Clinical trial NCT03879863
Conditions: Dry Eye
Sponsor: Aldeyra Therapeutics, Inc.
Start date: 2019-04-16; Completion date: 2019-10-04
Enrollment: 422 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The RENEW Trial is 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

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None
Interventions: intervention 1: Reproxalap Ophthalmic Solution (0.25%) QID intervention 2: Vehicle Ophthalmic Solution QID intervention 3: Reproxalap Ophthalmic Solution (0.25%) QID to BID intervention 4: Vehicle Ophthalmic Solution QID to BID
Intervention descriptions: intervention 1: Reproxalap Ophthalmic Solution (0.25%) administered QID for twelve weeks intervention 2: Vehicle Ophthalmic Solution administered QID for twelve weeks intervention 3: Reproxalap Ophthalmic Solution (0.25%) administered QID for four weeks, followed by BID administration for eight weeks intervention 4: Vehicle Ophthalmic Solution administered QID for four weeks, followed by BID administration for eight weeks

Protocol documents:
SAP_002.pdf: 
 
 
STATISTICAL ANALYSIS PLAN  
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: Part 1 
 
 
Sponsor:   
 
Aldeyra Therapeutics, Inc. 
 
 
 
 
 
 
Protocol Number: 
ADX-102-DED-012 Part 1 
 
 
Author:   
 
 
 
 
 
 
 
 
Date:    
 
31/OCT/2019 
Version:  
 
2.0 
 
 
 
 
 
 
 
 
 
 
 


SIGN


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Table of Contents 
1. 
Introduction............................................................................................................................... 7 
2. 
Study Objectives ...................................................................................................................... 7 
2.1 Primary Measures .................................................................................................................... 7 
2.2 Key Secondary Measure .......................................................................................................... 7 
2.3 Secondary Measures ............................................................................................................... 7 
2.4 Exploratory Measures .............................................................................................................. 8 
2.5 Safety Measures ...................................................................................................................... 8 
2.6 Statistical Hypotheses .............................................................................................................. 8 
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 .................................................................................................................... 15 
7. 
Analysis Populations .............................................................................................................. 15 
7.1 Intent-to-Treat......................................................................................................................... 15 
7.2 Per Protocol............................................................................................................................ 16 
7.3 Safety ..................................................................................................................................... 16 
8. 
General Statistical Considerations ......................................................................................... 16 
8.1 Unit of Analysis....................................................................................................................... 16 
8.2 Missing or Inconclusive Data Handling .................................................................................. 16 
8.3 Definition of Baseline ............................................................................................................. 16 
8.4 Data Analysis Conventions .................................................................................................... 17 
8.5 Adjustments for Multiplicity ..................................................................................................... 17 
9. 
Disposition of Subjects ........................................................................................................... 18 
10. 
Demographic and Pretreatment Variables ............................................................................. 19 
10.1 Demographic Variables .......................................................................................................... 19 
10.2 Pretreatment Variables .......................................................................................................... 19 
11. 
Medical History and Concomitant Medications ...................................................................... 19 
11.1 Medical History ....................................................................................................................... 19 
11.2 Concomitant Medications ....................................................................................................... 19 
12. 
Dosing Compliance and Treatment Exposure ....................................................................... 20 


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12.1 Dosing Compliance ................................................................................................................ 20 
12.2 Treatment Exposure ............................................................................................................... 21 
13. 
Efficacy Analyses ................................................................................................................... 21 
13.1 Primary Analysis .................................................................................................................... 21 
13.1.1 
Ocular Dryness Score ................................................................................................ 22 
13.1.2 
Fluorescein Nasal Staining ........................................................................................ 23 
13.2 Key Secondary Analyses ....................................................................................................... 24 
13.2.1 
 Dryness ... 25 
13.3 Secondary Analyses .............................................................................................................. 26 
13.3.1 
Fluorescein Staining 
 ................................................................. 26 
13.3.2 
Unanesthetized Schirmer’s Test ................................................................................ 27 
13.3.3 
Ocular Dryness through Visit 5 (Day 29) ................................................................... 28 
14. 
Exploratory Analyses ............................................................................................................. 29 
14.1.1 
Visual Analog Scale ................................................................................................... 29 
14.1.2 
Ocular Discomfort Scale 
 ............................................................ 30 
14.1.3 
Symptom Questionnaire 
 ...................... 31 
14.1.4 
Ocular Surface Disease Index© .................................................................................. 32 
14.1.5 
Symptom Assessment in Dry Eye .............................................................................. 33 
14.1.6 
 Itching Scale 
 ............. 34 
14.1.7 
Lissamine Green Staining (
) ......................................................... 35 
14.1.8 
Tear Film Break-Up Time ........................................................................................... 35 
14.1.9 
Tear Osmolarity .......................................................................................................... 36 
15. 
Safety Analyses ..................................................................................................................... 37 
15.1 Adverse Events ...................................................................................................................... 37 
15.2 Visual Acuity (ETDRS) ........................................................................................................... 39 
15.3 Slit-Lamp Biomicroscopy Examination ................................................................................... 39 
15.4 Intraocular Pressure ............................................................................................................... 40 
15.5 Dilated Fundoscopy Examination........................................................................................... 40 
16. 
Changes from Protocol-Stated Analyses ............................................................................... 41 
17. 
Revision History ..................................................................................................................... 41 
18. 
Tables ..................................................................................................................................... 41 
19. 
Listings ................................................................................................................................... 46 
20. 
Figures ................................................................................................................................... 47 
 
 


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List of Abbreviations 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical 
BID 
Bis in die (Twice Daily) 
CAC 
Conjunctival Allergen Challenge 
 
 
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 
OU 
Oculus Uterque (Both Eyes) 
PDF 
Portable Document Format 
PP 
Per Protocol 


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PPOD 
Per Protocol Ocular Dryness 
PPFSN 
Per Protocol Fluorescein Nasal Score 
PT 
Preferred Term 
Q-B 
QID to BID dosing 
Q-Q 
QID to QID dosing 
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 
 
 
SE 
Standard Error 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TEAE 
Treatment-Emergent Adverse Event 
TFBUT 
Tear Film Break-Up Time 
VA 
Visual Acuity 
VAS 
Visual Analog Scale 
WHODrug 
World Health Organization Drug Dictionary 
 
 


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1. Introduction 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and reporting for 
Part 1 of protocol ADX-102-DED-012, version 2.0 dated 5 MAR 2019. This statistical analysis plan pertains 
to Part 1 only. The statistical analysis plan for Part 2 will be finalized after database lock for Part 1.  
This SAP is being written with due consideration of the recommendations outlined in the most recent 
International Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials and the most recent ICH E3 Guideline, entitled Guidance for Industry: Structure 
and Content of Clinical Study Reports. 
This SAP describes the data that will be analyzed and the subject characteristics, efficacy, and safety 
assessments that will be evaluated. This SAP provides details of the specific statistical methods that will 
be used. The statistical analysis methods presented in this document will supersede the statistical analysis 
methods described in the clinical protocol. If additional analyses are required to supplement the planned 
analyses described in this SAP, they may be completed and will be identified in the clinical study report. 
2. Study Objectives 
2.1 
Primary Measures 
The coprimary efficacy measures for the trial are the following: 
• 
Subject-reported ocular dryness score measured by the Visual Analog Scale (VAS) (0-100 scale). 
The population used for analysis of ocular dryness will be the intent-to-treat ocular dryness (ITTOD) 
population, which consists of subjects who have a baseline ocular dryness score of ≥ 3 
 
). 
• 
Fluorescein staining of the nasal region (FSN) score graded on the 
 (0-4 scale). 
The population used for analysis of FSN score will be intent-to-treat fluorescein nasal score 
(ITTFSN) population, which consists of subjects who have a baseline (Day 1) FSN score of ≥ 2. 
2.2 
Key Secondary Measure 
The key secondary efficacy measures for the trial include the following: 
• 
Symptom Questionnaire for Dryness 
2.3 
Secondary Measures 
The secondary efficacy measures for the trial include the following: 
• 
Fluorescein staining (
 
 
 
• 
Unanesthetized Schirmer’s Test 


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• 
Ocular Dryness through Week 4 (0-100 VAS) 
2.4 
Exploratory Measures 
The exploratory efficacy measures for the trial include the following: 
• 
Burning/Stinging, Itching, Foreign Body Sensation, Eye Discomfort, Photophobia, and Pain Score 
(0-100 VAS) 
• 
Discomfort Scale 
• 
 
Symptom Questionnaire 
 
 
• 
Ocular Surface Disease Index (OSDI)© 
• 
Symptom Assessment in Dry Eye (SANDE) questionnaire 
• 
Ocular Itching Scale 
• 
Lissamine green staining (
 
 
 
• 
Tear film break-up time (TFBUT) 
• 
Tear osmolarity 
2.5 
Safety Measures 
The safety measures for the trial include the following: 
• 
Visual acuity (VA) at distance utilizing an Early Treatment of Diabetic Retinopathy Study (ETDRS) 
chart 
• 
Slit-lamp evaluation 
• 
Adverse event (AE) query (reported, elicited and observed) 
• 
Intraocular Pressure (IOP) 
• 
Dilated fundoscopy 
2.6 
Statistical Hypotheses 
The following hypotheses will be tested comparing reproxalap to vehicle. In Part 1, null hypothesis testing 
will be conducted for each dosing regimen (four times daily [QID] to twice daily [BID], and QID) separately. 
Dryness and staining null hypotheses must be rejected for the dosing regimen to claim efficacy.  The null 
and alternative hypotheses, based on the primary variables, are as follows: 
H01: There is no difference between reproxalap and vehicle in the overall mean change 
from baseline in VAS ocular dryness score in the ITTOD population from Week 2 to Week 
12.  


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H11: The overall mean change from baseline in VAS ocular dryness score is greater with 
reproxalap than with vehicle in the ITTOD population from Week 2 to Week 12. 
H02: There is no difference between reproxalap and vehicle in the overall mean change 
from baseline in fluorescein staining in the nasal region using the 
scale in the 
ITTFSN population from Week 2 to Week 12.  
H12: The overall mean change from baseline in fluorescein staining in the nasal region 
using the 
scale is greater with reproxalap than with vehicle in the ITTFSN 
population from Week 2 to Week 12. 
3. Study Design and Procedures 
3.1 
General 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 four times daily (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 [Day -14] to Visit 2 [Day 1]), two 90-minute exposures in the 
 
 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 
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 (approximately 100 subjects per arm): 
A1. Reproxalap administered QID for twelve weeks (Q-Q) 
A2. Vehicle administered QID for twelve weeks (Q-Q) 
B1. Reproxalap administered QID for four weeks, followed by BID administration for eight weeks (Q-B) 
B2. Vehicle administered QID for four weeks, followed by BID administration for eight weeks (Q-B) 
The results of A1 will be compared to the results of A2. The results of B1 will be compared to the results of 
B2.  


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Subjects, the Sponsor, the Contract Research Organization (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. 
Subjects, the Sponsor, the CRO, investigators, and site personnel will be masked to treatment assignment. 
Table 1 shows the scheduled study visits, their planned study day (note that there is no Day 0 and that Day 
1 corresponds to the day of randomization), and the acceptable visit window for each study visit: 
Table 1. Scheduled Study Visits, Planned Study Days, and Visit Windows 
Scheduled Visit 
Planned Study Day 
Visit Window 
Visit 1 
Day -14 
± 2 Days 
Visit 2 
Day 1 
N/A 
Visit 3 
Day 8 
± 2 Days 
Visit 4 
Day 15 
± 2 Days 
Visit 5 
Day 29 
± 2 Days 
Visit 6 
Day 43 
± 2 Days 
Visit 7 
Day 57 
± 3 Days 
Visit 8 
Day 71 
± 3 Days 
Visit 9 
Day 85 
± 3 Days 
3.2 
Schedule of Visits and Assessments 
The schedule of visits and assessments is provided below for Part 1 of the study. 
 


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Table 2. Part 1 Schedule of Visits and Measurements 
 
Procedure 
Visit 1 
Day -14±2 
Visit 2 
Day 1 
Visit 3 
Day 8±2 
Visit 4 
Day 
15±2 
Visit 5 
Day 
29±2 
Visit 6 
Day 
43±2 
Visit 7 
Day 
57±3 
Visit 8 
Day 
71±3 
Visit 9 
Day  
85 ± 3 
Pre 
 
Post 
 
Pre 
 
Post 
 
Non 
 
Non 
 
Non 
 
Non 
 
Non 
 
Non 
 
Non 
 
Informed Consent / HIPAA 
X 
 
 
 
 
 
 
 
 
 
 
Medical / Medication History and 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical / Medication Update 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 Exposure 
X 
X 
 
 
 
 
 
 
 
Vehicle Run-In Dispensation 
 
X 
 
 
 
 
 
 
 
 
 
Vehicle Run-In Instillation 
 
X 
X 
 
 
 
 
 
 
 
 
Vehicle Run-in Collection 
 
 
X 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
 
 
 
Study Drug Dispensation 
 
 
 
X 
X2 
X 
X 
X2 
X 
X2 
 
Study Drug Instillation 
 
 
 
X 
 
 
 
 
 
 
 
Study Drug Collection 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Review of Qualification Criteria 
X 
X 
X 
X 
 
 
 
 
 
 
 
Adverse Event Query 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test 
X1 
 
 
 
 
 
 
 
 
 
X1 
Multi-Symptom VAS 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
SANDE Questionnaire 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 Discomfort 
Scale 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Symptom Questionnaire 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Procedure 
Visit 1 
Day -14±2 
Visit 2 
Day 1 
Visit 3 
Day 8±2 
Visit 4 
Day 
15±2 
Visit 5 
Day 
29±2 
Visit 6 
Day 
43±2 
Visit 7 
Day 
57±3 
Visit 8 
Day 
71±3 
Visit 9 
Day  
85 ± 3 
Pre 
 
Post 
 
Pre 
 
Post 
 
Non 
 
Non 
 
Non 
 
Non 
 
Non 
 
Non 
 
Non 
 
 
 Itching 
Scale 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
OSDI© Questionnaire 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Visual Acuity (ETDRS) 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Slit-lamp Biomicroscopy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tear Osmolarity 
 
 
X 
 
 
 
X 
 
 
 
X 
TFBUT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fluorescein Staining 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lissamine Green Staining 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Schirmer’s Test 
X 
 
X 
 
 
 
X 
 
 
 
X 
Intraocular Pressure 
 
X 
 
 
 
 
 
 
 
 
X 
Dilated Fundoscopy 
 
X 
 
 
 
 
 
 
 
 
X 
Exit Subject from Study 
 
 
 
 
 
 
 
 
 
 
X 
1: To women of child-bearing potential, as defined. 
2The previous study drug kit is redispensed. 
 
 
 
 
 
 
 
 
 
 


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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 and Visit 2 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. 
Subjects are to be stratified by Visit 2 (Day 1, Baseline) Pre
 ocular dryness score (on the Ocular 
Discomfort & 4-Symptom Questionnaire) and Visit 2 (Day 1, Baseline) Pre-
 fluorescein nasal 
staining score in the study eye using the following strata: 
a. Ocular Dryness Score ≥ 3 and Fluorescein Nasal Staining Score ≥ 2 
b. Ocular Dryness Score ≥ 3 and Fluorescein Nasal Staining Score < 2 
c. Ocular Dryness Score < 3 and Fluorescein Nasal Staining Score ≥ 2 
d. Ocular Dryness Score < 3 and Fluorescein Nasal Staining Score < 2 
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.  
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), 
 and/or the Sponsor should be notified before unmasking investigational product (IP). 
 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 
 and/or the medical monitor prior to unmasking the identity of the IP, if possible.
 
will ask the site to complete and send them the Unmasking Request Form. 
will notify Aldeyra and 
jointly will determine if the unmasking request should be granted. They may consult the medical monitor 


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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. 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 
Sample Size Part 1: 
Based on the results of a Phase 2b clinical trial of reproxalap in dry eye disease subjects (ADX-102-
DED-009), for the primary outcome measurements of FSN and ocular dryness score, approximately 100 
subjects per randomized arm will be evaluated in ADX-102-DED-012. Estimates were obtained for the 
mean difference between reproxalap and vehicle with all post-treatment visits combined, the intra-
subject standard deviation (SD), and the estimated correlation between repeated measures. As a 
conservative measure the following practices were adopted: (1) the estimated correlation was increased 
by 25%, (2) the estimated SD was increased by 25%, and (3) four repeated measures (rather than the 
six planned) were assumed. Sample size estimates were made assuming an alpha of 0.05 and power 
of 90% for the two efficacy populations. 
 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). The assumptions for parameters used in sample size calculation 
are listed below.  
Parameters assumption for ITTFSN population:  
Targeted 
Power 
Sample 
Size 
Repeated 
Measures 
LS Mean 
Difference 
Standard 
Deviation 
Correlation 
Coefficient 
Type I 
Error 
0.9 
78 
4 
-0.2967 
0.53 
0.5749 
0.05 
Parameters assumption for ITTOD population:  
Targeted 
Power 
Sample 
Size 
Repeated 
Measures 
LS Mean 
Difference 
Standard 
Deviation 
Correlation 
Coefficient 
Type I 
Error 
0.9 
108 
4 
-0.3952 
0.73 
0.7783 
0.05 
Sample Size Part 2: 


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Estimated treatment differences, SDs, and correlation coefficients from Part 1 will be used to 
determinate sample sizes and estimate power in Part 2, which is expected to require approximately 200-
400 subjects per treatment arm. 
6. Data Preparation 
Electronic Case Report Forms (eCRF) will be developed by 
 
. 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 iMedNet™ v1.191.0 or higher.  
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 
in consultation with 
.  
All analyses outlined in this document will be carried out after the following have occurred: 
• All data management requirements are met according to 
 standard operating procedures 
(SOP), including data entry, performance of edit and validation checks, documentation and 
resolution of data queries, and database lock with written authorization provided by appropriate 
, Aldeyra and 
 personnel. 
• Protocol deviations have been identified and status defined (major/minor deviations). 
• Analysis populations have been determined. 
• Randomized treatment codes have been unmasked. 
7. Analysis Populations 
7.1 
Intent-to-Treat 
Intent-to-Treat Population: The intent-to-treat (ITT) population includes all randomized subjects. 
Subjects in the ITT population will be analyzed as randomized. In addition, two populations are further 
defined for the primary analysis:  
• 
ITTOD Population – The ITTOD population includes subjects in the ITT population with baseline 
ocular dryness score ≥ 3 (Ocular Discomfort and 4-Symptom Questionnaire). 
• 
ITTFSN Population – The ITTFSN population includes subjects in the ITT population with 
baseline fluorescein nasal staining score ≥ 2.  


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7.2 
Per Protocol 
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. In addition, two populations are further defined for the primary analysis:  
• 
PPOD Population – The PPOD population includes subjects in the PP population with baseline 
ocular dryness score ≥ 3 (Ocular Discomfort and 4-Symptom Questionnaire). 
• 
PPFSN Population – The PPFSN population includes subjects in the PP population with 
baseline FSN score ≥ 2.  
7.3 
Safety 
Safety Population: The safety population includes all randomized subjects who have received at least 
one dose of study drug. Subjects in the safety population will be analyzed as treated.  
8. General Statistical Considerations 
8.1 
Unit of Analysis 
Safety endpoints will be analyzed for both eyes. For subject-level efficacy endpoints, the unit of analysis 
will be the subject. For efficacy endpoints assessed on each eye individually, the unit of analysis will be 
the study eye as defined by the following:  
 
 
 
 
8.2 
Missing or Inconclusive Data Handling 
The primary analyses using mixed model repeated measures (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.  
No other secondary efficacy endpoints, exploratory endpoints, or safety endpoints will be imputed. 
8.3 
Definition of Baseline 
Baseline measures are defined as the last non-missing measure prior to the initiation of randomized 
study treatment at Visit 2 (Day 1) prior to 
 Change from baseline will be calculated as follow-up 


