The RENEW Trial: A Multi-Center, Randomized, Double-Masked, Parallel-Group, Vehicle-Controlled, Adaptive Phase 3 Clinical Trial to Assess the Safety and Efficacy of Reproxalap 0.25% Ophthalmic Solution Compared to Vehicle in Subjects With Dry Eye Disease
Phase: PHASE3
Conditions: Dry Eye
Sponsor: Aldeyra Therapeutics, Inc.

Reproxalap Ophthalmic Solution  
Aldeyra Therapeutics, Inc.  
Clinical Trial Protocol: ADX-102-DED-012 
Final V2.0 5Mar2019 
 
Clinical Trial Protocol: ADX-102-DED-012 
Protocol Title: 
The RENEW Trial: A Multi-Center, Randomized, 
Double-Masked, Parallel-Group, Vehicle-
Controlled, Adaptive Phase 3 Clinical Trial to 
Assess the Safety and Efficacy of Reproxalap 
0.25% Ophthalmic Solution Compared to Vehicle 
in Subjects with Dry Eye Disease 
Protocol Number: 
ADX-102-DED-012 
Study Phase: 
3 
Investigational Product 
Name: 
Reproxalap Ophthalmic Solution (0.25%) 
IND/IDE/PMA Number: 
 
Indication: 
Dry Eye Disease 
Investigators: 
Multi-center 
Sponsor: 
Aldeyra Therapeutics, Inc. 
131 Hartwell Ave. 
Lexington, MA 02421 USA 
Contract Research 
Organization: 
Ora. Inc. 
300 Brickstone Square, 3rd Floor 
Andover, MA 01810 USA 
 
 
 
 
 
 
 
 
Date 
Original Protocol: 
15 February 2019 
Amendment 1: 
05 March 2019 

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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. 
 
SPONSOR PERSONNEL 
ORA PERSONNEL 
MEDICAL MONITOR 

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Clinical Trial Protocol: ADX-102-DED-012 
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SYNOPSIS 
Protocol Title: 
The RENEW Trial: A Multi-Center, 
Randomized, Double-Masked, Parallel-
Group, Vehicle-Controlled, Adaptive Phase 
3 Clinical Trial to Assess the Safety and 
Efficacy of Reproxalap 0.25% Ophthalmic 
Solution Compared to Vehicle in Subjects 
with Dry Eye Disease 
Protocol Number: 
ADX-102-DED-012 
Investigational Product: 
1) Reproxalap 0.25% Ophthalmic 
Solution (reproxalap) 
2) Vehicle Ophthalmic Solution (vehicle) 
Study Phase: 
3 
Overall Study Design: 
Structure: 
Multi-center, randomized, double-masked, 
parallel-group, vehicle-controlled, adaptive 
clinical trial comprised of two parts 
Part 1 and Part 2 
Prior to randomization into either Part 1 or 
Part 2, subjects will receive 14 consecutive 
days (± 2) of vehicle, self–administered 
QID in both eyes, between Visits 1 and 2. 
Subjects randomized in Part 1 will not be 
eligible to participate in Part 2. 
Part 1 
1:1:1:1 randomization into one of four 
treatment arms (100 subjects per arm): 
A1. Reproxalap administered QID for 
twelve weeks 
A2. Vehicle administered QID for 
twelve weeks 
B1. Reproxalap administered QID for 
four weeks, followed by BID 
administration for eight weeks 
B2. Vehicle administered QID for four 
weeks, followed by BID administration 
for eight weeks 
The results of A1 will be compared to the 

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Visit 1; 
11. Be a woman who is pregnant, nursing, 
or planning a pregnancy during the 
trial; 
12. Be unwilling to submit a urine 
pregnancy test at Visit 1 and Visit 9 (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); 
13. Be a man or woman of childbearing 
potential who is not using 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 males or 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 study; 
14. Have a known allergy and/or sensitivity 
to reproxalap or the test article 
excipients; 
15. Have a condition or be in a situation 
which 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 study; 
16. Be currently enrolled in an 
investigational drug or device study or 
have used an investigational drug or 
device within 30 days of Visit 1; 
17. Have previously participated in a 
reproxalap ophthalmic solution study; 
18. Be currently using any medication 

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be used to determinate sample sizes and estimate power in Part 2, which is expected to require 
approximately 200-400 subjects per treatment group. 
Co-primary Endpoint Efficacy Analysis for Part 1 and Part 2: 
• 
The co-primary symptom endpoint will be achieved in either Part 1 or Part 2 if the 
change from baseline in subject-reported ocular dryness score 
 assessed 
using 
from Week 2 to Week 12, in 
reproxalap-treated subjects is statistically significantly lower than that of vehicle-treated 
subjects in the corresponding vehicle arm. The population used for analysis of ocular 
dryness score will be subjects who have a baseline (Day 1) ocular dryness 
 
 
• 
 
 
 
 
 
 
 
 
 
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-012.......................................................................1 
SYNOPSIS..................................................................................................................3 
TABLE OF CONTENTS..........................................................................................12 
LIST OF ABBREVIATIONS ............................................................................................15 
1 
INTRODUCTION ....................................................................................................17 
2 
Clinical Studies of Reproxalap Ophthalmic Solution ...............................................18 
2.1 
Minimization of Risk ......................................................................................28 
3 
STUDY OBJECTIVES .............................................................................................28 
4 
CLINICAL HYPOTHESES .....................................................................................28 
5 
OVERALL STUDY DESIGN ..................................................................................29 
6 
STUDY POPULATION ...........................................................................................31 
6.1 
Number of Subjects (approximate) ................................................................31 
6.2 
Study Population Characteristics ....................................................................31 
6.3 
Inclusion Criteria ............................................................................................31 
6.4 
Exclusion Criteria ...........................................................................................32 
6.5 
Withdrawal Criteria (if applicable) ................................................................34 
7 
STUDY PARAMETERS ..........................................................................................34 
7.1 
Efficacy Measures and Endpoints ..................................................................34 
7.1.1 
Primary Efficacy Measure(s) ............................................................34 
7.1.2 
Co-Primary Efficacy Endpoints ........................................................34 
7.1.3 
Secondary Efficacy Measure(s) ........................................................35 
7.1.4 
Exploratory Measure(s) ....................................................................35 
7.1.5 
Secondary Efficacy Endpoint(s) .......................................................35 
7.1.6 
Criteria for Effectiveness ..................................................................35 
7.2 
Safety Measures .............................................................................................36 
8 
STUDY MATERIALS .............................................................................................36 
8.1 
Study Treatment(s) .........................................................................................36 
8.1.1 
Study Treatment(s)/ Formulation(s): ................................................36 
8.1.2 
Description of and Justification for the Route of Administration, 
Dosage, Dosage Regimen, and Treatment Period(s): .......................36 
8.1.3 
Instructions for Use and Administration ...........................................36 
8.2 
Other Study Supplies ......................................................................................37 
9 
STUDY METHODS AND PROCEDURES ............................................................37 
9.1 
Subject Entry Procedures ...............................................................................37 
9.1.1 
Overview ...........................................................................................37 
9.1.2 
Informed Consent..............................................................................37 
9.1.3 
Washout Intervals .............................................................................37 
9.1.4 
Procedures for Final Study Entry ......................................................38 
9.1.5 
Methods for Assignment to Treatment Groups: ...............................38 
9.2 
Concurrent Therapies .....................................................................................38 
9.2.1 
Prohibited Medications/Treatments ..................................................38 
9.2.2 
Escape Medications ..........................................................................39 
9.2.3 
Special Diet or Activities ..................................................................39 

