Clinical trial NCT03916042
Conditions: Dry Eye
Sponsor: Aldeyra Therapeutics, Inc.
Start date: 2019-04-23; Completion date: 2019-11-22
Enrollment: 206 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Multi-Center, Phase 2, Randomized, Double-Masked, Parallel-Group, Vehicle-Controlled, Clinical Trial to Assess the Safety and Efficacy of Reproxalap Ophthalmic Solution (0.25% Novel Formulation) 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% Novel Formulation) QID to BID intervention 2: Vehicle Ophthalmic Solution (0.25% Novel Formulation) QID to BID
Intervention descriptions: intervention 1: Reproxalap Opthalmic Solution (0.25% Novel Formulation) administered QID for four weeks, followed by BID administration for eight weeks intervention 2: Vehicle Ophthalmic Solution administered QID for four weeks, followed by BID administration for eight weeks

Protocol documents:
Prot_000.pdf: 
Reproxalap Ophthalmic Solution  
Aldeyra Therapeutics, Inc.  
Clinical Trial Protocol: ADX-102-DED-013 
Final V2.0 17Dec2019 
 
Clinical Trial Protocol: ADX-102-DED-013 
Protocol Title: 
A Multi-Center, Phase 2, Randomized, Double-
Masked, Parallel-Group, Vehicle-Controlled, 
Clinical Trial to Assess the Safety and Efficacy of 
Reproxalap Ophthalmic Solution (0.25% Novel 
Formulation) Compared to Vehicle in Subjects 
with Dry Eye Disease 
Protocol Number: 
ADX-102-DED-013 
Study Phase: 
2 
Investigational Product 
Name: 
Reproxalap Ophthalmic Solution (0.25% Novel 
Formulation) 
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 
 
 
 
 
 
 
 
 
 
 
08 March 2019 
Amendment 1: 
17 December 2019 




Reproxalap Ophthalmic Solution  
Aldeyra Therapeutics, Inc.  
Clinical Trial Protocol: ADX-102-DED-013 
Final V2.0 17Dec2019 
 
 
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SYNOPSIS 
Protocol Title: 
A Multi-Center, Phase 2, Randomized, 
Double-Masked, Parallel-Group, Vehicle-
Controlled, Clinical Trial to Assess the 
Safety and Efficacy of Reproxalap 
Ophthalmic Solution (0.25% Novel 
Formulation) Compared to Vehicle in 
Subjects with Dry Eye Disease 
Protocol Number: 
ADX-102-DED-013 
Investigational Product: 
1) Reproxalap Ophthalmic Solution 
(0.25% Novel Formulation) 
2) Vehicle Ophthalmic Solution (vehicle) 
Study Phase: 
2 
Overall Study Design: 
Structure: 
Multi-center, double-masked, parallel-
group, vehicle-controlled, randomized 
clinical trial 
Prior to randomization , subjects will 
receive 14 consecutive days 
 of 
vehicle, self–administered QID in both 
eyes, between Visits 1 and 2. 
Randomization will be 1:1 into one of two 
treatment arms (100 subjects per arm): 
1. Reproxalap administered QID for 
four weeks, followed by BID 
administration for eight weeks 
2. Vehicle administered QID for four 
weeks, followed by BID 
administration for eight weeks 
 
Primary Objective: 
Evaluation of the safety and efficacy of 
reproxalap compared to vehicle for the 
treatment of dry eye disease 
Duration: 
Approximately 14 weeks (98 days) 
including 12 weeks of treatment 
Summary of Visit Schedule: 
Nine visits over the course of 
approximately 14 weeks 


Reproxalap Ophthalmic Solution  
Aldeyra Therapeutics, Inc.  
Clinical Trial Protocol: ADX-102-DED-013 
Final V2.0 17Dec2019 
 
 
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 
Visit 1 = Day -14 ± 2, 
 Screening  
 
Visit 2 = Day 1, 
Confirmation/ 
Baseline 
 
Visit 3 = Day 8 ± 2, 1-Week Follow-
Up 
 
Visit 4 = Day 15 ± 2, 2-Week Follow-
Up 
 
Visit 5 = Day 29 ± 2, 4-Week Follow-
Up 
 
Visit 6 = Day 43 ± 2, 6-Week Follow-
Up 
 
Visit 7 = Day 57 ± 3, 8-Week Follow-
Up 
 
Visit 8 = Day 71 ± 3, 10-Week Follow-
Up 
 
Visit 9 = Day 85 ± 3, 12-Week Follow-
Up & Study Exit 
Measures Taken to Reduce Bias: 
Randomization will be used to avoid bias 
in the assignment of subjects to test article, 
to increase the likelihood that known and 
unknown subject attributes (e.g., 
demographics and baseline characteristics) 
are evenly balanced across treatment 
groups, and to enhance the validity of 
statistical comparisons across treatment 
groups. Stratification will be used to 
balance treatment assignments within key 
subgroups. Masked treatment will be used 
to reduce the potential of bias during data 
collection and evaluation of clinical 
endpoints. 
Study Population Characteristics: 
Number of Subjects: 
Approximately 500 subjects will be 
screened to enroll approximately 200 
subjects (100 per treatment group). 
Condition/Disease: 
Dry Eye Disease (DED) 






Reproxalap Ophthalmic Solution  
Aldeyra Therapeutics, Inc.  
Clinical Trial Protocol: ADX-102-DED-013 
Final V2.0 17Dec2019 
 
 
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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. 
 