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visit value minus baseline value. Intraocular pressure and dilated fundoscopy will have baseline 
measures recorded at Visit 1 (Day -14).  
8.4 
Data Analysis Conventions 
All data analysis will be performed by 
 after the study is completed and the database has been 
locked and released for unmasking. Statistical programming and analyses will be performed using 
Statistical Analysis Software® (SAS®) Version 9.4 or higher. Output will be provided in rich text format 
(RTF) for tables and portable document format (PDF) for tables, listings, and figures using landscape 
orientation. All study data will be listed by subject, treatment, and visit (as applicable) based on all 
randomized subjects unless otherwise specified. 
Summaries for continuous and ordinal variables will include the number of observations (n), arithmetic 
mean, SD, median, minimum, and maximum. Effect size relative to baseline for efficacy endpoints will 
also be reported and will be calculated as the mean change from baseline divided by the SD at baseline.  
Minima and maxima will be reported with the same precision as the raw values; means, medians and 
effect sizes will be presented to one additional decimal place than reported in the raw values. Standard 
deviations will be presented to two additional decimal places than reported in the raw values. Summaries 
for discrete variables will include frequency counts and percentages. All percentages will be rounded to 
one decimal place (i.e., XX.X%). Differences between active treatment arms and vehicle will be 
calculated as Active – Vehicle and change from baseline will be calculated as Follow-up Visit – Baseline. 
Cohen’s d effect size will also be reported and will be calculated as the difference in means divided by 
the pooled SD.  The baseline measure will be defined as the last non-missing measure prior to initiation 
of investigational treatment.  
All statistical tests will be two-sided with a significance level of 0.05 (α = 0.05) unless otherwise specified. 
Confidence intervals (CI) for differences between treatment arms will be two-sided at 95% confidence. 
All p-values will be rounded to four decimal places; p-values less than 0.0001 will be presented as 
“<0.0001”; p-values greater than 0.9999 will be presented as “>0.9999.” 
Unless otherwise specified, summaries will be presented by treatment arm and, where appropriate, visit. 
8.5 
Adjustments for Multiplicity 
The hypothesis testing in Part 1 is performed within each dosing regimen separately. A sequential 
(closed) testing procedure will be used to control the overall type I error rate within each dosing regimen 
due to multiple comparisons for the coprimary endpoints. The order of treatment comparisons is as 
follows:  
1. Reproxalap administered QID for twelve weeks versus Vehicle administered QID for twelve 
weeks (Arm A1 vs Arm A2) 


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2. Reproxalap administered QID for four weeks, followed by BID administration for eight weeks 
versus Vehicle administered QID for four weeks, followed by BID administration for eight weeks 
(Arm B1 vs Arm B2)  
The second comparison will be considered valid only if the first comparison is statistically significant for 
either of the co-primary endpoints. 
A stronger type I error control is implemented within each dosing regimen by requiring that the 
hypothesis testing for both coprimary endpoints must be statistically significant to claim success in Part 
1. Hence, multiplicity adjustment will not be applied within each dosing regimen. 
9. Disposition of Subjects 
Subject disposition will be presented in terms of the numbers and percentages of subjects who were 
randomized, completed the study, and discontinued from the study. Subjects who are not discontinued 
from the study will be considered study completers. Disposition will be summarized by treatment arm 
and for all subjects. 
The number of randomized subjects in each of the analysis populations (ITTOD, ITTFSN, ITT, PPOD, 
PPFSN, PP, and Safety) will be displayed by treatment. The ITTOD, ITTFSN, and ITT populations use 
treatment as randomized; PPOD, PPFSN, PP, and Safety populations use treatment as treated. 
Percentages are based on the total number of subjects randomized in each treatment arm. 
The number and percentage of subjects prematurely discontinued from the study and the reasons for 
study discontinuation will be summarized by treatment arm for all randomized subjects. The reasons for 
study discontinuation that will be summarized include: AE(s), Protocol Violation(s), Administrative 
Reasons, Sponsor Termination of the Study, Subject Choice, and Other. A subject listing will be provided 
that includes the date of and reason for premature study discontinuation. 
The number and percentage of subjects with major protocol deviations will be summarized by treatment 
arm for all randomized subjects. The protocol deviations that will be summarized include: Informed 
Consent, Inclusion/Exclusion and Randomization, Test Article/Study Drug Instillation and Assignment 
at Site, Improper Protocol Procedures at Site, Site’s Failure to Report Serious Adverse Event (SAE)/AE, 
Visit out of Window (missed, early, late), Subject’s Non-compliance with Test Article/Study Drug, 
Subject’s Use of Prohibited Concomitant Medication, Subject’s Failure to Follow Instructions, and Other. 
A subject listing will be provided that includes the date of the deviation, the deviation code, the deviation 
description, and the classification of whether the deviation was judged to be major or minor. 
In addition, subject listings will be provided that include inclusion and exclusion criteria violations and 
exclusions from the ITT, PP, and Safety populations. 


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10. Demographic and Pretreatment Variables 
10.1 
Demographic Variables 
The demographic variables collected in this study include age, sex, race, ethnicity, and iris color (OD 
and OS). Demographic variables will be summarized for the ITT and Safety populations, separately. 
Age (years) will be summarized, overall and by treatment, using continuous descriptive statistics. Age 
will also be categorized as follows: <65 years and ≥65 years. Age will be reported in years and calculated 
using the following formula: 
Age (years) = (Informed Consent Date – Date of Birth) / 365.25, truncated as an integer 
The number and percentage of subjects will be presented, overall and by treatment arm, for age 
category, sex, race, ethnicity, and iris color (right eye [OD] and left eye [OS]).  
A subject listing that includes all demographic variables will be provided. 
10.2 
Pretreatment Variables 
Baseline disease characteristics will be summarized by treatment arm for ITTOD, ITTFSN, and ITT 
populations using continuous descriptive statistics for ocular dryness score (0 – 100 VAS); fluorescein 
nasal region score using 
scale); fluorescein staining score (
 
 
 
unanesthetized Schirmer’s test; VA; and IOP. The scale for each assessment is provided in the 
variables’ respective subsection in Section 13 and Section 15 of this SAP. 
11. Medical History and Concomitant Medications 
11.1 
Medical History 
Ocular medical history will be summarized using discrete summary statistics and presented by treatment 
arm at the subject and event level by System Organ Class (SOC) and Preferred Term (PT) using the 
Safety population. Non-ocular medical history will be similarly summarized at the subject and event 
level. 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. MedDRA 22.0 will be used to code medical history terms. 
Listings of medical history will be generated separately for ocular and non-ocular data. 
11.2 
Concomitant Medications 
Ocular and non-ocular concomitant medications will be coded using WHO Drug Dictionary (WHODrug 
Global, B3, March 2019) and summarized to the therapeutic drug class (Anatomical Therapeutic 


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Chemical [ATC] 4 classification) and preferred name. If the ATC 4 classification is not provided, then 
the next lowest classification that is provided in the coding dictionary will be used. The preferred name 
will be defined as the active ingredient; if the active ingredient is not provided or includes more than two 
ingredients (e.g., multivitamins), then the drug name will be summarized as the preferred name. Any 
uncoded terms will be summarized under the ATC classification and preferred name of “Uncoded.” 
Concomitant medications are defined as those medications listed as having been taken (1) prior to 
initiation of study drug administration and continuing for any period of time following the first 
administration of study drug or (2) at any time following the first administration of study drug. Prior 
medications are reported medications that have been taken prior to initiation of study drug administration 
but not during the study. 
Concomitant medications will be summarized using the ITT population. Medications will be tabulated for 
each treatment arm using frequencies and percentages. Subjects may have more than 1 medication 
per ATC text. At each level of subject summarization, a subject will be counted once if he/she reports 1 
or more medications. Percentages will be based on the number of subjects in each treatment arm. 
Listings of concomitant medications will be generated separately for ocular and non-ocular data. 
12. Dosing Compliance and Treatment Exposure 
12.1 
Dosing Compliance 
Dosing compliance (% compliance) will be assessed by calculating the number of doses taken and 
comparing that to the number of expected doses as follows: 
Compliance (%) = 
Number of Doses Taken 
x 100% 
Number of Expected Doses 
The number of actual doses taken will be recorded from the eCRF. The number of expected doses that 
will be used for calculating compliance will be calculated as follows: 
• 
For subjects in dosing arms Q-Q: 4 x {[Date of Study Completion/Discontinuation – Date of Visit 
2 (Day 1)] + 1}, regardless of study completion status 
• 
For subjects in dosing arms Q-B that discontinue prior to Visit 5 (Day 29): 4 x {[Date of 
Discontinuation – Date of Visit 2 (Day 1)] + 1}  
• 
For subjects in dosing arms Q-B that complete the study or discontinue on or after Visit 5 (Day 
29): 4 x {[Date of Visit 5 (Day 29) – Date of Visit 2 (Day 1)] + 1} + 2 x [Date of Study 
Completion/Discontinuation – Date of Visit 5 (Day 29)] 


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For subjects who do not receive a dose of study drug per in office instillation, the number of expected 
doses will be 0 and compliance will be defined as 0.  
A categorical dosing compliance variable will also be derived as non-compliant (<80%), compliant 
(≥80% and ≤125%), and over compliant (>125%). 
Dosing compliance (%) will be summarized with continuous descriptive statistics for each treatment arm, 
using the Safety population. The compliance category defined above will be summarized with discrete 
summary statistics.  
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 in days using the 
following: 
Extent of Exposure (days) = [Date of Study Completion/Discontinuation – Date of Visit 2 (Day 1)] + 1 
Extent of treatment exposure for subjects who were lost to follow-up will be calculated in days using the 
following: 
Extent of Exposure (days) = [Date of Last Recorded Visit – Date of Visit 2 (Day 1)] + 1 
Extent of treatment exposure (days) for each subject exposed to study drug will be summarized with 
continuous descriptive statistics for each treatment arm, using the Safety population.  
Subject listings of  study drug exposure and dosing compliance will be produced. 
13. Efficacy Analyses 
13.1 
Primary Analysis 
The co-primary endpoints for symptom and sign are as follows: 
• 
The co-primary symptom endpoint is the overall mean change from baseline in subject-reported 
ocular dryness score (0 - 100 VAS) 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 of ≥ 3 (
 
). 
• 
The co-primary sign endpoint is the overall mean change from baseline in fluorescein nasal 
region score (0-4 scale) from Week 2 to Week 12. The population used for analysis of fluorescein 


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nasal region score will be subjects who have a baseline (Day 1) fluorescein nasal region score of ≥ 
2 (
).  
Change from baseline for both endpoints will be calculated as Visit – Baseline, where a positive 
difference indicates a worsening of dry eye signs or symptoms and a negative difference indicates an 
improvement of dry eye signs or symptoms. Reproxalap and vehicle Q-Q dosing arms will be compared 
in separate tables  from reproxalap and vehicle Q-B dosing arms. Treatment comparisons between 
active treatment arm and vehicle will be calculated as Active – Vehicle. All primary endpoints will be 
described in subject listings. 
13.1.1  OCULAR DRYNESS SCORE 
Subjects will be asked to subjectively rate ocular dryness (both eyes [OU]) by placing a vertical mark on 
the horizontal line to indicate the level of discomfort. The length of the assessment line is 100 mm; a 
measure of 0 mm corresponds to “No Discomfort” and 100 mm corresponds to “Maximal Discomfort.” 
Ocular dryness score (0-100 VAS) will be summarized for Visit 3 (Day 8) to Visit 9 (Day 85) by treatment 
arms using continuous descriptive statistics. Overall mean change from baseline from week 2 to week 
12 for each treatment arm in ocular dryness score will be compared between active treatment and 
vehicle. The primary analysis will use an MMRM adjusted for baseline ocular dryness score (0-100 
VAS), treatment arm, visit, and the interaction of treatment arm and visit as fixed effects and subject as 
the random effect. Least squares (LS) means for each treatment arm and the LS mean difference 
between treatment arms for the overall mean change from baseline from week 2 to week 12 and change 
from baseline for each visit will be presented from the model together with standard errors (SE), two-
sided p-values, and two-sided 95% CIs. Primary analysis will be performed on the ITTOD population 
with observed data only. 
 
 
 
 
 
 
 
 
 
 
 
 


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All post-baseline data from the two treatment groups will be included in the models. Comparisons 
between two treatment arms (e.g., between reproxalap Q-Q and vehicle Q-Q) for overall mean change 
from baseline from week 2 to week 12 and change from baseline at a given visit will be obtained by 
comparing the corresponding LS mean estimates.  
Change from baseline will also be analyzed using analysis of covariance (ANCOVA) models adjusted 
for baseline ocular dryness score and treatment arm. Two-sample t-tests and Wilcoxon rank sum tests 
will be used as sensitivity analyses. Cohen’s d effect size will be reported for differences in change from 
baseline between treatment arms. 
Markov chain Monte Carlo (MCMC) imputation with the ITTOD population will used for the sensitivity 
analysis under MAR assumption. A single imputation will first impute non-monotone missing data using 
MCMC to obtain a dataset with a monotone missing pattern. Then, MCMC will be used to perform twenty 
imputations from the dataset with monotone missingness. The primary endpoint will be re-analyzed to 
confirm the results from the primary analysis.  
As a sensitivity analysis, the primary efficacy endpoint of ocular dryness score will also be analyzed 
with missing data imputated using a control-based pattern mixture model under the assumption of a 
missing not at random mechanism. A single imputation will first impute non-monotone missing data 
using MCMC to obtain a dataset with a monotone missing pattern. Then, a control-based pattern 
mixture model will used to perform twenty imputations from the dataset with monotone missingness.  
The MMRM model outlined in the primary analysis will be used for analysis of the MCMC and control-
based pattern mixture model imputed datasets. ANCOVA models adjusted for baseline ocular dryness 
score (0-100 VAS) and treatment arm and two-sample t-tests will also serve as sensitivity analyses.  
Primary efficacy analyses will be performed with the PPOD population for  additional sensitivity 
analysis using an MMRM as described for the ITTOD with observed data only analyses.  
The LS Means for ocular dryness score overall mean change from baseline from week 2 to week 12 will 
be displayed graphically in a bar chart with standard error bars for the active treatment and vehicle arms 
based on the MMRM analysis of the ITTOD population with observed data only. 
13.1.2 FLUORESCEIN NASAL STAINING 
 
 
  
Fluorescein nasal staining will be summarized for Visit 3 (Day 8) to Visit 9 (Day 85) by treatment arms 
for the study eye using continuous descriptive statistics. Overall mean change from baseline from week 
2 to week 12 for each treatment arm in fluorescein nasal staining will be compared between active 


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treatment and vehicle. Primary analysis will use a MMRM as described in section 13.1.1 adjusted for 
baseline FSN score, treatment arm, visit, and the interaction of treatment arm and visit as fixed effects 
and subject as the random effect. The LS means for each treatment arm and the LS mean difference 
between treatment arms for the overall mean change from baseline from week 2 to week 12 and change 
from baseline at each visit will be presented from the model together with SEs, two-sided p-values, and 
two-sided 95% CIs. Primary analysis will be performed on the ITTFSN population with observed data 
only. 
Change from baseline will also be analyzed using ANCOVA models adjusted for baseline FSN score 
and treatment arm. Two-sample t-tests and Wilcoxon rank sum tests will be used as sensitivity analyses. 
Cohen’s d effect size will be reported for differences in change from baseline between treatment arms. 
Markov chain Monte Carlo Imputation will be used for sensitivity analysis for the ITTFSN population 
under MAR assumption. A single imputation will first impute non-monotone missing data using MCMC 
to obtain a dataset with a monotone missing pattern. Then, MCMC will be used to perform twenty 
imputations from the dataset with monotone missingness. The primary endpoint will be re-analyzed to 
confirm the results from the primary analysis. 
As a sensitivity analysis, the primary efficacy endpoint of fluorescein nasal staining will also be analyzed 
with missing data imputated using a control-based pattern mixture model under the assumption of a 
missing not at random mechanism. A single imputation will first impute non-monotone missing data 
using MCMC to obtain a dataset with a monotone missing pattern. Then, a control-based pattern mixture 
model will used to perform twenty imputations from the dataset with monotone missingness. 
ANCOVA models adjusted for baseline FSN score and treatment arm and two sample t-tests will also 
be conducted as sensitivity analyses to assess robustness of the results of the sensitivity analyses. 
Further, primary efficacy analyses will be performed with the PPFSN population with observed data only 
for sensitivity analysis using MMRM.  
The LS Means for FSN overall mean change from baseline from week 2 to week 12 will be displayed 
graphically in a bar chart with standard error bars for the active treatment and vehicle arms based on 
the MMRM analysis of the ITTFSN population with observed data only.  
13.2 
Key Secondary Analyses 
Key secondary efficacy variables will be summarized using continuous descriptive statistics (n, mean, 
SD, median, minimum, maximum) by visit and treatment arm. Two-sample t-tests and Wilcoxon rank 
sum tests will be used to analyze the efficacy variables for visit-based data between treatment dosing 
schedule Q-Q arms A1 and A2 and, separately, dosing schedule Q-B arms B1 and B2. Cohen’s d effect 
size will be reported for the differences in treatment arms at each visit. 


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Change from baseline in key secondary efficacy variables will be summarized by visit and treatment 
arm using continuous descriptive statistics and change from baseline effect size. When applicable, 
MMRM will be used to analyze overall mean change from baseline from week 2 to week 12 and change 
from baseline by visit as described in section 13.1.1. Further sensitivity analysis will be conducted using 
ANCOVA models with terms for baseline value and treatment arm. Two-sample t-tests and Wilcoxon 
rank sum tests will also be used for sensitivity analysis. Cohen’s d effect size will be reported for 
differences in change from baseline between treatment arms. Paired t-tests will be used to assess 
change from baseline within each treatment arm.  
All key secondary efficacy analyses will be performed on the ITT population with observed data only 
and PP population with observed data only. No imputation will be performed for secondary analyses. All 
key secondary endpoints will be described under subject listings. 
 
 
13.2.1 
 
 
DRYNESS 
 
 
 
  
Visit-based data will be summarized using continuous descriptive statistics for dryness by treatment 
arm. Change from baseline will also be summarized with continuous descriptive statistics. 
Two-sample t-tests and Wilcoxon rank sum tests will be used to analyze differences between treatment 
arms at each visit between active treatment and vehicle. The differences in means, two-sided 95% CIs 
for the difference in means, and two-sided p-values will be reported. Cohen’s d effect size will be 
reported for the differences in treatment arms at each visit. 
Overall mean change from baseline will be analyzed using MMRM in manner described in section 13.1.1 
with adjustment for baseline dryness score, visit, treatment arm, and interaction between treatment arm 
and visit. Change from baseline by visit will also be analyzed. The LS means, LS mean differences, 
SEs, two-sided 95% CIs for LS means, two-sided 95% CIs for the difference in means, and two-sided 
p-values will be reported from the MMRM. Sensitivity analysis will include ANCOVA adjusted for 
baseline dryness score and treatment arm, two-sample t-tests, and Wilcoxon rank sum test. Cohen’s d 
effect size will be reported for differences in change from baseline between treatment arms. The LS 
means, LS mean differences, SEs, two-sided 95% CIs for the difference in means, and two-sided p-


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values will be reported from the sensitivity analyses where applicable. Paired t-tests will be used to 
analyze change from baseline within each treatment arm. 
Analyses will use ITT population with observed data only and PP population with observed data only. 
13.3 
Secondary Analyses 
Secondary efficacy variables will be summarized using continuous descriptive statistics (n, mean, SD, 
median, minimum, maximum) by visit and treatment arm. Two-sample t-tests and Wilcoxon rank sum 
tests will be used to analyze the efficacy variables for visit-based data between treatment dosing 
schedule Q-Q arms A1 and A2 and, separately, dosing schedule Q-B arms B1 and B2. Cohen’s d effect 
size will be reported for the differences in treatment arms at each visit. 
Change from baseline in secondary efficacy variables will be summarized by visit and treatment arm 
using continuous descriptive statistics and change from baseline effect size. When applicable, MMRM 
will be used to analyze overall mean change from baseline from week 2 to week 12 and change from 
baseline by visit as described in section 13.1.1. Further sensitivity analysis will be conducted using 
ANCOVA models with terms for baseline value and treatment arm. Two-sample t-tests and Wilcoxon 
rank sum tests will also be used for sensitivity analysis. Cohen’s d effect size will be reported for 
differences in change from baseline between treatment arms. Paired t-tests will be used to assess 
change from baseline within each treatment arm.  
All secondary efficacy analyses will be performed on the ITT population with observed data only and PP 
population with observed data only. No imputation will be performed for secondary analyses. All 
secondary endpoints will be described under subject listings. 
The following secondary efficacy variables will be tested: 
• Fluorescein staining 
 
 
 
• Unanesthetized Schirmer’s test 
• Ocular Dryness through Visit 5 (Day 29) (0 - 100 VAS) 
13.3.1 FLUORESCEIN STAINING 
 
 
Fluorescein staining will be conducted at all visits and Pre- and Post-
 for Visits 1 (Day -14) and 
Visits 2 (Day 1). Grading will be conducted 
 
 
 Comparisons will be made 
between reproxalap arms and vehicle arms within the same dosing schedule. 


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Visit-based data will be summarized using continuous descriptive statistics for each region and sum 
score. Change from baseline will also be summarized using continuous descriptive statistics. 
Two-sample t-tests and Wilcoxon rank sum tests will be used to analyze differences between treatment 
arms at each visit between active treatment and vehicle. The differences in means, two-sided 95% CIs 
for the difference in means, and two-sided p-values will be reported. Cohen’s d effect size will be 
reported for the differences in treatment arms at each visit. 
Overall mean change from baseline from week 2 to week 12 will be analyzed using MMRM in manner 
described in section 13.1.1 with adjustment for baseline fluorescein staining score, visit, treatment arm, 
and interaction between treatment arm and visit. Change from baseline by visit will also be analyzed. 
The LS means, LS mean differences, SEs, two-sided 95% CIs for LS means, two-sided 95% CIs for the 
difference in means, and two-sided p-values will be reported from the MMRM. Sensitivity analysis will 
include ANCOVA adjusted for baseline fluorescein staining score and treatment arm, two-sample t-tests, 
and Wilcoxon rank sum test. Cohen’s d effect size will be reported for differences in change from 
baseline between treatment arms. The LS means, LS mean differences, SEs, two-sided 95% CIs for 
the difference in means, and two-sided p-values will be reported from the sensitivity analyses where 
applicable. Paired t-tests will be used to analyze change from baseline within each treatment arm.  
Analyses will use ITT population with observed data only and PP population with observed data only.  
13.3.2 UNANESTHETIZED SCHIRMER’S TEST 
Unanesthetized Schirmer’s test will be conducted at Visits 1 (Day -14) Pre-
 2 (Day 1) Pre-
 
5 (Day 29), and 9 (Day 85). 
 
 
 Lower values indicate less tears produced in the eye. Comparisons will 
be made between reproxalap arms and vehicle arms within the same dosing schedule. Analyses will 
only be produced for study eye. 
Visit-based data will be summarized using continuous descriptive statistics by treatment arm. Change 
from baseline will also be summarized with continuous descriptive statistics. 
Two-sample t-tests and Wilcoxon rank sum tests will be used to analyze differences between treatment 
arms are each visit between active treatment and vehicle. The differences in means, two-sided 95% CIs 
for the difference in means, and two-sided p-values will be reported. Cohen’s d effect size will be 
reported for the differences in treatment arms at each visit. 
Overall mean change from baseline from week 4 to week 12 will be analyzed using MMRM in manner 
described in section 13.1.1 with adjustment for baseline unanesthetized Schirmer’s test reading, visit, 
treatment arm, and interaction between treatment arm and visit. Change from baseline by visit will also 


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be analyzed. The LS means, LS mean differences, SEs, two-sided 95% CIs for LS means, two-sided 
95% CIs for the difference in means, and two-sided p-values will be reported from the MMRM. Sensitivity 
analysis will include ANCOVA adjusted for baseline unanesthetized Schirmer’s test reading and 
treatment arm, two-sample t-tests, and Wilcoxon rank sum test. Cohen’s d effect size will be reported 
for differences in change from baseline between treatment arms. The LS means, LS mean differences, 
SEs, two-sided 95% CIs for the difference in means, and two-sided p-values will be reported from the 
sensitivity analyses where applicable. Paired t-tests will be used to analyze change from baseline within 
each treatment arm. 
Analyses will use ITT population with observed data only and PP population with observed data only.  
13.3.3 OCULAR DRYNESS THROUGH VISIT 5 (DAY 29) 
Ocular dryness (OU) will recorded at Visit 5 (Day 29) using the VAS. Subject will be asked to subjectively 
rate ocular dryness by placing a vertical mark on the horizontal line to indicate the level of discomfort. 
The length of the assessment line is 100 mm; a measure of 0 mm corresponds to “No Discomfort” and 
100 mm corresponds to “Maximal Discomfort.” Comparisons will be made between reproxalap arms and 
vehicle arms within the same dosing schedule. 
Visit-based data will be summarized using continuous descriptive statistics for each region and sum 
score by treatment arms by visit. Change from baseline will also be summarized with continuous 
descriptive statistics. 
Two-sample t-tests and Wilcoxon rank sum tests will be used to analyze differences between treatment 
arms at each visit between active treatment arms and vehicle arms. The differences in means, two-
sided 95% CIs for the difference in means, and two-sided p-values will be reported. Cohen’s d effect 
size will be reported for the differences in treatment arms at each visit. 
Overall mean change from baseline from week 1 to week 4 will be analyzed using MMRM adjusted for 
baseline ocular dryness score, treatment arm, visit, the interaction of treatment arm and visit as fixed 
effects and subject as the random effect. Change from baseline by visit will also be analyzed. The LS 
means, LS mean differences, SEs, two-sided 95% CIs for LS means, two-sided 95% CIs for the 
difference in means, and two-sided p-values will be reported from the MMRM. Sensitivity analysis will 
include ANCOVA adjusted for baseline ocular dryness score and treatment arm, two-sample t-tests, and 
Wilcoxon rank sum test. Cohen’s d effect size will be reported for differences in change from baseline 
between treatment arms. The LS means, LS mean differences, SEs, two-sided 95% CIs for LS means, 
two-sided 95% CIs for the difference in means, and two-sided p-values will be reported from the 
sensitivity analyses where applicable. Paired t-tests will be used to analyze change from baseline within 
each treatment arm.  


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Analyses will use ITT population with observed data only and PP population with observed data only.  
14. Exploratory Analyses 
Exploratory efficacy variables will be summarized using continuous descriptive statistics (n, mean, SD, 
median, minimum, maximum, and Cohen’s d effect size relative to baseline)  by visit and treatment arm. 
Two-sample t-tests and Wilcoxon rank sum tests will be used to analyze the efficacy variables for visit-
based data between active treatment arms and vehicle. Cohen’s d effect size will be reported for the 
differences in treatment arms at each visit. 
Change from baseline in exploratory efficacy variables will be summarized by visit and treatment arm 
using continuous descriptive statistics. When applicable, MMRM will be used to analyze overall mean 
change from baseline and change from baseline by visit as described in section 13.1.1. Further 
sensitivity analysis will be conducted using ANCOVA models with terms for baseline value and treatment 
arm. Two-sample t-tests and Wilcoxon rank sum tests will also be used for sensitivity analysis. Cohen’s 
d effect size will be reported for differences in change from baseline between treatment arms. Paired t-
tests will be used to assess change from baseline within each treatment arm.  
All exploratory efficacy analyses will be performed on the ITT population with observed data only. No 
imputation will be performed for exploratory analyses. All exploratory endpoints will be described under 
subject listings. 
The following exploratory efficacy variables will be tested for Part 1: 
• 
Burning/Stinging, Itching, Foreign Body Sensation, Eye Discomfort, Photophobia, and Pain 
Score (0 – 100 VAS)  
• 
 Discomfort 
 
• 
Symptom Questionnaire 
• 
OSDI© 
• 
SANDE Questionnaire 
• 
Itching 
 
• 
Lissamine green staining 
 
 
• 
TFBUT 
• 
Tear osmolarity 
14.1.1 VISUAL ANALOG SCALE 
Ocular symptoms of the VAS will be recorded at all visits. Subject will be asked to subjectively rate 
ocular symptom (OU) by placing a vertical mark on the horizontal line to indicate the level of discomfort. 
The length of the assessment line is 100 mm; a measure of 0 mm to “No Discomfort” and 100 mm 


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corresponds to “Maximal Discomfort.” The ocular symptoms used for exploratory analysis are 
Burning/Stinging, Itching, Foreign Body Sensation, Eye Discomfort, Photophobia, and Pain Score. 
Comparisons will be made between reproxalap arms and vehicle arms within the same dosing schedule. 
Visit-based data will be summarized using continuous descriptive statistics for each symptom by 
treatment arm. Change from baseline will also be summarized with continuous descriptive statistics. 
Two-sample t-tests and Wilcoxon rank sum tests will be used to analyze differences between treatment 
arms at each visit between active treatment and vehicle. The differences in means, two-sided 95% CIs 
for the difference in means, and two-sided p-values will be reported. Cohen’s d effect size will be 
reported for the differences in treatment arms at each visit. 
Overall mean change from baseline from week 2 to week 12 will be analyzed using MMRM in manner 
described in section 13.1.1 with adjustment for baseline ocular symptom score, visit, treatment arm, and 
interaction between treatment arm and visit. Change from baseline by visit will also be analyzed. The 
LS means, LS mean differences, SEs, two-sided 95% CIs for LS means, two-sided 95% CIs for the 
difference in means, and two-sided p-values will be reported from the MMRM. Sensitivity analysis will 
include ANCOVA adjusted for baseline ocular symptom score and treatment arm, two-sample t-tests, 
and Wilcoxon rank sum test. The LS means, LS mean differences, SEs, two-sided 95% CIs for the 
difference in means, and two-sided p-values will be reported from the sensitivity analyses where 
applicable. Cohen’s d effect size will be reported for differences in change from baseline between 
treatment arms. Paired t-tests will be used to analyze change from baseline within each treatment arm. 
Analyses will be performed on the ITT population with observed data only. 
14.1.2 OCULAR DISCOMFORT SCALE 
 
Ocular discomfort scores will be subjectively graded by the subjects using the 
 
Discomfort Scale at all post-baseline visits and Visits 1 (Day -14) and 2 (Day 1) at Pre-
.
 
 
 Comparisons will be made 
between reproxalap arms and vehicle arms within the same dosing schedule. 
Visit-based data will be summarized using continuous descriptive statistics for each symptom by 
treatment arm. Change from baseline will also be summarized with continuous descriptive statistics. 
Two-sample t-tests and Wilcoxon rank sum tests will be used to analyze differences between treatment 
arms at each visit between active treatment and vehicle. The differences in means, two-sided 95% CIs 
for the difference in means, and two-sided p-values will be reported. Cohen’s d effect size will be 
reported for the differences in treatment arms at each visit. 


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Overall mean change from baseline from week 2 to week 12 will be analyzed using MMRM in manner 
described in section 13.1.1 with adjustment for baseline discomfort score, visit, treatment arm, and 
interaction between treatment arm and visit. Change from baseline by visit will also be analyzed. The 
LS means, LS mean differences, SEs, two-sided 95% CIs for LS means, two-sided 95% CIs for the 
difference in means, and two-sided p-values will be reported from the MMRM. Sensitivity analysis will 
include ANCOVA adjusted for baseline discomfort score and treatment arm, two-sample t-tests, and 
Wilcoxon rank sum test. Cohen’s d effect size will be reported for differences in change from baseline 
between treatment arms. The LS means, LS mean differences, SEs, two-sided 95% CIs for the 
difference in means, and two-sided p-values will be reported from the sensitivity analyses where 
applicable. Paired t-tests will be used to analyze change from baseline within each treatment arm. 
Analyses will be performed on the ITT population with observed data only. 
14.1.3 
SYMPTOM QUESTIONNAIRE 
 
 
 
 
 Questionnaires will be recorded at all visits including 
Visit 1 (Day -14) at Pre-
® and Visit 2 (Day 1) at Pre-
 and Post-
 Comparisons will be 
made between reproxalap arms and vehicle arms within the same dosing schedule.  
Visit-based data will be summarized using continuous descriptive statistics for each symptom by 
treatment arm. Change from baseline will also be summarized with continuous descriptive statistics. 
Two-sample t-tests and Wilcoxon rank sum tests will be used to analyze differences between treatment 
arms at each visit between active treatment and vehicle. The differences in means, two-sided 95% CIs 
for the difference in means, and two-sided p-values will be reported. Cohen’s d effect size will be 
reported for the differences in treatment arms at each visit. 
Overall mean change from baseline will be analyzed using MMRM in manner described in section 13.1.1 
with adjustment for baseline symptom score, visit, treatment arm, and interaction between treatment 
arm and visit. Change from baseline by visit will also be analyzed. The LS means, LS mean differences, 
SEs, two-sided 95% CIs for LS means, two-sided 95% CIs for the difference in means, and two-sided 
p-values will be reported from the MMRM. Sensitivity analysis will include ANCOVA adjusted for 
baseline symptom score and treatment arm, two-sample t-tests, and Wilcoxon rank sum test. Cohen’s 
d effect size will be reported for differences in change from baseline between treatment arms. The LS 
means, LS mean differences, SEs, two-sided 95% CIs for the difference in means, and two-sided p-
values will be reported from the sensitivity analyses where applicable. Paired t-tests will be used to 
analyze change from baseline within each treatment arm. 


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Analyses will be performed on the ITT population with observed data only. 
14.1.4 OCULAR SURFACE DISEASE INDEX© 
The OSDI© is assessed on a scale of 0 to 4, where 0 = None of the Time, 1 = Some of the Time, 2 = 
Half of the Time, 3 = Most of the Time, and 4 = All of the Time. The OSDI© asks the following 12 
questions at the subject level: 
Have you experienced any of the following during the last week? 
1) Eyes that are sensitive to light? 
2) Eyes that feel gritty? 
3) Painful or sore eyes? 
4) Blurred vision? 
5) Poor vision? 
Have problems with your eyes limited you in performing any of the following during the last week? 
6) Reading? 
7) Driving at night? 
8) Working with a computer or bank machine (ATM)? 
9) Watching TV? 
Have your eyes felt uncomfortable in any of the following situations during the last week? 
10) Windy conditions? 
11) Places or areas with low humidity (very dry)? 
12) Areas that are air conditioned? 
The total OSDI© score is calculated by the following: 
OSDI© = 
(Sum of Scores) x 25 
# of Questions Answered 
Note that the number of questions answered in the denominator should exclude those questions with a 
response of “N/A.”  
Ocular Surface Disease Index© will be assessed pre-
 at Visit 1 (Day -14), pre-
 at Visit 2 (Day 
1), and all post-baseline visits. 
Comparisons will be made between reproxalap arms and vehicle arms within the same dosing schedule. 


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Visit-based data will be summarized using continuous descriptive statistics for each question score and 
total OSDI© score by treatment arm. Change from baseline will also be summarized with continuous 
descriptive statistics. 
Two-sample t-tests and Wilcoxon rank sum tests will be used to analyze differences between treatment 
arms at each visit between active treatment and vehicle. The differences in means, two-sided 95% CIs 
for the difference in means, and two-sided p-values will be reported. Cohen’s d effect size will be 
reported for the differences in treatment arms at each visit. 
Overall mean change from baseline from week 2 to week 12 will be analyzed using MMRM in manner 
described in section 13.1.1 with adjustment for baseline OSDI question score, visit, treatment arm, and 
interaction between treatment arm and visit. Change from baseline by visit will also be analyzed. The 
LS means, LS mean differences, SEs, two-sided 95% CIs for LS means, two-sided 95% CIs for the 
difference in means, and two-sided p-values will be reported from the MMRM. Sensitivity analysis will 
include ANCOVA adjusted for baseline OSDI question score and treatment arm, two-sample t-tests, and 
Wilcoxon rank sum test. Cohen’s d effect size will be reported for differences in change from baseline 
between treatment arms. The LS means, LS mean differences, SEs, two-sided 95% CIs for the 
difference in means, and two-sided p-values will be reported from the sensitivity analyses where 
applicable. Paired t-tests will be used to analyze change from baseline within each treatment arm. 
Analyses will be performed on the ITT population with observed data only. 
14.1.5 SYMPTOM ASSESSMENT IN DRY EYE 
Subjects will be asked to complete the SANDE Questionnaire at all post-baseline visits including Pre-
 Visit 1 (Day –14) and Pre-
 Visit 2 (Day 1). First, the subject will be asked to place a vertical 
line to indicate how often, on average, their eyes feel dry and/or irritated. Second, the subject will be 
asked to place a vertical line to indicate how severe, on average, they feel their symptoms of dryness 
and/or irritation are. The length of the assessment line is 100 mm. For frequency, 100 mm corresponds 
to “All the Time” and 0 mm corresponds to “Rarely.” For severity, 100 mm corresponds to “Very Severe” 
and 0 mm corresponds to “Very Mild.” The total SANDE questionnaire score is calculated by multiplying 
the frequency of symptoms score with the severity of symptoms score and obtaining the square root. 
Visit-based data will be summarized using continuous descriptive statistics for frequency, severity, and 
total SANDE score by treatment arm. Change from baseline will also be summarized with continuous 
descriptive statistics. Comparisons will be made between reproxalap arms and vehicle arms within the 
same dosing schedule. 
Two-sample t-tests and Wilcoxon rank sum tests will be used to analyze differences between treatment 
arms at each visit between active treatment and vehicle. The differences in means, two-sided 95% CIs 


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for the difference in means, and two-sided p-values will be reported. Cohen’s d effect size will be 
reported for the differences in treatment arms at each visit. 
Overall mean change from baseline from week 2 to week 12 will be analyzed using MMRM in manner 
described in section 13.1.1 with adjustment for baseline SANDE score, visit, treatment arm, and 
interaction between treatment arm and visit. Change from baseline by visit will also be analyzed. The 
LS means, LS mean differences, SEs, two-sided 95% CIs for LS means, two-sided 95% CIs for the 
difference in means, and two-sided p-values will be reported from the MMRM. Sensitivity analysis will 
include ANCOVA adjusted for baseline SANDE score and treatment arm, two-sample t-tests, and 
Wilcoxon rank sum test. Cohen’s d effect size will be reported for differences in change from baseline 
between treatment arms. The LS means, LS mean differences, SEs, two-sided 95% CIs for the 
difference in means, and two-sided p-values will be reported from the sensitivity analyses where 
applicable. Paired t-tests will be used to analyze change from baseline within each treatment arm. 
Analyses will be performed on the ITT population with observed data only. 
14.1.6 
 ITCHING 
 
 
Subjects will rate the severity of their ocular itching symptom in both eyes, according to the following 
scale from 0 to 4 where 0 = None and 4 = An incapacitating itch with an irresistible urge to rub. Half (0.5) 
grade increments may be used. Questionnaires will be recorded at Visit 1 (Day -14) at Pre-
, Visit 
2 (Day 1) at Pre-
, and at all post-baseline visits. Comparisons will be made between reproxalap 
arms and vehicle arms within the same dosing schedule. Analyses will be provided for study eye only.  
Visit-based data will be summarized using continuous descriptive statistics by treatment arm. Change 
from baseline will also be summarized with continuous descriptive statistics. 
Two-sample t-tests and Wilcoxon rank sum tests will be used to analyze differences between treatment 
arms at each visit between active treatment and vehicle. The differences in means, two-sided 95% CIs 
for the difference in means, and two-sided p-values will be reported. Cohen’s d effect size will be 
reported for the differences in treatment arms at each visit. 
Overall mean change from baseline from week 2 to week 12 will be analyzed using MMRM in manner 
described in section 13.1.1 with adjustment for baseline CAC score, visit, treatment arm, and interaction 
between treatment arm and visit. Change from baseline by visit will also be analayzed. The LS means, 
LS mean differences, SEs, two-sided 95% CIs for LS means, two-sided 95% CIs for the difference in 
means, and two-sided p-values will be reported from the MMRM. Sensitivity analysis will include 
ANCOVA adjusted for baseline CAC score and treatment arm, two-sample t-tests, and Wilcoxon rank 
sum test. Cohen’s d effect size will be reported for differences in change from baseline between 
treatment arms. The LS means, LS mean differences, SEs, two-sided 95% CIs for the difference in 


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means, and two-sided p-values will be reported from the sensitivity analyses where applicable. Paired 
t-tests will be used to analyze change from baseline within each treatment arm. 
Analyses will be performed on the ITT population with observed data only. 
14.1.7 LISSAMINE GREEN STAINING 
 
Subjects will undergo lissamine green staining at all visits including Pre-
 and Post-
at Visits 
1 (Day -14) and 2 (Day 1). 
 
 
 
 
 Analyses will be provided for study eye only. Comparisons will be made between 
reproxalap arms and vehicle arms within the same dosing schedule. 
Visit-based data will be summarized using continuous descriptive statistics by treatment arm. Change 
from baseline will also be summarized with continuous descriptive statistics. 
Two-sample t-tests and Wilcoxon rank sum tests will be used to analyze differences between treatment 
arms at each visit between active treatment and vehicle. The differences in means, two-sided 95% CIs 
for the difference in means, and two-sided p-values will be reported. Cohen’s d effect size will be 
reported for the differences in treatment arms at each visit. 
Overall mean change from baseline from week 2 to week 12 will be analyzed using MMRM in manner 
described in section 13.1.1 with adjustment for baseline lissamine green staining score, visit, treatment 
arm, and interaction between treatment arm and visit. Change from baseline by visit will also be 
analyzed. The LS means, LS mean differences, SEs, two-sided 95% CIs for LS means, two-sided 95% 
CIs for the difference in means, and two-sided p-values will be reported from the MMRM. Sensitivity 
analysis will include ANCOVA adjusted for baseline lissamine green staining score and treatment arm, 
two-sample t-tests, and Wilcoxon rank sum test. Cohen’s d effect size will be reported for differences in 
change from baseline between treatment arms. The LS means, LS mean differences, SEs, two-sided 
95% CIs for the difference in means, and two-sided p-values will be reported from the sensitivity 
analyses where applicable. Paired t-tests will be used to analyze change from baseline within each 
treatment arm. 
Analyses will be performed on the ITT population with observed data only. 
14.1.8 TEAR FILM BREAK-UP TIME 
The TFBUT will be recorded at all visits including Pre-
 and Post-
 at Visits 1 (Day -14) and 2 
(Day 1). 
 
 


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Comparisons will be made between reproxalap arms and vehicle arms 
within the same dosing schedule. 
Visit-based data will be summarized using continuous descriptive statistics by treatment arm. Change 
from baseline will also be summarized with continuous descriptive statistics at each post-baseline visit. 
Two-sample t-tests and Wilcoxon rank sum tests will be used to analyze differences between treatment 
arms at each visit between active treatment and vehicle. The differences in means, two-sided 95% CIs 
for the difference in means, and two-sided p-values will be reported. Cohen’s d effect size will be 
reported for the differences in treatment arms at each visit. 
Overall mean change from baseline from week 2 to week 12 will be analyzed using MMRM in manner 
described in section 13.1.1 with adjustment for baseline TFBUT score, visit, treatment arm, and 
interaction between treatment arm and visit. Change from baseline by visit will also be analyzed. The 
LS means, LS mean differences, SEs, two-sided 95% CIs for LS means, two-sided 95% CIs for the 
difference in means, and two-sided p-values will be reported from the MMRM. Sensitivity analysis will 
include ANCOVA adjusted for baseline TFBUT score and treatment arm, two-sample t-tests, and 
Wilcoxon rank sum test. Cohen’s d effect size will be reported for differences in change from baseline 
between treatment arms. The LS means, LS mean differences, SEs, two-sided 95% CIs for the 
difference in means, and two-sided p-values will be reported from the sensitivity analyses where 
applicable. Paired t-tests will be used to analyze change from baseline within each treatment arm. 
Analyses will be performed on the ITT population with observed data only. 
14.1.9 TEAR OSMOLARITY 
Tear osmolarity will be measured at Visits 2 (Day 1) Pre-
, 5 (Day 29), and 9 (Day 85). Tear 
osmolarity will be taken once from the temporal canthus of each eye and the measurement will be 
recorded. A second reading may be taken if the first reading is out of range. A maximum of 2 attempts 
will be made per eye. Tear osmolarity will be measured in milliosmoles per liter (mOsm/L). Analyses will 
be provided for study eye only. Comparisons will be made between reproxalap arms and vehicle arms 
within the same dosing schedule. 
Visit-based data will be summarized using continuous descriptive statistics by treatment arm. Change 
from baseline will also be summarized with continuous descriptive statistics at each post-baseline visit. 
Two-sample t-tests and Wilcoxon rank sum tests will be used to analyze differences between treatment 
arms at each visit between active treatment and vehicle. The differences in means, two-sided 95% CIs 
for the difference in means, and two-sided p-values will be reported. Cohen’s d effect size will be 
reported for the differences in treatment arms at each visit. 


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Overall mean change from baseline from week 4 to week 12 will be analyzed using MMRM in manner 
described in section 13.1.1 with adjustment for baseline tear osmolarity score, visit, treatment arm, and 
interaction between treatment arm and visit. Change from baseline by visit will also be analyzed. The 
LS means, LS mean differences, SEs, two-sided 95% CIs for LS means, two-sided 95% CIs for the 
difference in means, and two-sided p-values will be reported from the MMRM. Sensitivity analysis will 
include ANCOVA adjusted for baseline tear osmolarity and treatment arm, two-sample t-tests, and 
Wilcoxon rank sum test. Cohen’s d effect size will be reported for the differences in treatment arms at 
each visit. The LS means, LS mean differences, SEs, two-sided 95% CIs for the difference in means, 
and two-sided p-values will be reported from the sensitivity analyses where applicable. Paired t-tests 
will be used to analyze change from baseline within each treatment arm. 
Analyses will be performed on the ITT population with observed data only. 
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 
subjects who experienced at least one TEAE, ocular TEAEs, non-ocular TEAEs, TE-SAEs, TEAEs by 
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:  


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• 
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. 
The relationship of each AE to the study drug should be determined by the investigator using these 
explanations: 


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• 
Definitely Related: Relationship exists when the AE follows a reasonable sequence from the 
time of IP administration, follows a known response pattern of the drug class, is confirmed by 
improvement on stopping the IP and no other reasonable cause exists. 
• 
Probably Related: Relationship exists when the AE follows a reasonable sequence from the 
time of IP administration, follows a known response pattern of the drug class, is confirmed by 
improvement on stopping the IP and the suspect IP is the most likely of all causes.  
• 
Possibly Related: Relationship exists when the AE follows a reasonable sequence from the time 
of administration, but could also have been produced by the subject’s clinical state or by other 
drugs administered to the subject. 
• 
Unlikely to be related: Relationship between the AE and IP is more than likely to be unrelated 
to IP administration but the relationship cannot be definitely attributed to another cause. 
• 
Not Related: Concurrent illness, concurrent medication, or other known cause is clearly 
responsible for the AE, the administration of the IP and the occurrence of the AE are not 
reasonably related in time, OR exposure to IP has not occurred. 
Subjects experiencing more than one AE within a given SOC or PT are counted once within that SOC 
or PT for the maximum relationship. All AEs, ocular AEs, non-ocular AEs, and SAEs will be presented 
in subject listings.  
15.2 
Visual Acuity (ETDRS) 
The logarithm of the minimum angle of resolution (logMAR) VA must be assessed using an ETDRS 
chart. The procedure used will be consistent with the recommendations provided for using the ETDRS 
eye chart. Visual acuity will be evaluated at the beginning of each visit in the study (i.e., prior to slit-lamp 
examination). Visual acuity testing should be done with most recent correction. 
The observed and change from baseline VA will be summarized for each eye (study eye and fellow eye) 
using continuous descriptive statistics by visit for each treatment arm and for all actively treated subjects. 
A subject listing of VA will also be produced.  
15.3 
Slit-Lamp Biomicroscopy Examination 
Slit lamp biomicroscopic observations will be graded as Normal or Abnormal. Abnormal findings will be 
categorized as clinically significant (CS) (i.e., findings that may interfere with study parameters or 
otherwise confound the data as determined by the investigator) or not clinically significant (NCS). Slit 
lamp biomicroscopic observations will be recorded at each visit, including Pre-
 and Post-
 for 
Visits 1 (Day -14) and 2 (Day 1).The following will be examined:  
• Cornea  
• Conjunctiva 


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• Anterior Chamber 
• Iris 
• Lens 
• Lid 
The results will be summarized using counts and percentages for each treatment arm at each visit for 
each eye (study eye and fellow eye). Percentages will be based on the number of subjects in each 
treatment arm with responses. Shift tables for the slit-lamp biomicroscopy parameters will also be 
provided comparing each follow-up visit to baseline. A subject listing of the slit-lamp biomicroscopy 
parameters will also be produced. 
15.4 
Intraocular Pressure 
Intraocular pressure will be measured in each eye by contact tonometry by the examiner at Visit 1 (Day 
-14) Post-
 and Visit 9 (Day 85). A single measurement is made to obtain a determination of IOP. 
The same tonometer employing the investigator’s standard technique will be used throughout the study. 
In addition, all reasonable efforts will be made to have the same examiner obtain all IOP measurements 
for a given subject. Intraocular pressure will be assessed by non-contact tonometry at each visit. Results 
will be taken from a single measurement and will be recorded in millimeters of Mercury (mmHg). 
The IOP values and changes from baseline for each eye (study eye and fellow eye) will be summarized 
using continuous descriptive statistics by visit and eye for each treatment arm. A subject listing of IOP 
will also be produced.  
15.5 
Dilated Fundoscopy Examination 
Dilated fundus exams will be performed using indirect ophthalmoscopy at Visit 1 (Day -14) Post
 
and Visit 9 (Day 85). The investigator will make observations of the vitreous, retina, macula, choroid and 
optic nerve.  
Observations will be graded as Normal or Abnormal. Abnormal findings that are CS (as determined by 
the investigator that may interfere with study parameters or otherwise confound the data) and those that 
are NCS will be described. An indirect fundoscopy examination should be performed if retinal disease 
is detected.  
The results will be summarized using counts and percentages for each treatment arm and for all actively 
treated subjects at each visit for each eye (study eye and fellow eye). Percentages will be based on the 
number of subjects in each treatment arm with responses. Shift tables for the undilated fundoscopy 
parameters will also be provided comparing each follow-up visit to baseline. A subject listing of the 
dilated fundoscopy parameters will also be produced. 


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16. Changes from Protocol-Stated Analyses 
The description of the testing strategy for multiple dosing regimens in Section 8.5 was revised from the 
protocol to specify that the QID for four weeks followed by BID for eight weeks dosing regimen statistical 
comparisons will be considered valid only if the QID for twelve weeks dosing regimen comparisons are 
statistically significant for either of the co-primary endpoints. 
 
17. Revision History 
 
18. Tables 
Table Number 
Title 
Population 
14.1.1 
SUBJECT DISPOSITION 
ALL 
RANDOMIZED 
SUBJECTS 
14.1.2.1 
DEMOGRAPHIC CHARACTERISTICS 
ITT 
14.1.2.2 
DEMOGRAPHIC CHARACTERISTICS 
SAFETY 
14.1.3.1 
BASELINE DISEASE CHARACTERISTICS 
ITTOD 
14.1.3.2 
BASELINE DISEASE CHARACTERISTICS 
ITTFSN 
14.1.3.3 
BASELINE DISEASE CHARACTERISTICS 
ITT 
14.1.4.1 
OCULAR MEDICAL HISTORY 
SAFETY 
14.1.4.2 
NON-OCULAR MEDICAL HISTORY 
SAFETY 
14.1.5.1 
OCULAR CONCOMITANT MEDICATIONS 
ITT 
14.1.5.2 
NON-OCULAR CONCOMITANT MEDICATIONS 
ITT 


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Table Number 
Title 
Population 
14.2.1.1.1 
OCULAR DRYNESS SCORE 
ITTOD 
WITH 
OBSERVED 
DATA ONLY 
14.2.1.1.2 
OCULAR DRYNESS SCORE 
ITTOD 
WITH 
MCMC 
14.2.1.1.3 
OCULAR DRYNESS SCORE 
ITTOD 
WITH 
PMM 
14.2.1.1.4 
OCULAR DRYNESS SCORE 
PPOD 
WITH 
OBSERVED 
DATA ONLY 
14.2.1.2.1 
FLUORESCEIN STAINING OF THE NASAL REGION 
ITTFSN WITH 
OBSERVED 
DATA ONLY 
14.2.1.2.2 
FLUORESCEIN STAINING OF THE NASAL REGION 
ITTFSN WITH 
MCMC 
14.2.1.2.3 
FLUORESCEIN STAINING OF THE NASAL REGION 
ITTFSN WITH 
PMM 
14.2.1.2.4 
FLUORESCEIN STAINING OF THE NASAL REGION 
PPFSN WITH 
OBSERVED 
DATA ONLY 
14.2.2.1.1 
 
 DRYNESS 
ITT 
POPULATION 
WITH 
OBSERVED 
DATA ONLY 
14.2.2.1.2 
 
DRYNESS 
PP 
POPULATION 
WITH 
OBSERVED 
DATA ONLY 


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Table Number 
Title 
Population 
14.2.3.1.1 
FLUORESCEIN STAINING 
 
ITT 
WITH 
OBSERVED 
DATA ONLY 
14.2.3.1.2 
FLUORESCEIN STAINING 
 
PP 
WITH 
OBSERVED 
DATA ONLY 
14.2.3.2.1 
UNANESTHETIZED SCHIRMER’S TEST  
ITT 
WITH 
OBSERVED 
DATA ONLY 
14.2.3.2.2 
UNANESTHETIZED SCHIRMER’S TEST  
PP 
WITH 
OBSERVED 
DATA ONLY 
14.2.3.3.1 
OCULAR DRYNESS THROUGH VISIT 5 (DAY 29) 
ITT 
WITH 
OBSERVED 
DATA ONLY 
14.2.3.3.2 
OCULAR DRYNESS THROUGH VISIT 5 (DAY 29) 
PP 
WITH 
OBSERVED 
DATA ONLY 
14.2.4.1 
VISUAL ANALOG SCALE 
ITT 
WITH 
OBSERVED 
DATA ONLY 
14.2.4.2 
DISCOMFORT SCALE 
ITT 
WITH 
OBSERVED 
DATA ONLY 
14.2.4.3 
 
 
 
 
 
SYMPTOM 
QUESTIONNAIRE 
ITT 
WITH 
OBSERVED 
DATA ONLY 
14.2.4.4 
OCULAR SURFACE DISEASE INDEX (OSDI) 
ITT 
WITH 
OBSERVED 
DATA ONLY 


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Table Number 
Title 
Population 
14.2.4.5 
SYMPTOM ASSESSMENT IN DRY EYE (SANDE) 
ITT 
WITH 
OBSERVED 
DATA ONLY 
14.2.4.6 
 
 
 
 
 
ITCHING SCALE 
ITT 
WITH 
OBSERVED 
DATA ONLY 
14.2.4.7 
LISSAMINE GREEN STAINING 
 
ITT 
WITH 
OBSERVED 
DATA ONLY 
14.2.4.8 
TEAR FILM BREAK-UP TIME (SEC) 
ITT 
WITH 
OBSERVED 
DATA ONLY 
14.2.4.9 
TEAR OSMOLARITY (MOSM/L) 
ITT 
WITH 
OBSERVED 
DATA ONLY 
14.2.5 
SUMMARY OF EFFICACY ANALYSES 
 
14.3.1.1 
OVERALL SUMMARY OF ADVERSE EVENTS BY TREATMENT 
ARM 
SAFETY 
14.3.2.1 
OCULAR ADVERSE EVENTS BY SYSTEM ORGAN CLASS AND 
PREFERRED TERM 
SAFETY 
14.3.2.2 
NON-OCULAR ADVERSE EVENTS BY SYSTEM ORGAN CLASS 
AND PREFERRED TERM 
SAFETY 
14.3.3.1 
OCULAR TREATMENT-EMERGENT ADVERSE EVENTS BY 
SYSTEM ORGAN CLASS AND PREFERRED TERM 
SAFETY 
14.3.3.2 
NON-OCULAR TREATMENT-EMERGENT ADVERSE EVENTS BY 
SYSTEM ORGAN CLASS AND PREFERRED TERM 
SAFETY 
14.3.4.1 
OCULAR TREATMENT-EMERGENT ADVERSE EVENTS BY 
SYSTEM ORGAN CLASS, PREFERRED TERM, AND MAXIMAL 
SEVERITY 
SAFETY 


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Table Number 
Title 
Population 
14.3.4.2 
NON-OCULAR TREATMENT-EMERGENT ADVERSE EVENTS 
(TEAES) BY SYSTEM ORGAN CLASS, PREFERRED TERM, AND 
MAXIMAL SEVERITY 
SAFETY 
14.3.5.1 
OCULAR TREATMENT-EMERGENT ADVERSE EVENTS BY 
SYSTEM 
ORGAN 
CLASS, 
PREFERRED 
TERM, 
AND 
STRONGEST RELATIONSHIP TO STUDY DRUG 
SAFETY 
14.3.5.2 
NON-OCULAR TREATMENT-EMERGENT ADVERSE EVENTS BY 
SYSTEM 
ORGAN 
CLASS, 
PREFERRED 
TERM, 
AND 
STRONGEST RELATIONSHIP TO STUDY DRUG 
SAFETY 
14.3.6.1 
OCULAR TREATMENT-EMERGENT ADVERSE EVENTS BY 
SYSTEM ORGAN CLASS, PREFERRED TERM, SEVERITY, AND 
STRONGEST RELATIONSHIP TO STUDY DRUG 
SAFETY 
14.3.6.2 
NON-OCULAR TREATMENT-EMERGENT ADVERSE EVENTS BY 
SYSTEM ORGAN CLASS, PREFERRED TERM, SEVERITY, AND 
STRONGEST RELATIONSHIP TO STUDY DRUG 
SAFETY 
14.3.7 
TREATMENT-EMERGENT ADVERSE EVENTS THAT LED TO 
PREMATURE DISCONTINUATION 
SAFETY 
14.3.8 
SERIOUS ADVERSE EVENTS 
SAFETY 
14.3.9 
VISUAL ACUITY (ETDRS) – LOGMAR 
SAFETY 
14.3.10.1 
SLIT LAMP BIOMICROSCOPY 
SAFETY 
14.3.10.2 
SHIFT IN SLIT LAMP BIOMICROSCOPY 
SAFETY 
14.3.11 
INTRAOCULAR PRESSURE (MMHG) 
SAFETY 
14.3.12.1 
DILATED FUNDOSCOPY 
SAFETY 
14.3.12.2 
SHIFT IN DILATED FUNDOSCOPY 
SAFETY 
14.3.13 
COMPLIANCE TO STUDY DRUG 
SAFETY 
14.3.14 
EXPOSURE TO STUDY DRUG 
SAFETY 


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19. Listings 
Listing Number 
Title 
16.1.7 
RANDOMIZATION SCHEDULE 
16.2.1.1 
SUBJECT DISPOSITION 
16.2.1.2 
INCLUSION/EXCLUSION 
16.2.2.1 
PROTOCOL DEVIATIONS 
16.2.3 
STUDY POPULATION INCLUSION 
16.2.4.1 
DEMOGRAPHICS 
16.2.4.2 
OCULAR MEDICAL HISTORY 
16.2.4.3 
NON-OCULAR MEDICAL HISTORY 
16.2.4.4 
OCULAR CONCOMITANT MEDICATIONS 
16.2.4.5 
NON-OCULAR CONCOMITANT MEDICATIONS 
16.2.5.1 
RUN-IN, RUN-IN INSTILLATION, AND RUN-IN REPLACEMENT 
16.2.5.2 
STUDY DRUG ASSIGNMENT, INSTILLATION, AND REPLACEMENT 
16.2.5.3 
STUDY DRUG EXPOSURE AND DOSING COMPLIANCE 
16.2.6.1 
VISUAL ANALOG SCALE 
16.2.6.2 
FLUORESCEIN CORNEAL AND CONJUNCTIVAL STAINING 
 
 
16.2.6.3 
UNANESTHETIZED SCHIRMER’S TEST 
16.2.6.4 
 OCULAR DISCOMFORT 
 
16.2.6.5 
CULAR DISCOMFORT 
 
16.2.6.6 
 
 
 
 
SYMPTOM 
QUESTIONNAIRE 
16.2.6.7 
OCULAR SURFACE DISEASE INDEX (OSDI) 
16.2.6.8 
SYMPTOM ASSESSMENT IN DRY EYE (SANDE) 
16.2.6.9 
 


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Listing Number 
Title 
16.2.6.10 
LISSAMINE GREEN CORNEAL AND CONJUNCTIVAL STAINING 
 
16.2.6.11 
TEAR FILM BREAK-UP TIME (TFBUT) 
16.2.6.12 
TEAR OSMOLARITY 
16.2.7.1 
ALL ADVERSE EVENTS 
16.2.7.2 
OCULAR ADVERSE EVENTS 
16.2.7.3 
NON-OCULAR ADVERSE EVENTS 
16.2.7.4 
SERIOUS ADVERSE EVENTS 
16.2.8.1 
VISUAL ACUITY (ETDRS) - LOGMAR 
16.2.8.2 
SLIT-LAMP BIOMICROSCOPY 
16.2.8.3 
INTRAOCULAR PRESSURE (IOP) 
16.2.8.4 
DILATED FUNDOSCOPY 
16.2.8.5 
PREGNANCY TEST 
20. Figures 
Figure Number 
Title 
Population 
14.2.1.1.1 
OCULAR DRYNESS SCORE OVERALL MEAN CHANGE FROM 
BASELINE FROM WEEK 2 TO WEEK 12, QID ARMS 
ITTOD WITH 
OBSERVED 
DATA ONLY 
14.2.1.2.1 
FLUORESCEIN STAINING OF THE NASAL REGION OVERALL MEAN 
CHANGE FROM BASELINE FROM WEEK 2 TO WEEK 12, QID ARMS 
ITTFSN 
WITH 
OBSERVED 
DATA ONLY 
14.2.2.1.1 
OCULAR DRYNESS SCORE OVERALL MEAN CHANGE FROM 
BASELINE FROM WEEK 2 TO WEEK 12, QID TO BID ARMS 
ITTOD WITH 
OBSERVED 
DATA ONLY 


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Figure Number 
Title 
Population 
14.2.2.2.1 
FLUORESCEIN STAINING OF THE NASAL REGION OVERALL MEAN 
CHANGE FROM BASELINE FROM WEEK 2 TO WEEK 12, QID TO BID 
ARMS 
ITTFSN 
WITH 
OBSERVED 
DATA ONLY 
 

Prot_000.pdf: 
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 


Reproxalap Ophthalmic Solution  
Aldeyra Therapeutics, Inc.  
Clinical Trial Protocol: ADX-102-DED-012 
Final V2.0 5Mar2019 
 
 
Confidential 
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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 


Reproxalap Ophthalmic Solution  
Aldeyra Therapeutics, Inc.  
Clinical Trial Protocol: ADX-102-DED-012 
Final V2.0 5Mar2019 
 
 
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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 










Reproxalap Ophthalmic Solution  
Aldeyra Therapeutics, Inc.  
Clinical Trial Protocol: ADX-102-DED-012 
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Confidential 
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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 






Reproxalap Ophthalmic Solution  
Aldeyra Therapeutics, Inc.  
Clinical Trial Protocol: ADX-102-DED-012 
Final V2.0 5Mar2019 
 
 
Confidential 
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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. 


Reproxalap Ophthalmic Solution  
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Clinical Trial Protocol: ADX-102-DED-012 
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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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Clinical Trial Protocol: ADX-102-DED-012 
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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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Clinical Trial Protocol: ADX-102-DED-012 
Final V2.0 5Mar2019 
 
 
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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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Clinical Trial Protocol: ADX-102-DED-012 
Final V2.0 5Mar2019 
 
 
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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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Clinical Trial Protocol: ADX-102-DED-012 
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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 
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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 
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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: 
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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.