle in reducing the signs and 
symptoms of DED.  
 
 


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4 OVERALL STUDY DESIGN 
ADX-102-DED-023 is a Phase 3, multi-center, randomized, double-masked, parallel design, 
vehicle-controlled trial designed to evaluate the efficacy and safety of 0.25% Reproxalap 
Ophthalmic Solution compared to vehicle in subjects with dry eye disease. Approximately 350 
subjects will be enrolled in the study. Male and female subjects at least 18 years of age with a 
subject-reported history of dry eye disease in both eyes and meeting all other eligibility criteria 
will be randomized to receive reproxalap or vehicle in a 1:1 ratio (approximately 150 subjects in 
each treatment group). 
 
 
Visit 1 
(Day -14 -16/+ 2): 
Screening  
• Informed Consent 
• Demographics, 
Medical/Medication 
& 
Ocular 
History 
• Urine Pregnancy Testing (as needed) 
• Symptom Questionnaires, Ocular Dryness VAS, 
Visual Acuity 
• 
 
 
 
 
 
 
• Slit Lamp Exam with Conjunctival Redness 
assessment 
• 
 
 
• CAE exposure (90 minutes) with Ocular Dryness 
VAS, 
 
 and 
Conjunctival Redness Assessment 
• Slit Lamp Exam with Conjunctival Redness 
assessment 
•
 
 
 
• Schirmer’s Test 
• IOP and Dilated Fundoscopy 
 
Visit 2 
 (Day 1): 
Randomization/Baseline 
• Medical/Medication Update: AE Query 
• Visual Acuity 
• Slit Lamp Exam 
• Symptom Questionnaires at specified time points 
• Conjunctival Redness at specified time points 
• In-Office Doses (QID)  
• Tear Collection & Schirmer’s Test at specified time 
points 
 
Visit 3 
(Day 2): 
CAE 
 
• Medical/Medication Update: AE Query 
• Urine Pregnancy Testing (as needed) 
• Visual Acuity, Slit Lamp Exam 
• Symptom Questionnaires 
• Conjunctival Redness at specified time points 
• 
 
  


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• CAE exposure (90 minutes) with Ocular Dryness 
VAS, and 
 
 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 600 subjects will be screened to enroll approximately 350 subjects 
across approximately 17 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; 
  
 
 
 
 
 
 
 
 
 
 


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5.4 
Exclusion Criteria 
Each subject may not meet any of the following criteria: 
1. Clinically significant slit lamp findings at Visit 1 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 (bacterial, viral, or fungal), 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 prescriptions (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 (logMAR) + 0.7 as assessed by Early Treatment of Diabetic Retinopathy 
Study (ETDRS) scale 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.  (Nonchildbearing potential is 


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defined as a woman who is permanently sterilized [e.g., has had a hysterectomy or 
tubal ligation], or is post-menopausal [without menses for 12 consecutive months]); 
14. If of childbearing potential (female or male), unwillingness to use an acceptable 
means of birth control. (Acceptable methods of contraception include: hormonal – 
oral, implantable, injectable, or transdermal contraceptives; mechanical – 
spermicide in conjunction with a barrier such as a diaphragm or condom; 
intrauterine device [IUD]; or surgical sterilization of partner.  For non-sexually 
active males or females, abstinence may be regarded as an adequate method of birth 
control; however, if the subject becomes sexually active during the study, he/she 
must agree to use adequate birth control as defined above for the remainder of the 
trial.); 
15. Known allergy and/or sensitivity to the test article or its components; 
16. A condition that the investigator feels may put the subject at significant risk, may 
confound the study results, or may interfere significantly with the subject’s 
participation in the trial; 
17. Current enrollment in an investigational drug or device study or have used an 
investigational drug or device within 30 days of Visit 1; 
18. Use of reproxalap ophthalmic solution in the past year; 
19. Current use of any medication 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  
• Schirmer’s Test overall mean change from baseline (CFB) before and after the 
fourth dose on Day 1  
• Schirmer’s Test greater than or equal to 10mm responder analysis of change 
from baseline before and after the fourth dose on Day 1 
6.2 
Safety Endpoints 
• Visual acuity 


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• Slit-lamp evaluation 
• Adverse event query 
• Intraocular Pressure (IOP) 
• Dilated fundoscopy 
6.3 
Secondary Endpoints 
• Overall mean CFB of Conjunctival Redness over 90 minutes in the CAE at 
Day 2 
• Overall mean CFB of Eye Dryness (VAS; Visual Analog Scale) over 90 
minutes in the CAE at Day 2 
• Overall mean CFB of Eye Dryness (VAS) assessed over Days 1 and 2 
(excluding CAE) 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 


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6.4 
Exploratory Endpoints 
• Change in tear RASP levels before and after Dose 1 and 2 on Day 1 and Dose 
3 on Day 2 
• Conjunctival redness, 
 
and visual 
analog scale dryness score by time point during the CAE 
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 
 
 
 
  
 
 
7.1.3 Study Drug Storage and Accountability 
The study drug must be stored in a secure area accessible only to the investigator 
and his/her designees. The study drug will be administered only to subjects 
entered into the clinical study, in accordance with the conditions specified in this 
protocol. 
  