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9.3 
Examination Procedures .................................................................................39 
9.3.1 
Procedures to be Performed at Each Study Visit with Regard to 
Study Objective(s) ............................................................................39 
9.3.2 
Visit 1: Day -14 ± 2 – CAE® Screening ...........................................39 
9.3.3 
Visit 2:  Day 1 – CAE® Confirmation and Baseline .........................40 
9.3.4 
Visit 3 (Day 8 ±2) .............................................................................42 
9.3.5 
Visit 4 (Day 15 ±2) ...........................................................................42 
9.3.6 
Visit 5 (Day 29 ±2) ...........................................................................43 
9.3.7 
Visit 6 (Day 43 ±2) ...........................................................................44 
9.3.8 
Visit 7 (Day 57 ±3) ...........................................................................45 
9.3.9 
Visit 8 (Day 71 ±3) ...........................................................................46 
9.3.10 Visit 9 (Day 85 ±3) ...........................................................................47 
9.3.11 Early Termination/Discontinuation ..................................................48 
9.3.12 General Safety Measures ..................................................................48 
9.4 
Schedule of Visits, Measurements and Dosing ..............................................48 
9.4.1 
Scheduled Visits................................................................................48 
9.4.2 
Unscheduled Visits ...........................................................................48 
9.5 
Compliance with Protocol ..............................................................................49 
9.6 
Subject Disposition .........................................................................................49 
9.6.1 
Completed Subjects ..........................................................................49 
9.6.2 
Discontinued Subjects .......................................................................49 
9.7 
Study Termination ..........................................................................................49 
9.8 
Study Duration ...............................................................................................49 
9.9 
Monitoring and Quality Assurance ................................................................50 
10 
ADVERSE EVENTS ................................................................................................50 
10.1 Adverse Event ................................................................................................50 
10.1.1 Severity .............................................................................................50 
10.1.2 Relationship to Investigational Product ............................................51 
10.1.3 Expectedness .....................................................................................51 
10.2 Serious Adverse Events ..................................................................................52 
10.3 Procedures for Reporting Adverse Events .....................................................52 
10.3.1 Reporting a Suspected Unexpected Adverse Reaction .....................52 
10.3.2 Reporting a Serious Adverse Event ..................................................53 
10.4 Procedures for Unmasking (if applicable) ......................................................53 
10.5 Type and Duration of the Follow-up of Subjects after Adverse Events ........54 
11 
STATISTICAL HYPOTHESES AND METHODS OF ANALYSES .....................54 
11.1 Analysis Populations ......................................................................................54 
11.2 Statistical Hypotheses .....................................................................................55 
11.3 Sample Size ....................................................................................................55 
11.4 Statistical Analysis .........................................................................................56 
11.4.1 General Considerations .....................................................................56 
11.4.2 Unit of Analysis ................................................................................57 
11.4.3 Missing Data .....................................................................................57 
11.4.4 Multiplicity Considerations ..............................................................57 
11.4.5 Primary Efficacy Analysis ................................................................58 
11.4.6 Secondary Efficacy Analysis ............................................................59 

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11.4.7 Exploratory Efficacy Analysis ..........................................................59 
11.4.8 Safety Variables ................................................................................59 
12 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES ....................................60 
12.1 Protection of Human Subjects ........................................................................60 
12.1.1 Subject Informed Consent.................................................................60 
12.1.2 Institutional Review Board (IRB) Approval .....................................60 
12.2 Ethical Conduct of the Study ..........................................................................60 
12.3 Subject Confidentiality ...................................................................................60 
12.4 Documentation ...............................................................................................61 
12.4.1 Retention of Documentation .............................................................61 
12.5 Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Investigational Product ...................................................................................61 
12.5.1 Labeling/Packaging...........................................................................61 
12.5.2 Storage of Investigational Product ....................................................62 
12.5.3 Accountability of Investigational Product ........................................62 
12.5.4 Return or Disposal of Investigational Product ..................................62 
12.6 Recording of Data on Source Documents and Case Reports Forms (CRFs) .62 
12.7 Publications ....................................................................................................62 
13 
REFERENCES .........................................................................................................63 
14 
 Appendices ...............................................................................................................65 
14.1 Appendix 1: Part 1 Schedule of visits and measurements ..............................65 
14.2 Appendix 2: Part 2 Schedule of visits and measurements ..............................67 
14.3 Appendix 3: Examination Procedures, Tests, Equipment, and Techniques ...69 
Appendix 4: Protocol Amendment Summary ....................................................................81 
Appendix 5: Sponsor and Ora Approvals ..........................................................................82 
Appendix 6: Investigator’s Signature ................................................................................83 
 
 
 
 
 

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LIST OF ABBREVIATIONS 
 
AE 
adverse event 
ANCOVA 
Analysis of covariance 
BCVA 
best-corrected visual acuity 
BID 
twice daily 
CAE 
controlled adverse environment 
CD 
compact disc 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CRF 
case report form 
CRO 
Contract research organization 
DED 
dry eye disease 
DHHS 
Department of Health and Human Services 
eCRF 
electronic case report form 
EKG 
Electrocardiogram 
ERC 
Ethical Review Committee 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
FSN 
Fluorescein staining nasal region 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
investigational new drug application 
IOP 
intraocular pressure 
IP 
investigational product 
IRB 
institutional review board 
ITT 
intent to treat 
ITTFSN 
intent to treat fluorescein nasal score 
ITTOD 
intent to treat ocular dryness 
IUD 
intrauterine device 
IWRS 
Interactive Web Response System 
LASIK 
laser in situ keratomileusis 