 
 
 
 
 
 
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 


Reproxalap Ophthalmic Solution  
Aldeyra Therapeutics, Inc.  
Clinical Trial Protocol: ADX-102-DED-013 
Final V2.0 17Dec2019 
 
 
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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 
known to cause ocular drying that has 
not been used on a stable dosing 
regimen for at least 30 days prior to 
Visit 1; 
19. Be unable or unwilling to follow 
instructions, including participation in 
all study assessments and visits; 
 
Evaluation Criteria: 
 
Efficacy Measures and Endpoints: 
Primary Endpoint 
 
Subject-reported ocular dryness 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Reproxalap Ophthalmic Solution  
Aldeyra Therapeutics, Inc.  
Clinical Trial Protocol: ADX-102-DED-013 
Final V2.0 17Dec2019 
 
 
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 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Measures: 
 
Visual acuity (VA) at distance 
utilizing an ETDRS chart 
 
Slit-lamp evaluation 
 
Adverse event (AE) query 
(reported, elicited, and observed) 
 
Intraocular Pressure (IOP) 
 
Dilated fundoscopy 
General Statistical Methods and Types of Analyses 
Sample Size: 
Based on the results of a Phase 2b clinical trial of reproxalap in dry eye disease subjects (ADX-
102-DED-009), for the outcome measurements of nasal fluorescein staining and ocular dryness 
VAS score, approximately 100 subjects per randomized arm will be evaluated in ADX-102-
DED-013. Sample size estimates were made assuming
 for 
the two efficacy populations, one with baseline staining severity of 
 and the 
other with dryness score severity of 
.  Using PASS (software version 14, NCSS, 


Reproxalap Ophthalmic Solution  
Aldeyra Therapeutics, Inc.  
Clinical Trial Protocol: ADX-102-DED-013 
Final V2.0 17Dec2019 
 
 
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LLC), the sample size estimated for staining was 39 per treatment arm (78 total); the sample 
size estimated for dryness score was 54 per treatment arm (108 total).  
Primary Endpoint Efficacy Analysis: 
 
The primary symptom endpoint will be achieved 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. 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. 


Reproxalap Ophthalmic Solution  
Aldeyra Therapeutics, Inc.  
Clinical Trial Protocol: ADX-102-DED-013 
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TABLE OF CONTENTS 
Clinical Trial Protocol: ADX-102-DED-013.......................................................................1 
SYNOPSIS..................................................................................................................3 
TABLE OF CONTENTS..........................................................................................11 
LIST OF ABBREVIATIONS ............................................................................................14 
1 
INTRODUCTION ....................................................................................................16 
2 
Clinical Studies of Reproxalap Ophthalmic Solution ...............................................17 
2.1 
Minimization of Risk ......................................................................................27 
3 
STUDY OBJECTIVES .............................................................................................27 
4 
CLINICAL HYPOTHESES .....................................................................................27 
5 
OVERALL STUDY DESIGN ..................................................................................28 
6 
STUDY POPULATION ...........................................................................................30 
6.1 
Number of Subjects (approximate) ................................................................30 
6.2 
Study Population Characteristics ....................................................................30 
6.3 
Inclusion Criteria ............................................................................................30 
6.4 
Exclusion Criteria ...........................................................................................31 
6.5 
Withdrawal Criteria (if applicable) ................................................................32 
7 
STUDY PARAMETERS ..........................................................................................33 
7.1 
Efficacy Measures and Endpoints ..................................................................33 
7.1.1 
Primary Efficacy Measure(s) ............................................................33 
7.1.2 
Primary Efficacy Endpoint ...............................................................33 
7.1.3 
Key Secondary Measure(s) ...............................................................33 
7.1.4 
Key Secondary Endpoint ..................................................................33 
7.1.6 
Secondary Efficacy Endpoint(s) .......................................................33 
7.1.7 
Exploratory Measure(s) ....................................................................34 
7.1.8 
Criteria for Effectiveness ..................................................................34 
7.2 
Safety Measures .............................................................................................34 
8 
STUDY MATERIALS .............................................................................................34 
8.1 
Study Treatment(s) .........................................................................................34 
8.1.1 
Study Treatment(s)/ Formulation(s): ................................................34 
8.1.2 
Description of and Justification for the Route of Administration, 
Dosage, Dosage Regimen, and Treatment Period(s): .......................34 
8.1.3 
Instructions for Use and Administration ...........................................35 
8.2 
Other Study Supplies ......................................................................................35 
9 
STUDY METHODS AND PROCEDURES ............................................................35 
9.1 
Subject Entry Procedures ...............................................................................35 
9.1.1 
Overview ...........................................................................................35 
9.1.2 
Informed Consent..............................................................................35 
9.1.3 
Washout Intervals .............................................................................36 
9.1.4 
Procedures for Final Study Entry ......................................................36 
9.1.5 
Methods for Assignment to Treatment Groups: ...............................36 
9.2 
Concurrent Therapies .....................................................................................36 
9.2.1 
Prohibited Medications/Treatments ..................................................37 
9.2.2 
Escape Medications ..........................................................................37 
9.2.3 
Special Diet or Activities ..................................................................37 