 
 
The study drug is to only be prescribed by the principal investigator or his/her 
named sub investigator(s), and is to only be used in accordance with this protocol. 
The study drug must only be distributed to subjects properly qualified under this 
protocol to receive study drug. The investigator must keep an accurate accounting 
of the study drug by maintaining a detailed inventory. This includes the amount of 
study drug received by the site, amount used, and the amount returned to the 
Sponsor upon the completion of the study.   
7.1.4 Instructions for Dispensation, Use, and Administration 
 
 
 


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7.2 
Other Study Supplies 
Tear collection supplies, Schirmer’s Test strips, Scale to weigh Schirmer’s strips, 2% 
preservative-free sodium Fluorescein Solution, Fluorescein Strips, ETDRS Series 
2000 Chart 1 & Chart 2, eye occluder, alcohol swabs. 
8 STUDY METHODS AND PROCEDURES 
8.1 
Subject Entry Procedures 
8.1.1 Overview 
Subjects as defined by the criteria in section 5.2, 5.3, and 5.4 will be considered 
for entry into the trial. 
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. 


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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 reproxalap or vehicle in a 1:1 ratio. Patients will be assigned a 
randomization number and kit number via IWRS. 
Both the randomization number and the assigned 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. 
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 (e.g., gender, date of birth, race, ethnicity) 
• Medical/Medication & Ocular History 
• Urine Pregnancy Test (as needed) 
• Symptom Questionnaires: 
 
 
 
 
 


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o Ocular Dryness Visual Analog Scale 
o 
 
 
 
• Visual Acuity (ETDRS) 
• Slit Lamp Biomicroscopy with Conjunctival Redness assessment 
• Fluorescein Staining 
 
 
 
• Inclusion/Exclusion Criteria Review 
• 
 
 
• CAE Exposure (90 minutes, 
 
with: 
 
 
  
 
 
 
 
 
 
 
 
• Slit Lamp Biomicroscopy with Conjunctival Redness assessment 
• Schirmer’s Test  
• Intraocular Pressure 
• Dilated Exam 
• Schedule for Visit 2 
Visit 2 (Day 1, Baseline and In-Office Dosing) 
• Medical/Medication Update 
• Adverse Event Query 
• Visual Acuity (ETDRS) 
• Slit Lamp Biomicroscopy 
• Symptom Questionnaires 
 
 
 
 
 
 
  
 
 
 
 
• Conjunctival Redness Photography 
• Inclusion/Exclusion Criteria Review 
• Randomization/Enrollment 
• Pre-Dose #1 Tear Collection (30 +/- 5 minutes pre-dose) 
• In-Office Dose #1 
• Post-Dose #1 Tear Collection (started within 10 + 2 minutes of dose)  
Wait 3 hours between doses 
 


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• Pre-Dose #2 Tear Collection (30 +/- 5 minutes pre-dose) 
• In-Office Dose # 2 
• Post-Dose #2 Tear Collection (started within 10 + 2 minutes of dose)  
Wait 30 minutes between doses 
 
• In-Office Dose #3 
• Conjunctival Redness Photography (10 minutes +/- 2 minutes post-
Dose #3) 
• Symptom Questionnaires started within 10 minutes + 2 minutes post-
 
 
  
 
  
 
  
 
 
 
  
Wait 30 minutes between doses 
• Pre-Dose #4 Schirmer’s Test (10 +/- 2 minutes pre-dose) 
o Weigh Schirmer’s Test strip before and after use 
• In-Office Dose #4 
• Post-Dose #4 Schirmer’s Test (started within 5 +/- 2 minutes of dose) 
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: 
 
 
 
 
 
 
 
 
 
 
 
• Pre-Dose #1 Tear Collection (30 +/- 5 minutes pre-dose) 
• In-Office Dose #1 within 10 minutes prior to CAE Entry 
• CAE Exposure (90 minutes) with: 
o 
 
   


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• In-Office Dose #2 (45 +/- 2 minutes into CAE exposure, administer by 
site staff)  
• Post-CAE exit Tear Collection (started within 5 + 2 minutes) 
• In-Office Dose #3 (started within 2 minutes post-tear collection) 
• Symptom Questionnaires started within 10 minutes + 2 minutes post- 
Dose #3: 
 