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LOCF 
last observation carried forward 
logMAR 
logarithm of the minimum angle of resolution 
LPS 
lipopolysaccharide 
MAR 
missing at random 
MDA 
malonyldialdehyde 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGD 
meibomian gland dysfunction 
MMRM 
Mixed Model Repeated Measures 
MNAR 
missing not at random 
NCS 
not clinically significant 
ND  
not done  
OD 
right eye 
OS 
left eye 
OSDI 
Ocular Surface Disease Index 
OU 
both eyes 
OTC 
over the counter 
PP 
per protocol 
QID 
Four times daily 
RASP 
reactive aldeyhyde species 
REML 
residual restricted maximum likelihood 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
 
 
SOP 
standard operating procedure 
TEAE 
Treatment-emergent adverse event 
TFBUT 
tear film break-up time 
VA 
visual acuity 
VAS 
Visual Analog Scale 
w/v 
weight per unit volume 
 
 

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1 INTRODUCTION 
Dry eye disease (DED) is a complex and chronic condition characterized by ocular 
discomfort, visual disturbance, tear film instability, increased tear osmolarity, and 
inflammation of the ocular surface that, in severe cases, can lead to loss of vision (Dry 
Eye Workshop 2007). Although estimates of the prevalence of dry eye disease vary 
considerably depending on the criteria used to define the disease, as many as 3.2 million 
women and 1.7 million men over the age of 50 are thought to have DED in the United 
States, and prevalence is projected to increase by 40% by 2030 as a result of population 
aging and increasing computer use (Schaumberg 2002, Schaumberg 2003, Schaumberg 
2009, Brewitt 2001).  
Reactive aldehyde species (RASP) are reactive organic molecules that bind to proteins, 
carbohydrates, lipids, and nucleic acids (Esterbauer 1991).  RASP that are not 
sequestered or otherwise protected in specific metabolic processes are toxic, and 
aldehyde binding to cellular constituents leads to inflammation via activation of NFκB 
and other pro-inflammatory mediators (Yadav 2013), molecular dysfunction (O'Brien 
2005), and the accumulation of indigestible metabolites, such as lipofuscin components 
in the retina (Boyer 2012).   
In biological systems, RASP are formed by a variety of processes, including the 
oxidation of alcohols, polyamine and glucose metabolism, and oxidative stress.  In non-
disease states, levels of RASP are low due to the near ubiquitous presence of aldehyde 
dehydrogenases and other enzymes that catabolize aldehydes.  However, in disease states, 
the capacity of aldehyde dehydrogenases to neutralize toxic aldehydes is exceeded, 
resulting in increased RASP levels. Elevation in the levels of RASP, particularly 
malonyldialdehyde (MDA), has been described in a variety of inflammatory ocular 
diseases, including pterygium, Behcet's Disease, Sjögren’s Syndrome, anterior uveitis, 
and dry eye disease (Sandikci 2003, Cejkova 2007, Balci 2011, Turk 2014, Choi 2016, 
Augustin 1995). 
Reproxalap is a novel small molecule, formulated for topical ophthalmic delivery, that 
functions as a RASP sequestering agent, or “trap,” which binds rapidly and irreversibly to 
RASP. By irreversibly trapping RASP, reproxalap is expected to diminish inflammation 
thought to be caused or exacerbated by elevated RASP levels in inflammatory ocular 
conditions. Reproxalap has demonstrated anti-inflammatory effects in numerous ocular 
and non-ocular preclinical models of inflammation: 
• In a rat model of lipopolysaccharide (LPS)-induced uveitis, topical ocular 
dosing of reproxalap significantly reduced inflammatory ocular effects and 
significantly reduced ocular levels of two pro-inflammatory cytokines.  
• In a rabbit ocular healing study, topical ocular reproxalap significantly 
reduced haze intensity and reduced the rate of haze development following 
photorefractive keratectomy. 
• In a model of LPS-induced systemic inflammation, a single intraperitoneal 
(IP) dose of reproxalap led to a significant reduction in levels of several pro-

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inflammatory cytokines, while also increasing levels of the anti-inflammatory 
cytokine IL-10. 
• In a phorbol 12-myristate-13-acetate-induced mouse model of contact 
dermatitis, IP administration of reproxalap significantly reduced edema. 
• In an oxazolone-induced, delayed-type hypersensitivity mouse model, IP 
administration of reproxalap significantly reduced edema and resulted in 
statistically significant reduction of tissue cytokines at the site of 
inflammation. 
• In a mouse model of lung inflammation, IP administration of reproxalap 
reduced infiltration of inflammatory cells and protein in the lung, and resulted 
in reductions in levels of pro-inflammatory cytokines.  
• In a model of radiation-induced mucositis in hamsters, subcutaneous 
administration of reproxalap significantly improved healing time and reduced 
fibrosis (scarring). 
In 1995, Augustin et al. (Augustin 1995) described elevations in tear MDA levels that 
correlated with severity in DED patients. Subsequently, Choi et al. (Choi 2016) reported 
that expression of MDA and 4-hydroxynonenal (another RASP commonly associated 
with inflammation) is increased in the tear film and ocular surface of patients with DED. 
Consistent with the literature that supports the notion that RASP mediate pro-
inflammatory toxicity in DED, the anti-inflammatory effects of the RASP scavenger 
reproxalap have been demonstrated in Phase 2 clinical trials in DED, noninfectious 
anterior uveitis, and allergic conjunctivitis. In aggregate, a broad array of preclinical and 
clinical evidence supports the use of reproxalap for the treatment of ocular inflammation, 
including DED. 
 
2 Clinical Studies of Reproxalap Ophthalmic Solution 
Reproxalap ophthalmic solution is in clinical development for the treatment of ocular 
inflammation.  The drug product, in various strengths, has completed a Phase 1 clinical 
trial, as well as a vehicle-controlled, double-masked Phase 2a clinical trial in allergic 
conjunctivitis; a vehicle-controlled, double-masked Phase 2b clinical trial in allergic 
conjunctivitis; a comparator-controlled, investigator-masked Phase 2 clinical trial in 
noninfectious anterior uveitis; a vehicle-controlled, double-masked Phase 2a clinical trial 
in DED; and a vehicle-controlled, double-masked Phase 2b clinical trial in DED.  Phase 3 
clinical trials in noninfectious anterior uveitis and allergic conjunctivitis are in progress.  
A total of 468 subjects have been exposed to topical ocular reproxalap in completed 
clinical trials.  
 