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Clinical Trial Protocol: ADX-102-DED-013 
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9.3 
Examination Procedures .................................................................................37 
9.3.1 
Procedures to be Performed at Each Study Visit with Regard to 
Study Objective(s) ............................................................................37 
9.3.2 
Visit 1: Day -14 ± 2 – 
Screening ...........................................37 
9.3.3 
Visit 2:  Day 1 – 
 
 and Baseline .........................38 
9.3.4 
Visit 3 (Day 8 ± 2) ............................................................................40 
9.3.5 
Visit 4 (Day 15 ± 2) ..........................................................................40 
9.3.6 
Visit 5 (Day 29 ± 2) ..........................................................................41 
9.3.7 
Visit 6 (Day 43 ± 2) ..........................................................................42 
9.3.8 
Visit 7 (Day 57 ± 3) ..........................................................................43 
9.3.9 
Visit 8 (Day 71 ± 3) ..........................................................................44 
9.3.10 Visit 9 (Day 85 ± 3) ..........................................................................44 
9.3.11 Early Termination/Discontinuation ..................................................45 
9.3.12 General Safety Measures ..................................................................45 
9.4 
Schedule of Visits, Measurements and Dosing ..............................................46 
9.4.1 
Scheduled Visits................................................................................46 
9.4.2 
Unscheduled Visits ...........................................................................46 
9.5 
Compliance with Protocol ..............................................................................46 
9.6 
Subject Disposition .........................................................................................47 
9.6.1 
Completed Subjects ..........................................................................47 
9.6.2 
Discontinued Subjects .......................................................................47 
9.7 
Study Termination ..........................................................................................47 
9.8 
Study Duration ...............................................................................................47 
9.9 
Monitoring and Quality Assurance ................................................................47 
10 
ADVERSE EVENTS ................................................................................................48 
10.1 Adverse Event ................................................................................................48 
10.1.1 Severity .............................................................................................48 
10.1.2 Relationship to Investigational Product ............................................48 
10.1.3 Expectedness .....................................................................................49 
10.2 Serious Adverse Events ..................................................................................49 
10.3 Procedures for Reporting Adverse Events .....................................................50 
10.3.1 Reporting a Suspected Unexpected Adverse Reaction .....................50 
10.3.2 Reporting a Serious Adverse Event ..................................................50 
10.4 Procedures for Unmasking (if applicable) ......................................................51 
10.5 Type and Duration of the Follow-up of Subjects after Adverse Events ........51 
11 
STATISTICAL HYPOTHESES AND METHODS OF ANALYSES .....................52 
11.1 Analysis Populations ......................................................................................52 
11.2 Statistical Hypotheses .....................................................................................53 
11.3 Sample Size ....................................................................................................53 
11.4 Statistical Analysis .........................................................................................53 
11.4.1 General Considerations .....................................................................53 
11.4.2 Unit of Analysis ................................................................................54 
11.4.3 Missing Data .....................................................................................54 
11.4.4 Multiplicity Considerations ..............................................................54 
11.4.5 Primary Efficacy Analysis ................................................................54 
11.4.7 Secondary Efficacy Analysis ............................................................55 


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Clinical Trial Protocol: ADX-102-DED-013 
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11.4.8 Exploratory Efficacy Analysis ..........................................................56 
11.4.9 Safety Variables ................................................................................56 
12 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES ....................................56 
12.1 Protection of Human Subjects ........................................................................56 
12.1.1 Subject Informed Consent.................................................................56 
12.1.2 Institutional Review Board (IRB) Approval .....................................57 
12.2 Ethical Conduct of the Study ..........................................................................57 
12.3 Subject Confidentiality ...................................................................................57 
12.4 Documentation ...............................................................................................57 
12.4.1 Retention of Documentation .............................................................57 
12.5 Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Investigational Product ...................................................................................58 
12.5.1 Labeling/Packaging...........................................................................58 
12.5.2 Storage of Investigational Product ....................................................58 
12.5.3 Accountability of Investigational Product ........................................58 
12.5.4 Return or Disposal of Investigational Product ..................................58 
12.6 Recording of Data on Source Documents and Case Reports Forms (CRFs) .59 
12.7 Publications ....................................................................................................59 
13 
REFERENCES .........................................................................................................60 
14 
 Appendices ...............................................................................................................62 
14.1 Appendix 1: Schedule of visits and measurements ........................................62 
14.2 Appendix 2: Examination Procedures, Tests, Equipment, and Techniques ...64 
Appendix 3: Protocol Amendment Summary ....................................................................76 
Key Secondary Endpoint ................................................................................77 
Secondary Efficacy Endpoint(s) .....................................................................77 
Secondary Efficacy Endpoint(s) .....................................................................77 
Appendix 4: Sponsor and Ora Approvals ..........................................................................80 
Appendix 5: Investigator’s Signature ................................................................................81 
 
 
 
 
 


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Clinical Trial Protocol: ADX-102-DED-013 
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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 


Reproxalap Ophthalmic Solution  
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Clinical Trial Protocol: ADX-102-DED-013 
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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 
SDC 
Statistics and Data Corporation 
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 
 
 


Reproxalap Ophthalmic Solution  
Aldeyra Therapeutics, Inc.  
Clinical Trial Protocol: ADX-102-DED-013 
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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 NFB 
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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Clinical Trial Protocol: ADX-102-DED-013 
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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 
minutes, was reported in most subjects treated in the Phase 1 and the allergic 
conjunctivitis and dry eye disease Phase 2 clinical trials, and in a small proportion of 






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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. The excipients in the novel formulation are similar to those that have been used in 
the non-clinical safety and previous clinical studies. The concentrations of the excipients 
in the novel formulation are varied in degree but well within the allowable limits for 
topical ophthalmic delivery.  Please refer to the Investigator’s Brochure for additional 
information.  
3 STUDY OBJECTIVES 
The overall objective of this study is to evaluate the safety and efficacy of Reproxalap 
Ophthalmic Solution (0.25% Novel Formulation) compared to Vehicle Ophthalmic 
Solution for the treatment of dry eye disease. 
4 CLINICAL HYPOTHESES 
The clinical hypotheses is that Reproxalap Ophthalmic Solution (0.25% Novel 
Formulation) is more effective than vehicle in reducing the signs and symptoms of DED.  












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The Sponsor and investigators may discontinue any subject for non-compliance, or for 
any medical reason.  
7 STUDY PARAMETERS 
7.1 
Efficacy Measures and Endpoints 
7.1.1 Primary Efficacy Measure(s) 
 Subject-reported ocular dryness 
 
7.1.2 Primary Efficacy Endpoint 
 The primary endpoint is the overall mean change from baseline in subject-
reported ocular dryness score 
 assessed using MMRM from Week 
2 to Week 12. The population used for analysis of ocular dryness score will be 
subjects who have a baseline ocular dryness score 
 
 
7.1.3 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
7.1.6 
 
 
 
 
 
 
 
 
 
 
 
 
  


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7.1.7 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.1.8 Criteria for Effectiveness 
The primary endpoint will be achieved if the overall mean change from baseline in 
subject-reported ocular dryness score 
 assessed 
 
 from Week 2 to Week 12, in reproxalap-treated 
subjects is statistically significantly lower than that of vehicle-treated subjects. The 
population used for analysis of ocular dryness score will be subjects who have a baseline 
(Visit 2) ocular dryness score of
 
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 Ophthalmic Solution (0.25% Novel Formulation) 
 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. 


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8.1.3 Instructions for Use and Administration 
 Reproxalap and vehicle are supplied as patient kits, with each kit containing 15 
foil pouches, and each foil pouch containing five single-dose units. 
 The vehicle solution consists of all components of the drug product solution with 
the exception of reproxalap. 
 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. 
 Reproxalap and vehicle should be stored refrigerated (2–8° C). Subjects will be 
instructed to store reproxalap and vehicle in a refrigerator (2–8° C). Five cavity 
unit dose ampules are packaged in aluminum foil pouches under nitrogen. Unit 
dose ampules are for SINGLE USE ONLY. 
 Subjects will receive four treatment kits. After Visit 5 all subjects will change 
their dosing regimen from QID to BID for the remainder of the treatment period. 
 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 






















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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 for a schedule of visits and measurements. 
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. 
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. Dosing compliance will be based on the unused ampule count. 
 
 
  
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. 


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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). 
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. 


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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 
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:  


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 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. 
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. 


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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. 
10.3.2 Reporting a Serious Adverse Event 
To ensure subject safety, all SAEs, regardless of relationship to the IP, must be 
immediately reported. All information relevant to the SAE must be recorded on the 
appropriate CRFs. The investigator is obligated to pursue and obtain information 
requested by Ora and/or the Sponsor in addition to that information reported on the CRF. 
All subjects experiencing a SAE must be followed up and the outcome reported. 
In the event of a SAE, the investigator must notify Ora and the Sponsor immediately; 
obtain and maintain in his/her files all pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and follow-up of the 
subject; provide Ora and the Sponsor with a complete case history, which includes a 
statement as to whether the event was or was not suspected to be related to the use of the 
IP; and inform the IRB/IEC of the SAE within their guidelines for reporting SAEs. 
Contact information for reporting SAEs: 
 
 
 
 
 
 


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10.4 
Procedures for Unmasking (if applicable) 
All subjects, investigators, and study personnel involved with the conduct of the study 
will be masked with regard to study drug treatment assignments. When medically 
necessary, the investigator may need to determine what treatment has been assigned to a 
subject. When possible (i.e., in non-emergent situations), Ora and/or the Sponsor should 
be notified before unmasking IP. Ora and/or the study Sponsor must be informed 
immediately about any unmasking event. 
If an investigator identifies a medical need for unmasking the treatment assignment of a 
subject, he/she should contact Ora and/or the medical monitor prior to unmasking the 
identity of the IP, if possible. Ora will ask the site to complete and send them the 
Unmasking Request Form. Ora will notify Aldeyra and jointly will determine if the 
unmasking request should be granted. They may consult the medical monitor as needed. 
The result of the request will be documented on the Unmasking Request Form. If 
approval is granted to unmask a subject, written permission via the Unmasking Request 
Form will be provided to the investigator. The investigator will unmask the subject 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-




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11.2 
Statistical Hypotheses 
The following hypothesis will be tested comparing reproxalap to vehicle at 12 weeks.  
The null hypotheses must be rejected for the dosing regimen to claim efficacy.  
 
 
   
 
 
 
11.3 
Sample Size 
Based on the results of a Phase 2b clinical trial of reproxalap in dry eye disease subjects 
(ADX-102-DED-009), for the outcome measurements of ocular dryness VAS score and 
nasal fluorescein staining, approximately 100 subjects per randomized arm will be 
evaluated in ADX-102-DED-013. Sample size estimates were made assuming an alpha of 
0.05 and power of 90% for the two efficacy populations, one with baseline staining 
severity of 2 units or more and the other with dryness score severity of 3 units or more.  
Using PASS (software version 14, NCSS, LLC), the sample size estimated for staining 
was 39 per treatment arm (78 total); the sample size estimated for dryness score was 54 
per treatment arm (108 total).  
11.4 
Statistical Analysis 
11.4.1 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 WHO Drug 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 
will be matched by dosing regimen and calculated as active minus vehicle. 
 
All analyses will be 2-sided at a significance level of 0.05. 95% confidence intervals will 
be provided where appropriate. 


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The statistical analysis plan (SAP) will serve as the final determinant of the statistical 
procedures, notwithstanding anything herein. 
11.4.2 Unit of Analysis 
Safety endpoints will be analyzed for both eyes.  For efficacy endpoints, the unit of 
analysis will be the study eye, or the “worst eye,” as defined by the following:  
 
 
 
 
 
 
 
 
11.4.3 Missing Data 
The primary analyses using MMRM method will be performed on the ITTOD and 
ITTFSN population with observed data only.  Efficacy analyses may also be conducted 
using the ITT, ITTOD, and ITTFSN populations with multiple imputation under missing 
at random (MAR) and missing not at random (MNAR) assumptions. Per-protocol 
population analysis may also be conducted to assess sensitivity. Further detail will be 
described in the SAP. 
11.4.4 Multiplicity Considerations 
A sequential (closed) testing procedure will be used to control the overall Type I error 
rate due to multiple comparisons for the primary, key secondary and secondary endpoint 
of fluorescein nasal staining score. The order of treatment comparisons is as follows:   
 
 
 
 
 
 
 
 
 
 
 
 
11.4.5 Primary Efficacy Analysis 
The overall mean change from baseline in 
 from Week 2 to 
Week 12 will be analyzed using 
 in subjects in the ITTOD population.   
The 
 will be fit with baseline value, treatment and visit, as well as the two-
way interaction between treatment and visit.  Change from baseline of the variable of 
interest (either ocular dryness or fluorescein nasal staining) will be the dependent 
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11.4.9 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), 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. 
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 


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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. 
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 


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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. 
 
 
 
 
 
 
 
 
 
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. 


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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. Ora 
and the Sponsor will have the final decision regarding the manuscript and publication. 
 
 


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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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APPENDIX 5: INVESTIGATOR’S SIGNATURE 
 
Protocol Title: 
A Multi-Center, Phase 2, Randomized, Double-Masked, 
Parallel-Group, Vehicle-Controlled, Clinical Trial to Assess the 
Safety and Efficacy of Reproxalap Ophthalmic Solution (0.25% 
Novel Formulation) Compared to Vehicle in Subjects with Dry 
Eye Disease 
Protocol Number: 
ADX-102-DED-013 
Final Date: 
17 December 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. 

SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS PLAN  
A Multi-Center, Phase 2, Randomized, Double-Masked, Parallel-Group, Vehicle-
Controlled, Clinical Trial to Assess the Safety and Efficacy of Reproxalap 
Ophthalmic Solution (0.25% Novel Formulation) Compared to Vehicle in 
Subjects with Dry Eye Disease 
 
Sponsor:   
 
Aldeyra Therapeutics, Inc. 
 
 
 
 
 
 
Protocol Number: 
ADX-102-DED-013 
 
 
Author:   
 
 
 
 
 
 
 
 
Date:    
 
30-DEC-2019 
Version:  
 
2.0 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
Page 2 of 51 
A Multi-Center, Phase 2, Randomized, Double-Masked, Parallel-Group, Vehicle-Controlled, 
Clinical Trial to Assess the Safety and Efficacy of Reproxalap Ophthalmic Solution (0.25% Novel 
Formulation) Compared to Vehicle in Subjects with Dry Eye Disease 
 
 
Protocol Number: 
ADX-102-DED-013 
Version:  
 
2.0  
Date:    
 
30-DEC-2019 
 
Statistical Analysis Plan Approval 
 
 
Prepared by:
 
 
 
 
 
 
 
Reviewed by
 
 
 
 
 
 
 
Approved by
 
 
 
 
 
Approved by
 
 
 
 


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Table of Contents 
1. 
Introduction............................................................................................................................... 7 
2. 
Study Objectives ...................................................................................................................... 7 
2.1 Primary Measures .................................................................................................................... 7 
2.2 Key Secondary Measures ........................................................................................................ 7 
2.3 Secondary Measures ............................................................................................................... 7 
2.4 Exploratory Measures .............................................................................................................. 8 
2.5 Safety Measures ...................................................................................................................... 8 
2.6 Statistical Hypotheses .............................................................................................................. 9 
3. 
Study Design and Procedures ................................................................................................. 9 
3.1 General Study Design .............................................................................................................. 9 
3.2 Schedule of Visits and Assessments ..................................................................................... 10 
4. 
Study Treatments ................................................................................................................... 13 
4.1 Method of Assigning Subjects to Treatment Arms ................................................................. 13 
4.2 Masking and Unmasking ........................................................................................................ 13 
5. 
Sample Size and Power Considerations ................................................................................ 14 
6. 
Data Preparation .................................................................................................................... 14 
7. 
Analysis Populations .............................................................................................................. 15 
7.1 Intent-to-Treat......................................................................................................................... 15 
7.2 Per Protocol............................................................................................................................ 15 
7.3 Safety ..................................................................................................................................... 15 
8. 
General Statistical Considerations ......................................................................................... 15 
8.1 Unit of Analysis....................................................................................................................... 15 
8.2 Missing or Inconclusive Data Handling .................................................................................. 16 
8.3 Definition of Baseline ............................................................................................................. 16 
8.4 Data Analysis Conventions .................................................................................................... 16 
8.5 Adjustments for Multiplicity ..................................................................................................... 17 
9. 
Disposition of Subjects ........................................................................................................... 17 
10. 
Demographic and Pretreatment Variables ............................................................................. 18 
10.1 Demographic Variables .......................................................................................................... 18 
10.2 Pretreatment Variables .......................................................................................................... 18 
11. 
Medical History and Concomitant Medications ...................................................................... 18 
11.1 Medical History ....................................................................................................................... 18 
11.2 Concomitant Medications ....................................................................................................... 19 
12. 
Dosing Compliance and Treatment Exposure ....................................................................... 19 


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12.1 Dosing Compliance ................................................................................................................ 19 
12.2 Treatment Exposure ............................................................................................................... 20 
13. 
Efficacy Analyses ................................................................................................................... 20 
13.1 Primary Analysis .................................................................................................................... 20 
13.1.1 
Ocular Dryness Score ................................................................................................ 21 
13.2 Key Secondary Analysis ........................................................................................................ 22 
13.2.1 
Fluorescein Nasal Staining 
 ................................................ 23 
13.3 Secondary Analyses .............................................................................................................. 24 
13.3.1 
Fluorescein Nasal Staining 
 25 
13.3.2 
Dryness from the Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire ...... 25 
13.3.3 
Fluorescein Staining (Ora Calibra® Scale) ................................................................. 26 
13.3.4 
Ocular Dryness (VAS) 
 27 
13.3.5 
Ocular Dryness Score 
 28 
13.3.6 
Fluorescein Nasal Staining 
 
...................................................................................................................... 28 
13.3.7 
Fluorescein Nasal Staining 
 
....................................................................................................................... 29 
13.3.8 
Dryness from the Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire 
 
 ............................................................................. 29 
14. 
Exploratory Analyses ............................................................................................................. 30 
14.1.1 
Visual Analog Scale ................................................................................................... 31 
14.1.2 
Ocular Discomfort Scale (Ora Calibra Scale) ............................................................ 32 
14.1.3 
Ocular Discomfort & 4-Symptom Questionnaire (Ora Calibra® Scale) ...................... 32 
14.1.4 
Ocular Surface Disease Index© .................................................................................. 33 
14.1.5 
Symptom Assessment in Dry Eye .............................................................................. 35 
14.1.6 
Conjunctival Allergen Challenge Ocular Itching Scale (Ora Calibra® Scale) ............. 35 
14.1.7 
Lissamine Green Staining (Ora Calibra® Scale) ......................................................... 36 
14.1.8 
Tear Film Break-Up Time ........................................................................................... 37 
14.1.9 
Tear Osmolarity .......................................................................................................... 38 
14.1.10 
Unanesthetized Schirmer’s Test ................................................................................ 38 
15. 
Safety Analyses ..................................................................................................................... 39 
15.1 Adverse Events ...................................................................................................................... 39 
15.2 Visual Acuity (ETDRS) ........................................................................................................... 41 
15.3 Slit-Lamp Biomicroscopy Examination ................................................................................... 41 
15.4 Intraocular Pressure ............................................................................................................... 42 
15.5 Dilated Fundoscopy Examination........................................................................................... 42 


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16. 
Changes from Protocol-Stated Analyses ............................................................................... 43 
17. 
Revision History ..................................................................................................................... 43 
18. 
Tables ..................................................................................................................................... 44 
19. 
Listings ................................................................................................................................... 49 
20. 
Figures ................................................................................................................................... 51 
 
List of Abbreviations 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical 
BID 
Bis in die (Twice Daily) 
CAC 
Conjunctival Allergen Challenge 
CAE 
Controlled Adverse Environment 
CI 
Confidence Interval 
CRO 
Contract Research Organization 
CS 
Clinically Significant 
eCRF 
Electronic Case Report Form 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FSN 
Fluorescein Staining of the Nasal Region 
ICH 
International Conference on Harmonisation 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
ITT 
Intent-to-Treat 
ITTFSN 
Intent-to-Treat Fluorescein Nasal Score 
ITTOD 
Intent-to-Treat Ocular Dryness 
IWRS 
Interactive Web Response System 
logMAR 
Logarithm of the Minimum Angle of Resolution 
LS 
Least Squares 
MAR 
Missing at Random 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
mmHg 
Millimeters of Mercury 
MMRM 
Mixed Model for Repeated Measures 
MNAR 
Missing Not at Random 
mOsm 
Milliosmoles 
NCS 
Not Clinically Significant 
OD 
Oculus Dexter (Right Eye) 
OS 
Oculus Sinister (Left Eye) 
OSDI 
Ocular Surface Disease Index 


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OU 
Oculus Uterque (Both Eyes) 
PDF 
Portable Document Format 
PP 
Per Protocol 
PPOD 
Per Protocol Ocular Dryness 
PPFSN 
Per Protocol Fluorescein Nasal Score 
PT 
Preferred Term 
QID 
Quater in Die (Four Times Daily) 
RTF 
Rich Text Format 
SAE 
Serious Adverse Event 
SANDE 
Symptom Assessment in Dry Eye 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SD 
Standard Deviation 
SDC 
Statistics & Data Corporation, Incorporated 
SE 
Standard Error 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TEAE 
Treatment-Emergent Adverse Event 
TFBUT 
Tear Film Break-Up Time 
TMF 
Trial Master File 
VA 
Visual Acuity 
VAS 
Visual Analog Scale 
WHODrug 
World Health Organization Drug Dictionary 
 
 










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Table 2. Schedule of Visits and Measurements 


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4. Study Treatments 
4.1 
Method of Assigning Subjects to Treatment Arms 
Before the initiation of study run-in at Visit 1 (Day -14), 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 (Day -14) and Visit 2 (Day 1) will be assigned 
a randomization number at the end of Visit 2 (Day 1). The Interactive Web Response System (IWRS) 
will be used to assign all randomization numbers. 
 
 
 
 
 
 
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.  
4.2 
Masking and Unmasking 
All subjects, investigators, and study personnel involved with the conduct of the study will be masked 
with regard to study drug treatment assignments. When medically necessary, the investigator may need 
to determine what treatment has been assigned to a subject. When possible (i.e., in non-emergent 
situations), Ora and/or the Sponsor should be notified before unmasking IP. Ora and/or the study 
Sponsor must be informed immediately about any unmasking event. 
If an investigator identifies a medical need for unmasking the treatment assignment of a subject, he/she 
should contact Ora and/or the medical monitor prior to unmasking the identity of the IP, if possible. Ora 
will ask the site to complete and send them the Unmasking Request Form. Ora will notify Aldeyra and 
jointly will determine if the unmasking request should be granted. They may consult the medical monitor 


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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 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 (Trial 
Master File). 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. 
5. Sample Size and Power Considerations 
Based on the results of a Phase 2b clinical trial 
 
 
 
 
 
 
 
6. Data Preparation 
Electronic Case Report Forms (eCRF) will be developed by Statistics & Data Corporation, Incorporated 
(SDC). Unless otherwise specified by Aldeyra, the eCRFs will follow SDTM standards. Data from source 
documents will be entered into the eCRF by site personnel.  
The clinical study database will be developed and tested in 
  
After data are entered into the clinical study database, electronic edit checks and data review will be 
performed. All data validation specifications and procedures are detailed in the Data Validation Manual 
as a separate document. When the database has been declared to be complete and accurate, the 
database will be locked. Any changes to the database after data have been locked can only be made 
with the approval of Aldeyra and Ora in consultation with SDC.  
All analyses outlined in this document will be carried out after the following have occurred: 
• 
 
 
 
 
 


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• 
 
 
7. Analysis Populations 
7.1 
Intent-to-Treat 
Intent-to-Treat Population: 
 
 
  
• 
 
 
 
 
  
7.2 
Per Protocol 
Per-Protocol Population: 
 
 
 
  
 
 
 
 
 
  
7.3 
Safety 
Safety Population: 
 
  
8. General Statistical Considerations 
8.1 
Unit of Analysis 
Safety endpoints will be analyzed 
 
 
 
 
 




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8.5 
Adjustments for Multiplicity 
 
 
   
 
 
 
 
 
 
 
 
 
9. Disposition of Subjects 
Subject disposition will be presented 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






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• 
 
  
 
 
 
 
 
  
 
 
 
 
  
A subject listing of dosing compliance and study drug accountability will also be produced. 
A subject listing of run-in, run-in instillation, and run-in replacement will be provided as well as study 
drug assignment, instillation, and replacement. 
12.2 
Treatment Exposure 
Extent of treatment exposure for completed or discontinued subjects will be calculated 
 
 
 
 
 
 
 
  
Subject listings of  study drug exposure and dosing compliance will be produced. 
13. Efficacy Analyses 
13.1 
Primary Analysis 
The primary endpoint is 
 
 
 
 


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The primary endpoint will be described in subject listings. 
13.1.1  OCULAR DRYNESS SCORE 
The subject will be asked to subjectively rate their ocular dryness 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 




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13.2.1 FLUORESCEIN NASAL STAINING FROM WEEK 1 TO WEEK 6 
Fluorescein nasal staining will be graded using the Ora Calibra® Corneal and Conjunctival Staining 
Scale 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  












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13.3.7 FLUORESCEIN NASAL STAINING 
 
 
 
 
 
 
 
 
Visit-based data will be summarized 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
13.3.8 DRYNESS FROM THE ORA CALIBRA® OCULAR DISCOMFORT & 4-SYMPTOM QUESTIONNAIRE 
 
 
 
  
Visit-based data will be summarized 
 
 
 


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14. Exploratory Analyses 
Exploratory efficacy variables will be summarized 
 
 
 
 
 
 
 
 
 
  
 
 
 
 














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14.1.8 TEAR FILM BREAK-UP TIME 
The TFBUT will be recorded 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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15. Safety Analyses 
All safety analyses will be conducted using the Safety population. 
15.1 
Adverse Events 
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.  
All AEs will be coded using the MedDRA 22.0.  
Treatment-emergent adverse events (TEAE) are defined as any event that occurs or worsens on or after 
the day that randomized study treatment is initiated. Adverse events recorded in the eCRF which began 
prior to treatment will not be included in the summary tables but will be included in the AE data listings. 
An overall summary will be presented that includes the number and percentage of subjects who 
experienced at least one AEs, ocular AEs, non-ocular AEs, SAEs, AEs by maximal severity, AEs by 
relationship to study drug, AEs leading to treatment discontinuation, and AEs resulting in death by 
treatment arm for the Safety population. In addition, overall TEAEs and the number and percentage of 
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maximal severity, TEAEs by relationship to study drug, TEAEs leading to treatment discontinuation, and 
TEAEs resulting in death by treatment arm for the Safety population.  
Separate summaries will be provided for the following categories of AEs:  
• 
Ocular AEs by SOC and PT 
• 
Non-ocular AEs by SOC and PT 
• 
Ocular TEAEs by SOC and PT 
• 
Non-ocular TEAEs by SOC and PT 
• 
Ocular TEAEs by SOC, PT, and maximal severity  
• 
Non-ocular TEAEs by SOC, PT, and maximal severity  
• 
Ocular TEAEs by SOC, PT, and strongest relationship to study drug 
• 
Non-ocular TEAEs by SOC, PT, and strongest relationship to study drug 
• 
Ocular TEAEs by SOC, PT, maximal severity, and strongest relationship to study drug 
• 
Non-ocular TEAEs by SOC, PT, maximal severity, and strongest relationship to study drug 
• 
TEAEs That Led to Premature Discontinuation 
• 
SAEs 
Adverse Events and TEAEs will be summarized using discrete summary statistics and presented by 
treatment arm and all subjects for the the Safety population. If a subject reports the same PT multiple 
times within the same SOC, that PT will only be reported once within that SOC. As with the PT, if a 
subject reports multiple conditions within the same SOC, that SOC will only be reported once. In the 
summary, SOC will be listed in ascending alphabetical order; PTs will be listed in order of descending 
frequency for all subjects within each SOC.  
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 assessment of severity is made 
irrespective of relationship to IP or seriousness of the event and should be evaluated according to the 
following scale: 
• 
Mild: Event is noticeable to the subject, but is easily tolerated and does not interfere with the 
subject’s daily activities. 
• 
Moderate: Event is bothersome, possibly requiring additional therapy, and may interfere with 
the subject’s daily activities. 
• 
Severe: Event is intolerable, necessitates additional therapy or alteration of therapy, and 
interferes with the subject’s daily activities. 
Subjects experiencing more than one AE within a given SOC or PT are counted once within that SOC 
or PT for the maximal severity.