  
 
  
 
  
 
 
 
  
• Post-Dose #3 Tear Collection (started within 15 + 2 minutes of dose) 
• Slit Lamp Biomicroscopy 
• Intraocular Pressure 
• Dilated Exam 
• Study Exit 
Early Termination/Discontinuation  
If a subject is discontinued from the study prior to Visit 3, then all safety evaluations 
that are to be performed at Visit 3 should be performed on the day of 
discontinuation (early termination) or at the discretion of the investigator.  
Adverse Events (both elicited and observed) and serious adverse events (SAEs) will 
be monitored throughout the trial.  The investigator will promptly review all 
adverse events (both elicited and observed) for accuracy and completeness.  All 
adverse events will be documented on the appropriate source document and case 
report form. 
If a female reports a pregnancy or has a positive pregnancy test during the study 
the investigator will notify 
 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 
. 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. 


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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. 
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 
 and will be clearly documented on the source document. 


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8.6 
Study Termination 
The clinical trial may be stopped at any time by the investigator, or 
 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, 
 quality assurance and or 
its designees may carry out on-site inspections and audits which may include source 
data checks. Therefore, direct access to the original source data will be required for 
inspections and audits.  All inspections and audits will be carried out giving 
consideration to data protection as well as subject confidentiality to the extent that 
local, state, and federal laws apply. 
9 ADVERSE EVENTS 
9.1 
Adverse Event 
For the purposes of this trial, an adverse event is defined as any untoward medical event 
occurring after the subject’s signing of the informed consent until they are exited from 
the trial. An adverse event can therefore be any unfavorable and unintended sign, 
symptom, or disease occurring after the subject started the clinical trial, without any 
judgment about causality. Any pre-existing medical condition that worsens during the 
trial will also be considered a new adverse event. Documentation regarding the adverse 
event should be made as to the nature, date of onset, end date, severity, relationship to 
study procedure, expectedness, action(s) taken, seriousness, and outcome of any sign 
or symptom observed by the investigator or reported by the patient upon indirect 
questioning.  
9.1.1 Severity 
Severity of an adverse event is defined as a qualitative assessment of the degree 
of intensity of an adverse event as determined by the investigator or reported to 
him/her by the patient/subject. The assessment of severity is made irrespective 
of relationship to study procedures or seriousness of the event and should be 
evaluated according to the following scale: 


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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; 
• 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: 


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• 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; 
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 
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• 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 
 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 
 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 
 in addition to that information reported on the source 
document. All subjects experiencing a serious adverse event must be followed 
up and the outcome reported. 
In the event of a serious adverse event, the investigator must notify 
 
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 
 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): 
 
 
 
 
 
 
 
 
 
 


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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), 
 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
 and/or the medical monitor prior to unmasking the identity 
of the IP, if possible. 
 will ask the site to complete and send them the Unmasking Request 
Form. 
 will notify Aldeyra and jointly will determine if the unmasking request should be 
granted. They may consult the medical monitor as needed. The result of the request will be 
documented on the Unmasking Request Form. If approval is granted to unmask a subject, 
written permission via the Unmasking Request Form will be provided to the investigator. The 
investigator will unmask the subject via IWRS. The investigator will complete the 
Unmasking Memo form and include it in the subject’s study file and provide a copy for the 
Trial Master File (TMF). For each unmasked request, the reason, date, signature, and name 
of the person who unmasked the subject, must be noted in the subject’s study file. 
 
9.5 
Procedures for Reporting Adverse Events 
Adverse events that are ongoing at the end of the study visit will be followed.  Phone calls 
will be placed with any subject who experiences an adverse event until the issue is resolved 
or the condition is considered ongoing and stable. 
10 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
10.1 Analysis Populations 
 The following analysis populations will be considered: 
• Intent-to-Treat Population – The intent-to-treat (ITT) population includes all 
randomized subjects. Subjects in the ITT population will be analyzed as randomized. 
 
• Per-Protocol Population – 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. 
 
• Safety Population – The safety population includes all randomized subjects who have 
received at least one dose of the investigational product. Subjects in the safety 
population will be analyzed as treated.  


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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 
 
  
  
 
 
  
 
 
 
  
 
 
  
 
 
 
10.3 Sample Size 
 
 
 
  
 
 
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 as the last non-missing measure prior to the initiation of 
randomized study treatment at Day 1.  Change from baseline will be calculated as follow-up 
visit value minus baseline value.  Treatment comparisons between active and vehicle calculated 
as active minus vehicle. 