In all clinical trials, no treatment-related serious adverse events (SAE) have been 
observed.  Generally mild to moderate transient ocular stinging, lasting only up to a few 

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clinical testing. Most adverse events (AEs) were reported by subjects treated with the 
0.5% formulations, and 11/12 subjects discontinued as a result of transient ocular 
irritation following instillation (1 subject in the 0.1% group, five in the 0.5% group, and 
six in the 0.5% lipid group). 
 
Statistically significant improvement from baseline was observed across a broad array of 
DED signs and symptoms. 
 
ADX-102-DED-009 was a multi-center, double-masked, vehicle-controlled clinical trial 
designed to assess the safety and activity of two concentrations of reproxalap (0.25% and 
0.1%) administered four times daily (QID) to DED patients. Three hundred male and 
female subjects at least 18 years of age with a subject-reported history of DED in both 
eyes and meeting all other eligibility criteria were randomized in a 1:1:1 ratio to receive 
either topical ocular reproxalap (0.25%), reproxalap (0.1%), or vehicle. 
Both concentrations of reproxalap demonstrated statistically significant and clinically 
relevant improvements from baseline and versus vehicle across multiple DED signs and 
symptoms. Figure 1 illustrates the broad pattern of activity on DED signs and symptoms 
of reproxalap 0.25% compared to vehicle in terms of improvement from baseline effect 
size at Week 12. 
 
Statistically significant improvements over baseline as measured by the
 
 (severity) questionnaire 
was evident as early as at Week 2. By Week 12, the 0.25% concentration was statistically 
superior to vehicle in change from baseline in overall ocular discomfort, dryness, and 

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A pre-specified analysis of subjects with baseline dryness symptom scores equal to or 
above the median (score of 3, range 0 to 5) indicated that subjects treated with the 0.25% 
concentration of reproxalap demonstrated statistically greater improvement from baseline 
than vehicle-treated subjects at Week 2 and at Week 12 (Figure 3). 
 
 
 

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Both concentrations of reproxalap demonstrated statistically significant improvements 
over baseline in lissamine green staining and fluorescein staining. At Week 2, the 0.25% 
concentration of reproxalap demonstrated statistically significant improvements over 
baseline in the total eye, corneal sum, and superior regions for both staining measures, 
and in the central and nasal regions for lissamine green staining. Through Week 12, 
statistically significant improvements over baseline lissamine green and fluorescein 
staining were evident in subjects treated with both reproxalap concentrations. Statistically 
significant differences in change from baseline favoring the 0.1% reproxalap group over 
vehicle were observed in nasal fluorescein staining at Week 12; statistically significant 
differences in change from baseline favoring the 0.25% reproxalap group over vehicle 
were observed in nasal region fluorescein staining at Week 8 and approached statistical 
significance at Week 12 (Figure 5). 

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A pre-specified analysis of subjects with baseline fluorescein nasal staining scores equal 
to or above the median 
 indicated that subjects treated with the 
0.25% concentration of reproxalap demonstrated statistically greater improvement from 
baseline than vehicle-treated subjects at Weeks 2, 8, and 12 (Figure 6). 

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Fluorescein nasal staining was assessed using a MMRM model containing treatment, 
time (Weeks 2, 4, 8, and 12), and the interaction of treatment and time. Across all time 
points in aggregate, improvement of 0.25% reproxalap over vehicle approached statistical 
significance (p = 0.0526). Change from baseline (CFB) was calculated using Week 0 as 
baseline, as shown in Figure 7.   
In conclusion, the ADX-102-DED-009 clinical trial demonstrated that 0.1% and 0.25% 
formulations of reproxalap produced statistically significant and clinically relevant 
improvements across multiple dry eye signs and symptoms. Safety concerns were not 

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evident following administration of either reproxalap concentration. Based upon the early 
onset, broad activity profile on dry eye signs and symptoms, and consistency of its 
statistically and clinically significant activity compared to baseline and to vehicle, the 
0.25% reproxalap concentration was selected to advance to Phase 3 testing in DED. 
 
2.1 
Minimization of Risk 
In clinical trials with reproxalap topical ocular solution in various strengths in different 
ocular indications, no safety signal or treatment-related SAE’s have been observed 
(Section 2).  Generally mild to moderate transient ocular discomfort and ocular stinging, 
lasting only up to a few minutes, was the most frequently reported AE.  
In addition, extensive in vitro and in vivo studies conducted to assess the safety, efficacy, 
and pharmacokinetics of reproxalap have shown that reproxalap is effective in animal 
models of inflammation, is not toxic to the eye, and can achieve therapeutically relevant 
concentrations in the eye. Nonclinical safety and toxicology studies of reproxalap 
administration by several routes of administration have consistently demonstrated 
reproxalap to be well tolerated, with no significant adverse findings at significant dose 
multiples of those expected in planned clinical trials. In aggregate, the nonclinical studies 
completed to date provide compelling evidence that reproxalap has the potential to 
ameliorate pathologic ocular inflammation without off-target pharmacological or toxic 
effects. Please refer to the Investigator’s Brochure for additional information.  
3 STUDY OBJECTIVES 
The study objectives are as stated below: 
• To evaluate the safety and efficacy of Reproxalap 0.25% Ophthalmic Solution 
compared to Vehicle Ophthalmic Solution for the treatment of dry eye disease. 
• Part 1 will confirm the dosing regimen (four times daily (QID) dosing for 12 
weeks, or QID dosing for four weeks followed by twice-daily (BID) dosing for 
weeks 5-12) to be utilized in Part 2 of this adaptive Phase 3 clinical trial. 
• Part 1 will confirm the sample size to be utilized in Part 2 of this adaptive Phase 3 
clinical trial. 
4 CLINICAL HYPOTHESES 
The clinical hypothesis is that Reproxalap 0.25% Ophthalmic Solution is more effective 
than vehicle in reducing the signs and symptoms of DED. 

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5 OVERALL STUDY DESIGN 
The clinical trial is an adaptive Phase 3, multi-center, randomized, double-masked, 
parallel-group, vehicle-controlled design with block enrollment, and is comprised of two 
parts (Part 1 and Part 2). Test article will be self-administered topically to the eye. 
 
Screening 
Prior to randomization into either Part 1 or Part 2, subjects will receive 14 consecutive 
days (± 2) of vehicle, self–administered QID in both eyes, between Visits 1 and 2. 
Subjects randomized in Part 1 will not be eligible to participate in Part 2. 
During the screening period (Visit 1 to Visit 2), two 90-minute exposures in the CAE® 
will be conducted to ascertain eligibility. Subjects who qualify will be randomized to 
receive study drug in a double-masked fashion for 84 days. At Visits 3 - 9, no CAE® 
exposure will occur but signs and symptoms will be assessed. 
 
Part 1 
Subjects will be randomized 1:1:1:1 into one of four treatment arms (100 subjects per 
arm): 
A1. Reproxalap administered QID for twelve weeks 
A2. Vehicle administered QID for twelve weeks 
B1. Reproxalap administered QID for four weeks, followed by BID administration 
for eight weeks 
B2. Vehicle administered QID for four weeks, followed by BID administration 
for eight weeks 
The results of A1 will be compared to the results of A2. The results of B1 will be 
compared to the results of B2.  
Subjects, the Sponsor, the CRO, investigators, and site personnel will be masked to 
treatment assignment. Subjects will not be masked to dosing regimen. 
The total number of expected participants in Part 1, including screen failures, is 
approximately 1,000 subjects. The duration of Part 1 is approximately 14 weeks (98 
days), including 12 weeks of treatment. 
 
Part 2 
Subjects will be randomized 1:1 to receive treatment with either reproxalap or vehicle for 
twelve weeks. Dosing regimen and subject number per arm will be determined based on 
the results of Part 1. The duration of Part 2 is approximately 14 weeks (98 days), 
including 12 weeks of treatment. 

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1. Have any clinically significant slit-lamp findings at Visit 1, including active 
blepharitis; meibomian gland dysfunction (MGD); lid margin inflammation; or 
active ocular allergies that require therapeutic treatment, or, in the opinion of the 
investigator may interfere with the assessment of the safety or efficacy of 
reproxalap or vehicle; 
2. Have or be diagnosed with an ongoing ocular infection (bacterial, viral, or fungal) 
or active ocular inflammation at Visit 1; 
3. Have worn contact lenses within 7 days of Visit 1 or anticipate using contact 
lenses during the study; 
4. Have used any eye drops within 2 hours of Visit 1; 
5. Have previously had laser-assisted in situ keratomileusis (LASIK) surgery within 
the last 12 months; 
6. Have used ophthalmic cyclosporine or lifitigrast 5.0% ophthalmic solution within 
90 days of Visit 1; 
7. Have any planned ocular and/or lid surgeries over the study period or any ocular 
surgery within 6 months of Visit 1; 
8. Have used temporary or permanent punctal plugs within 30 days prior to Visit 1 
or anticipate their use during the study period; 
9. Be currently taking any topical ophthalmic prescription (including medications 
for glaucoma) or over-the-counter (OTC) solutions, artificial tears, gels or scrubs, 
that cannot be discontinued for the duration of the trial (excluding medications 
allowed for the conduct of the study); 
10. Have corrected visual acuity (VA) greater than or equal to the logarithm of the 
minimum angle of resolution (logMAR)
 as assessed by Early Treatment of 
Diabetic Retinopathy Study (ETDRS) scale in both eyes at Visit 1; 
11. Be a woman who is pregnant, nursing, or planning a pregnancy during the trial; 
12. Be unwilling to submit a urine pregnancy test at Visit 1 and Visit 9 (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); 
13. Be a man or woman of childbearing potential who is not using 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 males or 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 study; 

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subjects who have a baseline (Visit 2) ocular dryness score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.2 
Safety Measures 
• 
Visual acuity at distance utilizing an ETDRS chart 
• 
Slit-lamp evaluation 
• 
Adverse event query (reported, elicited and observed) 
• 
IOP 
• 
Dilated fundoscopy  
8 STUDY MATERIALS 
8.1 
Study Treatment(s) 
8.1.1 Study Treatment(s)/ Formulation(s): 
• Reproxalap 0.25% Ophthalmic Solution (reproxalap) 
• Vehicle Ophthalmic Solution (vehicle) 
8.1.2 Description of and Justification for the Route of Administration, Dosage, Dosage 
Regimen, and Treatment Period(s): 
Topical ophthalmic dosing is the optimal route of administration for DED treatment. The 
dosage and dosage regimen were selected based on nonclinical and clinical studies 
described in Section 2. The proposed treatment period of 12 weeks is based on the Phase 
2 clinical trials and on the anti-inflammatory mechanism of action of reproxalap. 
8.1.3 Instructions for Use and Administration 
 
 
 
 
 
 

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• At the study site, all Investigational Product (IP) must be stored under the 
conditions specified in the Investigator’s Brochure in a secure area accessible 
only to the designated qualified clinical site personnel. All IP must be stored, 
inventoried and the inventories carefully and accurately documented according to 
applicable state, federal and local regulations, International Council on 
Harmonisation (ICH) Good Clinical Practices (GCPs) and study procedures. 
 
 
 
• Subjects in the all QID treatment regimen (Part 1, arms A1 and A2) will receive 
five treatment kits; subjects in the QID to BID treatment regimen (Part 1, arms B1 
and B2) will receive four treatment kits. 
• At a minimum, the immediate or secondary study drug packaging will provide the 
following information: study Sponsor identification, directions for use, required 
storage conditions, caution statements (including “New Drug–Limited by Federal 
Law to Investigational Use” language), and study identification. 
8.2 
Other Study Supplies 
Other study supplies include urine pregnancy tests, Schirmer’s test strips, sodium 
fluorescein, lissamine green, Fluress, Tropicamide, VAS rulers, and Tear Osmolarity 
cards. 
9 STUDY METHODS AND PROCEDURES 
9.1 
Subject Entry Procedures 
9.1.1 Overview 
Subjects as defined by the criteria in sections 6.3, 6.4, and 6.5 will be considered for 
entry into this study. 
9.1.2 Informed Consent 
Prior to a subject’s participation in the trial (i.e., changes in a subject’s medical treatment 
and/or study related procedures), the study will be discussed with each subject, and 
subjects wishing to participate must give written informed consent (and/or assent) 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 Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC). 
9.1.3 Washout Intervals 
Prohibited medications, treatments, and activities are outlined in the exclusion criteria 
(Section 6.4). 

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9.1.4 Procedures for Final Study Entry 
Subjects must meet all inclusion and none of the exclusion criteria. 
9.1.5 Methods for Assignment to Treatment Groups: 
Before the initiation of study run-in at Visit 1, each subject who provides written and 
informed consent will be assigned to a screening number. All screening numbers will be 
assigned in strict numerical sequence at a site and no numbers will be skipped or omitted. 
Each subject who meets all the inclusion and none of the exclusion criteria at Visit 1 and 
Visit 2 will be assigned a randomization number at the end of Visit 2. The Interactive 
Web Response System (IWRS) will be used to assign all randomization numbers. 
Subjects are to be stratified by Visit 2 (Baseline) Pre-CAE ocular dryness score (on the 
Ocular Discomfort & 4-Symptom Questionnaire) and Visit 2 (Baseline) Pre-CAE 
 
 
 
 
 
Randomization will continue until the sample size for the co-primary analysis described 
in Section 11.3 has been achieved.  
Randomization and kit numbers will be assigned automatically to each subject as they are 
entered into the IWRS.  
The site staff will dispense kit(s) required until the next visit. Both the randomization 
number and the dispensed study drug kit number(s) will be recorded on the subject’s 
source document and electronic case report form (eCRF). The Sponsor, investigators, and 
study staff will be masked during the randomization process and throughout the study to 
study drug treatment assignment but not dosing regimen. The dosing regimen will be 
indicated with a leading alphabetical notation with each randomization number of either 
Q-Q (Part 1, arms A1 and A2) or Q-B (Part 1, arms B1 and B2). 
9.2 
Concurrent Therapies 
The use of any concurrent medication, prescription or over-the-counter, is to be recorded 
on the subject’s source document and corresponding case report form (CRF) along with 
the reason the medication was taken. 
Concurrent enrollment in another investigational drug or medical device study is not 
permitted. 
9.2.1 Prohibited Medications/Treatments 
Disallowed medications/treatments during the study are outlined in the Exclusion Criteria 
(Section 6.4). 

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• BCVA Utilizing an ETDRS Chart  
• Slit Lamp Biomicroscopy  
 
 
 
 
 
 
 
 
 
 
 
 
• Study Drug Dispensation: Prior to discharge from the study site on Visit 5, subjects 
will be assigned a new study drug kit(s) via the IWRS and will also be re-dispensed 
the remaining unused ampules from their previous kit for at-home dosing up to Visit 
6. Depending on the assigned dosing regimen, subjects will be dispensed new kit(s) 
as follows:  
o Reproxalap/Placebo subjects in the all QID treatment regimen: 
 Subjects will continue to dose QID through the end of the 
treatment period 
 Subjects will be assigned two (2) kits at Visit 5 
o Reproxalap/Placebo subjects in the QID to BID treatment regimen:  
 Subjects will now be instructed to dose twice a day (BID) in each 
eye through the end of the treatment period 
 Subjects will be assigned one (1) kit at Visit 5 
• Subjects will again be educated on self–administration of study drug. Subjects will be 
instructed to NOT self–administer study drug on the morning of their next scheduled 
study visit (Visit 6)  
• AE Query 
• Subjects will be scheduled for Visit 6. 
 
9.3.7 Visit 6 (Day 43 ± 2) 
• Study Drug Collection 
• Medical/medication history update 
• AE query 
• Multi-symptom Visual Analogue Scale (VAS) 
• 
 

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9.3.11 Early Termination/Discontinuation 
If a subject is discontinued from the study prior to Visit 9 (Day 85 ± 3), then all safety 
evaluations that are to be performed at Visit 9 should be performed on the day of 
discontinuation (early termination) or at the discretion of the investigator. 
 
9.3.12 General Safety Measures 
As specified in each visit procedure, adverse events (AEs) (both elicited and observed) 
will be monitored throughout the study. All AEs (both elicited and observed) will be 
promptly reviewed by the investigator for accuracy and completeness. All AEs will be 
documented on the appropriate eCRF. 
If a female has a positive pregnancy test during the study, then 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. 
9.4 
Schedule of Visits, Measurements and Dosing 
9.4.1 Scheduled Visits 
Refer to Appendix 1: Part 1 Schedule of visits and measurements for a schedule of visits 
and measurements for Part 1.  Refer to Appendix 2: Part 2 Schedule of visits and 
measurements for a schedule of visits and measurements for Part 2. 
9.4.2 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 concomitant medications and/or treatments 
• Any other assessments needed in the judgment of the investigator. 

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9.5 
Compliance with Protocol 
Subjects will be instructed on proper instillation and storage of study drug at the end of 
Visits 1 through 8 and given written instructions. The subject’s used and unused study 
drug ampules will be collected at each visit from Visit 2 up to and including Visit 9 to 
assess dosing compliance.
 
 
 
These guidelines will be used by the Investigator for determining the subject’s necessary 
compliance for the study and for recording deviations from this compliance. 
9.6 
Subject Disposition 
9.6.1 Completed Subjects 
A completed subject is one who has not been discontinued from the study. 
9.6.2 Discontinued Subjects 
Subjects may be discontinued prior to their completion of the study due to: 
• 
subject request/withdrawal 
• 
AEs 
• 
protocol violations 
• 
administrative reasons (e.g., inability to continue, lost to follow up) 
• 
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/or Sponsor and will be clearly documented on the eCRF. 
9.7 
Study Termination 
The study may be stopped at any time by the investigator, the Sponsor, and/or Ora with 
appropriate notification. 
9.8 
Study Duration 
An individual subject’s participation will involve nine visits over approximately a 14-
week (~98 days) period (84 days of treatment and 14 days pre-screening). 

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9.9 
Monitoring and Quality Assurance 
During the course of the study an Ora monitor, or designee, will make routine site visits 
to review protocol compliance, assess IP accountability, 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/or audits which may include source data 
checks. Therefore, direct access to the original source data will be required for 
inspections and/or 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. 
10 ADVERSE EVENTS 
10.1 
Adverse Event 
An AE is defined as any untoward medical occurrence associated with the use of an IP in 
humans, whether or not considered IP-related. An AE can be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an IP, without any judgment about causality. An AE can arise 
from any use of the IP (e.g., off-label use, use in combination with another drug or 
medical device) and from any route of administration, formulation, or dose, including an 
overdose. An AE can arise from any delivery, implantation, or use of a medical device, 
including medical device failure, subject characteristics that may impact medical device 
performance (e.g., anatomical limitations), and therapeutic parameters (e.g., energy 
applied, sizing, dose release, and anatomic fit) associated with medical device use. 
All AEs spontaneously reported by the subject and/or in response to an open question 
from study personnel or revealed by observation, physical examination or other 
diagnostic procedures will be recorded in the source document and on the appropriate 
pages of the CRF. Any clinically relevant deterioration in clinical finding is considered 
an AE and must be recorded. When possible, signs and symptoms indicating a common 
underlying pathology should be noted as one comprehensive event. 
Documentation regarding the AE should be made as to the nature, date of onset, end date, 
severity, relationship to IP, action(s) taken, seriousness, and outcome of any sign or 
symptom observed by the physician or reported by the subject upon indirect questioning. 
Exacerbation of conditions related to the signs and symptoms of Dry Eye will not be 
reported as an AE. 
10.1.1 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 subject. The 

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assessment of severity is made irrespective of relationship to IP or seriousness of the 
event and should be evaluated according to the following scale: 
 
 
 
 
 
 
10.1.2 Relationship to Investigational Product 
The Investigator must assess whether they consider an AE to be drug-related.  In 
assessing this relationship, the Investigator must use information about the 
conditions/concurrent medication, and chronology of the event relative to drug 
administration.  The following definitions will be used:  
 Definitely Related 
 Probably Related 
 Possibly Related 
 Unlikely to be related 
 Not Related 
 
10.1.3 Expectedness 
The expectedness of an AE should be determined based upon existing safety information 
about the IP using these explanations: 
 Unexpected: An AE that is not listed in the Investigator’s Brochure (IB) or is not 
listed at the specificity or severity that has been observed. 
 Expected:  An AE that is listed in the IB at the specificity and severity that has been 
observed. 
 Not applicable: An AE unrelated to the IP. 
AE events that are mentioned in the IB as occurring with a class of products or as 
anticipated from the pharmacological/mechanical (or other) properties of the product, but 
are not specifically mentioned as occurring with the particular product under 
investigation are to be considered unexpected. 
The investigator should initially classify the expectedness of an AE, but the final 
classification is subject to the Medical Monitor’s determination. 

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10.2 
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 AE; 
Note: An AE is considered “life-threatening” if, in the view of either the investigator or 
Sponsor, its occurrence places the subject at immediate risk of death. It does not include 
an AE that, had it occurred in a more severe form, might have caused death. 
 Inpatient hospitalization or prolongation of existing hospitalization; 
Note: The term “inpatient hospitalization” refers to any inpatient admission (even if less 
than 24 hours). For chronic or long-term inpatients, inpatient admission includes transfer 
within the hospital to an acute/intensive care inpatient unit. Inpatient hospitalization does 
not include: emergency room visits; outpatient/same-day/ambulatory procedures; 
observation/short stay units; rehabilitation facilities; hospice facilities; nursing homes; or 
clinical research/phase 1 units. 
Note: The term “prolongation of existing hospitalization” refers to any extension of an 
inpatient hospitalization beyond the stay anticipated or required for the reason for the 
initial admission as determined by the investigator or treating physician. 
 A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions; 
Note: A serious adverse event (SAE) specifically related to visual threat would be 
interpreted as any potential impairment or damage to the subject’s eyes (e.g., 
hemorrhage, retinal detachment, central corneal ulcer or damage to the optic nerve). 
 A congenital anomaly/birth defect. 
 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 subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
10.3 
Procedures for Reporting Adverse Events 
All AEs and their outcomes must be reported to Ora, the Sponsor, and the IRB/IEC as 
required by the IRB/IEC, federal, state, or local regulations and governing health 
authorities and recorded on the appropriate CRF. Adverse Events will be collected after 
the signing of the Informed Consent. 
10.3.1 Reporting a Suspected Unexpected Adverse Reaction 
All AEs that are ‘suspected’ and ‘unexpected’ are to be reported to Ora, the Sponsor and 
the IRB/IEC as required by the IRB/IEC, federal, state, or local regulations and 
governing health authorities. 

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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 using 
IWRS. The investigator will complete the Unmasking Memo form and include it in the 
subject’s study file and provide a copy for the 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.  
Unmasked subjects will be discontinued from the study. 
10.5 
Type and Duration of the Follow-up of Subjects after Adverse Events 
The investigator will follow unresolved AEs to resolution until the subject is lost to 
follow-up or until the AE is otherwise classified. Resolution means the subject has 
returned to baseline state of health or the investigator does not expect any further 
improvement or worsening of the AE. If the subject is lost to follow-up, the investigator 
should make three reasonable attempts to contact the subject via telephone, post, or 
certified mail. All follow-up will be documented in the subject’s source document. Non-
serious AEs identified on the last scheduled contact must be recorded on the AE eCRF 
with the status noted.  
If the investigator becomes aware of any new information regarding an existing SAE 
(i.e., resolution, change in condition, or new treatment), a new SAE/Unanticipated Report 
Form must be completed and faxed to Ora within 24 hours of the site’s awareness of the 
new information. The original SAE form is not to be altered. The report should describe 
whether the event has resolved or continues and how the event was treated. 
11 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
11.1 
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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11.4.6 Secondary Efficacy Analysis 
Secondary efficacy variables will be analyzed using the same approach as the primary 
efficacy variable whenever possible. In case the 
 cannot be applied, 
following analysis method will be conducted:  
• The two-sample t-tests and Wilcoxon rank sum tests will be used to analyze the 
efficacy variables at each visit and summarize by visit and treatment group using 
descriptive statistics for the ITT population with observed data only.   
• Change from baseline in secondary efficacy variables will be summarized by visit 
and treatment group using descriptive statistics and analyzed by visit using 
ANCOVA models with terms for baseline value and treatment group, t-tests and 
Wilcoxon rank sum tests on the ITT population with observed data only.  
Further details of the analysis plan will be described in statistical analysis plan document 
(SAP). 
11.4.7  Exploratory Efficacy Analysis 
Exploratory efficacy analysis will be conducted for Part 1 and Part 2. Further details of 
the analysis plan will be described in SAP. 
 
11.4.8 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 term and maximal severity, by system 
organ class, preferred term and strongest relationship, and by system organ class, 
preferred term, maximal severity, and strongest relationship. Separate analyses will be 
performed for ocular specific and all adverse events (including systemic). 
Other safety endpoints including visual acuity, slit lamp biomicroscopy, intraocular 
pressure (IOP), tear osmolarity and dilated fundoscopy will be summarized by treatment 
group and visit using descriptive statistics.  Changes or shifts from baseline will also be 
summarized where appropriate.  For assessments performed by eye, worst eye (study eye) 
and fellow eye will be summarized separately. 

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12 COMPLIANCE WITH GOOD CLINICAL PRACTICES, 
ETHICAL CONSIDERATIONS, AND ADMINISTRATIVE ISSUES 
This study will be conducted in compliance with the protocol, current GCPs, ICH 
Guidelines, and in general, consistent with the Declaration of Helsinki. In addition, all 
applicable local, state, and federal requirements relevant to the use of IP in the countries 
involved will be adhered to. 
12.1 
Protection of Human Subjects 
12.1.1 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 subject’s parent or legal guardian prior to enrollment into the study. If the 
subject is under the legal age of consent, the consent form must be signed by a legal 
guardian or as required by state and/or local laws and regulations. 
All informed consent/assent forms must be approved for use by the Sponsor and receive 
approval/favorable opinion from an IRB/IEC 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 Ora prior to submission to the governing IRB/IEC 
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/or Sponsor and provided in 
writing by Ora and/or Sponsor prior to the consent process. 
12.1.2 Institutional Review Board (IRB) Approval 
This study is to be conducted in accordance with IRB regulations (U.S. 21 CFR Part 
56.103). The investigator must obtain appropriate IRB approval before initiating the 
study and re-approval at least annually. 
Only an IRB approved version of the informed consent form will be used. 
12.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles that originated 
with the Declaration of Helsinki. 
12.3 
Subject Confidentiality 
All personal study subject data collected and processed for the purposes of this study 
should be maintained by the investigator and his/her staff with adequate precautions as to 
ensure that the confidentiality of the data is in accordance with local, state, and federal 
laws and regulations. 

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Monitors, auditors and other authorized representatives of Ora, the Sponsor, the IRB/IEC 
approving this study, the FDA, the Department of Health and Human Services (DHHS), 
other domestic government agencies, and other foreign regulatory agencies will be 
granted direct access to the subject’s original medical and study records for verification 
of the data and/or clinical trial procedures. Access to this information will be permitted to 
the aforementioned individuals to the extent permitted by law. 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the IP may ultimately be marketed, but the subject’s 
identity will not be disclosed in these documents. 
12.4 
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 electrocardiograms (EKGs). The investigator’s copy of the 
CRFs serves as the investigator’s record of a subject’s study-related data. 
12.4.1 Retention of Documentation 
All study-related correspondence, subject records, consent forms, record of the 
distribution and use of all IP, and copies of CRFs should be maintained on file for at least 
two years after the last approval of a marketing application in an ICH region and until 
there are no pending or contemplated marketing applications in an ICH region; or until at 
least two years have elapsed since the formal discontinuation of clinical development of 
the IP. 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. The Sponsor must be notified in writing of the name and 
address of the new custodian. 
12.5 
Labeling, Packaging, Storage, Accountability, and Return or Disposal 
of Investigational Product 
12.5.1 Labeling/Packaging 
Investigational drug will be packaged and labeled into clinical kits. 
 
 
 
  
 
 

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12.5.2 Storage of Investigational Product 
 
12.5.3 Accountability of Investigational Product 
The IP 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 IP must only 
be distributed to subjects properly qualified under this protocol to receive IP. 
The investigator must keep an accurate accounting of the IP received from the supplier. 
This includes the amount of IP dispensed to subjects, amount of IP returned to the 
investigator by the subjects, and the amount returned or disposed upon the completion of 
the study. A detailed inventory must be completed for the IP. 
12.5.4 Return or Disposal of Investigational Product 
All IP will be returned to the Sponsor or their designee or destroyed at the study site. The 
return or disposal of IP will be specified in writing. 
12.6 
Recording of Data on Source Documents and Case Reports Forms 
(CRFs) 
The investigator is responsible for ensuring that study data is completely and accurately 
recorded on each subject’s CRF, source document, 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. 
Data entry of all enrolled and randomized subjects will use software that conforms to 21 
CFR Part 11 requirements and will be performed only by staff who have been trained on 
the system and have access to the system. Data will not be entered for screen failure 
subjects. An audit trail will be maintained within the electronic system to capture all 
changes made within the eCRF database. After the end of the study and database lock, 
compact discs (CDs) containing copies of all applicable subjects’ eCRFs will be provided 
to each Investigator Site to be maintained on file by the Investigator. 
12.7 
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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13 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. 
Balci M, Sahin S, Mutlu FM, Yağci R, Karanci P, Yildiz M. Investigation of oxidative 
stress in pterygium tissue. Mol Vis. 2011 Feb 9;17:443-7. PubMed PMID: 
21321673 
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. 
Brewitt H, Sistani F. Dry eye disease: the scale of the problem. Surv Ophthalmol. 2001 
Mar;45 Suppl 2:S199-202. Review. PubMed PMID: 11587143. 
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. 
Dry Eye Workshop. The definition and classification of dry eye disease: report of the 
Definition and Classification Subcommittee of the International Dry Eye 
WorkShop (2007). 
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. 
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. 
Sandikci R, Türkmen S, Güvenen G, Ayabakan H, Gülcan P, Koldas M, Ozbek Kir Z, 
Yenice N. Lipid peroxidation and antioxidant defence system in patients with 
active or inactive Behçet's disease. Acta Derm Venereol. 2003;83(5):342-6. 
PubMed PMID: 14609100. 
Schaumberg DA, Sullivan DA, Dana MR. Epidemiology of dry eye syndrome. Adv Exp 
Med Biol. 2002;506(Pt B):989-98. Review. PubMed PMID: 12614022. 
Schaumberg DA, Sullivan DA, Buring JE, Dana MR. Prevalence of dry eye syndrome 
among US women. Am J Ophthalmol. 2003 Aug;136(2):318-26. PubMed PMID: 
12888056. 
Schaumberg DA, Dana R, Buring JE, Sullivan DA. Prevalence of dry eye disease among 
US men: estimates from the Physicians' Health Studies. Arch Ophthalmol. 2009 
Jun;127(6):763-8. doi: 10.1001/archophthalmol.2009.103. 

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Turk A, Aykut M, Akyol N, Kola M, Mentese A, Sumer A, Alver A, Erdol H. Serum 
anti-carbonic anhydrase antibodies and oxidant-antioxidant balance in patients 
with acute anterior uveitis. Ocul Immunol Inflamm. 2014 Apr;22(2):127-32. doi: 
10.3109/09273948.2013.830753. 
Yadav UC, Ramana KV. Regulation of NF-κB-induced inflammatory signaling by lipid 
peroxidation-derived aldehydes. Oxid Med Cell Longev. 2013;2013:690545. doi: 
10.1155/2013/690545. 
 

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14.3 
Appendix 3: Examination Procedures, Tests, Equipment, and 
Techniques 

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APPENDIX 6: INVESTIGATOR’S SIGNATURE 
 
Protocol Title: 
The RENEW Trial: A Multi-Center, Randomized, Double-
Masked, Parallel-Group, Vehicle-Controlled, Adaptive Phase 3 
Clinical Trial to Assess the Safety and Efficacy of Reproxalap 
0.25% Ophthalmic Solution Compared to Vehicle in Subjects 
with Dry Eye Disease 
Protocol Number: 
ADX-102-DED-012 
Amendment 1 Date: 05 March 2019 
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 and the Sponsor in confidence and, when this 
information is submitted to an Institutional Review Board (IRB), Ethical Review 
Committee (ERC) 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.