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All analyses will be 2-sided at a significance level of 0.05. 95% confidence intervals 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 
 
 
 Assessment scales are 
detailed in the Appendices. 
10.4.3 Missing Data 
 
 
 
 
 
10.4.4 Multiplicity Considerations 
 
imary and secondary 
endpoints will be tested in the fixed testing sequence as follows: 
Primary Endpoint: 
1. Schirmer’s Test overall mean change from baseline (CFB) before and after the fourth 
dose on Day 1 
2. Schirmer’s Test greater than or equal to 10mm responder analysis of change from 
baseline before and after the fourth dose on Day 1 
Secondary Endpoints: 
3. Overall mean CFB of Conjunctival Redness over 90 minutes in the CAE at Day 2 
4. Overall mean CFB of Eye Dryness (VAS; Visual Analog Scale) over 90 minutes in the 
CAE at Day 2 
5. Overall mean CFB of Eye Dryness (VAS) assessed over Days 1 and 2 (excluding CAE) 
 
 
 
 
 
 
 
 
 


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No type I error control will be utilized for exploratory endpoints; thus, exploratory comparisons 
are considered hypothesis generating. 
10.4.5 Primary Efficacy Analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Estimand 1  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.4.7 Secondary Efficacy Analyses 
 
 
 
 
 
 
 
 
 
 
 
  
10.4.8 Exploratory Efficacy Analyses 
 
 
 
 
 
 
 may be conducted. Further details of the exploratory 
analysis plan will be described in SAP. 
10.4.9 Safety Variables 
Adverse events will be coded using the MedDRA dictionary. 
Frequencies and percentages will be provided per treatment group of subjects with treatment-
emergent adverse events (TEAEs), serious TEAEs, and TEAEs causing premature 
discontinuation. An adverse event is treatment-emergent if it occurs or worsens after the first dose 
of randomized study treatment. Furthermore, frequencies will be given of subjects with TEAEs by 
system organ class, by system organ class and preferred term, by system organ class, preferred 
term and maximal severity, by system organ class, preferred term and strongest relationship, and 
by system organ class, preferred term, maximal severity, and strongest relationship. Separate 
analyses will be performed for ocular specific and all adverse events (including systemic). 
Other safety endpoints including visual acuity, slit lamp biomicroscopy, intraocular pressure 
(IOP), and dilated fundoscopy will be summarized by treatment group and visit using descriptive 
statistics.  Changes or shifts from baseline will also be summarized where appropriate.  For 
assessments performed by eye, eyes will be summarized separately. 


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11 COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES 
The ADX-102-DED-023 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 
 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 
 and 
provided in writing by 
 prior to the consent process. 
11.1.2 Institutional Review Board (IRB) Approval 
The ADX-102-DED-023 clinical trial is to be conducted in accordance with 
Institutional Review Board regulations (U.S. 21 CFR Part 56.103). The investigator 
must obtain appropriate IRB approval before initiating the trial and re-approval at least 
annually. 
Only an IRB approved version of the informed consent form will be used. 
11.2 Ethical Conduct of the Study 
The ADX-102-DED-023 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. 


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Monitors, auditors and other authorized representatives of
, 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. 
 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 
 
 
 
 
11.5.2 Storage of Study Drug 
 
 
 
  
 
 


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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 used, 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 
The ADX-102-DED-023 clinical trial entails the collection of certain biospecimens 
from you, you should be aware that even if your personal identifiers are removed from 
the identifiable private information surrounding your biospecimens or removed from 
the biospecimens themselves, the information or biospecimens will not be used for 
future research in other studies or distributed to another investigator for future research 
studies without receiving additional informed consent from you for such activities. 
11.8 Publications 
Authorship and manuscript composition will reflect cooperation among all parties 
involved in the study. Authorship will be established before writing the manuscript.  
 
 


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12 REFERENCES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 1:  Schedule of Visits and Measurements 


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


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LogMAR Visual Acuity Calculations 
 
 
 
  
 
 
 
  
  
 
 
 
 
  
  
  
  
  
  
 
  
 
 
 
 
  
 
 


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Slit Lamp Biomicroscopy 
 
 
  
 
 
 
 
 
 
 
 
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Fluorescein Staining  
 
 
 
 
 
 
 
 
Conjunctival Redness Photography 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Procedure for Evaluating Intraocular Pressure 
 
 
  
  
 
  
 
 
 
 
Dilated Fundoscopy 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


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Visual Analogue Scale (VAS) 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 3:  Amendment Summary of Changes Table  


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Appendix 5:  Investigator’s Signature 
 
Protocol Title: 
The TRANQUILITY 2 Trial: A Multi-Center Randomized, Double-
Masked, Parallel Design, Vehicle-Controlled Phase 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-023 
Protocol Date: 
18May2022 
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 
 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. 
Signed: 
 
 
Date:  
 
 
Name:  
 
Title: Principal Investigator 
 
Site:  
 
Address:  
 
Phone Number: